PF287 MIDOSTAURIN IN COMBINATION WITH INTENSIVE CHEMOTHERAPY IS SAFE AND ASSOCIATED WITH IMPROVED REMISSION AND HIGHER TRANSPLANT RATES IN REMISSION ‐ A MULTI‐CENTER HISTORICAL CONTROL STUDY
Authors: T. Berger, U. Rozovski, Y. Moshe, S. Yaari, I. Hellmann, A. Apel, A. Aviram, M. Koren‐Michowitz, P. Raanani, R. Ram, Y. Ofran, O. Wolach
Journal: HemaSphere (2019)

Background: The phase 3 RATIFY trial demonstrated that adding the FLT3 inhibitor midostaurin to intensive chemotherapy improves outcome in younger patients with de‐novo FLT3‐mutated (FLT3+) AML. The toxicity and efficacy profile of adding midostaurin to chemotherapy in patients not originally included in the RATIFY study is unknown. Aims: To characterize midostaurin safety and efficacy in a ’real‐world’ setting. Methods: FLT3+ (ITD/TKD) Patients with AML (&gt;18 years) were eligible to receive midostaurin in Israel since April 2016. To control for toxicity and efficacy outcomes the results of midostaurin‐treated patients were compared to historical controls (FLT3+ AML diagnosed after January 2015). Data were extracted from patients’ records and collected from 5 centers in Israel. Patient and disease characteristics, event free (EFS) and overall survival (OS) were analyzed and compared between the groups. Results: Forty‐eight patients were included in the analysis with a mean follow up of 10.9 ( ± 9.3) months; 33 patients were treated with midostaurin and 15 patients were included in the historical control group. The median age of patients was 61 (range 27–78) years; 33% and 23% of the patients were older than 65 and 70 years, respectively. No differences were noted between the 2 group in terms of age, gender, performance status and comorbidity scales, presenting blood counts, extramedullary involvement, leukemia ontogeny and cytogenetics apart from NPM1‐mutation which was more prevalent in the midostaurin group (69.6% vs. 40%, p = 0.051). No differences were noted between the groups in terms of induction regimen or in cytarabine dosing for consolidation. Midostaurin was administered with 90 mg/m 2 daunorubicin in 11 patients (33%, comparable to control group). More patients in the midostaurin group received consolidation treatment (73% vs. 27%, p = 0.003). A full 14‐day midostaurin course was given to most patients during induction (72%). Ten patients (30%) experienced dose reductions or interruptions at different phases of therapy. Overall toxicity was comparable between the groups including febrile neutropenia rates (91% vs 93% of patients, respectively) and time to neutrophil and platelets recovery. Frequent (&gt;10%) non‐hematologic toxicities recorded were skin rash, gastrointestinal and hepatic toxicity, thrombotic events and HSV infections (comparable between groups). QTc prolongation led to discontinuation of midostaurin treatment in one patient. Adding midostaurin to 90 mg/m 2 daunorubicin for induction was not associated with excess toxicity. CR/CRi rates were 81% and 58% in the midostaurin and control groups, respectively (p = 0.13). Significantly more patients in the midostaurin group were transplanted in first remission (80% vs. 20%, p = 0.052). OS and EFS were higher, though not statistically significant, in the midostaurin vs. control group [not reached vs. 9 months (p = 0.09) and 13 vs. 5 months (p = 0.155), respectively; median follow‐up 8 months]. FLT3 allelic burden and NPM1 status did not affect survival. Summary/Conclusion: In this ‘real‐life’ setting, midostaurin was administered across all age groups, was well tolerated and did not add to toxicity, even when administered with higher doses of daunorubicin for induction. Significantly more patients in the midostaurin group were transplanted in first remission compared to historical controls and a trend toward higher overall survival was observed. Longer follow‐up and more patients are needed to assess the efficacy of adding midostaurin to chemotherapy in the off‐trial setting.