A Study to Compare the Efficacy and Safety of a Combined Regimen of Venetoclax and Obinutuzumab Versus Fludarabine, Cyclophosphamide, and Rituximab (FCR)/ Bendamustine And Rituximab (BR) in FIT Patients With Previously Untreated Chronic Lymphocytic Leukemia (CLL) Without DEL (17P) or TP53 Mutation

PFS was defined as the time from randomization to the first occurrence of disease progression (PD), or death from any cause. PD was assessed by the investigators using the International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria. PD was defined as any one of the following: Appearance of any new lesion such as enlarged lymph nodes (≥ 1.5 centimeters [cm]); increase by ≥ 50% in greatest diameter of any previous site (≥ 1.5 cm); increase in the spleen/liver size by ≥ 50% or de novo appearance of splenomegaly/hepatomegaly; increase in blood lymphocytes by 50% or more with at least 5x10^9/litres (L) B lymphocytes; transformation to a more aggressive histology; occurrence of cytopenia; post treatment: progression of any cytopenia, documented by a decrease of hemoglobin (Hb) ≥ 2 grams per deciliter (g/dL) or 10 g/dL, or by a decrease of platelet counts ≥ 50%/100x10^9/L, which occurs at least 3 months after treatment. Kaplan-Meier (K-M) method was used to determine PFS.

MRD response rate was determined as the percentage of participants with MRD-negativity measured in the PB using NGS using a cutoff of < 10^-4. MRD was considered negative if the result was < 1 CLL cell in 10,000 leukocytes. Percentages have been rounded off to the nearest decimal point.

MRD response rate=percentage of participants with MRD-negativity measured in BM using NGS (cutoff of <10^-4). MRD negativity=<1 CLL cell in 10,000 leukocytes. MRD in BM was assessed for participants with complete response (CR)/CR with incomplete blood count recovery (CRi) \& partial response (PR). CR=PB lymphocytes <4x10^9 /L; Absence of significant lymphadenopathy (nodes <1.5 cm in longest diameter); no hepatomegaly/splenomegaly; absence of disease/constitutional symptoms; BM at least normocellular for age, ≤30% of nucleated cells being lymphocytes. CRi=fulfilling CR criteria but with persistent anemia/thrombocytopenia/neutropenia. PR= ≥50% decrease in PB lymphocyte count from pre-treatment value; ≥50% reduction in lymphadenopathy (sum of longest diameter of up to 6 largest lymph nodes by physical exam \& 50% reduction in the sum of product of the diameter of up to 6 largest lymph nodes); ≥50% reduction of liver/spleen enlargement/normalization in size, if enlarged at baseline.

ORR was defined as the percentage of participants with overall response (OR) of CR, CRi, and PR as determined by the investigator according to the iwCLL guidelines. CR was defined as PB lymphocytes <4x10^9 /L; absence of significant lymphadenopathy (nodes <1.5 cm in longest diameter [LD]); no hepatomegaly/splenomegaly; absence of disease/constitutional symptoms; BM at least normocellular for age, ≤30% of nucleated cells being lymphocytes. CRi was defined as fulfilling CR criteria but with persistent anemia/thrombocytopenia/neutropenia. PR was defined as ≥50% decrease in PB lymphocyte count from pre-treatment value; ≥50% reduction in lymphadenopathy sum of longest diameter of up to 6 largest lymph nodes by physical exam and 50% reduction in the sum of product of the diameter of up to 6 largest lymph nodes); ≥50% reduction of liver/spleen enlargement/normalization in size, if enlarged at baseline.

CR rate was defined as the percentage of participants with CR or CRi. CR/CRi were defined according to the iwCLL guidelines. CR was defined as one of the following: PB lymphocytes (evaluated by blood and differential count) below 4 x 10^9 /L; absence of significant lymphadenopathy (nodes < 1.5 cm in LD or any extra nodal disease); no hepatomegaly; no splenomegaly; absence of disease or constitutional symptoms; BM at least normocellular for age, ≤30% of nucleated cells being lymphocytes. CRi was defined as participants fulfilling CR criteria but had persistent anemia, thrombocytopenia, or neutropenia. Percentages have been rounded off to the nearest decimal point.

MRD response rate was determined as the percentage of participants (with a CR/CRi) with MRD-negativity measured in the PB using NGS using a cutoff of < 10^-4. MRD was considered negative if the result was < 1 CLL cell in 10,000 leukocytes. CR/CRi were defined according to the iwCLL guidelines. CR was defined as one of the following: PB lymphocytes below 4 x 10^9 /L; absence of significant lymphadenopathy (nodes < 1.5 cm in LD or any extra nodal disease); no hepatomegaly; no splenomegaly; absence of disease or constitutional symptoms; BM at least normocellular for age, ≤30% of nucleated cells being lymphocytes. CRi was defined as participants fulfilling CR criteria but had persistent anemia, thrombocytopenia, or neutropenia. Percentages have been rounded off to the nearest decimal point.

MRD response rate was determined as the percentage of participants (with CR/CRi) with MRD-negativity measured in the BM using NGS using a cutoff of < 10^-4. MRD was considered negative if the result was < 1 CLL cell in 10,000 leukocytes. CR/CRi were defined according to the iwCLL guidelines. CR was defined as one of the following: PB lymphocytes below 4 x 10^9 /L; absence of significant lymphadenopathy (nodes < 1.5 cm in LD or any extra nodal disease); no hepatomegaly; no splenomegaly; absence of disease or constitutional symptoms; BM at least normocellular for age, ≤30% of nucleated cells being lymphocytes. CRi was defined as participants fulfilling CR criteria with CR but had persistent anemia, thrombocytopenia, or neutropenia. Percentages have been rounded off to the nearest decimal point.

DOR=time from first occurrence of a documented objective response (CR, CRi \& PR) to the time of PD as determined by the investigator, or death from any cause, whichever occurred first. CR, CRi, PR, \& PD were defined per the iwCLL guidelines. PD = any one of the following: appearance of any new lesion such as enlarged lymph nodes (≥ 1.5 cm); increase by ≥ 50% in greatest diameter of any previous site (≥ 1.5 cm); increase in the spleen/liver size by ≥ 50% or de novo appearance of splenomegaly/hepatomegaly; increase in blood lymphocytes by 50% or more with at least 5x10^9/L B lymphocytes; transformation to a more aggressive histology; occurrence of cytopenia; posttreatment: progression of any cytopenia, documented by a decrease of Hb ≥ 2 g/dL or 10 g/dL, or by a decrease of platelet counts ≥ 50%/100x10^9/L, which occurs at least 3 months after treatment. CR, CRi \& PR were defined as outlined in the description for ORR outcome measure. K-M method was used to determine DOR.

BOR=percentage of participants with CR/CRi/PR/stable disease (SD)/PD per the investigator. Participants with best response as CR/CRi/PR were considered responders while those reaching SD/PD were non-responders. SD=participants who have not achieved a CR or a PR, or who have not exhibited PD. PD=any one of the following: appearance of any new lesion such as enlarged lymph nodes (≥ 1.5 cm); increase by ≥ 50% in greatest diameter of any previous site (≥ 1.5 cm); increase in the spleen/liver size by ≥ 50% or de novo appearance of splenomegaly/hepatomegaly; increase in blood lymphocytes by 50% or more with at least 5x10^9/L B lymphocytes; transformation to a more aggressive histology; occurrence of cytopenia; posttreatment: progression of any cytopenia, documented by a decrease of Hb ≥ 2 g/dL or 10 g/dL, or by a decrease of platelet counts ≥ 50%/100x10^9/L, which occurs at least 3 months after treatment. CR, CRi and PR were defined as outlined in the description for ORR, OM number 5.

EFS was defined as the time between the date of randomization and the date of PD/relapse, death, or the start of a new anti-leukemic therapy. PD was defined as any one of the following: appearance of any new lesion such as enlarged lymph nodes (≥ 1.5 cm); increase by ≥ 50% in greatest diameter of any previous site (≥ 1.5 cm); increase in the spleen/liver size by ≥ 50% or de novo appearance of splenomegaly/hepatomegaly; increase in blood lymphocytes by 50% or more with at least 5x10^9/L B lymphocytes; transformation to a more aggressive histology; occurrence of cytopenia; posttreatment: progression of any cytopenia, documented by a decrease of Hb ≥ 2 g/dL or 10 g/dL, or by a decrease of platelet counts ≥ 50%/100x10^9/L, which occurs at least 3 months after treatment. K-M method was used to determine EFS.

OS was defined as the time between the date of randomization and the date of death due to any cause. K-M method was used to determine OS.

TLS risk reduction rate in the VEN + G arm was defined as the reduction in the percentage of participants who were TLS high-risk after 3 doses of obinutuzumab compared to the percentage of participants who were TLS high-risk at baseline. Risk for developing TLS were categorised into: Low - All measurable lymph nodes with the LD < 5 cm and < 25x10^9/L absolute lymphocyte count (ALC); Medium - Any measurable lymph node with the LD ≥5 cm but <10 cm OR ≥25x10^9/L ALC; High - Any measurable lymph node with the LD ≥10 cm or the presence of both ≥25x10^9/L ALC and any measurable lymph node with the LD ≥5 cm but <10 cm. Percentages have been rounded off to the nearest decimal point.

Reduction in mandatory hospitalizations during venetoclax ramp-up in the VEN + G arm participants was defined as the actual number of protocol-mandated hospitalizations for TLS monitoring during venetoclax ramp-up period after 3 doses of obinutuzumab compared to the number of protocol-mandated hospitalizations for TLS monitoring during venetoclax ramp-up expected at baseline. Ramp-up period for venetoclax was defined as period from Cycle 1, Days 22-28, and Cycle 2, Day 1-Day 7 where the 20 mg and 50 mg daily doses of venetoclax, were administered for participants at TLS-high risk requiring mandated hospitalizations (the hospitalizations at 100, 200 and 400 was only needed if the participant had a TLS event at one of the lower doses). Total number of hospitalizations in high-risk TLS participants at baseline (expected to be N=2 hospitalization) was compared with the number of protocol mandated hospitalizations during the first 2 doses of the ramp-up.

An AE was any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product, regardless of causal attribution. An AE can be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. A SAE was any AE that meets any of the following criteria: is fatal; is life-threatening; requires or prolongs inpatient hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to study drug; is a significant medical event in the investigator's judgment.

An AE was any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product, regardless of causal attribution. An AE can be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Participants who withdrew from the study due to AEs are being reported here.

The EORTC QLQ-C30 consists of 30 questions incorporated into 5 functional scales (physical, role, cognitive, emotional and social scales), 3 symptom scales (fatigue, pain, nausea, and vomiting scales), a global health status/global quality-of-life (GHS/QoL) scale, and 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). The functioning items were scored on a 4-point scale (1=Not at All to 4=Very Much). Raw average scale scores were linearly transformed to range from 0-100. Higher scores=higher response levels (i.e. higher functioning). FAS. Overall number analyzed=participants with data available for analysis. Number analyzed includes all with data at a given timepoint.

Time frame continued: Day 28 After Completion/Early Termination (ET) of Combination Therapy (VEN+G)/Day 28 After Treatment Completion (TC)/ET (FCR/BR)=Up to approximately 5.6 months; Change at Day 28 After TC/EC of Ven Monotherapy=Up to approximately 11 months.

The EORTC QLQ-C30 consists of 30 questions incorporated into five functional scales (physical, role, cognitive, emotional and social scales), three symptom scales (fatigue, pain, nausea, and vomiting scales), a GHS/QoL scale, and six single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). The functioning items were scored on a 4-point scale (1=Not at All to 4=Very Much). Raw average scale scores were linearly transformed to range 0-100 with higher scores indicating higher response levels (i.e. higher functioning). FAS. Overall number analyzed=participants with data available for analysis. Number analyzed is the number of participants with data available for analysis at a given timepoint.

Time frame continued: Day 28 After Completion/ ET of Combination Therapy (VEN+G)/Day 28 After TC/ET (FCR/BR)=Up to approximately 5.6 months; Change at Day 28 After TC/EC of Ven Monotherapy=Up to approximately 11 months.

The EORTC QLQ-C30 consists of 30 questions incorporated into five functional scales (physical, role, cognitive, emotional and social scales), three symptom scales (fatigue, pain, nausea, and vomiting scales), a GHS/QoL scale, and six single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). The 2 GHS/QoL items were scored on a 7-point scale (1= Very poor to 7=Excellent). Raw average scale scores were linearly transformed to range 0-100 with higher scores indicating higher response levels (i.e. better QoL). FAS. Overall number analyzed=participants with data available for analysis. Number analyzed is the number of participants with data available for analysis at a given timepoint.

Time frame continued (TFC): Day 28 After Completion/ET of Combination Therapy (VEN+G)/Day 28 After TC/ET (FCR/BR)=Up to approximately (approx) 5.6 months; Change at Day 28 After TC/EC of Ven Monotherapy=Up to approximately 11 months.

MDASI-CLL=25 items over 3 scales assessing core cancer \& CLL-related symptom severity \&symptom interference that a participant may have experienced in past 24 hours. Participants rated severity of 13 symptoms called mean core symptom severity (pain, fatigue, nausea, disturbed sleep, distressed, shortness of breath, remembering things, lack of appetite, drowsy, dry mouth, sadness, vomiting \& numbness/tingling) to assess mean core symptom severity score. Each symptom is scored from 0 (not present)-10 (as bad as you can imagine). Total score across all questions(0-130) was divided by number of questions. Mean score, ranged from 0-10. Lower scores=lower symptom severity. FAS. Overall number analyzed=participants with data available for analysis. Number analyzed includes all with data at a given timepoint.

TFC: Day 28 After Completion/ET of Combination Therapy (VEN+G)/Day 28 After TC/ET (FCR/BR)=Up to approx 5.6 months; Change at Day 28 After TC/EC of Ven Monotherapy=Up to approx11 months.

MDASI-CLL=25 items over 3 scales that assess core cancer \& CLL-related symptom severity, as well as symptom interference a participant may have experienced in past 24 hours. Participants were asked to rate the severity of 6 disease-specific symptoms called mean module symptom severity (night sweats, fever \& chills, lymph node swelling, diarrhea, easy bruising/bleeding \& constipation). Each symptom is scored on scale from 0-10, where 0=not present \& 10=as bad as you can imagine. The total score across all questions (0 to 60) was divided by the number of questions. The mean score, therefore, ranged from 0-10. Higher scores indicated more symptom severity. FAS. Overall number analyzed=participants with data available for analysis. Number analyzed includes all with data at a given timepoint.

Time frame continued: Day 28 After Completion/ET of VEN+G/Day 28 After TC/ET (FCR/BR)=Up to approximately 5.6 months; Change at Day 28 After TC/EC of Ven Monotherapy=Up to approximately 11 months.

MDASI-CLL consists of 25 items over 3 scales that assess core cancer \& CLL-related symptom severity, and symptom interference that a participant may have experienced in past 24 hours. Participants rated 6 mean interference on life questions (general activity, walking, work, mood, relations with other people \& enjoyment of life) to derive the Mean Interference Score. These were scored on a scale from 0 (symptom did not interfere)-10 (symptom interfered completely). Total score across all questions (0 to 60) was divided by number of questions. Mean score, therefore, ranged from 0-10. Higher scores=higher symptom interference. FAS. Overall number analyzed=participants with data available for analysis. Number analyzed=participants with data available for analysis at a given timepoint.

Time frame continued: Day 28 After Completion/ ET of Combination Therapy (VEN+G)/Day 28 After TC/ET (FCR/BR)=Up to approx 5.6 months; Change at Day 28 After TC/EC of Ven Monotherapy=Up to approx 11 months.