Improved Outcomes with Bu/Cy+Melphalan and Bu/Cy+Thiotepa Regimens in Haploidentical Hematopoietic Stem Cell Transplantation for Non-Down Syndrome Acute Megakaryoblastic Leukemia

Introduction Acute Megakaryoblastic Leukemia (AMKL) accounts for approximately 10% of pediatric Acute Myeloid Leukemia (AML) cases and about 1% of adult AML cases. While AMKL associated with Down syndrome generally has a favorable prognosis, non-Down syndrome AMKL (non-DS-AMKL) has a poor prognosis, with a 3-year overall survival rate of less than 40%. Currently, allogeneic hematopoietic stem cell transplantation is the only curative treatment available. This study aims to evaluate the efficacy of haploidentical hematopoietic stem cell transplantation for AMKL patients at our center, using modified regimens of Busulfan/Cyclophosphamide (Bu/Cy) combined with either Melphalan (MEL) or Thiotepa (TT). Methods From August 2015 to July 2024, we included non-DS-AMKL patients who underwent haploidentical hematopoietic stem cell transplantation (haplo-HCT) at Hebei Yanda Lu Daopei Hospital and Beijing Lu Daopei Hospital. The conditioning regimens were divided into three groups: Busulfan/Cyclophosphamide (Bu/Cy) (Fludarabine 30 mg/m²/day × 5 days; Cytarabine 2 g/m²/day × 5 days; Busulfan 3.2 mg/kg/day × 4 days; Cyclophosphamide 1.8 g/m²/day × 2 days; Etoposide 100 mg/m²/day × 2 days; Antithymocyte Globulin (ATG) 1.5 mg/kg/day × 5 days), Bu/Cy + MEL(55 mg/m²/day × 2 days), and Bu/Cy + TT (2.5 mg/kg/day × 2 days). Graft-versus-Host Disease (GVHD) prophylaxis included Cyclosporine A (CSA)/Tacrolimus (FK506) + Mycophenolate Mofetil (MMF) + Short-term Methotrexate (sMTX). The follow-up period for patients post-transplantation was until June 30, 2024. Results This study included 59 non-DS-AMKL patients (30 male, 29 female) with a median age of 2 years (range 1-9 years). Pre-transplant bone marrow status was complete remission (CR) in 44 cases and partial/no remission (PR/NR) in 15 cases. 1 patient underwent a third transplant, while the remaining 58 were first-time transplants. Donors were parents in 56 cases and siblings in 3. HLA matching was 5/10 in 44 cases and ≥6/10 in 15 cases. Stem cell sources were bone marrow (BM) and peripheral blood stem cells (PBSC). The regimens were: Bu/Cy (20 patients), Bu/Cy+ MEL (35 patients), and Bu/Cy +TT (4 patients). Median infused cell counts were: MNC, ×10⁸/kg (17.66, range 7.97-32.85); CD34+ cells, ×10⁶/kg (9.12, range 3.8-27.14); and CD3+ cells, ×10⁸/kg (3.87, range 0.9-19.38). The median follow-up was 24 months (range 2-84 months). All patients (100%) achieved engraftment, the median time of neutrophil engraftment was 13 days (range 9-21 days) and platelet engraftment was 9 days (range 4-46 days). At 1 month post-transplant, bone marrow evaluation showed complete donor-type chimerism in all patients. The overall survival (OS) was 54.2%. OS rates were 50% for Bu/Cy, 51.4% for Bu/Cy+MEL, and 100% for Bu/Cy+TT (P=0.301). For all CR patients, OS was 68.2% vs. 16.7% for NR/PR patients (P<0.001). Separately, OS was 52.9% for Bu/Cy, 75% for Bu/Cy+MEL, and 100% for Bu/Cy+TT (P=0.167). Post-transplant mortality was observed in 27 patients: 17 due to relapse, 6 due to graft-versus-host disease (GVHD), 2 due to gastrointestinal bleeding, 1 due to multiple organ failure, and 1 due to viral pneumonia. The cumulative incidence of relapse (CIR) was 28.8% overall (25% for Bu/Cy, 37.1% for Bu/Cy+MEL, and 0% for Bu/Cy+TT). Relapse rates were 15.9% for patients in CR and 66.7% for NR/PR. Among the 18 relapsed patients, 17 died and 1 survived. Transplant-related mortality (TRM) rates were 30% for Bu/Cy, 11.4% for Bu/Cy+MEL, and 0% for Bu/Cy+TT. The incidence of acute GVHD (aGVHD) was: Grade II-IV, 70% for Bu/Cy, 48.5% for Bu/Cy+MEL, and 25% for Bu/Cy+TT; Grade III-IV, 55% for Bu/Cy, 40% for Bu/Cy+MEL, and 0% for Bu/Cy+TT. Chronic GVHD (cGVHD) occurred in 30% of the Bu/Cy group, 51.4% of the Bu/Cy+MEL group, and 50% of the Bu/Cy+TT group. Cystitis rates were 20% for Bu/Cy and Bu/Cy+MEL, and 0% for Bu/Cy+TT. Cytomegalovirus (CMV) viremia was seen in 50% of the Bu/Cy group, 42.8% of the Bu/Cy+MEL group, and 75% of the Bu/Cy+TT group; Epstein-Barr virus (EBV) viremia in 15% of the Bu/Cy group, 14.2% of the Bu/Cy+MEL group, and 25% of the Bu/Cy+TT group. Conclusion Modified Bu/Cy+MEL or Bu/Cy+TT regimens for haplo-HCT offer better overall survival for non-Down syndrome AMKL patients in CR without increasing TRM compared to the traditional Bu/Cy regimen. These regimens also reduce the incidence of aGVHD (Grade II-IV). However, they appear to be less effective for patients in NR/PR.