Allo-HSCT from MUD/MRD As a Curative Treatment in Paroxysmal Nocturnal Hemoglobinuria

Introduction: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare acquired clonal abnormality of the hematopoietic stem cell caused by somatic mutation in the phosphatidylinositol glycan-class A (PIG-A) gene located on the short arm of the X chromosome. Cells with lack phosphatidylinositol glycoproteins are more sensitive to complement-mediated lysis. Despite the efficient symptomatic treatment of hemolytic PNH with eculizumab, allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative treatment of the disease, although outcomes presented in the past were controversial.

Material and methods: We report 32 allo-HSCTs: 31 from MUD and 1 from MRD performed for PNH in 2004-2014. Median age of recipients was 28 years (range 20-55) and donors 33(19-53), median time from diagnosis to allo-HSCT was 18(2-307) months. Median size of PNH clone was 80% granulocytes (0.41%-98%). Indication for allo-HSCT was aplastic/hypoplastic bone marrow (15 pts), overlapping MDS (2 pts), severe course of PNH with hemolytic crises and transfusion-dependency without access to eculizumab (15 pts). Additional risk factors were Budd-Chiari syndrome and hepatosplenomegaly (1 pt), history of renal insufficiency requiring hemodialyses (2 pts) and chronic hepatitis B (1 pt). The preparative regimen consisted of treosulfan 3x14 g/m2 plus fludarabine 5x30 mg/m2 (25 pts) or treosulfan 2x10 g/m2 plus cyclophosphamide 4x40 mg/kg (7 pts). Standard GVHD prophylaxis consisted of cyclosporine-A, methotrexate and pre-transplant ATG or thymoglobulin in MUD-HSCT. 2 pts instead cyclosporine-A received mycophenolate mofetil and tacrolimus. Source of cells was bone marrow (12 pts) or peripheral blood (20 pts) with median 7.7x10(8)NC/kg, 5.3x10(6)CD34+cells/kg, 24.2x10(6)CD3+cells/kg. Myeloablation was complete in all pts with median 9 days (6-13) of absolute agranulocytosis <0.1 G/l. Median number of transfused RBC and platelets units was 8.5(1-16) and 8(3-18).

Results All pts engrafted, median counts of granulocytes 0.5 G/l, platelets 50 G/l and Hb 10 g/dl were achieved on days 17.5(13-33), 17.5(11-39) and 19.5(11-34). Acute GVHD grade I,II and III was present in 14, 6 and 1 pt, limited chronic GVHD in 11 pts. LDH decreased by 77%(5%-91%) in first 30 days indicating disappearance of hemolysis. 100% donor chimerism was achieved in all pts. In 1 patient donor chimerism decreased to 83% what was treated with donor lymphocytes infusion (DLI). 2 patients died, 1 previously hemodialysed pt died on day +102 in a consequence of nephrotoxicity complicating adenoviral/CMV hemorrhagic cystitis and second on day +56 because of severe pulmonary infection. Complications in survivors were FUO (7 pts), CMV reactivation (8), VOD (1), neurotoxicity (1), venal thrombosis (1), hemorrhagic cystitis (1) and mucositis (8). 30 pts (93.7%) are alive 42 months (1-85) post-transplant and are doing well without treatment. Complete disappearance of PNH clone was confirmed by flow cytometry in all surviving pts.

Conclusions: Our results indicate, that allo-HSCT with treosulfan-based conditioning is effective and well tolerated curative therapy in PNH.