Fludarabine, cyclophosphamide, and melphalan (FCM) preconditioning in haploidentical hematopoietic stem cell transplantation for severe aplastic anemia: Update of a prospective, multicenter, single-arm clinical study

Abstract

Abstract Background: Haematopoietic stem cell transplantation (HSCT) is a crucial treatment for severe aplastic anemia (SAA). However, there is no standardized preconditioning regimen for patients without matched sibling or unrelated donors. Achieving successful engraftment remains a significant challenge in haploidentical HSCT, controlling transplantation-related complications and reducing transplantation-related mortality are urgent issues that need to be addressed. New conditioning regimens are still worth exploring. Objective: We conducted a prospective, multi-center clinical study to explore the efficacy and safety of a novel preconditioning regimen consisting of fludarabine, cyclophosphamide, and melphalan (FCM) in haploidentical HSCT for the treatment of SAA. Methods: Patients who were diagnosed with SAA according to NCCN guidelines and required haplo-identical HSCT were recruited. Patients with active infections or bleeding, severe liver or kidney dysfunction, ECOG > 2, <3 or >65 years old, psychiatric disorders, or pregnancy were excluded. The preconditioning regimen included: 30mg/m² fludarabine for 6 days, 50mg/kg cyclophosphamide on day -7 and day -5, 100mg/m² melphalan on day -2, and 2mg/kg ATG on day -1. The prevention of acute graft-versus-host disease (aGVHD) consisted of post-transplantation cyclophosphamide (PTCy) and short-term methotrexate ± other drugs, detailed aGVHD prophylaxis was determined according to each center’s decision. Chimerism was assessed on days +28, +60, +90 post-transplantation and then once half year. The primary endpoints was graft failure rate, the second endpoint were the incidence of transplantation-related complications, 2-year overall survival (OS) and disease-free survival (DFS). This study was approved by the Ethic Committee of 920th Hospital of Joint Logistics Support Force and was registered at www.clinicaltrial.gov as NCT06378060. Results: From April 2024 to May 2025, 25 SAA patients from 7 transplantation centers who underwent haploidentical HSCT were enrolled. The male-to-female ratio was 11:14, with a median age of 26 years (IQR 15-38). All patients achieved successful engraftment, with median times to neutrophil and platelet engraftment of 13 days (IQR 11-14) and 12days (IQR 11-14), respectively. One patient experienced poor graft function and developed aGVHD after donor stem cell transfusion, resulting in death on day +110. No seizures, severe mucositis, cardiac events, or bleeding events occurred during transplantation. The incidences of grade II-IV and grade III-IV aGVHD were 20% and 4%, respectively. Hemorrhagic cystitis occurred in 8% of patients. Epstein-Barr Virus (EBV) and cytomegalovirus (CMV) reactivation rates were 16% and 20%, respectively. Three patients developed pulmonary fungal infections post-transplantation, they were resolved after antifungal treatment. One patient developed post-transplant lymphoproliferative disorder (PTLD), she was cured by the treatment of rituximab. Till August 2025, the median follow-up time was 13.1 months, with 24 patients surviving. The transplantation-related mortality (TRM) rate was 4%. Conclusion: The FCM conditioning regimen in haplo-identical HSCT for severe aplastic anemia achieves a high engraftment rate with good safety and low infection rates.