Courtney Dinardo, MD
Leslie Ellis, MD
In elderly patients with untreated acute myeloid leukemia (AML), venetoclax (Venclexta), given at a 400-mg dose, with an azacitidine backbone led to durable responses with a tolerable safety profile, according to data from a phase Ib dose-escalation and -expansion study. Response rates were high regardless of the dose of venetoclax, but the 400-mg dose was optimal in terms of response and risk-benefit ratio.
These results were originally presented at the 2018 ASCO Annual Meeting by Courtney Dinardo, MD, of the Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston. The study was later discussed at the Best of ASCO Chicago by Leslie Ellis, MD, along with other top selected abstracts in leukemia.1,2
The oral BCL2 inhibitor venetoclax has synergistic and antileukemic activity when combined with hypomethylating agents such as decitabine or azacitidine. BCL2 is an antiapoptotic protein that inhibits cell death and has been found to be variably but highly expressed in AML. BCL2 expression in patients with AML is associated with chemotherapy resistance and poor outcomes.
Study Methods
In this open-label, phase Ib trial, the investigators sought to determine the optimal dose and efficacy of venetoclax in combination with decitabine or azacitidine in elderly patients (≥ 65 years) with untreated AML and a white blood cell count of less than 25,000/mm3.
“The investigators wanted people to have a white blood cell count of less than 25,000/mm3 to decrease the chances of patients developing tumor-lysis syndrome,” said Dr. Ellis, a hematologist-oncologist at Wake Forest Baptist Health, Winston-Salem, North Carolina. “Certainly, for any of us who have given venetoclax with our bulky chronic lymphocytic leukemia patients, we understand that can be a risk.”
Patients were randomized to receive either a decitabine or azacitidine backbone. Venetoclax was coadministered daily with 20 mg/m2 of decitabine on days 1 to 5 or 75 mg/m2 of azacitidine on days 1 to 7, each 28-day cycle. Venetoclax was dosed at 400, 800, or 1,200 mg in the escalation phase and 400 or 800 mg in the expansion phase. Complete remission, complete remission with incomplete blood cell count recovery, overall survival, and adverse events were evaluated.
Best Complete Remission: 400-mg Dose
Data cutoff was July 2017. Of 145 patients included in the study, slightly over half were male (56%), with a median age of 74 years. About 10% of patients received hydroxyurea ahead of the study to meet eligibility criteria, and 25% of patients had an antecedent hematologic disorder for which they did not receive a hypomethylating agent.
In the escalation phase, 60, 74, and 11 patients received venetoclax at 400, 800, and 1,200 mg, respectively (the 1,200-mg dose was not well tolerated, and the cohort was discontinued). Key grade 3 or worse adverse events included febrile neutropenia (43%), thrombocytopenia (23%), and neutropenia (16%).
Combination Therapy for AML
- In elderly patients with untreated AML, a 400-mg dose of venetoclax in combination with either azacitidine or decitabine led to durable responses.
- Although response rates were high regardless of the dose of venetoclax, 400 mg had an optimal risk-benefit profile compared with 800 mg.
- Both hypomethylating agents led to responses, but the highest complete response rates were seen with venetoclax at 400 mg and azacitidine.
At the 400-mg dose of venetoclax, the rate of complete remission/complete remission with incomplete blood cell count recovery was 73% (76% with azacitidine and 71% with decitabine). At the 800-mg dose of venetoclax, complete remission/complete remission with incomplete blood cell count recovery rates with azacitidine and decitabine were 57% and 73%, respectively. Regardless of the dose of venetoclax or the type of hypomethylator backbone patients received, overall response rates were 80% or higher across all subgroups.
“The group that had the best complete remission/complete remission with incomplete blood cell count recovery rate, at 76%, were patients who received the 400-mg dose of venetoclax with an azacitidine backbone,” said Dr. Ellis. “Notably, the median time to response for treatment with a hypomethylator in combination with venetoclax was one to two cycles, which is certainly quicker than what we expect to see when we treat patients with a hypomethylator alone (three to four cycles before maximal benefit).”
For patients who achieved a complete remission or complete remission with incomplete blood cell count recovery, minimal residual disease was assessed. Almost 50% of patients in the 400-mg venetoclax/azacitidine cohort achieved minimal residual disease negativity.
“Preliminary data suggest that 400 mg of venetoclax has the optimal benefit-risk profile in combination with decitabine or azacitidine, which demonstrated a tolerable safety profile with deep responses and durable outcomes in elderly patients with AML,” the investigators reported.
Responses in Elderly and High-Risk Groups
Of patients with poor-risk cytogenetics, 59% still achieved a complete remission or complete remission with incomplete blood cell count recovery. The patients with the longest duration of response were those who had an antecedent hematologic disorder.
Even in this highest-risk group—patients with poor-risk cytogenetics—there was an overall response rate of 75%, with a median duration of response of more than 6 months.— Leslie Ellis, MD
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“Even in this highest-risk group—patients with poor-risk cytogenetics—there was an overall response rate of 75%, with a median duration of response of more than 6 months,” Dr. Ellis noted. “If we look at the duration of response after a complete remission or complete remission with incomplete blood cell count recovery was achieved, we see that no matter how we break it down, the median duration of response was more than 9 months, with a median duration of response of more than 12 months in patients who received the 400-mg venetoclax dose.”
Regardless of the dose of venetoclax, median overall survival was almost 18 months, with 50% survival at 1 year. “If we compare this with historical data for patients treated with azacitidine alone, they have a median overall survival of 10 months,” she said. “Certainly, there is improvement when venetoclax is added.”
Ongoing clinical trials are focusing on moving this regimen into the front-line setting. ■
DISCLOSURE: Dr. Ellis has received honoraria from, is a consultant/advisor to, and is on the speakers bureau for Alexion Pharmaceuticals; she has also received travel expenses from the American Society of Hematology and Alexion Pharmaceuticals.
REFERENCES
1. Dinardo CD, Pratz KW, Potluri J, et al: Durable response with venetoclax in combination with decitabine or azacitadine in elderly patients with acute myeloid leukemia. 2018 ASCO Annual Meeting. Abstract 7010. Presented June 4, 2018.
