Haploidentical stem cell transplantation with post-transplant cyclophosphamide can be considered a viable option in children with Fanconi anemia, particularly in resource-limited settings given the high costs of hematopoietic stem cell transplantations, with an overall survival of 68.4%.

Peripheral blood stem cells provide early engraftment, decreasing the risk of prolonged neutropenia and sepsis, with a focus on maintaining CD34 and CD3 dose of a minimum of 5 × 106/kg and 1.5 × 108/kg recipient body weight, respectively, in the infused graft.

Supportive care measures, including N-acetyl cysteine infused concomitantly with cyclophosphamide on day +3 and day +4, can help decrease the incidence of severe mucositis and transaminitis and thereby reduce regimen-related toxicity.

Monitoring ferritin as a surrogate marker for IL-6 levels and cytokine release syndrome with log increases combined with clinical features as the basis for instituting early steroids can decrease the mortality associated with cytokine release syndrome.

Ruxolitinib can be a useful second-line agent for chronic graft-versus-host disease (GVHD) with good responses in those with skin and mouth GVHD.

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. 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. Nineteen children (male/female, 0.75:1) underwent 21 haplo-HSCTs with PTCy. Fludarabine, low-dose cyclophosphamide, and 200 centi-gray total body irradiation were included in the conditioning regimen with 25 mg/kg PTCy on days +3 and +4. Haplo-graft was from a sibling in 38% and father in 57% of transplants. The source of stem cells was peripheral blood stem cells in 81% and bone marrow in 19% of transplants, with a median CD34 dose of 5.0 × 106/kg. We documented engraftment in 84% and primary graft failure in 10% of transplants. N-acetylcysteine (NAC) was infused concomitantly during cyclophosphamide in 13 children. Grade 2 and 3 mucositis was lower among those who received NAC as compared to those who did not (30% and 15% versus 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 nonavailability of IL-6 levels. A 1- or 2-log increase in the titers of ferritin associated with clinical features guided the early addition of steroids in the periengraftment period. The mean survival was found to be less among those with high serum ferritin (>10,000 ng/dL) in the periengraftment period as compared to those with ferritin <10,000 ng/dL (mean survival of 25 ± 10 months versus 50 ± 6 months, respectively). The overall survival in our cohort was 68.4%, with a mean survival time of 41.5 months (95% confidence interval, 29.3 to 53.8 months), with a statistically significant correlation between inferior outcome and having received over 15 transfusions before HSCT (P = .01). 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 NAC during cyclophosphamide infusion helps reduce oxygen free radical related tissue damage and regimen-related toxicity.

Fanconi anemia

Haploidentical stem cell transplantation

Post-transplant cyclophosphamide

Ruxolitinib

N-acetyl cysteine

Ferritin

© 2020 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.