The Favorable Outcome of Allo-HCT from MUD Following Treosulfan-Based Conditioning in Paroxysmal Nocturnal Hemoglobinuria

Although allo-HCT has a potential to cure patients with paroxysmal nocturnal hemoglobinuria (PNH), experience with allo-HCT from matched unrelated donors (MUD) is limited and favorable conditioning treatment for PNH has not been established. We report results of 8 allo-HCTs from MUD (matched in HLA-A,B,C,DR,DQ alleles) performed for PNH with treosulfan-based conditioning in years 2004–2008 in Katowice, Poland. Median age of recipients was 27 years (range 20–35) and donors 33(28–43), median time from diagnosis to transplantation was 20(15–36) months. Median size of PNH clone was 90% granulocytes (range 4%–95%), 4 donors were female and their recipients were male, AB0 incompatibility was minor in 5 pairs, major in 1 and bi-directional in 1 pair. Indication for transplantation despite severe refractory hemolysis with transfusion-dependency (observed in 6 pts) was aplastic or hypoplastic bone marrow and pancytopenia (5 pts), MDS (1 pt), severe course of PNH exacerbating with hemolytic crises (1 pt). Additional risk factors included thrombotic history with Budd-Chiari syndrome and hepatosplenomegaly (1 pt), history of renal insufficiency requiring hemodialyses (1 pt) and additional serological risk factors for hemolysis (1 pt). The preparative regimen consisted of treosulfan 3×14 g/m2 plus fludarabine 5×30 mg/m2 (7 pts) and treosulfan 2×10 g/m2 plus cyclophosphamide 4×40 mg/kg (1 pt). GVHD prophylaxis consisted of thymoglobuline 3×2 mg/kg pretransplant, cyclosporine-A 3 mg/kg/d since day -1 and methotrexate on days 1,3,6,(11). Transplanted cells were harvested from bone marrow (5 donors) and peripheral blood (3 donors) with median numbers 3.0 and 10.9 ×10(8)NC/kg, 3.0 and 6.9 ×10(6)CD34+ cells/kg, 27.5 and 427.7 ×10(6)CD3+ cells/kg, respectively. Myeloablation was complete in all pts with median 10 days (5–14) of absolute agranulocytosis <0.1 G/l. Median number of transfused RBC units was 7 (1–12) and of single-donor platelets units 9 (3–15). All pts engrafted, median granulocyte count of 1.0 G/l was achieved on day 17 (12–22), platelets 50 G/l on day 21 (9–30) and Hb 10 g/dl on day 30 (16–50). No serious acute GVHD was observed, grade I was transiently present in 4 pts and grade II in 3 pts. Transient limited chronic GVHD was observed in 2 pts. Hemolysis gradually decreased. 100% donor chimerism was present in the bone marrow on day +100 at latest in all pts. 1 previously hemodialysed pt died on day 102 in a consequence of nephrotoxicity complicating adenoviral/CMV haemorrhagic cystitis. Complications in survivors included FUO (2 pts), CMV reactivation (2), VOD (1), neurotoxicity (1), venal thrombosis (1), hemorrhagic cystitis (1) and mucositis (1). 7 pts (87.5%) are alive and are currently doing well under ambulatory control with no signs of hemolysis and without need for further hematological treatment, median follow-up is 23 months (2–44). Complete disappearance of PNH clone was confirmed by flow cytometry in all surviving pts. We conclude that MUD allo-HCT with treosulfan-based conditioning can be effectively and relatively safely used in PNH patients and thus it should be considered as a valuable therapeutic option in PNH.