Efficacy and Safety of Allogenic Hematopoietic Stem Cell Transplant in Paroxysmal Nocturnal Hemoglobinuria: A Single Centre Study from Pakistan

Background: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired disorder of clonal hematopoiesis¹ .The resulting abnormalities in complement regulatory proteins can manifest as hemolysis, thrombosis, and marrow failure². The management and clinical outcomes of patients with PNH significantly changed with the development of complement inhibitor therapies³. Allogenic Hematopoietic stem cell transplant (HSCT) despite being the sole curative option for PNH is not recommended as first line therapy owing to its toxicities ^4,5. Current indications for HSCT include a suboptimal response to eculizumab, severe AA/PNH, clonal evolution to myelodysplastic syndrome (MDS), or acute myelogenous leukemia². However, in low and middle income countries (LMIC) where complement inhibitor therapies are not available, allogenic HSCT still remains the only treatment option for classical PNH as well as for PNH in the setting of another specified bone marrow disorder.

Objective: To analyze the efficacy and safety of Allogenic HSCT in patients with paroxysmal nocturnal hemoglobinuria (PNH).

Study design: Observational, retrospective study.

Place and duration of study: Armed Forces Bone Marrow Transplant Centre/ National Institute of Blood and Marrow Transplant (AFBMTC/NIBMT) Rawalpindi, Pakistan, from June 2008 till February 2022.

Methodology: From June 2008 till February 2022, a total of 65 patients of PNH were registered at AFBMTC/NIBMT. Out of these16 patients underwent allogenic HSCT and were included in the final retrospective analysis. PNH diagnosis was confirmed by flow cytometry by the demonstration of GPI-negative cells in at least two cell lineages i.e neutrophils, red blood cells (RBCs) in 62.5% (n=10) patients and by fluorescent aerolysin (FLAER)-based assay in 37.5% (n=6) patients. Median time from diagnosis to transplant was 380 days. All patients received HLA identical sibling donor HSCT. Stem cell source was Bone marrow harvest (BMH), BMH plus peripheral blood stem cell (PBSC) and PBSC alone in 81% (n=13), 12.5% (n=2) and 6% (n=1) patients respectively. Graft versus host disease (GVHD) prophylaxis was with Antithymocyte globulin (ATG) + Cyclosporin (CSA) in patients receiving NMA conditioning or ATG + CSA + short term Methotrexate (MTX) in those receiving MAC.

Results:

Median age of the study cohort was 24 years (range, 18 to 42 years) and all were male. 68.7% (n=11) patients received immunosuppressive therapy before HSCT with partial or no response. History of thrombosis prior to HSCT was present in only one patient (cPNH).

Allogenic HSCT done for classical PNH (cPNH) in 75% (n=12) patients and for PNH in the setting of another specified bone marrow disorder (PNH/AA) in 25% (n=4) patients. Patients with classical PNH received Myeloablative conditioning (MAC) i.e Flu150Bu12.8^IV (75%, n=9), Bu16Cy120 (8.3%, n=1), or Flu150Cy200 (8.3 %, n=1) except for one patient who received Flu150Cy160. Patients with PNH/AA, received non myeloablative conditioning (NMA) i.e Flu150Cy120, except for one who received Flu150Bu12.8^IV_. Out of 16 patients, 94% (n=15) patients achieved successful engraftment with full donor chimerism. One patient (cPNH) had Primary graft failure. Median time to neutrophil and platelet engraftment was day +12 and day +22 respectively. Disease relapse was monitored by donor chimerism till Day +180 post BMT and thereafter by peripheral blood counts. PNH clone post BMT was not tested. Incidence of acute GVHD grade I/II involving skin and gut, was 25% (n=4). No incidence of chronic GVHD was noted. One patient (PNH/AA) had secondary graft failure on Day +46. With a median post-transplant follow-up of 15 months (range, 4 to 157) overall survival (OS) was 93.7% and disease-free survival (DFS) was 87.5%.

Conclusion:

In resource constrained, LMIC, where complement inhibitor therapies are currently unavailable, allogenic HSCT remains the valid option for treatment of PNH, with good overall survival rate and acceptable treatment related toxicites.

No relevant conflicts of interest to declare.