P484: gemtuzumab-based induction chemotherapy combined with midostaurin for flt3 mutated aml. updated toxicity and interim survival analysis from the ncri aml19v2 “midotarg” pilot trial

Background: Following the RATIFY study, Midostaurin in combination with “7 + 3” like chemotherapy became the standard of care for patients with newly diagnosed FLT3 mutated (mut) AML. The ALFA 0701 trial suggested a benefit for Gemtuzumab Ozogamicin (GO) in FLT3mut AML that was also apparent in a meta-analysis of GO in induction (Hills et al. JCO, 2014,15(9):986. The combination of GO-based induction with Midostaurin has not been formally assessed with respect to safety, response and survival in FLT3mut AML. Aims: To assess the safety and efficacy of Midostaurin and Gemtuzumab (in a single or fractionated dose) given with induction chemotherapy therapy in newly diagnosed FLT3mut AML. Methods: The NCRI AML19 v2 trial randomised patients generally aged 18-60y with newly diagnosed AML without known adverse karyotype to receive DA 3 + 10 (Daunorubicin 60mg/m2 on days 1, 3 & 5 plus AraC 100mg/m2 bd on days 1-10) plus either a single dose of GO (3mg/m2 on day 1, DAGO1) or two doses (3mg/m2, capped at 5mg on days 1 and 4, DAGO2). Patients with a FLT3-ITD or TKD could enter the “Midotarg” pilot and receive 50mg bd of Midostaurin (m) for 14 days following completion of chemotherapy, and following the second induction (DA 3 + 8 without GO) and 2 courses of HDAC consolidation and as maintenance for 12 cycles in non-transplanted patients. Patients with FLT3ITD without NPM1mut were recommended for allogeneic transplantation in CR1. Patients with NPM1mut were only recommended for transplant if MRD positive in the peripheral blood (PB) by RT-qPCR post course 2 (PB PC2+). From November 2020 to November 2021, 77 patients were enrolled into the Midotarg pilot receiving DAGO1m (n=39) or DAGO2m (n=38). 59 had a FLT3 ITD and 22 a FLT3-TKD (and 4 had both). RT-qPCR MRD monitoring for patients with NPM1mut (n=48) was performed following each cycle of chemotherapy. Primary and key secondary endpoints were overall response rate (CR+CRi), MRD and overall survival (OS). Results were compared with an earlier cohort of 119 FLT3mut patients treated in AML19v1 with the same chemotherapy (DAGO1/DAGO2) without Midostaurin Results: Patients had a median age of 52 yrs. 16 (20%) were >60 yrs. We have previously reported that the combination was well tolerated with no increase in haematological or non-haematological toxicity. Day 60 mortality was 0%. Overall response (CR + CRi) was achieved in 82% (DAGO1m) and 91% (DAGO2m). Median follow-up is 15 months. Estimated OS at 18 months was 82% (Figure 1) and was 81% and 84% for DAGO1m and DAGO2m respectively. This compares with 18m OS of 72% in patients treated with DAGO alone in AML19v1 (Figure 1) (68% DAGO1; 76% DAGO2). 46/77 evaluable patients had NPM1mut, in these patients PB PC2 MRD negativity was 75% and 86% with DAGO1m and DAGO2m respectively. This compares with 61% and 74% in 65 evaluable patients with DAGO1 and DAGO2 without Midostaurin. End of treatment BM MRD negativity was 68% vs 74% for DAGO1m and DAGO2m respectively compared to 46% and 56% without Midostaurin. Summary/Conclusion: The addition of Midostaurin to DAGO1 and DAGO2 chemotherapy was safe in both younger and older patients with promising survival although follow up is short. The fractionated schedule (DAGO2) gave a higher proportion of MRD negativity post course 2 in patients with FLT3mut/NPM1mut and this is associated with a greatly reduced risk of relapse and death. DAGO2m is being taken forward in a randomised comparison against DA plus Midostaurin. Figure 1a. Overall Survival in AML19v1 (DAGO1/DAGO2 combined) Figure 1b. Overall Survival in AML19v2 (Midotarg)Keywords: FLT3, AML, Mylotarg