Hematopoietic stem cell transplantation with alpha/beta T lymphocyte and CD19 cell depletion in adolescents and young adults with paroxysmal nocturnal hemoglobinuria using the immune-ablative conditioning and “peritransplant” therapy with eculizumab
The main goal was to optimize hematopoietic stem cell transplantation (HSCT) approach among adolescents and young adults with paroxysmal nocturnal hemoglobinuria (PNH) by means of Graft-versus-host disease (GVHD) and posttransplant complications risk lowering.
Materials and methods
We report our experience of HSCT from HLA-matched unrelated donors using TCR alfa/beta and CD19 depletion in 5 pts (1M/4F) with PNH, developed after successful immunosuppressive therapy (IST) of acquired aplastic anemia (AA). Median age of pts at the moment of transplantation was 17.8 years (range 14.5-22.7), median interval from IST to PNH was 4 years (5mo – 6.5 y). In all patients non-severe pancytopenia was present: granulocytes 0.8х109/l (0.8-1.8х109/l) platelets 106х109/l (27-143х109/l) and Hb -78 g/l, median PNH clone size in granulocytes was 94 (range 75-99)%. One pts previously developed sinus thrombosis. Conditioning consisted of thoraco-abdominal irradiation 4-6 Gy, cyclophosphamide 100 mg/kg, fludarabine 150 mg/m2 and antithymocyte globulin (ATG) or alemtuzumab. Eculizumab was given from day (-7) till day (+14) (every 7 days, only 4 times). GVHD prophylaxis was tacrolimus +/- methotrexate. Infusedgraft characteristics were: CD34+ – 8.1х106/kg, CD3TCRab+ – 150х103/kg, CD3gd+ – 7.3х106/kg, СD19+ – 221х103/kg, NK – 6.4х108/kg.
Engraftment was achieved in all 5 pts with a median of 15 (12-18) и 13 (10-18) days for granulocytes and platelets, respectively. Skin acute GVHD grade I developed in only 1 pt, and subsided with short course of glucocorticoids. CMV reactivation occurred in 1 pt; there were no episodes of Epstein- Barr Virus (EBV) or Adenovirus (AdV) reactivation. Full donor myeloid chimerism was established in all cases by day +30. Immune reconstitution was delayed until 6 months after transplant but no severe infections occurred. All pts are alive for 1.7-5.5 years (med 4 years) after HSCT with normal hematopoiesis and immune function, full donor chimerism and no late sequelae.
Transplantation of TCRalfa/beta and CD19 depleted hematopoietic cells from matched unrelated donor after immunoablative conditioning and supported with short course of eculizumab is perfectly safe and efficient technology leading to cure in young patients with PNH.
Paroxysmal nocturnal hemoglobinuria, TCR alfa/beta and CD19 depletion, transplantation, adolescents, young adults.