Autoimmune Cytopenias Following Allogeneic Hematopoietic Stem Cell Transplant in Pediatric Patients: A Case-Control Cohort Study

Abstract

Introduction Autoimmune cytopenia (AIC) is a rare, but serious complication of allogeneic hematopoietic cell transplantation (HCT), and treatment for post-HCT AIC can have severe short- and long-term consequences. We sought to identify AIC risk factors and evaluate treatment-related late effects, in order to better guide management. Methods We performed a retrospective case-control study of pediatric patients who underwent HCT at Children's Hospital Colorado from June 2005 to March 2019. We compared clinical and transplant-related characteristics, chimerism, immune reconstitution, outcomes and late effects between patients who developed AICs (n=20) and a control group (n=40) matched by primary disease category and donor source. Results The incidence of AIC was 5.6% amongst all patients who received allogeneic HCT in the study timeframe (n=354). Of these, 75% had non-malignant disease (n=15). Thirteen developed autoimmune hemolytic anemia (65%), 5 had immune thrombocytopenia (25%), 1 had Evans syndrome (5%) and 1 had autoimmune neutropenia (5%). Median time to AIC was 219 days (range 97-1205 days). There was no difference between AIC patients and controls in gender, age at HCT, conditioning regimen, serotherapy, total body irradiation (TBI), GVHD prophylaxis, chronic GVHD, or time to neutrophil and platelet recovery. Compared to controls, more AIC patients had ABO mismatch (50% vs. 40%, p=0.07), and a higher proportion of grade I-II acute GVHD (93.9% vs. 50%, p=0.06), but was not statistically significant. Seventeen patients (85%), had >95% donor chimerism immediately prior to development of AIC. Fifteen patients (75%) received steroids as part of first-line therapy for AIC and 17 patients (85%) received rituximab as part of all therapy. Eleven patients (64.7%) received rituximab as part of first-line therapy. Only 25% of patients (n=5) responded to initial therapy. Median time to resolution of AIC was 12.0 months (range 10 days to 90 months). Strikingly, 12 patients (70.6%) are still receiving intravenous immune globulin (IVIG) replacement for hypogammaglobulinemia at least 1-year after HCT at a median time of 597.5 days (range 83-3715 days) from last rituximab dose. Iron overload was more prevalent in AIC patients compared to controls (n=8 vs n=1, p=0.0004, median of 2.3 years after HCT). The overall survival (OS) of the AIC cohort was similar to the control group (85% vs 82.5%). No patients in the AIC cohort died from AIC-related complications. In the AIC cohort, 2 patients died from sepsis and 1 patient died from relapsed disease. Conclusions In this case-control study of pediatric HCT patients, AIC was not associated with mixed chimerism or GVHD. The majority of AIC cases did not respond to first-line therapy and required multiple treatment modalities to achieve a complete response. Late effects from AIC-directed therapies include prolonged hypogammaglobulinemia and iron overload.