P547: upfront intensive treatment analysis of the italian cohort study on flt3-mutated aml patients (flam): the impact of a flt3 inhibitor addition to standard chemotherapy in the real-life setting

Background: Midostaurin in combination with standard chemotherapy represents the standard of care for the treatment of newly-diagnosed (ND) FLT3-mutated Acute Myeloid Leukemia (AML) patients. However, data on the effectiveness of upfront FLT3 inhibitors (FLT3i) usage as compared to chemotherapy in a real-life setting are still scarce. Aims: to investigate the effect of the addition of a FLT3 inhibitor to first-line intensive treatment on clinical outcomes in an Italian, observational, multicenter cohort study of FLT3-mutated AML patients. Methods: to reach the study aim, data from the Italian non-interventional study of FLT3 mutated AML patients (FLAM - NCT03547258) were used. Only ND FLT3-mut AML patients receiving upfront intensive treatment between Jan 2012 and May 2021 were considered in this analysis. The main study endpoints were the composite complete remission rate (cCR which included CR and CR with incomplete hematologic recovery [CRi]), the overall survival (OS) and the relapse-free survival (RFS). Data were collected in accordance with GCP and Helsinki declaration. The study has been approved by Ethic Committees of all 33 participating sites. Results: Overall, 547 FLT3-mutated AMLs were registered in FLAM study, of which 394/547 (72.0%) received an upfront intensive treatment and have been considered in this analysis: 92/394 (23.4%) received a FLT3 inhibitor in combination with intensive chemotherapy during the first-line of treatment (FLT3i group) whereas 302/394 (76.6%) patients received a standard chemotherapy program (CT group). The median age at diagnosis of the 394 patients was 59 (min-max: 18-83) years. Regarding FLT3 mutational status, 341/394 (86.5%) patients harbored a FLT3-ITD mutation, 45/394 (11.4%) a TKD mutation and 5/394 (1.3%) both mutations at diagnosis, with 218/394 (55.3%) patients harboring a co-occurring NPM1 mutation. 324/394 had a normal karyotype (80.2%). Thus, according to available data 352/373 (94%) patients had an intermediate ELN22 risk. No statistically significant difference between FLT3i and the CT group has been documented with respect to the above mentioned factors, except for platelet count at diagnosis, higher in FLT3i group (64.5 vs 49 x 10^9/L, p=0.007). In the FLT3i group, Midostaurin was administered in 86/92 (93.5%) patients, while 6/92 (6.5 %) patients received Sorafenib. The median number of consolidation cycles in patients achieving a response after induction or re-induction (n=8) was 2 (range 1-4) in both groups. Overall, 34/92 (37%) patients of the FLT3i and 75/302 (24.8%) of the CT group received a subsequent HSCT in 1st complete remission. According to available data, the composite cCR rate was 77% (49/64) in the FLT3i group and 66% (146/222) in the CT group (p = 0.10). With a median follow-up of 34.5 months, the median OS was 34.9 (95% CI, 16.8 to Not Reached [NR]) and 12.7 months (95% CI, 11.6 to 13.9) in the FLT3i and CT group, respectively (log-rank test p<0.001, HR for treatment equals to 0.5, 95% CI, 0.32 to 0.72, p< 0.001, Fig 1a). The effect of treatment on OS was still present even when HSCT was included into the model as a time-dependent covariate (HR for treatment equals to 0.5, 95% CI, 0.33 to 0.76, p = 0.001). The RFS was 18.9 (95% CI, 9.2 to NR) in the FLT3i and 7.6 months (95% CI, 5.7 to 10.2) in the CT group (p = 0.01, Fig.1b). Summary/Conclusion: this study confirmed the benefit of incorporating a FLT3i in the real-life upfront intensive treatment of ND FLT3-mut AML patients. The FLAM study was supported by Daiichi-Sankyo. #CP and #GM equally contributed.Keywords: Induction chemotherapy, Acute myeloid leukemia, FLT3, flt3 inhibitor