PB1724 FLT3 MUTATED AML: THE ROLE OF CLADRIBINE AND MIDOSTAURIN ADDED TO THE STANDARD INTENSIVE CHEMOTHERAPY ‐ SINGLE CENTRE EXPERIENCE FROM UMC LJUBLJANA, SLOVENIA
Authors: Anzej Doma S. , Škerget M. , Novak P. , Pajič T. , Sever M. 
Published: June 2019

Background:

The FLT3 ITD mutation in a patient with acute myeloid leukemia (AML) is associated with a poor outcome. Midostaurin is the first multikinase inhibitor approved for the treatment of adults with newly diagnosed FLT3 positive AML. The drug has been available in Slovenia from July 2017 and used in all eligible FLT3 patients. Furthermore, following encouraging results shown by the Polish Adult Leukemia Group, we have been adding cladribine to standard combination DA3+7 induction (namely DAC) for all AML patients aged 60 years or less since 2014.

Aims:

To compare the outcome of FLT3 positive AML patients treated with DA3+7 or DAC with further addition of midostaurin.

Methods:

We retrospectivelly analyzed all consecutive FLT3 positive AML patients, aged 60 years or less, treated with intensive chemotherapy between years 2012‐2018. Bone marrow (or in some cases peripheral blood) RNA was used for FLT3 mutation detection. FLT3 ITD mutation was detected by reverse transcription PCR (RT‐PCR) and gel electrophoresis analysis. FLT3 D836 mutation detection was carried out by RT‐PCR and Restriction Fragment Length Polymorphism technique using restriction enzyme EcoRV. From 01/2012 – 04/2014 DA3 + 7 was used, while from 05/2014 – 12/2018 DAC (addition of 5 mg/m2 of cladribine in a 3‐hour infusion on days 1‐5 to DA3 + 7) was used for all AML patients aged 60 years or less eligible for intensive chemotherapy. Remission was assessed by bone marrow aspiration in the aplastic phase and before the first consolidation therapy. Consolidation treatment was intermediate or high dose cytosar. Midostaurin was added according to indication no later than in the first consolidation phase (2x50 mg from day 8‐21). All patients with FLT3 ITD mutation and available donor were transplanted. Patients who had not achieved remission after induction chemotherapy proceeded with rescue chemotherapy and allogeneic transplantation. Patients who were not transplanted continued maintenance treatment with midostaurin 2x50 mg continuously for one year.

Results:

There were 39 FLT3 positive AML patients aged 60 years or less who were treated with intensive chemotherapy in the period 2012‐2018: 16 with DA3 + 7 and 23 with DAC. There was no difference between the baseline characteristics between the groups (Table 1). Remission after induction was achieved in 9/16 patients in the DA group (1 patient was treated with midostaurin during induction) and 19/23 in the DAC group (5 patients received midostaurin during the induction), p = 0,072. Survival was significantly better in the DAC group in which overall 12/23 patients were treated with midostaurin compared to DA3 + 7 where only 1 patient was treated with midostaurin; p = 0,028. The proportion of patients with allogeneic transplant was similar (7/16 in the DA and 11/23 in the DAC group; p = 0,802). When comparing patients with or without midostaurin treatment the survival was significantly better in patients treated with midostaurin (p = 0,005), however, the median observation time was only 11 months. The addition of midostaurin to DAC did not increase toxicity.

Summary/Conclusion:

Addition of cladribine and midostaurin to standard DA3 + 7 improved survival in FLT3 positive AML patients. No new safety signals were noted in patients receiving DAC + midostaurin. Further follow‐up is required to evaluate influence of midostaurin in combination with DAC induction chemotherapy on progression free survival and overall survival.

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