Gilteritinib is a potent second-generation FLT3 inhibitor approved globally for relapsed/refractory FLT3-mutated AML. The PASHA trial evaluated whether moving gilteritinib into the frontline setting could improve outcomes beyond those achieved with midostaurin, which has been the standard FLT3-targeted therapy combined with intensive chemotherapy since the RATIFY study.

A total of 768 patients with newly diagnosed FLT3-mutated AML were randomized to receive intensive chemotherapy plus either gilteritinib or midostaurin during induction, consolidation, and one year of maintenance therapy.

Safety Outcomes-

• Treatment-related adverse events (TRAEs) due to gilteritinib or midostaurin were 40% in both arms; corresponding Grade ≥3 rates were 23% for gilteritinib and 19% for midostaurin. 

• Serious AE rate was 68% in GILT vs 59% in midostaurin. 

• 30-day mortality: 5% with gilteritinib and 3% with midostaurin.

• 60-day mortality: 9% with gilteritinib and 6% with midostaurin.

KOL Insights-

“The favorable EFS and RFS trends seen with gilteritinib support its greater antileukemic activity in the frontline setting. The absence of a corresponding overall survival benefit should be interpreted in the context of subsequent therapies, as a higher proportion of patients treated with midostaurin received gilteritinib-based salvage therapy and allogeneic transplantation after relapse, potentially mitigating survival differences between the arms.”– Expert Opinion

“Although the results were not practice-changing, the study provides important insights that advance the field and inform future therapeutic development. Such well-conducted academic collaborations are critical to improving our understanding of disease biology and treatment optimization. The contributions of the participating patients, investigators, and collaborative groups deserve recognition for helping move the field forward.”– Expert Opinion

Conclusion-

AML is the most common acute leukemia in adults, accounting for approximately 80% of acute leukemia cases. FLT3 mutations occur in roughly 25–30% of newly diagnosed AML patients and are associated with increased relapse risk and poorer outcomes, making FLT3 inhibition a cornerstone of modern AML treatment.

The Phase III PASHA trial represents the first direct comparison of a second-generation FLT3 inhibitor against midostaurin in newly diagnosed FLT3-mutated AML. Although gilteritinib significantly reduced morphologic relapse and showed a strong numerical improvement in event-free survival, it failed to improve overall survival, the study's primary endpoint. The findings suggest that widespread post-relapse use of gilteritinib and transplantation may have mitigated survival differences between treatment arms. Overall, PASHA reinforces midostaurin as the current frontline standard of care while highlighting the complexity of demonstrating overall survival gains in an era of increasingly effective salvage therapies.