FLT3 Inhibitor Improves AML Survival With or Without Stem-Cell Transplant

HOUSTON -- Post-transplant maintenance with an FLT3 inhibitor significantly improved overall survival (OS) in FLT3-positive acute myeloid leukemia (AML), according to a subgroup analysis of a randomized trial.

Patients who underwent allogeneic transplant in first complete remission (CR1), followed by quizartinib (Vanflyta) maintenance, had almost a 60% reduction in the survival hazard versus patients who received placebo after transplant (HR 0.42). Patients who did not undergo transplant had lower OS, but patients who received quizartinib maintenance still fared better than those randomized to placebo.

Among patients undergoing transplant, patients benefited from quizartinib regardless of whether they achieved measurable residual disease (MRD)-negative status, but the benefit appeared greater in patients who were MRD-positive prior to transplant, reported Alexander Perl, MD, of the University of Pennsylvania in Philadelphia, at the Society of Hematologic Oncology meeting.

"The addition of quizartinib provided a clinically meaningful and statistically significant improvement in overall survival compared with standard induction and consolidation therapy alone," said Perl. "Irrespective of whether allo-transplant was performed, there was longer survival with quizartinib versus placebo throughout the study.

"This was maintained regardless of the MRD level, which may have reflected the effect of post-transplant maintenance with quizartinib, which the study was not designed to identify specifically. There were no new safety signals identified in patients who underwent transplant."

One of the most common mutations associated with AML, FLT3 internal tandem duplication (ITD) occurs in about a fourth of all cases and is associated with worse OS, which is improved by allogeneic stem cell transplant. The QuANTUM-First trial evaluated the FLT3-ITD inhibitor quizartinib as maintenance therapy following standard induction and consolidation therapy with or without transplant in patients with AML and FLT3-ITD.

The primary results showed that the addition of quizartinib doubled OS versus placebo (31.9 vs 15.1 months), which supported the recent FDA approval of quizartinib. Perl reported findings from an analysis that examined that impact of transplant on outcomes and the interplay between transplantation, MRD status, and quizartinib.

QuANTUM-First involved 539 randomized patients, 348 of whom entered consolidation therapy and 157 who underwent transplantation while in CR1. An additional 196 patients had transplants outside of CR1.

Among the 157 patients, about half received ablative conditioning therapy and 60%-70% received ablative or reduced-intensity conditioning. A third of the patients had matched-sibling donors and about half had unrelated donors. The stem-cell source was peripheral blood in about 80% of cases.

Median follow-up was 38 months. Patients in CR1 at the time of transplantation had a 36-month OS of almost 80% with quizartinib maintenance versus 60%-65% with placebo.

"Whether patients had undergone transplant or no transplant at any time on the study, quizartinib was associated with better survival, but the best survival was in patients on quizartinib who underwent transplant," said Perl. "There's not an impact in terms of whether quizartinib is associated with better survival based on MRD, but there's greater separation between the [survival] curves in the MRD-positive patients."

No consistent pattern of toxicity emerged among patients treated with quizartinib, he added. More stomatitis occurred in patients treated with quizartinib whereas placebo was associated with more febrile neutropenia and decreased appetite.

Following the presentation, the discussion focused on what a member of the audience considered a high rate of dropout prior to transplantation. Of about 850 patients eligible for transplantation, 539 were selected, representing a dropout rate of about 40%, said Hagop Kantarjian, MD, of the University of Texas MD Anderson Cancer Center in Houston.

"That reflects the notion that FLT3-positive AML is a very high-risk situation, where many patients can decompensate very quickly, and that's not reflected in any presentation [of QuANTUM-First data]," said Kantarjian. "What should we tell community oncologists to say when they see a patient with AML and a high white-cell count? Many AML experts say don't worry about it, just give them a little [therapy] and they'll be all right. I don't think that's the proper way of managing them."

Perl said the dropout rate did not owe to early deaths; some patients dropped out for complications such as abnormal liver function, renal failure, or a change in EKG status.

With regard to Kantarjian's question about management recommendations, Perl added, "These are really high-risk patients. They often present with hyperleukocytosis. A good number of the patients had white blood cell counts over 100,000. They need to be in centers that are experienced with management of these oncologic emergencies. I think the critical thing is that this is not something you want to be doing in a center that isn't high volume."

In response to another question, Perl said the trial had a placebo control because the FLT3 inhibitor midostaurin (Rydapt) was not yet widely available outside the U.S. when QuANTUM-First began.

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