Cytotherapy · 2025
Long-term outcomes of αβ T-cell/CD19 B-cell-depleted peripheral blood stem cell transplantation from unrelated donors in pediatric and adolescent patients with severe aplastic anemia: a single-center study.
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Shasheleva Darya, Shelikhova Larisa, Ilyushina Maria, Dunaykina Maria, Klimentova Maria, Perminova Margarita, Zavidnyi Timofei, Kozlovskaya Svetlana, Goronkova Olga, Kurnikova Elena, Pershin Dmitry, Muzalevsky Yakov, Kazachenok Alexey, Brilliantova Varvara, Baydildina Dina, Balashov Dmitry, Novichkova Galina, Maschan Alexey, Maschan Michael
Аннотация
BACKGROUND AIMS: Hematopoietic stem cell transplantation (HSCT) from matched unrelated donor (MUD) is a curative option for severe aplastic anemia (SAA) patients, refractory to horse anti-thymocyte globulin (ATG) and cyclosporin A (CsA) mmunosuppression. Although the results of MUD HSCT in SAA have improved significantly, graft-versus host disease (GVHD) remains a serious problem, associated with significant morbidity and mortality. We investigated the role of alpha/beta T cell depletion of the graft as a way to improve the results of MUD HSCT in SAA.
METHODS: Forty-seven patients with SAA were treated since September 2012 till February 2022. Median age at HSCT was 12.4 (3-22.7) years, 26 males/21 females. All patients were either refractory or relapsed (35:12) after combined immune suppression therapy, 5 pts had concurrent severe hemolytic paroxysmal nocturnal hemoglobinuria (PNH). The median time from diagnosis to transplant was 1.2 years (0.5-11.8 years). Preparative regimen included cyclophosphamide 100 mg/kg, fludarabine 150 mg/kg, ATGAM at 100 mg/kg (27pts) or thymoglobulin 5 mg/kg (15 pts) and 6 Gy thoraco-abdominal irradiation. Thiotepa at 10 mg/kg and rituximab at 200 mg/m2 were used in a proportion of cases. Patients with PNH (n = 5) received eculizumab 600 mg once every 7 days from -7 to +14 days. Post-transplant GVHD prophylaxis included tacrolimus till day 180. Peripheral blood stem cell (PBSC) grafts were depleted of T cell receptor (TCR) alpha/beta cells and CD19 cells with CliniMACS device, as recommended by the manufacturer. Patients received a median of 9.2 (2.7-18.30) х106 CD34 per kg, 21.8 (0.85-316)x103 αβ T cells per kg.
RESULTS: Forty-six patients (cumulative incidence (CI) 0.96 (95% 0.9-1)) engrafted with a median of 14 (7-24) days for white blood cells (WBC) and 12 (9-18) days for platelets. In 8 patients after MUD transplantation secondary graft failure (rejection) developed, cumulative incidence was 0.15 (95% 0.08-0.3), three of them was successfully retransplanted. CI of acute graft-versus host disease (aGVHD) grade II-IV was 0.15 (95% 0.08-0.29). No cases of grade III-IV aGVHD were registered. CI of chronic graft versus host disease (cGVHD) was 0.11 (95% 0.05-0.25). All were mild and off-IST at last follow-up. A median follow-up is 9 years. Ten patients died. At a median follow-up of 9 years, the overall survival was 79% (67-90). Failure-free survival was 72% (60-85) and the GRFS was 72% (60-85).
CONCLUSIONS: TCR alpha/beta depletion is a robust platform for allogeneic HSCT from MUD in severe aplastic anemia. Results should be further improved by additional measures to control viral infections and prevent rejection.
METHODS: Forty-seven patients with SAA were treated since September 2012 till February 2022. Median age at HSCT was 12.4 (3-22.7) years, 26 males/21 females. All patients were either refractory or relapsed (35:12) after combined immune suppression therapy, 5 pts had concurrent severe hemolytic paroxysmal nocturnal hemoglobinuria (PNH). The median time from diagnosis to transplant was 1.2 years (0.5-11.8 years). Preparative regimen included cyclophosphamide 100 mg/kg, fludarabine 150 mg/kg, ATGAM at 100 mg/kg (27pts) or thymoglobulin 5 mg/kg (15 pts) and 6 Gy thoraco-abdominal irradiation. Thiotepa at 10 mg/kg and rituximab at 200 mg/m2 were used in a proportion of cases. Patients with PNH (n = 5) received eculizumab 600 mg once every 7 days from -7 to +14 days. Post-transplant GVHD prophylaxis included tacrolimus till day 180. Peripheral blood stem cell (PBSC) grafts were depleted of T cell receptor (TCR) alpha/beta cells and CD19 cells with CliniMACS device, as recommended by the manufacturer. Patients received a median of 9.2 (2.7-18.30) х106 CD34 per kg, 21.8 (0.85-316)x103 αβ T cells per kg.
RESULTS: Forty-six patients (cumulative incidence (CI) 0.96 (95% 0.9-1)) engrafted with a median of 14 (7-24) days for white blood cells (WBC) and 12 (9-18) days for platelets. In 8 patients after MUD transplantation secondary graft failure (rejection) developed, cumulative incidence was 0.15 (95% 0.08-0.3), three of them was successfully retransplanted. CI of acute graft-versus host disease (aGVHD) grade II-IV was 0.15 (95% 0.08-0.29). No cases of grade III-IV aGVHD were registered. CI of chronic graft versus host disease (cGVHD) was 0.11 (95% 0.05-0.25). All were mild and off-IST at last follow-up. A median follow-up is 9 years. Ten patients died. At a median follow-up of 9 years, the overall survival was 79% (67-90). Failure-free survival was 72% (60-85) and the GRFS was 72% (60-85).
CONCLUSIONS: TCR alpha/beta depletion is a robust platform for allogeneic HSCT from MUD in severe aplastic anemia. Results should be further improved by additional measures to control viral infections and prevent rejection.