SNPMiner Trials by Shray Alag


SNPMiner SNPMiner Trials (Home Page)


Report for Mutation V617F

Developed by Shray Alag, 2020.
SNP Clinical Trial Gene

There are 48 clinical trials

Clinical Trials


1 Efficacy of Tyrosine Kinase Inhibition in Reducing Eosinophilia in Patients With Myeloid and/or Steroid-Refractory Hypereosinophilic Syndrome

The purpose of this study is to evaluate the safety and efficacy of the tyrosine kinase inhibitor, imatinib mesylate (Gleevec ) in reducing peripheral blood eosinophilia in patients with the myeloid form of hypereosinophilic syndrome (HES). Patients with the hypereosinophilic syndrome who meet a set of criteria designed to select patients with the myeloid form of the disease, as well as patients without myeloid disease who are refractory to standard therapy for HES, will be admitted on this protocol. A thorough clinical evaluation will be performed with emphasis on potential sequelae of eosinophil-mediated tissue damage. A baseline bone marrow will be obtained to exclude leukemia or lymphoma and to assess the degree and nature of eosinophilopoiesis. Bone marrow, blood cells and/or serum will also be collected to test for the presence of a recently described mutation that is associated with imatinib-responsiveness in HES, and to provide reagents (such as DNA, RNA, and specific antibodies) and for use in the laboratory to address issues related to the mechanism of action of imatinib mesylate in HES. Imatinib mesylate will be initiated at a dose of 400 mg daily, the FDA-approved dose for the treatment of chronic myelogenous leukemia. In patients who demonstrate a complete clinical and hematologic response to imatinib therapy and who do not have life-threatening disease, the dose will be decreased gradually to 100mg daily and then discontinued. In order to minimize bone marrow suppression, other myelosuppressive agents will be tapered and discontinued during the first week of therapy with imatinib mesylate. Complete blood counts will be performed weekly for the first month and biweekly thereafter. Clinical assessments will be performed every three months to assess progression of end organ damage. In patients who demonstrate a complete clinical and hematologic response to imatinib therapy and who do not have life-threatening disease, the dose will be decreased gradually to 100 mg daily and then discontinued. In the event of clinical, hematologic or molecular relapse during the taper, the imatinib dose will be increased to a maximum of 600 mg daily to achieve a second remission. Laboratory monitoring will be performed as above except for molecular monitoring which will be monitored monthly if drug is discontinued or molecular relapse occurs. Once a stable dosing regimen is achieved for greater than or equal to 6 months in subjects who have undergone dose descalation or greater than or equal to 2 years in subjects receiving 300-400 mg of imatinib daily who did not qualify for dose de-escalation, the frequency of NIH visits and end organ assessments will be decreased to 6 months, with molecular monitoring every 3 months and monthly routine laboratory assessments.

NCT00044304 Eosinophilic Myeloid Neoplasm Hypereosinophilic Syndrome Drug: Imatinib Drug: Ruxolitinib
MeSH:Hypereosinophilic Syndrome Syndrome

abnormal tyrosine kinase (i.e., FIP1L1-PDGFRA, JAK2 V617F). --- V617F ---

Primary Outcomes

Description: The percentage of subjects who reach and eosinophil count in the normal range

Measure: peripheral blood absolute eosinophil count.

Time: one month (for imatinib) and 3 months (for ruxolitinib).

Secondary Outcomes

Description: The % of subjects who reach an eosinophil count in the normal range

Measure: peripheral blood eosinophil count

Time: 3,6,9 and 12 months

Description: The % of subjects who reach an eosinophil count below 1500/mm3

Measure: peripheral blood eosinophil count

Time: 1, 3, 6, 9, and 12 months

Description: The % of subjects who achieve molecular remission on therapy

Measure: abnormal tyrosine kinase (i.e., FIP1L1-PDGFRA, JAK2 V617F)

Time: every 3 months for 5 years

Description: The duration of remission following cessation of therapy

Measure: clinical, hematologic and molecular remission

Time: every 3 months for 5 years

2 Molecular Changes and Biomarkers in Chronic Myeloproliferative Disorders

The three main chronic myeloproliferative disorders are polycythemia vera (PV), essential thrombocythemia (ET) and idiopathic myelofibrosis (IMF). These are clonal neoplastic diseases characterized by proliferation of one or more hematopoietic lineages. Recently a mutation of the Janus Kinase 2 (JAK2) gene that leads to the substitution of phenylalanine for valine at position 617 of the JAK2 protein, JAK2 V617F, has been found in 76% to 97% of patients with PV, 29% to 57% of patients with ET and 50% of patients with IMF. This mutation confers constitutive activity on to the JAK2 protein and appears to play an important role in the pathobiology of these conditions. However, not all patients with myeloproliferative disorders have this mutation and it may not be the primary cause of these diseases. The primary goal of this prospective natural history study is to investigate the molecular basis of these diseases in groups of patients who have JAK2 V617F and in those who do not. A second goal is to identify biomarkers for PV and the other myeloproliferative disorders that are easier to measure than JAK2 V617F. Approximately, 150 patients with myeloproliferative disorders will be studied over 3 years. The studies will involve the collection of 40 mL to 50 mL of peripheral blood from each subject. The blood will be used to assess neutrophil gene and protein expression, gene polymorphisms, and plasma protein levels.

NCT00433862 Polycythemia Vera Essential Thrombocytosis Idiopathic Myelofibrosis Neutrophils Chronic Myeloproliferative Disorders
MeSH:Polycythemia Vera Primary Myelofibrosis Polycythemia Myeloproliferative Disorders Thrombocytosis Thrombocythemia, Essential Disease
HPO:Myeloproliferative disorder Polycythemia Thrombocytosis

Recently a mutation of the Janus Kinase 2 (JAK2) gene that leads to the substitution of phenylalanine for valine at position 617 of the JAK2 protein, JAK2 V617F, has been found in 76% to 97% of patients with PV, 29% to 57% of patients with ET and 50% of patients with IMF. --- V617F ---

The primary goal of this prospective natural history study is to investigate the molecular basis of these diseases in groups of patients who have JAK2 V617F and in those who do not. --- V617F ---

A second goal is to identify biomarkers for PV and the other myeloproliferative disorders that are easier to measure than JAK2 V617F. --- V617F ---


3 A Phase 2, Prospective, Randomized, Multicenter, Double-blind, Active-control, Parallel-group Study to Determine the Safety of and to Select a Treatment Regimen of CC-4047 (Pomalidomide) Either as Single-agent or in Combination With Prednisone to Study Further in Subjects With Myelofibrosis With Myeloid Metaplasia

The purpose of this study is to determine the safety of and to select a treatment regimen of pomalidomide (CC-4047) either as single-agent or in combination with prednisone to study further in patients with myelofibrosis with myeloid metaplasia (MMM).

NCT00463385 Myelofibrosis With Myeloid Metaplasia Myeloid Metaplasia Myelofibrosis Drug: Pomalidomide Drug: Prednisone Drug: Placebo to pomalidomide Drug: Placebo to prednisone
MeSH:Primary Myelofibrosis Metaplasia

Percentage of participants who achieved a clinical response, presented by participants with positive and negative janus kinase 2 (JAK2) V617F mutation results at Baseline.. Number of Participants With Adverse Events (AEs). --- V617F ---

Primary Outcomes

Description: A clinical responder was defined as either: A baseline red blood cell (RBC)-transfusion-dependent participant with a ≥ 56 consecutive day RBC transfusion-free period after the first dose of study drug, or A baseline RBC-transfusion-independent participant with an increase in hemoglobin of 2.0 g/dL or more from baseline for ≥ 56 consecutive days in the absence of RBC transfusions, or A participant with either a ≥ 50% reduction in palpable splenomegaly of a spleen that was ≥ 10 cm at baseline or a spleen that was palpable at > 5 cm and became not palpable. Participants who discontinued the study early without achieving clinical response were counted as non-responders.

Measure: Percentage of Participants With a Clinical Response Within the First 6 Cycles of Treatment

Time: Up to 168 days

Secondary Outcomes

Description: A clinical responder was defined as either: A baseline red blood cell (RBC)-transfusion-dependent participant with a ≥ 56 consecutive day RBC transfusion-free period after the first dose of study drug, or A baseline RBC-transfusion-independent participant with an increase in hemoglobin of 2.0 g/dL or more from baseline for ≥ 56 consecutive days in the absence of RBC transfusions, or A participant with either a ≥ 50% reduction in palpable splenomegaly of a spleen that was ≥ 10 cm at baseline or a spleen that was palpable at > 5 cm and became not palpable. Participants who discontinued the study early without achieving clinical response were counted as non-responders.

Measure: Percentage of Participants With a Clinical Response Within the First 12 Cycles of Treatment

Time: Up to 336 days

Description: The time to the first clinical response achieved within 168 days after the first study drug dosing date was calculated for participants who achieved a clinical response as: Start date of the first clinical response - the first study drug date +1. A clinical responder was defined as either: A baseline red blood cell (RBC)-transfusion-dependent participant with a ≥ 56 consecutive day RBC transfusion-free period after the first dose of study drug, or A baseline RBC-transfusion-independent participant with an increase in hemoglobin of 2.0 g/dL or more from baseline for ≥ 56 consecutive days in the absence of RBC transfusions, or A participant with either a ≥ 50% reduction in palpable splenomegaly of a spleen that was ≥ 10 cm at baseline or a spleen that was palpable at > 5 cm and became not palpable.

Measure: Time to the First Clinical Response

Time: Up to 168 days

Description: For RBC-transfusion-dependent patients, duration of response was calculated as the last day of response - first day of response +1, where the last day of response was the date of the first RBC-transfusion administrated at or more than 56 days after the response started. For patients who did not receive a subsequent transfusion after the response started, the end date of response was censored at the day of last hemoglobin assessment. For RBC-transfusion-independent patients, the duration of response was calculated as the last day of response - first day of response +1, where the last day of response was the earlier of the date of a hemoglobin increase of < 2.0 g/dL and the date of a RBC transfusion at ≥ 56 days after the response started. For patients whose hemoglobin measurements were always ≥ 2.0 g/dL and never received a RBC transfusion after response started, the end date of the response was censored at the date of last hemoglobin measurement. Kaplan-Meier methodology was used.

Measure: Duration of First Clinical Response

Time: Up to 40 months

Description: The FACT-An comprises the four subscales of the 27-item FACT-General Scale (FACT-G), Physical Well-being, Social/Family Well-being, Emotion Well-being, Functional Well-Being, and the Additional Concerns Anemia subscale. Questions are rated on a scale from 0 to 4, where higher scores indicate more impact on quality of life. Physical Well-being consists of 7 questions, the subscale score ranges from 0-28; Social/Family Well-being consists of 7 questions, the subscale score ranges from 0-28; Emotion Well-being consists of 6 questions, the subscale score ranges from 0-24; Functional Well-Being consists of 7 questions, the subscale score ranges from 0-28; Anemia subscale consists of 20 questions, the subscale score ranges from 0-80; Total FACT-An score ranges from 0-188.

Measure: Change From Baseline in Functional Assessment of Cancer Therapy-Anemia (FACT-An) Subscale and Total Scores

Time: Baseline and Cycle 6 (168 days).

Description: Change from Baseline in hemoglobin for participants with a clinical response within the first 6 cycles of treatment.

Measure: Change From Baseline in Hemoglobin Concentration for Responders

Time: Baseline, Cycle 6 (168 days)

Description: Change from Baseline in hemoglobin for participants without a clinical response within the first 6 cycles of treatment.

Measure: Change From Baseline in Hemoglobin Concentration for Non-Responders

Time: Baseline, Cycle 6 (168 days)

Description: Participants rated abdominal discomfort or pain over the previous week on a scale from zero to ten, where zero is no discomfort or pain and ten is the worst pain imaginable.

Measure: Change From Baseline in Likert Abdominal Pain Scale

Time: Baseline and Cycle 6 (168 days)

Description: Percentage of participants who achieved a clinical response, presented by participants with positive and negative janus kinase 2 (JAK2) V617F mutation results at Baseline.

Measure: Percentage of Participants With Clinical Response by Baseline JAK2 Assessment

Time: Up to 336 days

Description: A serious AE (SAE) was defined as any AE which resulted in death or was life-threatening, required or prolonged inpatient hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, or constituted an important medical event (events that may have jeopardized the patient or required intervention to prevent one of the outcomes listed above). The severity of AEs were graded according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE, Version 3.0) or according to the following scale: Grade 1 = Mild; Grade 2 = Moderate; Grade 3 = Severe; Grade 4 = Life-threatening; Grade 5 = Death. The Investigator determined the relationship between study drug and the occurrence of an AE as "Not Related" or "Related" (since the study was double-blinded, a patient receiving only prednisone could have an AE that was judged as related to pomalidomide, and vice-versa).

Measure: Number of Participants With Adverse Events (AEs)

Time: From date of the first dose of the study drug until discontinuation or the data cut-off date (up to approximately 45 months).

4 An Open-Label Study of Oral CEP-701 in Patients With Polycythemia Vera or Essential Thrombocytosis With the JAK2 V617F Mutation

This is an 18-week open-label, multicenter study to evaluate the efficacy and tolerability of CEP-701 (lestaurtinib) treatment in patients with Polycythemia Vera (PV) and patients with Essential Thrombocytosis (ET).

NCT00586651 Polycythemia Vera Essential Thrombocytosis Drug: lestaurtinib
MeSH:Polycythemia Vera Polycythemia Thrombocytosis Thrombocythemia, Essential
HPO:Polycythemia Thrombocytosis

An Open-Label Study of Oral CEP-701 in Patients With Polycythemia Vera or Essential Thrombocytosis With the JAK2 V617F Mutation. --- V617F ---

Determine whether a specific reduction in the JAK2 V617F allele has been indicated in this study.. null. --- V617F ---

- The patient has a detectable JAK2 V617F mutation. --- V617F ---

Primary Outcomes

Measure: Determine whether a specific reduction in the JAK2 V617F allele has been indicated in this study.

Time: 18 weeks +

Secondary Outcomes

Measure: - improvements in hemoglobin values, neutrophil count, and platelet count. - reduction in dose of hydroxyurea - reduction in splenic enlargement - rate of phlebotomy

Time: 18 weeks +

5 A Phase IIA Study of the Histone-deacetylase Inhibitor ITF2357 in Patients With JAK-2 V617F Positive Chronic Myeloproliferative Diseases

Primary Objective: To evaluate efficacy and safety of ITF2357 in the treatment of patients with JAK2V617F positive myeloproliferative diseases [Polycythemia Vera (PV), Essential Thrombocytosis (ET), Myelofibrosis (MF)]. Efficacy was evaluated by ad hoc haematological and clinical criteria for PV and ET, and by internationally established response criteria (EUMNET criteria) for MF. Safety was evaluated by number of subjects experiencing an Adverse Event (AE), type, frequency, severity, timing and relatedness of AEs, including changes in vital signs and clinical laboratory results. Secondary Objective: To evaluate the JAK2 mutated allele burden by quantitative Real-Time Polymerase Chain Reaction (qRTPCR).

NCT00606307 Myeloproliferative Diseases Drug: ITF2357
MeSH:Myeloproliferative Disorders
HPO:Myeloproliferative disorder

A Phase IIA Study of the Histone-deacetylase Inhibitor ITF2357 in Patients With JAK-2 V617F Positive Chronic Myeloproliferative Diseases. --- V617F ---

Phase IIA Study of the HDAC Inhibitor ITF2357 in Patients With JAK-2 V617F Positive Chronic Myeloproliferative Diseases Primary Objective: To evaluate efficacy and safety of ITF2357 in the treatment of patients with JAK2V617F positive myeloproliferative diseases [Polycythemia Vera (PV), Essential Thrombocytosis (ET), Myelofibrosis (MF)]. --- V617F ---

A serious AE (SAE) is defined as an untoward (unfavourable) medical occurrence that at any dose results in death, or is life-threatening or requires inpatient hospitalisation or prolongation of existing hospitalisation, or results in persistent or significant disability/incapacity or is a congenital anomaly/birth defect.. Inclusion Criteria: - Signed Informed Consent Form - Male or female, age ≥ 18 years - Confirmed diagnosis of PV/ET/MF according to the revised World Health Organisation criteria - JAK-2 V617F positivity - In need of cytoreductive therapy when hydroxyurea is not indicated (e.g. --- V617F ---

positive serology IgM) - Known HIV infection - Active hepatitis B and/or C infection - History of other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates use of an investigational drug or that might affect interpretation of the results of the study or render the subject at high risk from treatment complications - Eastern Cooperative Oncology Group (ECOG) performance status 3 or greater - Platelets count <100x109/L within 14 days before enrolment - Absolute neutrophil count <1.2x109/L within 14 days before enrolment - Percentage of blast cells in peripheral blood >10% within 14 days before enrolment - Serum creatinine >2xULN (Upper limit of normal) - Total serum bilirubin >1.5xULN - Serum AST (aspartate aminotransferase) / ALT (alanine aminotransferase) > 3xULN - Interferon alpha within 14 days before enrolment - Hydroxyurea within 14 days before enrolment - Anagrelide within 7 days before enrolment - Any other investigational drug within 28 days before enrolment Inclusion Criteria: - Signed Informed Consent Form - Male or female, age ≥ 18 years - Confirmed diagnosis of PV/ET/MF according to the revised World Health Organisation criteria - JAK-2 V617F positivity - In need of cytoreductive therapy when hydroxyurea is not indicated (e.g. --- V617F ---

Primary Outcomes

Description: Patients with Objective Response were defined as those patients achieving a complete, major, moderate or minor (only for Myelofibrosis patients) response during the experimental treatment course. The "best response" is reported hereunder by intensity of response.

Measure: Number of Patients With Objective Responses (Complete, Major, Moderate or Minor Responses), in Terms of Best Overall Response

Time: Every single week from week 1 to week 24 of treatment

Secondary Outcomes

Description: This outcome was assessed by quantitative real time Polymerase Chain Reaction (RT PCR). At each time point, the number of patients is the following: Screening: N=29 Week 12: N=20 Week 24: N=18 EOT: N=24. End of treatment corresponds to the last visit performed before treatment discontinuation.

Measure: Change in JAK2 Mutated Allele Burden

Time: At screening, at week 12, at week 24, at the end of treatment (EOT) visit

Description: An adverse event (AE) is any untoward occurrence in a patient or clinical investigation subject administered with a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An AE can therefore be any unfavourable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. The adverse events must to be followed to the end of study (28 days after the last study drug intake). A serious AE (SAE) is defined as an untoward (unfavourable) medical occurrence that at any dose results in death, or is life-threatening or requires inpatient hospitalisation or prolongation of existing hospitalisation, or results in persistent or significant disability/incapacity or is a congenital anomaly/birth defect.

Measure: Number of Subject Experiencing an Adverse Event

Time: At weekly visits (Days 8, 15, 22, 36, 43, 50, 64, 71, 78, 99, 127, 155); At monthly visits (Days 29, 57, 85 113, 141,169); at end of treatment visit

6 A Multicenter, Open Label Phase I/II Study of CEP-701 (Lestaurtinib) in Adults With Myelofibrosis

Myelofibrosis is the gradual replacement of bone marrow (place where most new blood cells are produced) by fibrous tissue which reduces the body's ability to produce new blood cells and results in the development of chronic anemia (low red blood cell count). One of the main distinctions of myelofibrosis is "extramedullary hematopoesis", the migration or traveling of the blood-forming cells out of the bones to other parts of the body, such as the liver or spleen, resulting in an enlarged spleen and liver. Treatment for myelofibrosis is unsatisfactory and there is no medication that is specifically used in the treatment of myelofibrosis. There is a protein that is found to be present in the majority of myelofibrosis patients (JAK2) and the drug Lestaurtinib is being studied to see if it will stop this protein from functioning and thereby help control the disease. This study is divided into two Phases (1 & 2). In phase 1 we will be looking for the dose of study medication (Lestaurtinib) that will be the highest dose a patient can take without experiencing serious side effects, maximum tolerated dose (MTD). In phase 2, after the MTD dose has been established in phase 1, we will be investigating how well CEP-701 (Lestaurtinib) works at suppressing the protein (JAK2). The investigators also wish to find out important biologic characteristics or features of myelofibrosis through an additional correlative biomarker study (MPD-RC #107). The correlative biomarker study is a study that is related to the main study, but is looking to answer different questions than the main study. The purpose of the biomarker study is to understand the causes of MPD and to develop improved methods for the diagnosis and treatment of these diseases, while the main study is trying to find out how well CEP-701 (Lestaurtinib) will work in treating the myeloproliferative disease.

NCT00668421 Myelofibrosis Essential Thrombocythemia Polycythemia Vera Drug: CEP-701 (Lestaurtinib)
MeSH:Pol Polycythemia Vera Primary Myelofibrosis Polycythemia Thrombocytosis Thrombocythemia, Essential
HPO:Polycythemia Thrombocytosis

To estimate the efficacy of a novel kinase inhibitor in subjects with myelofibrosis, as determined by a reduction in JAK2 V617F allele frequency in peripheral blood neutrophils.. null. --- V617F ---

3. The subject has a detectable JAK2 V617F mutation. --- V617F ---

Primary Outcomes

Measure: To determine the safety and maximum tolerated dose of a novel kinase inhibitor in subjects with myelofibrosis.

Time: 2 years

Measure: To estimate the efficacy of a novel kinase inhibitor in subjects with myelofibrosis, as determined by a reduction in JAK2 V617F allele frequency in peripheral blood neutrophils.

Time: 2 years

Secondary Outcomes

Measure: To estimate the incidence, severity, and attribution of treatment-emergent adverse events.

Time: 2 years

Measure: To estimate the rate of complete or major clinical-hematological response from treatment with Lestaurtinib (CEP-701) in this subject population as measured by the EUMNET response criteria.

Time: 2 years

7 A Phase II Study of MK-0683 in Patients With Polycythaemia Vera and Essential Thrombocythaemia.

The aim of the present study is to evaluate the efficacy and safety of MK-0683 in the treatment of PV and ET. This agent has most recently been shown to be a potent inhibitor of the autonomous proliferation of haematopoietic cells of PV and ET patients carrying the JAK2 V617F mutation. Accordingly, it may be anticipated that MK-0683 - by decreasing the JAK2 allele burden - may influence clonal myeloproliferation and in vivo granulocyte, platelet and endothelial activation , which are considered to be major determinants of morbidity and mortality ( thrombosis, bleeding, extramedullary haematopoiesis , myelofibrosis ) in these disorders. The effects of MK-0683 at the molecular level will be studied by global/ focused gene expression profiling, epigenome profiling and proteomics.

NCT00866762 Polycythemia Vera Essential Thrombocythemia Drug: HDAC inhibitor (MK-0683)
MeSH:Polycythemia Vera Polycythemia Thrombocytosis Thrombocythemia, Essential
HPO:Polycythemia Thrombocytosis

This agent has most recently been shown to be a potent inhibitor of the autonomous proliferation of haematopoietic cells of PV and ET patients carrying the JAK2 V617F mutation. --- V617F ---

Primary Outcomes

Measure: To evaluate the efficacy of study drug (MK-0683) in the treatment of patients with PV and ET.

Time: one year

Secondary Outcomes

Measure: To study changes in bone marrow morphology before and after treatment with study drug.

Time: one year

8 Molecular Study of Factors Involved in JAK-STAT Signalling Pathway in Familial Myeloproliferative Disorders

The main goal of the study is to progress in our understanding of the molecular basis of myeloproliferative disorders of the bone marrow (polycythemia vera, essential thrombocythemia, primary myelofibrosis). The study will focus on the genes encoding factors implicated in the JAK-STAT pathway which has an essential role in these diseases

NCT00873574 Myeloproliferative Disorders Biological: Blood samples and buccal swabs
MeSH:Myeloproliferative Disorders Disease
HPO:Myeloproliferative disorder

The recent identification of a recurrent activating tyrosine kinase mutation V617F in the JAK2 gene provides a breakthrough in the understanding of the molecular mechanisms of these diseases. --- V617F ---

The investigators have shown actually that the mutation V617F is a somatic one which is variably expressed among patients in the same family.Other somatic mutations and inherited factors, still unknown, may explain these discrepancies. --- V617F ---

JAK-STAT pathway has an essential role in non-CML MPD as was shown by the functional consequences of the V617F JAK2 mutation. --- V617F ---

Primary Outcomes

Measure: Allelic frequency comparison between the 2 cohorts

Time: At the inclusion visit

Secondary Outcomes

Measure: Undescribed gene mutations.

Time: At the inclusion visit

9 Phase II Trial of Oral Panobinostat (LBH589), a Novel Deacetylase Inhibitor (DACi) in Patients With Primary Myelofibrosis (PMF), Post Essential Thrombocythemia (ET) Myelofibrosis and Post- Polycythemia Vera (PV) Myelofibrosis

This study will assess the safety and efficacy of Panobinostat as a single agent in the treatment of Primary Myelofibrosis, Post-Polycythemia Vera and Post-Essential Thrombocythemia. There will be two cohorts - patients with JAK2 mutation and patients without JAK2 mutation.

NCT00931762 Primary Myelofibrosis Post-Polycythemia Vera Post-Essential Thrombocytopenia Drug: Panobinostat
MeSH:Polycythemia Vera Thrombocytopenia Primary Myelofibrosis Polycythemia
HPO:Polycythemia Thrombocytopenia

To compare the response to panobinostat in patients with the JAK2 V617F mutation to those without the JAK2 V617F mutation. --- V617F ---

To compare the response to panobinostat in patients with the JAK2 V617F mutation to those without the JAK2 V617F mutation. --- V617F --- --- V617F ---

(The presence of a JAK2 V617F mutation is not required for study entry) 2. Patients must meet the following laboratory criteria: - Patients can be either JAK2 V617F mutated or wild type - Serum potassium, magnesium, phosphorous, sodium, total calcium (corrected for serum albumin) or ionized calcium within normal limits (WNL) for the institution Note: Potassium, magnesium, phosphorous, sodium, and/or calcium supplements maybe given to correct values that are < LLN. --- V617F ---

(The presence of a JAK2 V617F mutation is not required for study entry) 2. Patients must meet the following laboratory criteria: - Patients can be either JAK2 V617F mutated or wild type - Serum potassium, magnesium, phosphorous, sodium, total calcium (corrected for serum albumin) or ionized calcium within normal limits (WNL) for the institution Note: Potassium, magnesium, phosphorous, sodium, and/or calcium supplements maybe given to correct values that are < LLN. --- V617F --- --- V617F ---

Primary Outcomes

Measure: To evaluate the overall response (CR, PR, and clinical improvement) to oral panobinostat as a single agent at 40 mg daily every Monday, Wednesday and Friday in patients with myelofibrosis.

Time: Upon enrollment of 13 participants into each cohort of the study and at the end of the study.

Secondary Outcomes

Measure: To compare the response to panobinostat in patients with the JAK2 V617F mutation to those without the JAK2 V617F mutation

Time: Upon enrollment of 13 participants into the study and at the end of the study

Measure: To evaluate the symptomatic improvement of myelofibrosis patients treated with panobinostat using the Myelofibrosis Symptom Assessment Form (MF-SAF) at baseline and after 2 and 4 months of treatment

Time: Upon enrollment of 13 participants in each cohort and at the end of the study

Measure: To evaluate the symptomatic improvement of myelofibrosis patients treated with panobinostat using the Myelofibrosis Symptom Assessment Form (MF-SAF) at baseline and after 2 and 4 months of treatment

Time: throughout the study

Measure: To assess compliance to panobinostat treatment as assessed by monthly capsule counts

Time: at the end of the study

10 A Phase I Study of Oral Arsenic Trioxide With or Without Ascorbic Acid in Adults With Myelofibrosis

This phase I trial studies the side effects and best dose of arsenic trioxide with or without ascorbic acid in treating patients with myelofibrosis. Drugs used in chemotherapy, such as arsenic trioxide, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving arsenic acid together with ascorbic acid may kill more cancer cells.

NCT01014546 Essential Thrombocythemia Polycythemia Vera Primary Myelofibrosis Drug: Arsenic Trioxide Dietary Supplement: Ascorbic Acid Other: Laboratory Biomarker Analysis Other: Pharmacological Study
MeSH:Polycythemia Vera Primary Myelofibrosis Polycythemia Thrombocytosis Thrombocythemia, Essential
HPO:Polycythemia Thrombocytosis

To estimate the efficacy of arsenic trioxide with ascorbic acid in subjects with myelofibrosis, as determined by a reduction in Janus kinase 2 (JAK2) V617F, JAK22T875N, and mutations of the thrombopoietin receptor (MPL515L/K) allele frequency in peripheral blood neutrophils. --- V617F ---

Primary Outcomes

Description: The frequency of toxicities will be tabulated by grade across all dose levels and courses. The frequency of toxicities will also be tabulated for the dose chosen as the MTD.

Measure: Adverse events, and their attribution throughout the study

Time: Up to 30 days post-treatment

Description: DLT is defined as any non-hematologic treatment-emergent grade 3 or greater adverse event deemed possibly, probably, or definitely related to the study drug. Exceptions are grade 3 nausea or vomiting, unless in the setting of maximal antiemetic treatment. Hematologic toxicities are not included in the definition of a DLT. The frequency of toxicities will be tabulated by grade across all dose levels and cycles.

Measure: Dose-limiting toxicity (DLT) as assessed by the National Cancer Institute (NCI) Common Toxicity Criteria (CTC) version 3.0 (Stage 1)

Time: At 28 days

Description: The frequency of toxicities will be tabulated by grade across all dose levels and cycles. The frequency of toxicities will also be tabulated for the dose chosen as the MTD.

Measure: Maximum tolerated dose (MTD), defined as the dose level at which 0 or 1 of 6 subjects experience DLT, and 2 of 3 or 2 of 6 experience DLT at the next higher dose level, assessed by the NCI CTC version 3.0 (Stage 1)

Time: At 28 days

Secondary Outcomes

Measure: Change in absolute number of circulating CD34+ cells in the peripheral blood (Stage 2 only)

Time: Baseline to 24 weeks

Measure: Change in JAK2/MPL (Stage 2 only)

Time: Baseline to 24 weeks

Description: Including: sVCAM-1, NE, MMP-2, MMP-9, SDF-1, TGF-B, and VEGF.

Measure: Change in plasma levels of chemokines as measured by ELISA (Stage 2)

Time: Baseline to 24 weeks

Description: Including: sVCAM-1, NE, MMP-2, MMP-9, SDF-1, TGF-B, and VEGF.

Measure: Change in plasma levels of cytokines as measured by ELISA (Stage 2)

Time: Baseline to 24 weeks

Description: Including: soluble vascular cell adhesion molecule 1 (sVCAM-1), neutrophil elastase (NE), matrix metalloproteinases 2 and 9 (MMP-2 and MMP-9), stromal cell derived growth factor-1 (SDF-1), TGF-B, and VEGF.

Measure: Change in plasma levels of proteases as measured by enzyme-linked immunosorbent assay (ELISA) (Stage 2)

Time: Baseline to 24 weeks

Measure: Disease response assessed using the IWG-MRT response criteria

Time: Up to 24 weeks

11 Phase II Trial of Erlotinib in Patients With JAK-2 V617F Positive Polycythemia Vera

The primary objective of this study is to determine the overall response rate to erlotinib in patients with polycythemia vera (PV). Response rate will be assessed by improvement in the complete blood count, ultrasound of the spleen, and JAK2 molecular status. It is purposed in this study to explore a possible molecular targeting of the driving mechanism of PV.

NCT01038856 Polycythemia Vera Drug: Erlotinib
MeSH:Polycythemia Vera Polycythemia
HPO:Polycythemia

Phase II Trial of Erlotinib in Patients With JAK-2 V617F Positive Polycythemia Vera. --- V617F ---

Trial of Erlotinib in Patients With JAK-2 V617F Positive Polycythemia Vera The primary objective of this study is to determine the overall response rate to erlotinib in patients with polycythemia vera (PV). --- V617F ---

Primary Outcomes

Measure: Overall Response Rate to Include Complete Hematological Response, Complete Molecular Response, Partial Hematological Response, and Minimal Hematological Response

Time: Day 15

Secondary Outcomes

Measure: Toxicity

Time: First assessment at day 15, subsequent assessments at 28 day intervals for an average of 1 year

Measure: Improvement in Splenomegaly Size

Time: 4 months, end of treatment and 12 months end of treatment

Measure: Decrease of Mutant JAK2V617F Allele Burden

Time: every 2 months until end of treatment and 12 months after end of treatment

12 A Phase 1 Study of LY2784544 in Patients With JAK2 V617F-Positive Myeloproliferative Disorders

The purpose of this study is to find out the safe dose range of the study drug in patients with myeloproliferative disorders.

NCT01134120 Myeloproliferative Disorders Thrombocythemia, Essential Polycythemia Vera Primary Myelofibrosis Drug: LY2784544
MeSH:Polycythemia Vera Primary Myelofibrosis Polycythemia Thrombocytosis Myeloproliferative Disorders Thrombocythemia, Essential
HPO:Myeloproliferative disorder Polycythemia Thrombocytosis

A Phase 1 Study of LY2784544 in Patients With JAK2 V617F-Positive Myeloproliferative Disorders. --- V617F ---

has post-ET MF - Have a quantifiable JAK2 V617F mutation - Have discontinued all previous approved therapies for myeloproliferative disorders, including any chemotherapy, immunomodulating therapy (for example, thalidomide, interferon-alpha), immunosuppressive therapy (for example, corticosteroids greater than 10 mg/day prednisone or equivalent), radiotherapy, and erythropoietin, thrombopoietin, or granulocyte colony stimulating factor for at least 14 days and recovered from the acute effects of therapy. --- V617F ---

Primary Outcomes

Measure: Determination of a recommended Phase 2 dosing regimen

Time: Time of first dose until last dose

Measure: Number of participants with clinical significant effects

Time: Time of first dose until last dose

Secondary Outcomes

Measure: Preliminary pharmacokinetics of LY2784544 (Cmax)

Time: Part A1: Day 1,2,15, and 29; Part A2: Day 7, 14, 21, 28, 29, 56, and 57; Part B: Day 1, 29, 57, and 113

Measure: Preliminary pharmacokinetics of LY2784544 (AUC)

Time: Part A1: Day 1,2,15, and 29; Part A2: Day 7, 14, 21, 28, 29, 56, and 57; Part B: Day 1, 29, 57, and 113

Measure: Malignant clone burden

Time: Part A1: Baseline (2 times), Weeks 13, 21 and every 6 months while patient is on study; Parts A2 and B: Baseline (2 times), Weeks 5, 8, 17, 25 and every 6 months while patient is on study

13 Single Arm Salvage Therapy With Pegylated Interferon Alfa-2a for Patients With High Risk Polycythemia Vera or High Risk Essential Thrombocythemia Who Are Either Hydroxyurea Resistant or Intolerant or Have Had Abdominal Vein Thrombosis

The aim of this research is to look at two conditions, Essential Thrombocythemia (ET) and Polycythemia Vera (PV). ET causes people to produce too many blood cells called platelets and PV causes too many platelets and red blood cells to be made. Platelets are particles which circulate in the blood stream and normally prevent bleeding and bruising. Having too many platelets in the blood increases the risk of developing blood clots, which can result in life threatening events like heart attacks and strokes. When the number of red blood cells is increased in PV this will slow the speed of blood flow in the body and increases the risk of developing blood clots. It is important for patients with ET or PV who are at risk of blood clots to receive drugs which will minimize the risks of developing these blood clots but at the moment the investigators are not sure which drugs will best control the disorder. The purpose of this study is to look at the effectiveness of giving patients who have been diagnosed with ET and PV a study drug regimen using Aspirin and PEGASYS (also known as Pegylated interferon alfa-2a, instead of the standard treatment drug called Hydroxyurea (or hydroxycarbamide or Hydroxyurea), for whom this drug may not be suitable. The drug may not be suitable either because it is not adequately controlling the number of blood cells or some specific side effects occur.

NCT01259817 High Risk Polycythemia Vera High Risk Essential Thrombocythemia Drug: PEGASYS Drug: Aspirin
MeSH:Polycythemia Vera Polycythemia Thrombocytosis Thrombocythemia, Essential
HPO:Polycythemia Thrombocytosis

To measure the impact of Pegylated Interferon Alfa-2a on JAK2-V617F, CALR, hematopoietic cell clonality in platelets and granulocytes in females, bone marrow histopathology, and cytogenetic abnormalities.. --- V617F ---

For these patients the following additional inclusion/exclusion criteria apply: - > 3 months since onset of SVT - SVT treated with oral anticoagulants but no aspirin - Liver enzymes not > 2 times the normal value - Absence of encephalopathy, refractory or infected ascites, esophageal varicose of grade > 1 at time of trial entry - Bone marrow biopsy confirmed diagnosis of PV or ET - JAK2-V617F mutations present - These patients may have a normal blood count at trial entry - Age over 18 years (no upper age limit) - Able and willing to comply with study criteria - Signed and informed consent to participant in this study - Willing to participate in associated correlative science biomarker study - Serum creatinine < 1.5 x upper limit of normal - AST and ALT < 2 x upper limit of normal - Total bilirubin within normal limits Exclusion Criteria: - Patients cannot have any other form of chemotherapy for their MPD (other than hydroxyurea). --- V617F ---

The point mutation in JAK2 encodes a valine to phenylalanine change at position 617 (JAK2 V617F), and confers constitutive tyrosine kinase activity. --- V617F ---

Introducing the mutation into the bone marrow of mouse models recapitulates the PV phenotype (complete with evolution to bone marrow fibrosis) and inhibitors of JAK2 attenuate the growth of cell lines bearing the mutation in vitro and in vivo, suggesting that JAK2 V617F is a pathophysiologically relevant therapeutic target. --- V617F ---

It is estimated that 95% of PV cases carry JAK2 V617F, while 50 to 60% of ET and PMF cases are JAK2 V617F+. --- V617F ---

Primary Outcomes

Measure: Evaluate the ability of Pegylated Interferon Alfa-2a to achieve Complete Response or Partial Response in patients with (1) high risk polycythemia vera or (2) high risk essential thrombocythemia or (3) splanchnic vein thrombosis

Time: 4 years

Secondary Outcomes

Measure: To evaluate the toxicity and tolerability of therapy Pegylated Interferon Alfa-2a in each of the 3 strata by recording the number of adverse events that occur during the study by using CTC 4.0 as the guide.

Time: 4 years

Measure: To measure the impact of Pegylated Interferon Alfa-2a on key biomarkers of the disease(s)by measuring the JAK2 allele burden.

Time: 4 years

Description: Improvement in disease symptoms will be measured by the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) instrument being used in this study.

Measure: To evaluate specific pre-defined toxicity and tolerance of Pegylated Interferon Alfa-2a through a sequential structured symptom assessment package of patient reported outcome instruments.

Time: 4 years

Description: We plan to capture the rate of disease progression to a more advanced myeloid malignancy.

Measure: To estimate survival, and incidence of development of myelodysplastic syndrome, myelofibrosis, or leukemic transformation during therapy Pegylated Interferon Alfa-2a.

Time: 4 years

Description: Capture and record the cardiovascular events that occur during the study.

Measure: Estimate the observed incidence of major cardiovascular events during therapy Pegylated Interferon Alfa-2a.

Time: 4 years

Description: The impact of PEGASYS on JAK2 will be measured by the allele burden; hematopoietic cell clonality will be measured by whether patients with clonal disease return to polyclonal; bone marrow histopathology will be measured by going from abnormal to normal; cytogenetic abnormalities will be measured by seeing if the cytogenetics go from abnormal to normal.

Measure: To measure the impact of Pegylated Interferon Alfa-2a on JAK2-V617F, CALR, hematopoietic cell clonality in platelets and granulocytes in females, bone marrow histopathology, and cytogenetic abnormalities.

Time: 4 years

14 Randomized Trial of Pegylated Interferon Alfa-2a Versus Hydroxyurea Therapy in the Treatment of High Risk Polycythemia Vera (PV) and High Risk Essential Thrombocythemia (ET)

This research is looking at two conditions, Essential Thrombocythemia (ET) and Polycythemia Vera (PV). ET causes people to produce too many blood cells called platelets and PV causes too many platelets and red blood cells to be made. Platelets are particles which circulate in the blood stream and normally prevent bleeding and bruising. Having too many platelets in the blood increases the risk of developing blood clots, which can result in life threatening events like heart attacks and strokes. When the number of red blood cells is increased in PV this will slow the speed of blood flow in the body and increases the risk of developing blood clots. The purpose of this study is to look at the effectiveness of giving participants who have been diagnosed with ET or PV one of two different study regimens over time. The study subject will be followed for their condition for about 5 years. The subject will be randomized into one of two study regimens, either Pegylated Interferon Alfa-2a (PEGASYS) or Aspirin and Hydroxyurea (also called Hydroxycarbamide). The subject must be newly diagnosed or already receiving treatment for either PV or ET. Each of the study drugs used in this study is already being used to treat subjects with ET or PV currently, but the investigators are unsure which study drug is better.

NCT01259856 High Risk Polycythemia Vera High Risk Essential Thrombocythemia Drug: PEGASYS Drug: Hydroxyurea Drug: Aspirin
MeSH:Polycythemia Vera Polycythemia Thrombocytosis Thrombocythemia, Essential
HPO:Polycythemia Thrombocytosis

The impact of PEGASYS on JAK2 will be measured by the allele burden; hematopoietic cell clonality will be measured by whether patients with clonal disease return to polyclonal; bone marrow histopathology will be measured by going from abnormal to normal; cytogenetic abnormalities will be measured by seeing if the cytogenetics go from abnormal to normal.To compare the impact of therapy on JAK2-V617F (JAK2), CALR, hematopoietic cell clonality in platelets and granulocytes in females, bone marrow histopathology, and cytogenetic abnormalities.. Number of Participants With Progression of Disease or Death. --- V617F ---

Primary Outcomes

Description: Number of participants with Complete Remission after 12 months of therapy assessed by hematologic response rates two strata of patients with high risk polycythemia vera (PV) or high risk essential thrombocythemia (ET). Complete remission means no evidence of disease.

Measure: Number of Participants With Complete Remission (CR)

Time: 12 months

Description: Number of participants with Partial Remission after 12 months of therapy assessed by hematologic response rates two strata of patients with high risk polycythemia vera (PV) or high risk essential thrombocythemia (ET). Partial Remission means decrease in the size of a tumor, or in the extent of cancer in the body, in response to treatment.

Measure: Number of Participants With Partial Remission (PR)

Time: 12 months

Secondary Outcomes

Description: Number of Participants with Grade 3 and Grade 4 Hematological and Non-hematological Events using the Common Terminology Criteria for Adverse Events (CTCAE) 4.0 to assess the toxicity, safety and tolerability of therapy (Pegylated Interferon Alfa-2a vs. Hydroxyurea).

Measure: Number of Participants With Grade 3 and Grade 4 Hematological and Non-hematological Events

Time: 4 years

Description: Change in the Total Symptom Score which assessed improvement in disease symptoms measured by the change in TSS from the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) instrument being used in this study from baseline to 12 months. This 19 item instrument includes the previously validated 9 item brief fatigue inventory (BFI), symptoms related to splenomegaly, inactivity, cough, night sweats, pruritus, bone pains, fevers, weight loss, and an overall quality of life assessment. Each item is scored from 0-10 with full scale from 0-190, with higher scores mean worse symptoms.

Measure: Change in the Total Symptom Score (TSS)

Time: baseline and 12 months

Description: To compare the impact of therapy (Pegylated Interferon Alfa-2a vs. Hydroxyurea) on key biomarkers of the disease(s) by measuring the JAK2 allele burden.

Measure: JAK2 Allele Burden

Time: 4 years

Description: The impact of PEGASYS on JAK2 will be measured by the allele burden; hematopoietic cell clonality will be measured by whether patients with clonal disease return to polyclonal; bone marrow histopathology will be measured by going from abnormal to normal; cytogenetic abnormalities will be measured by seeing if the cytogenetics go from abnormal to normal.To compare the impact of therapy on JAK2-V617F (JAK2), CALR, hematopoietic cell clonality in platelets and granulocytes in females, bone marrow histopathology, and cytogenetic abnormalities.

Measure: Allele Burden

Time: 4 years

Description: Survival and incidence of development of myelodysplastic syndrome, myelofibrosis, or leukemic transformation after therapy To estimate survival and incidence of development of myelodysplastic syndrome, myelofibrosis, or leukemic transformation after therapy (Pegylated Interferon Alfa-2a vs. Hydroxyurea) by capturing the rate of progression to a more advanced myeloid malignancy.

Measure: Number of Participants With Progression of Disease or Death

Time: 4 years

Measure: Number of Participants With Major Cardiovascular Events After Therapy

Time: 4 years

15 Natural Killer Cells and Polycythemia Vera (Vaquez's Disease)

Natural Killer cells (NK) are pivotal cells of innate immunity, that sense defective expression of HLA class I molecules and are complementary to specific cytotoxic T lymphocytes. A defect in NK cell cytotoxicity has been described in some hematopoietic malignancies such as acute myeloid leukemia, multiple myeloma, myelodysplastic syndroms. This defect is at least partially linked to a decreased or absent expression of some activating NK cell molecules, more particularly the so-called Natural Cytotoxicity Receptors (NCRs) NKp30, NKp44 and NKp46. Some old publications have demonstrated defective NK cytotoxicity in myeloproliferative syndroms (chronic myeloid leukemia, primary thrombocytosis, polycythemia vera). The investigators more particularly focused their attention on polycythemia vera (Vaquez's disease), a myeloproliferative disease characterized by the recently describet mutation V617F of the JAK2 tyrosine kinase. The investigators will precise the mechanisms leading to this cytotoxicity defect, the investigators also will evaluate the implication of V617F mutation on NK physiology, and will study the interactions between NK cells and hematopoietic progenitors.

NCT01284712 Polycythemia Vera Biological: blood sample
MeSH:Polycythemia Vera Polycythemia
HPO:Polycythemia

The investigators more particularly focused their attention on polycythemia vera (Vaquez's disease), a myeloproliferative disease characterized by the recently describet mutation V617F of the JAK2 tyrosine kinase. --- V617F ---

The investigators will precise the mechanisms leading to this cytotoxicity defect, the investigators also will evaluate the implication of V617F mutation on NK physiology, and will study the interactions between NK cells and hematopoietic progenitors. --- V617F ---

Primary Outcomes

Measure: To describe immunologic anomalies in polycythemia vera

Time: 2 years

16 An Exploratory, Observational, Multicentre Study to Investigate the Impact of the Presence of JAK2 (V617F) Mutation on Treatment Response in Patients With Essential Thrombocythaemia Treated With XAGRID® (Anagrelide Hydrochloride)

This study is hypothesis-generating to explore the impact of JAK2 (V617F) mutation status on the treatment response to anagrelide hydrochloride

NCT01352585 Essential Thrombocythemia (ET) Drug: Anagrelide hydrochloride
MeSH:Thrombocytosis Thrombocythemia, Essential
HPO:Thrombocytosis

An Exploratory, Observational, Multicentre Study to Investigate the Impact of the Presence of JAK2 (V617F) Mutation on Treatment Response in Patients With Essential Thrombocythaemia Treated With XAGRID® (Anagrelide Hydrochloride). --- V617F ---

Exploratory Multi-centre Trial In Patients With ET Treated With XAGRID® This study is hypothesis-generating to explore the impact of JAK2 (V617F) mutation status on the treatment response to anagrelide hydrochloride Number of Patients With Platelet Count ≤600x10^9/L After 12 Months. --- V617F ---

Primary Outcomes

Description: A platelet count of ≤600x10^9/L after 12 months is considered at least a partial response.

Measure: Number of Patients With Platelet Count ≤600x10^9/L After 12 Months

Time: 1 year

Secondary Outcomes

Description: A platelet count of ≤400x10^9/L after 12 months is considered a complete response.

Measure: Number of Patients With Platelet Count ≤400x10^9/L After 12 Months

Time: 1 year

Measure: Platelet Count

Time: 1 year

Measure: Red Blood Cell (RBC) Count

Time: 1 year

Measure: White Blood Cell (WBC) Count

Time: 1 year

Measure: Differential WBC Count

Time: 1 year

Measure: Hemoglobin Concentration

Time: 1 year

Measure: Hematocrit Level

Time: 1 year

17 Danish Study of Low-dose Interferon Alpha Versus Hydroxyurea in the Treatment of Philadelphia Chromosome Negative (Ph-)Chronic Myeloid Neoplasms.

The purpose of the study is to compare the efficacy and toxicity including quality of life of two types of low-dose interferon alpha compounds (PegIntron and Pegasys) with hydroxyurea (Hydrea), and to investigate the occurence of neutralizing antibodies against recombinant interferon.

NCT01387763 Polycythemia Vera Essential Thrombocythemia Primary Myelofibrosis Drug: PegIntron Drug: Pegasys Drug: PegIntron Drug: Pegasys Drug: Hydrea
MeSH:Polycythemia Vera Primary Myelofibrosis Polycythemia Thrombocytosis Thrombocythemia, Essential Neoplasms
HPO:Neoplasm Polycythemia Thrombocytosis

Molecular responses (JAK V617F allele burden) are assessed by qPCR according to the ELN guidelines.. toxicity (discontinuation of therapy due to intolerability). --- V617F ---

In 2005 major breakthrough in our understanding of the molecular pathophysiology was achieved with the identification of the JAK2 V617F mutation which is present in almost all patients with PV (98%) and about half of patients with ET and PMF. --- V617F ---

Within recent years IFN-alpha has demonstrated a capacity of inducing deep molecular remission (evaluated by JAK2 V617F qPCR) and normalisation of bone marrow morphology. --- V617F ---

If patients have a sustained deep molecular response (below 1 % JAK2 V617F mutated alleles for 12 months) therapy will be stopped to asses the sustainability of the remission off therapy.Patients over the age of 75 and intolerant or resistant to hydroxyurea will be offered rescue treatment with orally busulfan (Myleran). --- V617F ---

Primary Outcomes

Description: Molecular responses (JAK V617F allele burden) are assessed by qPCR according to the ELN guidelines.

Measure: molecular response (changes from baseline)

Time: 18, 36 and 60 months

Secondary Outcomes

Description: The proportion of patients treated with PegIntron, Pegasys and Hydrea who need to discontinue therapy due to intolerability

Measure: toxicity (discontinuation of therapy due to intolerability)

Time: 18 months

Description: Quality of life will be evaluated according to EORTC QLQ C-30 and MPN-SAF

Measure: Quality of life (changes from baseline)

Time: 4, 12, 24, 36, 48 and 60 months

Description: A bone marrow sample will be evaluated in order to detect and grade changes in bone marrow morphology.

Measure: Histopathological response (changes from baseline)

Time: 36 and 60 months

Description: investigation of the sustainability of an obtained molecular remission (< 1% JAK2V617F mutated alleles) after discontinuation of interferon- alpha( Pegasys, PegIntron, Multiferon) or Hydrea.

Measure: Sustained molecular response (changes from level at time of discontinuation of therapy)

Time: 12, 24 and 36 months

Description: Proportion of patients treated with Peintron and Pegasys who have developed neutralizing antibodies.

Measure: Neutralizing antibodies against PegIntron and Pegasys

Time: 24 months

Description: Hematological response will be evaluated according to the ELN guidelines.

Measure: hematological response

Time: 12 months

18 A Phase II, Multicenter, Open Label, Single Arm Study of SAR302503 in Subjects Previously Treated With Ruxolitinib and With a Current Diagnosis of Intermediate or High-Risk Primary Myelofibrosis, Post-Polycythemia Vera Myelofibrosis, or Post-Essential Thrombocythemia Myelofibrosis

Primary Objective: - To evaluate the efficacy of once daily dose of SAR302503 in subjects previously treated with ruxolitinib and with a current diagnosis of intermediate-1 with symptoms, Intermediate-2 or high-risk primary myelofibrosis (PMF), post-polycythemia vera myelofibrosis (Post-PV MF), or post-essential thrombocythemia myelofibrosis (Post-ET MF) based on the reduction of spleen volume at the end of 6 treatment cycles; Secondary Objectives: - To evaluate the effect of SAR302503 on Myelofibrosis (MF) associated symptoms as measured by the modified Myelofibrosis Symptom Assessment Form (MFSAF) diary - To evaluate the durability of splenic response - To evaluate the splenic response to SAR302503 by palpation at the end of Cycle 6 - To evaluate the splenic response to SAR302503 at the end of Cycle 3 - To evaluate the effect of SAR302503 on the Janus kinase 2 (JAK2) V617F allele burden - To evaluate the safety and tolerability of SAR302503 in this population - To evaluate plasma concentrations of SAR302503 for population PK analysis, if warranted

NCT01523171 Hematopoietic Neoplasm Drug: SAR302503
MeSH:Hematologic Neoplasms Primary Myelofibrosis
HPO:Hematological neoplasm Leukemia

Phase II, Open Label, Single Arm Study of SAR302503 In Myelofibrosis Patients Previously Treated With Ruxolitinib Primary Objective: - To evaluate the efficacy of once daily dose of SAR302503 in subjects previously treated with ruxolitinib and with a current diagnosis of intermediate-1 with symptoms, Intermediate-2 or high-risk primary myelofibrosis (PMF), post-polycythemia vera myelofibrosis (Post-PV MF), or post-essential thrombocythemia myelofibrosis (Post-ET MF) based on the reduction of spleen volume at the end of 6 treatment cycles; Secondary Objectives: - To evaluate the effect of SAR302503 on Myelofibrosis (MF) associated symptoms as measured by the modified Myelofibrosis Symptom Assessment Form (MFSAF) diary - To evaluate the durability of splenic response - To evaluate the splenic response to SAR302503 by palpation at the end of Cycle 6 - To evaluate the splenic response to SAR302503 at the end of Cycle 3 - To evaluate the effect of SAR302503 on the Janus kinase 2 (JAK2) V617F allele burden - To evaluate the safety and tolerability of SAR302503 in this population - To evaluate plasma concentrations of SAR302503 for population PK analysis, if warranted Response Rate (RR), defined as the proportion of subjects who have a ≥35% reduction from baseline in volume of spleen at the end of Cycle 6 as measured by Magnetic Resonance Imaging (MRI) (or CT scan in subjects with contraindications for MRI). --- V617F ---

Primary Outcomes

Measure: Response Rate (RR), defined as the proportion of subjects who have a ≥35% reduction from baseline in volume of spleen at the end of Cycle 6 as measured by Magnetic Resonance Imaging (MRI) (or CT scan in subjects with contraindications for MRI)

Time: 6 months

Secondary Outcomes

Measure: Symptom Response Rate (SRR): Proportion of subjects with a ≥50% reduction from baseline to the end of Cycle 6 in the total symptom score using the modified MFSAF

Time: 6 months

Measure: Duration of spleen response, measured by MRI (or CT scan in subjects with contraindications for MRI)

Time: 6 months

Measure: Proportion of subjects with a ≥50% reduction in length of spleen by palpation from baseline at the end of Cycle 6

Time: 6 months

Measure: Response Rate at the end of Cycle 3, defined as the proportion of subjects who have a ≥35% reduction from baseline in volume of spleen at the end of Cycle 3 as measured by MRI (or CT scan in subjects with contraindications for MRI)

Time: 6 months

Measure: Percent change of spleen volume at the end of Cycles 3 and 6 from baseline as measured by MRI (or CT scan in subjects with contraindications for MRI)

Time: 6 months

Measure: Safety, as assessed by clinical, laboratory, ECG, and vital sign events; graded by the NCI CTCAE v4.03

Time: approximately 5 years

Measure: Plasma concentrations of SAR302503

Time: 4 months

Measure: The effect of SAR302503 on the JAK2V617F allele burden

Time: 2 years

19 A Phase 2 Study of LY2784544 in Patients With Myeloproliferative Neoplasms

The primary purpose of this study is to measure the response rate in participants with the myeloproliferative neoplasms (MPNs), polycythemia vera (PV), essential thrombocythemia (ET), or myelofibrosis (MF) when treated with LY2784544, including those who have demonstrated an intolerance to, failure of primary response to, or have demonstrated disease progression while on ruxolitinib.

NCT01594723 Neoplasms, Hematologic Drug: 120 mg LY2784544
MeSH:Hematologic Neoplasms Myeloproliferative Disorders Neoplasms
HPO:Hematological neoplasm Leukemia Myeloproliferative disorder Neoplasm

Inclusion Criteria: - Have a diagnosis of polycythemia vera (PV), essential thrombocythemia (ET), or myelofibrosis (MF) as defined by the World Health Organization (WHO) diagnostic criteria for myeloproliferative neoplasms (Swerdlow et al. 2008) and meet the following additional subtype specific criteria: - PV: have failed or is intolerant of standard therapies or refuses to take standard medications - ET: have failed or is intolerant of standard therapies or refuses to take standard medications - MF (participants with MF must meet at least 1 of the following): have intermediate 1, intermediate 2, or high-risk MF according to the Dynamic International Prognostic Scoring System (DIPPS Plus) for Primary Myelofibrosis (Gangat et al. 2011); or have symptomatic MF with spleen greater than 10 centimeter (cm) below left costal margin; or have post-polycythemic MF; or have post-ET MF - All PV, ET, and MF participants must meet the following criteria: o Have a quantifiable level of janus kinase 2 with a valine to phenylalanine substitution at amino acid 617 (JAK2 V617F) mutation. --- V617F ---

This inclusion criterion will not apply to the subset of participants in Cohorts 10 and 11 that must be negative for the JAK2 V617F mutation - Are ≥ 18 years of age - Have given written informed consent prior to any study-specific procedures - Have adequate organ function, including: Hepatic: Direct bilirubin ≤1.5 times upper limits of normal (ULN), alanine transaminase (ALT), and aspartate transaminase (AST) ≤2.5 times ULN; Renal: Serum creatinine ≤1.5 times ULN; Bone Marrow Reserve: Absolute neutrophil count (ANC) ≥1000/microliter (mcL), platelets ≥50,000/mcL for participants with ET or PV and ≥25,000/mcL for participants with MF - Have a performance status of 0, 1, or 2 on the Eastern Cooperative Oncology Group (ECOG) scale - Have discontinued all previous approved therapies for Myeloproliferative Neoplasms (MPNs), including any chemotherapy, immunomodulating therapy (for example, thalidomide, interferon-alpha), immunosuppressive therapy (for example, corticosteroids >10 mg/day prednisone or equivalent), radiotherapy, and erythropoietin, thrombopoietin, or granulocyte colony stimulating factor for at least 14 days and recovered from the acute effects of therapy. --- V617F ---

An exception to this criterion will be allowed for participants with a prior history of Budd-Chiari Syndrome who are being treated with warfarin or one of its derivatives - Have received a hematopoietic stem cell transplant - Have a second primary malignancy that in the judgment of the Investigator and Sponsor may affect the interpretation of results - Have an active fungal, bacterial, and/or known viral infection including human immunodeficiency virus (HIV) or viral (A, B, or C) hepatitis (screening is not required) - Have a history of congestive heart failure with New York Heart Association (NYHA) Class >2 (NYHA Class 1 and 2 are eligible), unstable angina, recent myocardial infarction (within 6 months prior to administration of study drug), or documented history of ventricular arrhythmia Inclusion Criteria: - Have a diagnosis of polycythemia vera (PV), essential thrombocythemia (ET), or myelofibrosis (MF) as defined by the World Health Organization (WHO) diagnostic criteria for myeloproliferative neoplasms (Swerdlow et al. 2008) and meet the following additional subtype specific criteria: - PV: have failed or is intolerant of standard therapies or refuses to take standard medications - ET: have failed or is intolerant of standard therapies or refuses to take standard medications - MF (participants with MF must meet at least 1 of the following): have intermediate 1, intermediate 2, or high-risk MF according to the Dynamic International Prognostic Scoring System (DIPPS Plus) for Primary Myelofibrosis (Gangat et al. 2011); or have symptomatic MF with spleen greater than 10 centimeter (cm) below left costal margin; or have post-polycythemic MF; or have post-ET MF - All PV, ET, and MF participants must meet the following criteria: o Have a quantifiable level of janus kinase 2 with a valine to phenylalanine substitution at amino acid 617 (JAK2 V617F) mutation. --- V617F ---

Primary Outcomes

Measure: Percentage of Participants with an Objective Response (Objective Response Rate)

Time: Baseline until Disease Progression (PD) or Participant Stops Study (Estimated up to 24 Months)

Secondary Outcomes

Measure: Percentage of Participants with a Molecular Response (Molecular Response Rate)

Time: Baseline until PD or Participant Stops Study (Estimated up to 24 Months)

Measure: Percentage of Participants with Hematological Improvement (Hematological Improvement Rate)

Time: Baseline until PD or Participant Stops Study (Estimated up to 24 Months)

Measure: Change in Spleen Size

Time: Baseline until PD or Participant Stops Study (Estimated up to 24 Months)

Measure: Change in Bone Marrow Fibrosis Grade

Time: Baseline until PD or Participant Stops Study (Estimated up to 24 Months)

Measure: Change in Number of Thrombotic or Hemorrhagic Events

Time: 3 Months prior to Study Drug (historic) until PD or Participant Stops Study (Estimated up to 24 Months)

Measure: Change in Number of Phlebotomies and Transfusions

Time: Baseline until PD or Participant Stops Study (Estimated up to 24 Months)

Measure: Duration of Response

Time: Confirmed Response to PD or Death from Any Cause (Estimated up to 24 Months)

Measure: Time to Best Response

Time: Baseline to Confirmed Response (Estimated up to 6 Months)

Measure: Change in Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF)

Time: Baseline until PD or Participant Stops Study (Estimated up to 24 Months)

Measure: Time to Treatment Failure

Time: Baseline to PD, Death from Any Cause or Participant Stops Study (Estimated up to 24 Months)

Measure: Time to Disease Progression

Time: Baseline to Measured PD (Estimated up to 24 Months)

Measure: Progression Free Survival (PFS)

Time: Baseline to PD or Death from Any Cause (Estimated up to 24 Months)

Measure: Change in Activities of Daily Living (ADL)/ Instrumental Activities of Daily Living (IADL)

Time: Baseline until PD or Participant Stops Study (Estimated up to 24 Months)

Measure: Change in EuroQol - 5 dimensions (EQ-5D) Index Score

Time: Baseline until PD or Participant Stops Study (Estimated up to 24 Months)

Measure: Change in International Prognosis Scoring System Scales (IPSS)

Time: Baseline until PD or Participant Stops Study (Estimated up to 24 Months)

Measure: Pharmacokinetics (PK): Maximum Concentration (Cmax) of LY2784544

Time: Predose up to Day 84

Measure: PK: Time of Maximal Concentration (Tmax) of LY2784544

Time: Predose up to Day 84

Measure: Change in Liver Size

Time: Baseline until PD or Participant Stops Study (Estimated up to 24 Months)

Measure: Change in 6-item Physician Symptom Assessment

Time: Baseline until PD or Participant Stops Study (Estimated up to 24 Months)

20 A Large-scale Trial Testing the Intensity of CYTOreductive Therapy to Prevent Cardiovascular Events In Patients With Polycythemia Vera (PV)

CYTO-PV is a phase III Prospective, Randomized, Open-label, with Blinded Endpoint evaluation (PROBE), multi-center, clinical trial in patients with diagnosis of Polycythemia vera (PV) treated at the best of recommended therapies (e.g.adequate control of standard cardiovascular risk factors). Irrespective of randomized interventions, all patients will be administered low-dose aspirin (when not contraindicated), i.e.the standard antithrombotic treatment in PV patients. The purpose of this study to demonstrate that a more intensive cytoreductive therapy, plus low-dose aspirin when not contraindicated, with phlebotomy and/or hydroxyurea (HU), aimed at maintaining hematocrit (HCT) < 45% is more effective than a less intensive cytoreduction (either with phlebotomy or HU plus low-dose aspirin when not contraindicated) maintaining HCT in the range of 45-50% in the reduction of CV deaths plus thrombotic events (stroke, acute coronary syndrome [ACS], transient ischemic attack [TIA], pulmonary embolism [PE], splanchnic thrombosis, deep vein thrombosis [DVT], and any other clinically relevant thrombotic event), in patients with Polycythemia Vera treated at the best of recommended therapies (e.g. adequate control of standard cardiovascular risk factors).

NCT01645124 Polycythemia Vera Drug: Hydroxyurea Procedure: Phlebotomy
MeSH:Polycythemia Vera Polycythemia
HPO:Polycythemia

However, both pragmatic reasons and the consideration of the clinical condition under study (see: age, comorbidity, polytherapy) support the decision to adopt a generalized policy of surveillance specifically on: Hypotension or syncope after phlebotomy; renal dysfunction (creatinine); liver dysfunction (ALT, AST, symptoms); White blood cell count; Platelet count; Bleeding.. Inclusion Criteria: Males and females aged 18 years or more are eligible for the study if they meet all the following inclusion criteria: - New diagnosis of PV according to WHO 2007 diagnostic criteria including Jak 2 V617F mutation status; - Old diagnosis of PV confirmed with JAK-2 positivity and clinical course of the disease; - Ability and willingness to comply with all study requirements; - Written informed consent (obtained before any study specific procedure). --- V617F ---

Inclusion Criteria: Males and females aged 18 years or more are eligible for the study if they meet all the following inclusion criteria: - New diagnosis of PV according to WHO 2007 diagnostic criteria including Jak 2 V617F mutation status; - Old diagnosis of PV confirmed with JAK-2 positivity and clinical course of the disease; - Ability and willingness to comply with all study requirements; - Written informed consent (obtained before any study specific procedure). --- V617F ---

Primary Outcomes

Description: To demonstrate that in patients with PV treatment with aggressive cytoreductive therapy aimed at maintaining HCT < 45% is more effective than cytoreductive therapy aimed at maintaining HCT between 45 and 50% in the reduction CV deaths plus thrombotic events (PEP: stroke, acute coronary syndrome [ACS], transient ischemic attack [TIA], pulmonary embolism [PE], abdominal thrombosis, deep vein thrombosis [DVT], and peripheral arterial thrombosis). The minimum clinically relevant beneficial effect is set at a 30% reduction of risk of the PEP.

Measure: Reduction of PEP (Primary End Point)defined as CV deaths plus thrombotic events

Time: Expected average of 5 years

Secondary Outcomes

Description: The events included in the PEP, arterial and venous thrombosis, major and minor thrombosis as well as hospitalization for any reason, hospitalization for CV reason, malignancy and PV-related malignancy (progression to myelofibrosis, myelodysplastic or leukemic transformation) will be analyzed separately to assess the full benefit/risk profile of experimental treatments.

Measure: PEP plus minor thrombosis, hospitalization and malignancy

Time: Expected average of 5 years

Other Outcomes

Description: Background knowledge suggests that no specific safety precautions are to be adopted for phlebotomy and HU administration. However, both pragmatic reasons and the consideration of the clinical condition under study (see: age, comorbidity, polytherapy) support the decision to adopt a generalized policy of surveillance specifically on: Hypotension or syncope after phlebotomy; renal dysfunction (creatinine); liver dysfunction (ALT, AST, symptoms); White blood cell count; Platelet count; Bleeding.

Measure: Aadverse Events

Time: Expected average of 5 years

21 Long-term Study Evaluating the Effect of Givinostat in Patients With JAK2V617F Positive Chronic Myeloproliferative Neoplasms

This is a multicenter, open label, long-term study testing the long-term safety, tolerability and efficacy of Givinostat in patients with Polycythemia Vera, Essential Thrombocythemia, primary Myelofibrosis, Post-Polycythemia Vera Myelofibrosis, Post-Essential Thrombocythemia Myelofibrosis following core protocols in chronic myeloproliferative neoplasms and/or patient-named compassionate use program (if regulated/allowed by the local regulations, e.g. for Italy D.M. 8/5/2003 "Uso terapeutico di medicinale sottoposto a sperimentazione clinica" published on G.U. n. 173 of 28 July 2003, and the following amendments). Patients will continue at their last tolerable dose and treatment schedule of Givinostat monotherapy. If patients previously received Givinostat in combination with other drugs during a core protocol or a compassionate use program (if regulated/allowed by the local regulations, e.g. for Italy D.M. 8/5/2003 "Uso terapeutico di medicinale sottoposto a sperimentazione clinica" published on G.U. n. 173 of 28 July 2003, and the following amendments), they will be treated at the last tolerable dose of the combination. Assessment of safety and efficacy will be performed at each quarterly visit and each visit will also include laboratory tests and ECG examination. During the visits the clinical benefit will be assessed by Investigator according to the revised European LeukemiaNet response criteria (for PV and ET) and EUMNET response criteria (for MF). The dose of Givinostat will be modified for protocol specified toxicities. The treatment may continue up to Marketing Authorization of Givinostat, currently planned in the next 5 years (note: only for Germany, this long-term study is initially limited up to 2 years of treatment). Patients may discontinue study treatment at any time and remain on study therapy as long as they derive clinical benefit. Safety will be monitored at each visit throughout the entire duration of the study. In case the approved label will not cover the whole study population, Givinostat will be provided by the Sponsor to those patients not fulfilling the criteria for the approved label of the drug that are still deriving benefit from Givinostat at the time of its commercial availability.

NCT01761968 Chronic Myeloproliferative Neoplasms Drug: Givinostat
MeSH:Myeloproliferative Disorders Neoplasms
HPO:Myeloproliferative disorder Neoplasm

reduction of the allele burden of the mutated Janus Kinase 2 in the position V617F). --- V617F ---

Primary Outcomes

Description: To obtain information on the long-term efficacy of Givinostat in patients with chronic myeloproliferative neoplasms following core protocols or compassionate use program: Number of patients experiencing adverse events; Type, incidence, and severity of treatment-related adverse events. To determine the long term safety and tolerability of Givinostat in patients with chronic myeloproliferative neoplasms following core protocols or compassionate use program: For Polycythemia Vera and Essential Thrombocythemia, Complete response and partial response rate according to the revised clinico-haematological European LeukemiaNet response criteria; For Myelofibrosis, complete response, major response, moderate response and minor response rate according to European Myelofibrosis Network response criteria. Note that these assessment will be repeated periodically (each 3 months) during the study. In fact, the treatment will continue up to Marketing Authorisation of Givinostat.

Measure: Long-term safety and efficacy

Time: 3 months

Other Outcomes

Description: To evaluate the effect of Givinostat on each single response parameter according to the revised European LeukemiaNet (for Polycythemia Vera and Essential Thrombocythemia) and European European Myelofibrosis Network response criteria (for Myelofibrosis). Note that this assessment will be repeated periodically (each year) during the study. In fact, the treatment will continue up to Marketing Authorisation of Givinostat.

Measure: Clinical exploratory endpoint

Time: 1 year

Description: To evaluate the molecular response (i.e. reduction of the allele burden of the mutated Janus Kinase 2 in the position V617F). Note that this assessment will be repeated periodically (each year) during the study. In fact, the treatment will continue up to Marketing Authorisation of Givinostat.

Measure: Molecular exploratory endpoint

Time: 1 year

Description: To identify potential other markers predictive of clinical benefit of Givinostat (e.g. potential pharmacodynamic markers). Note that this assessment will be repeated periodically (each year) during the study. In fact, the treatment will continue up to Marketing Authorisation of Givinostat.

Measure: Biomolecular exploratory endpoint

Time: 1 year

22 A Two-part Study Top Assess the Safety and Preliminary Efficacy of Givinostat in Patients With JAK2V617F Positive Polycythemia Vera

This is a two-part, multicenter, open label, non-randomized, phase Ib/II study to assess the safety and tolerability, Maximum Tolerated Dose and preliminary efficacy of Givinostat in patients with JAK2V617F positive Polycythemia Vera. Part A is the dose finding part while Part B is assessing the preliminary efficacy. Patients will be enrolled either in Part A or Part B and transition from one part to the other is not allowed. Eligible patients for this study will have a confirmed diagnosis of Polycythemia Vera according to the revised World Health Organization criteria. Only if the enrolment in Part A is slow (i.e. < 5 patients enrolled in 3 months), eligibility for this part of the study may be expanded to all patients with chronic myeloproliferative neoplasms. Study therapy will be administered in 28 day cycles (4 weeks of treatment). Disease response will be evaluated according to the European LeukemiaNet criteria after 3 and 6 cycles (i.e. at weeks 12 and 24, respectively) of treatment with Givinostat for both parts of the study. All phlebotomies performed in the first 3 weeks of treatment will not be counted to assess the clinico-haematological response. The study will last up to a maximum of 24 weeks of treatment. However, after completion of the trial, all patients achieving clinical benefit will be allowed to continue treatment with Givinostat (at the same dose and schedule) in a long-term study. Safety will be monitored at each visit throughout the entire duration of the study. Treatment will be administered on an outpatient basis and patients will be followed regularly with physical and laboratory tests, as specified in the protocol; in case of hospitalization, the treatment will be continued or interrupted according to the Investigators' decision.

NCT01901432 Polycythemia Vera Drug: Givinostat
MeSH:Polycythemia Vera Polycythemia
HPO:Polycythemia

dose group was not available for PK analysis.. Inclusion Criteria: 1. Patients must be able to provide informed consent and be willing to sign an informed consent form; 2. Patients must have an age ≥18 years; 3. Patients must have a confirmed diagnosis of Polycythemia Vera according to the revised World Health Organization criteria; 4. Patients must have mutated Janus Kinase 2 (mutation V617F) positive disease; 5. Patients must have an active/not controlled disease defined as 1. hematocrit ≥ 45% or hematocrit <45% in need of phlebotomy, and 2. platelet count > 400 x109/L, and 3. white blood cell count > 10 x109/L; 6. Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1 in Part A, ECOG performance status ≤ 2 in Part B within 7 days of initiating study drug; 7. Female patient of childbearing potential has a negative serum or urine pregnancy test within 72 hours of the first dose of study therapy; 8. Use of an effective means of contraception for women of childbearing potential and men with partners of childbearing potential; 9. Adequate and acceptable organ function within 7 days of initiating study drug; 10. --- V617F ---

Inclusion Criteria: 1. Patients must be able to provide informed consent and be willing to sign an informed consent form; 2. Patients must have an age ≥18 years; 3. Patients must have a confirmed diagnosis of Polycythemia Vera according to the revised World Health Organization criteria; 4. Patients must have mutated Janus Kinase 2 (mutation V617F) positive disease; 5. Patients must have an active/not controlled disease defined as 1. hematocrit ≥ 45% or hematocrit <45% in need of phlebotomy, and 2. platelet count > 400 x109/L, and 3. white blood cell count > 10 x109/L; 6. Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1 in Part A, ECOG performance status ≤ 2 in Part B within 7 days of initiating study drug; 7. Female patient of childbearing potential has a negative serum or urine pregnancy test within 72 hours of the first dose of study therapy; 8. Use of an effective means of contraception for women of childbearing potential and men with partners of childbearing potential; 9. Adequate and acceptable organ function within 7 days of initiating study drug; 10. --- V617F ---

Primary Outcomes

Description: Evaluations were performed on the type, incidence and severity of TEAEs, graded according to Common Terminology Criteria for Adverse Events (CTCAE) v. 4.03, following administration of givinostat for up to 6 cycles of treatment in Part A. Grades 1 through 5 were as follows: Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe or medically significant but not immediately life threatening or requiring hospitalisation; Grade 4: Life threatening consequences; Grade 5: Death related to AE. Results are reported as number of patients with TEAEs for each of the indicated categories. Definitions: drug-related TEAE / treatment-emergent serious adverse event (TESAE) corresponded to reasonable suspicion that the TEAE / TESAE was associated with the use of the study drug, according to investigator assessment; discontinuation refers to discontinuation from treatment.

Measure: Number of Patients Experiencing Treatment-emergent Adverse Events (TEAEs) in Part A of the Study

Time: 168 days (up to Cycle 6 Day 28 in Part A).

Description: The MTD of givinostat was based only on Cycle 1 DLTs. A DLT was defined as the following drug-related toxicity: Grade 4 hematological toxicity, or Grade 3 febrile neutropenia, or Grade ≥3 non-hematological toxicity (with the exception Grade 3 diarrhea without adequate supportive care lasting less than 3 days, and Grade 3 nausea or vomiting without adequate supportive care lasting less than 3 days), or Any drug-related serious AE, or Any toxicity clearly not related to disease progression or intercurrent illness requiring interruption of dosing for more than 3 days during first cycle. At end of Cycle 1, for the third patient in each DL, the safety of the 3 patients treated for 1 cycle was reviewed and it was decided if the dose should be escalated or not. Results are reported as the number of patients with DLT events for Cycle 1 in Part A.

Measure: Number of Dose Limiting Toxicities (DLTs) After 1 Cycle in Part A of the Study

Time: 28 days (up to Cycle 1 Day 28 in Part A).

Description: Evaluations were performed on the type, incidence and severity of TEAEs, graded according to CTCAE v. 4.03, following administration of givinostat at the MTD for up to 3 cycles of treatment in Part B. Grades 1 through 5 were as follows: Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe or medically significant but not immediately life threatening or requiring hospitalisation; Grade 4: Life threatening consequences; Grade 5: Death related to AE. Results are reported as number of patients with TEAEs for each of the indicated categories. Definitions: drug-related TEAE / TESAE corresponded to reasonable suspicion that the TEAE / TESAE was associated with the use of the study drug, according to investigator assessment; discontinuation refers to discontinuation from treatment.

Measure: Number of Patients Experiencing TEAEs After 3 Cycles in Part B of the Study

Time: 84 days (up to Cycle 3 Day 28 in Part B).

Description: ORR, CR and PR following administration of givinostat at MTD for 3 cycles in Part B, reported as percentage of patients with a response. Response was evaluated according to the clinico-hematological European LeukemiaNet (ELN) response criteria. If Investigator's clinical response assessment (taking into account the overall medical judgment of the specific patient's case) was not in agreement with exact application of the ELN response criteria, the Investigator's assessment superseded the mathematical application of these criteria and was used for analysis. CR defined as: Hematocrit (HCT) <45% without phlebotomy, and Platelets ≤400 x10^9/litre (L), and White Blood Cell count ≤10 x10^9/L, and Normal spleen size, and No disease-related systemic symptoms (i.e. pruritus, headache, microvascular disturbances). PR defined as: Patients not fulfilling CR and HCT <45% without phlebotomy, or Response in ≥3 other criteria.

Measure: Overall Response Rate (ORR) (i.e. Complete Response [CR] and Partial Response [PR]) After 3 Cycles in Part B of the Study

Time: 84 days (up to cycle 3 Day 28 in Part B).

Secondary Outcomes

Description: ORR following administration of givinostat after 3 cycles and after 6 cycles in Part A, reported as percentage of patients with a response. Response was evaluated according to the clinico-hematological ELN response criteria. If Investigator's clinical response assessment (taking into account the overall medical judgment of the specific patient's case) was not in agreement with exact application of the ELN response criteria, the Investigator's assessment superseded the mathematical application of these criteria and was used for analysis. Analysis performed using the dataset for all Part A patients combined.

Measure: ORR After 3 Cycles and After 6 Cycles in Part A of the Study

Time: 84 and 168 days (up to Cycle 3 Day 28 and Cycle 6 Day 28 in Part A).

Description: ORR following administration of givinostat at the MTD for 6 cycles in Part B, reported as percentage of patients with a response. Response was evaluated according to the clinico-hematological ELN response criteria. If Investigator's clinical response assessment (taking into account the overall medical judgment of the specific patient's case) was not in agreement with exact application of the ELN response criteria, the Investigator's assessment superseded the mathematical application of these criteria and was used for analysis.

Measure: ORR After 6 Cycles in Part B of the Study

Time: 168 days (up to Cycle 6 Day 28 in Part B).

Description: Evaluations were performed on the type, incidence and severity of TEAEs, graded according to CTCAE v. 4.03, following administration of givinostat at the MTD for up to 6 cycles of treatment in Part B. Grades 1 through 5 were as follows: Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe or medically significant but not immediately life threatening or requiring hospitalisation; Grade 4: Life threatening consequences; Grade 5: Death related to AE. Results are reported as number of patients with TEAEs for each of the indicated categories. Definitions: drug-related TEAE / TESAE corresponded to reasonable suspicion that the TEAE / TESAE was associated with the use of the study drug, according to investigator assessment; discontinuation refers to discontinuation from treatment. Results are reported as number of patients with TEAEs for each of the indicated categories.

Measure: Number of Patients Experiencing TEAEs After 6 Cycles in Part B of the Study

Time: 168 days (up to Cycle 6 Day 28 in Part B).

Description: Pharmacokinetic (PK) evaluation of givinostat and metabolites (ITF2374 and ITF2375) by assessment of Cmax following administration of givinostat for 1 cycle in Part A. PK calculations were performed by standard non-compartmental analysis. Results are reported for Cycle 1 Day 1 and Cycle 1 Day 28. Note: concentration data for ITF2374 (Cycle 1 Day 1 and Cycle 1 Day 28) and for ITF2375 (Cycle 1 Day 1) in the DL0 dose group of Part A were not available for PK analysis.

Measure: Assessment of Maximum Plasma Concentration (Cmax) of Givinostat and Metabolites (ITF2374 and ITF2375) in Part A of the Study

Time: Blood samples were collected in Part A on Cycle 1 Day 1: pre-dose and 2, 3 and 8 hours post-dose; and on Cycle 1 Day 28: pre-dose and 1, 2, 4 and 8 hours post-dose.

Description: PK evaluation of givinostat and metabolites (ITF2374 and ITF2375) by assessment of Tmax following administration of givinostat for 1 cycle in Part A. PK calculations were performed by standard non-compartmental analysis. Results are reported for Cycle 1 Day 1 and Cycle 1 Day 28. Note: concentration data for ITF2374 (Cycle 1 Day 1 and Cycle 1 Day 28) and for ITF2375 (Cycle 1 Day 1) in the DL0 dose group of Part A were not available for PK analysis.

Measure: Assessment of Time to Maximum Plasma Concentration (Tmax) of Givinostat and Metabolites (ITF2374 and ITF2375) in Part A of the Study

Time: Blood samples were collected in Part A on Cycle 1 Day 1: pre-dose and 2, 3 and 8 hours post-dose; and on Cycle 1 Day 28: pre-dose and 1, 2, 4 and 8 hours post-dose.

Description: PK evaluation of givinostat and metabolites (ITF2374 and ITF2375) by assessment of Tlast following administration of givinostat for 1 cycle in Part A. PK calculations were performed by standard non-compartmental analysis. Results are reported for Cycle 1 Day 1 and Cycle 1 Day 28. Note: concentration data for ITF2374 (Cycle 1 Day 1 and Cycle 1 Day 28) and for ITF2375 (Cycle 1 Day 1) in the DL0 dose group of Part A were not available for PK analysis.

Measure: Assessment of Time of the Last Detectable Concentration (Tlast) of Givinostat and Metabolites (ITF2374 and ITF2375) in Part A of the Study

Time: Blood samples were collected in Part A on Cycle 1 Day 1: pre-dose and 2, 3 and 8 hours post-dose; and on Cycle 1 Day 28: pre-dose and 1, 2, 4 and 8 hours post-dose.

Description: PK evaluation of givinostat and metabolites (ITF2374 and ITF2375) by assessment of AUClast following administration of givinostat for 1 cycle in Part A. PK calculations were performed by standard non-compartmental analysis and AUClast was calculated using the linear trapezoidal rule. Results are reported for Cycle 1 Day 1 and Cycle 1 Day 28. Note: concentration data for ITF2374 (Cycle 1 Day 1 and Cycle 1 Day 28) and for ITF2375 (Cycle 1 Day 1) in the DL0 dose group of Part A were not available for PK analysis.

Measure: Assessment of Area Under Plasma Concentration Versus the Time Curve up to the Last Detectable Concentration (AUClast) of Givinostat and Metabolites (ITF2374 and ITF2375) in Part A of the Study

Time: Blood samples were collected in Part A on Cycle 1 Day 1: pre-dose and 2, 3 and 8 hours post-dose; and on Cycle 1 Day 28: pre-dose and 1, 2, 4 and 8 hours post-dose.

Description: PK evaluation of givinostat and metabolites (ITF2374 and ITF2375) by assessment of AUC0-12 following administration of givinostat for 1 cycle in Part A. PK calculations were performed by standard non-compartmental analysis and AUC0-12 was calculated using the linear trapezoidal rule. Results are reported for Cycle 1 Day 1 and Cycle 1 Day 28. Note:concentration data for ITF2374 (Cycle 1 Day 1 and Cycle 1 Day 28) across all dose groups and for ITF2375 (Cycle 1 Day 1) in the DL0 dose group of Part A were not available for PK analysis.

Measure: Assessment of Area Under Plasma Concentration Versus the Time Curve in the Dosing Interval (0-12 Hours) (AUC0-12) of Givinostat and Metabolites (ITF2374 and ITF2375) in Part A of the Study

Time: Blood samples were collected in Part A on Cycle 1 Day 1: pre-dose and 2, 3 and 8 hours post-dose; and on Cycle 1 Day 28: pre-dose and 1, 2, 4 and 8 hours post-dose.

Description: PK evaluation of givinostat and metabolites (ITF2374 and ITF2375) by assessment of Cmax following administration of givinostat for 2 cycles in Part B. PK calculations were performed by standard non-compartmental analysis. Following definition of the MTD in Part A, during Part B Cycle 1, givinostat was administered at 100 mg b.i.d. and during Part B Cycle 2 was administered at 100 mg, 75 mg and 50 mg b.i.d. (since dose reductions due to TEAEs were allowed from Cycle 2 onwards, as per protocol). Results are reported for Cycle 1 Day 1 and Cycle 2 Day 28 for the doses administered during Part B. Note: PK evaluation for the givinostat 75 mg and 50 mg b.i.d. dose groups for Cycle 1 Day 1 was not applicable (since all received givinostat 100 mg b.i.d.). Additionally, concentration data for ITF2375 (Cycle 1 Day 28) in the 50 mg b.i.d. dose group was not available for PK analysis.

Measure: Assessment of Cmax of Givinostat and Metabolites (ITF2374 and ITF2375) in Part B of the Study

Time: Blood samples were collected in Part B on Cycle 1 Day 1: pre-dose and 2, 3 and 8 hours post-dose; and on Cycle 2 Day 28: pre-dose and 1, 2, 4 and 8 hours post-dose.

Description: PK evaluation of givinostat and metabolites (ITF2374 and ITF2375) by assessment of Tmax following administration of givinostat for 2 cycles in Part B. PK calculations were performed by standard non-compartmental analysis. Following definition of the MTD in Part A, during Part B Cycle 1, givinostat was administered at 100 mg b.i.d. and during Part B Cycle 2 was administered at 100 mg, 75 mg and 50 mg b.i.d. (since dose reductions due to TEAEs were allowed from Cycle 2 onwards, as per protocol). Results are reported for Cycle 1 Day 1 and Cycle 2 Day 28 for the doses administered during Part B. Note: PK evaluation for the givinostat 75 mg and 50 mg b.i.d. dose groups for Cycle 1 Day 1 was not applicable (since all received givinostat 100 mg b.i.d.). Additionally, concentration data for ITF2375 (Cycle 1 Day 28) in the 50 mg b.i.d. dose group was not available for PK analysis.

Measure: Assessment of Tmax of Givinostat and Metabolites (ITF2374 and ITF2375) in Part B of the Study

Time: Blood samples were collected in Part B on Cycle 1 Day 1: pre-dose and 2, 3 and 8 hours post-dose; and on Cycle 2 Day 28: pre-dose and 1, 2, 4 and 8 hours post-dose.

Description: PK evaluation of givinostat and metabolites (ITF2374 and ITF2375) by assessment of Tlast following administration of givinostat for 2 cycles in Part B. PK calculations were performed by standard non-compartmental analysis. Following definition of the MTD in Part A, during Part B Cycle 1, givinostat was administered at 100 mg b.i.d. and during Part B Cycle 2 was administered at 100 mg, 75 mg and 50 mg b.i.d. (since dose reductions due to TEAEs were allowed from Cycle 2 onwards, as per protocol). Results are reported for Cycle 1 Day 1 and Cycle 2 Day 28 for the doses administered during Part B. Note: PK evaluation for the givinostat 75 mg and 50 mg b.i.d. dose groups for Cycle 1 Day 1 was not applicable (since all received givinostat 100 mg b.i.d.). Additionally, concentration data for ITF2375 (Cycle 1 Day 28) in the 50 mg b.i.d. dose group was not available for PK analysis.

Measure: Assessment of Tlast of Givinostat and Metabolites (ITF2374 and ITF2375) in Part B of the Study

Time: Blood samples were collected in Part B on Cycle 1 Day 1: pre-dose and 2, 3 and 8 hours post-dose; and on Cycle 2 Day 28: pre-dose and 1, 2, 4 and 8 hours post-dose.

Description: PK evaluation of givinostat and metabolites (ITF2374 and ITF2375) by assessment of AUClast following administration of givinostat for 2 cycles in Part B. PK calculations were performed by standard non-compartmental analysis and AUClast was calculated using the linear trapezoidal rule. Following definition of the MTD in Part A, during Part B Cycle 1, givinostat was administered at 100 mg b.i.d. and during Part B Cycle 2 was administered at 100 mg, 75 mg and 50 mg b.i.d. (since dose reductions due to TEAEs were allowed from Cycle 2 onwards, as per protocol). Results are reported for Cycle 1 Day 1 and Cycle 2 Day 28 for the for the doses administered during Part B. Note: PK evaluation for the givinostat 75 mg and 50 mg b.i.d. dose groups for Cycle 1 Day 1 was not applicable (since all received givinostat 100 mg b.i.d.). Additionally, concentration data for ITF2375 (Cycle 1 Day 28) in the 50 mg b.i.d. dose group was not available for PK analysis.

Measure: Assessment of AUClast of Givinostat and Metabolites (ITF2374 and ITF2375) in Part B of the Study

Time: Blood samples were collected in Part B on Cycle 1 Day 1: pre-dose and 2, 3 and 8 hours post-dose; and on Cycle 2 Day 28: pre-dose and 1, 2, 4 and 8 hours post-dose.

Description: PK evaluation of givinostat and metabolites (ITF2374 and ITF2375) by assessment of AUC0-12 following administration of givinostat for 2 cycles in Part B. PK calculations were performed by standard non-compartmental analysis and AUClast was calculated using the linear trapezoidal rule. Following definition of the MTD in Part A, during Part B Cycle 1, givinostat was administered at 100 mg b.i.d. and during Part B Cycle 2 was administered at 100 mg, 75 mg and 50 mg b.i.d. (since dose reductions due to TEAEs were allowed from Cycle 2 onwards, as per protocol). Results are reported for Cycle 1 Day 1 and Cycle 2 Day 28 for the doses administered during Part B. Note: PK evaluation for the givinostat 75 mg and 50 mg b.i.d. dose groups for Cycle 1 Day 1 was not applicable (since all received givinostat 100 mg b.i.d.). Additionally, concentration data for ITF2374 (Cycle 1 Day 28) across all dose groups and for ITF2375 in the 50 mg b.i.d. dose group was not available for PK analysis.

Measure: Assessment of AUC0-12 of Givinostat and Metabolites (ITF2374 and ITF2375) in Part B of the Study

Time: Blood samples were collected in Part B on Cycle 1 Day 1: pre-dose and 2, 3 and 8 hours post-dose; and on Cycle 2 Day 28: pre-dose and 1, 2, 4 and 8 hours post-dose.

23 Hydroxyurea in Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is a serious and eventually fatal disease damaging the lungs and the heart. It results from narrowing and eventual blockage of small blood vessels in the lung, due to abnormal proliferation of cells in the blood vessel (arterial). Patients with PAH suffer from fatigue, shortness of breath, low oxygen levels, blood clots and heart failure. No therapies reverse the disease process in the lung arteries, however there are three approved drugs that can temporarily dilate the vessels and improve symptoms. However, all three drugs have significant side effects and toxicities, they do not work effectively in many patients, survival remains on average only 2 to 3 years once symptoms begin, and none of these drugs prevent the underlying disease process in the small arteries of the lung. PAH is known to develop in patients with a pre-existing class of bone marrow diseases called myeloproliferative disorders (MPDs). We and others have recently shown that patients with PAH have bone marrow changes similar to those seen in patients with MPDs, even without other signs and symptoms of those bone marrow diseases such as anemia or high platelet and white blood cell counts. Compared to healthy volunteers, patients with PAH have a higher frequency of immature stem and progenitor cells able to produce blood cells and vascular wall cells in their bone marrow. They also have higher circulating numbers of these cells in the blood, and increased localization of these cells in the lung blood vessels. When immature bone marrow cells from PAH patients and normal volunteers were infused into mice, the mice receiving PAH marrow cells developed similar lung and heart problems to PAH patients, suggesting that the bone marrow problem is a primary cause of the lung problems, and that the increased numbers of immature bone marrow cells in the bone marrow and blood of PAH patients causes the lung blood vessel disease. The drug hydroxyurea is used to inhibit the abnormally high level of bone marrow cell proliferation in patients with MPDs. It has been shown to reduce the numbers of circulating immature bone marrow cells in patients with MPDs. Hydroxyurea has been available for almost fifty years, and has been used to treat patients with MPDs, sickle cell anemia, and congenital heart disease for very prolonged periods of time, up to twenty or more years in individual patients. It has an excellent long-term safety profile and few side effects and is generally well tolerated. It does not appear to result in an increased rate of leukemia even with many years of treatment. In the current protocol, we hypothesize that treating patients with PAH with hydroxyurea will decrease the level of circulating immature bone marrow cells and interrupt the abnormal narrowing and occlusion of lung arteries. We will treat patients with moderately severe primary (no known underlying cause) PAH with 6 months of hydroxyurea, carefully monitoring side effects and adjusting dosage as necessary, and measure the effect on circulating immature cells, lung blood vessel pressures, other blood markers of active PAH, and exercise tolerance.

NCT01950585 Pulmonary Hypertension Drug: Hydroxyurea
MeSH:Hypertension, Pulmonary Familial Primary Pulmonary Hypertension Hypertension
HPO:Hypertension Pulmonary arterial hypertension

- HIV positivity - Moribund status or concurrent hepatic, renal, cardiac, neurologic, pulmonary, infectious, or metabolic disease of such severity that it would preclude the patient s ability to tolerate protocol therapy, or that death within 30 days is likely - Presence of 9;22 BCR/ABL translocation as detected by conventional bone marrow cytogenetics or PCR for BCR/ABL transcript, or presence of JAK2 V617F mutation in bone marrow or peripheral blood cells. --- V617F ---

Primary Outcomes

Measure: The change in concentration of CD34+ circulating progenitors from baseline to 6 months (24 weeks (+/- 7 days)) on hydroxyurea.

Time: ongoing

24 Effects of Sympathicomimetic Agonists on the Disease Course and Mutant Allele Burden in Patients With JAK2-mutated Myeloproliferative Neoplasms. A Multicenter Phase II Trial.

The aim of this phase II study is to test a novel concept in the treatment of patients with myeloproliferative neoplasms (MPN), a disease of the bone marrow. With no current cure available, MPN are a group of chronic leukemias (blood cancers) in which patients produce too many blood cells. These increased blood cell numbers cause problems to the patient such as bleedings or thrombosis and some patients may progress to acute leukemia, a life threatening condition. Most MPN patients have a gene mutation called JAK2-V617F. The disease is maintained by mutant MPN stem cells that reside in the bone marrow in specialized locations called "niches". These niches need connections to the nervous system. New findings show that these connections are destroyed by the presence of the mutated MPN stem cells. Research teams found that some drugs (beta3-sympathicomimetics) can restore these damaged niches and at the same time reduce the MPN disease manifestation in a mouse model of MPN. Such sympathicomimetic drugs are already being used to treat patients with asthma or hyperactive bladder. These drugs have shown to have only few side effects. The study tests the effects of the beta-3-sympathicomimetic drug Mirabegron (Betmiga®) on MPN disease in 39 patients that carry a JAK2-V617F mutation. The hypothesis is that Mirabegron will have a beneficial effect on bone marrow niche cells and will thereby improve the disease manifestation in MPN patients. This study should provide a rapid answer whether targeting the nervous system of the niche cells could be useful for patients with MPN and warrants to be tested in larger and more long-term studies.

NCT02311569 Myeloproliferative Neoplasm Primary Myelofibrosis Essential Thrombocythemia Polycythemia Vera Drug: Mirabegron
MeSH:Polycythemia Vera Primary Myelofibrosis Polycythemia Myeloproliferative Disorders Thrombocytosis Thrombocythemia, Essential Neoplasms
HPO:Myeloproliferative disorder Neoplasm Polycythemia Thrombocytosis

Most MPN patients have a gene mutation called JAK2-V617F. --- V617F ---

The study tests the effects of the beta-3-sympathicomimetic drug Mirabegron (Betmiga®) on MPN disease in 39 patients that carry a JAK2-V617F mutation. --- V617F ---

Patients are defined as success for this endpoint, if they show a reduction of the JAK2-V617F allelic burden of 50% or more 24 weeks ± 4 weeks after registration when compared to baseline, and if they did not start a new MPN treatment before. --- V617F ---

Reduction in the burden of mutated alleles of ≥25% at 24 weeks (Red-25@24): Patients are defined as success for the Red-25@24 endpoint, if they show a reduction of the Jak2-V617F allelic burden of 25% or more 24 weeks ± 4 weeks after registration when compared to baseline, and if they did not start a new MPN treatment before. --- V617F ---

Reduction in the burden of mutated alleles of ≥25% at 12 weeks (Red-25@12) defined in the same way as the Red-25@24 endpoint, but evaluated at 12 weeks ± 4 weeks after registration.. Inclusion Criteria: - Histologically or cytologically confirmed diagnosis of JAK2-V617F positive ET, PV or PMF at primary diagnosis or pretreated - JAK2-V617F mutant allele burden > 20% in the peripheral blood at study entry - Patient must give written informed consent before registration - WHO performance status 0-2 - Age ≥ 18 years - Adequate hematological values: neutrophils ≥ 1.5 x 109/L, platelets ≥ 100 x 109/ L - Adequate hepatic function: bilirubin ≤ 1.5 x ULN, AST/ALT/AP ≤ 2.5 x ULN - Adequate renal function (calculated creatinine clearance > 50 mL/min, according to the formula of Cockcroft-Gault) - Women are not breastfeeding. --- V617F ---

Reduction in the burden of mutated alleles of ≥25% at 12 weeks (Red-25@12) defined in the same way as the Red-25@24 endpoint, but evaluated at 12 weeks ± 4 weeks after registration.. Inclusion Criteria: - Histologically or cytologically confirmed diagnosis of JAK2-V617F positive ET, PV or PMF at primary diagnosis or pretreated - JAK2-V617F mutant allele burden > 20% in the peripheral blood at study entry - Patient must give written informed consent before registration - WHO performance status 0-2 - Age ≥ 18 years - Adequate hematological values: neutrophils ≥ 1.5 x 109/L, platelets ≥ 100 x 109/ L - Adequate hepatic function: bilirubin ≤ 1.5 x ULN, AST/ALT/AP ≤ 2.5 x ULN - Adequate renal function (calculated creatinine clearance > 50 mL/min, according to the formula of Cockcroft-Gault) - Women are not breastfeeding. --- V617F --- --- V617F ---

Inclusion Criteria: - Histologically or cytologically confirmed diagnosis of JAK2-V617F positive ET, PV or PMF at primary diagnosis or pretreated - JAK2-V617F mutant allele burden > 20% in the peripheral blood at study entry - Patient must give written informed consent before registration - WHO performance status 0-2 - Age ≥ 18 years - Adequate hematological values: neutrophils ≥ 1.5 x 109/L, platelets ≥ 100 x 109/ L - Adequate hepatic function: bilirubin ≤ 1.5 x ULN, AST/ALT/AP ≤ 2.5 x ULN - Adequate renal function (calculated creatinine clearance > 50 mL/min, according to the formula of Cockcroft-Gault) - Women are not breastfeeding. --- V617F ---

Inclusion Criteria: - Histologically or cytologically confirmed diagnosis of JAK2-V617F positive ET, PV or PMF at primary diagnosis or pretreated - JAK2-V617F mutant allele burden > 20% in the peripheral blood at study entry - Patient must give written informed consent before registration - WHO performance status 0-2 - Age ≥ 18 years - Adequate hematological values: neutrophils ≥ 1.5 x 109/L, platelets ≥ 100 x 109/ L - Adequate hepatic function: bilirubin ≤ 1.5 x ULN, AST/ALT/AP ≤ 2.5 x ULN - Adequate renal function (calculated creatinine clearance > 50 mL/min, according to the formula of Cockcroft-Gault) - Women are not breastfeeding. --- V617F --- --- V617F ---

Three genes are frequently mutated in MPN and are implicated to be the phenotypic driver mutations: more than 95% of PV patients carry a somatic JAK2-V617F mutation, while about half of the remaining PV patients (2-3%) display mutations in JAK2 exon 12. Thus, almost all patients with PV have somatic mutations in the JAK2 gene. --- V617F ---

The mutational profiles of ET and PMF are more diverse: JAK2-V617F is found in 50-60% of the patients, whereas the recently described mutations in calreticulin (CALR) occur in 20-25% of the patients. --- V617F ---

Ruxolitinib, recently approved for PMF with splenomegaly, is effective in reducing spleen size and improving quality of life, but has little effect on the JAK2-V617F mutant allele burden and has so far not been reported to induce remissions. --- V617F ---

Furthermore, in a mouse model of MPN expressing the human JAK2-V617F mutation, this effect was found to be caused by early glial and sympathetic nerve damage and apoptosis of nestin+ MSCs triggered by the mutant HSCs. --- V617F ---

Mice with JAK2-V617F driven MPN treated with a beta-3-sympathicomimetic agonist not only restored nestin+ MSCs numbers, but also showed correction of thrombocytosis, neutrophilia, and bone marrow fibrosis, and efficiently reduced mutant hematopoietic progenitor numbers in bone marrow and peripheral blood. --- V617F ---

Primary Outcomes

Description: Primary endpoint of the trial is reduction in the burden of mutated alleles of ≥50% at 24 weeks (Red-50@24). Patients are defined as success for this endpoint, if they show a reduction of the JAK2-V617F allelic burden of 50% or more 24 weeks ± 4 weeks after registration when compared to baseline, and if they did not start a new MPN treatment before. All other evaluable patients will be considered as failures for this endpoint.

Measure: Reduction in the burden of mutated alleles of ≥50% at 24 weeks.

Time: at 24 weeks

Secondary Outcomes

Description: Reduction in the burden of mutated alleles of ≥50% at 12 weeks (Red-50@12) defined in the same way as the primary endpoint, but evaluated at 12 weeks ± 4 weeks after registration.

Measure: Reduction in the burden of mutated alleles of ≥50%

Time: at 12 weeks

Description: Reduction in the burden of mutated alleles of ≥25% at 24 weeks (Red-25@24): Patients are defined as success for the Red-25@24 endpoint, if they show a reduction of the Jak2-V617F allelic burden of 25% or more 24 weeks ± 4 weeks after registration when compared to baseline, and if they did not start a new MPN treatment before. All other evaluable patients will be considered as failures for this endpoint.

Measure: Reduction in the burden of mutated alleles of ≥25%

Time: at 24 weeks

Description: Reduction in the burden of mutated alleles of ≥25% at 12 weeks (Red-25@12) defined in the same way as the Red-25@24 endpoint, but evaluated at 12 weeks ± 4 weeks after registration.

Measure: Reduction in the burden of mutated alleles of ≥25%

Time: at 12 weeks

25 Phase II Study of P1101 in Early Myelofibrosis

This pilot phase II trial studies P1101 (polyethyleneglycol [PEG]-proline-interferon alpha-2b) in treating patients with myelofibrosis. PEG-proline-interferon alpha-2b is a substance that can improve the body's natural response and may slow the growth of myelofibrosis.

NCT02370329 Primary Myelofibrosis Secondary Myelofibrosis Other: Laboratory Biomarker Analysis Biological: PEG-Proline-Interferon Alfa-2b Other: Quality-of-Life Assessment
MeSH:Primary Myelofibrosis

To evaluate the impact of P1101 on bone marrow and histological features of myelofibrosis including cytogenetics, blast percentage, fibrosis, and JAK2-V617F allele burden by cohort (early vs intermediate-2/high risk). --- V617F ---

Primary Outcomes

Description: The proportion of successes will be estimated by the number of successes divided by the total number of evaluable patients. Confidence intervals for the true success proportion will be calculated according to the approach of Duffy and Santner.

Measure: Best overall response (CR, PR, or CI) as determined by International Working Group Criteria

Time: Up to 3 years

Secondary Outcomes

Description: The maximum grade for each type of adverse event will be recorded for each patient, and frequency tables will be reviewed to determine patterns. Additionally, the relationship of the adverse event(s) to the study treatment will be taken into consideration.

Measure: Incidence of adverse events, as measured by National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 (NCI CTCAE v4)

Time: Up to 3 years

Description: The distribution of survival time will be estimated using the method of Kaplan-Meier.

Measure: Survival time

Time: Time from registration to death due to any cause, assessed up to 3 years

Other Outcomes

Description: Patient-reported symptoms and QOL will be described at each time point using the mean, confidence interval, median, and range. Changes in individual symptoms, changes in a symptom scale composed of symptoms specific to MF patients, and changes in the MPN TSS will be investigated. Graphical procedures will include stream plots of individual patient scores and plots of average values over time. Correlational analyses will be done to determine the relationships among patients-reported symptoms and QOL, as well as with clinical outcomes and clinician-assessed symptoms.

Measure: Changes in patient-reported symptoms and QOL as measured by MPN-SAF

Time: Baseline to up to 3 years

26 Molecular Disease Profile of Haematological Malignancies. A Prospective Registry Study by the Rete Ematologica Lombarda (REL) Clinical Network

In this prospective multicentric study, the University of Pavia together with the Fondazione IRCCS Policlinico San Matteo, Pavia and the IRCCS Fondazione Maugeri, Pavia, Italy will provide a systematic analysis of gene mutations in hematological malignancies by using NGS techniques. Patients with a conclusive diagnosis of haematological malignancies according to WHO criteria referred to the Rete Ematologica Lombarda clinical network (REL, www.rel-lombardia.net) will be enrolled. The investigators will analyse genomic DNA extracted from hematopoietic cells at different time points of patient disease. The study contemplates the use of molecular platforms (Next Generation Sequencing, NGS) aimed at the identification of recurrent mutations in myeloid and lymphoid neoplasms, respectively. Screening of gene mutations by NGS will be prospectively implemented in the context of REL clinical network. Patient samples will be analyzed at diagnosis and sequentially during the course of the disease at specific timepoints. The researchers will analyze the correlations between somatic mutations, specific clinical phenotypes (according to the WHO classification) and disease evolution. This will allow to: 1) identify new recurrent genetic mutations involved in the molecular pathogenesis of hematological malignancies; 2) define the role of mutated genes, distinguishing between genes which induce a clonal proliferation of hematopoietic stem cells, and genes which determine the clinical phenotype of the disease; 3) identify mutations which are responsible for disease evolution; 4) define the diagnostic/prognostic role of the identified mutations, and update the current disease classifications and prognostic scores by including molecular parameters. A systematic biobanking of biological material will be provided.

NCT02459743 Hematological Malignancies
MeSH:Hematologic Neoplasms Neoplasms
HPO:Hematological neoplasm Leukemia Neoplasm

In 2005 the University of Pavia described the diagnostic and prognostic significance of the JAK2 V617F mutation in myeloproliferative neoplasms (MPN): this mutation was included into the WHO classification of MPN and innovative anti-JAK2 drugs were developed. --- V617F ---

Primary Outcomes

Measure: Cumulative incidence of gene mutations in principal clone and subclones in each hematological malignancy

Time: 3 years

Secondary Outcomes

Measure: Genotype-phenotype correlations between clinical characteristics and mutational status

Time: 3 years

Measure: Overall survival and disease-free survival according to clinical and biological risk factors at diagnosis and during disease evolution

Time: 3 years

27 Ruxolitinib in Combination With High Dose Therapy and Autologous Stem Cell Transplantation for Myelofibrosis

To determine the safety of the approach of giving RUXOLITINIB before and after an autologous stem cell transplant, as measured by graft failure or death.

NCT02469974 Myelofibrosis MF Drug: RUXOLITINIB / INC 424 Drug: Filgrastim Drug: Busulfan
MeSH:Primary Myelofibrosis

Changes in Jak 2 V617F allele burden when present will be measured by quantitative RT-PCR. --- V617F ---

Primary Outcomes

Description: Safety of this approach as measured by graft failure or death

Measure: Safety of combining ruxolitinib with autologous HSCT measured by graft failure or death

Time: 2 years

Secondary Outcomes

Description: Total CD34+ cell dose will be calculated based on results of flow cytometric analysis and patient's weight.

Measure: CD34 cells

Time: 4 years

Measure: The regimen related mortality (RRM)

Time: day 100

Measure: The regimen related mortality (RRM)

Time: day 365

Measure: Rate of engraftment/graft failure

Time: 4 years

Measure: Time of engraftment for neutrophils and platelets

Time: 4 years

Measure: The incidence of serious infectious complications

Time: up to 1 year post transplant

Description: The myelofibrosis score will be assessed as per the European Consensus Grading published by Thiele Grading Description at 365 days as compared to 180 days

Measure: Changes in marrow fibrosis score

Time: at 180 and 365 days post-transplant

Description: Changes in FISH abnormalities when present will be measured by cytogenetics.

Measure: Change in FISH allele

Time: at 365 days post-transplant

Description: Changes in Jak 2 V617F allele burden when present will be measured by quantitative RT-PCR

Measure: Change in JAK allele

Time: at 365 days post-transplant

Description: Overall efficacy will be rated on a scale as complete remission, partial remission, clinical improvement, or stable disease

Measure: Rate of response

Time: at 6 months post-transplant

Description: Overall efficacy will be rated on a scale as complete remission, partial remission, clinical improvement, or stable disease

Measure: Rate of response

Time: at 1 year post-transplant

28 A Phase 1 Study of the EZH2 Inhibitor Tazemetostat in Pediatric Subjects With Relapsed or Refractory INI1-Negative Tumors or Synovial Sarcoma

This is a Phase I, open-label, dose escalation and dose expansion study with BID (suspension) and TID (tablet) oral dose of tazemetostat. Subjects will be screened for eligibility within 14 days of the planned first dose of tazemetostat. A treatment cycle will be 28 days. Response assessment will be evaluated after 8 weeks of treatment and subsequently every 8 weeks while on study. The study has two parts: Dose Escalation and Dose Expansion. Dose escalation for subjects with the following relapsed/refractory malignancies: - Rhabdoid tumors: - Atypical teratoid rhabdoid tumor (ATRT) - Malignant rhabdoid tumor (MRT) - Rhabdoid tumor of kidney (RTK) - Selected tumors with rhabdoid features - INI1-negative tumors: - Epithelioid sarcoma - Epithelioid malignant peripheral nerve sheath tumor - Extraskeletal myxoid chondrosarcoma - Myoepithelial carcinoma - Renal medullary carcinoma - Other INI1-negative malignant tumors (e.g., dedifferentiated chordoma) (with Sponsor approval) - Synovial Sarcoma with a SS18-SSX rearrangement Dose Expansion at the MTD or the RP2D - Cohort 1 -(closed to enrollment) ATRT - Cohort 2 - MRT/RTK/selected tumors with rhabdoid features - Cohort 3 - INI-negative tumors: - Epithelioid sarcoma - Epithelioid malignant peripheral nerve sheath tumor - Extraskeletal myxoid chondrosarcoma - Myoepithelial carcinoma - Renal medullary carcinoma - Chordoma (poorly differentiated or de-differentiated) - Other INI1-negative malignant tumors (e.g., dedifferentiated chordoma) with Sponsor approval - Cohort 4 -(closed to enrollment) Tumor types eligible for Cohorts 1 through 3 or synovial sarcoma with SS18-SSX rearrangement

NCT02601937 Rhabdoid Tumors INI1-negative Tumors Synovial Sarcoma Malignant Rhabdoid Tumor of Ovary Drug: Tazemetostat
MeSH:Sarcoma Sarcoma, Synovial Rhabdoid Tumor Neoplasms
HPO:Neoplasm Sarcoma Soft tissue sarcoma Synovial sarcoma

JAK2 V617F) observed in cytogenetic testing and DNA sequencing. --- V617F ---

Primary Outcomes

Description: The incidence and severity of treatment-emergent adverse events (AEs) qualifying as protocol-defined DLTs in Cycle 1 will guide establishment of the protocol defined RP2D and/or MTD

Measure: To determine the MTD or the RP2D (Dose Escalation)

Time: 1 cycle/28 days

Measure: Dose expansion: Number of subjects with objective response using disease appropriate standardized response criteria

Time: Assessed every 8 weeks for duration of study participation which is estimated to be 24 months

Secondary Outcomes

Measure: Dose escalation: Number of subjects with objective response using disease appropriate standardized response criteria

Time: Assessed every 8 weeks for duration of study participation which is estimated to be 24 months

Measure: Dose Expansion: Progression-free survival (PFS)

Time: At 24 and 56 weeks post treatment using Kaplan-Meier method

Measure: Dose Expansion: Overall Survival (OS)

Time: At 24 and 56 weeks post treatment using Kaplan-Meier method

Measure: Incidence of treatment-emergent adverse events as a measure of safety and tolerability

Time: Adverse events assessed from first dose through 30 days post last dose

Measure: Pharmacokinetics profile of tazemetostat and its metabolite (plasma): Cmax

Time: Days 1 and 15

Measure: Pharmacokinetics profile of tazemetostat and its metabolite (plasma): Tmax

Time: Days 1 and 15

Measure: Pharmacokinetics profile of tazemetostat and its metabolite (plasma): AUC(0-t)

Time: Days 1 and 15

Measure: Pharmacokinetics profile of tazemetostat and its metabolite (plasma): AUC(0-12)

Time: Days 1 and 15

Measure: Pharmacokinetics profile of tazemetostat and its metabolite (plasma): t1/2

Time: Days 1 and 15

Measure: Pharmacokinetics profile of tazemetostat and its metabolite (plasma): CL/F

Time: Day 15

Measure: Pharmacokinetics profile of tazemetostat and its metabolite (plasma): Vd/F

Time: Day 15

Measure: Pharmacokinetics profile of tazemetostat and its metabolite (plasma): Ka

Time: Day 15

Measure: Pharmacokinetics profile of tazemetostat and its metabolite (plasma): Ctrough

Time: Day 1 of cycles 2, 3 and 4

29 A Phase II, Multicenter Study of the EZH2 Inhibitor Tazemetostat in Adult Subjects With INI1-Negative Tumors or Relapsed/Refractory Synovial Sarcoma

This is a Phase II, multicenter, open-label, single arm, 2-stage study of tazemetostat 800 mg BID (twice daily) and 1600 mg QD (once daily). Subjects will be screened for eligibility within 21 days of the planned date of the first dose of tazemetostat and enrolled into one of 8 cohorts: Cohort using tazemetostat 800 mg BID - Cohort 1 (Closed for enrollment): MRT, RTK, ATRT, and selected tumors with rhabdoid features, including small cell carcinoma of the ovary hypercalcemic type [SCCOHT], also known as malignant rhaboid tumor of the ovary [MRTO] - Cohort 2 (Closed for enrollment): Relapsed or refractory synovial sarcoma with SS18-SSX rearrangement - Cohort 3 (Closed for enrollment): Other INI1 negative tumors or any solid tumor with an EZH2 gain of function (GOF) mutation, including: epithelioid malignant peripheral nerve sheath tumor (EMPNST), extraskeletal myxoid chondrosarcoma (EMC), myoepithelial carcinoma, other INI1-negative malignant tumors with Sponsor approval (e.g., dedifferentiated chordoma) any solid tumor with an EZH2 GOF mutation including but not limited to Ewing's sarcoma and melanoma - Cohort 4 (Closed for enrollment): Renal medullary carcinoma (RMC) - Cohort 5 (Closed for enrollment): Epithelioid sarcoma (ES) - Cohort 6 (Opened for enrollment): Epithelioid sarcoma (ES) undergoing mandatory tumor biopsy - Cohort 7 (Opened for enrollment): Poorly differentiated chordoma (or other chordoma with Sponsor approval) Cohort using tazemetostat 1600 mg QD • Cohort 8 (Opened for enrollment): Epitheliod sarcoma Subjects will be dosed in continuous 28-day cycles. (Note: if treatment with study drug is discontinued prior to completing 2 years, subjects will be followed for a maximum duration of 2 years from start of study drug dosing.) Response assessment will be performed every 8 weeks while on study. Treatment with tazemetostat will continue until disease progression, unacceptable toxicity or withdrawal of consent, or termination of the study.

NCT02601950 Malignant Rhabdoid Tumors (MRT) Rhabdoid Tumors of the Kidney (RTK) Atypical Teratoid Rhabdoid Tumors (ATRT) Selected Tumors With Rhabdoid Features Synovial Sarcoma INI1-negative Tumors Malignant Rhabdoid Tumor of Ovary Renal Medullary Carcinoma Epithelioid Sarcoma Poorly Differentiated Chordoma (or Other Chordoma With Sponsor Approval) Any Solid Tumor With an EZH2 GOF Mutation Drug: Tazemetostat
MeSH:Sarcoma Sarcoma, Synovial Rhabdoid Tumor Chordoma Carcinoma, Medullary Kidney Neoplasms Neoplasms
HPO:Chordoma Neoplasm Renal neoplasm Sarcoma Soft tissue sarcoma Synovial sarcoma

JAK2 V617F) observed in cytogenetic testing and DNA sequencing. --- V617F ---

Primary Outcomes

Measure: Number of subjects with objective response using disease appropriate standardized response criteria

Time: Assessed every 8 weeks for duration of study participation which is estimated to be 24 months

Description: The number of subjects with CR, PR, or stable disease (SD) at 16 week assessment

Measure: Progression-free survival (PFS) rate for Cohort 2 (Relapsed/Refractory Synovial Sarcoma)

Time: 16 weeks of treatment

Measure: Assess the effects of tazemetostat on tumor immune priming for Cohort 6

Time: Through study completion, an average of 2 years

Measure: Assess the safety and tolerability of tazemetostat 1600 mg QD for Cohort 8

Time: Through study completion, an average of 2 years

Secondary Outcomes

Measure: Duration of response in subjects in Cohorts 1, 2, 3, 4, 5, 6 and 7 and in Cohorts 1, 3, 4, 5, 6 and 7 combined for subjects achieving a complete response (CR) and partial response (PR) following oral administration of tazemetostat 800 mg BID

Time: Assess every 8 weeks for duration of study participation which is estimated to be 24 months

Description: The number of subjects with confirmed CR, PR or SD at 32 week assessment

Measure: Disease control rate (DCR) in subjects with epithelioid sarcoma (Cohort 5) and epithelioid sarcoma undergoing mandatory biopsy (Cohort 6) following oral administration of tazemetostat 800 mg BID

Time: 32 weeks of treatment

Description: ORR (confirmed CR+PR, RECIST 1.1)

Measure: Overall response rate ORR for Cohort 2 (relapsed/refractory synovial sarcoma) and Cohort 6 (epithelioid sarcoma undergoing mandatory biopsy) following oral administration of tazemetostat 800 mg BID

Time: Assessed every 8 weeks for duration of study participation which is estimated to be 24 months

Description: The time from date of first dose of study treatment to the earlier of the date of first documented disease progression or date of death due to any cause

Measure: PFS for each cohort

Time: 24, 32 and 56 weeks of treatment

Description: The time from the date of the first dose of study treatment to the date of death due to any cause

Measure: OS for each cohort

Time: 24, 32 and 56 weeks of treatment

Measure: Incidence of treatment-emergent adverse events as a measure of safety and tolerability

Time: Adverse events assessed from first dose through 30 days post last dose

Measure: Pharmacokinetics profile of tazemetotstat and its metabolite (plasma): Cmax

Time: Days 1 and 15

Measure: Pharmacokinetics profile of tazemetotstat and its metabolite (plasma): Tmax

Time: Days 1 and 15

Measure: Pharmacokinetics profile of tazemetotstat and its metabolite (plasma): AUC(0-t)

Time: Days 1 and 15

Measure: Pharmacokinetics profile of tazemetotstat and its metabolite (plasma): AUC(0-12)

Time: Days 1 and 15

Measure: Pharmacokinetics profile of tazemetotstat and its metabolite (plasma): t1/2

Time: Days 1 and 15

Measure: Pharmacokinetics profile of tazemetotstat and its metabolite (plasma): CL/F

Time: Days 1, 15, 29, 43, and 57

Measure: Pharmacokinetics profile of tazemetotstat and its metabolite (plasma): Vd/F

Time: Days 1, 15, 29, 43, and 57

Measure: Pharmacokinetics profile of tazemetotstat and its metabolite (plasma): Ka

Time: Days 1, 15, 29, 43, and 57

Measure: Pharmacokinetics profile of tazemetotstat and its metabolite (plasma): Ctrough

Time: Days 29, 43 and 57

Description: IHC assessments of changes in the level of H3K27-Me3 following tazemetostat dosing

Measure: Investigate the pharmacodynamics (PD) effects of tazemetostat in tumor tissue

Time: At week 8

Measure: Duration of response in subjects with epithelioid sarcoma in Cohort 8 at 1600 mg QD.

Time: Assess every 8 weeks for duration of study participation which is estimated to be 24 months

Description: The number of subjects with confirmed CR, PR or SD at 32 week assessment

Measure: Disease control rate (DCR) in subjects with epithelioid sarcoma (Cohort 8) following oral administration of tazemetostat 1600 mg QD

Time: 32 weeks of treatment

Description: ORR (confirmed CR+PR, RECIST 1.1)

Measure: Overall response rate ORR for subjects with epithelioid sarcoma (Cohort 8) following oral administration of tazemetostat 1600 mg QD

Time: Assessed every 8 weeks for duration of study participation which is estimated to be 24 months

30 Risk Factors for Variceal Bleeding in Egyptian Patients With Non-Cirrhotic Portal Hypertension

Background & Aims: Non-cirrhotic portal hypertension (NCPH) represents a relatively infrequent group of conditions. This work aimed at determining causes of NCPH and evaluating the role of some clinical, laboratory, imaging and endoscopic parameters in prediction of variceal bleeding in an Egyptian cohort with NCPH. Methods: Sixty patients with non-cirrhotic portal hypertension and oesophageal varices were included. All underwent complete clinical evaluation, laboratory investigations, Color Doppler ultrasonography, platelet count/spleen diameter (mm) ratio and upper gastrointestinal endoscopy. Patients were classified into two groups according to variceal bleeding: (1) Group I: twenty six patients with history of bleeding or had an attack of bleeding during one year follow-up; and (2) Group II: thirty four patients without bleeding.

NCT02635815 Portal Hypertension Procedure: Upper gastrointestinal endoscopy
MeSH:Hypertension, Portal Hypertension
HPO:Hypertension Portal hypertension

It was done only for patients with Budd-Chiari syndrome and extrahepatic portal vein thrombosis: anticardiolipin antibodies, lupus anticoagulant, antinuclear antibodies, protein C, S, antithrombin III, factor V Leiden G1691A mutation, prothrombin gene G20210A mutation, methylene tetrahydrofolate reductase C677T mutation by PCR, Janus tyrosine kinase-2 (JAK II) V617F mutation by PCR (to exclude myeloproliferative disorders) and flow cytometry for CD55 and CD59 (to exclude paroxysmal nocturnal hemoglobinuria); (4) Abdominal ultrasonography: for liver size, echogenicity, spleen size, portal vein diameter and ascites; (5) Color Doppler ultrasonographic study: was done in the morning after an overnight fasting using a color Doppler unit with a 3.5 MHz convex probe for confirmation of portal vein (PV) patency and diameter, mean PV flow velocity (mean PVV) (cm/sec), PV direction of flow, splenic vein patency and diameter, presence of portosystemic collaterals and patency of hepatic veins; (6) Platelet count/spleen diameter ratio: calculated as: platelet count/ maximum spleen bipolar diameter by ultrasound in mm; (7) Ultrasonography guided liver biopsy: for diagnosis of NCPH and exclusion of cirrhotic portal hypertension; and (8) Upper gastrointestinal endoscopy using the Pentax video endoscope EG 3440. --- G1691A --- --- G20210A --- --- C677T --- --- V617F ---

Primary Outcomes

Measure: The presence or absence of variceal bleeding within one year of follow up.

Time: 1 year

31 A Phase II Single-Arm Study of the Efficacy and Safety of Oral Rigosertib in Patients With Myelofibrosis (MF) and Anemia

The goal of this clinical research study is to learn if rigosertib can help to control MF in patients with anemia. The safety of this drug will also be studied. This is an investigational study. Rigosertib is not FDA-approved or commercially available. It is currently being used for research purposes only. The study doctor can explain how the study drug is designed to work. Up to 35 participants will be enrolled in this study. All will be enrolled at MD Anderson.

NCT02730884 Leukemia Myelofibrosis Anemia Splenomegaly Drug: Rigosertib Behavioral: Questionnaire
MeSH:Anemia Primary Myelofibrosis Splenomegaly
HPO:Anemia Splenomegaly

Measurement of JAK2 V617F allele burden in BM samples, if not done within 6 months prior to Screening, must be provided with the Screening BM biopsy/aspirate report (patients are eligible regardless of JAK2 mutation status); 3. Anemia or RBC-transfusion dependence defined as follows: a) Anemia: defined for the purpose of this protocol as 1) a hemoglobin level <10 g/L on every determination over 84 days before study-entry, without RBC-transfusions, or 2) a hemoglobin level <10 g/L on a patient that is receiving RBC-transfusions periodically but not meeting criteria for transfusion-dependent patient as defined below. --- V617F ---

Primary Outcomes

Description: Spleen response defined as ≥ 35% spleen volume reduction from Baseline, which must be confirmed by MRI or CT measurement per revised International Working Group for Myelofibrosis Research and Treatment (IWG MRT) response criteria.

Measure: Change in Spleen Volume

Time: Baseline and 48 weeks

Description: Anemia response defined as the proportion of transfusion-independent patients with Hgb increase of at least 2 g/dL from Baseline or the proportion of transfusion-dependent patients becoming transfusion independent for at least 12 weeks as defined in 2013 International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) criteria.

Measure: Change in Anemia Response

Time: Baseline and 48 weeks

Secondary Outcomes

Description: Symptoms response defined as the proportion of patients achieving ≥ 50% reduction in the Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (MPN-SAF TSS) at any time before Week 48.

Measure: Symptoms Response

Time: 48 weeks

32 Assessment of the Prevalence of Major Psychiatric Disorders in a Cohort of Women With Clinical Criteria Corresponding to Pure, Abortive-form, Obstetrical, Antiphospholipid Syndrome

The primary objective of this study was to evaluate and compare the prevalence of the following psychiatric pathologies (based on the MINI5.0.0 questionnaire) among 3 groups of women (Leiden versus aP1Ab-positive versus thrombophilia-negative) with similar obstetrical histories 10 years after their initial assessment/diagnosis. - Mood disorders, including depressive episodes during the previous two weeks, recurrent depressive disorders at any point in life, dysthymia in the last two years, or any current or past manic episode; - Anxiety disorders, including current agoraphobia, current panic disorders, agoraphobia with panic disorders, current social phobia, generalized anxiety in the last 6 months, or current posttraumatic stress syndrome; - Apparent psychotic syndromes, including isolated or recurrent psychotic syndromes, past or present (clinically validated), - Current alcohol or drug problems (dependence or abuse).

NCT02833194 Antiphospholipid Syndrome Factor V Leiden Thrombophilia
MeSH:Thrombophilia Antiphospholipid Syndrome Syndrome Mental Disorders Problem Behavior
HPO:Behavioral abnormality Hypercoagulability

Exclusion Criteria: - Any history of thrombotic events or any treatment given during previous pregnancies that might have modified the natural course of the condition - Women whose pregnancy losses could be explained by infectious, metabolic, anatomic or hormonal facotrs, or associated with paternal or maternal chromosomal causes - Seropositivity for HIV, hepatitis B or C - Women with antithrombin, protein C, or protein S deficiency, and women with abnormal fibrinogen or with the JAK2 V617F mutation were further excluded. --- V617F ---

Primary Outcomes

Measure: Mini Internationl Neuropsychiatric Interview 5.0.0

Time: 10 years

33 The Prognostic Value of PGF and sFlt1 Variations Induced by the First Low-molecular-weight-heparin Injections in Women With Obstetrical Antiphospholipids Antibody Syndrome Starting a New Pregnancy and Following Treatment in Accordance With International Recommendations

The primary objective of this study is to evaluate plasmatic concentrations of free PGF and sFlt1 for blood samples taken before a first low-molecular-weight-heparin injection and also for blood samples taken on the 4th day of injections (the latter correspond to the first systematic control of platelet counts) in women who have an obstetric antiphospholipid antibody syndrome and who are initiating a new pregnancy with recommended treatment. Our goal is to test the prognostic value of these data on the occurrence of: - pregnancy loss categorized as embryonic loss (before 10 weeks gestation), fetal death (before 20 weeks gestation), stillbirths (from 20 weeks gestation to delivery), and neonatal death defined before reaching 28 days of age. - ischemic placental pathology (pre-eclampsia, retro-placental hematoma, birth of a small-for-gestational-age infant)

NCT02855047 Antiphospholipid Syndrome
MeSH:Antiphospholipid Syndrome Syndrome

- Women in the APS subgroup: persistently positive for LA, and/or aCL and/or aBeta2GP1 - Women initiating a new pregnancy during the 18 month observational period after obstetric APS diagnosis Exclusion Criteria: - Any history of thrombotic events or any treatment given during previous pregnancies that might have modified the natural course of the condition - Women whose pregnancy losses could be explained by infectious, metabolic, anatomic or hormonal factors, or associated with paternal or maternal chromosomal causes - Seropositivity for HIV, hepatitis B or C - Women with antithrombin, protein C, or protein S deficiency, and women with abnormal fibrinogen or with the JAK2 V617F mutation were further excluded. --- V617F ---

Primary Outcomes

Description: The primary endpoint was a composite outcome that included any of the following events occurring after 19 completed weeks during the observed pregnancy: preeclampsia, abruptio placenta, or fetal growth restriction (< 10th percentile), summarized as the so-called placenta-mediated complications PMCs.

Measure: Presence/absence of at least one of the following: preeclampsia, abruptio placenta, or fetal growth restriction (< 10th percentile)

Time: 19 weeks gestation

34 Efficacy of Heat-shock Protein (HSP) Inhibitors in Myeloproliferative Syndromes (MPS): Fundamental Observational in Vitro Study Using Samples From a Collection

Heat-shock proteins (HSP) have been very highly conserved throughout the evolution of species and are characterized by their chaperone function, thanks to their ability to prevent aggregation and to promote the renaturation/break down of damaged proteins. Among other targets, they also chaperone JAK2, a key step that is deregulated in signalling in myeloproliferative syndromes (MPS) because of the JAK2V617F mutation. These HSP also have a potent cytoprotective action through their multiples inhibiting effects on apoptotic processes. Little is known about levels of HSP expression, in particular for HSP70 and HSP27, in MPS cells. However, in vitro studies of different cell models have shown the interest of HSP90 inhibitors in slowing cell proliferation in MPS. These results have been confirmed in animal models with results in terms of blood counts and overall survival. In addition, it seems that the V617F mutated form of JAK2 is more sensitive than the wild-type to HSP90 inhibitors. Finally, inhibitors of HSP90 remain efficacious with regard to the inhibition of cell growth, even in cases of resistance to JAK2 inhibitors. Nonetheless, HSP90 inhibitors are known to stimulate the expression of other HSP, notably HSP27 and HSP70, which are, through their properties, tumorigenic and could lead to an escape phenomenon. Thus the combined use of several HSP inhibitors could be beneficial, and eventually present synergistic effects on the inhibition of tumour processes.

NCT02873832 Myeloproliferative Syndrome Biological: Blood sample Other: Flow cytometry Other: western blot
MeSH:Myeloproliferative Disorders Syndrome
HPO:Myeloproliferative disorder

In addition, it seems that the V617F mutated form of JAK2 is more sensitive than the wild-type to HSP90 inhibitors. --- V617F ---

Primary Outcomes

Description: Level of protein expression using flow cytometry and western blot

Measure: Comparing the level of expression of HSP (HSP90, HSP70, HSP27) between cells from a collection of samples of patients with myeloproliferative disease and healthy controls .

Time: through study completion, an average of 1 year

Secondary Outcomes

Measure: Cell death after in vitro treatment with different HSP inhibitors

Time: through study completion, an average of 1 year

35 A Phase 1 Study of Ruxolitinib, Steroids and Lenalidomide for Relapsed/Refractory Multiple Myeloma (RRMM) Patients

This is a phase 1, multicenter, open-label study evaluating the safety and efficacy of ruxolitinib, steroids and lenalidomide among MM patients who currently show progressive disease.

NCT03110822 Multiple Myeloma Drug: Ruxolitinib Oral Tablet [Jakafi] Drug: Lenalidomide Drug: Methylprednisolone
MeSH:Multiple Myeloma Neoplasms, Plasma Cell
HPO:Multiple myeloma

The activating JAK2 V617F mutation results in uncontrolled cytokine and growth factor signaling, and is believed to play a key role in the pathophysiology of myeloproliferative neoplasms. --- V617F ---

Primary Outcomes

Description: MTD will be determined by measuring incidence of the dose-limiting toxicities (DLTs) per dose level, of ruxolitinib in combination with steroids and lenalidomide for MM patients currently with progressive disease.

Measure: Determination of maximum tolerated dose (MTD) of ruxolitinib in combination with steroids and lenalidomide [Tolerability].

Time: 30 months

Description: Safety will be measured by counting the occurrence of adverse events throughout the study, graded via Common Terminology Criteria for Adverse Events (CTCAE) v 4.03 criteria

Measure: Incidence of Treatment-Emergent Adverse Events [Safety]

Time: 54 months

Secondary Outcomes

Description: Overall response rate (ORR) is defined as CR + VGPR + PR

Measure: Overall response rate (ORR) as a measure of efficacy

Time: 54 months

Description: Clinical benefit rate is defined as ORR + MR

Measure: Clinical benefit rate (CBR) as a measure of efficacy

Time: 54 months

Description: Progression-free survival will be measured in months as the time from initiation of therapy to progressive disease or death from any cause, whichever occurs first

Measure: Progression Free Survival (PFS)

Time: 54 months

Description: Time to response, defined as the time from the initiation of therapy to the first evidence of confirmed clinical benefit defined as > minimal response (MR, including patients who achieved a complete response (CR), very good partial response (VGPR), partial response (PR), or MR

Measure: Assessment of the time to response as a measure of efficacy

Time: 54 months

Description: Duration of response, defined as the time (in months) from the first response to progressive disease

Measure: Assessment of the duration of response as a measure of efficacy

Time: 54 months

Description: Overall survival, defined as the time (in months) from initiation of therapy to death from any cause or last follow-up visit

Measure: Assessment of the overall survival (OR) as a measure of efficacy

Time: 54 months

Description: Response to initial therapy (ruxolitinib and methylprednisolone alone) will be compared to the response to therapy with addition of lenalidomide (ruxolitinib, lenalidomide, methylprednisolone)

Measure: Assessment of response in additional cohort

Time: 54 months

36 A Phase I Study of Single Agent Tazemetostat in Subjects With Advanced Solid Tumors and B-Cell Lymphomas With Hepatic Dysfunction

This phase I trial studies the best dose and side effects of tazemetostat in treating patients with solid tumors or B-cell lymphomas with liver dysfunction that have spread to other places in the body or cannot be removed by surgery. Tazemetostat may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

NCT03217253 Ann Arbor Stage III B-Cell Non-Hodgkin Lymphoma Ann Arbor Stage IV B-Cell Non-Hodgkin Lymphoma Metastatic Malignant Solid Neoplasm Stage III Hepatocellular Carcinoma AJCC v7 Stage IIIA Hepatocellular Carcinoma AJCC v7 Stage IIIB Hepatocellular Carcinoma AJCC v7 Stage IIIC Hepatocellular Carcinoma AJCC v7 Stage IV Hepatocellular Carcinoma AJCC v7 Stage IVA Hepatocellular C Stage IVA Hepatocellular Carcinoma AJCC v7 Stage IVB Hepatocellular Carcinoma AJCC v7 Unresectable Solid Neoplasm Other: Laboratory Biomarker Analysis Other: Pharmacological Study Drug: Tazemetostat
MeSH:Lymphoma Carcinoma Lymphoma, Non-Hodgkin Carcinoma, Hepatocellular Lymphoma, B-Cell Neoplasms
HPO:B-cell lymphoma Carcinoma Hepatocellular carcinoma Lymphoma Neoplasm Non-Hodgkin lymphoma

JAK2 V617F) observed in cytogenetic testing and DNA sequencing - Has a prior history of T-acute lymphoblastic lymphoma (T-LBL)/T-acute lymphoblastic leukemia (ALL) Inclusion Criteria: - Patients must have histologically and/or cytologically confirmed solid tumors or B cell lymphoma that are metastatic or unresectable and for which standard treatment options do not exist; patients with hepatocellular carcinoma are eligible without pathological diagnosis if diagnosed on the basis of blood work and imaging - Patients with evaluable disease will be eligible - All patients must have completed any prior chemotherapy, targeted therapy and major surgery, >= 28 days before study entry; for daily or weekly chemotherapy without the potential for delayed toxicity, a washout period of 14 days may be acceptable, and questions related to this can be discussed with study principal investigator - Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%) - Life expectancy of greater than 3 months - Able to swallow and retain orally-administered medication and does not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels - All prior treatment-related toxicities must be Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 grade =< 1 (except alopecia) at the time of enrollment - Leukocytes >= 3,000/mcL - Absolute neutrophil count >= 1,500/mcL - Platelets >= 100,000/mcL - Hemoglobin >= 90 g/L (9.0 g/dL) - Creatinine within normal institutional limits OR calculated creatinine clearance >= 60 mL/min/1.73 --- V617F ---

JAK2 V617F) observed in cytogenetic testing and DNA sequencing - Has a prior history of T-acute lymphoblastic lymphoma (T-LBL)/T-acute lymphoblastic leukemia (ALL) Ann Arbor Stage III B-Cell Non-Hodgkin Lymphoma Ann Arbor Stage IV B-Cell Non-Hodgkin Lymphoma Metastatic Malignant Solid Neoplasm Stage III Hepatocellular Carcinoma AJCC v7 Stage IIIA Hepatocellular Carcinoma AJCC v7 Stage IIIB Hepatocellular Carcinoma AJCC v7 Stage IIIC Hepatocellular Carcinoma AJCC v7 Stage IV Hepatocellular Carcinoma AJCC v7 Stage IVA Hepatocellular C Stage IVA Hepatocellular Carcinoma AJCC v7 Stage IVB Hepatocellular Carcinoma AJCC v7 Unresectable Solid Neoplasm Lymphoma Carcinoma Lymphoma, Non-Hodgkin Carcinoma, Hepatocellular Lymphoma, B-Cell Neoplasms PRIMARY OBJECTIVES: I. To determine safety, tolerability and recommended phase 2 dose (RP2D) of tazemetostat in patients with varying degrees of hepatic dysfunction. --- V617F ---

Primary Outcomes

Description: Frequency and severity of adverse events will be tabulated using counts and proportions detailing frequently occurring, serious and severe events of interest. Adverse events will be summarized using all adverse events experienced, although a sub-analysis may be conducted including only those adverse events in which the treating physician deems possibly, probably or definitely attributable to study treatment.

Measure: Incidence of adverse events of tazemetostat in patients with varying degrees of hepatic dysfunction assessed using Common Terminology Criteria for Adverse Events version 5.0

Time: Up to 2 years

Description: RP2D will be determined.

Measure: Recommended phase 2 dose (RP2D) of tazemetostat in patients with varying degrees of hepatic dysfunction

Time: Up to 2 years

Secondary Outcomes

Description: Plasma concentrations will be measured by Q2 Solutions using a validated Liquid chromatography (LC)/mass spectrometry (MS)/MS assay. Molecular and clinical predictors of clinical outcomes will be investigated using logistic regression and Cox proportional hazards models. Potential predictors include clinical predictors and molecular correlates. Descriptive statistics and plotting of data will also be used to better understand potential relationships. Given the small sample size, and exploratory nature of these endpoints, all pharmacodynamic analyses conducted will be considered exploratory. All analyses will be considered exploratory and inference will be performed with appropriate caution.

Measure: Pharmacokinetic (PK) profiles of tazemetostat in patients with varying degrees of hepatic dysfunction

Time: Up to course 4 day 1 (day 85)

Description: Molecular and clinical predictors of clinical outcomes will be investigated using logistic regression and Cox proportional hazards models. Potential predictors include clinical predictors and molecular correlates. Descriptive statistics and plotting of data will also be used to better understand potential relationships. All analyses will be considered exploratory and inference will be performed with appropriate caution.

Measure: Antitumor activity of tazemetostat

Time: Up to 2 years

Description: Molecular and clinical predictors of clinical outcomes will be investigated using logistic regression and Cox proportional hazards models. Potential predictors include clinical predictors and molecular correlates. Descriptive statistics and plotting of data will also be used to better understand potential relationships. All analyses will be considered exploratory and inference will be performed with appropriate caution.

Measure: Antitumor activity of tazemetostat in population with tumors with aberrations in EZH2 or SWI/SNF complex pathways

Time: Up to 2 years

Description: Response will be assessed using the Response Evaluation Criteria in Solid Tumors (RECIST) criteria 1.1

Measure: Objective confirmed response

Time: Up to 2 years

Description: Response will be assessed using the RECIST criteria 1.1.

Measure: Duration of response

Time: Up to 2 years

Description: Response will be assessed using the RECIST criteria 1.1.

Measure: Best response

Time: Up to 2 years

37 Genomic Screening for Hereditary Erythrocytosis and Related Diseases

Unexplained polycythemias are rare diseases, and therefore, the collection of data inherent to these diseases will not only improve their characterisation, but also allow stratification according to the risks and the course of the disease. The objective of this project is to constitute a database on the disease which will allow us to better understand it and in due course improve its management. The GENRED project thus bears uniquely on the collection of information, which will be gathered throughout the usual management of patients for this type of disease.

NCT03263364 Hereditary Erythrocytosis/Idiopathic Erythrocytosis
MeSH:Polycythemia
HPO:Polycythemia

The required tests are: complete blood counts - Blood electrolytes - Arterial and venous gazes - Serum erythropoietin dosage - Liver function tests - JAK2 mutations (both V617F and exon 12) - Bone marrow aspirate and/or biopsy and/or endogenous BFU-E culture - Abdominal ultrasound - Lung function tests Inclusion Criteria: The characteristics of the patients included in the database will be described in terms of numbers and percentages for qualitative variables and in terms of means and standard deviations or medians and interquartile intervals for quantitative variables. --- V617F ---

The required tests are: complete blood counts - Blood electrolytes - Arterial and venous gazes - Serum erythropoietin dosage - Liver function tests - JAK2 mutations (both V617F and exon 12) - Bone marrow aspirate and/or biopsy and/or endogenous BFU-E culture - Abdominal ultrasound - Lung function tests Hereditary Erythrocytosis/Idiopathic Erythrocytosis Polycythemia null --- V617F ---

Primary Outcomes

Measure: Germline mutations that cause Hereditary Erythrocytosis/Idiopathic Erythrocytosis

Time: at baseline

38 A Phase II Study of Tazemetostat (EPZ-6438) in Recurrent or Persistent Endometrioid or Clear Cell Carcinoma of the Ovary, and Recurrent or Persistent Endometrioid Endometrial Adenocarcinoma

This phase II trial studies how well tazemetostat works in treating patients with ovarian or endometrial cancer that has come back (recurrent). Drugs used in chemotherapy, such as tazemetostat, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading.

NCT03348631 FIGO Grade 1 Endometrial Endometrioid Adenocarcinoma FIGO Grade 2 Endometrial Endometrioid Adenocarcinoma Recurrent Endometrial Endometrioid Adenocarcinoma Recurrent Ovarian Carcinoma Recurrent Ovarian Clear Cell Adenocarcinoma Recurrent Ovarian Endometrioid Adenocarcinoma Recurrent Uterine Corpus Carcinoma Other: Laboratory Biomarker Analysis Drug: Tazemetostat
MeSH:Carcinoma Adenocarcinoma Carcinoma, Endometrioid Adenocarcinoma, Clear Cell
HPO:Carcinoma

JAK2 V617F) observed in cytogenetic testing and deoxyribonucleic acid (DNA) sequencing - A prior history of T-cell lymphoblastic lymphoma (T-LBL)/T-cell acute lymphoblastic leukemia (T-ALL) - Severe, active co-morbidity per the treating investigator's discretion - Pregnant or lactating patients - Known human immunodeficiency virus (HIV) positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with tazemetostat; in addition, treatments involved in this protocol may be immunosuppressive, increasing the risk of lethal infections in this patient population - Treatment with strong inhibitors or inducers of CYP3A within 14 days of registration and during the study treatment Inclusion Criteria: - Pathologically (histologically or cytologically) proven diagnosis of recurrent or persistent ovarian endometrioid or clear cell carcinoma, OR recurrent or persistent endometrioid endometrial adenocarcinoma; patients with recurrent endometrial cancer must have mismatch repair (MMR) immunohistochemistry completed; if they are found to be mismatch repair deficient, they should be offered treatment with immune checkpoint inhibition before consideration for treatment on trial; primary ovarian tumors must be at least 50% endometrioid or clear cell morphology, or have histologically documented recurrence with at least 50% endometrioid or clear cell morphology; institutional pathology reports must be provided indicating at least 50% endometrioid or clear cell morphology for ovarian tumors (primary or recurrent lesions) - All patients must have measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1; measurable disease is defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded); each lesion must be >= 10 mm when measured by computed tomography (CT), magnetic resonance imaging (MRI) or caliper measurement by clinical exam; or >= 20 mm when measured by chest x-ray; lymph nodes must be > 15 mm in short axis when measured by CT or MRI - Patients must have had at least one, but no more than 3, prior cytotoxic regimens for management of primary disease; unlimited prior hormonal therapy, targeted therapy (including immunotherapy) or antiangiogenic therapy will be permitted - Patients must have completed prior therapy: - Chemotherapy: cytotoxic - At least 28 days since last dose of chemotherapy prior to registration. --- V617F ---

JAK2 V617F) observed in cytogenetic testing and deoxyribonucleic acid (DNA) sequencing - A prior history of T-cell lymphoblastic lymphoma (T-LBL)/T-cell acute lymphoblastic leukemia (T-ALL) - Severe, active co-morbidity per the treating investigator's discretion - Pregnant or lactating patients - Known human immunodeficiency virus (HIV) positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with tazemetostat; in addition, treatments involved in this protocol may be immunosuppressive, increasing the risk of lethal infections in this patient population - Treatment with strong inhibitors or inducers of CYP3A within 14 days of registration and during the study treatment FIGO Grade 1 Endometrial Endometrioid Adenocarcinoma FIGO Grade 2 Endometrial Endometrioid Adenocarcinoma Recurrent Endometrial Endometrioid Adenocarcinoma Recurrent Ovarian Carcinoma Recurrent Ovarian Clear Cell Adenocarcinoma Recurrent Ovarian Endometrioid Adenocarcinoma Recurrent Uterine Corpus Carcinoma Carcinoma Adenocarcinoma Carcinoma, Endometrioid Adenocarcinoma, Clear Cell PRIMARY OBJECTIVE: I. To assess the clinical activity (overall response rate) of tazemetostat in patients with recurrent or persistent endometrioid or clear cell ovarian carcinoma, and patients with recurrent or persistent endometrioid endometrial adenocarcinoma. --- V617F ---

Primary Outcomes

Measure: Tumor response as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1

Time: Up to 6 months

Secondary Outcomes

Measure: Tumor response in patients with ARID1A mutations using tumor response as defined by RECIST v 1.1

Time: Up to 6 months

Measure: Incidence of adverse events according to grade of toxicity by organ or organ system

Time: Up to 5 years

Description: Will be characterized by quartiles and the median of the distribution with confidence intervals. Kaplan-Meier plots will show an estimate of the survival function for these populations.

Measure: Progression-free survival

Time: From study entry to time of progression or death, whichever occurs first, assessed up to 5 years

Description: Will be characterized by quartiles and the median of the distribution with confidence intervals. Kaplan-Meier plots will show an estimate of the survival function for these populations.

Measure: Overall survival

Time: From study entry to time of death or the date of last contact, assessed up to 5 years

Other Outcomes

Description: Associations between BAF250a and ARID1A mutations may be examined with contingency table analysis (e.g. potentially including Chi-square analyses or Spearman's correlation).

Measure: ARID1A mutational status

Time: Up to 6 months

Description: Associations between BAF250a and ARID1A mutations may be examined with contingency table analysis (e.g. potentially including Chi-square analyses or Spearman's correlation).

Measure: BAF250a expression by immunohistochemistry

Time: Up to 6 months

39 Concomitant Ruxolitinib Induction and Maintenance With Cytarabine Based Chemotherapy in Secondary Acute Myelogenous Leukemia Evolving From Myeloproliferative Neoplasm

This trial aimed to investigate the therapeutic efficacy of ruxolitinib in combination with cytotoxic chemotherapy for post-myeloproliferative neoplasm secondary acute myeloid leukemia.

NCT03558607 Secondary Acute Myelogenous Leukemia Evolving From Myeloproliferative Disorder Drug: Ruxolitinib
MeSH:Leukemia Neoplasm Metastasis Leukemia, Myeloid Leukemia, Myeloid, Acute Myeloproliferative Disorders Neoplasms
HPO:Acute megakaryocytic leukemia Acute myeloid leukemia Leukemia Myeloid leukemia Myeloproliferative disorder Neoplasm

JAK2 V617F mutation, which is a hallmark of MPN, has been reported to be carried in approximately 35-50% of patients with post-MPN AML. --- V617F ---

Primary Outcomes

Measure: complete remission rate

Time: After 12 months from induction chemotherapy

Measure: complete remission with incompletre recovery rate

Time: After 12 months from induction chemotherapy

Secondary Outcomes

Description: from the date of transplantation to death from any cause

Measure: Overall survival

Time: 3, 6, 12, 24 months after induction chemotherapy

Description: from the date of transplantation to the date of disease progression or death from any cause

Measure: Progression-free survival

Time: 3, 6, 12, 24 months after induction chemotherapy

Description: according to CTCAE version 4.03

Measure: Toxicity profile

Time: 3, 6, 12, 24 months after induction chemotherapy

40 Arterial Function and Atherosclerosis in Patients With JAK2 V167F Positive Essential Thrombocythemia

The aim of the study is to examine (a) whether patients with JAK2 V617F positive ET in comparison to age-and sex-matched, apparently healthy control subjects show more advanced progression of arterial stiffness, pulse-wave velocity and coronary calcium score in a 4 year observation period, and (b) whether the burden of JAK2 V617F mutation correlates with the measured vascular parameters. All subjects will be examined twice. The first visit already took place between the years 2014 - 2015 and the second visit will take place between 2018-2019. All participants will have signed their informed consent before entering the study. Each visit will consist of completing a structured questionnaire (on personal and family medical history, risk factors for CVD and medication), physical examination, donating a blood sample for laboratory tests and undergoing carotid ultrasound and coronary calcium measurement oft the extent of coronary artery calcification. At the first and the second examination the JAK2 V617F allele burden, i.e. the percentage of mutated alleles, will be determined from genomic DNA in peripheral blood.

NCT03828422 Atherosclerosis Diagnostic Test: imaging
MeSH:Atherosclerosis Thrombocytosis Thrombocythemia, Essential
HPO:Atherosclerosis Thrombocytosis Type IV atherosclerotic lesion

Arterial Function and Atherosclerosis in Essential Thrombocythemia The aim of the study is to examine (a) whether patients with JAK2 V617F positive ET in comparison to age-and sex-matched, apparently healthy control subjects show more advanced progression of arterial stiffness, pulse-wave velocity and coronary calcium score in a 4 year observation period, and (b) whether the burden of JAK2 V617F mutation correlates with the measured vascular parameters. --- V617F ---

Arterial Function and Atherosclerosis in Essential Thrombocythemia The aim of the study is to examine (a) whether patients with JAK2 V617F positive ET in comparison to age-and sex-matched, apparently healthy control subjects show more advanced progression of arterial stiffness, pulse-wave velocity and coronary calcium score in a 4 year observation period, and (b) whether the burden of JAK2 V617F mutation correlates with the measured vascular parameters. --- V617F --- --- V617F ---

At the first and the second examination the JAK2 V617F allele burden, i.e. the percentage of mutated alleles, will be determined from genomic DNA in peripheral blood. --- V617F ---

Change of carotid artery stiffness (expressed by beta-stiffness index and pulse wave velocity) in JAK2 V617F positive ET patients in comparison to healthy control subjects in a 4-year period.. Do patients with JAK2 V617F positive ET in comparison to age-and sex-matched, apparently healthy control subjects show more advanced progression of carotid artery stiffness (expressed as two interrelated parameters, the beta-stiffness index and the pulse wave velocity) in a 4 year observation period?. --- V617F ---

Change of carotid artery stiffness (expressed by beta-stiffness index and pulse wave velocity) in JAK2 V617F positive ET patients in comparison to healthy control subjects in a 4-year period.. Do patients with JAK2 V617F positive ET in comparison to age-and sex-matched, apparently healthy control subjects show more advanced progression of carotid artery stiffness (expressed as two interrelated parameters, the beta-stiffness index and the pulse wave velocity) in a 4 year observation period?. --- V617F --- --- V617F ---

Change of carotid artery plaque score in JAK2 V617F positive ET patients in comparison to healthy control subjects in a 4-year period.. Do patients with JAK2 V617F positive ET in comparison to age-and sex-matched, apparently healthy control subjects show more advanced progression of carotid plaque score in a 4 year observation period? --- V617F ---

Change of carotid artery plaque score in JAK2 V617F positive ET patients in comparison to healthy control subjects in a 4-year period.. Do patients with JAK2 V617F positive ET in comparison to age-and sex-matched, apparently healthy control subjects show more advanced progression of carotid plaque score in a 4 year observation period? --- V617F --- --- V617F ---

Thus, the carotid plaque score ranges from 0 (absence of plaques, best) to 6 (plaques present in all segments on both sides, worst outcome).. Change of coronary calcium burden in JAK2 V617F positive ET patients in comparison to healthy control subjects in a 4-year period.. Do patients with JAK2 V617F positive ET in comparison to age-and sex-matched, apparently healthy control subjects show more advanced progression of coronary calcium score in a 4 year observation period?. --- V617F ---

Thus, the carotid plaque score ranges from 0 (absence of plaques, best) to 6 (plaques present in all segments on both sides, worst outcome).. Change of coronary calcium burden in JAK2 V617F positive ET patients in comparison to healthy control subjects in a 4-year period.. Do patients with JAK2 V617F positive ET in comparison to age-and sex-matched, apparently healthy control subjects show more advanced progression of coronary calcium score in a 4 year observation period?. --- V617F --- --- V617F ---

Change of digital endothelial function, expressed as the Reactive Hyperemia Index, in JAK2 V617F positive ET patients in comparison to healthy control subjects in a 4-year period.. Do patients with JAK2 V617F positive ET in comparison to age-and sex-matched, apparently healthy control subjects show greater changes digital endothelial function, expressed as the Reactive Hyperemia Index (RHI), in a 4 year observation period? --- V617F ---

Change of digital endothelial function, expressed as the Reactive Hyperemia Index, in JAK2 V617F positive ET patients in comparison to healthy control subjects in a 4-year period.. Do patients with JAK2 V617F positive ET in comparison to age-and sex-matched, apparently healthy control subjects show greater changes digital endothelial function, expressed as the Reactive Hyperemia Index (RHI), in a 4 year observation period? --- V617F --- --- V617F ---

RHI ranges from 1 (no augmentation of pulsation with reactive hyperemia, i.e. worst outcome) to values above 2 (good endothelial response to reactive hyperemia).. Association of the JAK2 V617F mutation burden with the coronary calcium burden.. Quantification of JAK2 V617F mutation burden and its correlation with the coronary calcium burden.. Inclusion Criteria: - patients with JAK2 V617F positive essential thrombocythemia - age-and sex-matched apparently healthy control subjects Exclusion Criteria: - personal history of any atherosclerotic vascular disease (myocardial infarction, angina pectoris, peripheral arterial disease, aortic disease, transient ischemic attack or ischemic stroke) - chronic kidney disease stage 3 and above - known cancer - chronic inflammatory disease - autoimmune disease - pregnancy Inclusion Criteria: - patients with JAK2 V617F positive essential thrombocythemia - age-and sex-matched apparently healthy control subjects Exclusion Criteria: - personal history of any atherosclerotic vascular disease (myocardial infarction, angina pectoris, peripheral arterial disease, aortic disease, transient ischemic attack or ischemic stroke) - chronic kidney disease stage 3 and above - known cancer - chronic inflammatory disease - autoimmune disease - pregnancy Atherosclerosis Atherosclerosis Thrombocytosis Thrombocythemia, Essential 1. Patients and control subjects Patients are selected from the database of the Department of Haematology at University Medical Centre Ljubljana, Slovenia, who were diagnosed with JAK2 V617F positive ET between 2011 and 2014. --- V617F ---

RHI ranges from 1 (no augmentation of pulsation with reactive hyperemia, i.e. worst outcome) to values above 2 (good endothelial response to reactive hyperemia).. Association of the JAK2 V617F mutation burden with the coronary calcium burden.. Quantification of JAK2 V617F mutation burden and its correlation with the coronary calcium burden.. Inclusion Criteria: - patients with JAK2 V617F positive essential thrombocythemia - age-and sex-matched apparently healthy control subjects Exclusion Criteria: - personal history of any atherosclerotic vascular disease (myocardial infarction, angina pectoris, peripheral arterial disease, aortic disease, transient ischemic attack or ischemic stroke) - chronic kidney disease stage 3 and above - known cancer - chronic inflammatory disease - autoimmune disease - pregnancy Inclusion Criteria: - patients with JAK2 V617F positive essential thrombocythemia - age-and sex-matched apparently healthy control subjects Exclusion Criteria: - personal history of any atherosclerotic vascular disease (myocardial infarction, angina pectoris, peripheral arterial disease, aortic disease, transient ischemic attack or ischemic stroke) - chronic kidney disease stage 3 and above - known cancer - chronic inflammatory disease - autoimmune disease - pregnancy Atherosclerosis Atherosclerosis Thrombocytosis Thrombocythemia, Essential 1. Patients and control subjects Patients are selected from the database of the Department of Haematology at University Medical Centre Ljubljana, Slovenia, who were diagnosed with JAK2 V617F positive ET between 2011 and 2014. --- V617F --- --- V617F ---

RHI ranges from 1 (no augmentation of pulsation with reactive hyperemia, i.e. worst outcome) to values above 2 (good endothelial response to reactive hyperemia).. Association of the JAK2 V617F mutation burden with the coronary calcium burden.. Quantification of JAK2 V617F mutation burden and its correlation with the coronary calcium burden.. Inclusion Criteria: - patients with JAK2 V617F positive essential thrombocythemia - age-and sex-matched apparently healthy control subjects Exclusion Criteria: - personal history of any atherosclerotic vascular disease (myocardial infarction, angina pectoris, peripheral arterial disease, aortic disease, transient ischemic attack or ischemic stroke) - chronic kidney disease stage 3 and above - known cancer - chronic inflammatory disease - autoimmune disease - pregnancy Inclusion Criteria: - patients with JAK2 V617F positive essential thrombocythemia - age-and sex-matched apparently healthy control subjects Exclusion Criteria: - personal history of any atherosclerotic vascular disease (myocardial infarction, angina pectoris, peripheral arterial disease, aortic disease, transient ischemic attack or ischemic stroke) - chronic kidney disease stage 3 and above - known cancer - chronic inflammatory disease - autoimmune disease - pregnancy Atherosclerosis Atherosclerosis Thrombocytosis Thrombocythemia, Essential 1. Patients and control subjects Patients are selected from the database of the Department of Haematology at University Medical Centre Ljubljana, Slovenia, who were diagnosed with JAK2 V617F positive ET between 2011 and 2014. --- V617F --- --- V617F --- --- V617F ---

RHI ranges from 1 (no augmentation of pulsation with reactive hyperemia, i.e. worst outcome) to values above 2 (good endothelial response to reactive hyperemia).. Association of the JAK2 V617F mutation burden with the coronary calcium burden.. Quantification of JAK2 V617F mutation burden and its correlation with the coronary calcium burden.. Inclusion Criteria: - patients with JAK2 V617F positive essential thrombocythemia - age-and sex-matched apparently healthy control subjects Exclusion Criteria: - personal history of any atherosclerotic vascular disease (myocardial infarction, angina pectoris, peripheral arterial disease, aortic disease, transient ischemic attack or ischemic stroke) - chronic kidney disease stage 3 and above - known cancer - chronic inflammatory disease - autoimmune disease - pregnancy Inclusion Criteria: - patients with JAK2 V617F positive essential thrombocythemia - age-and sex-matched apparently healthy control subjects Exclusion Criteria: - personal history of any atherosclerotic vascular disease (myocardial infarction, angina pectoris, peripheral arterial disease, aortic disease, transient ischemic attack or ischemic stroke) - chronic kidney disease stage 3 and above - known cancer - chronic inflammatory disease - autoimmune disease - pregnancy Atherosclerosis Atherosclerosis Thrombocytosis Thrombocythemia, Essential 1. Patients and control subjects Patients are selected from the database of the Department of Haematology at University Medical Centre Ljubljana, Slovenia, who were diagnosed with JAK2 V617F positive ET between 2011 and 2014. --- V617F --- --- V617F --- --- V617F --- --- V617F ---

RHI ranges from 1 (no augmentation of pulsation with reactive hyperemia, i.e. worst outcome) to values above 2 (good endothelial response to reactive hyperemia).. Association of the JAK2 V617F mutation burden with the coronary calcium burden.. Quantification of JAK2 V617F mutation burden and its correlation with the coronary calcium burden.. Inclusion Criteria: - patients with JAK2 V617F positive essential thrombocythemia - age-and sex-matched apparently healthy control subjects Exclusion Criteria: - personal history of any atherosclerotic vascular disease (myocardial infarction, angina pectoris, peripheral arterial disease, aortic disease, transient ischemic attack or ischemic stroke) - chronic kidney disease stage 3 and above - known cancer - chronic inflammatory disease - autoimmune disease - pregnancy Inclusion Criteria: - patients with JAK2 V617F positive essential thrombocythemia - age-and sex-matched apparently healthy control subjects Exclusion Criteria: - personal history of any atherosclerotic vascular disease (myocardial infarction, angina pectoris, peripheral arterial disease, aortic disease, transient ischemic attack or ischemic stroke) - chronic kidney disease stage 3 and above - known cancer - chronic inflammatory disease - autoimmune disease - pregnancy Atherosclerosis Atherosclerosis Thrombocytosis Thrombocythemia, Essential 1. Patients and control subjects Patients are selected from the database of the Department of Haematology at University Medical Centre Ljubljana, Slovenia, who were diagnosed with JAK2 V617F positive ET between 2011 and 2014. --- V617F --- --- V617F --- --- V617F --- --- V617F --- --- V617F ---

40 patients (14 male and 26 female) with JAK2 V617F positive ET without clinically apparent cardiovascular disease signed the informed consent and were enrolled in the study in 2014 - 2015 for the first examination and 36 (12 male and 24 female) of them are expected to participate also in 2018-19. --- V617F ---

3. JAK2 V617F/G1849T allele burden The ipsogen JAK2 MutaQuant Kit, Qiagen (ZDA) (Ref: No. 673523) will be used for the detection and quantification of JAK2 V617F/G1849T allele in genomic DNA extracted from peripheral blood of patients and also control subjects. --- V617F ---

3. JAK2 V617F/G1849T allele burden The ipsogen JAK2 MutaQuant Kit, Qiagen (ZDA) (Ref: No. 673523) will be used for the detection and quantification of JAK2 V617F/G1849T allele in genomic DNA extracted from peripheral blood of patients and also control subjects. --- V617F --- --- V617F ---

A SNP specific primer selectively amplifies the JAK2 V617F allele which is detected with a real-time qPCR instrument that quantifies the PCR products. --- V617F ---

The JAK2 V617F allele burden will be calculated and expressed as the percentage of JAK2 V617F mutated alleles throughout the whole JAK2 record. --- V617F ---

The JAK2 V617F allele burden will be calculated and expressed as the percentage of JAK2 V617F mutated alleles throughout the whole JAK2 record. --- V617F --- --- V617F ---

The association between the parameters of vascular function / morphology and the JAK2 V617F allele burden will be assessed by the Pearson correlation coefficient. --- V617F ---

Primary Outcomes

Description: Do patients with JAK2 V617F positive ET in comparison to age-and sex-matched, apparently healthy control subjects show more advanced progression of carotid artery stiffness (expressed as two interrelated parameters, the beta-stiffness index and the pulse wave velocity) in a 4 year observation period?

Measure: Change of carotid artery stiffness (expressed by beta-stiffness index and pulse wave velocity) in JAK2 V617F positive ET patients in comparison to healthy control subjects in a 4-year period.

Time: the first visit in 2014-2015 and the second visit in 2018-2019

Description: Do patients with JAK2 V617F positive ET in comparison to age-and sex-matched, apparently healthy control subjects show more advanced progression of carotid plaque score in a 4 year observation period? Scoring of atherosclerotic plaques will be done according to the Rotterdam Study. The presence of at least one plaque in each segment of the extracranial carotid arterial bed, (the common carotid artery and the bulb, the internal carotid artery and the external carotid artery) on either side is scored 1 point. Thus, the carotid plaque score ranges from 0 (absence of plaques, best) to 6 (plaques present in all segments on both sides, worst outcome).

Measure: Change of carotid artery plaque score in JAK2 V617F positive ET patients in comparison to healthy control subjects in a 4-year period.

Time: the first visit in 2014-2015 and the second visit in 2018-2019

Description: Do patients with JAK2 V617F positive ET in comparison to age-and sex-matched, apparently healthy control subjects show more advanced progression of coronary calcium score in a 4 year observation period?

Measure: Change of coronary calcium burden in JAK2 V617F positive ET patients in comparison to healthy control subjects in a 4-year period.

Time: the first visit in 2014-2015 and the second visit in 2018-2019

Description: Do patients with JAK2 V617F positive ET in comparison to age-and sex-matched, apparently healthy control subjects show greater changes digital endothelial function, expressed as the Reactive Hyperemia Index (RHI), in a 4 year observation period? The RHI is the ratio of the pletysmographic amplitude of the digital arteries during maximal reactive hyperemia and the basal amplitude. RHI ranges from 1 (no augmentation of pulsation with reactive hyperemia, i.e. worst outcome) to values above 2 (good endothelial response to reactive hyperemia).

Measure: Change of digital endothelial function, expressed as the Reactive Hyperemia Index, in JAK2 V617F positive ET patients in comparison to healthy control subjects in a 4-year period.

Time: the first visit in 2014-2015 and the second visit in 2018-2019

Description: Quantification of JAK2 V617F mutation burden and its correlation with the coronary calcium burden.

Measure: Association of the JAK2 V617F mutation burden with the coronary calcium burden.

Time: at inclusion in the years 2014-2015, and at the second visit in 2018-2019

41 A Pilot Study of Tazemetostat and MK-3475 (Pembrolizumab) in Advanced Urothelial Carcinoma

This phase I/II trial studies the side effects and best dose of tazemetostat and how well it works when given together with pembrolizumab in treating patients with urothelial carcinoma that has spread to nearby tissue or lymph nodes or other places in the body (locally advanced/metastatic). Tazemetostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving tazemetostat and pembrolizumab may work better in treating patients with urothelial carcinoma compared to pembrolizumab without tazemetostat.

NCT03854474 Locally Advanced Urothelial Carcinoma Metastatic Urothelial Carcinoma Stage III Bladder Cancer AJCC v8 Stage IIIA Bladder Cancer AJCC v8 Stage IIIB Bladder Cancer AJCC v8 Stage IV Bladder Cancer AJCC v8 Stage IVA Bladder Cancer AJCC v8 Stage IVB Bladder Cancer AJCC v8 Biological: Pembrolizumab Drug: Tazemetostat
MeSH:Carcinoma Urinary Bladder Neoplasms Carcinoma, Transitional Cell
HPO:Bladder neoplasm Carcinoma

JAK2 V617F) observed in cytogenetic testing and deoxyribonucleic acid (DNA) sequencing are not eligible - Patients with a prior history of T-cell lymphoblastic lymphoma (T-LBL) or T-cell acute lymphoblastic leukemia (T-ALL) are not eligible - Patients who have received prior PD-L1/PD-1/PD-L2 or EZH2 inhibitor therapy are not eligible - Patients who have had a prior monoclonal antibody within 4 weeks prior to study day 1 are not eligible - Patients with a known additional malignancy that is progressing or requires active treatment are not eligible. --- V617F ---

Primary Outcomes

Description: Response rates will be summarized in each cohort by proportions and 95% exact confidence intervals. Time to progression will be summarized using the Kaplan-Meier product limit curve.

Measure: Objective response rate (ORR)

Time: Up to 1 year

Secondary Outcomes

Description: Will be assessed using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5. All adverse events will be summarized as to type, grade, timing, frequency and attribution using frequencies and percentages

Measure: Incidence of adverse events

Time: Up to 30 days after treatment discontinuation

Other Outcomes

Description: Will determine if EZH2, H3K27me3 and mutations in genes associated with histone methylation determine disease response to EZH2 and PD1. Each gene will be related to response using Fisher's exact test.

Measure: EZH2 and H3K27me3 chromatin methylation and mutations in genes associated with histone methylation

Time: Baseline

42 Tazemetostat Expanded Access Program for Adults With Solid Tumors

Patients with following conditions are eligible to enroll in the EAP: - Epithelioid Sarcoma (ES) - Spindle cell sarcoma - Sinonasal carcinoma - Small Cell Carcinoma of the Ovary Hypercalcemic Type (SCCOHT) - Thoracic sarcoma - Poorly differentiated chordoma These conditions must be serious or life-threatening at the time of enrollment and appropriate, comparable, or satisfactory alternative treatments must have been tried without clinical success. Patients with conditions not listed above are not eligible for the tazemetostat EAP

NCT03874455 Epithelioid Sarcoma Spindle Cell Sarcoma Sinonasal Carcinoma Smal Small Cell Carcinoma of the Ovary Hypercalcemic Type Thoracic Sarcoma Poorly Differentiated Chordoma Drug: Tazemetostat
MeSH:Carcinoma Sarcoma Chordoma Carcinoma, Small Cell Small Cell Lung Carcinoma Carcinoma, Ovarian Epithelial
HPO:Carcinoma Chordoma Sarcoma Small cell lung carcinoma Soft tissue sarcoma

JAK2 V617F) observed in cytogenetic testing and DNA sequencing. --- V617F ---


43 PCM1-JAK2 Fusion Gene Detection in Patients With Therapy Related Myelodysplastic Syndrome / Acute Myeloid Leukemia Patients

The term "therapy-related" leukemia is descriptive and is based on a patient's history of exposure to cytotoxic agents. Although a causal relationship is implied, the mechanism remains to be proven. These neoplasms are thought to be the direct consequence of mutational events induced by the prior therapy Therapy-related myelodysplastic syndromes / acute myeloid leukemia (t- MDS / t-AML) is now considered a single entity, called therapy-related myeloid neoplasms based on the current World Health Organization WHO classification2,. It is a well-recognized clinical syndrome occurring as a late complication following Cytotoxic agents and ionizing radiotherapy in the treatment of most cancer types: Hodgkin lymphoma (HL), non-Hodgkin lymphoma (NHL), acute lymphoblastic leukemia (ALL), sarcoma, and ovarian and testicular cancerThe incidence of t-MDS/AML following conventional therapy ranges from 0.8% to 6.3% at 20 years. The median time to development of t-MDS/AML is 3 to 5 years, with the risk decreasing markedly after the first decade Two types of t-MDS/AML are recognized in the WHO classification depending on the causative therapeutic exposure: an alkylating agent/radiation-related type and a topoisomerase II inhibitor-related type. Alkylating agent-related t-MDS/AML usually appears 4 to 7 years after exposure to the mutagenic agent .The reciprocal translocation t(8;9) (p22;p24) between the short arm of chromosome 8 and the long arm of chromosome 9 is a recurrent abnormality that fuses the Janus activated kinase 2 (JAK2) to the human autoantigen pericentriolar material 1 gene (PCM1) , with breakage and reunion at bands 8p11 and 9q3410Due to PCM1-JAK2 gene fusion, the coiled-coil domains of PCM1 mediate an oligomerization that brings together the linked JAK2 domains resulting in a constitutively activated tyrosine kinase domain of JAK2The most common mechanism for JAK2 activation in hematologic malignancies is the point mutation at position 617 (V617F). The consequences of JAK2 activation are neoplastic transformation and abnormal cell proliferation in various malignancies - So, translocations involving the JAK2 locus are considered of oncogenic importance in acute leukemias and myelodysplastic/ myeloproliferative diseases. - Patients with this abnormality present with broad clinical spectrum ranging from chronic to acute hematological diseases with myeloid or lymphoid appearance

NCT03943394 Detection of PCM1-JAK2 Fusion Gene by FISH in the Two Types of t-MDS/AML and Relationship Between PCM1-JAK2 Fusion Gene and Cumulative Dose, Dose Intensity Other: fresh samples are obtained from patients for detction of PCM1- JAK2 fusion gene

Alkylating agent-related t-MDS/AML usually appears 4 to 7 years after exposure to the mutagenic agent .The reciprocal translocation t(8;9) (p22;p24) between the short arm of chromosome 8 and the long arm of chromosome 9 is a recurrent abnormality that fuses the Janus activated kinase 2 (JAK2) to the human autoantigen pericentriolar material 1 gene (PCM1) , with breakage and reunion at bands 8p11 and 9q3410Due to PCM1-JAK2 gene fusion, the coiled-coil domains of PCM1 mediate an oligomerization that brings together the linked JAK2 domains resulting in a constitutively activated tyrosine kinase domain of JAK2The most common mechanism for JAK2 activation in hematologic malignancies is the point mutation at position 617 (V617F). --- V617F ---

The most common mechanism for JAK2 activation in hematologic malignancies is the point mutation at position 617 (V617F). --- V617F ---

Primary Outcomes

Description: Using fresh sample from patients with myeloid neoplasm to search for PCM1-JAK2 fusion gene in the 2 types of thaerap related myeloid neoplasm , studying relationship between PCM1-JAK2 and dose intensity and time of exposure, and studying relationship between PCM1-JAK2 and other cytogenetic abnormalities by using FISH technique and

Measure: Detection of PCM1-JAK2fusion gene

Time: 24 months

44 Modulation of Morbidity and Disease Progression in Polycythemia Vera (PV) and Essential Thrombocythemia (ET) Patients With Obstructive Sleep Apnea (OSA) by CPAP

This early phase I trial studies how well the use of a continuous positive airway pressure (CPAP) machine works in treating obstructive sleep apnea in patients with polycythemia vera or essential thrombocythemia. Obstructive sleep apnea is a condition where a person stops breathing during sleep, and is estimated to affect 30 to 50 percent of patients with polycythemia vera or essential thrombocythemia. A patient with obstructive sleep apnea typically snores, has disrupted sleep, experiences morning headaches, and has daytime sleepiness. Patients diagnosed with obstructive sleep apnea are typically treated with a device called CPAP. The CPAP provides pressurized air that keeps upper air passages open during sleep and may prevent them from narrowing or collapsing as occurs during snoring or sleep apnea.

NCT03972943 CALR Gene Mutation Essential Thrombocythemi Essential Thrombocythemia JAK2 Gene Mutation MPL Gene Mutation Obstructive Sleep Apnea Syndrome Polycythemia Vera Procedure: Continuous Positive Airway Pressure Other: Patient Observation Other: Questionnaire Administration
MeSH:Polycythemia Vera Apnea Sleep Apnea Syndromes Sleep Apnea, Obstructive Polycythemia Thrombocytosis Thrombocythemia, Essential
HPO:Apnea Obstructive sleep apnea Polycythemia Sleep apnea Thrombocytosis

Paired Wilcoxon tests will be used to analyze variables that are highly skewed or otherwise non-Gaussian in distribution.. Change in JAK2 V617F allele burden. --- V617F ---

Primary Outcomes

Description: Will be tested at the two-sided 0.025 significance level to provide overall control of the type I error for the co-primary endpoints at 0.05. The endpoints will be summarized by mean, median, range, standard deviation, interquartile range and boxplots. Scatterplots will be used to show bivariate associations. An assessment of normality will be made prior to statistical testing. Paired t tests will be used to analyze endpoints that are sufficiently Gaussian in distribution. Paired Wilcoxon tests will be used to analyze variables that are highly skewed or otherwise non-Gaussian in distribution.

Measure: Change in Myeloproliferative Neoplasm Symptom Assessment Form - Total Symptom Score (MPN-SAF TSS)

Time: Baseline, after 3 months, and after 6 months on trial

Description: Will be tested at the two-sided 0.025 significance level to provide overall control of the type I error for the co-primary endpoints at 0.05. The endpoints will be summarized by mean, median, range, standard deviation, interquartile range and boxplots. Scatterplots will be used to show bivariate associations. An assessment of normality will be made prior to statistical testing. Paired t tests will be used to analyze endpoints that are sufficiently Gaussian in distribution. Paired Wilcoxon tests will be used to analyze variables that are highly skewed or otherwise non-Gaussian in distribution.

Measure: Change in JAK2 V617F allele burden

Time: Baseline, after 3 months, and after 6 months on trial

Other Outcomes

Description: Assessed by Snoring, Tiredness, Observed Apnea, Blood Pressure, Body Mass Index, Age, Neck Circumference and Gender (STOP-BANG) questionnaire. The proportion of patients whose results indicate a diagnosis of OSA will be calculated. All patients with a diagnosis of OSA, regardless of whether they are enrolled to the treatment component of the study, will be counted towards the assessment of prevalence. An assessment of normality will be made prior to statistical testing. Paired t tests will be used to analyze endpoints that are sufficiently Gaussian in distribution. Paired Wilcoxon tests will be used to analyze variables that are highly skewed or otherwise non-Gaussian in distribution.

Measure: Proportion of patients with a diagnosis of obstructive sleep apnea (OSA)

Time: During the OSA screening

Description: The endpoints will be summarized by mean, median, range, standard deviation, interquartile range and boxplots. Scatterplots will be used to show bivariate associations. An assessment of normality will be made prior to statistical testing. Paired t tests will be used to analyze endpoints that are sufficiently Gaussian in distribution. Paired Wilcoxon tests will be used to analyze variables that are highly skewed or otherwise non-Gaussian in distribution.

Measure: Leucocytes, platelets, red cell counts, and tumor necrosis factor (TNF) analysis

Time: Baseline, after 3 months, and after 6 months on trial

Description: Will be measured in blood samples taken from all patients. OSA-related adverse events reported in the Treatment Cohort at these timepoints will be correlated with these marker levels. Pearson or Spearman correlation will be used to assess correlation between thrombo-inflammatory markers and oximetric abnormalities.

Measure: Thrombotic and inflammatory marker levels for all patients

Time: Baseline, after 3 months, and after 6 months on trial

45 A Phase III, Randomised, Open-label, Multicenter International Trial Comparing Ruxolitinib With Either HydRoxycarbamIDe or Interferon Alpha as First Line ThErapy for High Risk Polycythemia Vera

The trial will be a phase III, randomised-controlled, multi-centre, international, open-label trial consisting of ruxolitinib versus best available therapy, where best available therapy is a choice of interferon alpha, any formulation permitted (IFN) or hydroxycarbamide (HC), and which will be elected by the Investigator prior to randomisation.

NCT04116502 Polycythemia Vera Drug: Ruxolitinib Drug: Hydroxycarbamide Drug: Interferon-Alpha
MeSH:Polycythemia Vera Polycythemia
HPO:Polycythemia

Peripheral blood JAK2 V617F allele burden. --- V617F ---

Symptom burden/(QALY)quality of life years gained 7. Health economics including cost utility and cost effectiveness analyses 8. Peripheral blood JAK2 V617F allele burden according to ELN response criteria 9. Rates of discontinuation 10. --- V617F ---

Primary Outcomes

Description: Event Free Survival

Measure: Event Free Survival (EFS)

Time: the time from randomisation to the date of the first major thrombosis/haemorrhage, death,transformation to Myelodisplastic Syndromes, Acute Myeloid Leukaemia or Post-polycythemia Vera Myelofibrosis, if within the ~3 year trial period

Secondary Outcomes

Description: As defined in the protocol, combined and split to venous and arterial

Measure: Major thrombosis

Time: Occuring while on treatment (over 3 years)

Description: As defined in the protocol

Measure: Major haemorrhage

Time: Occuring while on treatment (over 3 years)

Description: Transformation to PPV-MF

Measure: Transformation to PPV-MF

Time: Occuring while on treatment (over 3 years)

Description: Transformation to MDS and/or AML

Measure: Transformation to MDS and/or AML

Time: Occuring while on treatment (over 3 years)

Description: As defined by ELN response criteria at 1 year

Measure: Complete Haematological remission (CHR)

Time: 1 year post-treatment

Description: As measured via MPN-SAF

Measure: Symptom burden/Quality of life (MPN-SAF)

Time: Questionnaires collected at baseline, weeks 12, 26, 39, 55, months 15, 18, 24, 30 and 36

Description: As measured via MDASI

Measure: Symptom burden/Quality of life (MDASI)

Time: Questionnaires collected at baseline, weeks 12, 26, 39, 55, months 15, 18, 24, 30 and 36

Description: As measured via EQ-5D

Measure: Symptom burden/Quality of life (EQ-5D)

Time: Questionnaires collected at baseline, weeks 12, 26, 39, 55, months 15, 18, 24, 30 and 36

Description: Including cost utility and cost effectiveness analyses as defined by the protocol (e.g. QALYs)

Measure: Health economics

Time: At the end of the trial (trial duration of approximately 8 years)

Description: According to ELN response criteria

Measure: Peripheral blood JAK2 V617F allele burden

Time: At baseline and annually throughout the trial (from baseline until approximately 3 years post-randomisation)

Description: Trial discontinuation

Measure: Rates of discontinuation

Time: From treatment prior to protocol defined 3 years

Description: collected according to CTCAE version 4.0 and the MITHRIDATE protocol

Measure: Rate and severity of adverse events

Time: Continuous throughout the trial (from randomisation until approximately 3 years post-randomisation))

Description: in patients with splenomegaly

Measure: Spleen response

Time: Response at 1 year post randomisation

Description: Time free from venesection

Measure: Time free from venesection

Time: Defined as the mean time between venesections while on trial treatment (treatment duration of 3 years)

Description: Malignancy independent to the original diagnosis

Measure: Secondary malignancy

Time: Occuring throughout the trial (from randomisation until approximately 3 years post-randomisation)

Description: Change in QRisk score

Measure: Change in QRisk score

Time: Collected at baseline and years 1, 2 and 3

Other Outcomes

Description: Progression of marrow fibrosis (bone marrow collected and analysed at the Weatherall Institute of Molecular Medicine (WIMM) in Oxford

Measure: Progression of marrow fibrosis

Time: Occuring throughout the trial (from randomisation to approximately 3 years post-randomisation)

Description: Impact of treatment on molecular signatures of disease (as analysed by the WIMM in Oxford)

Measure: Impact of treatment on molecular signatures of disease

Time: Occuring throughout the trial (from randomisation to approximately 3 years post-randomisation)

Description: within the stem/progenitor cell compartment (as analysed by the WIMM in Oxford)

Measure: Clonal involvement

Time: Occuring throughout the trial (from randomisation to approximately 3 years post-randomisation)

Description: (acquisition of additional mutations, as analysed by the WIMM in Oxford)

Measure: Clonal evolution

Time: Occuring throughout the trial (from randomisation to approximately 3 years post-randomisation)

Description: of other disease-association mutations (as analysed by the WIMM in Oxford)

Measure: Reduction of peripheral blood allele burden

Time: Occuring throughout the trial (from randomisation to approximately 3 years post-randomisation)

Description: and any change over time (as analysed by the WIMM in Oxford)

Measure: Assessment of the prevalence of clonality markers for haematological disease

Time: Occuring throughout the trial (from randomisation to approximately 3 years post-randomisation)

Description: (angina, acute coronary syndrome, acute MI; arrhythmia)

Measure: Cardiac event

Time: Occuring throughout the trial (from randomisation to approximately 3 years post-randomisation)

Description: Pulmonary hypertension as assessed clinically

Measure: Pulmonary hypertension

Time: Occuring throughout the trial (from randomisation to approximately 3 years post-randomisation)

Description: e.g. angiogram, angioplasty, CABG

Measure: Coronary intervention

Time: Occuring throughout the trial (from randomisation to approximately 3 years post-randomisation)

Description: e.g. LVEF% on ECHO/MUGA and/or NYHA classification

Measure: Deterioration in cardiac function

Time: Occuring throughout the trial (from randomisation to approximately 3 years post-randomisation)

Description: TIA, haemorrhagic CVA, non-haemorrhagic CVA

Measure: Cerebrovascular event

Time: Occuring throughout the trial (from randomisation to approximately 3 years post-randomisation)

Description: peripheral vascular disease: claudication, carotid stenosis

Measure: Arterial vascular event

Time: Occuring throughout the trial (from randomisation to approximately 3 years post-randomisation)

Description: including DVT, PE, Cerebral, splanchnic, other

Measure: Venous thrombosis

Time: Occuring throughout the trial (from randomisation to approximately 3 years post-randomisation)

Description: Pregnancy loss

Measure: Pregnancy loss

Time: Occuring throughout the trial (from randomisation to approximately 3 years post-randomisation)

46 Tazemetostat Expanded Access Program for Adults With Epithelioid Sarcoma

A multicenter, open-label expanded access program to provide access to tazemetostat to Epithelioid Sarcoma (ES) patients in serious need who are otherwise unable to participate in a clinical study or whom access is not available through marketed product in the US.

NCT04225429 Epithelioid Sarcoma Drug: Tazemetostat
MeSH:Sarcoma
HPO:Sarcoma Soft tissue sarcoma

JAK2 V617F) observed in cytogenetic testing and DNA sequencing. --- V617F ---


47 A Prospective, Single-center Clinical Trial of Pegylated Interferon Alfa-2b Versus Interferon Alfa Therapy in the Treatment of Childhood Essential Thrombocythemia

Objectives: To compare the efficacy and safety in children (<18 years) diagnosed as essential thrombocythemia treated with the Pegylated Interferon Alfa-2b vs. Interferon Alfa. Study Design: A prospective, open-label, nonrandomized, single-center clinical trial

NCT04226950 Essential Thrombocytopenia Drug: Recombinant Interferon Alpha Drug: Pegylated interferon alfa-2b
MeSH:Thrombocytopenia Thrombocytosis Thrombocythemia, Essential
HPO:Thrombocytopenia Thrombocytosis

- Platelet count ≥ 450 × 109 / L for more than 6 months(If the patient has JAK2 V617F, CALR or MPL gene mutation, the history may be less than 6 months) - Platelet count ≥ 1000 × 109 / L at screening - The guardians has provided written informed consent prior to enrollment Exclusion Criteria: - Known to meet the criteria for primary myelofibrosis or polycythemia vera by 2016 WHO criteria - Presence of any life-threatening co-morbidity - Secondary thrombocytosis - Familial thrombocytosis - Resistance, or intolerance, or any contraindications to interferon - Interferon is used in the past 1 month before enrollment - Patients with previous or present thrombosis or active bleeding - WBC<4× 109 / L - HGB<110g/L - Poor control of thyroid dysfunction - Patients with a prior malignancy within the last 3 years - Patients with severe cardiac or pulmonary dysfunction - Severe renal damage (creatinine clearance < 30 ml / min) - Severe liver dysfunction (ALT or AST > 2.5×ULN) - Patients diagnosed as diabetes with poor control - Patients with hepatitis B virus, hepatitis C virus replication or HIV infection - Patients with a history of drug / alcohol abuse (within 2 years before the study) - Patients that have participated in other experimental researches within one month before enrollment - History of psychiatric disorder - Any other circumstances that the investigator considers that the patient is not suitable to participate in the trial Inclusion Criteria: - <18 years old - Male or Female - Diagnosis of essential thrombocythemia according to the 2016 WHO criteria. --- V617F ---

- Platelet count ≥ 450 × 109 / L for more than 6 months(If the patient has JAK2 V617F, CALR or MPL gene mutation, the history may be less than 6 months) - Platelet count ≥ 1000 × 109 / L at screening - The guardians has provided written informed consent prior to enrollment Exclusion Criteria: - Known to meet the criteria for primary myelofibrosis or polycythemia vera by 2016 WHO criteria - Presence of any life-threatening co-morbidity - Secondary thrombocytosis - Familial thrombocytosis - Resistance, or intolerance, or any contraindications to interferon - Interferon is used in the past 1 month before enrollment - Patients with previous or present thrombosis or active bleeding - WBC<4× 109 / L - HGB<110g/L - Poor control of thyroid dysfunction - Patients with a prior malignancy within the last 3 years - Patients with severe cardiac or pulmonary dysfunction - Severe renal damage (creatinine clearance < 30 ml / min) - Severe liver dysfunction (ALT or AST > 2.5×ULN) - Patients diagnosed as diabetes with poor control - Patients with hepatitis B virus, hepatitis C virus replication or HIV infection - Patients with a history of drug / alcohol abuse (within 2 years before the study) - Patients that have participated in other experimental researches within one month before enrollment - History of psychiatric disorder - Any other circumstances that the investigator considers that the patient is not suitable to participate in the trial Essential Thrombocytopenia Thrombocytopenia Thrombocytosis Thrombocythemia, Essential This is a prospective, open-label, nonrandomized, single-center clinical trial between Interferon Alfa and Pegylated Interferon Alfa-2b in childhood essential thrombocythemia (<18 years). --- V617F ---

Primary Outcomes

Description: Proportion of subjects with a platelet count <600×109/L after 3 months of treatment will be evaluated.

Measure: Change in platelet count

Time: 3 months

Secondary Outcomes

Description: To compare the complete hematologic response rates between different treatment groups

Measure: The complete hematologic response rates

Time: 3 months

Description: Time to response in platelet count (<600×109/L) between different treatment groups

Measure: Time to response in platelet count

Time: 3 months

Description: To compare the proportion of subjects that display change on key biomarkers of the disease- JAK2V617F, CALR, MPL mutations.

Measure: Impact of therapy on key biomarkers

Time: 12 months

Description: To estimate incidence of major cardiovascular and thrombotic events (defined as cardiovascular death, myocardial infarction, stroke, transient ischemic attack, pulmonary embolism, Budd Chiari syndrome, deep vein thrombosis, and any other clinically relevant thrombotic event) while on active treatment or observation following end of treatment between different treatment groups

Measure: Incidence of major cardiovascular and thrombotic events

Time: 12 months

Description: To estimate incidence of development of myelodysplastic disorders, myelofibrosis, or leukemic transformation between different treatment groups

Measure: Incidence of development of myelodysplastic disorders, myelofibrosis, or leukemic transformation.

Time: 12 months

Description: To compare the proportion of subjects that display change in Myeloproliferative Neoplasm Symptom Assessment Form total symptom score (0-100 scores, higher scores mean a worse outcome) between different treatment groups.

Measure: Change in Myeloproliferative Neoplasm Symptom Assessment Form total symptom score

Time: 3 months

Description: To compare incidence of specific pre-defined toxicity including fatigue, flu-like symptoms, dizziness, injection site necrosis, dyspnea, pain, depression, blurred Vision, insomnia, anorexia, weight Loss, weakness, pruritis, sweating, fever, decreased Libido, hot Flashes, flushing.

Measure: Specific pre-defined toxicity

Time: 12 months

Description: To compare the proportion of subjects that display change on bone marrow histopathology

Measure: Impact of therapy on bone marrow histopathology

Time: 12 months

Description: To compare the proportion of subjects that display change on cytogenetic abnormalities.

Measure: Impact of therapy on cytogenetic abnormalities

Time: 12 months

Description: To compare the incidence of death while on active treatment or observation following end of treatment

Measure: Death while on active treatment or observation following end of treatment

Time: 12 months

48 A Phase I, Open-label Multi-dose Pharmacokinetic and Safety Study of Oral Tazemetostat in Subjects With Moderate and Severe Hepatic Impairment With Advanced Malignancies

This is a phase 1, 2-part, global, multicenter, open-label, PK, safety and tolerability study of oral tazemetostat in subjects with either advanced solid tumors, or hematological malignancies and normal hepatic function or moderate, or severe hepatic impairment.

NCT04241835 Hepatic Impairment Advanced Malignant Solid Tumor Drug: Tazemetostat
MeSH:Liver Diseases
HPO:Abnormality of the liver Decreased liver function Elevated hepatic transaminase

JAK2 V617F) observed in cytogenetic testing and DNA sequencing 12. --- V617F ---

Primary Outcomes

Description: When administered as a single and multi-dose in subjects with advanced malignancies and moderate or severe hepatic impairment, compared with subjects with advanced malignancies and normal hepatic function

Measure: To evaluate the pharmacokinetics (PK) of tazemetostat and its metabolite EPZ 6930, AUC0-t: area under the plasma concentration-time curve from time 0 to the time of the last quantifiable concentration

Time: 0 to 72 hours post dose on Day 1 and Day 15

Description: When administered as a single and multi-dose in subjects with advanced malignancies and moderate or severe hepatic impairment, compared with subjects with advanced malignancies and normal hepatic function

Measure: To evaluate the pharmacokinetics (PK) of tazemetostat and its metabolite EPZ 6930, AUC0-∞: area under the plasma concentration-time curve from time 0 extrapolated to infinity

Time: 0 to 72 hours post dose on Day 1 and Day 15

Description: When administered as a single and multi-dose in subjects with advanced malignancies and moderate or severe hepatic impairment, compared with subjects with advanced malignancies and normal hepatic function

Measure: To evaluate the pharmacokinetics (PK) of tazemetostat and its metabolite EPZ 6930, AUC0-72: area under the plasma concentration-time curve from time 0 to 72 hours post dose

Time: 0 to 72 hours post dose on Day 1 and Day 15

Description: When administered as a single and multi-dose in subjects with advanced malignancies and moderate or severe hepatic impairment, compared with subjects with advanced malignancies and normal hepatic function

Measure: To evaluate the pharmacokinetics (PK) of tazemetostat and its metabolite EPZ 6930, Cmax: observed maximum plasma concentration

Time: 0 to 72 hours post dose on Day 1 and Day 15

Description: When administered as a single and multi-dose in subjects with advanced malignancies and moderate or severe hepatic impairment, compared with subjects with advanced malignancies and normal hepatic function

Measure: To evaluate the pharmacokinetics (PK) of tazemetostat and its metabolite EPZ 6930, Tmax: observed time at Cmax

Time: 0 to 72 hours post dose on Day 1 and Day 15

Description: When administered as a single and multi-dose in subjects with advanced malignancies and moderate or severe hepatic impairment, compared with subjects with advanced malignancies and normal hepatic function

Measure: To evaluate the pharmacokinetics (PK) of tazemetostat and its metabolite EPZ 6930, λz: terminal phase elimination rate constant

Time: 0 to 72 hours post dose on Day 1 and Day 15

Description: When administered as a single and multi-dose in subjects with advanced malignancies and moderate or severe hepatic impairment, compared with subjects with advanced malignancies and normal hepatic function

Measure: To evaluate the pharmacokinetics (PK) of tazemetostat and its metabolite EPZ 6930, t1/2: terminal elimination half-life

Time: 0 to 72 hours post dose on Day 1 and Day 15

Secondary Outcomes

Description: Severity of adverse events experienced by all subjects with at least 1 dose or partial dose of tazemetostat will be evaluated by the Investigator based on the CTCAE, version 5.0

Measure: To evaluate the number of participants with treatment-emergent adverse events as assessed by CTCAE v5.0

Time: Through study completion, an average of 1 year

Description: Investigators will note any new clinically significant findings (e.g., not noted at screening) or changes in intensity of conditions that occurred after the initial tazemetostat administration

Measure: To evaluate the number of abnormalities or changes in intensity of conditions noted during the physical exam

Time: Through study completion, an average of 1 year

Description: Investigators will note any clinically significant changes from baseline in systolic and diastolic blood pressure measured in units of millimeters of mercury (mmHg)

Measure: To evaluate change in blood pressure

Time: Through study completion, an average of 1 year

Description: Investigators will note any clinically significant changes from baseline in heart rate measured in units of beats per minute (BPM)

Measure: To evaluate change in heart rate

Time: Through study completion, an average of 1 year

Description: Investigators will note any clinically significant changes from baseline in body temperature measured in degrees Fahrenheit or Celsius

Measure: To evaluate change in body temperature

Time: Through study completion, an average of 1 year

Description: Investigators will note any changes in concomitant medications from baseline in all subjects with at least 1 dose or partial dose of tazemetostat

Measure: To evaluate changes in concomitant medications

Time: Through study completion, an average of 1 year

Description: Investigators will report any clinically significant changes from baseline in the RR interval (sec) as noted by a 12 lead electrocardiogram (ECG)

Measure: To evaluate change in electrical activity of the heartbeat, RR interval

Time: Through study completion, an average of 1 year

Description: Investigators will report any clinically significant changes from baseline in the PR interval (sec) as noted by a 12 lead electrocardiogram (ECG)

Measure: To evaluate change in electrical activity of the heartbeat, PR interval

Time: Through study completion, an average of 1 year

Description: Investigators will report any clinically significant changes from baseline in the QRS complex (sec) as noted by a 12 lead electrocardiogram (ECG)

Measure: To evaluate change in electrical activity of the heartbeat, QRS complex

Time: Through study completion, an average of 1 year

Description: Investigators will report any clinically significant changes from baseline in the QT interval (sec) as noted by a 12 lead electrocardiogram (ECG)

Measure: To evaluate change in electrical activity of the heartbeat, QT interval

Time: Through study completion, an average of 1 year

Description: Investigators will note any clinically significant changes in hematological clinical laboratory values from baseline in all subjects with at least 1 dose or partial dose of tazemetostat using laboratory reference ranges

Measure: To evaluate changes in clinical laboratory values, hematology

Time: Through study completion, an average of 1 year

Description: Investigators will note any clinically significant changes in serum chemistry clinical laboratory values from baseline in all subjects with at least 1 dose or partial dose of tazemetostat using laboratory reference ranges

Measure: To evaluate changes in clinical laboratory values, serum chemistry

Time: Through study completion, an average of 1 year

Description: Investigators will note any clinically significant changes in urinalysis clinical laboratory values from baseline in all subjects with at least 1 dose or partial dose of tazemetostat using laboratory reference ranges

Measure: To evaluate changes in clinical laboratory values, urinalysis

Time: Through study completion, an average of 1 year


HPO Nodes


HP:0002664: Neoplasm
Genes 1489
WHCR ATP7A PHOX2B KRT17 IL2RG HMGA2 PORCN KRAS TET2 IDH2 FLT3 ERCC4 AR BRCA1 BRCA2 GATA1 TCF4 TCTN3 GPR101 SMAD7 KRT6B PIK3CA KCNJ10 MAP2K2 REST TTC37 MC2R TRPS1 SIX6 ALX4 PIK3CA BRAF TP53 STK11 TSR2 EXT2 EDN1 RNF43 TRNL1 ATM SDHC EXT1 BCL10 BAP1 NF1 OCRL TP53 CHD7 TINF2 ERCC6 NF1 MAFA PMS2 ASXL1 PHOX2B CTNNB1 CR2 RET TCTN3 C11ORF95 PTPN3 PIEZO2 ABCB11 SETBP1 PDCD10 LRP5 LMOD1 MALT1 ASXL1 LZTR1 TINF2 RAD51C RECQL4 MAP2K1 FOXO1 PTCH2 RPS20 FLI1 BMPR1A SMARCAD1 BMPR1A MAP3K8 DNASE1L3 SUFU TP53 FOXP1 PTCH1 PDGFRB ND1 PIK3CA ZSWIM6 SETD2 INS NRAS HBB MEN1 AIP CLCNKB RPS10 HFE COX2 TSC2 DHH CTRC MEN1 EYA1 BRCA1 GINS1 MSH3 GLI2 TRNS1 HABP2 SSX1 SUFU PRKN CD81 TNFSF12 MYH11 KIT VEGFC WWOX H19 SDHD FGF3 TNFRSF1B RMRP XRCC2 HRAS MTM1 EPHB2 PLCD1 NBN CDKN1B TUBB RECQL4 EDNRB VHL ACAN MSH6 CDKN2B DCC TJP2 HRAS CDKN2A VHL REST NKX2-1 ANTXR1 RPL35 DNM2 FGFR3 SNAI2 NLRP1 ACTG2 GNB1 EWSR1 CBFB NSD1 FLCN ERBB2 MLH1 H19 EIF2AK4 RPL10 TMEM107 TRNK RAD54L RAD51C INPP5E NFKB1 CDKN1A KDM6B F13B SLC26A2 TRNS1 RPL26 CYLD H19 PTEN PTPN11 DCLRE1C MPL FLCN NEK1 MITF MSH3 NUTM1 IL7 STAT3 TRNS2 TG ERCC3 MNX1 NRAS MLH3 TSC1 GLI3 CDK4 SDHC NF1 BRCA2 CIB1 ATRX BRCA2 ADAMTS3 ZFPM2 COL2A1 TET2 ZIC2 SLCO2A1 BLM GJA1 MAP3K1 PIK3CA SDHA RTEL1 CDK4 KCNH1 SH2B3 APC ESCO2 FANCC TERT USP9X APC RAD54B NF2 SDHB RPS14 PPP2R1B RPS19 RPL35A MSH2 WRAP53 RASA1 LMNA ACVRL1 POLH SDHB DIS3L2 PIGA GNPTAB CXCR4 MSH2 SLC25A13 BMP2 NNT PSENEN FOXI1 APC IL1RN MITF ACD PTEN MPL RUNX1 ERCC3 ERCC4 DLEC1 CHEK2 BRCA2 JAK2 SBDS BRCA1 SDHD SEMA3D MSH6 HFE TREM2 APC CCDC22 MINPP1 DISP1 FAM20C MAP2K1 ALK BRCA1 STIM1 SLC25A13 RFWD3 HRAS GLI1 TET2 DVL3 COL7A1 HMBS TFAP2A ICOS CALR PTEN UROD DKC1 FDPS LIG4 TXNRD2 SRSF2 ND5 SDHD CHEK2 NRAS BCL6 GPC3 XPC MEN1 ERCC2 AXIN2 MYC RAD51 GBA KIF1B SDHB EXT2 EXT2 NTHL1 SRY RPGRIP1L MPL MTOR CASP8 RB1CC1 IGF2 FANCC ERCC4 WRN PGM3 VHL ING1 PLAG1 WT1 MYLK KLLN PIK3CA G6PC RPS7 MCM4 ANTXR1 POLH BRCA2 DLL1 OGG1 WRN F13A1 SBDS EFL1 TAF15 GLI3 GPC3 KRAS CDKN2B MAPK1 DIS3L2 GPR101 NRTN DKC1 KLLN NSUN2 MAP3K1 ERBB2 PHKG2 SRGAP1 CYLD NBN ALK MAX WT1 ACTB PALB2 TBX18 FIBP CASP10 DVL1 TYR MSH2 RECQL4 PIGL EDN3 WT1 ATP7B RPL27 RET USP8 FGFR2 PDGFRL H19 CCND1 ATM AXIN2 COL7A1 AKT1 TERT MUTYH HOXD13 DICER1 THPO GDF5 CEL SDHB EXT2 SRP72 TERT TRNF TP53 LIN28B APC NPM1 FGFR3 PTEN SMPD1 SLC22A18 SDHC PRDM16 KIT STK11 RPL11 LETM1 CALR SDHC RB1 PIK3CA PLCB4 COL4A5 CASP8 SKI H19 COL1A1 CC2D2A CASP10 GCGR GLI3 PIK3CA RPS29 RSPO1 PTEN MYSM1 BAP1 SRY UBE2T BRCA1 USP8 COL7A1 RNASEH2B KIF1B MN1 RELA SMAD4 VHL SH3KBP1 BCR CD79B SRP54 SRP54 SSX2 CHRNG RPL18 NF1 WWOX RERE LZTS1 WT1 MSH3 TYROBP ASCL1 IKBKG ABCC6 FAH KIT GDNF FANCE TERT BIN1 FANCL KIF11 SDHB WDPCP SLC6A17 TP53 HNF1A KEAP1 POLE HSPA9 SMO PTCH2 PTCH1 PMS1 ELMO2 BCL2 NSD2 EXT1 SRD5A3 STAT6 MVD TERC SF3B1 MNX1 FGFR1 CYSLTR2 POU2AF1 SMARCB1 NOD2 GJB2 SDHC FLT4 KRT9 CDH1 IRF1 SEC23B MYCN MGMT RPL10 RPL5 KIF7 TCF3 KRAS MUTYH TMEM127 KRAS IGH CTSC GNAS CD28 WWOX HNF1A BUB1B MC1R WNT10A CBL WT1 BRAF ADAR GAS1 GTF2E2 SMARCB1 RPS17 PARN TMEM127 BRIP1 SHH SRC GNAI3 STAR GDNF SLC22A18 FOXH1 SNAI2 GPC4 TNFRSF13C KARS1 TBC1D24 BMPR1A TET2 CD27 CASP8 DHCR7 KDSR HNF1A SH3GL1 PNP USB1 TSC2 TRIP13 TMEM67 EDN3 PMS1 PTPN11 GNA11 CREB1 ADA RAG2 PRSS1 KCNQ1 GPR101 PRF1 MTAP FANCA MSH6 TRNQ BRCA2 KRT1 RNASEL POU6F2 ACD SCN9A APC NSD2 INTU BRAF POU6F2 BRCA2 RB1 GTF2H5 PIK3CA FANCM TARS1 BRAF CASR RET VHL GPR143 TRNP GCM2 TMEM231 CPLANE1 RPS15A SOX9 GFI1B EPCAM MEN1 TERT KRAS SDHAF2 NF1 TRIP13 GATA2 SLC26A4 APC MPLKIP SAMD9L IL6 GNAS IGH AKT1 FANCD2 ESR1 SDHA APC MYF6 RASGRP1 SMAD4 MLLT10 LIG4 CPLANE1 BRCA2 MC1R MRE11 DLST SUFU LMO1 SDHB ABCA5 RMRP SDHC NUP214 AKT1 SMARCD2 DLC1 C1S TRNW THPO CHEK2 KIT SLC37A4 BCHE KCNJ11 ARID1B APC2 SAMD9 TMC6 SLX4 TNFRSF13B FGFR1 TRNH RAD21 KCNN3 DKC1 VANGL1 AXIN2 TCOF1 RPS19 SLC26A2 GPR35 CR2 TFAP2A KRAS FGFR3 PRKCD JAK2 EGFR AIP CTNNB1 KCNJ10 FANCI LYST TET2 SLC25A11 TP53 TCTN3 MUTYH ANTXR2 SEMA3C MMP1 AKT1 PDX1 JAK2 TCIRG1 PTCH1 MUC5B EXT1 DNMT3A BMPR1A SERPINA1 FAN1 CDC73 PTCH2 PIK3CA H19 FERMT1 GPC3 RET RET APC PALLD LPP BRD4 GNAS BMPR1B MAPRE2 DICER1 CTC1 TAL1 DICER1 STK11 HRAS GATA1 BCL10 KCNE3 XRCC4 HNF4A BDNF KLF11 SF3B1 MLH3 GNAQ TRPV3 IGLL1 PAX7 CRKL GDNF GATA2 ARL6IP6 ENG PTCH1 NEK9 TSC1 RNF139 ERCC3 PDGFRA IL2RG CTHRC1 WT1 BAP1 ATP7A SRP54 ABCC8 ESCO2 GPC4 OFD1 TNFSF15 APPL1 RNF6 CTSA TNFRSF1B TP53 PHOX2B DCLRE1C DDB2 BCL10 BCR KRT14 ALX3 EVC2 CD70 SMARCB1 AHCY SDHAF2 RAD51D SPINK1 SDHD ATM GABRD WT1 FASLG CTBP1 NOTCH1 NF2 DPM1 ERCC6 STS PHOX2B BUB1 FLT4 L2HGDH LAMC2 NTHL1 STAG3 ENG SDHD CTNNB1 DAXX NRAS MST1 MSTO1 SLC26A4 RAF1 STS FGFR3 EXOC6B VAMP7 NELFA HRAS ANTXR2 LEMD3 TNFSF12 GPC4 MLH1 SMAD4 RAD50 SUFU TRIP13 REST GNAS CBL RHBDF2 ASXL1 SMAD4 TCF4 ERCC6 WT1 BRAF APC TRIM28 TERT DNAJC21 RPL15 PAX3 SETBP1 CDH1 GNAS SMARCB1 AKT1 ASCL1 KRAS NAB2 ERCC5 RECQL4 KRAS DNMT3A EDN3 POLD1 FAM149B1 CDKN1C KRAS TP53 SMARCE1 PTEN PALB2 SEMA4A TEK NBN NHP2 GPC3 ETV6 FGF8 COL11A2 SMAD4 RNASEH2A NRAS MC1R TDGF1 FGFRL1 FGFR1 CTNNB1 IGH DNAJC21 CCND1 RET DIS3L2 DHCR24 CARD14 BRCA2 SQSTM1 NFKB2 TRNQ NDP SFTPA2 PAX4 COL7A1 TP53 RSPRY1 IFNG HMMR PALB2 FAT4 MBTPS2 MDM2 KRAS GNAS C2CD3 POT1 ABL1 WNT5A FANCE ABL1 ICOS SDHD RAD21 NSD1 SOS1 IL12A LIG4 PIK3CA TBXT RAD51 EWSR1 FZD2 FLNA BRCA2 NRAS TWIST1 TET2 TSC1 INHBA CAT CTNNB1 PIGL IRF1 PTCH2 TRNH MLH1 GFI1 CDC73 RET FANCD2 EVC NF2 TNPO3 SOX2 DYNC2H1 HRAS NEK1 CCND1 KRT10 AKT1 KIT PALB2 VHL CYLD IL1B GJC2 MLH1 SDHC FGFR2 CYP2A6 FOXE1 ARMC5 ERCC2 SLC25A11 LAMA3 FLCN BRCA1 BIRC3 MVK TOP2A PDGFB TCF4 RFWD3 ATP6V1B2 GDNF GATA4 CTNNB1 CDKN1B C2CD3 BRCA2 FUZ STK11 AKT1 FGFR2 SHOX TGFBR1 BTK LEMD3 FIBP SF3B1 SUFU PRLR NR5A1 FN1 ERBB2 CD19 RNR1 PTPN11 KIT RAD51 WAS PTEN TGFBR2 RPS24 CYLD RNF113A MYO1H ALX3 JAK2 BLM CTNNB1 CDKN2A PARN SH2B3 POLD1 CHEK2 COX1 KRT1 EXT1 BRAF PRCC MSH2 GATA2 REST NRAS RB1 TINF2 BMPR1A NR4A3 AGGF1 SIX3 RAG1 ND4 COL2A1 CDKN2A SDHD TREX1 WNT10A SEC23B XPA MET TP53 CDKN1B RPS27 PCNA HMBS RPS26 KIT FGFR2 TRIM37 HPGD ERCC5 PAX6 SLX4 PICALM PSAP FCN3 BMPR1A USF3 XPC DNAJC21 KRT16 BUB3 H19-ICR GPC6 STAC3 RPS28 FANCA RNF43 AP2S1 PDGFB DYNC2LI1 CYP11B1 ABCA5 PTCH1 TERF2IP KRAS DYNC2LI1 CDH1 CDC73 TERC SPRED1 PDGFB TRNF MTMR14 MAD2L2 FOXI1 ERCC2 GJB4 KAT6B MSH6 FASLG KRAS SEC23A RUNX1 CD19 WASHC5 KIT HLA-DRB1 WRAP53 FLT3 CEP57 KDR TREX1 TMEM216 PDGFRA ERCC3 KIT NOTCH3 WIPF1 TERC CTLA4 NQO2 CDKN2A RSPO1 STK4 PTPN11 GJB2 KRAS MET SPINK1 PDGFRB RHOH BUB1 ND6 CDKN2C TFE3 EP300 CHIC2 HNF1B NUMA1 BRCA1 SRY FLCN MLH3 SCN10A GNPTAB KRAS NODAL TGFBR2 PPM1D DOCK8 EPAS1 PHOX2B OCA2 KCNQ1OT1 CYP2D6 ITK DICER1 PRKCD ASPSCR1 SUFU IDH1 RUNX1 ATRX FOXC2 MFN2 SAMD9L SCN4A KIF1B DHH POLE VHL POLR1D KCNAB2 BRAF SLC12A3 CARMIL2 ENPP1 NRAS LRRC8A KIT SH2B3 MST1R CEBPA NRAS MRAP TP53 ND5 FH LAMB3 CALR SLC37A4 PERP KLHDC8B FH SFTPC TGIF1 CHEK2 SLC17A9 SLC22A18 TERT CDH23 MDH2 KRT17 PTEN FGFR3 RB1 YY1 ELANE EP300 SPRTN GJB3 XPA IDH2 MAGT1 ATR GNA14 OFD1 IL7R GREM1 ESCO2 HRAS PRKAR1A MMP1 TP53 KRT17 COL14A1 RHBDF2 MPL OFD1 RYR1 IFIH1 SCN11A IDH1 JAK2 WT1 TP53 ARSA LIG4 CCBE1 FANCG KCNH1 ELANE COL18A1 HACE1 NUP214 MYC CD79A AR CDH1 BRIP1 WT1 BCR BUB1B ERCC3 KRIT1 NBN IGF2 FANCF PDGFRA BLNK PCGF2 MSH6 MEN1 FAS BRIP1 PTH1R SIX1 RNF6 BRAF DHCR7 BMPER BUB1B TP53 RET CTLA4 HABP2 ARHGAP26 DLST GCK ERCC2 RAD54L POLE HSPG2 GNA11 ADA SMAD4 BCL10 RB1 STAT1 TAF1 RPS14 BCR IL12RB1 IRF5 TMC8 TNFRSF13B CYP26C1 CALR POT1 MINPP1 POLR1C CD28 ATP7A HNF1B ERCC2 ACVR1 RPL31 VANGL1 TP63 ERCC4 SLC45A2 OFD1 LMX1B PIK3CA ASCC1 TET2 IGF2R BARD1 TUBB IGF2 BTK MSTO1 CIB1 PHB CDKN2A TNFRSF10B KIAA0753 TBX2 FOXE1 EPCAM TNFRSF13C SLC26A2 ATRX MGAT2 SKIV2L CXCR4 PIK3R1 RTEL1 TSC1 HAX1 SDHB PRKAR1A DDB2 GFI1 CDH23 XRCC3 PMVK TP53 PIK3CA GJB2 NF2 KLF6 AR ZSWIM6 SDHB CDC73 PIK3CA CCND1 GJB6 ATM SOS1 NOTCH3 DDX41 TSC2 FLT4 FGFR3 RASA1 GDF2 F5 PMS2 PTEN HBB TSC2 CASP10 ADA2 AIP WT1 LETM1 PNP COMP TRIM28 TP53 PALB2 RAD51C CCL2 CDC73 SH2D1A COX3 ZAP70 PIK3CA CYP11B2 PDGFRB PTPN11 PHOX2B FH KIT HNF4A RNASEH2C MYD88 PDE6D JAG1 TYR SEC23A FH NPM1 PHKA2 DICER1 PIK3CA HFE GNAQ DMRT3 MS4A1 MYH8 VANGL2 SHOX PUF60 GATA2 BAP1 B3GALT6 TRNS2 HRAS HDAC4 FANCG SAMHD1 GATA2 LIG4 AXIN1 TNFRSF4 OPCML PRKN FGFR2 ECM1 TGFBR2 LMNA WDPCP KCNQ1OT1 BLK GCM2 ALX1 NRAS KIT AAGAB FAH MAX RARA NEUROD1 TGFBR2 MYD88 PHF21A IDH1 MLH1 FANCB CPLX1 SMARCA4 EXTL3 AIP TERT BCL10 XIAP IGF2 SASH1 PIK3R1 PTEN NAGS TMC6 NBEAL2 NOP10 JAK2 SDHB MSH2 ECE1 BARD1 APC PMS2 CCM2 JAK2 MMEL1 RET SDHA SDHD IGHM CACNA1S FAS NR0B1 POT1 SPIB TAL2 NF2 CDON WT1 TET2 PTPRJ CD96 TRNL1 DOCK8 DCC MPL GNAQ CREBBP CDKN2A TRNK MSR1 KRT5 PRKAR1A ERBB3
HP:0000822: Hypertension
Genes 418
PDE11A WT1 BBS10 TGFB2 COL1A1 KCTD1 MLX ND5 SCNN1A GPR101 TRNS2 B2M CFI NOTCH3 ALX4 TNFRSF11A GATA5 EXT2 LYZ MUC1 ERCC6 TRNL1 STOX1 COX3 PRKACA MTTP BSCL2 TRNS1 PKD2 KRT8 TRNL1 SLC2A10 CDH23 LEMD3 WT1 TBX1 TRIM28 KCTD1 ND1 CYTB WNK1 ELP1 WDR19 AIP COX2 LOX TGFBR2 GCH1 KRT18 SCNN1B CORIN UFD1 CFH SCNN1G HGD PDE11A COL4A4 BRCA2 NR3C1 CACNA1D LMNA FBN1 ND1 TRNQ VHL JMJD1C CBS RPGRIP1L TGFBR3 POR SDHD TRNS1 ALMS1 CACNA1H TSC1 LRP6 CD2AP FBN1 COX2 DYRK1B SEC24C ADA2 HPSE2 NF1 LDLRAP1 HLA-DRB1 WNK4 ACVRL1 CCND1 FBN1 VHL GLA PDE3A ABCG8 SH2B3 MMP2 SLC52A2 ARMC5 SLC25A11 ERCC4 BBIP1 PAM16 HLA-DPA1 PDE8B ACAT1 LMNA GLA GUCY1A1 MAFB DIS3L2 COL5A2 NKX2-5 CYP11B1 TRNL1 BBS1 FGFR2 LEMD3 MYH7 PPARG FLT1 FN1 COMT MYMK MTRR FOXF1 FN1 CFB MKKS SDHD CYP11B1 MGP SDCCAG8 GJA1 SH2B3 CYP17A1 SUGCT TGFB3 COX1 ANGPTL6 ELN ACTN4 REST HMBS HSD11B2 ND5 SDHD SMAD4 ND4 KCNJ5 LRIG2 NPHP1 TRNQ FMO3 HMBS PTPN22 FGFR2 GBA ELN KIF1B SDHB SLC2A10 COX1 ENG RREB1 CCR6 CYP11B1 PLIN1 CCN2 LMX1B ACTA2 CD46 VHL CACNA1D G6PC PPARG MMP14 NPHP1 WRN APOA1 GP1BB KCNJ5 GPC3 ARHGAP31 RFC2 SMAD3 ND6 MAX SCNN1B ND6 CTLA4 PRTN3 SCNN1G RET PLIN1 USP8 C3 XYLT1 HLA-B XYLT2 FGA TRNC TRNF EPAS1 APOB BBS7 BBS2 BNC2 FOXE3 SDHC IQCB1 NOS3 BBS9 ABCC6 KIF1B COL4A5 H19 EDA2R CYP17A1 ELN PKHD1 HBB ENPP1 LIMK1 TBL2 LZTFL1 CPOX CEP164 USP8 CALR KIF1B SLC37A4 ZMPSTE24 TRNF SERPINA6 TMEM67 VHL JAK2 MDH2 ARMC5 SMARCAL1 FUZ ABCC6 TRNW POU3F4 SDHB NSMCE2 OFD1 MEF2A WT1 KLHL3 XPNPEP3 HIRA GNAS TP53 PDE3A CEP19 BANF1 SPRY2 INVS ADA2 BBS1 FBN1 NOD2 SDHC CLIP2 ERCC8 HSD11B2 NPHP3 TMEM127 HLA-DPB1 TNFRSF11B SDCCAG8 DLST MC4R CEP290 EGFR STAT1 TMEM127 COL3A1 YY1AP1 CAV1 COQ7 INVS ADA2 NOTCH1 TRNK BBS12 NFIX TRIP13 TRPC6 IDUA OFD1 LMX1B WDR35 ENPP1 BMPR2 CEP290 MFAP5 LMNA TRNK MKS1 POU6F2 PKD1 CC2D2A MAT2A MYH11 LDLR RET COL3A1 VHL CCDC28B SCN2B SDHB NOTCH2 ECE1 CDH23 IFT27 TRNV SMAD4 TRIM32 SDHAF2 GNAS MYLK ALMS1 ARL6 TSC2 AIP PRKAR1A WT1 ITGA8 TRIM28 ARVCF GTF2I LARS2 TRNW THPO COX3 CYP11B2 TMEM237 SLC37A4 CYP11B1 IFT172 COL5A1 SMAD6 TRAF3IP1 TMEM70 TRNH FH DNAJB11 NFU1 CFHR1 TBX1 BBS4 KCNJ5 COL4A3 AIP TRNS2 NR3C1 MLXIPL NPHP1 LMNA GUCY1A1 EDA SLC25A11 ACTA2 SCNN1A CFHR3 FMR1 LMNA TTC8 PRKG1 PRKACA TGFBR1 FIG4 ELP1 BAZ1B IL12B MAX IRF5 NPHP4 PHF21A ABCC6 RET WDPCP YY1AP1 CUL3 COL4A3 ADAMTSL4 BBS5 SLC52A3 OSGEP GANAB GNAS CYP21A2 TRNE SDHB ABCB6 VAC14 JAK2 RET SDHA PRKAR1A SDHD PCSK9 GDNF WT1 TET2 NR3C2 SMAD4 CLCN2 ABCG5 MPL C8ORF37 GTF2IRD1 VANGL1 TRNK THBD PRKAR1A
HP:0001873: Thrombocytopenia
Genes 412
CTC1 TBXAS1 RNASEH2C SRP54 MYORG SLC20A2 TET2 MYH9 HLCS CD40LG ERCC6L2 XPR1 CFI IVD SCARB2 UBE2T MPL DOCK6 RBPJ VPS33A EFL1 FASLG STOX1 OCRL TINF2 FOXP3 PRKCD CR2 IRAK1 FCGR2C GBA ACTN1 TINF2 PSMB8 NHEJ1 IL7R TNFSF12 CFI TINF2 LAT NHP2 TBX1 DHFR TERT DNAJC21 VWF SAMHD1 G6PC3 MECOM UROS FASLG CORIN UFD1 GP9 SBDS NHP2 MYSM1 CD81 TNFSF12 CFH RNASEH2A LRBA ARHGEF1 DNAJC21 ITGA2B DCLRE1C XRCC2 HELLPAR NFKB2 NOP10 JMJD1C CD46 PALB2 RAG2 DGUOK FCGR2A WAS POMP KDM6A FANCE ABL1 NHP2 ICOS NFKB1 FCGR2B CA2 HLA-DRB1 FAS RAD51 MMAA STAT3 SEC24C STT3B C1R GBA AGK FANCD2 TET2 VWF RTEL1 ITGB3 ANKRD11 CDC42 TERT FANCC IFNG IRF2BP2 PEPD GUCY1A1 SPATA5 GBA ACD BCOR RUNX1 FLT1 COMT ACP5 GBA ERCC4 MVK CFB SBDS WAS NFKB1 NFKB2 GBA GP1BB MMACHC CDC42 MAP2K1 GATA1 BRCA1 PARN STIM1 RFWD3 KIF15 PCCA PSMB4 DNASE1 TET2 BRAF GATA2 ABCA1 ZBTB16 NUMA1 TINF2 DKC1 ITGB3 UROS TREX1 SALL4 HYOU1 STAT5B GBA MMUT C1QA RAG2 TERC MMUT JAK2 FANCB RREB1 FANCA MPL HOXA11 SLC35A1 ELANE FANCC CD46 SLFN14 MAD2L2 KRAS FOXP3 RUNX1 MMUT CD19 SARS2 SBDS WRAP53 ACAD9 GP1BB EFL1 GFI1B NABP1 TREX1 FARS2 SLC19A2 WIPF1 TERC DKC1 NSUN2 ETV6 NBN USP18 PTPN11 WAS STAT3 SP110 SRC PRF1 EOGT RARA SALL4 HLCS C3 CD109 MYH9 TERT TNFAIP3 MECOM PRF1 SC5D ITGA2 ITK SMPD1 PRKCD ABCD4 FLI1 ATRX NOS3 GATA1 NPM1 TPP2 COL4A5 ANKRD26 MTOR TCN2 TUBB1 PRDX1 WFS1 NRAS PRKAR1A OSTM1 SLC46A1 DGKE FIP1L1 MYSM1 HPS5 UBE2T RNASEH2B PML TBL1XR1 SRP54 SMARCAL1 GNA14 ACAD9 FANCE ESCO2 FANCL RFX5 ATP7B OCLN IFIH1 JAK2 MPIG6B HIRA PSAP LIG4 PHGDH SLC35A1 TERC FANCG SF3B1 KMT2D BRIP1 SLC19A2 ADAMTS13 BCR GATA1 NBN FANCF PSMB9 ALG8 GP9 CD36 TALDO1 FAS PDGFB CLCN7 PCCB CD81 NOTCH1 STIM1 ADAR LMBRD1 STAT1 FYB1 PARN TMEM165 RFXANK TNFRSF13C TNFRSF13B STX11 GALC CALR PNP USB1 CIITA RFXAP ADA FLNA COG1 BTK FANCA NBEAL2 CASP10 FANCM RTEL1 SLC46A1 TNFSF11 ARHGAP31 RBM8A ITGA2B CTLA4 SLC7A7 GFI1B RBM8A COG4 LBR PDGFRB RAG1 SAMD9L RAG1 FANCD2 GBA TFRC RASGRP1 CASP10 GP1BB BRCA2 PNP DLL4 TNFRSF11A STAT4 RAD51C HLA-B ARVCF SH2D1A SMARCD2 LARS2 ZAP70 PTPN22 SMARCAL1 RNASEH2C TREX1 SAMD9 BTNL2 APOE SLX4 NPM1 GATA1 COG6 IKZF1 SLC7A7 DKC1 ARPC1B MS4A1 VPS45 CFHR1 RPS19 PLAU TBX1 PRKCD BLOC1S6 GATA1 FANCG APOE FANCI LYST SAMHD1 TET2 STT3B LIG4 SCARB2 CFHR3 DIAPH1 LYST SNX10 RNASEH2A FLI1 CTLA4 FANCB GP1BB TERT GATA1 PRKACG XIAP SPP1 NBEAL2 CTC1 NOP10 GP1BA MMAB GP1BA FAS CFH VPS33A HOXA11 TALDO1 NIPBL GP1BA MPL MAD2L2 CYCS AP3B1 IFIH1 GP1BA THBD SPATA5 TERT ERBB3 WIPF1
Protein Mutations 2
G20210A V617F
SNP 0
Protein Mutations 1
V617F
SNP 0
Protein Mutations 1
V617F
SNP 0
HP:0000708: Behavioral abnormality
Genes 2208
SMC1A FUS ABCA12 NAA10 SLC18A2 AP1S2 SYNJ1 DNAJC6 UBE3A ST3GAL5 C9ORF72 TCF4 PTS NAA10 RRM2B OTUD6B NFIX C12ORF65 PAH IFT172 EDN1 PIGC HNF1B ZC3H14 SETD5 PSMD12 PROM1 C8ORF37 GRN TUBB3 OCRL PACS1 PRNP SMARCC2 GLUD2 KCNJ2 PEX10 GCDH HADHA CTNNB1 USP9X CNKSR2 B3GALNT2 RPIA ERAP1 MAPT CLTCL1 POLG PRPH2 NDST1 TRNN CSF1R GRIN2A SUFU TSPAN7 PRPF4 DEAF1 TUB NFIX MED13L SCN1A PRMT7 MYO7A PIGG NDUFA6 NDUFS1 NDST1 PRKCG GABRD CRY1 POMK SIM1 MAPT BSCL2 PRPF6 GUCA1A KPTN CNGA1 NDUFS3 SMG9 GNE SLC3A1 LARP7 ARHGEF18 PC ACOX1 FGFR3 PRPF3 PRNP CST6 SRPX2 DNM1 CPLX1 ADAM9 LARP7 MLH1 CLP1 POLG RPL10 FTSJ1 FIG4 TIMM8A GNAT2 FCGR2B KDM6B P2RY11 ACSF3 TRNS1 RPGRIP1 GRIN1 SDHC VPS13A HERC1 CHMP2B SLC9A6 LEPR IGF1 THOC2 ANKRD11 SQSTM1 GNAS GAMT CIB2 EFHC1 LRPPRC MECP2 HSD17B10 EZH2 UPF3B MRPS22 PAK3 WARS2 SCN11A POLH MAPT SNORD115-1 AP4E1 GCH1 PSEN1 PRRT2 TMEM240 PRPS1 ECHS1 C9ORF72 GABRD CHI3L1 MAPT POMT1 CHRNA2 VRK1 ADAT3 CWC27 BCKDK MVK CLN8 C8ORF37 ASPA SCN9A SLC52A2 SPG7 CTNS PDGFRB AP2M1 RERE GATA4 STXBP1 HCN1 SMPD1 HMBS AGTR2 TBX1 SLC6A1 NUMA1 ND5 TAF15 PRPS1 SDHA XPC AGRN PRPH2 ATAD3A ARL6 FTL UBA5 ERCC2 ABCA4 ADAT3 MAGEL2 DMD STAT5B HK1 CEP57 TULP1 SUCLA2 NUS1 SDHB KMT2A TMEM106B EXT2 SRY UROC1 MTOR COL1A2 COX7B HCN1 DEAF1 AP1B1 PROP1 NSDHL GUCA1A MAPT PANK2 HDAC8 COG4 KCTD17 NDUFS7 HNRNPA2B1 CLRN1 VCP GLI3 KCNJ5 NABP1 TKT ESR1 PIEZO2 MAPK1 UQCC2 NSUN2 GNB3 PER3 PROK2 SPR PLXND1 FAT4 GRN PHGDH SYT1 IGF1 HLCS ADH1B ATP13A2 ARL3 NDUFA10 SOD1 IRF6 CYP27A1 GABRA2 DCAF17 KCNA1 PRDM8 SLC26A4 NDUFS1 SLC18A2 USP7 PRODH ND2 SMC3 SDHC VAMP1 TBX1 PLCB4 HLA-DQB1 PCDH19 TRIO GLRA1 PDE4D DHTKD1 CDHR1 PSEN1 MECP2 DNMT1 FUS LMNB1 SHROOM4 SLC46A1 PSAP LHX1 TBX4 APP GK KIF11 RNASEH2B ARL2BP NDUFA9 SLC6A19 GSS ZBTB20 GABRB3 RPS23 ZSWIM6 MFN2 SH3KBP1 CHD2 SCN2A MAPT TBR1 EPG5 NKX2-5 ITPR3 ZNF365 SLC9A7 FUZ ASCL1 IKBKG FANCE ALG13 CSF1R ARSA NPHP1 FAM161A CDH23 SLC6A17 PLCB4 UBE2A SNCB NDE1 ACY1 PPOX GNAS DEPDC5 GUCY2D RBM12 FOXRED1 DNA2 SH2B1 C19ORF12 CHMP2B TOR1A SNCA ARCN1 TBC1D24 PDE10A ACADL NOD2 SDHC NDUFV1 HTRA2 SEC23B SETD5 RPL10 SIK1 NRXN1 KIAA1549 MECP2 GFM1 CFAP410 AARS2 ASXL3 HLA-B MYO7A ARID2 ADAR HTT TBC1D24 MBTPS2 GTF2E2 GNAI3 HECW2 ZNF365 AP4S1 BMPR1A DHCR7 ADA2 SLC25A19 NKX2-5 RLBP1 RPGR ST3GAL5 GLUD1 SQSTM1 ADGRV1 TTI2 CILK1 IL23R PMS1 SLC25A20 KMT5B KCNA2 NEK2 FOXC2 SLC1A2 RPS6KA3 ATXN1 CERKL GPR101 NDUFS8 COQ2 ND1 ADNP MSH6 NDUFA13 RRM2B PGAP3 PGAP1 BRAF GTF2H5 SON PIK3CA TTLL5 ATP6V1A MOG KCNJ11 VHL GPR143 EIF2B3 SDHAF1 AIMP1 CTLA4 FBXO7 EPCAM NDN KCNQ3 UBA5 ABCD1 HESX1 HPRT1 FA2H COASY PEX13 ELOVL5 MPLKIP MBD5 HARS1 UNC119 CDKL5 AKT1 CLN6 TBK1 ATP1A1 PRPF31 MYORG COMT CEP152 PDHA1 ALG1 MC1R TCF4 NDUFB11 TNFRSF11A PCNT OTUD6B HLA-B GTF2I KCNT1 PCDH19 PEX1 EPM2A RTN4IP1 TMEM237 UPF3B PTPN22 SYNGAP1 PRPH2 PPP2R2B TREX1 CLRN1 FGFR1 OPA1 CPOX MFSD8 NLGN3 PSEN1 PPP2R5D CRBN ALG12 LHCGR FGFR3 TMEM231 PTCHD1 USP27X ATXN3 PGAP2 WDR26 GJB1 LYST TRIO RPE65 AVP TANGO2 CHCHD10 DHX30 AHSG LYST ATXN8OS SPATA7 HCRT ADGRV1 WWOX AHR GATAD2B GABRG2 ERLIN2 KPTN CACNA1C ATP6 PDGFRB ZNF711 GNAS PARS2 OTX2 MED12 NONO MED12 SCN2A GRIN1 ARX DCAF17 BPTF GRIN2B MLH3 TMEM231 STX1B ABCA7 FMR1 HTR2A TRPV4 CACNA2D2 MYOD1 ABAT SEMA3E SCN1A SPRY4 RERE PRKAR1B MTHFR MTHFR ARSG PTCHD1 GUCY2D HGSNAT ATRX HLA-DRB1 HLA-A HTT ALS2 KRT86 TRIP12 ATP1A3 RPGR DRD2 PDGFB SLC2A1 FGF12 STXBP1 ACTB BCR NOTCH3 CACNA2D4 SDHD BEST1 ABCC8 FSCN2 GABRD LINS1 CRX ERCC6 PRODH CRB1 NKX2-1 ADH1C FMR1 ESS2 DPF2 IDUA IRAK1 HCFC1 CTSH SACS PDE4D TBK1 MST1 CA4 MSTO1 ATP2A2 ATF6 RAC1 HSD17B10 SQSTM1 PEX19 FTL VCP CIC PDE4D SARDH NAGA DOK7 TCF4 MFRP MCCC1 SCN1B UNC93B1 TAC3 TWIST1 SMARCB1 PDGFRB CLCN4 HTR2A TP63 ITM2B JPH3 MEF2C PSEN2 SAG GDAP2 GNAO1 CEP78 EBP MED12 TK2 PNKP FUS PHIP IL1RAPL1 MERTK HNRNPA2B1 CACNA1A CAMTA1 PGK1 PRNP IQSEC2 PGAP3 SIL1 CTNS NR3C1 RSPRY1 CACNA1G TRNQ NDP TP63 SIN3A VPS53 PRRT2 VPS35 TRIM8 DPYD CC2D2A CHRNA7 SNCA AP3B2 VLDLR PQBP1 ATXN3 SDHD ATP6AP2 IL12A NTRK1 PARK7 CACNA1G AMACR SLC25A20 ITGB6 FGD1 ALMS1 LAMB1 TSC1 NDUFS2 NTRK2 PRPH2 MCOLN1 PRRT2 HDAC8 ADA2 SMC1A FBXO31 DHDDS RET RNF125 SUCLA2 TFAP2B ATXN2 TSHR GLA FGFR2 ARMC5 ERCC2 SLC25A11 C9ORF72 IQSEC2 WDR73 PTPN22 GUCA1B CACNA1A STXBP1 CNGA3 ASAH1 PPOX GRIA3 NAXD KCNJ10 NACC1 DLG3 SPG21 PDE6C GBA HIVEP2 SKI UBTF EXT2 FLT1 COMT GBA ATXN8 MTFMT NAA10 ROM1 KISS1 TGFBR2 CDC42 PIGY CARS2 COX1 SQSTM1 DEAF1 CIZ1 DHPS SEPSECS MEF2C ZBTB16 KIAA1109 SMARCA2 FGD1 ND4 PCNA PTEN TREX1 TSHB NMNAT1 ZNF423 MED25 XPA FKRP CNKSR2 PCNA HMBS RAI1 GJB6 CNGB3 C1QA ELN CBS SLC25A1 AIPL1 CYP27A1 USF3 COX15 XPC NAT8L ARV1 NDUFA11 AP2S1 RAI1 DHX38 PET100 SPRED1 CCR1 EMC1 ERCC2 PRPH DPP6 RLBP1 SLC18A3 GCLC JRK AARS1 BMP4 SETD2 COMT CYP27B1 HTT NDUFV1 BCS1L GJB2 OPN1MW RARA C9ORF72 ALDH18A1 TOR1A DNMT1 HLA-DQB1 CPT1A SLC25A22 PPT1 HNF1B IFT88 KCNJ13 SLC6A3 GLT8D1 ADH1C SDHD GLE1 GJA8 EPAS1 SLC2A1 DRAM2 NLRP3 TRNS2 CDH15 HEXA KDM6A NDUFAF4 RDH12 NGLY1 SNCAIP ATXN7 RTN4R IDH3A PIGT NPM1 ARHGEF6 TMEM106B BCKDHB GLRB CLN8 INSR SIN3A SLC12A3 WFS1 CISD2 GRN TREM2 ST3GAL3 CHST6 USH1G IL6 LIMK1 SNCA ZFYVE26 SYN1 FIP1L1 TBL2 CHMP2B ENTPD1 CLDN16 LSS CPOX NADK2 TWNK PMPCA MSX1 TBL1XR1 TSHR PRNP INPP5E XPR1 KIZ RGS9 ATPAF2 MDH2 PRPF8 MEIS2 MMADHC YY1 USH2A XPA ALG11 SETBP1 ST14 SNCA ATXN10 FKTN KNL1 SLC20A2 SOX2 NEUROD2 PRNP ALG3 NDUFAF2 ATP7B SLC6A8 TMCO1 GUCY2D TMEM240 ARNT2 HIRA GNE ACSL4 SLC25A19 ARSA REV3L CEP250 SNX14 FGF8 APP GLE1 RAD21 GDI1 NDUFAF3 TREM2 DGUOK HARS1 POLG UNC13A GPT2 TMEM106B TRAPPC9 GABRA1 PIGO ERCC3 OPN1MW ANTXR1 RAB11B OPN1MW POC1B NBN PLA2G6 EIF2B2 AHDC1 MED23 SCN1B WDR45 PCCB GJA5 HCRT SGCE SLC45A1 DLST AUTS2 GRIN2A MC4R CCNF RLIM MECP2 TMEM138 TMLHE PANK2 AMER1 DUSP6 IRF5 NDUFAF5 FGFR1 MECP2 TP63 VCP SLC45A2 GABBR2 RAI1 TBX2 NSMF NDUFS4 PER2 CACNA1H TBC1D7 PAH CFAP410 COL3A1 HAX1 RHO ALS2 KRT81 KCNQ2 PIGP SDHB GRIN2D ECE1 LINS1 SLC7A7 FGFR1 CDH23 HAL TK2 GJB2 IQSEC2 SLC45A1 ATRX NEXMIF GJB6 TREM2 TLK2 ALMS1 PMS2 HBB PUS3 PIGV EIF2B1 TSC2 AIP CACNA1A CASR BCORL1 NLGN4X PNP SLC6A17 NDUFS4 CHD1 NPHP4 AFF2 DCTN1 CDC73 WHRN PIGL LHX4 CYP11B2 TGFBI GABRG2 NAA15 TCN2 P4HTM ARG1 HNF4A BCOR TMEM70 NDUFA13 LTBP3 IKZF1 TTC8 MRE11 GNAQ NRL CFAP43 LRRK2 SLITRK1 NDUFA2 CLIP1 ALDH5A1 DNAJC12 RGS9BP ARSA ZEB2 NAGLU PON3 MLXIPL SPAST COL13A1 VAC14 GJB2 PWAR1 GATM RAX2 ATCAY ANK3 POGZ TBP ARX PACS1 TACSTD2 ELP1 BAZ1B CACNA1F MAX PEX1 NDUFV2 SCN8A SETBP1 KDM5C SLC22A5 TUSC3 NDUFS8 PARK7 ACTG1 SPP1 DYM SORL1 PMP22 SDHB MSH2 GPHN NEXMIF MMEL1 RET SDHA ALG11 SYT2 SCN1A IFT140 POGZ RAB39B CHD2 FOXP1 SYT1 SCN3A DBT SPIB NF2 NIPBL CISD2 SMAD4 WDR11 NDUFA1 PCDH15 GTF2IRD1 CREBBP FBLN1 IFIH1 CLTC SH2B1 CRX NDUFS7 MID2 DLAT EPG5 SARS1 PYCR2 RP1 CLDN10 FMN2 ERCC4 ENTPD1 CXORF56 KYNU CSNK1D HLCS SLC12A6 GPR101 APOL2 TWNK GBA MITF KCNT1 KCNB1 CACNA1A SPART NDUFAF3 PDE6H CNTNAP2 KIF14 ATF6 VPS33A TRNL1 APOE LINGO1 CRBN PIKFYVE ALG6 GM2A PPARGC1A PPP2CA CABP4 GBA DISC2 ALKBH8 TACO1 AGA RPS20 DPH1 DYNC1I2 RUNX2 CUL4B ANK3 TRNL2 DCPS PDE10A C9ORF72 TBX1 NR2F1 SLC19A3 ABCA4 B4GALNT1 SCN2A ND1 DOCK6 RHO MAPK8IP3 SAMHD1 PRPH2 ELP1 SETD2 SLC6A5 KMT2E MEN1 HS6ST1 AIP CLCNKB NFASC COX2 AP3D1 AASS ITPA GCH1 UBQLN2 CORIN USH2A SASS6 ATXN3 BCKDHA LRRK2 VEGFC PAK3 SARS1 FBP1 CNNM4 MATR3 C12ORF4 SLC6A4 CHD8 SH2B1 SNRPN TBC1D23 TSHR PLCD1 HLA-DQB1 AIFM1 SPART NPHP4 NKX2-1 SLC7A14 CKAP2L BCL11B CC2D1A CBS ATP5F1A CDHR1 UBE2A LMX1B FIG4 COX7B NSD1 ACADS TBR1 IPW TSHR MEFV FRMPD4 DGCR2 HDC CRX TMEM216 ACSL4 DNMT1 WASHC4 DDX3X KANSL1 FGFR1 STAT3 CYP2R1 SOX5 KRT12 POLG2 SCAPER SEC24C HNRNPA1 AFF2 ALG13 C1R HPSE2 TNFSF4 LTBP2 POMT1 POLG TYROBP TRRAP HCN1 BMP2 TMEM67 PDE6C AVPR2 CACNB4 SDHA SDHB SDHB POMC ZC4H2 TACR3 WDR4 SUOX ATP13A2 ACAT1 ZDHHC9 PNPLA6 NDUFA12 TBCK SYN2 MED25 NDUFV2 BCOR TIMM50 EDNRA MTRR CRADD TSPYL1 NTRK1 SZT2 CDKL5 ATP13A2 VPS13A SDHD TREM2 PDZD7 AFG3L2 TREM2 POLR3A SLC1A4 GNB5 NPC1 MAN1B1 PDE6G SLC25A13 APP DRD5 DNASE1 LARGE1 ELN YWHAG PTEN DCTN1 AVPR2 FGFR3 NDUFAF6 PROM1 TREX1 PIGP PSMD12 SEMA4A NPHP1 DNAJC6 FMO3 HNF1A SNAP25 MUSK ALAD HGSNAT FGF17 TELO2 PEX26 NONO FGF14 CAMTA1 CASK REEP6 DGCR6 RREB1 TWNK SLC2A1 SMARCA2 SLC19A3 GPC4 PSAT1 TARDBP GNAT2 CC2D1A GYS2 SLC33A1 KLLN POMT2 FGF14 STXBP1 GABRG2 DDX3X RAI1 POLH SCN8A HLA-DRB1 SERAC1 TECR LMAN2L AQP2 TICAM1 MAPT GP1BB PSEN1 ATP13A2 CYFIP2 GATAD2B NDUFAF1 PCDH19 MC4R COG5 FRMPD4 TWNK POLA1 AUTS2 AHDC1 PFN1 SHANK3 FOXE3 TYR GNRHR PIGL ATP7B AP1S2 GNRH1 USP8 NFIB GRN CHAT C8ORF37 ZNF81 RSRC1 DGCR8 GABBR2 CXORF56 NEFH DPAGT1 OFD1 TRNF MKRN3-AS1 RBBP8 ACTL6B SLC19A3 APOL4 NEK1 LAS1L NDUFA6 TRAK1 SMPD1 CHD7 CLTC PRDM16 ATXN10 FLI1 COLQ GABRA1 PEX6 ALDH5A1 CNTNAP2 SLC35A3 FOXG1 TSEN54 SKI COASY SLITRK1 FGFR3 HTR2A RIMS1 IL1RAPL1 GPT2 HFE PRKAR1A CTCF CD96 CACNA2D4 ATRX PEX2 USP8 NR2E3 KIF1B HLA-DRB1 UCHL1 PML SCN8A VHL AQP2 POMC DYRK1A PPP2R2B CLCN2 DDC SLC39A4 TARDBP HESX1 RERE NDUFS4 ERF RPGR TYROBP GLS TDP2 EIF2S3 GSN SDHA LEPR WFS1 PIGW CASR MECP2 GLRX5 NDUFS6 COG6 GABRB2 POU2AF1 SMARCB1 RNF13 PSAT1 KLF13 SCN2A CLIP2 MED12 QDPR HSD11B2 PLA2G6 GRIK2 NRXN1 CP VCP FTL PRPH2 GNS GNAI3 RORB GRIA3 TIMMDC1 TMEM127 ATAD1 TBC1D24 PROKR2 CNGA3 UBAC2 SGSH MED13L PNP NFIX MBTPS2 IDUA PLEC MBD5 ST3GAL5 RBPJ NAGS KISS1R NKX2-1 CNNM4 PCSK1 AP1S2 HOXA2 GPR143 NHS COQ2 KDM5B FOXE1 SLC2A1 NGLY1 DNAJC13 ATRX AGTPBP1 TYR MTPAP HTT TOMM40 GABRA2 SLC6A8 LMBRD1 BCOR KCNQ3 TARS1 ATN1 RET PIGV GNAT2 USP27X CHRNA7 CNGB3 DPYD KRAS ANOS1 SDHAF2 GBA TRAF3 POLG GRIN2A DUOX2 HLA-DQB1 GNAS EGF NACC1 RNF216 NALCN PREPL DOCK7 USP9X PPP3CA ARG1 NHLRC2 PDGFB OPN1LW PRKAR1A GBE1 POU1F1 CNGA3 AP4E1 KCNJ1 TRNE SLC39A4 CRYGC TRNW LRAT DNA2 PRKAR1A BCS1L TYR OVOL2 ARFGEF2 STUB1 ARID1B APC2 KMT2A NEFH PACS2 TRNH KMT2C ATP1A3 DAO PINK1 NFU1 PDE6A DDX11 NLRC4 CTSF RAB28 GPR35 TBX1 AP3B2 TYR HCCS KCNJ5 HESX1 RAPSN TTC8 NUBPL SNRPN SH3BP2 MCCC2 FMR1 CCDC47 OPN1LW KCTD17 ITM2B TBC1D24 TIMM8A NFIX AHI1 MAN1B1 RPGRIP1 HIBCH NPAP1 FRRS1L TUBB2B FAN1 CDC73 FAS POLA1 HNRNPA1 TBK1 AIRE RNF168 RPGR CERT1 LIPT1 PON2 NTRK2 LRMDA ELP2 PEX16 MANBA RUSC2 SOX3 GRIN2A TNIK SCN1A SLC25A1 PITPNM3 RPS6KA3 CRKL SURF1 VCP USH1C SCN8A POLG ARSA UBE3A WDR62 TBP NECAP1 CHMP2B TSC1 AGPAT2 TARDBP PEX5 DKK1 PDE11A SOX5 IYD ATP7A PLA2G6 TLR3 IMPA1 XK TNFSF15 CYP27B1 COL17A1 LAS1L OPTN SPG11 DDB2 AVPR2 JPH3 MAK ASH1L AHCY MAPK10 YWHAG APP IL12A MCOLN1 PWRN1 STOX1 KCNV2 GFM2 FLT4 BBS2 L2HGDH SOD1 IGF1R FMR1 PRKACA BSCL2 UCP2 RP9 POLR3A VPS13C KCNA2 STS CPS1 IL12A-AS1 WFS1 SURF1 GUCA1A EIF2B4 HDAC8 GNAS TTC19 POLA1 NLGN3 SRPX2 WNT10A MTPAP KMT2A NSD1 NEUROD2 SLC5A7 ZFYVE26 DNMT3A PITPNM3 SEMA4A UFD1 RARS1 EPM2A C9ORF72 PAX8 RNF135 PODXL RNASEH2A SATB2 C19ORF12 FGFR1 LHX3 TG CFAP43 CSNK2A1 HMGCL IDH3B WDR26 SNCA NDUFB11 JMJD1C MEIS2 RSPRY1 IFNG CHST6 MAN1B1 FCGR2A RPE65 ND3 C9ORF72 THRB SNORD116-1 CTCF HPRT1 GABRA5 SLC18A3 STAG2 ATF6 ZDHHC9 NSD1 NDUFS2 RTTN NUS1 DSG4 CHMP2B GIGYF2 CAT CHD2 CTNNB1 SETD5 PAX8 ATP13A2 PIGL ALDH3A2 IBA57 MAP11 FARS2 PRCD PIGQ PCARE BCAP31 COL1A1 FBP1 CACNA1F TNPO3 SLC25A4 MYT1L SLC2A3 ZNF513 TIMM50 DPYS COL1A1 SYT14 OCRL IDUA GJC2 ZMYND11 LAMB2 SLC52A2 ADNP LEP GABRG2 CUX2 METTL23 PUS7 IRF2BP2 TCF4 SPG21 STAT4 VCP C2CD3 DRAM2 SPATA5 TRNL1 NDUFAF4 EP300 MOG AUH SYP RPS6KA3 RAC1 HCN1 SLC1A3 PRPS1 STRADA ALDH3A2 DLD ATXN2 ADAMTS2 ASPA PDE6B RNF113A HMGCL KDM5C ZNF41 UNC80 SLC24A5 TNFRSF1A STS DNM1 CLP1 KIF15 PCCA SNCA VCP OPHN1 FGFR3 NDP OTC NUP88 DAOA SLC6A19 ABCC8 RGR NKX2-1 PEX14 WARS2 PTS IREB2 LRIG2 HLA-DRB1 NHS NSUN2 ASL ALPL PON1 ERCC5 ECM1 RSRC1 WAC PSAP CUL4B COX10 FRA16E JRK EYS SIGMAR1 PDHA1 PDGFB CYP11B1 SPECC1L NDUFS1 NDUFAF2 GCSH CTNS CACNA1D MBOAT7 NDUFB9 FOXRED1 NECTIN1 PDE6C EIF4G1 RP2 HERC2 HNF1A TREM2 PSEN1 RFC2 HNF4A ERCC3 PDE10A PRDM8 SGCE PUF60 PSEN1 KRAS IDS ND6 NOTCH3 ZBTB11 CNGB3 EZR GLDC WFS1 EP300 PEX3 COX15 NLGN4X HCRT CUX2 VDR GNA11 RAX2 ANG PSEN2 MBTPS2 TH PHOX2B PRPH MICOS13 KRT83 PRF1 NAGA LRAT PMM2 OCA2 FOXC2 KLRC4 ALS2 AIFM1 ZFPM2 PDCD1 GM2A POMGNT1 RPGRIP1 KCNAB2 PRKN CHD7 RDH11 TAT MAB21L1 PIGY PPM1D SHANK3 ARF1 SLC1A2 IMPG2 TBP CEP290 MAPT RBP3 PROKR2 TM4SF20 MPLKIP AP4M1 TAF1 ARMC5 TOPORS DNM1L PCYT1A STX16 NDUFS3 HPS6 HERC2 EEF1A2 GNAO1 TKT NLRP3 TGFBI TWNK DNM1 PRODH SLC5A2 IFIH1 HNRNPH2 ESPN TP53 RAI1 AFF4 GABRA1 FOXP1 IQSEC2 LIG4 MAPT SOBP SHANK3 ZNF408 SLC35C1 STAG1 ATP1A3 PSAP GRIA4 SIM1 TBK1 MAPT DCTN1 CACNA1A ALDH18A1 NIPBL NR2E3 ST3GAL3 PCGF2 TMEM126B LIAS TPO APP KLHL7 DHCR7 SEMA4A CNKSR2 CNGB1 NSDHL POLR3B VAPB ERCC2 DEAF1 PIGH HSPG2 DBH ADCY5 ABCA7 EHMT1 AGBL5 TAF1 SLC1A4 IL12RB1 CFAP410 CEP78 GABRB3 C4A NR4A2 ALS2 RDH5 SYNGAP1 PTPN22 CA4 TRHR WDR45 NHLRC1 SLC2A1 SLC35A3 CLCN4 ADSL EYS SLC1A3 PDE6H MAGEL2 ALG13 EHMT1 ERBB4 MSTO1 SYN1 MYO9A EEF1A2 AP4B1 EDC3 FLII TMEM237 SPR NOP56 MKRN3 MGAT2 PRNP CLN3 OPN1LW SLC12A3 POLG SLC46A1 CACNA1B DLG3 SCN1B PRNP DDB2 TBX1 TLR4 TINF2 PIK3CA NPC2 NDUFB10 TRNS1 NDUFAF5 COG4 SMAD4 ZNF408 MCTP2 SLC5A5 TCF20 C12ORF4 IL10 EIF2B5 SNX14 NALCN PRSS12 TSC2 PEX11B BRAT1 COA8 SEPTIN9 CLCN4 FBXO11 CDHR1 DNAJC5 MAPT FOXP2 STAT4 ARVCF FTSJ1 DUOXA2 GBA RORA COX3 TFAP2B ASPM CDKL5 RNASEH2C TREX1 TYR TTI2 GPHN NDUFA4 FH SLC7A7 TCF12 NLRP1 MBOAT7 EEF1A2 GJB6 PUF60 DHDDS SLC16A2 DMPK SLC25A12 TRNS2 HRAS HDAC4 SAMHD1 SLC24A5 NMNAT1 FGFR2 AP4M1 STAG2 SEMA4A TUBB2B FLCN SLC9A6 MAOA GABRG2 ATXN8OS PSEN1 EIF2S3 HNMT SNRNP200 ELOVL1 SLC25A15 PINK1 PRNP SLC13A5 SCN9A EXTL3 KAT6B DRD4 TNF SATB2 SLC52A3 DRD3 NPHP3 NAGS DCHS1 EPHA4 IQSEC1 PNPLA6 NOTCH2NLC SDHD MAOA LAMB2 PANK2 IMPDH1 PNKP NDUFB3 ANXA11 AIFM1 ALS2 MECP2 LEP NHLRC1 EML1 ASS1 CHCHD10 ITPR1 AMT CNNM2 PEX12 AP3B1 MED12 VANGL1 DCTN1
Protein Mutations 1
V617F
SNP 0
HP:0002104: Apnea
Genes 330
TRNF NDUFS7 DKK1 MKRN3-AS1 KIAA0586 CSPP1 PHOX2B OPA1 PRPH CTSD NDUFS1 USP7 CEP104 NGLY1 CPT2 COLQ GPR101 SLC2A1 PIGT VAMP1 TMEM237 PLCB4 EDN1 NDUFAF3 SKI FGFR3 MECP2 PWRN1 TRNL1 CHAT CC2D2A CISD2 RBM10 BUB1 BRAT1 SOD1 SCO2 PLAA PHOX2B MKS1 IDUA RET ND4 NADK2 SCN4A NDUFA9 GBA SLC6A9 CEP290 WFS1 TACO1 INPP5E DPH1 TCTN1 CEP290 RUNX2 CPLANE1 NDUFV1 MKS1 AMER1 TRNK KIAA0586 ASCL1 OFD1 TCF4 GDNF PIBF1 MCCC1 HERC2 TCTN2 GSN ND1 NDUFAF2 HSPD1 NEB GPHN PLCB4 PRMT7 CSPP1 TWIST1 SLC5A7 CLCN7 ASCL1 SFTPB COX2 GNE FOXRED1 AFF4 FAM149B1 DNA2 SURF1 ARCN1 TMEM67 NPHP1 CRYAB HTRA2 PEX5 NDUFS3 KIAA0556 KIF7 TMEM216 FBP1 GNE NDUFA11 ND3 PCGF2 LARP7 MYO9A LIAS AHDC1 FGFR3 TRNQ BUB1B PCCB SRPX2 RPGRIP1L ATP5F1A HSPG2 NDUFB8 CC2D2A GNAI3 TMEM138 SNORD116-1 CEP41 TBR1 IPW GNAI3 PTF1A TMEM107 PLPBP KCNQ2 INPP5E INPP5E TSPYL1 TMEM216 NFIX TRNS1 TMEM67 SLC25A20 NDUFS8 NEK1 NDUFS2 CTNNB1 FBN1 MAGEL2 COQ2 PCK1 FARS2 GABBR2 GPR101 COQ2 NGLY1 GLRA1 NDUFA13 MYO9A TRNL1 KIAA0753 RET FBP1 RNF125 PSAP TMEM237 NDUFS4 MKRN3 BRAF CHRNE PRNP LIFR ATN1 IDUA COL3A1 LAMB2 BMP2 FGFR2 SLC52A2 TECPR2 GABRG2 NDUFA2 TNFSF11 SDHA ZC4H2 NDUFAF2 NDN TCF4 NDUFAF5 B9D1 ND1 TCIRG1 CEP120 C2CD3 TRIP13 SNORD115-1 ARL13B CSPP1 NDUFA12 NACC1 BRAT1 ND6 SNX10 NALCN ECHS1 RARS2 BTD ACY1 SLC6A5 SKI NDUFV2 ND2 SLC5A7 AIP RPS6KA3 PDHA1 CPLANE1 PRPS1 GBA ND5 TSPYL1 DCTN1 MTFMT TRNW COX3 GLUL TSEN54 PLAA LIFR HMGCL DNA2 P4HTM CEP120 UNC80 PDE6D PCCA NDUFS2 SCN2A NDUFA4 TRNH D2HGDH LTBP3 COX1 SCN5A FGFR3 AHI1 NDUFA2 FGFR3 ND5 NDUFAF6 ATP6 ND4 AGRN ZNF423 TRNS2 HRAS SNAP25 COL13A1 RPGRIP1L ALPL MAGEL2 CEP57 NONO TCTN3 SNRPN SH3BP2 TECPR2 SLC25A1 KIAA0586 PWAR1 FGFR2 CCDC47 BUB3 POGZ SLC19A3 FLCN RPGRIP1L KIF5A PDHA1 NPAP1 NDUFS1 PEX13 PET100 ABCA3 TMEM237 NDUFS8 RAI1 ECHS1 TOE1 AHI1 SLC52A3 TRNV SLC18A3 SOX9 SLC18A3 CEP57 TMEM216 DST LIPT1 MECP2 CEP41 ARL3 SYT2 KAT6B GRIN2A NDUFV1 AHDC1 IDS HYLS1 SYT1 ND6 TMEM231 SYT1 SLC39A8 AHI1 SURF1 ACADSB EDN3 TRPV4 INPP5E BTD EP300 RERE ARMC9 ARMC9 CHAT COX15 PIBF1 NDUFA10 CREBBP SCN4A NEFH DPAGT1 TRNW
HP:0001392: Abnormality of the liver
Genes 1390
SRD5A3 WHCR CSPP1 ATP7A IL2RG MYORG NR1H4 IL17RC PEX1 B9D1 CD40LG TCF4 INSR SKIV2L RRM2B TTC37 HPD PEX11B NEU1 DOCK6 RBPJ CLEC7A RNF43 PSAP HNF1B HSD3B7 VPS33A LIPT1 EFL1 SDHC CEP290 TGFB1 CHD7 TINF2 FOXP3 PRKCD ALG6 CR2 C11ORF95 PTPN3 LACC1 ABCB11 KRT8 PLEKHM1 SETBP1 CASK PEX10 PKLR HADHA GBA TINF2 SLC4A1 AGA HADHA RPS20 IL7R TCIRG1 FLI1 GLIS3 CFI UQCRC2 IL17RA DNASE1L3 TRNK MRPL3 LCAT MPV17 TBX1 PEX11B TMEM70 KLF1 INS HBB NDUFS1 KMT2E HFE FASTKD2 ALG9 CTRC KRT18 SOS1 EIF2AK3 WDR35 PYGL FASLG CORIN BSCL2 ALG8 CD81 TNFSF12 RHAG FAN1 NCF2 LMNB2 ACADM H19 FBP1 GNE TNFRSF1B ND3 RMRP XRCC2 PC SLC29A3 ACOX1 COG8 RHAG SLC30A10 CDKN2B TJP2 COX6B1 SMPD1 SPTB WDR60 CBS RPGRIP1 SRD5A3 RPGRIP1L MLH1 ATP8B1 TRIM37 TMEM67 NHP2 SLC11A2 INPP5E NFKB1 CDKN1A HADHA CA2 ACSF3 H19 POLD1 AP1S1 F5 LYRM4 SLC2A1 KRT6B PCK1 POLG2 SEC24C HNRNPA1 DHDDS ALG13 AKT2 APOA1 B3GLCT GBA MPC1 KRT16 TET2 LDLRAP1 SLCO2A1 ACVRL1 KCNH1 PIGS APC TMEM67 USP9X CAV1 IFT122 TNFSF11 LRPPRC POMC BBIP1 B9D2 PEPD ACAT1 LMNA SPTA1 ACVRL1 GATA6 LPL DIS3L2 GNPTAB PHKG2 TNFRSF1A IDUA KRIT1 SLC25A13 BMP2 GPI SNX10 AKR1D1 BBS1 MED25 APC MAN2B1 MTRR ALAS2 ERCC4 PEX14 PNPLA2 PIEZO1 MVK PEX16 BRCA2 BCS1L SBDS TUFM VPS13A IFT140 SDCCAG8 GBA AMACR PFKM HFE PTPN11 APC INSR NPC1 CTNS TSFM PEX5 IFT172 BRCA1 IFT80 ERCC4 SLC25A13 RFWD3 PSMB4 HBA2 WDR19 ALDOA ELN ATP8B1 JAK2 MPI SMPD1 HMBS TBX1 ABCA1 ICOS UROD DCTN4 DKC1 LIG4 NBAS PEX3 TRNE ACADVL SDHA GPC3 TREX1 PEX10 CAV1 MYC HADHB HGSNAT GBA MMUT PEX26 RAB27A PEX12 PMM2 RREB1 RPGRIP1L CLDN1 MPL UQCRB MRPS16 UGT1A1 WDPCP FANCC HJV PEX13 CARS2 AP1B1 GYS2 PROP1 MRPS7 PEX2 PEPD G6PC MCM4 MMUT COG4 ABCC2 PEX26 HLA-DRB1 PPARG NDUFS7 NPHP1 VIPAS39 ABHD5 SBDS PIGA APOA1 GP1BB EFL1 VCP SLC17A5 COX4I2 GPD1 GPC3 CA2 DDRGK1 NDUFAF1 COG5 PHKA2 TWNK PHKG2 KRAS CYBC1 USP18 TMEM231 SP110 PEX1 CIDEC EOGT MSH2 IL2RB SLC39A8 MEFV TANGO2 FERMT3 ATP7B PDGFRL ATM TTC21B TERT HMGCS2 HOXD13 ENG MYH9 CEL LONP1 FGA SLCO1B3 CYP27A1 MIF DPAGT1 TERT TF CLCN7 TMEM107 CD247 NDUFA6 TRAF3IP2 DNAJC19 APOB SMPD1 CEP290 PRDM16 STK11 ND2 LETM1 ITCH LPIN2 PEX6 CASR SLCO1B1 POLG TPP2 IFT172 ZAP70 CNTNAP2 SKI H19 CYP19A1 ABCG8 PKHD1 CC2D2A CTCF GCGR CD96 PIK3CA GAA PSAP LHX1 PEX2 UBE2T PSAP ND4 PEX6 SLC29A3 TACO1 RNASEH2B POLG2 ZMPSTE24 RELA TMEM67 PCK2 POMC CD79B LBR SRP54 AKR1D1 SLC39A4 SC5D RPGRIP1L PLPBP SPTA1 RERE NKX2-5 NDUFS4 FAH CC2D2A COX20 GATA6 TERT TRAPPC11 ARSA HBA1 FANCL RFX5 PEX14 HNF1A FUCA1 OCLN DCDC2 TPI1 GUCY2D PSAP NSD2 PIK3C2A STAT6 CEP19 TERC SF3B1 NDUFS6 COG6 ACADL HADH RRAS POU2AF1 NOD2 CLIP2 NDUFV1 ERCC8 PEX5 HBB NPHP3 CAVIN1 PSMB9 RFXAP TCF3 NRXN1 FECH CP GFM1 GYPC CTSC SLCO1B3 CD28 NOTCH2 GNS HAMP CDAN1 CEP120 C1QBP ADAR CEP290 POLG2 HBG2 TIMMDC1 PARN EIF2AK3 RHAG ALDOB TNFRSF13C IL21R TRMT10C RFXANK BMPR1A STX11 CD27 CASP8 DHCR7 SGSH SLC25A19 HNF1A CSPP1 BBS12 RFT1 NLRP3 USB1 TRIP13 TMEM67 IDUA PMS1 CPT2 SLC25A20 RFXAP ADA HSD3B7 RAG2 WDR35 RMRP PCSK1 PRSS1 KCNQ1 FDX2 NDUFS8 CEP290 ND1 CCDC115 NGLY1 LMNA WDR60 FANCA MSH6 TMPRSS6 POU6F2 IL2RG NCF1 NSD2 STEAP3 INTU ADAMTSL2 SON PIK3CA FANCM LDLR KCNJ11 CLDN1 DLD TNFSF11 ABCA1 PIEZO1 ARHGAP31 RBM8A SLC13A5 NOTCH2 PEX6 EPCAM MEN1 KRAS TRIM32 PEX14 DUOX2 PDGFRB HBB UBR1 PEX13 RAG1 ABCC2 CIDEC TBX19 SDHA APC ARL6 XIAP RASGRP1 TCIRG1 SMAD4 NHLRC2 ALG1 BRCA2 POU1F1 ND5 DLL4 NDUFB11 TNFRSF11A HLA-B GTF2I EPB42 CTRC SLC22A5 PEX1 IL2RA RNU4ATAC SLC37A4 BCS1L BCHE KCNJ11 LMNA TFR2 TREX1 GUSB BTNL2 TRAF3IP1 SLX4 TNFRSF13B CYBA UGT1A1 DNAJB11 KCNN3 DKC1 PEX3 VPS45 APOE SCO1 GPR35 TBX1 CR2 ATP6 PRKCD JAK2 CTNNB1 HESX1 NPHP1 LMNA APOE FANCI LYST TET2 PEX13 TP53 NUBPL TRAF3IP1 CCDC47 PDX1 TANGO2 TTC8 LYST AP1B1 RNASEH2A MUC5B IL17F SERPINA1 PEX6 FAN1 PKLR NPHP3 C1S NPHP4 FBN1 UGT1A1 KRT18 CYP7B1 CIITA GPC3 HADH HJV KPTN XYLT1 PEX16 CYP7B1 APC UGT1A1 CPT1A BBS5 PALLD CTC1 NSMCE2 FADD TTC7A BCS1L FARSB DDRGK1 NPHP3 IFNGR1 CFTR PEX16 XRCC4 FGFR2 HNF4A MPV17 GALT SLC25A1 ACADM ALG9 KLF11 MLH3 CLCN7 IGLL1 UGT1A1 CLPB GBA TALDO1 KRT8 BTD ARSA PLAGL1 HK1 ALG2 DPM2 C8ORF37 DMD SLC40A1 SLC26A4 G6PD GALK1 AGPAT2 PEX5 PDGFRA SLC40A1 IL2RG IYD KLF1 WT1 BBS10 ATP7A RNASEH2C SRP54 ABCC8 PEX13 DYNC2H1 SLC20A2 ESCO2 GPC4 PAX8 CLCA4 C4B PCCB COG8 ABCB4 XK TNFSF15 APPL1 HEXB CPT2 PEX6 XPR1 CTSA IER3IP1 ACOX1 B2M TNFRSF1B YARS2 DCLRE1C HYMAI SCARB2 CD70 BSCL2 AHCY LYZ SPINK1 SOX10 IDUA ABCC8 GABRD WT1 FASLG ERCC6 FOXF1 STOX1 TBX19 CTBP1 DPM1 ATP8B1 PEX12 BSCL2 ENG UCP2 PKD2 RNU4ATAC FGFR2 SCYL1 COG7 DAXX MST1 PSMB8 BLVRA GPIHBP1 HADHA NELFA SURF1 TNFSF12 GPC4 SMAD4 PEX19 GNAS TRMU COX10 ALAS2 NAGA DOLK PEX2 NHP2 MCCC1 TRIM28 DHFR DNAJC21 CTSK SETBP1 PEX3 WDR19 NAB2 DPM3 RECQL4 MVK RFT1 LZTR1 G6PC3 ANK1 CDKN1C STN1 KRAS PALB2 SEMA4A EPB42 UFD1 NHP2 LIPE RIT1 RNASEH2A DCDC2 FGFRL1 HNRNPA2B1 STEAP3 PARS2 DNAJC21 LHX3 TG DCLRE1C HMGCL DIS3L2 FOS VPS33B TMEM199 BRCA2 RBCK1 HELLPAR NFKB2 CASR LMNA NOP10 SFTPA2 XRCC4 PAX4 JMJD1C RAF1 CD46 PALB2 RAG2 DGUOK COX8A ND3 CFTR FANCE ICOS RMND1 RFX6 NDUFS7 IL12A LIG4 KIF23 SCYL1 NDUFS2 HLA-DRB1 FAS NCF1 ARSB MKS1 SLC25A20 RAD51 EWSR1 ALMS1 GALE PEX26 TSC1 MMAA SLC4A1 KRT17 PAX8 ABCA1 PEX19 ZIC3 ADA2 EPB41 SERPINA1 CFTR NPHP3 MOGS FBP1 FANCD2 LBR TNPO3 SLC25A4 ATP11C LRP5 TSHR NEK1 CCND1 MET VHL ABCG8 IDUA TRMU WDR34 ABCB4 SPECC1L ERCC4 DYNC2H1 MKS1 GLB1 ASAH1 ATP6V1B2 SLC25A13 NEUROG3 ND1 TCIRG1 HSD17B4 CDKN1B LRP5 STK11 IL1RN COG1 NRAS ND6 GBA BTK AMACR ETFA ND2 PPARG FLT1 COMT DGUOK CD19 PRPS1 GBA HADHB POU1F1 DLD MKKS SEC63 TRMT5 TGFBR2 GBA HMGCL SLC4A1 HBB TRNS1 MRPL44 DDOST PCCA ABCB4 LIPA ABCD3 LIPE GATA2 BTK REST SUMF1 FUCA1 PEX3 AGGF1 PEX14 RAG1 UROS ANKS6 KCNN4 SDHD PTEN TREX1 TSHB APOC2 SLC2A1 GLB1 CDKN1B CPA1 ASL HMBS IL36RN KIT INPPL1 HYOU1 TRIM37 HPGD ELN PEX19 TGFB1 CBS CYP27A1 RAG2 TGFB1 PSAP MMUT COX10 COX15 KCNN4 CYBB HMOX1 H19-ICR NDUFA11 PLIN1 DYNC2LI1 NDUFAF2 TERC MAD2L2 NDUFB9 MSH6 KRAS CD3E FOXRED1 CD19 HBG2 TRNV PCCA HNF1A KIT WRAP53 GCLC C8ORF37 COX14 ACAD9 GNMT TREX1 ATP6AP1 RFC2 HNF4A CD3D SLC25A13 PEX12 TMEM67 TERC CTLA4 TRNN CDKN2A LMNA BCS1L IDS MET IL7R CDKN2C TSHR PLIN1 PET100 GPC1 CPT1A HNF1B NLRC4 BRCA1 PEX3 DPM3 JAM3 GNPTAB TRNW DLL4 JAK3 IFT140 MICOS13 DNAJC19 PNPLA2 PRF1 NAGA CEP55 SC5D PIGM PMM2 GALT BBS7 HLA-DRB1 ITK PRKCD NDUFAF4 BBS2 LIPA NGLY1 IDUA HAVCR2 IQCB1 MFN2 NOS3 SUMF1 BBS9 NDUFAF1 MYBPC3 SLC30A10 PEX26 PEX10 EPB41 KCNAB2 ACADVL GUSB CPT2 AGPAT2 HBB POLG ETFDH NRAS PEX16 GLRX5 LRRC8A COA8 OSTM1 LIMK1 NLRP3 TBL2 LZTFL1 FH CPOX CEP164 PNPLA6 SLC37A4 SPTB ABCB11 TWNK SFTPC ALDH7A1 INPP5E HBA1 ATPAF2 SHPK ICOS SLCO1B1 FCGR2A SPRTN FBXL4 MARS1 ALG11 TMEM67 KIAA0586 CPT2 IL7R NDUFS3 RASA2 ACAD9 AUH TKT ATP7B NSMCE2 RHBDF2 OFD1 CLCN7 IFIH1 JAK2 WT1 DZIP1L HIRA DPM2 PRKCSH GNE NCF2 SLC25A19 ARSA TFAM COX15 COG2 CEP83 SNX14 KCNH1 NEK8 BBS1 NDUFAF3 PSAP CD79A BRIP1 SEC63 ADAMTS13 ANTXR1 IGF2 FANCF PDGFRA BLNK ALG8 WDR19 PEX10 TMEM126B TPO TALDO1 FAS PDGFB CLCN7 DHCR7 BMPER IFT172 PCCB TP53 CTLA4 SDCCAG8 GCK NOTCH1 PTRH2 ADA NCF4 SLC35A2 SMAD4 STAT1 TTC37 GDF2 TMEM165 IL12RB1 RFXANK IRF5 NDUFAF5 TNFRSF13B PEX12 TRAPPC11 INVS CALR TRHR SPINK1 CD28 MECP2 SEC23B AGL ABCG8 CIITA WDR19 HBG1 GALNS OFD1 TMEM216 CC2D2A ABHD5 PEX2 LARS1 TTC21B GCDH RPGRIP1L STX1A IGF2R IGF2 BTK LIPA TRNL1 MKS1 COG2 SLC25A15 PKD1 CC2D2A TNFRSF13C SLC4A1 SP110 CASP10 ATRX PKHD1 PRKCSH HNF1B SKIV2L SOS2 KRT6A PIK3R1 TARS2 RRAS2 RTEL1 POLG TCTN2 CD55 GBE1 CCDC28B PRKAR1A SLC7A7 CYTB IFT27 NPC2 BSCL2 NDUFB10 COG4 SDHB SAA1 AP3D1 ITCH SLC5A5 PRSS1 SAR1B PEX11B RAG1 GDF2 ALMS1 F5 PMS2 COA8 GBA HBB TSC2 CASP10 CASR EXTL3 LETM1 NDUFS4 HAMP DYNC2LI1 TRIM28 PHKB PSMB8 RAD51C AKT2 ARVCF SH2D1A DUOXA2 ZAP70 LHX4 C15ORF41 RNU4ATAC POLR3A HNF4A AGA RNASEH2C TYMP IFT172 MYD88 JAG1 APOE LTBP3 ASAH1 NPM1 COG6 IKZF1 PHKA2 SLC7A7 CYBA HFE GLB1 NLRP1 CBL RFX5 MS4A1 HNF4A BBS4 ARSA NAGLU BTNL2 FAM111B PLEKHM1 DMPK AIRE BPGM MLXIPL FANCG EARS2 WDR35 SAMHD1 PGM1 AP1S1 AXIN1 LMNA ALDOB ADK PRSS2 KCNQ1OT1 HBA2 CAVIN1 BLK SNX10 PPARG RRM2B CYP7A1 IFT80 BAZ1B CTLA4 FAH SLC25A15 NEUROD1 PEX1 NDUFV2 PEX5 SLC22A5 MLH1 FANCB WDR34 CPLX1 IARS1 WDPCP EXTL3 TMEM216 TERT BOLA3 XIAP MYRF CTNNB1 CYBB SPTB GANAB NPHP3 NAGS CYC1 TTC7A NOP10 MSH2 APC UNC13D TRNW JAK2 MMEL1 MMAB IGHM MPI IFT43 MRAS NDUFB3 PCSK9 FAS STXBP2 ANK1 CFH PTPRC LBR SPIB VPS33A IL6 TET2 ASS1 NDUFA1 FECH ABCG5 MPL GTF2IRD1 PEX12 AP3B1 IFIH1 ETFB PEX19 PEX1 PRKAR1A ERBB3 A2ML1
Protein Mutations 4
C282Y G20210A H63D I148M
HP:0001903: Anemia
Genes 730
SRD5A3 NDUFS7 CTC1 KLF1 TBXAS1 SRP54 IL2RG TET2 RPS27 AMMECR1 SLC25A38 MLX CD40LG ERCC6L2 RPS24 YARS2 CFI DCLRE1C SCARB2 ALX4 UBE2T MPL TSR2 EXT2 MUC1 XRCC4 VPS33A FAM111A EFL1 WT1 FASLG TSR2 PNPO RPS29 SDHC BCL10 LAMC2 OCRL CHD7 TINF2 FOXP3 NT5C3A ENG PRKCD CR2 PLEKHM1 CASK IRAK1 DAXX MALT1 PKLR GBA TINF2 PSMB8 ZBTB20 SLC4A1 WFS1 NHEJ1 TACO1 RPL35A TCIRG1 FLI1 BMPR1A TNFSF12 CFI BMPR1A SMAD4 LAT ACVR1 COX10 ALAS2 MTRR FOXP1 LYRM7 DHFR TERT DNAJC21 RPL15 HBA1 CTSK KLF1 PGK1 HBB HBB CLCNKB RPS10 MTHFD1 FASTKD2 G6PC3 AASS BRCA1 ANK1 UROS EPB42 TEK FASLG SBDS NHP2 MYSM1 CD81 TNFSF12 RHAG CFH SMAD4 HBB LRBA NDUFS3 STEAP3 CDCA7 DNAJC21 CP DCLRE1C HMGCL RMRP XRCC2 RAG1 PGK1 F8 HELLPAR NFKB2 RECQL4 NPHP4 EPO RHAG COX6B1 REN COL7A1 SPTB RPL35 CD46 PALB2 RAG2 NDUFB8 SRD5A3 FTCD FCGR2A COX8A HPRT1 PTF1A WAS TBCE SPTA1 KDM6A FANCE ICOS SLC11A2 CLPX NFKB1 FCGR2B CA2 KIF23 HLA-DRB1 FAS ALAD RPL26 RAD51 EWSR1 MMAA SLC4A1 CAT NDUFS2 STAT3 SLC2A1 ADA2 EPB41 C1R APOA1 GBA ATRX FANCD2 TET2 UMPS SLCO2A1 ATP11C ACVRL1 KRT14 RTEL1 RPL5 ITGB3 GLA TMEM67 FANCC HBA2 DNMT3B HBA1 LAMA3 TNFSF11 BIRC3 SDHA RPS14 IFNG HAVCR2 IRF2BP2 RPS19 RPL35A PEPD TCIRG1 SPTA1 ACVRL1 GLA PIGA FANCL YARS2 STK11 NDUFA12 GPI SNX10 ECHS1 THRA RPL27 APC NDUFV2 ACD BCOR MTRR GBA ALAS2 ERCC4 PIEZO1 RPL26 HBG1 MVK AK1 STAT1 MTFMT CFB SBDS WAS NFKB1 AK2 IFT140 PFKM MMACHC RPS24 RNF113A HMGCL UMPS SLC4A1 HBB GATA1 BRCA1 TRNS1 PARN ZBTB24 STIM1 RFWD3 KIF15 PCCA HBA1 NDUFS2 ITGB4 PSMB4 DNASE1 HBA2 ABCD3 ALDOA RPS28 TET2 COL7A1 ACTN4 SMPD1 RPS17 ABCB7 ABCA1 ZBTB16 NUMA1 TINF2 DKC1 BMPR1A LIG4 RPS7 AGGF1 NDUFAF6 RAG1 UROS KCNN4 IREB2 NPHP1 RPL15 SLC2A1 FMO3 RPS27 RPS26 KIT ALPL HYOU1 STAT5B HPGD GBA C1QA TGFB1 SLX4 RAG2 TERC BMPR1A MMUT KCNN4 HMOX1 FANCB LAMA3 RPS28 SLC19A3 FANCA MPL STIM1 ELANE FANCC CD46 PET100 PGM3 SLC4A1 MAD2L2 ERCC2 EPHB4 KRAS FOXP3 RPS7 MMUT TGFB1 CD19 HBG2 KIT SARS2 SBDS WRAP53 GCLC COX14 EFL1 COX4I2 ORAI1 STING1 NABP1 CRIPT PUS1 CA2 FARS2 ERCC3 SLC19A2 WIPF1 SLC25A13 TERC DKC1 NSUN2 TRNN PHKG2 ETV6 NBN NDUFV1 STAT3 SP110 UBR1 PUS1 PRF1 RARA PHGDH IL2RB FERMT3 ATP7B RPL27 PET100 LCAT LAMB3 C3 COL7A1 HLA-B NLRC4 ENG CD59 COX15 NDUFA10 TERT TF TNFAIP3 LPIN2 MECOM PIGT DNAJC19 NDUFS1 PRF1 DNAJC19 GALT ITK PTEN PRKCD LIPA ABCD4 IDH1 STK11 RPL11 ATRX LPIN2 GATA1 NPM1 TPP2 SAMD9L ALAS2 KIF1B CD3G NDUFAF3 EPB41 ABCG8 SLC12A3 HBB POLG PRDX1 WFS1 NRAS CISD2 GLRX5 PRKAR1A LAMC2 COA8 OSTM1 RPS29 ATRX SCO2 NLRP3 SLC46A1 DGKE FIP1L1 MYSM1 UBE2T CPOX SLC29A3 LAMB3 TRNT1 TACO1 COL7A1 HBD SPTB NDUFA9 MTR PML GSS SMAD4 TRNT1 TBL1XR1 HBA1 SRP54 SHPK RPL18 SMARCAL1 SPTA1 ISCU DNM1L ELANE MARS1 IDH2 RPS26 GNA14 CAD IL7R COX20 GREM1 FANCE MMP1 HBA1 NDUFAF2 FANCL RFX5 NPHP1 ATP7B ATRX HBB HSPA9 CLCN7 JAK2 TPI1 MPIG6B SLC40A1 PSAP FOXRED1 LIG4 PHGDH SURF1 TERC FANCG SF3B1 KMT2D NOD2 BRIP1 SLC19A2 ADAMTS13 HBB RPL5 GATA1 NBN FANCF PDGFRA PSMB9 ALG8 FECH CP GYPC TALDO1 ABCB7 FAS PTH1R CLCN7 PCCB FAM111A HAMP CDAN1 PGM3 STIM1 DBH LMBRD1 ADA HBG2 GTF2E2 SMAD4 RPS17 STAT1 PARN RPS14 RFXANK RHAG TNFRSF13C TNFRSF13B STX11 CALR UROD ACAD8 NLRP3 PNP USB1 SEC23B RPL31 CIITA HBG1 RFXAP ADA LARS1 RAG2 RMRP COL4A1 FDX2 COQ2 PFKM COG1 CLCN7 BTK FANCA AMN NDUFA13 TF SEC61A1 NDUFS4 F2 SLC4A1 STEAP3 CASP10 ATRX GTF2H5 FANCM TARS1 KCNE1 RTEL1 SLC46A1 TNFSF11 ABCA1 CD55 PIEZO1 RBM8A ITGA2B CTLA4 PNPO SLC7A7 KCNQ1 RPS15A HELLS PLEC NDUFAF5 RPS10 SDHB ELMO2 HPRT1 HBB ANK1 MPLKIP ITGB4 RAG1 SAMD9L DDX41 IGH RAG1 SPTA1 IRX5 FANCD2 SDHA GDF2 COA8 GBA HBB TFRC RASGRP1 CASP10 TCIRG1 ADA2 NHLRC2 CASR COL7A1 PDHA1 BRCA2 PNP NPHP4 TNFRSF11A STAT4 RMRP PSMB8 RAD51C PCNT PLEC HBA2 HLA-B SH2D1A EPB42 SMARCD2 LARS2 ZAP70 RPL11 C15ORF41 SPTA1 IL2RA TCN2 PTPN22 SMARCAL1 TYMP MYD88 TFR2 GPX1 TREX1 SAMD9 BTNL2 PACS2 NDUFA4 SLX4 OPA1 GCLC NPM1 GATA1 COG6 IKZF1 PHKA2 ADAR SLC7A7 DKC1 NLRP1 MS4A1 VPS45 CFHR1 SCO1 RPS19 NDUFA2 PRKCD TMPRSS6 PLEKHM1 TP53 AIRE BPGM GATA1 FANCG RPS15A FANCI LYST TET2 TNFRSF4 CFHR3 MMP1 HBB SLC4A1 COL17A1 HBA2 LYST SNX10 HBB RRM2B CTLA4 PKLR IL12B PHF21A FERMT1 FANCB NDUFS8 SFXN4 HBB-LCR TERT GATA1 PRKACG XIAP SPP1 CUBN SPTB GSS CTC1 CCND1 TTC7A TTC7A NOP10 FARSB LIPT1 ABCB6 UNC13D IFNGR1 TRNW MMAB GATA1 PLA2G4A FAS HBB ANK1 CFH CLCN7 VPS33A SURF1 CBLIF TALDO1 AGXT HBA2 MMADHC HK1 GP1BA MAD2L2 ENG FECH G6PD TBXAS1 THBD TERT ERBB3
Protein Mutations 4
C282Y C677T H63D V617F
HP:0001744: Splenomegaly
Genes 481
MEFV PDGFRA KLF1 IL2RG GPC4 ABCB4 CD40LG TCF4 B2M TNFRSF1B TTC37 DCLRE1C SCARB2 BSCL2 LYZ NEU1 SOX10 PSAP IDUA HSD3B7 IL12A FASLG ERCC6 NOTCH1 DPM1 ATP8B1 CHD7 TINF2 FOXP3 PRKCD CR2 LACC1 ABCB11 RNU4ATAC PLEKHM1 CASK COG7 GBA MST1 PKLR GBA PSMB8 GPIHBP1 IL12A-AS1 AGA ERAP1 GLIS3 TNFSF12 GPC4 LAT DNASE1L3 DOLK LCAT TBX1 PIEZO1 CTSK KLF1 HBB AKT1 HFE G6PC3 ANK1 IRF8 UROS EPB42 PIK3CD FASLG UFD1 NHP2 BSCL2 CD81 TNFSF12 RHAG HBB DCDC2 NCF2 STEAP3 IGH TNFRSF1B DCLRE1C RMRP FOS RAG1 SLC29A3 NFKB2 CASR SMPD1 JMJD1C SPTB RAG2 FAT4 DGUOK RPGRIP1L MEFV ABL1 ICOS INPP5E NFKB1 CA2 SCYL1 FAS PTEN NCF1 ARSB MKS1 ALMS1 GALE MPL SLC4A1 F5 ABCA1 SEC24C ADA2 EPB41 APOA1 GBA ADAMTS3 TET2 LBR UMPS SLCO2A1 PIK3CA KCNH1 SH2B3 IDUA CAV1 TNFSF11 HAVCR2 PEPD ASAH1 ATP6V1B2 TCIRG1 SPTA1 STAT4 LPL GNPTAB PHKG2 IDUA IL1RN BMP2 GPI SNX10 AKR1D1 GBA AKT1 CFAP410 MPL COMT MAN2B1 DGUOK CD19 MVK GBA ALAS2 PIEZO1 MVK JAK2 VPS13A NLRP12 PTEN GBA GBA NPC1 CTNS SLC4A1 SH2B3 HBB TNFRSF1A GATA1 SH2B3 LIPA PSMB4 HBA2 ABCD3 ALDOA GATA2 JAK2 SMPD1 ICOS CALR SUMF1 DKC1 FUCA1 LIG4 RAG1 UROS KCNN4 PTEN BCL6 GPC3 APOC2 SLC2A1 FMO3 CAV1 INPPL1 HGSNAT HPGD GBA TGFB1 RAB27A JAK2 KCNN4 CYBB RREB1 RPGRIP1L CLDN1 MPL DYNC2LI1 HJV CCR1 PEX2 PEPD KRAS RUNX1 MCM4 MMUT COG4 HLA-DRB1 PPARG CD19 HBG2 HLA-DRB1 WRAP53 OTC APOA1 GP1BB SLC17A5 COX4I2 GPD1 TREX1 ATP6AP1 DDRGK1 TERC CTLA4 PHKG2 CYBC1 LMNA IDS IL7R IL2RB MEFV FERMT3 GPC1 CCND1 NLRC4 THPO FGA GNPTAB MIF TERT CLCN7 PRF1 PIGM HLA-DRB1 ITK SMPD1 PRKCD LIPA IDUA CALR ATRX LPIN2 KLRC4 GATA1 TPP2 SUMF1 SAMD9L IFT172 ZAP70 SLC30A10 EPB41 ABCG8 GUSB PKHD1 AGPAT2 HBB CC2D2A NRAS GLRX5 SH2B3 OSTM1 GAA NLRP3 CPOX PSAP CALR SPTB TMEM67 HBA1 JAK2 AKR1D1 SLC39A4 ICOS SPTA1 BACH2 IL7R FAH HBA1 DHCR24 ATP7B OCLN MPL DCDC2 CLCN7 JAK2 TPI1 MPIG6B HIRA GNE NCF2 BCL2 PIK3C2A CCBE1 SF3B1 KCNH1 CASP8 NOD2 ERCC8 BCR USB1 HBB CAVIN1 PSMB9 CARD11 MVK GYPC FAS IGH HLA-B CLCN7 CD28 NOTCH2 CTLA4 GNS HAMP CDAN1 BRAF ADA NCF4 PARN RHAG TNFRSF13C C4A TNFRSF13B STX11 CD27 UBAC2 SGSH CALR NLRP3 CD28 PNP USB1 SEC23B TMEM67 HBG1 IDUA IL23R ADA HSD3B7 RAG2 NLRC4 WDR35 PEX7 TET2 CCDC115 NGLY1 NEU1 LIPA NBEAL2 NCF1 CC2D2A TNFRSF13C SLC4A1 CASP10 SKIV2L RTEL1 ABCA1 PIEZO1 SLC7A7 TLR4 GFI1B NPC2 AP3D1 ITCH ANK1 IL10 ATM RAG1 XIAP GBA RASGRP1 CASP10 TCIRG1 CASR ALG1 TNFRSF11A TP53 PSMB8 ARVCF SH2D1A EPB42 THPO C15ORF41 IL2RA LMNA MYD88 GUSB APOE TNFRSF13B CYBA ASAH1 NPM1 GATA1 COG6 PHKA2 KCNN3 CYBA HFE GLB1 NLRP1 MS4A1 VPS45 GPR35 TBX1 CR2 PRKCD NAGLU BTNL2 BPGM APOE LYST TET2 TNFRSF4 CCDC47 JAK2 SLC4A1 HBA2 CAVIN1 LYST SNX10 PPARG RNASEH2A CTLA4 FAH PKLR FAS CYP7B1 GPC3 CYP7B1 XIAP CYBB SPTB PIK3R1 NBEAL2 CTC1 CCND1 NOP10 JAK2 DDRGK1 IFNGR1 JAK2 FAS ANK1 PTPRC VPS33A IL6 GBA TALDO1 BTD TET2 HK1 GP1BA MPL G6PD AP3B1 IFIH1 AGPAT2 TBXAS1 ERBB3 PHYH
SNP 0