Allogeneic Hematopoietic Cell Transplantation for SASH3 Deficiency

SASH3 deficiency is an X-linked combined immunodeficiency characterized by recurrent sinopulmonary, cutaneous, and mucosal infections, refractory autoimmune cytopenia, and immune dysregulation. We report here the first two cases of allogeneic hematopoietic cell transplantation (HCT) for SASH3 deficiency. Patient 1 was a 7-year-old with a history of refractory immune thrombocytopenia (ITP) who received bone marrow from his haploidentical mother. Conditioning was with alemtuzumab, busulfan (cumulative exposure 55.7 mg*h/L), fludarabine, and total body irradiation 200cGy. Graft-versus-host disease (GVHD) prophylaxis was with post-transplant cyclophosphamide, tacrolimus, and mycophenolate mofetil. His transplant course was complicated by severe veno-occlusive disease, adenovirus and CMV reactivation, grade I acute skin GVHD responsive to topical steroids, and presumed autoimmune neutropenia that resolved with high-dose intravenous immunoglobulin. Myeloid and T cell chimerism were 100% donor at all time points, and peripheral blood CD4 and CD8 T, CD19 B, and natural killer (NK) cell counts were normal at 1 year. He is alive and well 17 months post-HCT with no recurrence of ITP. Patient 2 was a 55-year-old with a history of recurrent sinopulmonary infections, refractory ITP, nodular regenerative hyperplasia with portal hypertension and massive splenomegaly, and chronic norovirus infection. He received peripheral blood stem cells from a matched unrelated donor after alemtuzumab, busulfan (cumulative exposure 52.5 mg*h/L), and fludarabine conditioning. GVHD prophylaxis was the same as patient 1. His transplant course was complicated by worsening of chronic norovirus, ITP flare, ultimately treated with daratumumab, and drug rash with eosinophilia and systemic symptoms (DRESS) syndrome treated with steroids and dupilumab. He developed a fungal pneumonia while on steroids for DRESS syndrome, as well as two episodes of bacterial pneumonia. Myeloid chimerism was 100% donor through 5 months post-HCT; T cell chimerism could not be assessed, given severe lymphopenia on steroids. He ultimately died on day +185 from multisystem organ failure in the setting of E. coli septic shock. In conclusion, the immune defect of SASH3 deficiency can be corrected with allogeneic HCT, and HCT may be considered for patients with severe disease manifestations. The optimal HCT regimen to ensure durable engraftment while minimizing toxicity remains to be elucidated.