Paroxysmal nocturnal hemoglobinuria: Transplant experience using post-transplant cyclophosphamide in a resource-limited setting Free

Introduction: Paroxysmal nocturnal hemoglobinuria (PNH) is a chronic, debilitating clonal hematopoietic stem cell disorder characterized by complement-mediated intravascular hemolysis, thrombosis, and varying degrees of bone marrow failure. PNH is broadly classified into classical PNH, which typically presents with hemolysis and thrombotic complications, and secondary PNH, which occurs in association with bone marrow failure syndromes such as aplastic anemia or myelodysplastic syndromes.

While allogeneic hematopoietic stem cell transplantation (HSCT) remains the only curative modality, it is associated with considerable morbidity and mortality. On the other hand, complement inhibitors (eculizumab, ravulizumab) have emerged as effective treatments with lower toxicity, though they are not curative. However, in low-resource settings like Nepal, the prohibitively high cost of complement inhibitors running into millions of rupees renders them inaccessible. Conversely, an allogeneic transplant in Nepal costs under $10,000, making it a more feasible albeit riskier option.

Here, we report our single-center experience with allogeneic HSCT using post-transplant cyclophosphamide (PTCy) for PNH patients in a low-income setting.

Methods: Medical records of seven patients with classical PNH who underwent allogeneic HSCT between 2020 and 2023 were retrospectively reviewed. Data on patient demographics, type of transplant, time from diagnosis to transplant, transplant-related complications, and outcomes were collected and analyzed.

Result: The mean age of patients was 30.7 years (median: 31; range: 25–36 years), with all seven patients being male.

The median time from diagnosis to transplant was 8 months, primarily due to scheduling delays associated with a limited transplant capacity and a waiting list at the only HSCT center currently operating in Nepal. All donors were siblings: 4 (57.1%) fully matched related donors (MRD) and 3 (42.9%) haploidentical donors. MRD transplant patients received Fludarabine/Melphalan (Flu/Mel) and haploidentical transplant received standard Baltimore protocol. All patients received peripheral blood stem cells (PBSCs), with a mean CD34+ cell dose of 10.57 × 10⁶/kg. All patient received post-transplant cyclophosphamide as GVHD prophylaxis along with tacrolimus and MMF.

Six patients achieved neutrophil and platelet engraftment. Median time to neutrophil engraftment: 15.5 days (range: 13–21 days) Median time to platelet engraftment: 17.5 days (range: 13–35 days).

Three patients (42.9%) died due to transplant-related complications. Causes of death included veno-occlusive disease in one MRD recipient at 40 days post-transplant, CMV pneumonitis with gastroenteritis in one haploidentical recipient at 24 days, and severe mucositis complicated by neutropenic fever and fungal pneumonia in another haploidentical recipient at 12 days post-transplant.

Four patients (57.1%) are alive and disease-free at a median follow-up of over 24 months. Among them, two patients developed CMV reactivation, which was well controlled with valganciclovir. One patient, who received a haploidentical transplant, developed mild oral chronic GVHD.

Conclusion: Allogeneic HSCT remains a potentially curative but high risk option for PNH patients, particularly in resource limited settings. Our experience highlights the significant transplant related morbidity and mortality, even with modern GVHD prophylaxis such as PTCy.Given the availability of safer, though non-curative, therapeutic alternatives like complement inhibitors, urgent advocacy is needed. Patient groups, healthcare providers, policy-makers, and international aid organizations must collaborate to improve access to life-saving treatments in low-income countries.