P592: GILTERITINIB IN COMBINATION WITH VENETOCLAX, LOW DOSE CYTARABINE AND ACTINOMYCIN D FOR FLT3 MUTATED RELAPSED OR REFRACTORY ACUTE MYELOID LEUKEMIA

Abstract

Background: A second generation FLT3 inhibitor Gilteritinib has become a standard of care for FLT3 mutated relapsed or refractory acute myeloid leukemia (FLT3m R/R AML). However, remission duration and overall survival remain unsatisfactory. Preliminary results of doublet Gilteritinib + Venetoclax and triplet Gilteritinib + Venetoclax + Hypomethylator regimens are encouraging. Herein, we report the quadruplet regimen consisting of Gilteritinib, Venetoclax, Low Dose Cytarabine and Actinomycin D (ACTIVE + G) for the treatment of FLT3m R/R AML in the clinical practice setting. Aims: To evaluate the efficacy and safety of the ACTIVE + G regimen. Methods: This was an observational, retrospective study. The patients were at least 18 years of age and had FLT3m R/R AML. All patients provided informed consent for treatment and data collection. The ACTIVE + G regimen consisted of Venetoclax 600mg/d p/o from day 1 up to day 28, Cytarabine 20mg/m2 s/c on days 1-10, Actinomycin D 12.5 µg/kg i/v on days 1-3 (on days 1-2 for patients ≥65 years) and Gilteritinib 120mg/d p/o starting from either day 4 or day 10 and continued up to day 28. Indications for stopping Venetoclax and Gilteritinib before day 28 were life-threatening infections or faster hematological recovery in responding patients. A second ACTIVE + G cycle was administered in non-responders without evidence of progressive disease after Cycle 1 or in responders with positive measurable residual disease (MRD). Responders after ACTIVE + G could proceed to either allogeneic stem cell transplantation (alloSCT) or maintenance therapy with Venetoclax, Low Dose Cytarabine and Gilteritinib. We evaluated baseline characteristics, composite CR (CRc = CR + CRi + CRp), overall response (ORR = CRc + MLFS), MRD negativity rates (<0.1% by multiparameter flow cytometry), overall survival (OS), relapse-free survival (RFS), grade 3-5 non-hematological toxicities and day 30 and day 60 mortality rates. Results: Fifteen patients had been treated with ACTIVE + G, of whom 8 (53%) were female. The median age was 66 years (34-87), median ECOG was 2 (0-3). FLT3-ITD mutation was confirmed in 80% (12/15) of cases and 20% (3/15) had FLT3-TKD. The most common co-mutations were NPM1 (53%, 8/15), DNMT3A (27%, 4/15), IDH1 (20%, 3/15) and IDH2 (20%, 3/15). Three patients (20%) had adverse cytogenetics. The median number of previous treatment lines was 2 (1-5). Twelve patients (80%) had received prior intensive chemotherapy, 3 patients (20%) had prior Venetoclax exposure and 9 patients (60%) had been previously treated with FLT3 inhibitors (Midostaurin – 7, Sorafenib – 1, Gilteritinib – 1). Three patients (20%) had relapsed after alloSCT. The majority of patients (80%, 12/15) had received 1 cycle of ACTIVE + G, 3 patients (20%) had been treated with 2 cycles. The CRc and the ORR were 67% (10/15) and 93% (14/15), respectively. MRD negativity was confirmed in 50% (5/10) of CRc cases. The median OS and RFS were 8.6 and 12.9 months, respectively. The most common non-hematological grade 3-5 adverse events were febrile neutropenia (73%, 11/15), sepsis/bacteremia (53%, 8/15), pneumonia (33%, 5/15) and secondary hemophagocytosis (13%, 2/15). Day 30 and day 60 mortality rates were 13% (2/15) and 20% (3/15), respectively. Image:Summary/Conclusion: A quadruplet regimen ACTIVE + G demonstrated high efficacy in this small group of R/R FLT3m AML patients irrespective of their prior exposure to FLT3 inhibitors or Venetoclax. The main toxicities were infectious complications attributable to prolonged myelosuppression. Prospective clinical trials are needed to verify our results.