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Venetoclax for the treatment of AML: Developments and progress in 2020

Dec 3, 2020

Venetoclax (Ven) was first approved by the U.S. Food and Drug Administration (FDA) for the treatment of chronic lymphocytic leukemia in January, 2016. Since then, it has increasingly been applied in the treatment of acute myeloid leukaemia (AML), particularly in patients not able to receive intensive chemotherapy, or as a result of age or comorbidities. The reduced intensity chemotherapy (RIC) regimens often used for these patients have limited success, with treatment failure and relapse being very common. B-cell leukemia/lymphoma-2 (BCL2) family members are known to play a role in cancer cell survival and chemoresistance. Venetoclax is a BCL2 inhibitor that has increasingly been assessed either as monotherapy or in combination treatment. Here we review key 2020 developments in our knowledge of venetoclax for the treatment of AML from publications, symposia, and a review of information presented on the AML Hub.

Molecular mutations in AML and response to treatment

Certain molecular mutations influence response rates in older patients treated with venetoclax combination therapy. During the 61st American Society of Hematology Meeting & Exposition, on Monday, December 9, 2019, Brenda Chyla presented an exploratory biomarker analysis from two phase I(b)/II studies exploring the combination of venetoclax with hypomethylating agents (NCT02203773) or low-dose cytarabine (LDAC) (NCT02287233) in older patients with AML, who were ineligible for induction chemotherapy.1

Patients with NPM1 or IDH1/2 mutations achieved higher response rates (> 70%) and prolonged overall survival (OS) regardless of which venetoclax combination therapy they received. Interestingly, outcomes (OS and complete response [CR] with incomplete hematological recovery [CR/CRi] rate) were better in patients with concurrent FLT3 and NPM1 mutations compared with those with a FLT3 mutation alone. Patients with TP53 mutations could achieve good responses, which were not sustained (median OS, 6.4 months). BCL-2 expression was not found to be a prognostic marker of response to venetoclax combination therapy in this population, as discussed on the AML Hub in January, 2020.1

Venetoclax combination therapies for AML

In November, 2018, the FDA granted accelerated approval for venetoclax in combination with azacitidine, decitabine, or LDAC for patients with newly diagnosed AML who are ineligible for intensive induction therapy due to age (≥ 75 years) or coexisting medical conditions.2

Venetoclax plus LDAC

In February, 2020, it was announced that the VIALE-C trial (NCT02287233), comparing venetoclax plus LDAC to LDAC alone, failed to meet its primary endpoint of significant OS improvement in patients with treatment-naïve AML who were ineligible for intensive chemotherapy.3,4 In May, 2020, Andrew Wei and colleagues published their findings in Blood, including both the safety and efficacy of combined RIC.5. In the trial, venetoclax plus LDAC led to a 25% reduction in the risk of death versus LDAC alone, but this was not statistically significant. The median OS was 8.4 months vs 4.1 months, for the two arms respectively (HR, 0.70; 95% CI, 0.50–0.99). However, the combination of venetoclax with LDAC was well-tolerated, with a good safety profile and clinically meaningful benefits, including for remission rates and event-free survival. The accelerated induction of remission and positive benefit-risk profile supports that venetoclax plus LDAC may be an important treatment option for patients needing a RIC approach.5

Venetoclax plus azacitidine

The VIALE-A trial (NCT02993523) investigated the combination of venetoclax plus azacitidine and met both of its primary endpoints of OS and CR/CRi rate improvement, as announced in March, 2020.6,7 The AML Hub has previously summarised the findings of the VIALE-A trial, as presented at the European Hematology Association (EHA) Annual Congress in 2020. The combination of venetoclax and azacitidine showed a 34% reduction in risk of death (HR, 0.66; 95% CI, 0.52–0.85; p < 0.001) at 20.5 months follow-up compared with azacitidine alone, with a significant increase in the median OS of the venetoclax plus azacitidine group to 14.7 months compared with 9.6 months for the azacitidine plus placebo group. Further to this, the combination therapy of venetoclax plus azacitidine was associated with higher response rates in patients with all of the somatic mutations analyzed. In an invited commentary for the AML Hub, Courtney Di Nardo discussed these results and suggested that with 66% of patients achieving response on venetoclax plus azacitidine vs 28% on azacitidine alone, venetoclax plus azacitidine should become the standard of care for this patient group.

Venetoclax plus actinomycin

Work around venetoclax and LDAC in combination with actinomycin D was presented by Andrius Žučenka, on the AML Hub in July, 2020. Originally presented at the 25th EHA Annual Congress, the study described patients with AML post allogeneic hematopoietic stem cell transplantation, who had a 2-year survival of < 20% and a median OS of 2–6 months. Their work identified a median OS of 14 months and an event-free survival of 8 months with the triplet therapy of venetoclax + LDAC + actinomycin D. Toxicities and safety were acceptable.8

Venetoclax plus decitabine for AML and high-risk myelodysplastic syndromes (MDS)

During the 2020 American Society of Clinical Oncology (ASCO) Annual Meeting, the AML Hub spoke to Marina Konopleva regarding an investigator-led trial exploring the use of venetoclax plus decitabine in elderly patients ( > 65 years) with either newly diagnosed or relapsed/refractory (R/R) AML. The median age was 72 years, with adverse risk factors present in around 63% of patients (30% with TP53 mutations). Newly diagnosed patients achieved an OS of 18 months and a 66% CR rate (84% CR/CRi), with limited adverse events and good overall treatment tolerability. Outcomes in patients with R/R AML or those treated for prior MDS were not as impressive, with response rates of approximately 40%, and 39%, respectively. Newly diagnosed patients with untreated MDS had higher response rates in the range of 67% but their median OS was fairly short. Longer follow-up data are awaited and needed to validate these results. Further information on this trial can be found here.

Venetoclax plus ivosidenib

In June, 2020, the AML Hub reported interim results on work by Curtis Lachowiez and colleagues, conducting a trial evaluating a new combination of venetoclax with ivosidenib for patients with IDH1-mutated hematological malignancies (NCT03471260).9 This study included dose-escalation and pharmacokinetic analysis, demonstrating increased metabolism and absorption of venetoclax when administered with ivosidenib.2 These results suggested that the combination of venetoclax and ivosidenib is an active, well-tolerated regimen for advanced IDH1-mutated myeloid malignancies, capable of achieving high CR rates and negative measurable residual disease in a clinically adverse patient population. Results relating to longer term safety data, clinical outcomes, and remission are awaited.9

The IDH1-mutant inhibitor ivosidenib alone has been demonstrated to achieve a 42.9% CR rate in treatment-naïve patients10 and a 32.8% CR among patients with R/R IDH1-mutated AML.11 These results led to the approval of frontline ivosidenib for both settings by the FDA in 2019 and 2018, respectively.

Venetoclax plus eprenetapopt and azacitidine in TP53-mutated AML

In July, 2020, the AML Hub reported on the expansion of a phase I clinical trial (NCT04214860)12 exploring eprenetapopt in combination with venetoclax and azacitidine in patients with AML with TP53 mutations. The trial will now include patients who will be treated with eprenetapopt plus azacitidine as frontline treatment. This decision was based on the results of two independent phase Ib/II trials that demonstrated the safety and good tolerability of the regimens.13,14 Further results from all three cohorts of this clinical trial are anticipated.


In an interview with the AML Hub in September, 2020, Daniel Pollyea discussed the changing landscape of venetoclax in the treatment of AML. There are patient populations for which venetoclax is clearly indicated and has improved outcomes within the context of clinical trials. Venetoclax-based therapy has also been shown to help achieve earlier and more sustained responses compared with other treatments when used off-label for patients who have poor prognostic risk factors for intensive chemotherapy. The findings of current and future clinical trials will hopefully provide further validation to such off-label observations and are eagerly anticipated.

  1. Chyla BJ. Response to venetoclax in combination with low intensity therapy (LDAC or HMA) in untreated patients with acute myeloid leukemia patients with IDH, FLT3 and other mutations and correlations with BCL2 family expresOral abstract #546. 61st American Society of Hematology (ASH) Annual Meeting & Exposition; Dec 9, 2019; Orlando, US.
  2. U.S Food and Drug Administration. FDA approves venetoclax in combination for AML in adults. Updated Dec 14, 2018. Accessed Mar 24, 2020.
  3. AbbVie. AbbVie provides update from phase 3 study evaluating VENCLEXTA® (venetoclax) in combination with low-dose cytarabine in newly-diagnosed patients with acute myeloid leukemia (AML). Published Feb 28, 2020. Accessed Mar 2, 2020.
  4. A study of venetoclax in combination with low dose cytarabine versus low dose cytarabine alone in treatment naive patients with acute myeloid leukemia who are ineligible for intensive chemotherapy. Updated Feb 28, 2020. Accessed Nov 26, 2020.
  5. Wei AH, Montesinos P, Ivanov V, et al.Venetoclax plus LDAC for newly diagnosed AML ineligible for intensive chemotherapy: a phase 3 randomized placebo-controlled trial. Blood. 2020;135(24):2137-2145. DOI: 1182/blood.2020004856
  6. Roche. Roche announces Venclexta/Venclyxto combination improved overall survival in people with previously untreated acute myeloid leukaemia. Published Mar 23, 2020. Accessed Nov 26, 2020.
  7. A study of venetoclax in combination with azacitidine versus azacitidine in treatment naïve subjects with acute myeloid leukemia who are ineligible for standard induction therapy. Updated Feb 28, 2020. Accessed Nov 26, 2020.
  8. Zucenka A, Pileckyte R, Trociukas I, et al. Venetoclax in combination with low dose cytarabine, actinomycin D and donor lymphocyte infusions for early relapse of acute myeloid leukemia after allogeneic stem cell transplantation. e-Poster presentation #294508. European Hematology Association (EHA) Annual Congress; Jun 12, 2020; Virtual.
  9. Lachowiez CA, Borthakur G, Loghavi S, et al. Phase Ib/II study of the IDH1-mutant inhibitor ivosidenib with the BCL2 inhibitor venetoclax +/− azacitidine in IDH1-mutated hematologic malignancies. J Clin Oncol. 2020;38(15_suppl):7500-7500. DOI: 1200/jco.2020.38.15_suppl.7500
  10. Roboz GJ, DiNardo CD, Stein EM, et al. Ivosidenib (IVO; AG-120) in IDH1-mutant newly-diagnosed acute myeloid leukemia (ND AML): Updated results from a phase 1 study. J Clin Oncol. 2019;37(15_suppl):7028-7028. DOI: 1200/JCO.2019.37.15_suppl.7028
  11. Pollyea DA, DiNardo CD, de Botton S, et al.Ivosidenib (IVO; AG-120) in mutant IDH1 relapsed/refractory acute myeloid leukemia (R/R AML): Results of a phase 1 study. J Clin Oncol. 2018;36(15; suppl):7000-7000. DOI: 1200/JCO.2018.36.15_suppl.7000
  12. APR-26 in combination with venetoclax and azacitidine in TP53-mutant myeloid malignancies. Updated Mar 19, 2020. Accessed Nov 26, 2020.
  13. Study of the safety and efficacy of APR-246 in combination with azacitidine. Updated Jan 30, 2020. Accessed Nov 26, 2020.
  14. Phase 1b/2 safety and efficacy of APR-246 w/azacitidine for tx of TP53 mutant myeloidneoplasms. Updated May 27, 2020. Accessed Nov 26, 2020.