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Outcomes with venetoclax in treating AML in real-world settings

Mar 24, 2022

The combination of venetoclax and hypomethylating agents has significantly improved outcomes and survival in patients with newly diagnosed acute myeloid leukemia (AML) who are ineligible for intensive chemotherapy.1 There is a continuous effort to investigate venetoclax further in alternative settings (e.g., combinations with other conventional agents), and in patients with poor risk cytogenetics, and relapsed/refractory (R/R) disease. The AML Hub has been providing an extensive coverage on the venetoclax trials, which can be found here.

Within our recent educational theme on venetoclax combinations in the AML setting, we summarize safety and efficacy findings of venetoclax from a retrospective analysis carried out in newly diagnosed or previously treated patients at an academic site; the results were published by Fleischmann et al.1 in the Journal of Cancer Research and Clinical Oncology.

Study design

A total of 56 consecutive patients (Table 1) were given venetoclax in a 28-day cycle in combination with:

  • Hypomethylating agents (HMAs): Decitabine 20 mg/m2/day intravenously on Days 1–5 or azacitidine 75 mg/m2 subcutaneously for 7 days, OR
  • Low-dose cytarabine (LDAC) 40 mg subcutaneously on Days 1–7

Conditioning regimens before allogeneic hematopoietic stem cell transplantation (allo-HSCT) included a reduced-toxicity conditioning (81.8% of patients) and myeloablative conditioning (18.2% of patients).

Venetoclax was given in different treatment cohorts and disease settings (Figure 1). Overall survival (OS), relapse-free survival (RFS), and overall response rate (ORR) of composite complete remission (CRc) + partial remission, were evaluated.

Figure 1. Venetoclax treatment diagram*

Allo-HSCT, allogeneic hematopoietic stem cell transplantation; HMA, hypomethylating agent; Ven, venetoclax.
*Adapted from Fleischmann et al.1
Includes two cases at relapse after second allo-HSCT.
Received Ven-HMA with intention to allo-HSCT.

Table 1. Patient characteristics*

Characteristic, % unless otherwise stated

N = 56

Median age, years (range)

66.5 (34–83)








AML diagnosis

              de novo






Cytogenetic risk









ELN risk category







              Not available


AML, acute myeloid leukemia; ECOG PS, Eastern Cooperative Oncology Group performance status; ELN, European LeukemiaNet; s-AML, secondary AML; t-AML, therapy-related AML.
*Adapted from Fleischmann et al.1
Data available in 55 patients.

Next-generation sequencing (NGS), performed in 54 patients, showed that at the initiation of venetoclax, 33.9% had no aberrations, followed by 16% with NPM1 mutation, 14.3% with FLT3-ITD mutations, and 12.5% with IDH1/2 mutations. TP53 mutations were detected in 8.9% of patients.


Median follow-up was 11.5 months (range, 6.1 – 22.3):

  • Median OS at the initiation of venetoclax treatment across cohorts
    • First line: 13.3 months (2.2–20.5)
    • Subsequent line: 5.0 months (0.8–24.3)
    • At relapse post-allo-HSCT: 4.0 months (1.5–22.1)
    • Prior to allo-HSCT: 11.5 months (10.4–22.3)
  • Median OS and progression-free survival (PFS) in patients achieving CRc were 20.8 months (range, 2.5–24.3) and 20.5 months (range, 2.6–24.3), respectively.
  • Median RFS was 10.2 months (2.2–24.3)
  • ORR for the whole cohort was 51.8% with a median time to first response in patients achieving CRc of 2.7 months (1.4–16.2).
    • First-line: 61.1%
    • Subsequent line: 52.2%
    • At relapse post-allo-HSCT: 42.8%
  • There was a decrease in transfusion of platelets and red blood cells required at Day 100 from venetoclax initiation.
    • Platelet: 63% → 47%
    • RBC: 76% → 55%

Analysis in different genetic subgroups

  • ORR in patients with intermediate-risk and high-risk cytogenetics were 57.5% and 42.8%, respectively.
    • FLT3-ITD mutation: 12.5%
    • NPM1 and/or IDH1/2 mutation: 71.4%
  • There was no difference in median OS among cytogenetic risk groups and ELN risk groups.
  • FLT3-ITD mutation was associated with a significantly inferior median OS of 3.4 months (vs 10.4 months in case of no FLT3-ITD mutation, p = 0.0002).
  • Median OS in patients with NPM1, IDH1/2 mutations without a FLT3-ITD mutation was 11.2 months (vs 5.0 months in the remaining cohort; p = 0.131), indicating an increased sensitivity to venetoclax therapy.

Outcomes by venetoclax dosage

The overall mean venetoclax dose was 149 mg (20.9–362.5) and the median treatment duration was 105 days (range, 18–674). Outcomes from patients with a mean daily dose of ≤100 mg were compared to those receiving >100 mg to evaluate the impact of venetoclax dosage (Table 2).

Table 2. Comparison of outcomes by venetoclax dose groups*


Patients receiving ≤100 mg
n = 22

Patients receiving >100 mg
n = 34

Median OS, months



ORR, %



PD on venetoclax, %



ORR, overall response rate; OS, overall survival; PD, progressive disease.
*Adapted from Fleischmann et al.1


Grade 3–4 adverse events (AEs) included:

  • Neutropenia: Grade 3 = 15%; Grade 4 = 30%
  • Thrombocytopenia: Grade 3 = 15%
  • Anemia: Grade 3 = 12%
  • Renal insufficiency: Grade 3 = 5%
  • Fatigue: Grade 3 = 7%
  • Nausea: Grade 3 = 9%

Nonrelapse mortality rate was 8.9% (n = 5) and two patients died in the first 30 days of treatment.


In this study, investigators attempted to clarify the efficacy of venetoclax-based combinations in real-world settings, commonly encountered in clinical practice. The findings demonstrated that the venetoclax-based combination approach was associated with encouraging response rates in first-line settings. Response rates were also found to be promising in relapsed/refractory AML, including relapse after allo-HSCT. Salvage treatment with venetoclax may allow patients failing conventional chemotherapy to have a potential curative allo-HSCT.

  1. Fleishmann M, Scholl S, Frietsch JJ, et al. Clinical experience with venetoclax in patients with newly diagnosed, relapsed, or refractory acute myeloid leukemia. J Cancer Res Clin Oncol. 2022. DOI: 1007/s00432-022-03930-5