Tailored conditioning for hematopoietic stem cell transplantation in children with Mendelian susceptibility to mycobacterial disease: A tale of two pathways for IFN-γ and IL-12 defects.

Mendelian susceptibility to mycobacterial disease (MSMD) is a rare group of inborn errors of immunity associated with significant morbidity due to mycobacterial infections. Hematopoietic stem cell transplantation (HSCT) is a curative option; however, persistent infections and high levels of interferon-γ (IFN-γ) create a hostile environment for stem cell proliferation and can mediate graft rejection. We describe the outcome of children with MSMD due to IFN-γ receptor and interleukin-12 (IL-12) defects who underwent HSCT in our unit from December 2015 to December 2023. We collected the data retrospectively from a review of patient charts and analyzed the outcomes. Seven children underwent eight procedures, including four with IFN-γ defects and three with IL-12 defects. The male-to-female ratio was 1.6:1, and the median age at HSCT was 4.5 years. Five received haploidentical HSCT, and two underwent matched family donor transplants; 75% used peripheral blood stem cells. IL-12-deficient cases engrafted well with fludarabine/treosulfan-based conditioning, whereas IFN-γ-deficient cases fared better with fludarabine/treosulfan/thiotepa-based conditioning due to a higher rejection risk. Acute graft-versus-host disease (GVHD) (grade 1-2, skin/gut) occurred in two children: one developed chronic liver GVHD after donor lymphocyte infusion. Cytomegalovirus reactivation occurred in four cases, which responded to ganciclovir or cidofovir. One primary graft failure was rescued with a second HSCT; one secondary graft failure led to death from invasive fungal infection. At a median follow-up of 8 years, the overall survival was 87%. One survivor has ongoing seizures, aggressive behavior, and endocrine dysfunctions requiring supportive care. HSCT is a curative option for children with MSMD. However, we need to understand gene mutation and individualize the approach to preparation and conditioning regimens to help optimize the outcome.