Change in Conditioning Regimen Improves Hematopoietic Stem Cell Transplant Outcomes in Children with Lysosomal Storage Disorders

Introduction For more than 40 years, hematopoietic cell transplant (HCT) has been utilized to deliver the deficient enzyme for a subset of lysosomal storage disorders (LSD) such as Hurler syndrome and metachromatic leukodystrophy. These are rare inherited disorders with significant multisystem issues. As newborn screening for these disorders becomes more prevalent, it is essential to develop HCT regimens which are well tolerated and continue to improve transplant related outcomes. Graft failure and immune cytopenia post-HCT have been a challenge in these diseases, as previously reported. Objective To analyze the post-transplant outcomes with B-cell targeted conditioning. Methods We retrospectively analyzed University of Minnesota's transplant database to identify patients with IMDs that underwent HCT using between October 2017 and June 30, 2023. The conditioning regimen was modified during this period to include plasma cell depletion using and/or pre and post-HCT B-cell depletion using rituximab. Overall survival and the incidence of graft failure was determined using standard definitions. Immune reconstitution and immune cytopenias were analyzed in the study period. Results A total of 34 patients underwent HCT for LSDs during the study period. Patient demographics are presented in Table 1. Four patients died during the study period, overall survival (OS) of 89% (Figure 1), two of these died due to transplant related complications. Since addition of pre- and post-HCT rituximab (n=24), there was no transplant related mortality or incidence of > grade 2 acute or chronic graft versus host disease. Within the largest subgroup of patients with Hurler syndrome (n=14), overall survival was 100% since addition of rituximab. One patient developed secondary graft failure requiring a second transplant. Median myeloid donor chimerism was stable and >98% at 2-years for all patients. Median lymphoid chimerism increased from 86% at day 100 (Interquartile range (IQR): 65-97) to 100% at 2 years post-HCT. B-cell immune reconstitution was delayed until day+100 but was in the normal range after day+180 post-HCT (median CD19 486 cells/microL, IQR 71-1035). Prior to the use of rituximab, early immune cytopenia was noted in 2 patients (20%); one with pancytopenia (D+47) and one with thrombocytopenia (D+63). Late single lineage immune cytopenia (after day 170 post-HCT) was noted in 4 (17%) patients (3 with immune hemolytic anemia and 1 with neutropenia) following the addition of rituximab to the conditioning. This was easily treatable, with patients responded well to steroids as the first line agent, with one patient requiring additional rituximab. Conclusion B-cell immune ablation pre- and post-HCT reduces immune cytopenia in children with LSDs. With younger children undergoing HCT, this regimen is well tolerated with reduced toxicity.