Comparison of the Treatments of Obinutuzumab + Venetoclax Versus Obinutuzumab + Chlorambucil in Patients With Chronic Lymphocytic Leukemia

PFS was determined according to IWCLL 2008 criteria and defined as the time from randomization to the first occurrence of PD or death from any cause. Disease progression was characterized by at least one of the following: 1) \>/= 50% increase in the absolute number of circulating lymphocytes to at least 5\*10\^9/L, 2) Appearance of new palpable lymph nodes (\> 15 mm in longest diameter) or any new extra-nodal lesion; 3) \>/= 50% increase in the longest diameter of any previous site of lymphadenopathy; 4) \>/= 50% increase in the enlargement of the liver and/or spleen; 5) Transformation to a more aggressive histology.

Time frame: Baseline until disease progression or death up to approximately 3.75 years

Population: ITT population was defined as all randomized participants.

The EORTC QLQ-C30 is a validated and reliable self-report measure consisting of 30 questions incorporated into five functional scales (physical, role, cognitive, emotional, and social scales), three symptom scales (fatigue, pain, nausea, and vomiting scales), and a global health status/global quality-of-life scale. The remaining single items (dyspnea, appetite loss, sleep disturbance, constipation, and diarrhea) assess the additional symptoms experienced by patients with cancer and the perceived financial burden of treatment. The 28 function and symptom items were scored on a 4-point scale that ranged from not at all to very much, and the 2 global health status/global quality-of-life items were scored on a 7-point scale that ranged from very poor to excellent. Raw average scale scores were linearly transformed to range 0-100 with higher scores indicating higher response levels (i.e., higher functioning, higher symptom severity).

Time frame: Baseline up to approximately 10.75 years

The EQ-5D-3L questionnaire is a generic, preference based health utility measure that assesses 5 health states (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) and is used to build a composite of the patient's health status. The EQ-5D-3L was employed in this study to calculate health utilities for economic modeling, which ranged 0-1. The EQ-5D-3L also contained a visual analog scale (VAS) to assess the participant's overall health, which ranged from 0-100 with a higher score indicating a worse health status.

Time frame: Baseline up to approximately 10.75 years

The MDASI-CLL is a questionnaire of 25 items related to CLL specific symptoms that a participant may have experienced in the past 24 hours. Participants were asked to rate the severity of 13 symptoms called mean core symptom severity (i.e., pain, fatigue, nausea, disturbed sleep, distressed, shortness of breath, remembering things, lack of appetite, drowsy, dry mouth, sadness, vomiting, and numbness or tingling), 6 disease-specific symptoms called mean module symptom severity (night sweats, fevers and chills, lymph node swelling, diarrhea, easy bruising or bleeding, and constipation) and 6 mean interference on life questions (i.e., general activity, walking, work, mood, relations with other people, and enjoyment of life) on a scale from 0 to 10 with 0 indicating that the symptom is not present or did not interfere with the participant's activities and 10 indicating as bad as you can imagine or interfered completely. Scores were averaged (range 0 to 10) for each of three parts.

Time frame: Baseline up to approximately 10.75 years

PD was defined as lymphadenopathy, \>=50% increase in liver or spleen size, \>=50% increase in lymphocyte count, transformation to a more aggressive histology or occurrence of cytopenia.

Time frame: Time from the first occurrence of a documented objective response to the time of PD as determined by the investigator or death from any cause, up to approximately 10.75 years

Time frame: Time between date of randomization and the date of disease progression/relapse on the basis of investigator-assessment, death, or start of a new anti-leukemic therapy, up to 10.75 years

An AE is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as AEs.

Time frame: Up to approximately 10.75 years

OS was defined as the time between the date of randomization and the date of death due to any cause.

Time frame: Baseline until death, up to approximately 10.75 years

CR: peripheral blood lymphocytes below 4x10\^9/L, absence of lymphadenopathy by physical examination and CT scan, no hepatomegaly or splenomegaly, absence of disease or constitutional symptoms, blood counts of neutrophils \>1.5\*10\^9/L, platelets \>100\*10\^9/L and hemoglobin \>110 g/L, bone marrow at least normocellular for age without clonal infiltrate (except for Cri). PR: any two for at least 2 months: \>/= 50% decrease in peripheral blood lymphocyte count from the pretreatment value, \>/=50% reduction in lymphadenopathy, \>/=50% reduction of liver and/or spleen enlargement, and at least one of the following blood counts: neutrophils \>1.5\*10\^9/L, platelets \>100\*10\^9/L and hemoglobin \>110 g/L. PD: lymphadenopathy, \>=50% increase in liver or spleen size, \>=50% increase in lymphocyte count, transformation to a more aggressive histology or occurrence of cytopenia. SD: a non-response and used to characterize participants who did not achieve a CR or a PR, and who have not exhibited PD.

Time frame: Baseline up to the completion of treatment assessment 3 months after treatment completion (up to approximately 15 months)

Population: ITT population was defined as all randomized participants.

Time frame: Up to approximately 10.75 years

CRR was defined as the rate of a clinical response of CR or CRi according to IWCLL 2008 criteria. CR requires all of the following: peripheral blood lymphocytes below 4x10\^9/L, absence of lymphadenopathy by physical examination and CT scan, no hepatomegaly or splenomegaly, absence of disease or constitutional symptoms, blood counts of neutrophils \>1.5\*10\^9/L, platelets \>100\*10\^9/L and hemoglobin \>110 g/L, bone marrow at least normocellular for age without clonal infiltrate (except for Cri).

Time frame: At the completion of treatment assessment 3 months after treatment completion (at approximately 15 months)

Population: ITT population was defined as all randomized participants.

OR was defined as complete response (CR), CR with incomplete bone marrow recovery (CRi), or partial response (PR) according to IWCLL 2008 criteria. CR requires all of the following: peripheral blood lymphocytes below 4x10\^9/L, absence of lymphadenopathy by physical examination and computed tomography (CT) scan, no hepatomegaly or splenomegaly, absence of disease or constitutional symptoms, blood counts of neutrophils \>1.5\*10\^9/L, platelets \>100\*10\^9/L and hemoglobin \>110 g/L, bone marrow at least normocellular for age without clonal infiltrate (except for Cri). PR: two of the following features for at least 2 months: \>/= 50% decrease in peripheral blood lymphocyte count from the pretreatment value, \>/=50% reduction in lymphadenopathy, \>/=50% reduction of liver and/or spleen enlargement, and at least one of the following blood counts: neutrophils \>1.5\*10\^9/L, platelets \>100\*10\^9/L and hemoglobin \>110 g/L.

Time frame: At the completion of treatment assessment 3 months after treatment completion (at approximately 15 months)

Population: ITT population was defined as all randomized participants.

Time frame: Baseline up to approximately 10.75 years

Time frame: Baseline up to approximately 10.75 years

MRD negativity was defined as having \< 1 CLL cell per 10,000 leucocytes in peripheral blood.

Time frame: At the completion of treatment assessment 3 months after treatment completion (at approximately 15 months)

Population: ITT population was defined as all randomized participants.

MRD negativity was defined as having \< 1 CLL cell per 10,000 leucocytes in bone marrow.

Time frame: Day 1 Cycle 9 or 3 months after last IV infusion at approximately 9 months

Population: ITT population was defined as all randomized participants.

MRD negativity was defined as having \< 1 CLL cell per 10,000 leucocytes in bone marrow.

Time frame: At the completion of treatment assessment 3 months after treatment completion (at approximately 15 months)

Population: ITT population was defined as all randomized participants.

MRD negativity was defined as having \< 1 CLL cell per 10,000 leucocytes in peripheral blood.

Time frame: Day 1 Cycle 9 or 3 months after last IV infusion, approximately 9 months

Population: ITT population was defined as all randomized participants.

OR was defined as CR, CRi or PR according to IWCLL 2008 criteria. CR required all of the following: peripheral blood lymphocytes below 4x10\^9/L, absence of lymphadenopathy by physical examination, no hepatomegaly or splenomegaly, absence of disease or constitutional symptoms, blood counts of neutrophils \>1.5\*10\^9/L, platelets \>100\*10\^9/L and hemoglobin \>110 g/L. PR: two of the following features for at least 2 months: \>/= 50% decrease in peripheral blood lymphocyte count from the pretreatment value, \>/=50% reduction in lymphadenopathy, \>/=50% reduction of liver and/or spleen enlargement, and at least one of the following blood counts: neutrophils \>1.5\*10\^9/L, platelets \>100\*10\^9/L and hemoglobin \>110 g/L.

Time frame: Day 1 Cycle 7 or 28 days after last IV infusion, approximately 6 months

Population: ITT population was defined as all randomized participants.

Time frame: Pre-venetoclax dose (0 hour) and 4 hours post- venetoclax dose on Day 1 Cycle 4

Population: Analysis population consisted of subjects from whom one or more plasma samples were collected and who had received at least one 400 mg dose of venetoclax. Pre-dose and post-dose data may not come from the same participants. Total number analyzed is therefore higher than the number analyzed for each time point.

PFS was determined according to IWCLL 2008 criteria and defined as the time from randomization to the first occurrence of progressive disease (PD) or death from any cause. Disease progression was characterized by at least one of the following: 1) \>/= 50% increase in the absolute number of circulating lymphocytes to at least 5\*10\^9/L, 2) Appearance of new palpable lymph nodes (\> 15 mm in longest diameter) or any new extra-nodal lesion; 3) \>/= 50% increase in the longest diameter of any previous site of lymphadenopathy; 4) \>/= 50% increase in the enlargement of the liver and/or spleen; 5) Transformation to a more aggressive histology.

Time frame: Baseline until disease progression or death up to approximately 3.75 years

Population: Intent-to-Treat (ITT) population was defined as all randomized participants.

Time frame: Pre-obinutuzumab infusion (0 hour) and end of obinutuzumab infusion on Day 1 Cycle 4

Population: Analysis population consisted of subjects from whom one or more serum samples were collected and who had received at least one dose of obinutuzumab and one dose of 400 mg venetoclax. Pre-dose and post-dose data may not come from the same participants. Total number analyzed is therefore higher than the number analyzed for each time point.

Time frame: Time between the date of randomization and the date of first intake of new anti-leukemic therapy, up to 10.75 years