Excellent Outcome of 1-Day Nonmyeloablative Salvage Regimen for Pediatric Patients with Graft Failure following Haploidentical Hematopoietic Stem Cell Transplantation.
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Haploidentical (haplo-) hematopoietic stem cell transplantation (HSCT) has been increasingly used as an alternative transplantation strategy for patients lacking a suitable HLA-matched donor. T cell depletion reduces the risk of graft-versus-host disease (GVHD) but at a cost of increased risk of graft failure, necessitating immediate retransplantation if a cryopreserved autologous graft is not available for rescue. Traditional high-intensity reconditioning with myeloablative and immunoablative regimens of approximately 1 week's duration aimed at further suppressing the recipient-derived immune system capable of rejecting the primary graft, is associated with high morbidity and mortality. A shortened and reduced-intensity conditioning regimen might reduce infection risk and mortality, but sustained engraftment would be a concern with lowered intensity. Here we report the excellent outcomes of 11 pediatric patients who received a 1-day reduced-intensity preparative regimen prior to retransplantation for graft failure following initial myeloablative haplo-HSCT for various malignant and nonmalignant disease conditions. This was a retrospective study conducted at the Hong Kong Children's Hospital, the sole territory-wide pediatric HSCT center in Hong Kong. All pediatric patients who were age ≤18 years at the time of initial haplo-HSCT and subsequently underwent salvage haplo-HSCT with a 1-day nonmyeloablative salvage regimen owing to graft failure between June 1, 2021, and May 31, 2024, were included. The salvage regimen consisted of fludarabine (30 mg/m2), cyclophosphamide (2000 mg/m2 or 60 mg/kg), and alemtuzumab (0.3 mg/kg), with or without total body irradiation (2 Gy), all administered 1 day before retransplantation. G-CSF-mobilized peripheral blood stem cells (PBSCs) were collected and transplanted fresh without ex vivo T cell depletion whenever possible, while cryopreserved PBSCs were used if fresh apheresis was not possible. GVHD prophylaxis consisted of cyclosporine, mycophenolate mofetil, tacrolimus, or sirolimus. A total of 11 patients were recruited, including 9 males and 2 females, with a median age of 8.8 years (range, 2.4 to 17.5 years). Underlying diseases included transfusion-dependent anemias (n = 7; beta-thalassemia major = 4, hemoglobin Hammersmith = 1, pyruvate kinase deficiency = 1, severe aplastic anemia = 1), chronic granulomatous disease (n = 1), acute lymphoblastic leukemia (n = 1), post-liver transplant lymphoproliferative disease (n = 1) and neuroblastoma (n = 1). The median interval between haplo-HSCT and administration of the 1-day regimen was 26 days (range, 18 to 50 days). Fresh PBSC grafts were used in 9 patients, and cryopreserved PBSC grafts were used in 2 patients. Median cell viability was 99.6%, with a median stem cell dose of 7.2 × 106 CD34+ cells/kg (range, 4.81 to 20.6 × 106 cells/kg) and a median total nucleated cell (TNC) dose of 8.0 × 108/kg (range, 5.17 to 10 × 108/kg). All 9 patients with fresh PBSC grafts demonstrated sustained engraftment and hematopoietic recovery. The median times to neutrophil and platelet engraftment were day +12 (range, days 10 to 19) and day +16 (range, days 10 to 35), respectively. No patient developed grade III/IV acute GVHD or severe chronic GVHD. Both patients with cryopreserved PBSC grafts experienced another graft failure, but 1 of them was successfully salvaged with another 1-day regimen using a fresh PBSC graft, and the other had autologous regeneration and underwent successful haplo-HSCT again from the same donor after full myeloablative conditioning. Overall survival for all 11 patients was 100% at a median follow-up of 35 months (range, 18 to 52 months). To conclude, local experience suggests that the modified 1-day reduced-intensity regimen in combination with fresh but not cryopreserved PBSC grafts is a feasible and promising approach to achieving sustained engraftment and is safe and appropriate for salvaging pediatric patients with graft failure requiring immediate retransplantation.