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 the destruction of hematopoietic cells through activation of the complement system with manifestations that can be lifethreatening including hemolysis, thrombosis, and marrow failure. Allogeneic hematopoietic cell transplantation (HCT) remains the sole cure for PNH, but eculizumab, a terminal complement inhibitor of C5, has been used to prevent complement-mediated hemolysis in patients with PNH since its approval by the Food and Drug Administration in 2007. We examined outcomes of HCT in patients with PNH to evaluate the effects of disease subtype, conditioning intensity, and eculizumab use either pre-HCT or post-HCT. Fifty-five patients with a diagnosis of PNH underwent at least 1 HCT, with 4 patients requiring a second HCT for graft failure. The median age at the time of first HCT was 30.0 years (range, 4.2 to 66.9 years). Seventeen patients (30.9%) had classical PNH, and 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 the patients, myeloid malignancy (myelodysplastic syndrome, myeloproliferative neoplasm, or acute myelogenous leukemia) in 21.8%, recurrent hemolysis in 20.0%, and thrombosis in 10.9%. Of the 55 first HCTs, 26 were performed with myeloablative conditioning, 27 were performed with reduced-intensity conditioning, and 2 sets of identical twins underwent HCT without any conditioning. Donor types included HLA-matched related in 38.2%, HLA-matched unrelated in 34.5%, single HLA-allele mismatched unrelated in 16.4%, umbilical cord blood in 5.5%, syngeneic in 3.6%, and HLA-haploidentical in 1.8%. The median duration of follow-up in surviving patients was 6.1 years (range, 2.1 to 46.1 years) after first HCT. The median time to neutrophil and platelet engraftment was 17 days and 19 days, respectively; all but 2 patients (96.3%) had sustained engraftment. Overall survival was 70% at 5 years. Neither the choice of conditioning intensity nor PNH subtype affected survival. Nineteen patients died during follow-up, including 12 patients before day +365. Six patients received treatment with eculizumab before HCT, and 2 were treated after HCT. All patients treated with eculizumab were alive at a median follow-up of 2.3 years (range, .2 to 6.9 years). Both patients treated with eculizumab after HCT had minimal to no acute GVHD (aGVHD), with grade I skin aGVHD in 1 patient and no aGVHD in the other patient, and no chronic GVHD at 2.1 and 4.1 years post-HCT, respectively. 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 2 patients who received eculizumab after HCT.

Real-World Healthcare Resource Utilization (HRU) and Costs of Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH) Receiving Eculizumab in a US Population

“…Taken together, the substantial direct medical costs and medical-related absenteeism costs associated with PNH further suggest that disease activity may not be well controlled despite treatment with eculizumab, and that the burden of disease appears greater among TD eculizumab users relative to TF eculizumab users. However, some case studies have shown that treatment with eculizumab may contribute to a reduction of morbidity prior to and complications following allogeneic hematopoietic stem cell transplantation among patients with PNH [27,28]. Additional research is needed to further delineate the use of eculizumab in the setting of transplantation.…”

Paroxysmal Nocturnal Hemoglobinuria in the Context of a Myeloproliferative Neoplasm: A Case Report and Review of the Literature

“…A retrospective series of 55 PNH patients undergoing hematopoietic stem cell transplantation (HSCT) included two cases associated with MF. The reported overall survival at 5 years was 70%, although the outcome of these two patients is not specified ( 22 ). Regarding outcome, four out of the total 23 patients reported (17.4%) died due to acute lymphoblastic/myeloid leukemia progression ( 16 , 17 ), infections, or liver failure secondary to refractory Budd–Chiari syndrome ( 18 ).…”

Graft rejection markers in children undergoing hematopoietic cell transplant for bone marrow failure

“…Furthermore, multiple studies have shown no adverse effect of pre-HCT eculizumab therapy on engraftment in patients with paroxysmal nocturnal hemoglobinuria. 27,28 Mei et al 29 published their experience with post-HCT eculizumab prophylaxis in 8 patients with paroxysmal nocturnal hemoglobinuria, and Cooper et al describe 2 additional patients. 27 Nine of 10 patients engrafted without issue, whereas 1 patient experienced graft failure.…”