A Study Evaluating Safety and Efficacy of Venetoclax in Combination With Azacitidine Versus Standard of Care After Allogeneic Stem Cell Transplantation (SCT) in Participants With Acute Myeloid Leukemia (AML)

• Venetoclax (Drug), also known as ABT-199, GDC-0199, VENCLEXTA: Tablet; Oral
• Azacitidine (Drug): Subcutaneous (SC) or intravenous (IV) injection
• Best Supportive Care (BSC) (Other): BSC is the best supportive care, without AML directed therapy, determined per the investigator and institutional guidelines.

Primary outcomes

• Number of Participants With Dose-Limiting Toxicities (DLTs) Following Administration of Venetoclax and Azacitidine (Part 1) [Up to 28 days]: DLTs were any of the hematologic, nonhematologic toxicities, adverse events (AEs) occurring following administration of venetoclax and AZA as described in the protocol and evaluated by the Investigator and the sponsor.
• Overall Survival (OS) (Part 2) [Up to approximately 41 months]: OS was defined as the time from the date of randomization to the date of death from any cause.

Secondary outcomes

• Morphologic Relapse-Free Survival (RFS) (Part 2) [Up to approximately 41 months]: Morphologic relapse from AML was defined as bone marrow blasts of >= 5% or reappearance of blasts in the peripheral blood not attributable to any other cause (e.g., bone marrow regeneration) in at least 2 peripheral blood samples at least one week apart or development of extramedullary disease after achieving a complete remission (CR) or complete remission with incomplete count recovery (CRi); or the date of death from any cause, whichever comes first as determined by the investigator.
• Composite Relapse-Free Survival (RFS) (Part 2) [Up to approximately 41 months]: Composite RFS was defined as the time from randomization from either morphologic relapse from AML, or non-morphologic relapse from AML, whichever comes first. Non-morphologic relapse from AML was defined as increase in disease burden determined by standard methods with reappearance or acquisition of new findings with or without change in anti-leukemic treatment per investigator decision due to cytogenetic abnormalities or change in molecular marker or measurable residual disease by multiparameter flow with sensitivity to at least 10\^-3; or the date of death from any cause, whichever came first as determined by the investigator.
• Graft-versus-Host Disease (GvHD)-Free, Relapse Free Survival (GRFS) (Part 2) [Up to approximately 41 months]: GRFS was defined as the time from the date of randomization to occurrence of disease relapse or incidence of GvHD or death from any cause.
• Rate of Participants Without Higher Grade of GvHD (Part 2) [90 days after randomization]: Rate of Participants without higher grade of GvHD was defined as the percentage of participants without grade 2 or higher for acute graft-versus-host disease (aGvHD) and moderate/severe for chronic graft-versus-host disease (cGvHD) assessed by investigator at 90 days after randomization.
• Change From Baseline in Physical Functioning Subscore as Measured by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-C30) (Part 2) [Baseline, Month 6]: The EORTC QLQ-C30 is a 30-item participant self-report questionnaire composed of both multi-item and single scales. The physical functioning score, reported here, ranged from 0 to 100, with a higher score indicating a better level of functioning. Positive changes from baseline indicate improvement.
• Change From Baseline in Patient Reported Outcomes Measurement Information System (PROMIS) Cancer Fatigue Short Form (SF) 7a Score (Part 2) [Baseline, Month 6]: PROMIS Cancer Fatigue SF 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 = Not at all, 2 = A little bit, 3 = Somewhat, 4 = Quite a bit, and 5 = Very much. The total raw score is the sum of the responses to each question and is converted to a T-score. The T-score re-scales the total raw score to a standardized score with a mean of 50 and a standard deviation of 10. T-Scores range from 29.4 to 83.2, with higher scores indicating more fatigue. Negative changes from baseline indicate improvement.
• Percentage of Participants With Measurable Residual Disease (MRD) Conversion in Participants With MRD >= 10^-3 at Baseline (Part 2) [Up to approximately 41 months]: MRD conversion rate was defined as the percentage of participants who convert to MRD < 10\^-3 after initiation of treatment. The population for MRD analysis included participants whose bone marrow was MRD positive (>=10\^-3, as determined by central flow cytometry) at baseline prior to randomization.
• Time to Deterioration in Global Health Status (GHS)/Quality of Life (QoL) in Adult Participants (Part 2) [Up to approximately 41 months]: Time to deterioration was defined as number of days from randomization to either deterioration of >= 5 points based on the EORTC QLQ-C30 version 3 or death due to any cause. 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.
• Change From Baseline in European Quality-of-Life-5 Dimensional-5-Level (EQ-5D-5L) Score [Baseline, Month 6]: The EQ-5D-5L is a generic preference instrument that has been validated in numerous populations and has 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression, each of which are rated on five levels of severity (1: no problems, 2: slight problems, 3: moderate problems, 4: severe problems, 5: extreme problems) with higher scores representing higher symptom burden. A negative change from baseline indicates improvement in health status.

Sex: All, ages: 12 Years to any

Inclusion Criteria:

* Participants must be at least 18 years old for Part 1 and, at least 12 years old for Part 2.
* Participant must be diagnosed with Acute Myeloid Leukemia (AML) by World Health Organization (WHO) criteria (2017) and either be planning for allogeneic stem cell transplantation or have received allogeneic stem cell transplantation within the past 60 days.
* Blast percentage in bone marrow before transplant must be < 10%.
* Blast count in peripheral blood must be "0" and Blast percentage in bone marrow must be < 5% after transplant.
* Participant meet adequate renal, hepatic and hematologic criteria as described in the protocol.
* Participants >= 17 years old must have a Karnofsky Performance Scale (KPS) score > 50 and participants between 12 to 16 years old must have a Lansky Play Performance Scale score > 40.

Exclusion Criteria:

* History of disease progression during prior treatment with venetoclax.
* History of any other malignancy within 2 years prior to study entry, except for: Adequately treated in situ carcinoma of the cervix uteri or carcinoma in situ of breast; basal cell carcinoma of the skin or localized squamous cell carcinoma of the skin; previous malignancy confined and surgically resected (or treated with other modalities) with curative intent; Myelodysplastic Syndrome, Myeloproliferative neoplasm (only allowed if it transformed to AML and AML should be the indication for marrow transplantation).
* Participant has known infection with HIV or history of being positive for hepatitis B virus (HBV) or hepatitis C virus (HCV) infection.
* Presence of clinical or laboratory symptoms/signs of extramedullary myeloid malignancy.

Participant flow

Outcome results

• Number of Participants With Dose-Limiting Toxicities (DLTs) Following Administration of Venetoclax and Azacitidine (Part 1) (Primary), Count of participants, Participants: Part 1: Venetoclax 200 mg QD 28 Days + Azacitidine 20 mg/m^2 QD 3; Part 1: Venetoclax 200 mg QD 14 Days + Azacitidine 20 mg/m^2 QD 0
• Overall Survival (OS) (Part 2) (Primary), Median, months: Part 2: Best Supportive Care NA (NA to NA); Part 2: Venetoclax 200 mg QD 28 Days + Azacitidine 20 mg/m^2 QD NA (NA to NA)
• Morphologic Relapse-Free Survival (RFS) (Part 2) (Secondary), Median, months: Part 2: Best Supportive Care NA (34.45 to NA); Part 2: Venetoclax 200 mg QD 28 Days + Azacitidine 20 mg/m^2 QD NA (NA to NA)
• Composite Relapse-Free Survival (RFS) (Part 2) (Secondary), Median, months: Part 2: Best Supportive Care NA (35.45 to NA); Part 2: Venetoclax 200 mg QD 28 Days + Azacitidine 20 mg/m^2 QD NA (NA to NA)
• Graft-versus-Host Disease (GvHD)-Free, Relapse Free Survival (GRFS) (Part 2) (Secondary), Median, months: Part 2: Best Supportive Care 11.1 (6.57 to 19.22); Part 2: Venetoclax 200 mg QD 28 Days + Azacitidine 20 mg/m^2 QD 12.2 (8.31 to 24.94)
• Rate of Participants Without Higher Grade of GvHD (Part 2) (Secondary), Number, percentage of participants: Part 2: Best Supportive Care 63.4 (56.62 to 69.86); Part 2: Venetoclax 200 mg QD 28 Days + Azacitidine 20 mg/m^2 QD 58.9 (51.97 to 65.54)
• Change From Baseline in Physical Functioning Subscore as Measured by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-C30) (Part 2) (Secondary), Least squares mean, score on a scale: Part 2: Best Supportive Care 5.29 +/- 1.29; Part 2: Venetoclax 200 mg QD 28 Days + Azacitidine 20 mg/m^2 QD 4.98 +/- 1.23
• Change From Baseline in Patient Reported Outcomes Measurement Information System (PROMIS) Cancer Fatigue Short Form (SF) 7a Score (Part 2) (Secondary), Least squares mean, score on a scale: Part 2: Best Supportive Care -1.5 +/- 0.35; Part 2: Venetoclax 200 mg QD 28 Days + Azacitidine 20 mg/m^2 QD -1.3 +/- 0.34
• Percentage of Participants With Measurable Residual Disease (MRD) Conversion in Participants With MRD >= 10^-3 at Baseline (Part 2) (Secondary), Number, percentage of participants: Part 2: Best Supportive Care 39.7 (30.69 to 49.16); Part 2: Venetoclax 200 mg QD 28 Days + Azacitidine 20 mg/m^2 QD 40.8 (31.95 to 50.18)
• Time to Deterioration in Global Health Status (GHS)/Quality of Life (QoL) in Adult Participants (Part 2) (Secondary), Median, months: Part 2: Best Supportive Care 1.1 (1.08 to 1.84); Part 2: Venetoclax 200 mg QD 28 Days + Azacitidine 20 mg/m^2 QD 1.6 (1.05 to 1.97)
• Change From Baseline in European Quality-of-Life-5 Dimensional-5-Level (EQ-5D-5L) Score (Secondary), Least squares mean, score on a scale: Part 2: Best Supportive Care -0.00 +/- 0.05; Part 2: Venetoclax 200 mg QD 28 Days + Azacitidine 20 mg/m^2 QD -0.06 +/- 0.05

Adverse events

Time frame: All-cause mortality and adverse event tables include events reported from the start of safety data collection to the end of the study. The median time on follow-up was 53.2, 60.2, 27.4, and 27.9 months for arms Part 1: Venetoclax 200 mg QD 28 Days + Azacitidine 20 mg/m^2 QD, Part 1: Venetoclax 200 mg QD 14 Days + Azacitidine 20 mg/m^2 QD, Part 2: Best Supportive Care, and Part 2: Venetoclax 200 mg QD 28 Days + Azacitidine 20 mg/m^2 QD, respectively.

Serious adverse events by term

121 more terms not shown.

Other adverse events by term

25 more terms not shown.

Limitations and caveats: This study was terminated due to strategic considerations.

65 more sites not listed.

• Study Protocol (PDF, 2025-04-08)
• Statistical Analysis Plan (PDF, 2023-11-16)

• ABBVIE INC., Study director, AbbVie

NIH grants: 2023