NLP SNP

This randomized phase III trial studies rituximab with bendamustine hydrochloride or ibrutinib to see how well they work compared to ibrutinib alone in treating older patients with previously untreated chronic lymphocytic leukemia. Monoclonal antibodies, such as rituximab, may block cancer growth in different ways by targeting certain cells. Drugs used in chemotherapy, such as bendamustine hydrochloride, 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. Ibrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. It is not yet known whether rituximab with bendamustine hydrochloride may work better than rituximab and ibrutinib or ibrutinib alone in treating chronic lymphocytic leukemia.

NCT01886872 Stage I Chronic Lymphocytic Leukemia Stage II Chronic Lymphocytic Leukemia Stage III Chronic Lymphocytic Leukemia Stage IV Chronic Lymphocytic Leukemia Drug: Bendamustine Hydrochloride Drug: Ibrutinib Other: Laboratory Biomarker Analysis Other: Quality-of-Life Assessment Biological: Rituximab

MeSH:Leukemia Leukemia, Lymphoid Leukemia, Lymphocytic, Chronic, B-Cell

HPO:Chronic lymphatic leukemia Leukemia Lymphoid leukemia

To assess whether the Fc fragment of IgG, low affinity IIIa, receptor (CD16a) (FCGR3A) polymorphism (rs396991) is correlated with depth of response (MRD status) to ibrutinib plus rituximab after 6 cycles, with secondary endpoints CR rate, rapidity of response, and progression-free survival (PFS).

Primary Outcomes

Description: The Kaplan-Meier method will be used to estimate the progression free survival distributions for each arm, with median estimates provided. Progression is defined as any one of the following: an increase in number of blood lymphocytes by >= 50% with >= 5000 B lymphocytes/mL in patients on Arm A or those on Arms 2 or 3 no longer receiving ibrutinib, >= 50% increase in the products of at least 2 lymph nodes on 2 consecutive determination 2 weeks apart, >= 50% increase in the size of the liver/spleen, transformation to a more aggressive histology, progression of any cytopenia (i.e. decrease of Hb levels > 2g/dL). Progression free survival time will be the time to either progression or death whichever occurs first.

Measure: Progression Free Survival (PFS)

Time: Time from study entry to the time of documented disease progression or death. The analysis was event driven, performed at 2.5 years after the last patient enrolled;up to 4 years.

Secondary Outcomes

Description: The Kaplan-Meier method will be used to estimate the rate of progression free survival at 2 years in each treatment arm. Progression is defined as any one of the following: an increase in number of blood lymphocytes by >= 50%, >= 50% increase in the products of at least 2 lymph nodes on 2 consecutive determination 2 weeks apart, >= 50% increase in the size of the liver/spleen, transformation to a more aggressive histology, progression of any cytopenia (i.e. decrease of Hb levels > 2g/dL). Progression free survival time will be the time to either progression or death whichever occurs first.

Measure: Progression Free Survival (PFS) Rate at 2 Years

Time: Time from study entry to the time of documented disease progression or death, assessed up to 2 years

Description: The Kaplan-Meier method will be used to estimate the rate of overall survival at 2 years in each treatment arm. OS will be measured from the date of registration to the date of the event (i.e., death) or the date of last follow-up to evaluate that event. Patients who are event-free at their last follow-up evaluation will be censored at that time point.

Measure: Overall Survival (OS) at 2 Years

Time: From the date of registration to the date of death, assessed up to 2 years

Description: The Kaplan-Meier method will be used to estimate median DOR. DOR is the time from first objective status to progression or death. CR requires all of the following: absence of lymphadenopathy > 1.5 cm on physical exam/CT scan, no hepatomegaly/splenomegaly on physical exam, no clonal B-cells in the blood, Normal CBC, bone marrow aspirate & biopsy must be normocellular for age. PR requires >= 50% decrease in peripheral lymphocyte count from pre-treatment value, >= 50% reduction in lymphadenopathy, and/or ≥ 50% reduction in splenomegaly/hepatomegaly. CR with exception of having bone marrow lymphoid CLL nodules will be considered a nodular PR (nPR). CR with exception of not having a bone marrow biopsy performed will be considered a clinical CR (CCR). PR with the exception of having less than a 50% reduction in peripheral lymphocyte count will be considered a PR except persistent lymphocytosis (PRL).

Measure: Duration of Response (DOR) (Complete Response [CR], CCR, Nodular Partial Response [nPR], Partial Response [PR], and PRL)

Time: From the date of first response until progression or death, performed at 2.5 years after the last patient enrolled; up to 4 years.

Description: Complete response (CR) requires all of the following: absence of lymphadenopathy >1.5 cm on physical exam/CT scan, no hepatomegaly/splenomegaly on physical exam, no clonal B-cells in the blood, Normal CBC, bone marrow aspirate & biopsy must be normocellular for age. Partial response (PR) requires >= 50% decrease in peripheral lymphocyte count from pre-treatment value, >= 50% reduction in lymphadenopathy, and/or ≥ 50% reduction in splenomegaly/hepatomegaly. CR with exception of having bone marrow lymphoid CLL nodules will be considered a nodular PR (nPR). CR with exception of not having a bone marrow biopsy performed will be considered a clinical CR (CCR). PR with the exception of having less than a 50% reduction in peripheral lymphocyte count will be considered a PR except persistent lymphocytosis (PRL).Overall response rate and corresponding exact binomial 95% CI provided.

Measure: Percentage of Patients Achieving Any Response to Treatment (Overall Response Rate [ORR] [Complete Response [CR], CCR, Nodular Partial Response [nPR], Partial Response [PR], and PRL])

Time: Performed at 2.5 years after the last patient enrolled;up to 4 years.

Measure: Percentage of Patients Achieving a Biopsy-proven Complete Response (CR)

Time: Performed at 2.5 years after the last patient enrolled; up to 4 years.

Description: Complete response (CR) requires all of the following: absence of lymphadenopathy > 1.5 cm on physical exam/CT scan, no hepatomegaly or splenomegaly on physical exam, no clonal B-cells in the blood, Normal CBC, bone marrow aspirate and biopsy must be normocellular for age. CR with exception of having bone marrow lymphoid CLL nodules will be considered a nodular PR (nPR). CR with exception of not having a bone marrow biopsy performed will be considered a clinical CR (CCR). Response rate and corresponding exact binomial 95% confidence intervals provided.

Measure: Percentage of Patients Achieving Complete (CR and CCR) or Nodular Partial Response (nPR)

Time: Performed at 2.5 years after the last patient enrolled; up to 4 years.

Description: Estimated using the number of patients who achieve minimal residual disease divided by the total number randomized to that treatment arm. Corresponding exact binomial 95% confidence intervals for MRD rates will be calculated.

Measure: Percentage of Patients Who Attain Minimal Residual Disease (MRD) Negative Status

Time: Cycle 9 Day 1 Evaluation

Description: The rate of grade 3, 4, or 5 treatment-related non-hematologic adverse events (toxicities) by arm; excludes adverse events occurring post-crossover for patients in Arm A

Measure: The Rate of Grade 3, 4, or 5 Treatment-related Non-hematologic Adverse Events (Toxicities)

Time: Performed at 2.5 years after the last patient enrolled; up to 4 years.

Other Outcomes

Description: Assessed using the Older Americans' Resources and Services Multidimensional Functional Assessment Questionnaire, Activities of Daily Living, Medical Outcomes Study physical functioning, Karnofsky performance status rated by a health care professional, Karnofsky performance status rated by the patient, timed "Up and Go", and number of falls in the last six months.

Measure: Geriatric Functional Status (Optional)

Time: Performed at 2.5 years after the last patient enrolled