Outcome and Risk Factors of Autoimmune Cytopenia after Hematopoietic Cell Transplantation for Children with Primary Immunodeficiency

Introduction Studies focusing on post-HCT AIC in large cohorts of patients transplanted for primary immunodeficiency (PID) are lacking. Objectives We conducted a retrospective analysis of incidence, risk factors, outcome of post-HCT AIC in children with PID and B-cell function following rituximab treatment. Methods Between January 1987-December 2018, 502 PID patients who underwent first HCT for PID at our center were included. Cumulative incidence (CI) of post-HCT AIC was calculated using a competing risk analysis, considering death as a competing event. Fine-and-Gray test was used to identify risk factors of AIC. The selected variables: gender, age at HCT, indication for HCT (SCID versus non-SCID PID), pre-HCT AIC, donor type, donor-recipient ABO matching, stem cell source, ex-vivo T-cell depletion (TCD), stem cell doses, conditioning regimen, serotherapy, GvHD prophylaxis, acute GvHD, chronic GvHD and viraemia. B-lymphocyte immune reconstitution kinetics was compared between surviving patients with post-HCT AIC without rituximab (n=18), post-HCT treated with rituximab (n=12) and controls (n=24). Results 36 (CI, 9%) developed post-HCT AIC, with median onset at 6.5 months (2.5 months - 18.2 years). On univariate analysis, pre-HCT AIC (Fig. A), mismatched donor, alemtuzumab (Fig. B), ATG, acute GvHD (Fig. C) and chronic GvHD were significantly associated with post-HCT AIC. After multivariate analysis, alemtuzumab (p=0.02) was independently associated with post-HCT AIC. Corticosteroid and high-dose IVIg (2gm/kg) achieved remission in 50% (n=18), additional rituximab led to remission in 25% (n=9), and the remaining 25% were treated with various modalities including sirolimus (n=5), bortezomib (n=3), mycophenolate mofetil (n=2), splenectomy (n=2), and second HCT (n=3). The mortality of post-HCT AIC reduced from 25% (4/16) prior to 2011 to 5% (1/20) after 2011. The median follow-up of 5.8 years (0.4-29.1) showed that 26 of 30 survivors (87%) were in complete remission, 4 (13%) were in remission with sirolimus and low dose steroid. Of 12 survivors who were treated with rituximab, immunoglobulin substitution was discontinued in 7 (52%), and 5 (48%) required on-going IVIg replacement. The median interval between HCT and rituximab was 1.95 years (0.96-19.9) in patients who were IVIg dependent and 0.73 (0.30-2.3) in patients who were IVIg-free on last follow-up (p=0.17). B-lymphocyte immune reconstitution kinetics was significant slowly in patients with post-AIC with/without rituximab (Fig. D). Conclusions 5-year CI of post-HCT AIC in children with PID was 9% and there is risk of very late onset post-HCT AIC in patients with Artemis and RAG1 mutations, and activated PI3 delta syndrome. Alemtuzumab pk study might play a role in reducing the incidence of post-HCT AIC. Sirolimus is an effective steroid-sparing immunomodulator in refractory/frequently relapsing post-HCT AIC.