Stem Cell Transplantation for Paroxysmal Nocturnal Hemoglobinuria: An on Going Joint Study of the AAWP EBMT Group and the French Society of Hematology
Authors: de Latour Régis Peffault , Schrezenmeier Hubert , Mary Jean Yves , Bacigalupo Andrea , De Souza Carmino , Willemze Roelof , Tichelli Andre , Passweg Jakob R. , Socié Gerard 
Published: October 2019

Abstract
Background: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare acquired disorder of hematopoietic stem cells. The disease is diagnosed with hemolytic anemia, marrow failure or episodes of venous thrombosis. Stem cell transplantation (SCT) is the only curative treatment. Until now, there are few reports of SCT in PNH and all but one includes small numbers of patients (Saso R et al, British Journal of Haematology, 1999).
Aim: To evaluate the outcome and survival risk factors of PNH patients after SCT according to clinical status of PNH at time of transplantation, and to perform a comparative analysis with a matched cohort of PNH patients without transplantation.
Methods: We analyzed the outcome of PNH patients who underwent SCT in Europe through the European Blood and Marrow Transplant (EBMT) Group Promise registry. An additional questionnaire was sent to all centers on PNH specific history and classification. One hundred and six hematological centers were contacted through the EBMT group. Non-transplanted PNH patients were previously reported to the French Society of Hematology registry (Peffault de Latour R et al, Blood 2008). Both populations will be matched according to the date of PNH complications known to be related to bad outcome (thrombosis, aplastic anemia and/or malignant disease).
Results: Between September 1978 and April 2007, 268 PNH patients were reported to the EBMT registry. Among those patients, 141 were updated (74 male, 52%) for the present study from 42 hematological centers. The 3 main indications for SCT were aplastic anemia (n=86, 61%), severe recurrent hemolytic crisis (n=43, 30% and thrombosis (n=31, 30%). Concerning disease subcategories recently described (Parker C et al, Blood 2005) 75 patients were transplanted because of PNH in the setting of another specified bone marrow disorder (54%) and 62 patients because of classical PNH (hemolysis without marrow failure, 45%). At time of SCT, the median age of the population was 30 years (IQR 23 to 36). The median interval from diagnosis of PNH to the time of SCT was 21 months (IQR 7 to 69). Eighty-nine patients were transplanted from HLA-identical siblings (64%). The source of stem cells was mostly bone marrow (n=95, 68%). The 2 main conditioning regimens consisted in Cyclophosphamide with Antihymoglobulin or Busulfan. The graft versus host disease (GvHD) prophylaxis associate ciclosporine with or without methotrexate in 102 patients (72%). During evolution, 9 patients did not engraft (6%). Acute GvHD of grade II or more developed in 35 patients (Grade III–IV, n=12). Chronic GvHD developed in 45 (limited, n=26; extensive, n=19). With a median follow-up (±SE) of 62.5 months (±6.2), 39 patients died. The 5-year survival rate was 70% (±4.2%). The main causes of death were infections (n=19), GvHD (n=9) and Hemorrhage (n=4). None of the variables examined for associations with transplant outcome were statistically significant predictors of survival including: age, interval from diagnosis to transplant, year of transplant, stem cell source, donor type, HLA-matching, indications for SCT and PNH subcategories. The non transplanted PNH population includes 401 patients, diagnosed in France from 1950 to 2005. The median follow-up (±SE) is 123.2 months (±9.8). The 10-year survival rate was 67.8% (±4.6%).
Conclusions: This study confirms on a large cohort of PNH patients that SCT using related or unrelated donor is a valuable curative option for PNH complications. Nevertheless, no survival associated risk factor was identified. Due to the reduced number of PNH SCT patients, the on-going matched-control analysis with non transplanted PNH patients is the only way to access the potential benefit of SCT in case of PNH complications.