Hematopoietic Cell Transplantation for Paroxysmal Nocturnal Hemoglobinuria in the Age of Eculizumab

Abstract

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired clonal hematopoietic cell disease characterized by destruction of hematopoietic cells through the activation of the complement system with manifestations that can be life threatening including hemolysis, thrombosis, and marrow failure. Allogeneic hematopoietic cell transplantation (HCT) remains the only cure for PNH, but eculizumab, a terminal complement inhibitor of C5, has been used to prevent complement mediated hemolysis in PNH since its FDA approval in 2007. We examined outcomes of HCT in PNH patients to evaluate the effects of disease subtype, conditioning intensity, and eculizumab use either pre- or post-HCT. Fifty-five patients with a diagnosis of PNH underwent at least one HCT, and 4 patients required a second HCT for graft failure. Median age at time of first HCT was 30.0 years (range 4.2 to 66.9 years). Seventeen patients (30.9%) had classical PNH while the remaining 38 patients had PNH associated with another marrow disorder (aplastic anemia in 26 of the 38). Indications for HCT included pancytopenia in 47.3% of patients, myeloid malignancy (MDS, MPN, or AML) in 21.8%, recurrent hemolysis in 20.0%, and thrombosis in 10.9%. Of first HCTs, 26 were performed with myeloablative conditioning, 27 with reduced-intensity conditioning, and two sets of identical twins underwent HCT without any conditioning. Donor sources included HLA-matched related (38.2%), HLA-matched unrelated (34.5%), single HLA-allele mismatched unrelated (16.4%), umbilical cord blood (5.5%), syngeneic (3.6%), and HLA-haploidentical (1.8%). Median follow-up for surviving patients was 6.1 years (range, 2.1 to 46.1 years) after first HCT. Median time to neutrophil and platelet engraftment was 17 and 19 days, respectively; all but two patients (96.3%) had sustained engraftment. Overall survival was 70% at 5 years. Neither the choice of conditioning intensity nor PNH sub-type affected survival. Nineteen patients died during follow-up, including 12 patients before day 365. Six patients received treatment with eculizumab prior to HCT and two were treated after HCT. All patients treated with eculizumab pre- or peri-HCT remain alive with a median follow-up of 2.3 years (range, 0.2 to 6.9 years). Both patients treated with eculizumab after HCT had minimal to no acute GVHD (grade I skin in one patient and no acute GVHD in the other patient) and no chronic GVHD at 2.1 and 4.1 years post-HCT. With the approval of eculizumab, the indications for HCT include persistent hemolysis, persistent thrombosis, and associated marrow failure. Administration of eculizumab before and after HCT warrants further study, particularly considering our observation of minimal to no GVHD in our two patients who received eculizumab after HCT.