More than half of older patients with untreated acute myeloid leukemia (AML) had rapid attainment of complete remission with the combination of venetoclax (Venclexta) and low-dose cytarabine, data from a single-arm clinical trial showed.
The regimen led to complete remission with or without blood-count recovery in 44 of 82 patients, with a median time to first response of 1.4 months. The cohort had a median response duration of 8.1 months and median overall survival (OS) of 10.1 months.
Patients without prior exposure to hypomethylating agents (HMAs) had a higher response rate, longer response duration, and better survival, Andrew H. Wei, MD, PhD, of the Alfred Hospital in Melbourne, Australia, and co-authors reported online in the Journal of Clinical Oncology.
“The high remission rate, low early mortality, rapid induction of remission, and durable length of remission make the combination with venetoclax an attractive and novel treatment option for older adults not suitable for intensive chemotherapy,” the authors concluded.
The results added to preliminary findings reported at the 2017 American Society of Hematology meeting. Last last year, the FDA approved the venetoclax-cytarabine combination for older patients with AML. Supporting data for the application included the study conducted by Wei and colleagues.
“Some of these patients can have durable responses that can be extended for a long period of time,” said co-author Stephen A. Strickland Jr., MD, of Vanderbilt-Ingram Cancer Center in Nashville, Tennessee. “This is something we haven’t seen a whole lot of in this patient population.”
Patients with newly diagnosed AML have a median age of 68 and often are ineligible for intensive chemotherapy, leaving them with few effective less-intensive options. Partly because of limited expectations for treatment success, many older patients with AML do not receive leukemia treatment, the authors noted.
Members of the B-cell leukemia/lymphoma-2 (BCL-2) family promote cell survival in cancer cells, and BCL-2 mediates chemoresistance and enhances leukemic blast and progenitor cells, Wei and co-authors continued.
Venetoclax, a selective oral BCL-2 inhibitor, achieved an objective response rate of 19% as single-agent therapy for patients with heavily pretreated AML. Resistance to the drug may be mediated by pro-survival proteins, such as MCL1, which is downregulated by HMAs and cytarabine, both of which worked synergistically with venetoclax against AML in preclinical studies. A preliminary clinical trial of venetoclax combined with an HMA showed a 61% complete response rate in older patients with untreated AML.
For the current study, Wei and colleagues reported findings from a prospective phase Ib/II clinical trial involving patients ≥60 with untreated AML. The treatment regimen consisted of venetoclax 600 mg/day and subcutaneous low-dose cytarabine (20 mg/m2 on days 1 and 10 of 28-day cycles). Outcomes of interest included safety, tolerability, response rate, duration of response, and overall survival.
The study population had a median age of 74, 49% had secondary AML, 71% had prior HMA treatment, and 32% had poor cytogenetics. During the dose-escalation phase of the trial, no dose-limiting toxicities occurred at the phase II dose of 600 mg/day.
The most commonly reported grade ≥3 adverse events were febrile neutropenia (42%), thrombocytopenia (38%), and decreased white blood cell count (34%). The most common nonhematologic adverse events (all grades) were nausea (70%), diarrhea (49%), hypokalemia (48%), and fatigue (43%).
The authors reported that 45 patients had venetoclax dose interruptions related to adverse events, most often between 28-day cycles because of delayed neutrophil and platelet recovery. Six patients required venetoclax dose reductions, primarily because of thrombocytopenia.
The 54% rate of complete remission included remission with incomplete hematologic recovery in 28%. The highest rates of complete response occurred in patients with de novo AML, with intermediate-risk cytogenetics, and with no prior HMA exposure (71%, 63%, 62%, respectively). Patients with no prior HMA exposure had a median response duration of 14.8 months and median overall survival of 13.5 months.
Patients who achieved a complete response with or without complete hematologic recovery had an estimated 12-month survival of 73%, as compared with 5% for patients who had no response. The 12-month OS was 100% for patients who had complete response with hematologic recovery and 49% for those who had complete response with incomplete recovery. Most patients who achieved remission became transfusion independent.
Strickland said the “impressive” results compare favorably with reported outcomes achieved with intensive chemotherapy.
“The results with this regimen and with venetoclax and hypomethylating agents look just as good or maybe even better than some intensive approaches,” said Strickland. “The question we’re now having to ask … is should we be changing the paradigm of treatment and looking for lower-intensity therapy first.”
“That’s obviously very controversial and we don’t have head-to-head studies of the less-intensive route versus more intensive treatment options. I think the next step is to try and figure out whether we can do just as well with a low-intensity approach or what is the role or best-identified population for less-intensive therapy.”
AbbVie and Genentech provided financial support and participated in the design, study conduct, and interpretation of data, as well as writing, review, and approval of the manuscript.
Wei disclosed relationships with Amgen, Servier, Novartis, Celgene, AbbVie, Roche/Genentech, Pfizer, and Janssen. Multiple co-authors disclosed relationships with the pharmaceutical industry and other commercial interests.
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Journal of Clinical Oncology
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