TY - JOUR
T1 - Molecular classification improves risk assessment in adult BCR-ABL1–negative B-ALL
AU - Paietta, Elisabeth
AU - Roberts, Kathryn G.
AU - Wang, Victoria
AU - Gu, Zhaohui
AU - Buck, Georgina A.N.
AU - Pei, Deqing
AU - Cheng, Cheng
AU - Levine, Ross L.
AU - Abdel-Wahab, Omar
AU - Cheng, Zhongshan
AU - Wu, Gang
AU - Qu, Chunxu
AU - Shi, Lei
AU - Pounds, Stanley
AU - Willman, Cheryl L.
AU - Harvey, Richard
AU - Racevskis, Janis
AU - Barinka, Jan
AU - Zhang, Yanming
AU - Dewald, Gordon W.
AU - Ketterling, Rhett Patrick
AU - Alejos, David
AU - Lazarus, Hillard M.
AU - Luger, Selina M.
AU - Foroni, Letizia
AU - Patel, Bela
AU - Fielding, Adele K.
AU - Melnick, Ari
AU - Marks, David I.
AU - Moorman, Anthony V.
AU - Wiernik, Peter H.
AU - Rowe, Jacob M.
AU - Tallman, Martin S.
AU - Goldstone, Anthony H.
AU - Mullighan, Charles G.
AU - Litzow, Mark R.
N1 - Funding Information:
This study was conducted, in part, by the ECOG-ACRIN Cancer Research Group (Peter J. O'Dwyer and Mitchell D. Schnall, Group Cochairs) and supported by the National Institutes of Health (NIH) National Cancer Institute under the following award numbers: U10CA180820, U10CA180794, UG1CA189859, UG1CA232760, UG1CA233234, and UG1CA233290. The authors acknowledge the support of Memorial Sloan Kettering Cancer Center Support Grant NIH P30 CA008748. This work was further supported by NIH National Cancer Institute R35 CA197695 and P30 CA021765 (C.G.M.), R01 CA198089 (A.M.), P30 CA118100-15 (C.L.W.), R50 CA211-542-04 (R.H.), UG1 CA233332 (O.A.-W. and R.L.L.), Leukemia Lymphoma Society SCOR 7013-17 (A.M.), the NIH National Institute of General Medical Sciences P50 GM115279 (C.G.M.), the American Lebanese Syrian Associated Charities of St Jude Children's Research Hospital (C.G.M.), Blood Cancer UK 15036 (A.V.M.), 15009 (B.P.), and Cancer Research UK C27995/A21019 (A.V.M. and A.K.F.). The authors acknowledge data provided by Foundation Medicine (Cambridge, MA), which were previously published.
Funding Information:
This study was conducted, in part, by the ECOG-ACRIN Cancer Research Group (Peter J. O'Dwyer and Mitchell D. Schnall, Group Cochairs) and supported by the National Institutes of Health (NIH) National Cancer Institute under the following award numbers: U10CA180820, U10CA180794, UG1CA189859, UG1CA232760, UG1CA233234, and UG1CA233290. The authors acknowledge the support of Memorial Sloan Kettering Cancer Center Support Grant NIH P30 CA008748. This work was further supported by NIH National Cancer Institute R35 CA197695 and P30 CA021765 (C.G.M.), R01 CA198089 (A.M.), P30 CA118100-15 (C.L.W.), R50 CA211-542-04 (R.H.), UG1 CA233332 (O.A.-W. and R.L.L.), Leukemia Lymphoma Society SCOR 7013-17 (A.M.), the NIH National Institute of General Medical Sciences P50 GM115279 (C.G.M.), the American Lebanese Syrian Associated Charities of St Jude Children's Research Hospital (C.G.M.), Blood Cancer UK 15036 (A.V.M.), 15009 (B.P.), and Cancer Research UK C27995/A21019 (A.V.M. and A.K.F.). The authors acknowledge data provided by Foundation Medicine (Cambridge, MA), which were previously published. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Mention of trade names, commercial products, or organizations does not imply endorsement by the US government.
Publisher Copyright:
© 2021 American Society of Hematology
PY - 2021/9/16
Y1 - 2021/9/16
N2 - 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.
AB - 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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U2 - 10.1182/blood.2020010144
DO - 10.1182/blood.2020010144
M3 - Article
C2 - 33895809
AN - SCOPUS:85113347637
SN - 0006-4971
VL - 138
SP - 948
EP - 958
JO - Blood
JF - Blood
IS - 11
ER -