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December 8, 2025

A novel reduced-toxicity conditioning regimen with busulfan/fludarabine/cyclophosphamide/anti-thymocyte globulin for severe aplastic anemia

Key Points

To investigate the efficacy and safety of a novel reduced-toxicity conditioning regimen for severe aplastic anemia.
Pilot study involving 10 patients with severe aplastic anemia undergoing allo-HSCT.
Conditioning regimen included busulfan, fludarabine, cyclophosphamide, and anti-thymocyte globulin.
Follow-up median duration of 47.6 months to evaluate outcomes.
All patients achieved sustained engraftment without transplant-related death.
Majority had disease-free survival and good quality of life after transplant.
Three patients developed acute graft-versus-host disease, with mild chronic cases observed.

Abstract

Abstract Introduction: Severe aplastic anemia (SAA) is a life-threatening bone marrow failure disorder, and allogeneic hematopoietic stem cell transplantation (allo-HSCT) from identical sibling or unrelated donor is the first-line therapy for SAA patients younger than 40 years-old. Using a reduced-toxicity conditioning regimen with lower-dose cyclophosphamide (Cy, 300mg/m2/day, 4 days) and adding fludarabine (Flu) to increase immune suppression, the transplant outcomes from unrelated donor have been improved remarkably but with 5%-10% engraftment failure. With Busulfan (Bu, 2 days)/Cy (50mg/kg/day, 4 days)/Anti-Thymocyte Globulin (ATG) conditioning, comparable results of haploidentical transplant to unrelated HSCT for SAA have been reported, but long-term toxicities of Bu for non-malignant disease need to be thought seriously. Aim: In present pilot study, the efficacy and safety of a novel reduced-toxicity conditioning regimen with Bu/Flu/Cy/ATG for SAA were investigated. Quality of life was also evaluated. Methods: Between January 2020 and September 2024, ten patients with SAA (male in 3, female in 7) underwent allo-HSCT as the first-line therapy in our hospital were enrolled. The median age was 11(5-37) years-old. The median disease course was 96 (41-204) days. Donor types included haploidentical (7/10), unrelated (2/10), and identical sibling (1/10). The conditioning regimen comprised Bu (0.8 mg/kg every 6 hours, 1 day, weight-adjusted dose for pediatric patients), Flu (30 mg/m²/day, 4 days), Cy (500 mg/m²/day, 4 days), and ATG with Thymoglobulin 2 mg/kg/day, 4 days in 3 patients or ATG-Fresenius 5 mg/kg/day, 4 days in 7 patients. Graft-versus-host disease (GVHD) prophylaxis included cyclosporine and mycophenolate mofetil for all patients, supplemented with either: short-term methotrexate(MTX, +1d 15mg/m², +4d, +8d, +11d 10mg/m², n=2) ; only CD25 monoclonal antibody(Basiliximab, +3d 20mg, n=1); or both(MTX as above plus Basiliximab, +3d 20mg, n=2; or MTX as above plus Recombinant humanized anti-CD25 monoclonal antibody, +4d, +8d, 1mg/kg, n=5). Grafts were peripheral blood stem cells (PBSC, 3 patients) or a combination of bone marrow and PBSC (7 patients). Results: With the median follow-up 47.6 (10.8-73.8) months, all patients achieved sustained engraftment. The median time for white blood cells and platelets engraftment was 13 (9-20) days, 19 (10-35) days, respectively. All patients have been disease-free survival (DFS) without transplant-related death. Three cases developed acute GVHD (aGVHD, grade II in 2, grade IV in 1), and 2 patients had mild chronic GVHD. Viral reactivation was observed in 8 patients (CMV in 2; BKV in 4; CMV and BKV in 1; CMV, EBV, and BKV in 1). Among 7 female patients, 5 of them old than 11 years-old, and 4/5 those cases had menstrual recovery spontaneously at median 5 (1-8) months post-transplant. A 37-year-old lady with grade IV aGVHD after collateral haploidentical transplant has no menstrual recovery yet due to at 10 months post-transplant with immunosuppressants now. Three male patients were 12, 19, 30 years-old, respectively. No births occurred in this cohort so far, and fertility issue in this series will be monitored continuously. Except for one patient experiencing cCVHD who reported a significant decrease in physical strength, the quality of life of all other patients remains unaffected. Conclusions: Allo-HSCT with our reduced-toxicity conditioning regimen for SAA has shown excellent efficacy and safety even 9 of 10 cases received transplants from alternative donors. All patients have achieved durable engraftment. Majority of them has obtained long-term DFS, and 8 of 10 patients have been GVHD-free survival. Majority of the patients are with good quality of life. Longer follow-up and larger series are needed to evaluate fertility and transplant outcomes with current protocol. Keywords: severe aplastic anemia (SAA), allogeneic hematopoietic stem cell transplantation (allo-HSCT), Busulfan (BU), Fludarabine (Flu), Cyclophosphamide (Cy), Anti-thymocyte globulin (ATG)

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