Long-Term Outcome of Allogeneic Stem Cell Transplantation in Patients with Combined Paroxysmal Nocturnal Hemoglobinuria and Aplastic Anemia (AA/PNH syndrome)

Background:Paroxysmal nocturnal hemoglobinuria (PNH) is a nonmalignant clonal disorder of hematopoietic stem cells characterized by a somatic mutation in the PIG-A gene, encoding the glycosyl phosphatidylinositol (GPI) moiety. PNH clones lack GPI-anchored proteins (GPI-AP) which inhibit the activation and cytolytic functions of complement. Recently, Eculizumab, humanized monoclonal antibody directed against complement component C5, has used increasingly for the patients with hemolytic PNH. However, the patients with PNH clone and bone marrow failure syndrome (i.e. aplastic anemia) should be treated as their predominant clinical manifestation. Allogeneic stem cell transplantation (SCT) can be curative treatment option especially for PNH patients with combined aplastic anemia (AA). The aim of the present study was to evaluate long-term outcome of allogeneic SCT in patients with AA/PNH.

Methods: Total of 27 patients with PNH clones underwent allogeneic SCT at our institution between Jan 1998 and Mar 2014. Among them, seven patients had classic PNH and 20 patients with cytopenia had AA/PNH (with bone marrow evidence of a concomitant AA). We analyzed long-term transplant outcomes in 20 patients with AA/PNH.

Results: There were 12 male and 8 female patients with a median age of 34 years (range, 13-51 years). The median interval from the diagnosis to transplantation was 8 months (range; 1-201 months). The median transfusions prior to SCT were 33 units (range; 8-208 units). Pre-transplant GPI-AP deficient neutrophils and erythrocytes were 46% (0-99) and 15.6% (0-88), respectively. Median white blood cell, absolute neutrophil count, hemoglobin, and platelet at transplant were 2.3×10⁹/L, 0.7×10⁹/L, 7.9 g/dL, and 21×10⁹/L, respectively. Median LDH level was 714 U/L (range; 273-6499 U/L) and 11 (55%) patients had LDH ≥1.5x upper normal limit. PNH patients with SAA (n=14), VSAA (n=4), or non-SAA (n=2) received SCT from sibling (s) donor (n=15) or unrelated (u) donor (n=5). The conditioning regimen for s-SCT consisted of fludarabine (180 mg/m²) + cyclophosphamide (CY, 100 mg/kg) + ATG (10 mg/kg) (n=11), or busulfex (12.8 mg/kg) + CY (120mg/kg) (n=4). The conditioning regimen for u-SCT was TBI (fractionated, 800 cGy) + CY (100-120 mg/kg) ± ATG (2.5 mg/kg). GVHD prophylaxis consisted of CsA + MTX in s-SCT and FK506 + mini-MTX in u-SCT, respectively. After a median follow-up of 57 months (range 4.7-122.1), the 5-year estimated OS rates were 90.0 ± 6.7%. Two patients died of treatment-related mortality (TRM), including acute GVHD (n=1) and cerebral hemorrhage (n=1), respectively. Except one patient with early TRM, 19 patients engrafted with no secondary graft-failure. The cumulative incidence of acute GVHD (≥grade II) and chronic GVHD was 25.0 ± 1.0% and 26.3 ± 10.4%, respectively. PNH clones disappeared at median 1.8 months (range 0.9-11.9) after SCT and reemerging of PNH clone was not observed in all patients.

Conclusion: This study showed that long-term transplant outcome in patients with AA/PNH were comparable to that of allogeneic SCT in SAA (the 3-year estimated OS rates were 92.7 and 89 % for s-SCT and u-SCT, respectively) at our institution (ASH Annual Meeting Abstracts 2012;120:4151). Therefore, application of allogeneic SCT should be considered in PNH patients with AA in case of availability of well matched donor.