Long-Term Outcome of Allogeneic Stem Cell Transplantation in Patients with Paroxysmal Nocturnal Hemoglobinuria with or without Aplastic Anemia

Background: Although recently, Eculizumab, humanized monoclonal antibody directed against complement component C5, has used increasingly for the patients with hemolytic paroxysmal nocturnal hemoglobinuria (PNH), allogeneic stem cell transplantation (allo-SCT) can be curative treatment option especially for PNH patients with combined aplastic anemia (AA). The aim of the present study was to evaluate long-term outcome of allo-SCT in patients with AA/PNH. In addition, patients with classic PNH who underwent allo-SCT in the pre-eculizumab era were also evaluated.

Methods: Total of 33 patients with PNH clones underwent allogeneic SCT at our institution between Jan 1998 and Jan 2016. Among them, seven patients had classic PNH and 26 patients with cytopenia had AA/PNH (with bone marrow evidence of a concomitant AA).

Results: There were 21 male and 12 female patients with a median age of 34 years (range, 13-56 years). Pre-transplant GPI-AP deficient neutrophils and erythrocytes were 5.6% (0-92) and 21% (0-98.5), respectively. Median white blood cell, absolute neutrophil count, hemoglobin, and platelet at transplant were 2.4×10⁹/L, 0.8×10⁹/L, 7.7 g/dL, and 27×10⁹/L, respectively. Median LDH level was 727 U/L (232-7721 U/L) and 19 (58%) patients had LDH ≥1.5x upper limit of normal. Classic PNH (n=7) and AA/PNH [SAA (n=15), VSAA (n=9), or non-SAA (n=2)] received SCT from HLA-matched sibling (MSD, n=24), unrelated (URD, n=7), or haplo-identical donor (Haplo-SCT, n=2). Since 2003, the conditioning regimen for MSD-SCT was changed from Busulfex (12.8 mg/kg) + cyclophosphamide (CY, 120 mg/kg) to fludarabine (180 mg/m²) + CY (100 mg/kg) + rATG (10 mg/kg). The conditioning regimen for URD-SCT and Haplo-SCT were TBI (800 cGy) + CY (100-120 mg/kg) ± rATG (2.5 mg/kg) and TBI 600cGy + Fludarabine (150 mg/m²) + rATG (5 mg/kg), respectively. After a median follow-up of 57 months (range 6.0-151.3), the 5-year estimated OS rates were 87.9 ± 5.7%. Four patients died of treatment-related mortality (TRM), including acute GVHD (n=1), pneumonia (n = 2), and cerebral hemorrhage (n=1), respectively. Except one patient with early TRM, 32 patients engrafted. Two patients who experienced delayed graft-failure received second transplant and recovered. The cumulative incidence of acute GVHD (≥grade II) and chronic GVHD was 27.3 ± 7.9% and 18.7 ± 7.0%, respectively. Among 25 patients with available follow-up data, PNH clone disappeared at median 3.0 months (range 0.7-45.5) after SCT and reemerging of PNH clones was observed in two patients; one patient showed re-appearance of 2.6% GPI-negative neutrophils at 12 months without PNH symptoms, but disappeared again at 21 months. Another patient suffered from labile graft and received a booster with peripheral blood stem cells.

Conclusion: This study showed that long-term transplant outcome in patients with AA/PNH were comparable to that of allogeneic SCT in SAA (the 3-year estimated OS rates were 92.7 and 89 % for MSD-SCT and URD-SCT, respectively) at our institution (ASH Annual Meeting Abstracts 2012;120:4151). Reduced-intensity conditioning regimen was sufficient for the eradication of PNH clone in allogeneic SCT. Therefore, application of allogeneic SCT should be considered in PNH patients with AA in case of availability of well matched donor.