Managing hypomorphic RAG1-associated severe combined immunodeficiency (SCID) prior to hematopoietic stem cell transplant (HSCT) represents a unique therapeutic challenge as clinicians are charged with preventing and treating opportunistic infections while often simultaneously controlling the consequences of immune dysregulation. We describe a particularly challenging case of treatment-resistant cytomegalovirus (CMV) viremia and significant inflammatory bowel disease in a Mennonite infant with hypomorphic RAG1-associated SCID, ultimately treated with unconditioned HSCT.
A Mennonite breastfed female with SCID secondary to homozygous RAG1 c.527G>T variants (older brother shared genotype) presented at 10 months old with an acute diarrheal illness, found to have cryptosporidium gastroenteritis and CMV viremia. She had rising CMV viral load despite treatment with ganciclovir, valganciclovir, foscarnet, and cidofovir sequentially, as well as 5 maternally derived CMV-specific cytotoxic T lymphocyte infusions. She had poor weight gain, chronic diarrhea, feed intolerance requiring parenteral nutrition, peri-rectal ulcers, and colonoscopy consistent with IBD. IBD was treated with triple antibiotic therapy alone given significant risk with further immunosuppression. B cell depletion with rituximab was pursued to eliminate potential anti–type I interferon antibody–producing B cells and augment CMV clearance. CMV-directed therapies were ultimately discontinued given continued treatment resistance and adverse side effects. She received an unconditioned haploidentical peripheral stem cell transplant with TCRαβ+/CD19+ cell depletion at 18 months old. Engraftment studies showed 34% donor chimerism in the T cell lineage at 3 months post-HSCT, which gradually increased to 80% at 1 year post-HSCT. At 1 year post-HSCT, immune phenotyping showed modestly increased naive T cells, normalized lymphocyte proliferative response to mitogen stimulation, and predominantly polyclonal TCR Vb repertoire. She remained with minimal B cell and myeloid donor engraftment and is maintained on immunoglobulin replacement therapy. Clinically, her GI disease improved with tolerance of complete enteral feeds since 10 months post-HSCT. At 1 year post-HSCT, her CMV viral load was undetectable.
We report a remarkably positive and unexpected outcome of rising T cell engraftment, clearance of previously treatment-resistant CMV viremia, and marked improvement in IBD symptoms after unconditioned HSCT for hypomorphic RAG1-associated SCID, adding to the field’s important and ever-growing experience in managing this challenging condition.
