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.

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Journal
Blood
Published
2026-11-02
DOI
https://doi.org/10.1182/blood.2025032369
Primary Topic
Acute Lymphoblastic Leukemia research
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article
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article

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

Patrick Andrew Brown, Karen R. Rabin, Mignon L. Loh, Lingyun Ji et al.
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Blood
Acute Lymphoblastic Leukemia research
article

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

Patrick Andrew Brown, Karen R. Rabin, Mignon L. Loh, Lingyun Ji, Scott G. Foy, Monta Brīvība, Stephen P. Hunger, Mary Shago, John B. Easton, David T. Teachey, Deepa Bhojwani, Heather L. Mulder, Daniel K. Putnam, Teena Bhatla, Samuel W. Brady, Charles Grenfell Mullighan, Yanling Liu, Wenan Chen, Stanley B Pounds, Ti‐Cheng Chang, Andrew J. Carroll, Emily M. Plyler, William L. Carroll, Laura E. Hogan, Pandurang S. Kolekar, Andrea McBride, Christian Deardorff, Xiang 'Anthony' Chen, Quang Tran, Zhikai Liang, Yuan Feng, Xiaotu Ma, Hanxia Li, Alexandra Stellwagen, Jinghui Zhang, Li Fan, Alexis Eckert, Tyler Jones, Gang Wu, Ying Shao
article en

Abstract

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.

Blood
University of Southern California (US), Newark Beth Israel Medical Center (US), Seattle Children's Hospital (US), St. Jude Children's Research Hospital (US), Nationwide Children's Hospital (US), Mayo Clinic (US), Children's Hospital of Philadelphia (US), Children's Hospital of Los Angeles (US), University of Richmond (US), University of California, San Francisco (US), University of Washington (US), Hospital for Sick Children (CA), Stony Brook University Hospital (US), University of Alabama at Birmingham (US), NYU Langone Health (US), Stony Brook Children's Hospital (US), National Institute of Research and Innovation (LV), New York University (US)
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Openalex Percentile: Top 12%
Acute Lymphoblastic Leukemia research
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