Genomic alterations associated with relapse in childhood B-ALL

Investigators performed whole-genome and transcriptome sequencing in 288 patients with childhood B-ALL enrolled in the AALL1331 clinical trial, including 183 diagnosis/first-relapse/germline trios and 105 additional first-relapse samples. They also analyzed 41 second-relapse samples. AALL1331 randomized patients to blinatumomab plus chemotherapy or chemotherapy alone.

Relapse-associated findings varied by leukemia subtype. In ETV6::RUNX1 disease, gain of the fusion allele or an ETV6 exon 5–RUNX1 exon 4 transcript was associated with higher first-relapse risk than the exon 5–exon 3 transcript. Hyperdiploid cases with 51–52 chromosomes were more prone to first relapse than those with at least 53 chromosomes, with an additive association for CREBBP mutations. IKZF1 alterations were enriched in Philadelphia-like disease, while NSD2 E1099K was commonly associated with relapse in TCF3::PBX1. These features accounted for 30% of first relapses (55 cases); about 3% were attributed to secondary B-ALL or germline predisposition. TCF3::PBX1/NT5C2 was linked to worse outcomes regardless of randomized treatment arm.

The findings characterize relapse-associated genomic features but do not establish a change in treatment or provide evidence that these markers improve clinical outcomes when used to guide care.