A Study of Venetoclax in Combination With Low Dose Cytarabine Versus Low Dose Cytarabine Alone in Treatment Naive Patients With Acute Myeloid Leukemia Who Are Ineligible for Intensive Chemotherapy

Overall survival is defined as the time from the date of randomization to the date of death. Participants who had not died were censored at the date they were last known to be alive on or before the cutoff date. Overall survival was analyzed using Kaplan-Meier methodology.

Time frame: From randomization until the primary analysis cut-off date of February 15 2019; the median follow-up time was 12.0 months (range: 0.2-17.0) in the placebo arm and 12.0 months (range: 0.1-17.6) in the venetoclax arm.

Population: The full analysis set included all randomized participants.

The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core (EORTC QLQ-C30) consists of a Global Health Status/Quality of Life (GHS/QoL) scale, a Financial Difficulties scale, 5 functional scales (Cognitive, Social, Physical, Emotional, and Role Functioning), and 8 symptom scales/items (Fatigue, Insomnia, Appetite Loss, Pain, Constipation, Diarrhea, Dyspnea, and Nausea and Vomiting). The GHS/QoL scale includes 2 questions in which participants were asked to rate their overall health and overall quality of life during the past week on a scale from 1 (very poor) to 7 (excellent). The 2 scores were averaged and transformed to a scale from 0 to 100, where a high score represents a high QoL. A positive change from baseline indicates better quality of life.

Time frame: Baseline and Day 1 of Cycles 3, 5, 7, and 9

Population: Full analysis set with available data at Baseline and each time point

PROMIS Fatigue SF 7a is a seven-item questionnaire that assesses the impact and experience of fatigue over the past 7 days. All questions employ the following five response options: 1 = Never, 2 = Rarely, 3 = Sometimes, 4 = Often, and 5 = Always. The PROMIS Fatigue 7a score is calculated as a T-score, which is a standardized score with a mean of 50 (based on the average for the United States general population) and a standard deviation (SD) of 10. Higher scores indicate higher levels of fatigue. A decrease in score (negative change from Baseline) indicates improvement in fatigue; the minimum important difference used in this study was 3 points.

Time frame: Baseline and Day 1 of Cycles 3, 5, 7, and 9

Population: Full analysis set with available data at baseline and each time point

Event-free survival is defined as the time from randomization to the date of progressive disease (PD), confirmed morphologic relapse from CR or CRi, treatment failure (failure to achieve CR, CRi or morphologic leukemia free state (MLFS) after at least 6 cycles of study treatment), or death from any cause, assessed by the investigator according to the modified IWG criteria. PD: * \> 50% increase in marrow blasts (minimum 15% increase required if blasts \< 30% at baseline); or persistent marrow blast \> 70% for ≥ 3 months; without at least a 100% improvement in ANC to an absolute level \> 0.5 × 10⁹/L, and/or platelets to \> 50 × 10⁹/L non-transfused; or * 50% increase in peripheral blasts to \> 25 × 10⁹/L; or * New extramedullary disease Participants with no events prior to the cut-off date were censored at their last assessment date; participants with no events prior to post-treatment therapy initiated before the cut-off date were censored on the start date of post-treatment therapy.

Time frame: From randomization until the primary analysis cut-off date of February 15, 2019; the median follow-up time was 12.0 months (range: 0.2-17.0) in the placebo arm and 12.0 months (range: 0.1-17.6) in the venetoclax arm.

Population: Full analysis set

Overall survival is defined as the time from the date of randomization to the date of death. Participants who had not died were censored at the date they were last known to be alive on or before the cutoff date. Overall survival was analyzed using Kaplan-Meier methodology. Overall survival was analyzed in participants with the following molecular markers: * Isocitrate dehydrogenase 1 and 2 (IDH1/2) mutation * FMS (Feline McDonough Sarcoma)-like tyrosine kinase 3 (FLT3) mutation

Time frame: From randomization until the primary analysis cut-off date of February 15, 2019; the median follow-up time was 12.0 months (range: 0.2-17.0) in the placebo arm and 12.0 months (range: 0.1-17.6) in the venetoclax arm.

Population: The full analysis set; participants in each mutation subgroup

The complete remission rate is defined as the percentage of participants with complete remission (CR) at any time during the study as assessed by the investigator. Response was based on physical examination, bone marrow results and hematology values according to the revised guidelines by the International Working Group (IWG) for AML. CR is defined as no morphologic evidence of AML and absolute neutrophil count ≥ 10³/μL, platelets ≥ 10⁵/μL, red blood cell transfusion independence, and bone marrow with \< 5% blasts, absence of circulating blasts and blasts with Auer rods; absence of extramedullary disease. Participants who had no IWG disease assessments were considered to be non-responders.

Time frame: Response was assessed at the end of Cycle 1 and every 3 cycles thereafter to the end of treatment. Median treatment duration at the 15 February 2019 cut-off date was 1.7 months (range: 0.1-14.2) and 3.9 months (range: 0.0-17.1) in each group respectively.

Population: Full analysis set

The percentage of participants who achieved a complete remission (CR) or complete remission with partial hematologic recovery (CRh) before initiation of Cycle 2 assessed by the investigator. CR is defined according to the revised guidelines by the IWG for AML as no morphologic evidence of AML, ANC count ≥ 10³/μL, platelets ≥ 10⁵/μL, RBC transfusion independence, and bone marrow with \< 5% blasts, absence of circulating blasts and blasts with Auer rods; absence of extramedullary disease. CRh is a derived response based on bone marrow blast and hematology lab values, achieved when when the following criteria are met: * Bone marrow with \< 5% blasts and * Peripheral blood neutrophil count of \> 0.5 × 10³/μL and * Peripheral blood platelet count of \> 0.5 × 10⁵/μL and * A 1-week platelet transfusion-free period prior to the hematology lab collection. Participants with no disease assessments were considered to be non-responders.

Time frame: Cycle 1, 28 days

Population: Full analysis set

The composite complete remission rate is defined as the percentage of participants with complete remission (CR) or complete remission with incomplete blood count recovery (CRi) at any time during the study as assessed by the investigator. Response was based on physical examination, bone marrow results and hematology values according to the revised guidelines by the International Working Group (IWG) for AML: CR: No morphologic evidence of AML and absolute neutrophil count (ANC) ≥ 10³/μL (1,000/μL), platelets ≥ 10⁵/μL (100,000/μL), red blood cell (RBC) transfusion independence, and bone marrow with \< 5% blasts, absence of circulating blasts and blasts with Auer rods; absence of extramedullary disease. CRi: All criteria as CR except for residual neutropenia \< 10³/μL or thrombocytopenia \< 10⁵/μL. If all criteria for CR are met except RBC transfusion independence, the CRi criteria are met. Participants who had no IWG disease assessments were considered to be non-responders.

Time frame: Response was assessed at the end of Cycle 1 and every 3 cycles thereafter to the end of treatment. Median treatment duration at the 15 February 2019 cut-off date was 1.7 months (range: 0.1-14.2) and 3.9 months (range: 0.0-17.1) in each group respectively.

Population: Full analysis set

The percentage of participants with complete remission or complete remission with incomplete blood count recovery AND minimal residual disease (MRD) as assessed by the investigator. Response was based on the modified IWG response criteria for AML: CR: No morphologic evidence of AML and ANC ≥ 10³/μL, platelets ≥ 10⁵/μL, red blood cell (RBC) transfusion independence, and bone marrow with \< 5% blasts, absence of circulating blasts and blasts with Auer rods; absence of extramedullary disease. CRi: All criteria as CR except for residual neutropenia \< 10³/μL or thrombocytopenia \< 10⁵/μL. If all criteria for CR are met except RBC transfusion independence, CRi criteria are met. MRD response (at lowest-point MRD value) was defined as having less than 10-³ residual blasts per leukocyte measured in the bone marrow, per European LeukemiaNet (ELN) recommendations. Participants who had no disease or MRD assessments were considered to be non-responders.

Time frame: Response was assessed at the end of Cycle 1 and every 3 cycles thereafter to the end of treatment. Median treatment duration at the 15 February 2019 cut-off date was 1.7 months (range: 0.1-14.2) and 3.9 months (range: 0.0-17.1) in each group respectively.

Population: Full analysis set

The composite complete remission rate is defined as the percentage of participants with complete remission (CR) or complete remission with incomplete blood count recovery (CRi) before initiation of Cycle 2, assessed by the investigator. Response was based on physical examination, bone marrow results and hematology values according to the revised guidelines by the IWG for AML: CR: No morphologic evidence of AML and absolute neutrophil count ≥ 10³/μL, platelets ≥ 10⁵/μL, red cell transfusion independence, and bone marrow with \< 5% blasts, absence of circulating blasts and blasts with Auer rods; absence of extramedullary disease. CRi: All criteria as CR except for residual neutropenia \< 10³/μL or thrombocytopenia \< 10⁵/μL. If all criteria for CR are met except for RBC transfusion independence, CRi criteria are met. Participants who had no IWG disease assessments were considered to be non-responders.

Time frame: Cycle 1, 28 days

Population: Full analysis set

Response was based on physical examination, bone marrow results and hematology values according to the revised guidelines by the IWG for AML: CR: No morphologic evidence of AML and ANC ≥ 10³/μL, platelets ≥ 10⁵/μL, RBC transfusion independence, and bone marrow with \< 5% blasts, absence of circulating blasts and blasts with Auer rods; absence of extramedullary disease. CRi: All criteria as CR except for residual neutropenia \< 10³/μL or thrombocytopenia \< 10⁵/μL. If all criteria for CR are met except RBC transfusion independence, CRi criteria is met. Participants who had no IWG disease assessments were considered to be non-responders. Response was analyzed in participants with the following mutations: * Isocitrate dehydrogenase 1 and 2 (IDH1/2) mutation * FMS-like tyrosine kinase 3 (FLT3) mutation

Time frame: Response was assessed at the end of Cycle 1 and every 3 cycles thereafter to the end of treatment. Median treatment duration at the 15 February 2019 cut-off date was 1.7 months (range: 0.1-14.2) and 3.9 months (range: 0.0-17.1) in each group respectively.

Population: Full analysis set participants in each mutation subgroup

The percentage of participants who achieved a complete remission (CR) or complete remission with partial hematologic recovery (CRh) at any time point during the study assessed by the investigator. CR is defined according to the revised guidelines by the IWG for AML as no morphologic evidence of AML, ANC count ≥ 10³/μL, platelets ≥ 10⁵/μL, RBC transfusion independence, and bone marrow with \< 5% blasts, absence of circulating blasts and blasts with Auer rods; absence of extramedullary disease. CRh is a derived response based on bone marrow blast and hematology lab values, achieved when the following criteria are met: * Bone marrow with \< 5% blasts and * Peripheral blood neutrophil count of \> 0.5 × 10³/μL and * Peripheral blood platelet count of \> 0.5 × 10⁵/μL and * A 1 week platelet transfusion-free period prior to the hematology lab collection. Participants with no disease assessments were considered to be non-responders.

Time frame: Response was assessed at the end of Cycle 1 and every 3 cycles thereafter to the end of treatment. Median treatment duration at the 15 February 2019 cut-off date was 1.7 months (range: 0.1-14.2) and 3.9 months (range: 0.0-17.1) in each group respectively.

Population: Full analysis set

The percentage of participants with complete remission or complete remission with partial hematologic recovery (CRh) AND MRD response as assessed by the investigator. CR is defined according to the modified IWG response criteria for AML as no morphologic evidence of AML, ANC ≥ 10³/μL, platelets ≥ 10⁵/μL, RBC transfusion independence, and bone marrow with \< 5% blasts, absence of circulating blasts and blasts with Auer rods; absence of extramedullary disease. CRh is achieved when the following criteria are met: * Bone marrow with \< 5% blasts and * Peripheral blood neutrophil count of \> 0.5 × 10³/μL and * Peripheral blood platelet count of \> 0.5 × 10⁵/μL and * A 1 week platelet transfusion-free period prior to the hematology lab collection. MRD response (at lowest-point MRD value) was defined as less than 10-³ residual blasts per leukocyte measured in the bone marrow, per ELN recommendations. Participants who had no disease or MRD assessments were considered to be non-responders.

Time frame: Response was assessed at the end of Cycle 1 and every 3 cycles thereafter to the end of treatment. Median treatment duration at the 15 February 2019 cut-off date was 1.7 months (range: 0.1-14.2) and 3.9 months (range: 0.0-17.1) in each group respectively.

Population: Full analysis set

The percentage of participants who achieved a complete remission or complete remission with partial hematologic recovery assessed by the investigator for participants with the following mutations: * Isocitrate dehydrogenase 1 and 2 (IDH1/2) mutation * FMS-like tyrosine kinase 3 (FLT3) mutation CR is defined according to the modified IWG criteria for AML as no morphologic evidence of AML, ANC ≥ 10³/μL, platelets ≥ 10⁵/μL, RBC transfusion independence, bone marrow with \< 5% blasts, absence of circulating blasts and blasts with Auer rods; absence of extramedullary disease. CRh is achieved when the following criteria are met: * Bone marrow with \< 5% blasts and * Peripheral blood neutrophil count \> 0.5 × 10³/μL and * Peripheral blood platelet count \> 0.5 × 10⁵/μL and * A 1 week platelet transfusion-free period prior to hematology lab collection. Participants with no disease assessments were considered non-responders

Time frame: Response was assessed at the end of Cycle 1 and every 3 cycles thereafter to the end of treatment. Median treatment duration at the 15 February 2019 cut-off date was 1.7 months (range: 0.1-14.2) and 3.9 months (range: 0.0-17.1) in each group respectively.

Population: Full analysis set participants in each mutation subgroup

The rate of conversion was calculated as the percentage of participants who were post-baseline platelet transfusion independent among participants who had a platelet transfusion within 8 weeks prior to the first dose of study drug (i.e. were transfusion dependent at Baseline). Platelet transfusion independence is defined as a period of at least 56 days with no platelet transfusion after the first dose of study drug and on or before the last dose of study drug plus 30 days, or disease progression, or confirmed morphological relapse, or death, or the data cut-off date, whichever occurred earlier.

Time frame: From first dose of study drug until 30 days after last dose up to the data cut-off date of 15 February 2019; Median time on treatment was 1.7 months (range: 0.1-14.2) in the placebo arm and 3.9 months (range: 0.0-17.1) in the venetoclax arm.

Population: Full analysis participants who were platelet transfusion dependent at Baseline

The post baseline platelet transfusion independence rate was calculated as the percentage of participants who achieved platelet transfusion independence post Baseline. Platelet transfusion independence is defined as a period of at least 56 consecutive days with no platelet transfusion after the first dose of study drug and on or before the last dose of study drug plus 30 days, or disease progression, or confirmed morphological relapse, or death, or the data cut--off date, whichever occurred earlier.

Time frame: From first dose of study drug until 30 days after last dose up to the data cut-off date of 15 February 2019; Median time on treatment was 1.7 months (range: 0.1-14.2) in the placebo arm and 3.9 months (range: 0.0-17.1) in the venetoclax arm.

Population: Full analysis set

The post baseline red blood cell (RBC) transfusion independence rate was calculated as the percentage of participants who achieved RBC transfusion independence post baseline. RBC transfusion independence is defined as a period of at least 56 consecutive days with no RBC transfusion after the first dose of study drug and on or before the last dose of study drug plus 30 days, or disease progression, or confirmed morphological relapse, or death, or the data cut-off date, whichever occurred earlier.

Time frame: From first dose of study drug until 30 days after last dose up to the data cut-off date of 15 February 2019; Median time on treatment was 1.7 months (range: 0.1-14.2) in the placebo arm and 3.9 months (range: 0.0-17.1) in the venetoclax arm.

Population: Full analysis set

The rate of conversion was calculated as the percentage of participants who were post-baseline RBC transfusion independent among participants who had an RBC transfusion within 8 weeks prior to the first dose of study drug (i.e. were transfusion dependent at Baseline). RBC transfusion independence is defined as a period of at least 56 days with no RBC transfusion after the first dose of study drug and on or before the last dose of study drug plus 30 days, or disease progression, or confirmed morphological relapse, or death, or the data cut-off date, whichever occurred earlier.

Time frame: From first dose of study drug until 30 days after last dose up to the data cut-off date of 15 February 2019; Median time on treatment was 1.7 months (range: 0.1-14.2) in the placebo arm and 3.9 months (range: 0.0-17.1) in the venetoclax arm.

Population: Full analysis set participants who were RBC transfusion-dependent at Baseline

Overall survival is defined as the time from the date of randomization to the date of death. Participants who had not died were censored at the date they were last known to be alive on or before the cutoff date. Overall survival was analyzed using Kaplan-Meier methodology.

Time frame: From randomization until the 6-month follow-up analysis cut-off date of August 15, 2019; the median follow-up time was 17.7 months (range: 0.2-20.8) in the placebo arm and 17.5 months (range: 0.1-23.5) in the venetoclax arm.

Population: Full analysis set