Early-Phase Trial Shows Venetoclax Plus HMA Has High Response Rates in Older Patients With AML

In a phase Ib dose-escalation and dose-expansion study published in Blood, two-thirds of older patients with acute myeloid leukemia (AML) responded to the combination of low-dose venetoclax plus azacitidine or decitabine, suggesting it may be an effective option for patients who may not be able to tolerate intensive chemotherapy. The regimen also produced “favorable responses” in high-risk subgroups, including patients with poor risk cytogenetics or secondary AML, the authors, led by Courtney D. DiNardo, MD, from the University of Texas MD Anderson Cancer Center, noted.

“Venetoclax in combination with azacitidine has demonstrated a synergistic effect in preclinical models of AML cells, [and] azacitidine may reduce levels of MCL1, an antiapoptotic protein critical in AML pathogenesis and a possible source of resistance to venetoclax,” Dr. DiNardo and co-authors explained. Based on this rationale, they evaluated the safety and efficacy of venetoclax in combination with hypomethylating agents (HMAs) in older patients with treatment-naïve AML.

Patients were eligible for the study if they met the following inclusion criteria:

  • aged ≥65 years at time of diagnosis of AML
  • ineligible for standard induction chemotherapy due to comorbidities (e.g., age >75 years, cardiac disease or prior anthracycline treatment, secondary AML, or high risk of treatment-related mortality)
  • no prior AML therapy
  • white blood cell (WBC) count of ≤25×109/L

A total of 145 patients (median age = 74 years; range = 65-86 years) were assigned to receive venetoclax at one of three doses plus either azacitidine 75 mg/m2 on days 1-7 or decitabine 20 mg/m2 on days 1-5 of a 28-day cycle:

  • 400 mg venetoclax with azacitidine (n=29) or decitabine (n=31)
  • 800 mg venetoclax with azacitidine (n=37) or decitabine (n=37)
  • 1,200 mg venetoclax with azacitidine (n=6) or decitabine (n=5)

During the venetoclax ramp-up period in the first treatment cycle, patients received preventive treatment for tumor lysis syndrome. In the presence of ongoing cytopenias, the study protocol allowed for interruption of venetoclax for up to 14 days until count recovery. The study protocol also allowed patients to receive supportive care, including transfusions, antimicrobial agents except for CYP3A4-inhibitor antifungal agents, and growth factor support.

The dose-expansion included patients who received venetoclax 400 mg or 800 mg with either HMA.

At baseline, most patients had a cytopenia (including 71% [n=103] with grade 3/4 neutropenia) and 74 patients (51%) and 71 patients (49%) had intermediate- or poor-risk cytogenetics, respectively.

During a median follow-up of 15.1 months (9.8-31.7 months), hematologic and gastrointestinal adverse events (AEs) were the most frequently reported toxicities, although the authors noted that most gastrointestinal AEs were grade 1/2 and did not contribute to study discontinuation. The most common grade 3/4 AEs were:

  • febrile neutropenia (43%)
  • decreased WBC count (31%)
  • anemia (25%)
  • thrombocytopenia (24%)
  • neutropenia (17%)
  • pneumonia (13%)

“Because patients with baseline cytopenias were included in the safety analysis, occurrence of many of the hematologic AEs began before study drug initiation and were attributed to underlying hematologic disease [rather than venetoclax treatment],” the researchers wrote.

They also observed a trend toward higher rates of hematologic and gastrointestinal AEs in the 1,200-mg vs. 400- and 800-mg groups (p>0.05), resulting in dose reduction to 800 mg in five patients. A total of 101 patients discontinued the study, the majority of whom experienced progressive disease.

Approximately 3 percent of the cohort died within 30 days following the first drug dose.

In the entire intent-to-treat population, the overall response rate (ORR) – which included complete response (CR), CR with incomplete hematologic recovery (CRi), and partial response – was 68 percent. Specifically, the rates of CR and CRi were 37 percent and 30 percent, respectively. Details about other secondary efficacy endpoints are presented in the TABLE.

In the dose-expansion cohort, the authors did not observe differences in ORR or CR/CRi rates between the two venetoclax doses:

  • ORR: 73% in the 400 mg group vs. 68% in the 800 mg group (p=0.57)
  • CR/CRi: 73% vs. 65% (p=0.35)

“Notably, the venetoclax 400 mg/HMA cohort achieved a CR/CRi rate of 73 percent, a median duration of CR/CRi of 12.5 months, and median overall survival (OS) not reached,” the authors reported. A phase III study of venetoclax 400 mg combined with azacitidine in adults with untreated AML who are ineligible for induction therapy is underway.

Bone marrow minimal residual disease (MRD) evaluations (assessed via multiparameter flow cytometry) were available for 83 of the 97 patients (86%) who achieved a CR/CRi. Of these, 28 patients (29%) had at least one assessment with an MRD of <10-3. Most of these MRD-responders were in the lower-dose venetoclax group: 17 at venetoclax 400 mg, 10 at 800 mg, and one at 1,200 mg. Neither median duration of response or OS had been reached at time of last follow-up.

Subgroup analyses also revealed that venetoclax combinations were similarly effective in patients with poor- and intermediate-risk cytogenetic profiles (CR/CRi rate = 60% and 74%, respectively), in patients >75 years (CR/CRi rate = 65%), and in patients with secondary AML (67%).

Although the researchers noted that these results compare favorably with results from trials of HMA monotherapy, they acknowledged that the findings from this early-phase trial are limited by the lack of a comparator arm.

The authors report financial relationships with AbbVie and Genentech, which supported the trial.


DiNardo CD, Pratz K, Pullarkat V, et al. Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia. Blood. 2018 October 25. [Epub ahead of print]

The addition of venetoclax to either azacitidine or decitabine overcomes many of the traditional adverse prognostic features common in older patients with AML, given that patients with secondary AML and FLT3– or IDH1/2-mutated disease had the same outcomes as those with de novo AML.

Given the remarkable complete response rates and reasonably good tolerance to the regimen of venetoclax plus an HMA, this regimen will likely become the standard of care for older patients with AML who are not eligible for standard induction chemotherapy.

Comparing venetoclax plus an HMA against standard cytarabine/daunorubicin induction chemotherapy as initial treatment of all older patients with AML would help permanently define whether the regimen here should become the standard of care for these patients. Achieving a complete remission in that high-risk population might then permit hematopoietic cell transplantation, opening up the possibility of curative therapy for those who previously did not have that opportunity.

Robert Hromas, MD
University of Texas Health
San Antonio, TX