Long-Term Efficacy of Allogeneic Hematopoietic Stem Cell Transplantation for 532 Patients with KMT2A-Rearranged Acute Leukemia

Introduction: Acute leukemia with KMT2A gene rearrangements poses significant clinical challenges due to its typical resistance to standard chemotherapy, resulting in higher relapse rates and lower long-term survival rates. These gene rearrangements result in the fusion of the KMT2A gene with various partner genes, creating fusion proteins such as KMT2A-MLLT2 (MLL-AF4), KMT2A-MLLT4 (MLL-AF6), KMT2A-MLLT3 (MLL-AF9), KMT2A-MLLT10 (MLL-AF10), and KMT2A-PTD (MLL-PTD/dupMLL),etc. The prognosis of patients with these rearrangements varies depending on the specific fusion partner, influencing survival outcomes and relapse rates. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains one of the most promising therapeutic options, offering the potential for long-term remission and improved survival for these patients. However, the efficacy of allo-HSCT in these patients with a large cohort and long term follow-up in rarely reported.

Methods: Between September 2012 and December 2023,a total of 532 consecutive patients with acute leukemia harboring KMT2A gene rearrangement who received all-HSCT at Hebei Yanda Lu Daopei Hospital and Beijing Lu Daopei Hospital were retrospectively analyzed.The efficacy of allo-HSCT was assessed by examining overall survival (OS) and disease-free survival rates(DFS), with further stratification based on the remission status prior to transplantation and the distribution of the five most prevalent KMT2A fusion types.

Results: Among the 532 patients, 387 were diagnosed with acute myeloid leukemia (AML), 139 were acute lymphoblastic leukemia (ALL), and 6 were mixed phenotype acute leukemia (MPAL). The cohort included 254 males and 278 females, with a median age of 15 years (range: 9 months to 66 years). The top five KMT2A fusion types were KMT2A-MLLT3 (111 cases), KMT2A-PTD (84 cases), KMT2A-MLLT2 (78 cases), KMT2A-MLLT4 (76 cases), and KMT2A-MLLT10 (69 cases). Remission status prior to transplantation included 309 cases in first complete remission (CR1), 116 cases in the ≥second complete remission (≥CR2), and 107 cases with no remission (NR). All patients achieved good engraftment, except three patients had primary graft failure. To the cutoff date of May 31, 2024, the median follow-up time was 34 months (range: 0-138 months).For the 532 patients, 3-year OS was （67.6 ± 2.1）%, and the 3-year DFS was （67.2 ± 2.1）%. Among patients in the CR1, ≥CR2, and NR groups 3-year OS rates were (79.7 ± 2.4)%, (55.9 ± 4.7)%, and (44.9 ± 5.1)%, respectively (P < 0.001),and the 3-year DFS were (79.0 ± 2.5)%, (54.7 ± 4.8)%, and (44.4 ± 5.0)% (P < 0.001),respectively. Specifically, the OS and DFS for patients with KMT2A-MLLT2 were as high as (72.3 ± 5.2)% and (71.1 ± 5.2)%, for the KMT2A-MLLT4 group were low as(55.0 ± 6.4)% and (48.7 ± 6.6)%, for KMT2A-MLLT3 were (71.4 ± 4.5)% and (69.5± 4.6)%, for KMT2A-MLLT10 were (69.0 ± 5.6)% and (67.6 ± 5.7)%, and for KMT2A-PTD were (63.4 ± 5.7)% and (62.6 ± 5.7)%.

Conclusion：This study underscores the efficacy of allo-HSCT in treating acute leukemia with KMT2A gene rearrangements, demonstrating a substantial improvement in the long-term survival. However, the presence of a remission status prior to transplantation is a crucial factor influencing the outcomes. Patients who did not achieve remission before transplantation faced significantly poorer outcomes, highlighting the need for effective pre-transplant therapies to induce remission. The study also reveals that the prognosis varies among different KMT2A fusion subtypes, with patients harboring KMT2A-MLLT4 fusions exhibiting notably worse outcomes. These findings suggest that tailored treatment approaches based on the specific KMT2A fusion subtype may be necessary to optimize therapeutic strategies and improve patient outcomes. Further randomized trials and longer follow-up time are needed to improve the prognosis for patients with these high-risk genetic features.