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Venetoclax Proves Active in Newly Diagnosed AML

August 30, 2022

September 2022

Leah Lawrence

Leah Lawrence is a freelance health writer and editor based in Delaware.

Two studies investigating the activity and safety of the BCL-2 inhibitor venetoclax support its use as part of first-line treatment in adults with newly diagnosed acute myeloid leukemia (AML). In the first study, Tapan M. Kadia, MD, of the University of Texas MD Anderson Cancer Center, and colleagues aimed to identify which patients receiving intensive chemotherapy might benefit from the addition of venetoclax.1 In the second study, Hong-Hu Zhu, MD, of Zhejiang University School of Medicine in China, and colleagues investigated the activity and safety of venetoclax plus 3+7 daunorubicin and cytarabine chemotherapy in adults with AML.2

Venetoclax With Induction Chemotherapy        

Dr. Kadia and colleagues conducted a post-hoc propensity score matched analysis of three prospective clinical trials in patients treated at MD Anderson Cancer Center. Patients were ages 18 or older, had newly diagnosed AML or high-risk myelodysplastic syndromes, and participated in trials incorporating purine analogues with anthracycline and cytarabine either with venetoclax plus intensive chemotherapy or with intensive chemotherapy alone. Patients treated with venetoclax (n=85) were matched to those treated with intensive chemotherapy alone (n=194).

The primary objectives were rate of measurable residual disease (MRD)-negative composite complete response (CR) and incidence of transition to allogeneic hematopoietic cell transplantation (alloHCT).

After a median of 30 months of follow-up, 86% of patients treated with venetoclax had MRD-negative composite CR compared with 61% of patients in the cohort receiving intensive chemotherapy alone (odds ratio [OR] = 3.2, 95% CI 1.5-6.7; p=0.0028).

According to Dr. Kadia, achievement of MRD-​negative remission is associated with a lower risk of relapse, a longer relapse-free survival, and therefore, improved overall survival (OS). Comparatively, persistent or positive MRD prior to transplant portends a higher risk of relapse.

“This regimen produced significantly higher rates of MRD-negative complete remissions compared to chemotherapy alone, and allowed more patients to move toward transplant,” Dr. Kadia said. “This was particularly apparent among those with intermediate- and adverse-risk AML, where this approach led to significantly improved OS compared to chemotherapy alone in our historical cohorts.”

When patients with European Leukemia Net (ELN) favorable risk were excluded, venetoclax was found to significantly improve OS in patients with intermediate or adverse ELN risk compared with intensive chemotherapy alone (not reached [95% CI, 24-not reached] vs. 21 months [95% CI 18-72]; hazard ratio [HR] = 0.43, 95% CI 0.20-0.92; p=0.030).

The overall incidence of alloHCT in responding patients was 79% with venetoclax plus intensive chemotherapy compared with 57% for chemotherapy alone (HR=1.52, 95% CI 1.11-2.08; p=0.012). Treatment with venetoclax improved event-free survival (EFS) (p=0.030), but OS was not significantly different between the two cohorts.

There were several limitations to the study, including its retrospective nature and a lack of information about post-protocol therapies. The researchers noted that, “although none of the patients in the venetoclax plus intensive chemotherapy cohort received venetoclax-based maintenance following [alloHCT] on protocol, it is possible a minority received off-label venetoclax-based maintenance outside of a clinical trial. Conversely, patients in the intensive chemotherapy cohort might have received venetoclax-based regimens as salvage therapy.”

According to Dr. Kadia, “If confirmed in phase III studies, this approach can be used in younger and fit patients with newly diagnosed AML (intermediate and adverse ELN risk) to achieve higher rates of CR and higher rates of alloHCT that can hopefully translate into higher rates of cure.”

Venetoclax Plus 3+7 Chemotherapy

A two-stage, single-arm, phase II trial conducted by Dr. Zhu and colleagues investigated the composite complete remission rate after one cycle of induction treatment with venetoclax plus 3+7 daunorubicin and cytarabine (DAV) chemotherapy in 33 adults with AML.

Included patients had previously untreated de novo AML and ECOG performance status of 0-2. Patients were treated with induction intravenous daunorubicin, intravenous cytarabine, and oral venetoclax. The length of treatment was 28 to 35 days per cycle with one or two treatment cycles.

“Our . . . DAV regimen achieved a high complete remission rate of 91%, providing more chance for patients to receive [alloHCT] for those with [transplantation] indications,” Dr. Zhu said.

The composite complete remission rate after one cycle of DAV was 91% for the entire cohort; 97% of patients who reached complete remission had undetectable MRD. With a median follow-up of 11 months, the estimated one-year OS was 97%, and the one-year EFS was 72%.

The researchers noted that one concern with venetoclax is increased myelosuppression. For that reason, they added venetoclax from days four to 11 rather than days one to 11. This regimen seemed to shorten the duration of myelosuppression, they wrote.

All patients experienced grade ≥3 neutropenia, thrombocytopenia, and anemia. Additionally, 55% of patients had grade ≥3 febrile neutropenia, 21% had pneumonia, and 12% had sepsis. No treatment-related deaths occurred.

“This is the first published phase II study of venetoclax combined with the [DAV] induction regimen that shows favorable response rates, a high rate of MRD-negativity among patients with response favorable survival data, and manageable adverse effects,” Dr. Zhu said.

He added that he expects these results to be validated by an ongoing randomized controlled trial his group is conducting to compare DAV to daunorubicin plus cytarabine.

In their discussion of the results, the researchers noted the study included only 33 patients and had a relatively short median follow-up duration.

Despite these potential limitations, Dr. Zhu said, “I believe the DAV regimen will become the front-line treatment of adult AML and be adopted in AML guidelines if the favorable results can be confirmed by subsequent randomized controlled trials.” 

Any conflicts of interest declared by the authors can be found in the original articles.


  1. Lachowiez CA, Reville PK, Kantarjian H, et al. Venetoclax combined with induction chemotherapy in patients with newly diagnosed acute myeloid leukaemia: a post-hoc, propensity score-matched, cohort study. Lancet Haematol. 2022;9(5):e350-e360.
  2. Wang H, Mao L, Yang M, et al. Venetoclax plus 3 + 7 daunorubicin and cytarabine chemotherapy as first-line treatment for adults with acute myeloid leukaemia: a multicentre, single-arm, phase 2 trial. Lancet Haematol. 2022;9(6):e415-e424.



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