Genomic drivers of leukemia and blinatumomab response in adult acute lymphoblastic leukemia - the ECOG-ACRIN E1910 study

The bispecific CD19/CD3 T-cell engaging antibody blinatumomab is efficacious in front-line therapy in B-cell acute lymphoblastic leukemia (B-ALL) but the biological determinants of response and resistance are incompletely understood. To examine the genomic determinants of outcome, we analyzed genomic and clinical data of 569 adults registered to the ECOG-ACRIN E1910 study of blinatumomab in BCR::ABL1-negative B-ALL (ClinicalTrials.gov NCT02003222). We identified 23 molecular subtypes including the high-risk subtypes BCR::ABL1 (20%), BCR::ABL1-like (18%), low hypodiploid (14%) and KMT2A-R (12%), and 267 putative driver genes. We identified a subtype characterized by CEBPA overexpression or elevated CEBPB expression due to chromosomal translocation-mediated enhancer hijacking, or insertions downstream of CEBPA that generate neoenhancers. Attainment of MRD-negativity patients after induction and intensification chemotherapy was more common in PAX5alt, TCF3::PBX1 and ZNF384-R B-ALL, and less common in BCR::ABL1-like and KMT2A-R B-ALL. Integration of genomic and clinical data suggested that the addition of blinatumomab to chemotherapy was associated with improved relapse-free and overall survival for several B-ALL subtypes, including hyperdiploid, PAX5alt, PAX5 P80R, BCR::ABL1-like JAK-STAT and KMT2A-R B-ALL, although small sample sizes for several subtypes indicate that confirmation is required. Alteration of TP53 or mutations associated with myeloid clonal hematopoiesis of indeterminate potential (CHIP) were identified in 15.3% and 9.8% of patients, respectively. The presence of these mutations was associated with older age at diagnosis and inferior outcome to chemotherapy. In summary, we define the landscape of genomic alterations of adult B-ALL, and identify genomic subtypes that may influence the efficacy of blinatumomab when combined with chemotherapy.

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Journal
Blood
Published
2026-10-05
DOI
https://doi.org/10.1182/blood.2026033793
Primary Topic
Acute Lymphoblastic Leukemia research
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article
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article

Genomic drivers of leukemia and blinatumomab response in adult acute lymphoblastic leukemia - the ECOG-ACRIN E1910 study

Martin S. Tallman, Matthew Joseph Wieduwilt, Ryan J. Mattison, Rupali Roy Bhave et al.
Blood
Acute Lymphoblastic Leukemia research
article

Genomic drivers of leukemia and blinatumomab response in adult acute lymphoblastic leukemia - the ECOG-ACRIN E1910 study

Martin S. Tallman, Matthew Joseph Wieduwilt, Ryan J. Mattison, Rupali Roy Bhave, Amit Kumar, Kristen Marie O’Dwyer, Brent Lee Wood, Selina M. Luger, Nikolai Alexandrovich Podoltsev, Qingsong Gao, Julie Bergeron, Shondra M. Pruett‐Miller, Elad Sharon, Yasser Abou Mourad, Evadnie Rampersaud, Yiping Fan, Deepa Jeyakumar, Petri Pölönen, Tara L. Lin, Pankit J. Vachhani, Hillard Michael Lazarus, Janis Racevskis, Bhavana Bhatnagar, Keith William Pratz, Kathryn G. Roberts, 钟晓明, Charles Grenfell Mullighan, Maria R. Baer, Harry Paul Erba, Richard F. Little, Ilaria Iacobucci, Cheryl L. Willman, Huimei Wei, Michelle Ann Elliott, Lindsey E. Montefiori, Shira Naomi Dinner, Jacob M. Rowe, Ti‐Cheng Chang, Daniel A. Arber, Ehab L. Atallah, Dimitrios Tzachanis, Daniel J. DeAngelo, Anjali S. Advani, Mark Robert Litzow, Michaela Liedtke, Noelle V. Frey, Aric C. Hall, Geoffrey L. Uy, Steven D. Gore, Rori Schreiber, Paul J. Shami, Zhuoxin Sun, Elizabeth Paietta, Adam Steven Asch, Richard M. Stone, Shaohua Lei, Shejal Patel, Wenchao Zhang, Yanming Zhang, Pradyumna Baviskar, Jun J Yang, Gang Wu
article en

Abstract

The bispecific CD19/CD3 T-cell engaging antibody blinatumomab is efficacious in front-line therapy in B-cell acute lymphoblastic leukemia (B-ALL) but the biological determinants of response and resistance are incompletely understood. To examine the genomic determinants of outcome, we analyzed genomic and clinical data of 569 adults registered to the ECOG-ACRIN E1910 study of blinatumomab in BCR::ABL1-negative B-ALL (ClinicalTrials.gov NCT02003222). We identified 23 molecular subtypes including the high-risk subtypes BCR::ABL1 (20%), BCR::ABL1-like (18%), low hypodiploid (14%) and KMT2A-R (12%), and 267 putative driver genes. We identified a subtype characterized by CEBPA overexpression or elevated CEBPB expression due to chromosomal translocation-mediated enhancer hijacking, or insertions downstream of CEBPA that generate neoenhancers. Attainment of MRD-negativity patients after induction and intensification chemotherapy was more common in PAX5alt, TCF3::PBX1 and ZNF384-R B-ALL, and less common in BCR::ABL1-like and KMT2A-R B-ALL. Integration of genomic and clinical data suggested that the addition of blinatumomab to chemotherapy was associated with improved relapse-free and overall survival for several B-ALL subtypes, including hyperdiploid, PAX5alt, PAX5 P80R, BCR::ABL1-like JAK-STAT and KMT2A-R B-ALL, although small sample sizes for several subtypes indicate that confirmation is required. Alteration of TP53 or mutations associated with myeloid clonal hematopoiesis of indeterminate potential (CHIP) were identified in 15.3% and 9.8% of patients, respectively. The presence of these mutations was associated with older age at diagnosis and inferior outcome to chemotherapy. In summary, we define the landscape of genomic alterations of adult B-ALL, and identify genomic subtypes that may influence the efficacy of blinatumomab when combined with chemotherapy.

Blood
Northwestern University (US), University of Maryland, Baltimore (US), St. Jude Children's Research Hospital (US), Cleveland Clinic (US), Mayo Clinic (US), Memorial Sloan Kettering Cancer Center (US), Montefiore Medical Center (US), Children's Hospital of Los Angeles (US), University of Wisconsin–Madison (US), University of Kansas (US), Duke University (US), Medical College of Wisconsin (US), Washington University in St. Louis (US), University of Utah (US), Hospital of the University of Pennsylvania (US), The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (US), Virginia Museum of History & Culture (US), Spinal Cord Injury BC (CA), Shaare Zedek Medical Center (IL), Bikur Cholim Hospital (IL), University of Rochester Medical Center (US), Hôpital Maisonneuve-Rosemont (CA), University of Alabama at Birmingham (US), Yale University (US), University of Chicago (US), University of California, Irvine Medical Center (US), BC Studies (CA), Dana-Farber Cancer Institute (US), UC Irvine Health (US), National Cancer Institute (US), Scripps Clinic (US), Children's Hospital of Richmond at VCU (US), Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Abramson Cancer Center (US), O'Neal Comprehensive Cancer Center, Wake Forest University Health Sciences (US), Wake Forest University (US), University of Oklahoma Health Sciences Center (US), University of Rochester (US), Case Western Reserve University (US), University of Pennsylvania (US), Stanford University (US)
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Acute Lymphoblastic Leukemia research
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