Harry P. Erba, MD, PhD
Harry P. Erba, MD, PhD, Professor of Medicine and Director of the Leukemia Program in the Division of Hematologic Malignancies and Cellular Therapy at Duke University School of Medicine, Durham, North Carolina, told The ASCO Post he was not surprised by one of the key findings reported by Smith et al, as nearly half of the patients received 7 days or less of venetoclax during their first cycle.
Physicians are concerned about the known risk of myelosuppression associated with venetoclax, he said. “They assume that many older patients cannot tolerate the combination of venetoclax and azacitidine. However, if the patient does not respond to therapy, the neutrophil count will also not recover. It is a fallacy that if you arbitrarily restrict the number of days of venetoclax during the first cycle you can decrease the risk of toxicity,” Dr. Erba said, citing a recent French retrospective analysis in which patients who preemptively received only 7 days of venetoclax (plus 7 days of azacitidine) had a rate of febrile neutropenia of 49% during the first cycle.1 “It takes time for the neutrophil count to recover after clearance of the disease.”
“You have to remember that in the VIALE-A trial [demonstrating the benefit of adding venetoclax to azacitidine],2 patients over the age of 75, even those with poor performance status, received azacitidine with up to 28 days of venetoclax from day 1. They tolerated it without an increase in early mortality, and there was an overall survival benefit,” he said, “so I don’t agree with the practice of holding the venetoclax…. I think we are fooling ourselves by cutting back on dosing before documenting clearance of the leukemia.”
Additional Considerations
Dr. Erba further pointed out that venetoclax has single-agent activity in relapsed/refractory IDH1-mutated AML. “Cutting back on the venetoclax dose during cycle 1 in this AML subtype to try to decrease myeloid toxicity, number one, will not avoid or shorten the duration of neutropenia, and number two, may be doing patients a disservice by restricting exposure to an effective agent.”
He said that, based on the potential for inadequate dosing in the current population, the assumption cannot be made that venetoclax is inferior to ivosidenib in IDH1-mutated AML—but he does prefer starting with the IDH1 inhibitor. “In my experience, which mirrors the experience with ivosidenib reported by Montesinos et al,3 neutrophils are improving in the first cycle and there is a lower incidence of febrile neutropenia. You can give the drug in the outpatient setting without risk of tumor lysis syndrome.
Furthermore, once a patient has achieved a response, there is much less need to adjust the dose and schedule of ivosidenib compared with that of venetoclax. The consistency of the ivosidenib dosing schedule every cycle is an important feature, especially for my older patients on multiple other medications.
Dr. Erba concluded, “For those reasons, I think it’s important to wait for mutational status and if IDH1-mutated, to start with ivosidenib and azacitidine and reserve the mutation-agnostic combination of venetoclax and azacitidine for the second line.”
DISCLOSURE: Dr. Erba reported financial relationships with Servier and AbbVie,
REFERENCES
2. DiNardo CD, Jonas BA, Pullarkat V, et al: Azacitidine and venetoclax in previously untreated acute myeloid leukemia. N Engl J Med 383:617-629, 2020.
3. Montesinos P, Recher C, Vives S, et al: Ivosidenib and azacitidine in IDH1-mutated acute myeloid leukemia. N Engl J Med 386:1519-1531, 2022.
