Cladribine, idarubicin, and AraC (CLIA) combined with a FLT3 inhibitor in patients with newly diagnosed FLT3-mutated Acute Myeloid Leukemia: A pooled analysis of prospective trials

Abstract

Abstract Introduction The incorporation of FLT3 inhibitors, cladribine, and high-dose cytarabine have been shown to improve outcomes in pts with newly diagnosed FLT3-mutated AML. Co-mutations, such as NPM1 and DNMT3A, may confer additional prognostic significance. We present a pooled analysis of frontline trials of intensive chemotherapy (IC) with CLIA in combination with FLT3 inhibitors, focused on outcomes by co-occurring mutations. Methods Patients (pts) 18-65 years with newly diagnosed FLT3-mutated AML, fit for IC, were enrolled on protocol with CLIA (cladribine 5 mg/m2 IV D1-5, araC 1.5-2 g/m2 IV D1-5, idarubicin 10 mg/m2 IV D1-3) plus gilteritinib (gilt) or sorafenib (soraf). During induction, pts received gilt 120 mg D1-14 or soraf 400 mg BID D1-14. Patients who achieved complete remission (CR)/CR with incomplete count recovery (CRi) could receive consolidation with 3 days of cladribine and araC and 2 days of idarubicin plus gilt 80-120 mg daily or soraf 400 mg BID. FLT3-mutations were detected using fluorescently labeled multiplex PCR followed by capillary electrophoresis (sensitivity of 10-2). Results From September 2014-March 2024, 48 pts (50% female) were enrolled; median age was 54 years (range, 21-65). Thirty-four (71%) pts had diploid, 9 (19%) had intermediate , and 4 (8%) had adverse cytogenetics. 42 pts (88%) had a FLT3-ITD mutation alone, 3 (6%) had a FLT3-D835 mutation alone, and 3 (6%) had co-occurring FLT3-ITD and D835 mutations. The median FLT3-ITD and FLT3-D835 allelic ratios (AR) were 0.31 (0.007-0.96) and 0.15 (0.1-0.16). The most common co-mutations included NPM1 (50%), DNMT3A (27%), N/KRAS (21%), IDH2 (19%), WT1 (10%), ASXL1 (8%), TET2 (8%), SRSF2 (8%), IDH1 (6%). Pts received a median of 2 (1-6) cycles. After a median of 1 (1-3) cycle to best response, CR/CRi was 83% (40/48), with 71% CR. Measurable residual disease (MRD)-negativity by flow cytometry was achieved in 35 (88%) pts, with 88% FLT3-negativity by capillary electrophoresis. There was 1 early death (2%) within 8 weeks. 31 pts (78%) underwent allogeneic stem cell transplant (SCT) in CR1 and 19 pts (61%) received post-SCT maintenance: 8 soraf, 6 gilt, 4 crenolanib, 1 AZA/VEN. After a 68-month median follow-up for all pts, median OS was not reached (NR), with 2- and 4-year OS of 67% and 62%. For CLIA/gilt, median OS was NR, with 2- and 4-year OS of 74% and 62%; for CLIA/soraf, the median OS was NR, with 2- and 4-year OS of 63% and 59% (p=0.56). The median EFS for all pts was NR, with 2- and 4-year EFS of 66% and 63%. For CLIA/gilt, the median EFS was NR, with 2- and 4-year EFS of 71% and 71%; for CLIA/soraf, the median EFS was NR, with 2- and 4-year EFS of 63% and 59% (p=0.57). With death as a competing risk, the 4-year CIR for CLIA/gilt was 6% vs. 4% for CLIA/soraf (p=0.84). The 4-year cumulative of incidence of death without relapse for CLIA/gilt was 12% vs. 26% for CLIA/soraf (p=0.39). Landmark analysis stratified by CR1 SCT vs. no SCT demonstrated 5-year OS of 81% vs. 54% (p=0.39) and 5-year EFS of 83% vs. 55% (p=0.24). The 2- and 4-year OS for NPM1mut was 73% and 73%% vs. 63% and 53% for NPM1wt , respectively (p=0.24). For pts with NPM1mut with co-mutation in DNMT3A, TET2, WT1, IDH1, and/or IDH2, 2- and 4-year OS was 76% and 76% vs. 62% and 53% in pts without this gene signature (p=0.14). For pts with NPM1mut alone vs. those with the gene signature, the 4-year OS was 60% vs. 76% (p=0.26). For pts with concomitant MDS-related mutations (ASXL1, RUNX1, SRSF2, SF3B1, U2AF1) vs. those without, median OS was 24 months vs NR with 4-year OS of 50% vs. 66%, respectively (p=0.21). There was no difference in pts with 'triple mutated’ AML (FLT3mut/DNMT3Amut/NPM1mut) vs. those without with 4-year OS of 69% vs. 62% (p=0.86). The most common adverse events (AE) for CLIA/soraf were febrile neutropenia (n=33), rash (n=16), nausea (n=7). The most common grade >3 AE were febrile neutropenia (n=28), rash (n=10). The most common AE for CLIA/gilt were elevated ALT/AST (n=17), febrile neutropenia (n=11), and rash (n=11); the most common grade>3 AE were febrile neutropenia (n=5) and elevated ALT/AST (n=3). Conclusion Long-term follow-up of CLIA with soraf or gilt demonstrates durable survival for pts with newly diagnosed FLT3-mutated AML. NPM1mut pts with co-mutations in either DNMT3A, TET2, WT1, IDH1, and/or IDH2 demonstrate particular sensitivity to these regimens andexperience superior outcomes with long-term OS of more than 75%.