Identifying novel genomic alterations in relapsed childhood B-ALL: a report from the Children's Oncology Group

Relapsed B-acute lymphoblastic leukemia (B-ALL) generally occurs due to the emergence of subclones resistant to therapy, leading to poor outcome. Here, we describe novel genomic alterations responsible for therapeutic resistance at a subtype level in a clinical trial (AALL1331) which randomized patients to blinatumomab and chemotherapy versus chemotherapy alone. We performed whole-genome and transcriptome sequencing on 288 patients (183 diagnosis/first relapse/germline trios and 105 additional patients with first-relapse samples) and analyzed 41 second-relapse samples. For ETV6::RUNX1, we showed that cases with gain of the fusion allele or with fusion transcript involving exon 5 of ETV6 and exon 4 of RUNX1 (E5-E4) had a higher risk of first relapse than cases with E5-E3. For the hyperdiploid subtype, we demonstrated that low modal chromosomal numbers (51-52) were more prone to first relapse than those with ≥53 chromosomes, with an additive effect of CREBBP mutations. We showed enrichment of IKZF1 alterations in the Philadelphia-like subtype and that NSD2 E1099K was commonly associated with relapse in TCF3::PBX1. Together, these new features accounted for 30% (n=55) of first relapses. Intriguingly, ~3% of relapses are related to secondary B-ALL or germline predisposition. We also compared genomic alterations at diagnosis and first relapse in relation to second relapse status in randomized patients, with TCF3::PBX1/NT5C2 linked to worse outcomes regardless of randomized arm. Together, our findings provide novel insights into the genomics of relapsed childhood B-ALL as well as in the context of blinatumomab therapy. This trial was registered at www.clinicaltrials.gov as # NCT0201853.