Outcomes of Haploidentical Stem Cell Transplantation in Patients with Fanconi Anemia; A Systematic Review

Abstract Introduction Fanconi anemia (FA) is the most common inherited cause of bone marrow failure syndrome, with an incidence of approximately 1 out of 100,000 births per year and a prevalence of 1 in 360 000 live births. Clinical presentation is variable, ranging from classic Fanconi phenotype to absence of somatic abnormalities. Despite advances in understanding disease genetics and pathogenesis, hematopoietic stem cell transplant (HSCT) remains the only curative treatment option for FA patients. However, the future risk of solid organ malignancies persists post-transplant. Although outcomes of allogeneic HSCT for FA are improving steadily but remains suboptimal and often limited by donor availability- especially in countries lacking matched unrelated donor registry. For patients lacking a suitable donor, a trial of androgen is considered but is not curative, and around half of patients will not respond. Haploidentical HSCT has been successfully utilized in the management of acquired severe aplastic anemia and hematological malignancies but only limited published literature is available on its use in inherited bone marrow failure syndromes. We conducted this systematic review to explore survival outcomes of FA patients receiving haploidentical HSCT to assess feasibility of this treatment for patients lacking a matched donor. Methods We conducted a literature search on Pubmed, Cochrane, Google Scholar, open grey, and embase databases using the keywords; Haploidentical Transplant and Fanconi anemia. We screened 236 articles according to the Prisma diagram. After thoroughly reading the titles and abstracts, 13 articles were included for data extraction, and results were compiled. Results We analyzed thirteen studies with haploidentical transplant as a treatment for FA, 7 were retrospective, and 6 were prospective. Diagnosis of FA was established by chromosomal breakage analysis and genetic mutation testing. The preferred donor for a haploidentical transplant was a first-degree relative and mother/sibling in most cases. The total number of patients with FA and other disorder who received haploidentical transplants were n=340. The median age at HSCT was 6.7 (0.25-44) years. Two hundred six were male, and 134 were female. The most common conditioning regimen for FA patients was fludarabine, cyclophosphamide, and total body irradiation (TBI) followed by anti-thrombocyte globulin. Mehta. et al. evaluated haploidentical transplant without TBI in the conditioning regimen. The most common regimen to prevent graft versus host disease (GVHD) was cyclosporin and mycophenolate mofetil. Uppulur. R et al., Bonfim. C et al., Thakar. M.S et al. and Ayas, M et al. also used post-transplant cyclophosphamide for in vivo T cell depletion. Zubicaray. J et al and Strocchio. L et al. did not use any post-transplant therapy. Cumulative Overall survival reported was 79.1%. Cumulative acute GVHD was seen in 38.2%, while cumulative chronic GVHD was seen in 18.6% of patients. The most common adverse events were acute and chronic GVHD, Evans syndrome, steroid-induced osteoporosis, and diabetes. Respiratory syncytial virus, pneumonia, candida sepsis reactivation, hemorrhagic cystitis, and mucositis were the most common infections. Conclusion Fanconi anemia is an inherited bone marrow failure syndrome with somatic abnormalities and increased risk of hematological and solid organ malignancies. In FA, allogeneic hematopoietic cell transplantation (HCT) has been shown to restore normal hematopoiesis in patients with matched related donor HCT and has shown excellent long-term survival. Currently, limited data is available reporting outcomes of haploidentical HSCT for FA patients. More studies are required to establish safety and efficacy profiles. Figure 1 Figure 1. Disclosures Anwer: Allogene Therapeutics: Research Funding; GlaxoSmithKline: Research Funding; Janssen pharmaceutical: Honoraria, Research Funding; BMS / Celgene: Honoraria, Research Funding.