Combined Upfront B-Cell and T-Cell Targeted Therapies for Treating TA-AIHA in Αβhaplo-HSCT Recipients: A New Paradigm

INTRODUCTION Transplant-associated autoimmune hemolytic anemia (TA-AIHA) impacts 1-5% of pediatric allogeneic hematopoietic stem cell transplant (HSCT). Little is known about its incidence and pathogenesis in αβ T-cell depleted haploidentical HSCT (αβhaplo-HSCT). We hypothesize that viral-induced T-cell dysregulation combined with B-cell reconstitution in post-αβhaplo-HSCT patients creates a conducive environment for TA-AIHA development. METHODS We reviewed our αβhaplo-cohort (122 patients, treated at Stanford Children's Health between 03/2017-08/2023) and we identified 7 cases of TA-AIHA. Data collection was approved by Stanford IRB and obtained by chart review. To assess the timing of B-cell reconstitution and the activation status of T cells (CD69+ and CD25+ expression) we analyzed peripheral blood samples obtained at days 30, 60, 90, and 180 post-HSCT. RESULTS The cumulative incidence of TA-AIHA in our αβhaplo-HSCT cohort is 5.7%. Median time to diagnosis of TA-AIHA is +151 days post-HSCT (range 131 – 229 days). Among the 7 patients included in the study, 6 experienced CMV reactivation either during the onset of or right before the diagnosis of TA-AIHA. Additionally, all patients had concurrent or preceding viral infections, as indicated in Table 1. The median time elapsing between B-cell appearance in the peripheral blood and TA-AIHA diagnosis was 30 days (range 11-110 days), suggesting that the combination of viral-induced T-cell activation and B-cell reconstitution represented that trigger for TA-AIHA (Table 2).All patients were started on steroids and IVIG as first-line treatment for TA-AIHA. All but one received 4 or more doses of upfront rituximab with steroid treatments. Five patients were treated with second-line agents, including T-cell targeted therapies such as abatacept or basiliximab (Table 1). Of the 2 patients who did not receive second-line agents, 1 died from respiratory failure secondary to COVID-19 which was diagnosed concomitantly with the patient's TA-AIHA. CONCLUSION Our findings indicate that, in αβhaplo-HSCT recipients, patients with TA-AIHA would benefit from upfront combined B-cell and T-cell targeted therapies to address the immune dysfunction affecting both immune subsets. In our case series, patient 7 received steroids + rituximab followed by abatacept 2 weeks later. This combinatorial approach yielded excellent results, as shown by resolution of hemolysis and transfusion independence. Further evaluation of the effectiveness of combined upfront B-cell and T-cell targeted therapies for TA-AIHA in αβhaplo-HSCT is under investigation at our center.