Alpha/beta-T-cell depleted hematopoietic stem cell transplantation from unrelated and haploidentical donors in children with idiopathic aplastic anemia

Introduction. Hematopoietic stem cell transplantation (HSCT) from an alternative donor is the main treatment option for patients with severe acquired aplastic anemia (AAA) refractory to combined immunosuppressive therapy with anti-thymocyte globulin and cyclosporine A. Although the outcomes of unrelated and haploidentical HSCTs have improved over the years, graft-versus-host disease (GVHD) continues to pose a major clinical challenge associated with significant morbidity and mortality. Aim: to present the outcomes of unrelated and haploidentical HSCTs with TCRαβ-depleted grafts in patients with AAA. Materials and methods. Eighty patients (42 males and 38 females) with AAA underwent HSCT between September 2012 and February 2022. The median age at transplantation was 10 (2.3–22.7) years. Seventy-eight patients received HSCT after relapse or refractory disease after one (n = 14) or two (n = 18) courses of immunosuppressive therapy. Two patients underwent HSCT as first-line treatment. The median time from diagnosis to transplantation was 1 (0.1–11.8) year. Conditioning regimen included cyclophosphamide (100–150 mg/kg), fludarabine (150 mg/kg), antithymocyte globulin (ATGAM (100 mg/kg) or thymoglobulin (5–10 mg/kg)), and thoracoabdominal irradiation (2–6 Gy). In some cases, additional medications such as melphalan (140 mg/m2), thiophosphamide (5–10 mg/kg), and rituximab (200 mg/m2) were used. Patients with paroxysmal nocturnal hemoglobinuria (n = 6) received eculizumab at a dose of 600 mg from day –7 to day +14 (every 7 days). Post-transplant GVHD prophylaxis included calcineurin inhibitors. TCRαβ/CD19 depletion was performed using a CliniMACS Plus system (Miltenyi Biotec, Bergish Gladbach, Germany). The median CD34+ cell dose in the graft was 10 (2.7–23.0) × 10⁶/kg, and the median TCRαβ+ cell dose was 26.6 (0.85–316.00) × 10³/kg. Results. The cumulative incidence of engraftment was 0,95 (95% confidence interval (CI) 0.9–1.0) with the median time to neutrophil recovery being 13 (9–24) days and to platelet recovery – 12 (7–25) days. Graft rejection occurred in 9 patients, the cumulative incidence of rejection was 0,11 (95% CI 0.06–0.20). Three of these patients underwent successful retransplantation. The cumulative incidence of grade II–III acute GVHD was 0,12 (95% CI 0.05–0.27) in the patients who had undergone unrelated donor HSCT versus 0,42 (95% CI 0.29–0.61) in the haploidentical HSCT recipients (p = 0.003). The cumulative incidence of chronic GVHD was 0,5 (95% CI 0.01–0.20) in the unrelated donor HSCT group and 0,21 (95% CI 0.12–0.38) in the haploidentical HSCT group (p = 0.02). The median follow-up was 6.4 years. Twenty-two (27.5%) patients died. Sixteen of them died of complications after the first HSCT; 4 deaths occurred due to complications associated with repeat HSCT. Two patients died after graft rejection due to infectious complications. The overall survival was 0,79 (95% CI 66–91) in the unrelated donor HSCT group and 0,66 (95% CI 51–81) in the haploidentical donor HSCT group. Conclusion. The use of TCRαβ/CD19-depleted HSCT from alternative donors ensured high engraftment rates and reduced the incidence of severe GVHD. However, there were no significant improvements in graft rejection or mortality.