Primary Outcomes

Description: We will summarize our findings for this endpoint independently as well within each cohort (del17p vs other cytogenetic groups). We will evaluate the proportion of patients who are progression-free and alive at two years or have gone on to transplant (treatment successes) over the total number of evaluable patients; eligible patients who received at least one dose of therapy are considered evaluable. Assuming that the number of treatment successes as defined above is binomially distributed, we will also include 95% binomial confidence intervals for the estimates corresponding to each cohort.

Measure: Determine the 2 Year Progression-free Survival (PFS) of Single Agent PCI-32765 in Patients With Relapsed and Refractory CLL.

Time: up to 2 years

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Secondary Outcomes

Description: Responders were subjects who achieved a complete response (CR), partial response (PR) or PR with persistent lymphocytosis. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.

Measure: Best Overall Response Rate Using the Revised International Workshop on Chronic Lymphocytic Leukemia (IWCLL) Working Group Guidelines

Time: up to 2 years

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Description: The 6 month overall response rates overall response rate (ORR). Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR

Measure: Number of Patients With 6 Month ORR of Single Agent Ibrutinib in Relapsed and Refractory CLL Patients

Time: Up to 6 months

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Description: Time from date of first treatment with ibrutinib until the date of death from any cause or the date of last contact for those alive.

Measure: Percentage of Patients With Overall Survival (OS)

Time: 2 years

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Description: Time from date of first treatment with ibrutinib until the date of progression or death from any cause. Those alive and progression free are censored at the date of last clinical assessment.

Measure: 2-year Kaplan-Meier Estimate of OS for Relapsed and Refractory CLL Patients Treated With Single Agent PCI-32765

Time: 2 years

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Description: Adverse events grade 3 or higher using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 with the attribution of either definite, possible or probable related.

Measure: Number of Patients With Adverse Events, Graded According to the NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0

Time: Up to 2 years post treatment

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Description: Percentage of patients with BTK C481S mutation or PLCG2 mutation

Measure: Resistance Studies of Ibrutinib

Time: Up to 4 years

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Measure: Decrease in Immune Suppression of CLL Cells

Time: up to 3 months

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Description: The number of participants with successful Allogenic Stem Cell Transplant

Measure: Effectiveness of Ibrutinib Bridging Patients to Allogeneic Stem Cell Transplant and Outcome of Patients Following This Intervention

Time: Up to 2 years

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Description: Cancer-Specific Stress was measured by the Impact of Event Scale-Revised Participants rated the intensity of these feelings using a five-point Likert scale ranging from 0=not at all to 4=extremely. Patients rated the frequency of their feelings or events for the previous week before treatment. The items were summed for a total score that ranged from 0 to 64

Measure: Cancer-Specific Stress as Measured by the Impact of Event Scale-Revised (IES-R)

Time: Up to 2 years

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Description: The Beck Depression Inventory-2nd edition is a 21-item measure of depressive symptoms. Scores were calculated representing the cognitive-affective and the somatic symptoms associated with depression (e.g. sadness, pessimism, loss of pleasure) during past month on scale from 0 to 3. Items were summed, with higher scores indicating more depressive symptoms. The scores on the scale from range from 0 to 42.

Measure: Cognitive-Affective Depressive Symptoms as Measured by the Beck Depression Inventory-2nd Edition (BDI-II)

Time: at 5 months

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Description: The Profile of Mood States-Short Form (POMS-SF) yields six subscales, Tension, Depression, Anger, Vigor, Fatigue, and Confusion. A total mood disturbance score is found by summing the six subscales. Total Mood Disturbance (TMD) scores range from -24 to 124 with higher scores indicating greater mood disturbance.

Measure: Negative Mood Quality of Life Measured by a 37-item Questionnaire

Time: at 5 months

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Description: SF-12 assesses aspects of quality of life including physical functioning, role functioning-physical, bodily pain, general health perceptions, vitality, social functioning, role functioning-emotional, and mental health. Subscale raw scores are transformed to put each subscale on a 0-100 range with higher scores indicative of greater functioning. Subscale scores are standardized based on US General Population norms and aggregated based on factor score coefficients into two component scores: the Physical Component Summary (PCS) and the Mental Component Summary (MCS). Component scores are norm-based t-scores meaning scores above 50 indicate better functioning than average functioning while scores below 50 indicate worse functioning.

Measure: Mental Health Quality of Life Was Measured by the Mental Component Summary Score of the Medical Outcomes Study

Time: at 5 months

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Description: The Fatigue Interference quality of life measures is a 11-item self reported questionnaire used to measure frequency, severity and daily pattern of fatigue Symptoms as well as impact of QOL in the past week. The Total Disruption Index (TDI) an 7 item subset of FSI was used. Items were rated on a 11-point Likert scale from 0=no interference to 10=extreme interference. Total scores could range from 0 to 70, with higher scores indicating greater fatigue interference.

Measure: Fatigue Symptom Inventory (FSI) Interference Quality of Life as Measured by a 11-item Total Disruption Index Sub Scale of Fatigue Symptoms Inventory

Time: at 5 months

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Description: Sleep problems quality of life measures is a six-item sleep problems index I of the Medical Outcomes Study-Sleep Scale used to assess sleep problems. Participants reported how often they experience six specific difficulties with sleep on a 6-point Likert scale (1=All of the time to 6=None of the time). Scores transformed into a 0-100 scale with higher scores indicating greater sleep problems.

Measure: Sleep Through Quality of Life as Measured by a Medical Outcomes Study-Sleep Scale

Time: at 5 months

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Description: Physical Health Quality of life measures were administered during screening and on Days 1 (±3), of Cycle 1, Day 1 (±3), of Cycle 2 and on day 1 (±7) of Cycles 3, 6, and then every 3 months thru Cycle 24 and at time of progression and /or end of treatment. SF-12 assesses aspects of quality of life including physical functioning, role functioning-physical, bodily pain, general health perceptions, vitality, social functioning, role functioning-emotional, and mental health. Subscale raw scores are transformed to put each subscale on a 0-100 range with higher scores indicative of greater functioning. Subscale scores are standardized based on US General Population norms and aggregated based on factor score coefficients into two component scores: the Physical Component Summary (PCS) and the Mental Component Summary (MCS). Component scores are norm-based t-scores meaning scores above 50 indicate better functioning than average functioning while scores below 50 indicate worse functioning.

Measure: Physical Health Quality of Life as Measured by a 12 Item Short-Form Health Survey

Time: up to 5 months

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Primary Outcomes

Description: Defined as the percentage of patients who have achieved any response better than stable disease after 12 cycles of combination ibrutinib and venetoclax treatment. All eligible patients who take one study dose of venetoclax will be considered evaluable and included in the denominator when calculating the ORR. ORR will be estimated with a 95% exact binomial confidence interval at the response assessment after 12 cycles of combination ibrutinib and venetoclax therapy, and 24 if applicable.

Measure: Overall response rate (ORR) (intervention cohort)

Time: After 12 cycles of combination therapy, assessed up to 3 years

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Description: Rate of mutation negative status will be estimated with a 95% exact binomial confidence interval at the response assessment after 12 cycles of combination ibrutinib and venetoclax therapy, and 24 if applicable.

Measure: Rate of mutation negative status (intervention cohort)

Time: After 12 cycles of combination therapy, assessed up to 3 years

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Secondary Outcomes

Description: Person-time incidence of developing a BTK C481S mutation will be calculated by dividing the number of new mutations observed while on ibrutinib therapy by the total number of months patients are receiving ibrutinib and were at risk.

Measure: Incidence of BTK C481S mutations (observation cohort)

Time: Up to 3 years

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Description: Will be calculated in the observation cohort from the date a BTK C481S mutation was first reported until the date of clinical disease progression by International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2018 criteria or death from any cause, whichever occurs first.

Measure: Progression-free survival (PFS) after development of a BTK C481S mutation (observation cohort)

Time: Up to 3 years

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Description: PFS will be calculated in the intervention cohort from the start date of combination therapy (C1D1) until the date of progressive disease or death from any cause. Will be described using the method of Kaplan-Meier.

Measure: PFS after adding venetoclax to ibrutinib (intervention cohort)

Time: Up to 3 years

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Description: OS will be calculated in the intervention cohort from the start date of combination therapy (C1D1) until the date of progressive disease or death from any cause. Will be described using the method of Kaplan-Meier.

Measure: Overall survival (OS) after adding venetoclax to ibrutinib (intervention cohort)

Time: Up to 3 years

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Description: Graded per National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 with the exception of hematologic adverse events. Adverse events will be summarized by type, severity and perceived attribution. Hematologic adverse events will be graded according to CLL-specific criteria described in the IWCLL 2018 guidelines. The maximum grade for each type of toxicity will be recorded for each patient and frequency tables will be reviewed to determine the toxicity patterns. In addition, will also summarize the number of patients who discontinue combination therapy due to adverse events.

Measure: Incidence of adverse events (intervention cohort)

Time: Up to 3 years

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Other Outcomes

Description: Univariable and multivariable analysis will be performed to determine what patient and disease characteristics are associated with development of ibrutinib resistance mutations. All standard CLL risk characteristics, prior treatments, and standard patient demographic information will be included.

Measure: Patient and disease characteristics associated with clinical disease progression (observation cohort)

Time: Up to 3 years

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Description: Univariable and multivariable analysis will be performed to determine what patient and disease characteristics are associated with development of ibrutinib resistance mutations. All standard CLL risk characteristics, prior treatments, and standard patient demographic information will be included.

Measure: Changes in allelic frequency of ibrutinib resistance mutations after their development (observation cohort)

Time: Up to 3 years

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Description: Univariable and multivariable analysis will be performed to determine what patient and disease characteristics are associated with development of ibrutinib resistance mutations. All standard CLL risk characteristics, prior treatments, and standard patient demographic information will be included.

Measure: Changes in allelic frequency of ibrutinib resistance mutations after addition of venetoclax (intervention cohort)

Time: Up to 3 years

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Description: For RNA-Seq data analysis, will first use FASTQC for the read quality recalibration, and then conduct removing, trimming, and filtering based on base quality scores and nucleotide distributions. Coverage BED (bedtools package) will be used for counting reads per feature per sample. Filtering of noise level counts across comparison groups will be used to reduce false positives. After filtering, differential expression will be tested using R package limma with voom normalization.

Measure: Novel resistance mechanisms to ibrutinib and ibrutinib/venetoclax combination therapy by whole exome and ribonucleic acid (RNA) sequencing (Seq)

Time: At baseline and at clinical relapse, assessed up to 3 years

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Description: Correlate with response to combination venetoclax and ibrutinib therapy. Descriptive statistics such as mean, standard deviation, median, range, etc., for continuous variables and proportions for discrete variables will be used to summarize correlative endpoints in each of the defined strata. Graphical summaries will also be used extensively to visualize the data and describe relationships between variables (e.g. boxplots of BH3 profiling by response status).

Measure: BH3 profiling

Time: Up to 3 years

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Primary Outcomes

Description: The primary end point will be met if > 50% patients attain response (half of patients responding without intolerance). Logistic regression may be utilized to assess the effect of patient prognostic factors on the response rate. Intent-to-treat analysis will be applied to the eligible patients.

Measure: Overall response rate (complete response + partial response)

Time: At the end of cycle 3 (each cycle is 28 days)

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Secondary Outcomes

Description: Logistic regression may be utilized to assess the effect of patient prognostic factors on the incidence of adverse events. Toxicity and safety data will be summarized by frequency tables for all patients and then will be reviewed for relatedness to acalabrutinib. Per-treated analysis will be performed to include any patient who received the treatment regardless of the eligibility nor the duration or dose of the treatment received. Also, time to event and time to event resolution will be calculated.

Measure: Incidence of adverse events

Time: At the end of cycle 3 (each cycle is 28 days)

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Description: The distribution of time-to-event endpoints including progression free survival will be estimated using the method of Kaplan and Meier. Comparison of time-to-event endpoints by important subgroups will be made using the log-rank test.

Measure: Progression free survival

Time: Up to 6 years

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Description: The distribution of time-to-event endpoints including overall survival will be estimated using the method of Kaplan and Meier. Comparison of time-to-event endpoints by important subgroups will be made using the log-rank test.

Measure: Overall survival

Time: Up to 6 years

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