Page 52 - Haematologica Vol. 107 - September 2022

ARTICLE - Acute Lymphoblastic Leukemia
Genetic and genomic analysis of acute lymphoblastic leukemia in older adults reveals a distinct profile of abnormalities: analysis of 210 patients from the UKALL14 and UKALL60+ clinical trials
Thomas Creasey,1 Emilio Barretta,1 Sarra L. Ryan,1 Ellie Butler,1 Amy A. Kirkwood,2 Daniel Leongamornlert,3 Elli Papaemmanuil,4 Pip Patrick,2 Laura Clifton-Hadley,2 Bela Patel,5 Tobias Menne,6 Andrew K. McMillan,7 Christine J. Harrison,1 Clare J. Rowntree,8 Nick Morley,9 David I. Marks,10 Adele K. Fielding11 and Anthony V. Moorman1
1Leukaemia Research Cytogenetics Group, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK; 2Cancer Research UK & UCL Cancer Trials Centre, UCL Cancer Institute University College London, London, UK; 3Sanger Institute, Cambridge, UK; 4Memorial Sloan Kettering Cancer Center, New York, NY, USA; 5Department of Haematology, Queen Mary University of London, London, UK; 6Northern Centre for Cancer Care, Newcastle-upon-Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK; 7Department of Haematology, Nottingham University Hospitals NHS Trust, Nottingham, UK; 8Department of Haematology, Cardiff and Vale University Health Board, Cardiff, UK; 9Department of Haematology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK; 10Department of Haematology, University Hospitals Bristol and Weston NHS Foundation Trust, Bristol, UK and 11UCL Cancer Institute, University College London, London, UK
Abstract
Despite being predominantly a childhood disease, the incidence of acute lymphoblastic leukemia (ALL) has a second peak in adults aged 60 years and over. These older adults fare extremely poorly with existing treatment strategies and very few studies have undertaken a comprehensive genetic and genomic characterization to improve prognosis in this age group. We performed cytogenetic, single nucleotide polymorphism (SNP) array and next-generation sequencing (NGS) analyses on samples from 210 patients aged ≥60 years from the UKALL14 and UKALL60+ clinical trials. BCR-ABL1-positive disease was present in 26% (55/210) of patients, followed by low hypodiploidy/near triploidy in 13% (28/210). Cytogenetically cryptic rearrangements in CRLF2, ZNF384 and MEF2D were detected in 5%, 1% and <1% of patients, respectively. Copy number abnormalities were common and deletions in ALL driver genes were seen in 77% of cases. IKZF1 deletion was present in 51% (40/78) of samples tested and the IKZF1plus profile was identified in over a third (28/77) of cases of B-cell precursor ALL. The genetic good-risk abnormalities high hyperdiploidy (n=2), ETV6-RUNX1 (no cases) and ERG deletion (no cases) were exceptionally rare in this cohort. RAS pathway mutations were seen in 17% (4/23) of screened samples. KDM6A abnormalities, including biallelic deletions, were discovered in 5% (4/78) of SNP arrays and 9% (2/23) of NGS samples, and represent novel, potentially therapeutically actionable lesions using EZH2 inhibitors. Outcome remained poor with 5-year event-free and overall survival rates of 17% and 24%, respectively, across the cohort, indicating a need for novel therapeutic strategies.
Correspondence:
T. Creasey
tom.creasey@ncl.ac.uk
A.V. Moorman
anthony.moorman@ncl.ac.uk
Received: Accepted: Prepublished:
May 17, 2021. September 9, 2021. November 18, 2021.
https://doi.org/10.3324/haematol.2021.279177
©2022 Ferrata Storti Foundation Published under a CC-BY-NC license
Introduction
Acute lymphoblastic leukemia (ALL) presents most com- monly in early childhood.1 However, the disease has a bi- modal incidence with a second smaller peak in adults aged 60 years old and over.2 Optimal care of these older adults (≥60 years) remains an area of unmet clinical need. Although they account for only 30-35% of diag- noses each year in adults, around 60% of disease-related deaths occur within this age group, and they are the only ALL patients not to have benefitted from the stepwise
improvements in prognosis driven through successive clinical trials in children and younger adults.2,3
Primary chromosomal abnormalities are one of the hall- marks of ALL and greatly influence treatment decisions and prognosis.4,5 Although BCR-ABL1 is well recognized as the most common genetic subgroup in adult ALL,5 to date, only limited biological characterization of older pa- tients beyond the conventionally defined risk groups has been performed. One recent study provided a compre- hensive genomic profile of 1,988 subjects with B-cell precursor (BCP)-ALL using a combination of transcrip-
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