Haploidentical stem cell transplantation with post-transplant cyclophosphamide in Fanconi anemia: improving outcomes with improved supportive care in India.

Abstract Introduction : Fanconi anemia is the most common inherited bone marrow failure syndrome, and hematopoietic stem cell transplantation (HSCT) is the only curative option. Post-transplant cyclophosphamide (PTCy) is challenging in this group of children, given their increased sensitivity to chemotherapy. Patients and methods : We performed a retrospective analysis of the data on children diagnosed with Fanconi anemia who underwent a haploidentical HSCT with PTCy from January 2014 to December 2019. Results : Nineteen children (M: F- 0.75:1) underwent 21 haplo-HSCTs with PTCy. Fludarabine, low dose cyclophosphamide, 200 centi-gray total body irradiation were included in the conditioning regimen with 25 milligram/kilogram of PTCy on days +3, +4. Haplo-graft was from a sibling in 38%, father in 57% transplants. The source of stem cells was peripheral blood stem cells in 81%, bone marrow in 19% transplants, median CD34 dose being 5.0 × 106/kilogram. We documented engraftment in 84% and primary graft failure in 10% transplants. N-acetylcysteine (NAC) was infused concomitantly during cyclophosphamide in 13 children. Mucositis of grade 2 and 3 were lower among those who received NAC as compared to those who did not (30% and 15% vs. 33% and 50%); while transaminitis was higher among those who did not receive the infusion. The incidence of acute graft versus host disease (GVHD) was 68%, and 81% of these were steroid responsive (grade I/II). We documented chronic GVHD in 25% children, predominantly involving the skin and mouth, which responded to low dose steroids and ruxolitinib. Serum ferritin was monitored twice weekly as a surrogate marker for cytokine release syndrome due to non-availability of IL6 levels. A one- or two-log increase in the titers of ferritin associated with clinical features guided the early addition of steroids in the peri-engraftment period. The mean survival was found to be less among those with high serum ferritin (>10000ng/dl) in the peri-engraftment period as compared to those with ferritin Conclusion : PTCy can be considered a viable option in children with Fanconi anemia, particularly in resource-limited settings given the high costs of HSCTs. Focused interventions in this subset of children help improve survival outcomes. Early identification of cytokine release syndrome and risk-adapted steroid therapy during engraftment helps prevent mortality. The concomitant use of N-acetyl cysteine during cyclophosphamide infusion helps reduce oxygen free radical related tissue damage and reduce regimen-related toxicity.