Successful Allogeneic Hematopoietic Cell Transplantation in Two Patients with IL-12Rβ1 Deficiency

IL-12Rβ1 deficiency is thought to be the most common etiology of Mendelian susceptibility to mycobacterial disease with incomplete penetrance and variable expressivity. Allogeneic hematopoietic cell transplantation (HCT) is potentially curative but has been rarely reported for this disease. We describe two affected patients successfully treated with HCT. P1 was a 21-month-old female (homozygous, c.1623_1624delinsTT, p.Gln542*) who presented with disseminated Mycobacterium avium complex (MAC) infection. Her infection partially responded to antimycobacterial therapy and interferon (IFN)-γ. She underwent myeloablative HCT at age 3.5 years from a 12/12 HLA-matched unrelated donor. Conditioning consisted of busulfan, cyclophosphamide, thiotepa, and fludarabine. Graft-versus-host disease (GVHD) prophylaxis included anti-thymocyte globulin, methotrexate, tacrolimus, and mycophenolate mofetil. She achieved neutrophil engraftment on D+31 but required romiplostim for chronic thrombocytopenia. Post-HCT course was complicated by (1) engraftment syndrome with cytokine release syndrome and encephalitis, treated with anakinra and intravenous immunoglobulin (IVIg), and (2) MAC-immune reconstitution inflammatory syndrome (IRIS) with severe adenoviral infection and pulmonary hemorrhage requiring extracorporeal membrane oxygenation support. Late complications included acute immune thrombocytopenia, treated with corticosteroids. She is now 12 years old and well. P2 was a 6-year-old female (homozygous, c.631C>T, p.Arg211*) who presented with disseminated Mycobacterium bovis infection (BCG-osis) despite antimycobacterial therapy and IFN-γ (NCT00018044). Her course was complicated by protein-losing enteropathy (PLE) from BCG mesenteric lymph node infection. She underwent HCT at age 11 years using peripheral blood stem cells from her 10/10 HLA-matched father after myeloablative conditioning with busulfan and fludarabine. GVHD prophylaxis included cyclophosphamide, tacrolimus, and mycophenolate mofetil. Post-HCT course was complicated by (1) engraftment syndrome, treated with corticosteroids and tocilizumab, and (2) BCG-IRIS managed with corticosteroids. Eltrombopag was given preemptively and empirically to mitigate the deleterious effects of an IFN-γ surge during IRIS on hematopoiesis; however, poor graft function still ensued, which resolved after emapalumab conditioning for a stem cell boost. She is currently well 5 years post-HCT with resolution of infection but persistent PLE. In summary, allogeneic HCT is a viable therapeutic approach for IL-12Rβ1-deficient patients with refractory mycobacterial disease, but it can be complicated by IRIS and poor engraftment. Therapies such as eltrombopag and emapalumab may be considered.