Immune Mediated Cytopenias Following Allogeneic Hematopoietic Cell Transplantation for Non-Malignant Disease: Risk Factors and Treatment Response in the Pediatric Population

Background: Immune mediated cytopenias (IMC) - isolated or combined hemolytic anemia, thrombocytopenia, and neutropenia - are increasingly recognized as potentially serious complications following allogeneic hematopoietic cell transplantation (HCT) for non-malignant disorders (NMD). However, IMC incidence, severity, response to therapy, and associated risk factors are not well defined.

Methods: Pediatric patients undergoing HCT for NMD between 2010 and 2017 at a single institution were identified, excluding those experiencing graft failure or death prior to day +100. Demographics and HCT characteristics were obtained from a prospectively-maintained, institutional database. A retrospective chart review identified cases of IMC with positive direct antiglobulin test, anti-platelet antibody, and/or anti-granulocyte antibody; and documented treatment(s) and response. Composite IMC severity, incorporating peak acuity and response to therapy, was defined as mild (outpatient management with supportive care or a single course of therapy), moderate (outpatient management with 2 or more courses of therapy), or severe (inpatient management with 2 or more courses of therapy). Factors hypothesized to be associated with IMC included younger age, reduced intensity conditioning, mixed or declining donor chimerism, and inherited metabolic disorder as indication for HCT. For the first year after transplant, peripheral blood donor chimerism, B-cell reconstitution, and IgG and IgM levels were obtained.

Results: A total of 271 NMD HCT recipients were included, with 53 (20%) exhibiting IMC, 20 (38% of cases) with multiple cell lines affected, diagnosed at a median of 131 days post-HCT (range, 30-264 days). IMC disease was mild, moderate, or severe in 56%, 32%, and 11%, respectively. For those with moderate or severe IMC, all received steroid therapy, with a response rate of 13%. Eighty-seven percent received additional therapy including IVIG, rituximab, bortezomib, and/or vincristine. Resolution of moderate IMC required an average of 2 individualized treatment courses, while severe IMC responded after an average of 6. Notably, no patients died of IMC. Univariate analysis revealed statistically significant association between IMC and younger age at HCT (median 3.1 vs. 7.1 years, p<0.01) and inherited metabolic disorder as the indication for HCT (p<0.01). Patient sex, recipient-donor HLA-match, stem cell graft source, intensity of conditioning, and presence of acute graft-versus-host disease were not significantly different between those with and those without IMC. Following HCT, a decline in peripheral blood donor CD3+ chimerism by at least 10% from day +60 to +100 was more common in those with IMC (p<0.01), although 50% of patients with IMC did not demonstrate a decrease in donor T-cell engraftment. The percent donor CD3+ chimerism at day +100 trended lower in the IMC group compared with the non-IMC group (71% vs 88.5%, p=0.10). The kinetics of patient B cell, IgG, or IgM recovery was not associated with IMC.

Conclusion: Immune mediated cytopenias following HCT for NMD in a large pediatric cohort was common at 20%, with nearly half of those affected exhibiting clinically significant courses before disease resolution. Elucidation of risk factors may inform modifications to conditioning regimens or other approaches to prevent IMC. We found younger age at HCT, inherited metabolic disorder as HCT indication, and declining donor T-lymphoid chimerism as risk factors for IMC. However, the pathogenesis of IMC post-HCT for NMD remains elusive. Further insights may arise from investigation into the role of infections/molecular mimicry and complement activation.