Elisabeth Paietta, Department of Oncology, Montefiore Medical Center, Bronx, NY
Kathryn G. Roberts, Department of Pathology, St Jude Children's Research Hospital, Memphis, TN
Victoria Wang, Department of Data Science, Dana-Farber Cancer Institute, Boston, MA
Zhaohui Gu, Department of Pathology, St Jude Children's Research Hospital, Memphis, TN
Georgina A N Buck, Clinical Trial Service Unit, Nuttfield Department of Population Health, Oxford, United Kingdom
Deqing Pei, Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, TN
Cheng Cheng, Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, TN
Ross L. Levine, Human Oncology and Pathogenesis Program-Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
Omar Abdel-Wahab, Human Oncology and Pathogenesis Program-Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
Zhongshan Cheng, Centre for Applied Bioinformatics, St Jude Children's Research Hospital, Memphis, TN
Gang Wu, Centre for Applied Bioinformatics, St Jude Children's Research Hospital, Memphis, TN
Chunxu Qu, Department of Pathology, St Jude Children's Research Hospital, Memphis, TN
Lei Shi, Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, TN
Stanley Pounds, Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, TN
Cheryl L. Willman, University of New Mexico Comprehensive Cancer Center, Albuquerque, NM
Richard Harvey, University of New Mexico Comprehensive Cancer Center, Albuquerque, NM
Janis Racevskis, Department of Oncology, Montefiore Medical Center, Bronx, NY
Jan Barinka, Department of Pathology, St Jude Children's Research Hospital, Memphis, TN
Yanming Zhang, Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY
Gordon W. Dewald, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
Rhett P. Ketterling, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
David Alejos, Department of Oncology, Montefiore Medical Center, Bronx, NY
Hillard M. Lazarus, Department of Medicine, University Hospitals Cleveland Medical Center, Case Western Reserve University, Cleveland, OH
Selina M. Luger, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA
Letizia Foroni, Centre for Haematology, Department of Medicine, Imperial College London Hammersmith Hospital, London, United Kingdom
Bela Patel, Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom
Adele K. Fielding, UCL Cancer Institute, London, United Kingdom
Ari Melnick, Division of Hematology and Medical Oncology, Department of Medicine, Weill Medical College of Cornell University, New York, NY
David I. Marks, Bristol Haematology and Oncology Centre, Bristol, United Kingdom
Anthony V. Moorman, Leukaemia Research Cytogenetics Group, Newcastle University Translational and Clinical Research Institute, Newcastle-upon-Tyne, United Kingdom
Peter H. Wiernik, Cancer Research Foundation, Bronx, NY
Jacob M. Rowe, Department of Hematology, Shaare Zedek Medical Center, Jerusalem, Israel
Martin S. Tallman, Leukemia Service, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, NY
Anthony H. Goldstone, University College London Hospitals, London, United Kingdom
Charles G. Mullighan, Department of Pathology, St Jude Children's Research Hospital, Memphis, TN
Mark R. Litzow, Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN

Document Type

Article

Publication Date

9-16-2021

Abstract

Genomic classification has improved risk assignment of pediatric, but not adult B-lineage acute lymphoblastic leukemia (B-ALL). The international UKALLXII/ECOG-ACRIN E2993 (#NCT00002514) trial accrued 1229 adolescent/adult patients with BCR-ABL1- B-ALL (aged 14 to 65 years). Although 93% of patients achieved remission, 41% relapsed at a median of 13 months (range, 28 days to 12 years). Five-year overall survival (OS) was 42% (95% confidence interval, 39, 44). Transcriptome sequencing, gene expression profiling, cytogenetics, and fusion polymerase chain reaction enabled genomic subtyping of 282 patient samples, of which 264 were eligible for trial, accounting for 64.5% of E2993 patients. Among patients with outcome data, 29.5% with favorable outcomes (5-year OS 65% to 80%) were deemed standard risk (DUX4-rearranged [9.2%], ETV6-RUNX1/-like [2.3%], TCF3-PBX1 [6.9%], PAX5 P80R [4.1%], high-hyperdiploid [6.9%]); 50.2% had high-risk genotypes with 5-year OS of 0% to 27% (Ph-like [21.2%], KMT2A-AFF1 [12%], low-hypodiploid/near-haploid [14.3%], BCL2/MYC-rearranged [2.8%]); 20.3% had intermediate-risk genotypes with 5-year OS of 33% to 45% (PAX5alt [12.4%], ZNF384/-like [5.1%], MEF2D-rearranged [2.8%]). IKZF1 alterations occurred in 86% of Ph-like, and TP53 mutations in patients who were low-hypodiploid (54%) and BCL2/MYC-rearranged (33%) but were not independently associated with outcome. Of patients considered high risk based on presenting age and white blood cell count, 40% harbored subtype-defining genetic alterations associated with standard- or intermediate-risk outcomes. We identified distinct immunophenotypic features for DUX4-rearranged, PAX5 P80R, ZNF384-R/-like, and Ph-like genotypes. These data in a large adult B-ALL cohort treated with a non-risk-adapted approach on a single trial show the prognostic importance of genomic analyses, which may translate into future therapeutic benefits.

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