A Study to Evaluate the Efficacy of Venetoclax Monotherapy in Relapsed/Refractory Participants With Chronic Lymphocytic Leukemia (CLL)

Complete remission rate is defined as the percentage of participants achieving a best response of complete remission (CR) or complete remission with incomplete marrow recovery (CRi) assessed by the investigator based on 2008 Modified International Workshop for Chronic Lymphocytic Leukemia National Cancer Institute-Working Group (IWCLL NCI-WG) criteria.

CR required all of the following:

• Peripheral blood lymphocytes < 4000/μL
• Absence of lymphadenopathy by physical examination and computed tomography scan
• No hepatomegaly or splenomegaly by physical examination
• Absence of disease or constitutional symptoms (unexplained fevers > 38°C, drenching night sweats, > 10% weight loss in last 6 months)
• Blood counts above the following:

• Neutrophils > 1500/μL
• Platelets > 100,000/μL
• Hemoglobin > 110 g/L
• Bone marrow at least normocellular for age, < 30% lymphocytes.

CRi was defined as for CR but with persistent cytopenia apparently unrelated to CLL but related to drug toxicity.

Complete remission rate is defined as the percentage of participants achieving a best response of complete remission (CR) or complete remission with incomplete marrow recovery (CRi) assessed by the investigator based on 2008 modified IWCLL NCI-WG criteria.

CR required all of the following:

• Peripheral blood lymphocytes < 4000/μL
• Absence of lymphadenopathy by physical examination and computed tomography scan
• No hepatomegaly or splenomegaly by physical examination
• Absence of disease or constitutional symptoms (unexplained fevers > 38°C, drenching night sweats, > 10% weight loss in last 6 months)
• Blood counts above the following:

• Neutrophils > 1500/μL
• Platelets > 100,000/μL
• Hemoglobin > 110 g/L
• Bone marrow at least normocellular for age, < 30% lymphocytes

CRi was defined as for CR but with persistent cytopenia apparently unrelated to CLL but related to drug toxicity.

Overall response rate was defined as the percentage of participants with an overall best response of CR, CRi, nodular partial remission (nPR), or confirmed partial remission (PR) based on the 2008 modified IWCLL NCI-WG criteria assessed by the investigator.

CR and CRi are defined above. nPR is defined as for CR but bone marrow nodules could be identified histologically.

For PR at least 2 of the following must be met:

• 50% decrease in peripheral blood lymphocyte count from the Baseline value;
• 50% reduction in lymphadenopathy;
• 50% reduction in the size of the liver and/or spleen (if abnormal prior to therapy);

In addition at least 1 of the following criteria must be met:

• Neutrophils > 1,500/μL or ≥ 50% improvement over Baseline;
• Platelets > 100,000/μL or ≥ 50% improvement over Baseline;
• Hemoglobin > 11.0 g/dL or ≥ 50% improvement over Baseline without transfusions or exogenous growth factors.

PR must have been confirmed at least 7 weeks later.

Duration of response was defined as the time from the date of first response (CR, CRi, nPR, or PR) to the earliest date that progressive disease (PD) was objectively documented (radiographic or clinical) or death. Duration of response was analyzed by Kaplan-Meier (K-M) methodology. If a participant was still responding the data were censored at the date of the last available disease assessment prior to the data cutoff date.

Time to progression was defined as the time from the date of first dose of venetoclax to the date of earliest PD (radiographic or clinical). Participants who did not experience disease progression were censored at the date of the last available disease assessment prior to the data cutoff date; participants with no post-baseline disease assessments were censored at the first dose date plus 1 day. Time to progression was estimated using Kaplan-Meier methodology.

Progression-free survival (PFS) was defined as the time from the date of first dose of venetoclax to the date of earliest PD (radiographic or clinical) or death. Participants who did not experience disease progression or death were censored at the date of the last available disease assessment prior to the data cutoff date; participants with no post-baseline tumor assessment or clinical assessment for progression were censored at the date of first dose plus 1 day. Progression-free survival was analyzed by Kaplan-Meier methodology.

Overall survival (time to death) was defined as the time from the first dose date of venetoclax to the date of death. If a participant had not died the data were censored at the date when they were last known to be alive prior to the cutoff date. Overall survival was analyzed using Kaplan-Meier methodology.

The FACT-Leu is a 44-item, leukemia-specific questionnaire designed to assess health-related quality of life (HRQoL) and leukemia-specific symptoms using a core set of questions (Functional Assessment of Cancer Therapy-General; FACT-G), and a cancer site-specific leukemia subscale. Questions are scored on a scale from 0 (not at all) to 4 (very much).

FACT-G consists of 27 general items divided into 4 primary HRQoL domains: Physical Well-being (PWB; 7 items; score range 0-28), Social/Family Well-being (SWB; 7 items; score range 0-28), Emotional Well-being (EWB; 6 items; score range 0-24), Functional Well-being (FWB; 7 items; score range 0-28). The leukemia subscale consists of 17 items (score range 0-68) that assess patient concerns relating to leukemia. Three summary scales were calculated: FACT-Trial Outcome Index composed of the PWB, FWB, and leukemia subscale (score range 0-124); FACT-G (score range 0-108) and the FACT-Leu Total (range 0-176). Higher scores reflect better HRQoL.

The FACIT-Fatigue questionnaire measures fatigue and its effect on functioning and daily activities. The FACIT-Fatigue includes 13 items answered on a 5-point rating scale based on a 7-day recall period. Scores range from 0 to 52, with lower scores reflecting greater fatigue.

The EQ-5D-5L is a generic measure of health status consisting of two parts: a descriptive system consisting of 5 items and a visual analog scale (VAS).

The descriptive system comprises five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. The participant is asked to rate each dimension on 5 levels of severity (1: no problems, 2: slight problems, 3: moderate problems, 4: severe problems, 5: extreme problems).

The scores for the 5 dimensions are used to compute a single health utility index score representing the general health status of the individual. The health index score ranges from zero (defined as a health state equivalent to being dead) to 1 (full health).

The EQ-5D-5L is a generic measure of health status consisting of two parts, a descriptive system consisting of 5 items and a visual analog scale (VAS).

The VAS assesses the participant's self-rated overall health on a scale from 0 (worst health imaginable) to 100 (best health imaginable).

Complete remission rate is defined as the percentage of participants achieving a best response of complete remission (CR) or complete remission with incomplete marrow recovery (CRi) assessed by the investigator based on 2008 modified IWCLL NCI-WG criteria.

CR required all of the following:

• Peripheral blood lymphocytes < 4000/μL
• Absence of lymphadenopathy by physical examination and computed tomography scan
• No hepatomegaly or splenomegaly by physical examination
• Absence of disease or constitutional symptoms (unexplained fevers > 38°C, drenching night sweats, > 10% weight loss in last 6 months)
• Blood counts above the following:

• Neutrophils > 1500/μL
• Platelets > 100,000/μL
• Hemoglobin > 110 g/L
• Bone marrow at least normocellular for age, < 30% lymphocytes.

CRi was defined as for CR but with persistent cytopenia apparently unrelated to CLL but related to drug toxicity.

Complete remission rate is defined as the percentage of participants achieving a best response of complete remission (CR) or complete remission with incomplete marrow recovery (CRi) assessed by the investigator based on 2008 modified IWCLL NCI-WG criteria.

CR required all of the following:

• Peripheral blood lymphocytes < 4000/μL
• Absence of lymphadenopathy by physical examination and computed tomography scan
• No hepatomegaly or splenomegaly by physical examination
• Absence of disease or constitutional symptoms (unexplained fevers > 38°C, drenching night sweats, > 10% weight loss in last 6 months)
• Blood counts above the following:

• Neutrophils > 1500/μL
• Platelets > 100,000/μL
• Hemoglobin > 110 g/L
• Bone marrow at least normocellular for age, < 30% lymphocytes

CRi was defined as for CR but with persistent cytopenia apparently unrelated to CLL but related to drug toxicity.

Overall response rate was defined as the percentage of participants with an overall best response of CR, CRi, nodular partial remission (nPR), or confirmed partial remission (PR) based on the 2008 modified IWCLL NCI-WG criteria assessed by the investigator.

CR and CRi are defined above. nPR is defined as for CR but bone marrow nodules could be identified histologically.

For PR at least 2 of the following must be met:

• 50% decrease in peripheral blood lymphocyte count from the Baseline value;
• 50% reduction in lymphadenopathy;
• 50% reduction in the size of the liver and/or spleen (if abnormal prior to therapy);

In addition at least 1 of the following criteria must be met:

• Neutrophils > 1,500/μL or ≥ 50% improvement over Baseline;
• Platelets > 100,000/μL or ≥ 50% improvement over Baseline;
• Hemoglobin > 11.0 g/dL or ≥ 50% improvement over Baseline without transfusions or exogenous growth factors.

PR must have been confirmed at least 7 weeks later.

Duration of response was defined as the time from the date of first response (CR, CRi, nPR, or PR) to the earliest date that progressive disease (PD) was objectively documented (radiographic or clinical) or death. Duration of response was analyzed by Kaplan-Meier (K-M) methodology. If a participant was still responding the data were censored at the date of the last available disease assessment prior to the data cutoff date.

Time to progression was defined as the time from the date of first dose of venetoclax to the date of earliest PD (radiographic or clinical). Participants who did not experience disease progression were censored at the date of the last available disease assessment prior to the data cutoff date; participants with no post-baseline disease assessments were censored at the first dose date plus 1 day. Time to progression was estimated using Kaplan-Meier methodology.

Progression-free survival (PFS) was defined as the time from the date of first dose of venetoclax to the date of earliest PD (radiographic or clinical) or death. Participants who did not experience disease progression or death were censored at the date of the last available disease assessment prior to the data cutoff date; participants with no post-baseline tumor assessment or clinical assessment for progression were censored at the date of first dose plus 1 day. Progression-free survival was analyzed by Kaplan-Meier methodology.

Overall survival (time to death) was defined as the time from the first dose date of venetoclax to the date of death. If a participant had not died the data were censored at the date when they were last known to be alive prior to the cutoff date. Overall survival was analyzed using Kaplan-Meier methodology.

The MRD negativity rate is defined as the percentage of participants who had MRD negative status with less than one CLL cell per 10,000 leukocytes (< 10-⁴) in peripheral blood and bone marrow. MRD was evaluated using next-generation sequencing. Per protocol, peripheral blood MRD assessments were to be collected from all participants at Week 24 and Week 48 and at the time the bone marrow assessment for confirmation of CR/CRi, and bone marrow (BM) MRD assessments were to be collected for participants undergoing a bone marrow procedure for confirmation of CR/CRi. Participants with no blood or BM MRD assessments were included in the calculation of MRD negativity rate as not having MRD negative status.

The MRD negativity rate is defined as the percentage of participants who had MRD negative status with less than one CLL cell per 10,000 leukocytes (< 10-⁴) in peripheral blood and bone marrow. MRD was evaluated using next-generation sequencing. Per protocol, peripheral blood MRD assessments were to be collected from all participants at Week 24 and Week 48 and at the time the bone marrow assessment for confirmation of CR/CRi, and bone marrow (BM) MRD assessments were to be collected for participants undergoing a bone marrow procedure for confirmation of CR/CRi. Participants with no blood or BM MRD assessments were included in the calculation of MRD negativity rate as not having MRD negative status.