The Hematologist

January-February 2020, Volume 17, Issue 1

Venetoclax Regimens in Acute Myeloid Leukemia: Do We Have the Answers?

Kristen M. O'Dwyer, MD Assistant Professor of Medicine
Wilmot Cancer Institute, University of Rochester, Rochester, NY
Eric Huselton, MD Assistant Professor, Department of Medicine, Hematology/Oncology
University of Rochester, Rochester, NY

Published on: January 13, 2020

It has been one year since the U.S. Food and Drug Administration granted accelerated approval to venetoclax in combination with azacitidine or decitabine, or low-dose cytarabine for the treatment of newly diagnosed acute myeloid leukemia (AML) in older patients (>75 years) or patients with comorbidities that precluded the use of intensive induction chemotherapy.1 The approval was based on data from two early phase, non-randomized trials that demonstrated improved rates of complete remission and duration of remission.2,3 In 2019, the venetoclax and azacitidine combination seems to have been enthusiastically adopted as the de facto standard of care for this patient population at many academic centers and in the community, providing optimism for treatment in patients with historically poor outcomes. These data from two early-phase trials, along with “real-world” data from a single institution, pose the question of whether the existing data are sufficient to accept the azacytidine-venetoclax combination as the new standard of care for induction therapy in older adults with AML. We chose this topic as the year’s most immediate therapeutic issue in AML because it dominated discussions in the clinic with patients, in professional meetings among colleagues of the adult cooperative cancer groups, and with the pharmaceutical industry with regard to the design of future clinical trials for AML.

Furthermore, clinical trial enrollment stalled in 2019 for trials that did not contain a venetoclax combination. Many academic experts feel they have enough data to support a paradigm change based on the impressive response rates from the early-phase studies. Other experts are concerned that the response rates, though impressive, may not be associated with survival benefits, and they await data from the international randomized phase III studies. The latter studies are evaluating venetoclax or placebo in combination with azacitidine (NCT02993523) or low-dose cytarabine (NCT03069352) before committing to this regimen as the new standard of care. The three articles discussed represent the “best” information to date for defining the treatment of older patients with AML with a combination containing venetoclax.

The trial led by Dr. Courtney DiNardo and colleagues was a multicenter, phase Ib, dose escalation study of an induction regimen of venetoclax combined with a hypomethylating agent (azacitidine or decitabine) in treatment-naïve, older patients with AML.4 Efficacy was evaluated in 145 patients who were 65 years or older and considered ineligible for intensive induction with cytarabine and anthracycline. Patients received ventoclax at 400 mg, 800 mg, or 1,200 mg daily in combination with standard doses of azactidine (75 mg/m2 intravenously or subcutaneously, days 1-7) or decitabine (20 mg/m2 intravenously, days 1-5). In the expansion phase of the trial, patients received venetoclax 400 mg or 800 mg combined with a hypomethylating agent. No patients were allowed prior exposure to a hypomethylating agent. The median age for the cohort was 74 years, and most patients (62%) had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 1. Fifty-one percent of patients had intermediate risk cytogenetics, and 49 percent had poor risk cytogenetics; 25 percent of the cohort had secondary AML and 25 percent had TP53 mutations. The complete remission (CR) rate was 37 percent, and the CR with incomplete count recovery (CRi) rate was 30 percent, for an overall response rate (CR/CRi) of 68 percent. The median time to first response was 1.2 months (range, 0.8-13.5 months), and the median time to best response was 2.1 months. Response rates were similar between patients treated with decitabine and azacitidine. The CR/CRi for the venetoclax 400 mg and hypomethylating agent cohort was 73 percent, and 68 percent for the venetoclax 800 mg and hypomethylating cohort. The median duration of response was 11.3 months, and the median overall survival (OS) was 17.5 months. The most common grade 3-4 adverse events included myelosuppression (leukopenia, 31%; anemia, 25%; thrombocytopenia, 24%; neutropenia, 17%; and infection: febrile neutropenia in 43%, pneumonia in13%, and bacteremia/sepsis in 10%). Of note, 21 patients in the study proceeded to allogeneic hematopoietic stem cell transplantation despite being considered ineligible for intensive induction therapy at the time of study enrollment.

The trial led by Dr. Andrew Wei and colleagues was a phase Ib/II study that assessed the safety and efficacy of an induction regimen of venetoclax and low-dose cytarabine in newly diagnosed AML patients.3 The study enrolled 82 adult patients aged 60 years or older and considered ineligible for intensive induction with cytarabine and anthracycline. In this trial, however, patients who received prior treatment with a hypomethylating agent for a diagnosis of the myelodysplastic syndrome were eligible for enrollment. Forty-nine percent of the patients in this trial had secondary AML, and 29 percent of the cohort had received treatment with a hypomethylating agent. Sixty percent of the cohort had intermediate risk cytogenetics, and 32 percent had poor risk cytogenetics. Venetoclax was administered at 600 mg daily in combination with cytarabine 20 mg/m2 by subcutaneous injection once daily on days 1 to 10. The median age of the cohort was 74 years, and most patients (56%) had an ECOG PS of 1. The CR rate was 26 percent and the CRi rate was 28 percent, for a CR/CRi of 54 percent. The median time to first response was 1.4 months. The median OS for the entire cohort was 10.1 months. Subgroup analysis showed that patients with no antecedent hematologic disorder had a CR/CRi rate of 71 percent as compared to patients with secondary AML who had a CR/CRi of 35 percent. Similarly, patients with no prior treatment with a hypomethylating agent had a CR/CRi of 62 percent as compared to 33 percent for patients who had previous treatment with a hypomethylating agent. The 30-day mortality rate was 6 percent.

To explore the outcomes of patients treated with the venetoclax and azacitidine combination, but not in the setting of a clinical trial (i.e., the “real-world” experience), Dr. Amanda Winters and colleagues presented a comparison of 33 patients treated with venetoclax and azacitidine, but not enrolled on trial, versus a 33-patient cohort treated on a clinical study using the same regimen.5

The clinical outcomes for the real-world patients were inferior to that of patients enrolled on a clinical trial, despite utilizing the same treatment regimen and receiving treatment from the same clinical team at a single institution that has great expertise and experience with the therapeutic regimen. The CR/CRi was lower for the real-world- patients (63%) than patients treated on a clinical trial (84.9%). The difference in response rate was attributed to the prior exposure of a hypomethylating agent in the real-world patients who had a diagnosis of an antecedent hematologic disorder. The median OS was significantly shorter for real-world patients (381 days) as compared to the clinical trial cohort (880 days). The toxicity profiles were similar to the reported early-phase studies and included myelosuppression and infection. The early death rate (within 60 days) was 13 percent for the entire cohort, and all deaths were related to disease progression. While this data set is small, it is informative and provides the first examination of the real-world experience in the “post-venetoclax approval era,” as compared to the patients who met strict eligibility criteria of the early-phase clinical trials. In fact, these real-world data come from an academic institution with considerable experience with the therapeutic regimen and supportive care needs of this vulnerable patient population and may have resulted in better than expected “real-world” outcomes.

2019 has been the year of widespread adoption of venetoclax combination therapy in community and academic practice for the treatment of AML in older adults. Collectively, the early-phase clinical trial data and real-world data demonstrated the benefit of combination therapy in improved response rates, yet many practical questions remain for clinicians should this regimen be established as the standard of care. Some of the most important questions are: How do the long-term survival and toxicity of combination therapy compare with azacitidine or low-dose cytarabine monotherapy? Will “real-world” older adults with AML, those with significant comorbid conditions, benefit from the addition of venetoclax? Or will the combination have an unfavorable benefit-risk profile in a broader population? Finally, for older adults with good performance status, which is the best regimen? Should intensive induction therapies remain the standard for older fit patients? Unfortunately, the ongoing phase III trials will not help us answer these questions because the inclusion criteria are similar to the phase Ib trial, including adults 75 years or older or those with mild organ dysfunction, but excluding those with grade 2 NYHA class 2 symptoms or other significant organ dysfunction. Until data from the ongoing randomized phase III studies are available, clinicians must rely on data from early-phase or retrospective studies or consultation from colleagues to make treatment decisions for their patients.

Results of Each Regimen for Acute Myeloid Leukemia
RegimenNo. of PatientsCR + CRiMedian duration of CR + Cri (Months)Median OS (Months)Historical Control, Overall Response RateHistorical Control, Median OS (Months)
VEN 400 mg + HMA46073%12.5Not reached25-27%6,77.7-10.4
VEN 600 mg + LDAC3

 No prior HMA
 Prior HMA therapy







“Real-world” VEN + AZA53363%10.5 (321 days)12.127.8%710.4 7
“On-trial” VEN + AZA3384.9%Not reached28.8  

Abbreviations: AZA, azacytidine; CR + Cri, composite response rate (complete remission + complete remission with incomplete count recovery); HMA, hypomethylating agent; LDAC, low-dose cytarabine; OS, overall survival; VEN, venetoclax.


  1. U.S. Food and Drug Administration. FDA approves venetoclax in combination for AML in adults. U.S. Food and Drug Administration. Updated December 14, 2018.
  2. DiNardo CD, Pratz KW, Letai A, et al. Safety and preliminary efficacy of venetoclax with decitabine or azacitidine in elderly patients with previously untreated acute myeloid leukaemia: a non-randomised, open-label, phase 1b study. Lancet Oncol. 2018;19:216-228.
  3. Wei AH, Strickland SA Jr, Hou JZ, et al. Venetoclax combined with low-dose cytarabine for previously untreated patients with acute myeloid leukemia: results from a phase Ib/II study. J Clin Oncol. 2019;37:1277-1284.
  4. DiNardo CD, Pratz K, Pullarkat V, et al. Venetoclax combined with decitabine or azacitidine in treatment-naïve, elderly patients with acute myeloid leukemia. Blood. 2019;133:7-17.
  5. Winters AC, Gutman JA, Purey E, et al. Real-world experience of venetoclax with azacitidine for untreated patients with acute myeloid leukemia. Blood Adv. 2019;3:2911-2919.
  6. Kantarjian HM, Thomas XG, Dmoszynska A, et al. Multicenter, randomized, open-label, phase III trial of decitabine versus patient choice, with physician advice, of either supportive care or low-dose cytarabine for the treatment of older patients with newly diagnosed acute myeloid leukemia. J Clin Oncol. 2012;30:2670-2677.
  7. Dombret H, Seymour JF, Butrym A, et al. International phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with >30% blasts. Blood. 2015;126:291-299.
  8. Dennis M, Hills RK, Russell NH, et al. An evaluation of 17 years of low dose cytarabine as therapy for AML patients not fit for intensive treatment, including patients with adverse cytogenetics, shows improving survival, potential underutilization and highlights the need for new therapy. Blood. 2017;130:3874.
  9. Kantarjian H, O'Brien S, Cortes J, et al. Results of intensive chemotherapy in 998 patients age 65 years or older with acute myeloid leukemia or high-risk myelodysplastic syndrome: predictive prognostic models for outcome. Cancer. 2006;106:1090-1098.

Conflict of Interests

Dr. O'Dwyer and Dr. Huselton indicated no relevant conflicts of interest. back to top