4  Venetoclax in AML

4.1 Venetoclax and azacitidine in untreated patients with therapy-related acute myeloid leukemia, antecedent myelodysplastic syndromes or chronic myelomonocytic leukemia(Pullarkat et al. 2025)

• This study evaluated the combination of venetoclax with azacitidine in treating secondary acute myeloid leukemia (sAML), which includes therapy-related AML (tAML) and AML arising from antecedent myelodysplastic syndrome or chronic myelomonocytic leukemia (A-MDS/CMML).

• The research analyzed 125 treatment-naïve sAML patients from two clinical trials (VIALE-A and M15-358) who were ineligible for intensive chemotherapy due to age (≥75 years) or comorbidities. The combination treatment demonstrated significantly higher complete remission rates compared to azacitidine monotherapy in both tAML (61% vs 11%) and A-MDS/CMML (66% vs 31%) patients.

• The venetoclax+azacitidine combination also showed longer duration of response (21.0 months vs 5.8 months) and improved overall survival (15.9 months vs 10.6 months) compared to azacitidine monotherapy. Patients with intermediate cytogenetic risk, complex karyotypes, and specific mutations (FLT3, IDH1/2) particularly benefited from the combination therapy.

• The safety profile was manageable, with febrile neutropenia, thrombocytopenia, and neutropenia being the most common adverse events. The authors conclude that the venetoclax+azacitidine combination represents an important treatment option for sAML patients ineligible for intensive chemotherapy.

4.2 Ventoclax dosing

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Studies on Venetoclax dosing schedule in acute myeloid leukemia (AML): 7 vs 14 vs 21 vs 28 days.

Study	Ven.7.days	Ven.14.days	Ven.21.days	Ven...21.days	Ven.28.days
Willekens et al.	✓	✓	✓	✓	✓
Blood Cancer Journal	N = 82			N = 111
CR/CRi	72%	72%
Neutropenic fever	48%	55%
RBC transfusion	84%	83%
Platelet transfusion	62%	77%
Overall survival	11.2 months	10.3 months
8-week mortality	6%	16%
Karrar et al.	×	✓	✓		✓
Am J Hematol		N = 40	N = 41		N = 189
CR/CRi		68%	66%		62%
≥Grade 3 neutropenia		45%	39%		42%
≥Grade 3 infection		20%	18%		28%
≥Grade 3 thrombocytopenia		48%	38%		41%
Overall survival		18.6 months	21.3 months		13.2 months
Aiba et al.	×	✓	×		✓
Ann Hematol		N = 8			N = 13
CR/CRi		75%			80%
Neutropenic fever		38%			80%
RBC transfusion independence		88%			60%
Platelet transfusion independence		88%			80%
Overall survival		Not reached			8.5 months
Kanaya et al.	×	✓	✓		✓
Blood		N = 31	N = 51		N = 18
CR/CRi		68%	51%		39%
Grade 4 neutropenia		68%	78%		50%
Neutropenic fever		55%	47%		39%
Overall survival		Not reached	14.3 months		10.9 months
Ginosyan et al.	×	✓	✓		✓
Blood		N = 11	N = 43		N = 31
CR/CRi		27%	72%		68%
Overall survival		6.1 months	17.6 months		15.7 months
Cui et al.	×	✓	×		×
Hematology		N = 36
CR/CRi		68%
≥Grade 3 neutropenia		28%
≥Grade 3 neutropenic fever		19%
≥Grade 3 thrombocytopenia		25%
Overall survival		17 months
Note: CR/CRi complete remission with (CR) or without count recovery (CRi), RBC red blood cell.

• An ongoing phase 2 randomized study, a substydy of BEAT AML trial (NCT03013998), comparing the efficacy and toxicity of 28-day vs 14 day-Ven-azacitidine in patients with ND-AML.

4.3 FLAG-IDA-VEN

4.3.1 Publications

• Longterm results here (DiNardo et al. 2025)

4.3.2 Regimen

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Figure 4.1: Treatment Schedule for Induction and Consolidation Regimens

• Treatment schedule for FLAG-IDA + VEN. Note that the idarubicin dose in induction differs for the ND (8 mg/m2) and RR (6 mg/m2) cohorts. Pegfilgrastim may be given in lieu of continued daily filgrastim after chemotherapy is completed. *Venetoclax is given for 7 days each cycle and requires dose adjustment if concomitant cytochrome P450 3A inhibitors are administered. #The protocol allows for two further cycles of idarubicin in consolidation and it is often given during cycles 3 and 5. However, it may be omitted in patients in deep remission with persistent cytopenias.

4.4 VENETOCLAX 7 days vs standard dose (Willekens et al. 2025)

DiNardo, Courtney D., Wei-Ying Jen, Koichi Takahashi, et al. 2025. “Long Term Results of Venetoclax Combined with FLAG-IDA Induction and Consolidation for Newly Diagnosed and Relapsed or Refractory Acute Myeloid Leukemia.” Leukemia 39 (4): 854–63. https://doi.org/10.1038/s41375-025-02531-8.

Pullarkat, Vinod, Keith W. Pratz, Hartmut Döhner, et al. 2025. “Venetoclax and Azacitidine in Untreated Patients with Therapy-Related Acute Myeloid Leukemia, Antecedent Myelodysplastic Syndromes or Chronic Myelomonocytic Leukemia.” Blood Cancer Journal 15 (1). https://doi.org/10.1038/s41408-025-01263-3.

Willekens, Christophe, Alexandre Bazinet, Samy Chraibi, et al. 2025. “Reduced Venetoclax Exposure to 7 Days Vs Standard Exposure with Hypomethylating Agents in Newly Diagnosed AML Patients.” Blood Cancer Journal 15 (1). https://doi.org/10.1038/s41408-025-01269-x.