Impact of FLT3 Inhibitor Maintenance Therapy on Post-Transplant Outcomes in FLT3-Mutated AML Patients: A Real World Analysis from the German Registry for Hematopoietic Stem Cell Transplantation and Cell Therapy (DRST)

Introduction: FLT3 is mutated in 30% of AML and is associated with poor prognosis due to frequent and early relapse, leading to poor outcomes even after allo-SCT. Clinical trials using post-transplant FLT3 inhibitors have demonstrated feasibility, safety, and encouraging outcomes. This study, conducted by the DRST, aims to assess the impact of FLT3 inhibitors on the outcomes in a large cohort of FLT3-mutated AML patients post allo-HCT. Patients and Methods: We identified 923 patients (52% male, 48% female) who underwent allo-SCT for, HLA compatible donors between the years 2011-2023 for FLT3-mutated and were reported to DRST. The median age at transplant was 54 years (range 18-77). Seventy percent had a Karnofsky index >80%. The median time from diagnosis to transplant was 120 days (range 37-789). Ninety-five percent received PBSC grafts, and 51% underwent myeloablative conditioning. All patients were transplanted in CR1; 21% were MRD+, 24% were MRD-, and 55% had unknown MRD status. Thirteen percent (n=123) received mainly off-label use of FLT3-inhibitor maintenance after allo-SCT (41% Sorafenib, 34% Midostaurin, 3% Gilteritinib, 22% unknown), while 43% (n=400) did not and in 43% (n=400) it was unknown. Results: The 5-year relapse-free (RFS) and overall survival (OS) for the entire population was 53% (95% CI [49; 57]) and 62% (95% CI [58; 66]), respectively. Patients receiving maintenance therapy had statistically significant higher RFS with HR 2.1 (95% CI [1.4; 3.2], p<0.0001) and 5-year RFS 70% (95% CI [61; 80]) vs. 47% (95% CI [42; 54]), as well as OS (HR 2.9 (95% CI [1.7; 4.9]), p<0.0001, 5-year OS 81% (95% CI [73; 91]) vs. 57% (95% CI [51; 63])). Graft-versus-host disease relapse-free survival (GRFS) was significantly improved with maintenance therapy: HR 1.6 (95% CI [1.2; 2.2], p=0.0024) and 5-year GRFS 45% (95% CI [35; 58]) vs. 33% (95% CI [27; 39]). Non-relapse mortality (NRM) was significantly lower in the maintenance group (HR 4.8 (95% CI [1.8; 13.1]), p=0.002) with 5-year NRM 4% (95% CI [0; 8]) vs. 19% (95% CI [15; 24]). The cumulative incidence of relapse (CIR) at 5 years was comparable between both groups: 26% (95% CI [17; 35]) vs. 33% (95% CI [28; 39]), and the CIR over time was not statistically significant but with a positive impact of maintenance therapy (HR 1.5 (95% CI [1.0; 2.2]), p=0.078). In subgroup analysis based on MRD status, both MRD+ and MRD- subgroups showed improved OS and RFS with maintenance therapy. MRD positive patients had a 5-year OS of 75% (95% CI [60; 92]) with maintenance vs. 52% (95% CI [41; 67]) without (HR 2.8 (95% CI [1.3; 5.8]), p=0.0034), and a 5-year RFS of 64% (95% CI [50; 82]) with maintenance vs. 44% (95% CI [34; 57]) without (HR 1.9 (95% CI [1.0; 3.4]), p=0.0273). MRD negative patients had a 5-year OS of 87% (95% CI [76; 98]) with maintenance vs. 58% (95% CI [49; 69]) without (HR 3.4 (95% CI, [1.4; 8.5]), p=0.0021), and a 5-year RFS of 77% (95% CI [65; 92]) with maintenance vs. 45% (95% CI [36; 56]) without (HR 2.8 (95% CI [1.4; 5.6]), p=0.0010). There were no statistically significant differences in CIR, but a positive impact of maintenance therapy in both, MRD+ and MRD- subgroups. NRM was comparable in the MRD+ group, but MRD- patients receiving maintenance had lower NRM (5-year NRM 3% (95% CI [0; 7])) compared to those who did not (5-year NRM 23% (95% CI [15; 31]), HR 8.4 (95% CI [1.1; 62.6]), p=0.0380). There were no statistically significant differences in GRFS for MRD+ patients, while MRD- patients showed higher GRFS with maintenance (5-year GRFS 54% (95% CI [38; 77])) vs. without (5-year GRFS 37% (95% CI [29; 48]), HR 1.9 (95% CI [1.1; 3.3]), p=0.0091). Conclusion: Real world data from a large national registry showed that maintenance therapy with FLT3 inhibitors significantly improves RFS and OS in FLT3-mutated AML patients, irrespective of MRD status.