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Combination therapy with venetoclax demonstrates activity in AML
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The BCL-2 inhibitor venetoclax appears to have clinical activity in patients with acute myeloid leukemia when used in combination with either cytarabine or a hypomethalating agent, according to the results of two studies presented at the ASCO Annual Meeting.
Both studies examined the use of venetoclax (Venclexta; AbbVie, Genentech) “in previously untreated older patients who are unfit to receive intensive chemotherapy,” according to Olga Frankfurt, MD, associate professor of medicine at Northwestern University’s Feinberg School of Medicine, and showed “significant activity.”
Addition of venetoclax improves response to low-dose cytarabine
The first trial, a nonrandomized, open-label, phase 1/phase 2 dose-escalation/expansion study, evaluated the safety and preliminary efficacy of venetoclax in combination with low-dose cytarabine. Patients aged 65 and older (n = 18; 66.7% men; median age, 74 years) received oral venetoclax once a day on days 1 to 28 and 20 mg/m2 subcutaneous cytarabine daily on days 1 through 10 of each 28-day cycle.
Dose escalation with venetoclax followed a 3 + 3 design. Dose-limiting toxicities, including grade 4 toxicity, platelet count < 25,000/μL or absolute neutrophil count < 500/μL within 14 days of the last venetoclax dose, were assessed during cycle 1, up to day 42.
Adverse events with greater than or equal to a 30% prevalence included nausea (77.8%), anemia (55.6%), febrile neutropenia, neutropenia and fatigue (38.9% each), and vomiting, diarrhea and hypokalemia (33.3% each). No clinically significant tumor lysis syndrome was observed.
“The optimal dose of venetoclax was determined to be 600 mg per day because of thrombocytopenia — without any evidence of residual leukemia — in 2 patients receiving the 800 mg dose,” Frankfurt said.
The combination of venetoclax and low-dose cytarabine resulted in an overall response rate of 44%, with 4 patients achieving complete remission and 4 patients achieving complete remission without complete marrow recovery, Frankfurt told HemOnc Today. Resistant disease was observed in 8 patients and 2 died prior to being evaluated.
“Granted, an ORR of 44% is not 90%, or 100% — but it’s better than the 10% that we see with single-agent low-dose cytarabine,” she said.
Venetoclax plus hypomethylating agents improve outcomes in high-risk patients
Results seen with venetoclax in combination with either decitabine (Dacogen, Otsuka)
or azacitidine (Vidaza, Celgene) were “even better” than those seen with venetoclax in combination with low-dose cytarabine, according to Frankfurt.
The second trial, a phase 1b study, was conducted in treatment-naive patients aged 65 years and over with an ECOG performance status greater than or equal to 2 and a karyotype of intermediate or poor risk who were not eligible for standard induction therapy. Patients were divided into 2 groups. Patients in arm A received IV decitabine 20 mg/m2 daily on days 1 through 5 of each 28-day cycle; patients in arm B were treated with subcutaneous or IV azacitidine 75 mg/m2 daily on days 1 through 7 of each 28-day cycle. All patients were treated with orally administered, continuous venetoclax once per day. Dose escalation for venetoclax followed a 3 + 3 design, with a final dose level of 1,200 mg. Objectives include safety, preliminary efficacy, and biomarker evaluations.
The presentation reviewed results in 39 patients (49% men; median age, 74 years); arm A included 20 patients and arm B included 19. Median time in the study was 111 days (range, 6 to 375 days).
ORR was 76%, with complete responses observed in 13 patients and complete response with incomplete marrow recovery observed in 11. Part remissions were observed in 2 patients. Median time to complete response/complete response with incomplete bone marrow recovery was 29.5 days (range, 24 to 112 days).
Biomarker analysis was completed in 34 patients at 400 mg and 800 mg doses of venetoclax. Poor-risk cytogenetics and IDH1/2 mutations were reported in 24% (8/34) and 32% (11/34) of patients; ORR was 88% (7/8) and 82% (9/11), respectively.
The most common treatment-emergent adverse events were nausea (54%), febrile neutropenia (41%), diarrhea (44%), decreased appetite (33%) and peripheral edema (31%). The most common Grade 3/4 treatment-emergent adverse events were febrile neutropenia (41%) and neutropenia (33%); the most frequent, serious adverse event was febrile neutropenia (28%). Six deaths occurred during the study period; 3 were due to disease progression and 1 each was due to sepsis, respiratory failure and bacteremia.
Four relapses occurred, all in patients in arm A.
No dose-limiting toxicity was reported. The maximum tolerated dose had not been reached at the time the results were presented.
“The ORR was 76%,” Frankfurt said. “Among 8 patients with poor-risk cytogenetics — which is a notoriously high-risk group of patients who are refractory to treatment — 7 achieved a response. This is very exciting and very promising.” – by Julia Ernst, MS
References:
Lin TL, et al. Abstract 7007. Presented at: ASCO Annual Meeting; June 3-7, 2016; Chicago.
Pollyea DA, et al. Abstract 7009. Presented at: ASCO Annual Meeting; June 3-7, 2016; Chicago.