ALL-079 Association of T-Cell Receptor Repertoire Diversity With L-Asparaginase Hypersensitivity in Childhood Acute Lymphoblastic Leukemia

Abstract

Asparaginase is an indispensable component of therapy for childhood acute lymphoblastic leukemia (ALL) but is very commonly associated with allergy which causes morbidity and poorer outcomes. The exact aspects of T-cell immunity underpinning association with asparaginase allergy has yet to be characterized. To evaluate the associations of T-cell receptor (TCR) repertoire and its diversity with asparaginase hypersensitivity in children with ALL. Longitudinal TCR-sequencing of 180 bone marrow samples across 3 time-points (diagnosis, post-induction, post-consolidation) from 67 children with ALL treated on the frontline Ma-Spore ALL 2010 trial. 12 out of 67 children (17.9%) had allergy in our cohort, representing 16 episodes of varying severity. First, we evaluated the association of TCR-repertoire diversity early on in treatment with the occurrence of subsequent allergy. We found that a higher TCR diversity at all time-points was significantly associated with late allergy (P=0.03 for Shannon's entropy, P=0.01 for inverse Simpson's index). This TCR diversity was characterized by a higher proportion of infrequent clones occurring <0.5% (P=0.008). Patients with allergy had significantly lower proportion of shared clonotypes (P=0.003). Examining the dynamic changes of the TCR repertoire between diagnosis and week 5 for each patient, allergic patients had a much less similar clonotypic set between timepoints compared to non-allergic patients (P=0.003). In fact, patients with a similarity coefficient of <0.05 (i.e., demonstrated greater longitudinal variability in their clonotypes) had an 8.1-fold risk of allergic event (95% CI 1.7 - 39.1, P=0.001). Evaluating the TCR-repertoire before and after an allergy, we found that there was convergence of TCR towards a common antigen, where clonotypes became more closely related after an allergy. Finally, we found that allergic patients had a lower proportion of public clonotypes (i.e., public clonotypic sequences found on VDJDB database) compared to non-allergic patients (P=0.02), supporting the "hygiene hypothesis" as a predisposing factor in the development of allergy. A TCR-repertoire that is more diverse and more dynamically changing increases the chance of having a matching reactive clonotype, which increases risk of allergy. Understanding the immunological basis of T-cell response in allergy may help in developing strategies to mediate this common toxicity.