Azacitidine and Venetoclax Followed By Sequential Gilteritinib Is an Effective Alternative in Very Frail Patients with FLT3-Mutated Acute Myeloid Leukemia
Authors: Nedumannil Rithin , Matley Chelsea , Bajel Ashish , Levis Mark J. , Wei Andrew H 
Published: December 2024

Background:
Treatment outcomes of newly diagnosed FMS-like tyrosine kinase 3 (FLT3)-mutated (FLT3mut) acute myeloid leukemia (AML) ineligible for intensive chemotherapy are suboptimal. Neither the FLT3 inhibitor gilteritinib (GIL) nor the BCL2 inhibitor venetoclax (VEN) appear effective in improving survival outcomes in combination with azacitidine (AZA) in frontline elderly adults with FLT3-ITD AML. In older, unfit patients, azacitidine and venetoclax (AZA-VEN) may lead to prolonged cytopenias and infectious complications, making it difficult to sustain repeated cycles of therapy. Triple combination of GIL with AZA-VEN appears to further exacerbate these issues. We hypothesized that sequential delivery of GIL after initial cytoreduction with AZA-VEN would be an efficacious and less toxic alternative in elderly or frail patients with FLT3mut AML unable to tolerate repeated cycles of AZA-VEN.
Methods:
Patients with FLT3-ITD AML ineligible for intensive chemotherapy and initially treated with AZA-VEN were included. Patients achieving initial marrow blast clearance (&lt;5%) but not considered fit to continue AZA-VEN due to frailty, poor performance status or medical complications were assessed for persistent disease using next generation sequencing (NGS) for FLT3-ITD measurable residual disease (MRD), with a limit of detection of 0.001%. Patients confirmed to have persistent FLT3-ITD were commenced on GIL monotherapy.
Results:
Seven patients received sequential treatment with AZA-VEN followed by GIL. Median age was 78 (range 70-90) years and ECOG was 2 (range 2-3). Six patients had de novo AML and one had secondary AML from essential thrombocythemia. All patients had diploid karyotype and FLT3-ITD mutation (median allelic ratio 0.38 [range 0.03-0.7]) while two patients also harboured FLT3-TKD D835Y co-mutation. Two patients (29%) had ELN 2022 adverse risk disease. AZA-VEN was commenced in all patients, with a median of two (range 1-2) cycles administered. Complications related to AZA-VEN included infection/sepsis (pneumonia in 57%), prolonged neutrophil/platelet count recovery (57%), intensive care unit (ICU) admission (29%), tumour lysis syndrome (TLS, 29%) and venous thromboembolism (14%). All patients except one achieved morphologic remission but had FLT3-ITD MRD detected (median variant allele frequency [VAF] 1.482% [range 0.058-15.862%]) following AZA-VEN.
Patient frailty precluded the administration of further AZA-VEN therapy; GIL monotherapy was subsequently commenced at a continuous dose of 80-120 mg daily in 28-day cycles. 5/6 tested patients had a reduction in FLT3-ITD MRD (to a median VAF of 0.002% [range 0-0.129%]) after a median of three (range 1-5) treatment cycles, with three patients (43%) achieving FLT3-ITD MRD-negative remission. One patient (14%) experienced indolent progression of FLT3mut AML after 6 months but continued to maintain stable disease following an increase in GIL dose from 80 mg daily to 120 mg daily. With a median follow-up of 11.9 (range 2.6-61.5) months, median overall survival (OS) was not reached; 57% of patients were alive at 12 months with one treatment-unrelated relapse-free death. At the data cut-off date (15/JUL/2024), all vital patients continued treatment with a median duration of GIL therapy of 8.8 (range 1.2-58.3) months.
Conclusion:
Despite the small cohort size, our data suggests that sequential treatment with AZA-VEN followed by GIL is safe, deliverable and effective in maintaining disease control in FLT3mut AML patients who are frail, comorbid and otherwise unable to tolerate ongoing AZA-VEN therapy.