Successful Second Transplantation with Thiotepa-Containing Reduced-Intensity Conditioning in Hypomorphic RAG1 Deficiency

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Background Busulfan (Bu)-containing conditioning regimens are widely used in hematopoietic stem cell transplantation for severe combined immunodeficiency (SCID), including recombination-activating gene (RAG) deficiency, because they facilitate the achievement of stable donor chimerism. However, when Bu cannot be administered due to complications such as pulmonary toxicity, the optimal alternative conditioning strategy remains unclear. Case Presentation A patient was diagnosed with hypomorphic RAG1 deficiency at 4 months of age following the onset of Pneumocystis pneumonia. During the clinical course, autoimmune hemolytic anemia (AIHA) developed and required prolonged management before adequate disease control was achieved. At 18 months of age, after stabilization of the patient’s general condition, HLA 6/6 antigen–matched cord blood transplantation was performed using fludarabine (Flu), melphalan (LPAM), antithymocyte globulin (ATG), and low-dose total body irradiation (TBI) as the conditioning regimen. After transplantation, the patient developed severe diarrhea due to mucosal injury, followed by stage 4 intestinal graft-versus-host disease (GVHD). GVHD improved after treatment with human bone marrow–derived mesenchymal stem cells (hMSC-BM), and the patient was discharged at 2 years and 2 months of age. However, mixed donor chimerism persisted. At approximately 2 years and 6 months of age, the patient was readmitted with recurrent respiratory infections. Concurrently, watery diarrhea and hematochezia developed, and lower gastrointestinal endoscopy revealed multiple ulcerative lesions consistent with gastrointestinal GVHD. Steroid-refractory GVHD progressed despite treatment with ruxolitinib, vedolizumab, and additional hMSC-BM infusions. Because of persistent immune dysfunction with recurrent airway infections, progressive pulmonary impairment, and declining donor chimerism, re-transplantation was indicated. At 3 years and 7 months of age, bone marrow transplantation from an HLA-matched older sibling was performed using a conditioning regimen consisting of Flu, LPAM, ATG, low-dose TBI, and thiotepa (TT). Neutrophil engraftment was achieved on day 17. Gastrointestinal GVHD resolved after re-transplantation, and recurrent respiratory infections disappeared. Four years after transplantation, the patient remains well with sustained 100% donor chimerism. Conclusion In this case, thiotepa-containing conditioning enabled successful re-transplantation and durable full donor chimerism without severe adverse events when Bu could not be used. This regimen may represent a potential alternative conditioning strategy for SCID patients with similar clinical constraints.

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