Gilteritinib for FLT3 Mutated r/r AML: Is the Reality Admirable?
Authors: Disha Disha , Singh Aakanksha , Halder Rohan , Palatty Roy , Agrawal Narendra , Panda Tribikram , Tikare Nakul , Ahmed Rayaz , Bhurani Dinesh 
Published: December 2024

Introduction:

Patients with relapsed/refractory (r/r) FLT3 mutated (m) AML often have poor responses to conventional salvage chemotherapy. The phase III ADMIRAL trial reported a statistically significant overall survival benefit in the gilteritinib group compared to the chemotherapy group. But are these results reproduced in the real-world scenario, especially in the Indian setting? We sought to analyze this issue through this study.

Methods:

We retrospectively analyzed r/r FLT3 mutated AML patients who received gilteritinib as monotherapy or in combination with salvage chemotherapy. All 6 patients involved in the study were administered midostaurin as part of the induction regimen-3 in combination with intensive chemotherapy with anthracyclines, and the other 3 in combination with hypomethylating agents. Following relapse, all 6 patients were treated with gilteritinib (120mg) in combination with hypomethylating agents.

Results:

Among the 6 patients included in the study, only five could be assessed for disease response due to worsening fungal meningoencephalitis, leading to poor neurological status and the requirement of mechanical ventilation in one of the patients. The percentage of patients who achieved complete remission with complete or partial hematological recovery was 60% (3/5 patients), while MRD (measurable residual disease) negativity was achieved in only one patient. The median duration to absolute neutrophil count (ANC) &gt; 500/uL recovery was 49 days, which led to a significant increase in infectious complications given the prolonged duration of neutropenia, which might be explained by hypo-cellular marrow (&lt;10% cellularity) among all the patients who achieved remission. Among the patients included in the study, 67% (4/6) developed lung IFI (invasive fungal infection) during the neutropenic phase, while 1 patient had fungal meningoencephalitis requiring mechanical ventilation and ultimately succumbed to it. The incidence of carbapenem-resistant bloodstream infections was 67% (4/6), all of them requiring inotropic support & ICU admission. The rates of infectious complications in the real-world scenario are significantly higher than those reported in the trial at 46.7%. Only 2 patients among 6 (34%) could be bridged to allogeneic stem cell transplantation but both succumbed due to sepsis and worsening of underlying IFI during transplant. The median overall survival (OS) was 2.1 months, which is significantly shorter than reported in the ADMIRAL trial (9.3 months).

Though treatment with gilteritinib resulted in morphological remission in 3 patients (60%), however, did not culminate in survival benefit because of the higher incidence of neutropenic infections, especially invasive fungal infections.

Conclusions:

The prolonged duration of neutropenia increases the risk of infectious complications manifold, not culminating in survival benefits. Though this study is limited by its retrospective nature and a small number of patients, it highlights a dire need for novel more selective targeted therapy in r/r FLT3 mutated AML with less profound myelo-suppression.