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The combination approach based on venetoclax (VEN) with azacytidine (AZA) has significantly improved outcomes for elderly patients with acute myeloid leukemia (AML). This innovative approach has led to higher rates of overall response, measurable residual disease (MRD)-negative remissions, and overall survival compared with AZA monotherapy. As a result, this combination has emerged as the gold-standard treatment for elderly or unfit patients with AML who are not eligible for intensive therapy. In younger, fit patients with AML, intensive induction and consolidation chemotherapy is commonly used as a first-line approach; however, relapse continues to be the main reason for treatment failure in approximately 30–40% of patients. Efforts to improve MRD-negative response rates and to facilitate the transition to allogeneic hematopoietic stem cell transplantation, particularly in high-risk AML, have inspired trials exploring the combination of intensive chemotherapy with targeted agents. VEN, a first-in-class anti-BCL2 agent, combined with intensive chemotherapy regimens has shown deep MRD-negative remissions, producing prolonged event-free survival and enhancing the transition to allogeneic transplant in first-complete-remission patients. These benefits support the incremental advantages of adding VEN to intensive chemotherapy approaches across ELN risk subcategories, and provides a robust benchmark to design future trials.
Trial/Reference |
Design |
Primary Endpoint |
Number of Patients |
Patients Enrolled |
Response |
Outcomes |
Early Mortality |
---|---|---|---|---|---|---|---|
daunorubicin + cytarabine + venetoclax (DAV)/[17] |
phase II |
composite complete remission rate |
36 |
patients aged 18–60 years |
CRc 6 rate: 91% |
estimated 1-year OS 11: 97% estimated 1-year EFS 12: 72% |
30-day mortality: 0% |
daunorubicin + cytarabine + venetoclax (DAV 2 + 6)/[18] |
phase II |
overall response rate |
42 |
patients aged 16–60 years |
ORR 7: 92.9%; 87.9% of the CR 8 patients with undetectable MRD 9 |
estimated 12-month OS 11: 83.1% estimated 12-month EFS 12: 82.7% estimated 12-month DFS 13: 92% |
30-day mortality: 2.4% |
daunorubicin + cytarabine + venetoclax (5 + 2 + VEN)/[19] |
phase Ib |
optimal dose schedule of venetoclax with 5 + 2 |
69 |
patients aged ≥65 years with de novo or s-AML 1 or t-AML 2 |
overall response (CR 8/Cri 10) rate: 73% |
median OS 11: 15.4 months |
30-day mortality: 6% |
daunorubicin + cytarabine + venetoclax (5 + 2 + VEN)/[20] |
retrospective clinical trial |
composite complete remission |
12 |
patients aged ≥ 60 years |
CR 8 rate: 91.7% All patients with poor-risk achieved CR 8 |
estimated 1-year EFS 12: 75%. Estimated 1-year OS 11 rate: 100% |
30-day mortality: 0% |
cyclophosphamide + cytarabine + venetoclax (VCA)/[21] |
pilot study |
complete remission rate |
25 |
adult AML 3 |
CR 8/Cri 10: 92%; all these patients had undetectable MRD 9 |
Estimated 12-month OS 11: 79.3%. |
/ |
fludarabine + cytarabine + idarubicin + filgastrim + venetoclax (FLAG-IDA + VEN)/[22] |
phase Ib/II |
overall response rate |
45 |
patients aged ≥18 (including de novo, sAML 1, tAML 2, tsAML 4, or high-risk MDS 5) |
ORR 7: 98%; among CR 8 patients, 93% MRD 9 negative |
estimated 24-month EFS 12: 64% estimated 24-month OS 11: 76%, |
30-day mortality: 0% 60-day mortality: 0% |
fludarabine + cytarabine + idarubicin + venetoclax (V-FLAI)/[23] |
phase I/II trial |
complete remission rate |
57 |
European LeukemiaNet intermediate- or high-risk adult AML 3 (median age 54 years; 18–65) |
CR 8 rate: 84%; MRD 9 negative: 74% |
probability of 12-month OS 11: 76% |
30-day mortality: 1.8% 60-day mortality 5.3% |
cladribine + cytarabine + idarubin + venetoclax (CLIA + VEN)/[24] |
phase II |
complete response rate |
67 |
patients aged ≤65 years with newly diagnosed AML 3 or high-risk MDS 5 |
CRc 7 rate: 96%; among CR 8 patients, 90% MRD 9 negative |
estimated 12-month OS 11: 86.5% estimated 24-month OS 11: 86.5% estimated 12-month EFS 12: 71.8% estimated 24-month EFS 12: 69.7% |
30-day mortality: 2% 60-day mortality 3% |
CPX-351 + venetoclax (CPX-351 + VEN)/[25] |
phase Ib/II |
the safe dose and schedule |
5 |
patients aged ≥ 18 years |
CR 8/CRi 10: 80%; 75% MRD 9 negative |
1-year estimated OS 11: 75% |
30-day mortality: 0% 60-day mortality: 0% |
1 s-AML = secondary acute myeloid leukemia. 2 t-AML = therapy-related acute myeloid leukemia. 3 AML = acute myeloid leukemia. 4 ts-AML = treated secondary acute myeloid leukemia. 5 MDS = myelodysplastic syndrome. 6 CRc = composite complete remission. 7 ORR = overall response rate. 8 CR = complete remission. 9 MRD = minimal residual disease. 10 CRi = complete remission with incomplete bone marrow recovery. 11 OS = overall survival. 12 EFS = event-free survival. 13 DFS= disease-free survival.
Trial/Reference |
Design |
Primary Endpoint |
Number of Patients |
Patients Enrolled |
Response |
Outcomes |
Early Mortality |
---|---|---|---|---|---|---|---|
fludarabine + cytarabine + idarubicin + filgastrim + venetoclax (FLAG-IDA+ VEN)/[26] |
phase Ib/II |
overall response rate |
49 |
patients aged ≥ 18 |
CR 1/CRi 2 rate: 67% (69% were MRD 3-negative); 46% proceeded to HSCT 4 |
estimated 1-year EFS 7: 41% estimated 1-year OS 8: 68% |
30-day mortality: 0% 60-day mortality: 4.4% |
fludarabine + cytarabine + idarubicin + filgastrim + venetoclax (FLAG-IDA + VEN)/[32] |
real-life analysis |
/ |
24 |
patients aged ≥ 18 |
CRc 5: 72% for the entire cohort and 91% in patients treated for post-HCT 4 relapse |
12-month RFS 9: 67% 12-month OS 8: 50% |
30-day mortality: 12%; 60-day mortality: 48% |
fludarabine + cytarabine + idarubicin + venetoclax (FLAVIDA)/[29] |
real-life analysis |
/ |
13 |
patients aged ≥ 18 |
ORR 6: 69%, with a median duration of CR 1/CRi 2 of 7.3 months |
estimated 6-month EFS 7: 52% estimated 6-month OS 8: 76%, |
/ |
high-dose cytarabine + mitoxantrone + venetoclax (HAM + VEN)/[31] |
phase I/II |
dose-limiting toxicity |
12 |
patients aged ≥ 18 |
CR 1/CRi 2 rate: 92% (62.5% were MRD 3-negative); |
/ |
30-day mortality: 8.3% |
CPX-351 + venetoclax (CPX-351 + VEN)/[25] |
phase Ib/II |
the safe dose and schedule |
26 |
patients aged ≥ 18 |
CR 1/CRi 2 rate: 46% (78% were MRD 3-negative). |
1-year estimated OS 8: 39%; in responding patients, the median OS 8 was 26.9 months |
30-day mortality: 12% 60-day mortality: 19% |
+ cytarabine +/− idarubicin + venetoclax/[33] |
phase Ib/II |
the safe dose and schedule |
38 |
patients between 2 and 22 years |
ORR 6: 69%; 80% of patients who achieved a CR 1/CRi 2 proceeded to HSCT 4 |
/ |
/ |
1 CR = complete remission. 2 Cri = complete remission with incomplete bone marrow recovery. 3 MRD = minimal residual disease. 4 HSCT = hematopoietic stem cell transplantation. 5 CRc = composite complete remission. 6 ORR = overall response rate. 7 EFS = event-free survival. 8 OS = overall survival. 9 RFS = relapse-free survival.