TOPLINE

Adding quizartinib after intensive chemotherapy was associated with improved 5-year overall survival among older patients with FLT3-mutated AML in subgroup analyses, but not in the overall trial population, where quizartinib was associated with increased nonrelapse mortality. No additional benefit was seen with extended quizartinib maintenance therapy in the overall population or the wild-type FLT3 AML group.

METHODOLOGY

• Prior studies have supported the use of quizartinib, a TKI that targets FLT3, for FLT3-mutated disease, but the benefit of adding quizartinib to intensive chemotherapy in older adults with newly diagnosed AML remains uncertain.
• To address this, researchers conducted a randomized, open-label, phase 3 trial including 463 patients (median age, 68 years) with previously untreated AML or high-risk myelodysplastic syndrome who were fit for intensive chemotherapy.
• Participants were randomly assigned to receive oral quizartinib 40 mg/d (n = 232) or no quizartinib (n = 231) for 14 days starting 2 days after the completion of chemotherapy courses 2 and 3, plus an additional 28 days. Patients allocated to the quizartinib group were further randomly assigned 1:1 to either 12 additional 28-day maintenance courses (long quizartinib; n = 116) or no further treatment (short quizartinib; n = 116). Patients received standard intensive chemotherapy, which included daunorubicin, cytarabine, and gemtuzumab ozogamicin, before entering the quizartinib randomization.
• The primary outcome was overall survival irrespective of FLT3 status; other outcomes included relapse-free survival, cumulative incidence of relapse, and cumulative incidence of death in remission. The median follow-up duration was 76 months.

TAKEAWAY

• In the overall population, the 5-year rate of overall survival was 35% with quizartinib and 33% with no quizartinib irrespective of FLT3 status (hazard ratio [HR], 0.99; P = .937). Similarly, no significant differences were observed in the 5-year rate of relapse-free survival (26% vs 29%; HR, 1.04; P = .746) or the cumulative incidence of relapse (52% vs 57%; HR, 0.83; P = .185).
• In subgroup analyses, adding quizartinib to chemotherapy was associated with improved 5-year overall survival among patients with FLT3 mutations (47% vs 25%; HR, 0.59; P = .024). The greatest benefit was observed in patients with FLT3-ITD mutations, where quizartinib was associated with higher 5-year overall survival (44% vs 22%; HR, 0.61; P = .055).
• Among patients receiving quizartinib, extending therapy with maintenance did not provide additional benefit, and outcomes numerically favored shorter exposure, particularly among those with FLT3-mutated disease, although the study was not powered to determine whether shorter therapy was superior.
• Quizartinib was associated with an increased risk for nonrelapse mortality (22% vs 14%; HR, 1.64; P = .032). Adverse events were similar between patients who received and did not receive quizartinib, except for cardiac adverse events which were more frequent in both quizartinib groups. Overall, 10 of 15 cardiac events of grade 3-4, including QT prolongation and atrial fibrillation, were considered possibly related to quizartinib. Febrile neutropenia was the most common adverse event of grade 3-4 in all groups.

IN PRACTICE

“Significant survival benefit was demonstrated in FLT3-mutated patients, primarily through a reduction in the risk of relapse,” the authors of the study wrote, adding, however, that the role of FLT3 inhibitor maintenance therapy after frontline intensive therapy remains unclear, particularly because this study was not designed to independently evaluate maintenance strategies.

SOURCE

The study, led by Steven Knapper, School of Medicine, Cardiff University, Cardiff, Wales, was published online in Blood.

LIMITATIONS

The study’s open-label design without placebo control may have introduced reporting bias, particularly for cardiac adverse events where formal ECG monitoring was not mandated in the control group. Maintenance benefit remained unclear because the maintenance comparison was not powered to establish superiority of longer therapy. Increased nonrelapse deaths were observed with quizartinib, with infections accounting for the largest proportion of deaths in remission.

DISCLOSURES

The study received funding from Cancer Research UK, while Daiichi Sankyo supplied the drug and supported distribution costs. Knapper disclosed receiving research support from Novartis, travel support from Servier, and consulting fees from AbbVie, Astellas, Jazz Pharmaceuticals, Novartis, Pfizer, and Servier. Full disclosures are noted in the original article.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.