Successful Allogenic Stem Cell Transplantation Using Radiation-Free Reduced Intensity Conditioning in Idiopathic Pediatric Severe Aplastic Anemia - a Single Center Experience

Background: Childhood idiopathic severe aplastic anemia (SAA) treated with hematopoietic cell transplantation (HCT) from an HLA-matched sibling donor (MSD) has an overall survival (OS) of >90%. Immunosuppressive therapy (IST) is recommended in patients who lack MSD. Recently, unrelated donor (URD) and haploidentical (HI) transplants have gained favor due to better outcomes with reduced intensity regimens that include low dose total body irradiation (TBI) to avert graft rejection with cyclophosphamide and/or fludarabine. However, avoiding TBI to prevent potential long-term toxicities from the same, could benefit recipients, especially young children. We tested a radiation-free, reduced intensity conditioning (RIC) regimen in pediatric SAA and report outcomes.

Methods: We retrospectively analyzed 23 patients, consecutively transplanted at St. Louis Children’s Hospital between 2013 and 2023. The median age at diagnosis was 10 years (range, 3-19). Fourteen (61%), failed IST prior to transplant. All patients received alemtuzumab (48 mg, day -21 to 18), fludarabine (150 mg/m²; day -8 to -4) and melphalan (140 mg/m²; day -3). Thiotepa (8 mg/kg; day -4) was included for mismatched or cord blood transplants (CBT). GVHD prophylaxis included tacrolimus (tapered after 6-9 months), abatacept (10 mg/kg/dose; 5 doses until day 100 if CBT, 8 doses until day 365 if marrow donor), methotrexate (7.5 mg/m² on days 1, 3 and 6 if marrow donor) and mycophenolate mofetil (until day 28 if CBT).

Results: Twelve patients (52%) received MSD, 9 (39%) URD and 2 (8%) HI transplants. Thirteen (56%) were HLA-matched (8/8), others were one-antigen mismatched (7/8). Bone marrow was the primary graft source in 18 (78%), peripheral blood in 3 (13%) and cord in 2 (8%) patients. The median age at HCT was 11 years (range, 3-20). The median time from diagnosis to HCT was earlier in MSD than URD and HI groups (3.5 months versus 9 months respectively). Twenty-two patients survived beyond day +30 and achieved 100% donor chimerism. One died on day +1 due to pneumocystis and staphylococcal infections diagnosed pre-transplant. Neutrophil and platelet engraftment were comparable in MSD and URD/HI groups (median at 15 and 30 days respectively). At 1 year post HCT, all survivors exhibited full donor myeloid and lymphoid chimerism of > 95%. The absolute lymphocyte numbers for CD4 T cells (median 548 cells/µL, range, 283-1056), CD8 (median 354 cells/µL, range, 282-1996) and B cells (median 379 cells/µL, range, 270-900) reached normal range at 1 year post-HCT. One patient developed steroid responsive grade I acute skin GVHD. No patient had graft failure or chronic GVHD. OS and event-free survival were 95% at a median follow-up of 48 months (range, 12-144). No patient developed malignancy or clonal hematopoiesis during the follow-up period. Toxicities included bacterial infections in 2 (8%) and asymptomatic viral reactivation in 10 patients (43%) within 100 days post-transplant. Late complications (>day 100) included 1 patient with rituximab-responsive autoimmune hemolytic anemia, 5 (22%) with delayed puberty/secondary amenorrhea, 2 (8%) with thyroid dysfunction, 1 with growth hormone deficiency, and 4 (17%) with depression, memory or attention abnormalities that impacted school performance.

Conclusion: Overall, this radiation-free RIC regimen afforded excellent disease-free survival rates in children with SAA irrespective of donor source, HLA-match, and recipient age. This approach provides an alternative conditioning regimen in patients that can benefit from avoiding radiation exposure. Late complications primarily affected endocrine and gonadal function, likely influenced by both pre-transplant factors such as iron overload and transplant conditioning.