Adding venetoclax (Venclexta) to a gilteritinib (Xospata) regimen appeared to improve outcomes in refractory/relapsed FLT3-mutated acute myeloid leukemia (AML), a new industry-funded phase 1b study reported.
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Outcomes in AML are poor. As the study notes, most patients relapse and face a median overall survival of 4-7 months even with standard chemotherapy. Gilteritinib, a selective oral FLT3 inhibitor, is Food and Drug Administration–approved for the 30% of relapsed/refractory patients with AML who have FLT3 mutations.
“The general sentiment is that, although some patients have great benefit from gilteritinib monotherapy, there is room to improve the quality, frequency, and duration of responses with combinations,” said hematologist Andrew Brunner, MD, of Massachusetts General Hospital in Boston, in an interview. He was not involved with the study research.
For the new open-label, dose-escalation/dose-expansion study, led by hematologist Naval Daver, MD, of the University of Texas MD Anderson Cancer Center, Houston, researchers enrolled 61 patients (56 with FLT3 mutations) from 2018 to 2020. The median age was 63 years (range 21-85).
The subjects were assigned to get a recommended phase 2 dose of 400 mg venetoclax once daily and 120 mg gilteritinib once daily.
Over a median follow-up of 17.5 months, the median remission time was 4.9 months (95% confidence interval, 3.4-6.6), and the patients with FLT3 mutations survived a median of 10 months.
“The combination of venetoclax and gilteritinib was tolerable at standard doses of each drug, generated remarkably high response rates, and markedly reduced FLT3-internal tandem duplications mutation burden. … Early mortality was similar to gilteritinib monotherapy,” the authors wrote.
Eighty percent of patients experienced cytopenias, and “adverse events prompted venetoclax and gilteritinib dose interruptions in 51% and 48%, respectively.”
About 60% of patients who went on to receive allogeneic hematopoietic stem cell transplantation were alive at the end of follow-up, “suggesting that VenGilt [the combo treatment] could be an effective bridge to transplant in young/fit patients with relapsed FLT3mut AML,” the researchers wrote.
All patients withdrew from the study by November 2021 for several reasons such as death (n=42), adverse events (n=10), and disease progression (29); some had multiple reasons.
Dr. Brunner said the study is “an important step toward evaluating a new potential regimen.”
The remission duration, FLT3 molecular response, and median overall survival “seem quite encouraging for a severe disease like AML in relapse,” he said. However, he added that the drug combo “would need to be evaluated in a randomized and, ideally, placebo-controlled setting to know if this is a significant improvement.”
He also highlighted the high number of severe cyptopenias with associated complications such as death. “Whether this is acceptable depends on the patient and circumstances,” he said. “But it does suggest that this regimen would potentially be for more robust patients, particularly since the group that did best were those who went to transplant later.”
Pending more research, Dr. Brunner said, “I am not sure I would use [the combination treatment] over gilteritinib monotherapy, for instance. But there may be settings where no other options are available, and this could be considered, particularly if a transplant option is a next step.”
The study was funded by AbbVie, Genentech, and Astellas. The study authors report multiple disclosures; some are employed by Astellas, AbbVie, and Genentech/Roche.
Dr. Bronner reports running clinical trials, advisory board service and/or consultation for Acceleron, Agios, Abbvie, BMS/Celgene, Keros Therapeutics, Novartis, Takeda, GSK, AstraZeneca, Janssen, and Gilead.