In a comparison of real-world outcomes for two common first-line regimens for acute myeloid leukemia (AML) with mutations in isocitrate dehydrogenase 1 (IDH1), treatment with the IDH1-targeted agent ivosidenib plus a hypomethylating agent was associated with better outcomes than venetoclax plus a hypomethylating agent. The differences, however, may not reflect the efficacy of the two agents, but rather, the ability of patients to receive adequate doses of venetoclax, researchers said at the 2023 American Society of Hematology Annual Meeting & Exposition.¹

In a large, balanced cohort of nearly 300 patients with newly diagnosed IDH1-mutated AML, those treated with ivosidenib plus a hypomethylating agent had higher rates of complete response and complete response plus incomplete count or incomplete platelet recovery; achieved complete responses faster; and had longer event-free survival. However, the analysis also showed that only 23% of the venetoclax/hypomethylating agent group received the approved 28 days of treatment per cycle and 42% received no more than 7 days of treatment per cycle, said B. Douglas Smith, MD, of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore.

“I think the plan from the institutions seemed to be to treat people for shorter windows of time…. These data help us see that in the real-world application, the patient’s provider may not be following the formal FDA [U.S. Food and Drug Administration] label, and this raises the question of how that has impacted the response rate, which seems lower than we would have expected,” he said.

“These data help us see that in the real-world application, the patient’s provider may not be following the formal FDA [U.S. Food and Drug Administration] label….”

— B. DOUGLAS SMITH, MD

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The findings were based on a nationwide retrospective chart review of 283 patients with IDH1-mutated AML ineligible for intensive chemotherapy and treated instead with those two doublets. The two doublets have not been robustly compared, and post hoc analyses have been small and constrained by low numbers of patients with IDH1-mutated disease and clustering of IDH1 and IDH2. Dr. Smith and his colleagues, therefore, evaluated a large population from community and academic settings “to see how these treatments play out in the real world.”

More About the Study

Of the 283 patients, 182 received ivosidenib plus a hypomethylating agent and 101 received venetoclax plus a hypomethylating agent and were followed for at least 6 months. Baseline characteristics were similar, with about 60% deemed at intermediate cytogenetic risk and 15% at high risk; more patients in the venetoclax group were treated in the academic setting (68.3% vs 55.5%; P = .035), and more of the ivosidenib group had favorable cytogenetic risk (24.7% vs 12.9%; P = .026). About one-quarter of both groups had experienced disease progression from myelodysplastic syndrome. Endpoints included events likely to occur within 6 months of follow-up, including response rate, tolerability, bridge to transplant, and acute care episodes.

Treatment Response

Complete responses were documented for 42.9% of the ivosidenib group and 26.7% of the venetoclax group (P = .007). Complete response plus complete response with incomplete count or incomplete platelet recovery was achieved by 83.2% and 49.5%, respectively (P = .025). Median time to best response was 3.3 months with ivosidenib and 4.1 months with venetoclax (P = .02), Dr. Smith reported.

The regimen was a bridge to allogeneic transplant for 11.5% of the ivosidenib group and 5.0% of the venetoclax group (P = .066); at 6 months, the event-free survival rate (complete response within 24 weeks, no relapse or death) was 56.0% vs 39.6%, a 33% reduction in risk with ivosidenib plus a hypomethylating agent (P = .044).

Dose and Schedule Intensity

Given anecdotal reports of variations in the use of venetoclax, the researchers captured information about the drug’s delivery. “Some surprising and interesting things came from this,” he said. “We found very few patients outside of the scheduled dose escalation of venetoclax changed their dose of venetoclax or ivosidenib during treatment. Once patients started therapy, they maintained the same dose of the drug throughout. But what was interesting was that only 23% of patients received the full 28 days, which is the dose approved by the FDA. This did not appear related to toxicity; rather, it seemed to be a preemptive plan made by the team to deliver less than the recommended 28 days.”

“We found very few patients outside of the scheduled dose escalation of venetoclax changed their dose of venetoclax or ivosidenib during treatment.”

— B. DOUGLAS SMITH, MD

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“The modified venetoclax schedule may explain the inferior onset and rate of complete response and highlights the challenge of navigating the dosing tradeoff of efficacy vs safety.”

— B. DOUGLAS SMITH, MD

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Additionally, 42% of patients received no more than 7 days of treatment with venetoclax. Specifically, 44.6% received 4 to 11 days, 22.8% received 27 or 28 days, and 32.7% received 15 to 25 days of treatment. For each regimen, 37% of patients discontinued treatment, Dr. Smith reported.

“The modified venetoclax schedule may explain the inferior onset and rate of complete response and highlights the challenge of navigating the dosing tradeoff of efficacy vs safety,” he commented.

Safety Profiles

“Despite the modified schedule of venetoclax, patients receiving venetoclax plus [a hypomethylating agent] had a higher early incidence of febrile neutropenia and greater need for unscheduled acute care than those receiving ivosidenib plus [a hypomethylating agent],” he reported. Neutropenic fever occurring in the first treatment cycle was documented for 7.0% receiving venetoclax [plus a hypomethylating agent], vs 1.6% receiving ivosidenib [plus a hypomethylating agent] (P = .009) and “unscheduled acute care” was necessary for 42.9% vs 70.3%, respectively (P < .001), leading to the appearance of greater toxicity early in the venetoclax course, Dr. Smith observed.

The findings emphasize the need for early mutational testing of AML patients, so that clinicians can consider ivosidenib plus azacitidine as their front-line choice for newly diagnosed IHD1-mutated disease, Dr. Smith said. He noted that the wait time for mutational results in this analysis was 7 days—“well within the 14- to 20-day median times to treatment.” 

DISCLOSURE: Dr. Smith has served as a consultant to Bristol Myers Squibb, Novartis, Pfizer, and Servier.

REFERENCE

1. Smith BD, Lachowiez CA, Ambinder AJ, et al: A comparison of acute myeloid leukemia regimens: hypomethylating agents combined with ivosidenib or venetoclax in newly diagnosed patients with IDH1 mutations: A real-world evidence study. 2023 ASH Annual Meeting & Exposition. Abstract 971. Presented December 11, 2023.