Page 62 - Haematologica Vol. 107 - September 2022

ARTICLE - Genetic abnormalities in older ALL patients
T. Creasey et al.
pressor function through KDM6A abnormalities dispropor- tionately affects males and has been postulated to explain the skewed gender distribution of T-ALL. To our knowl- edge, our study is the first to demonstrate KDM6A dis- ruption in a significant proportion of older adults with ALL, most of whom had B-cell disease. Most interestingly, we have highlighted homozygous KDM6A deletions in female patients, and no evidence of skewed gender distribution. Loss of KDM6A function, resulting in EZH2 overactivity, has been shown to play an important pathogenic role in urothelial bladder cancer45 and functional analyses have demonstrated susceptibility of KDM6A-null cell lines to the Food and Drug Administration-approved EZH2 in- hibitor tazemetostat.45 Our findings therefore identify a proportion of patients who may respond to EZH2 in- hibition, a treatment as yet untested in ALL.
We also discovered recurrent small focal intragenic dele- tions in LEMD3 in 6% (5/78) of cases. LEMD3 regulates bone morphogenic protein and transforming growth factor b signaling and to date has not been implicated in cancer.46 The significance of these deletions remains spe- culative, particularly as some were confined to introns. Recurrent RAS pathway mutations were identified in al- most one fifth of patients (4/23), all of whom had BCR- ABL1-negative ALL. These activate RAS signaling and are potentially therapeutically actionable through MEK in- hibition (e.g., with selumetinib).
Older adults with ALL fare extremely poorly with current chemotherapeutic approaches. Various studies have dem- onstrated the disproportionate treatment toxicities ex- perienced by this group of patients, leading to treatment omissions or delays.20 Our analysis confirms the additional challenges posed by the high proportion of poor-risk gen- etic subgroups. Moving forward, the comprehensive identification of druggable targets such as KDM6A abnor- malities, JAK-STAT-activating rearrangements or RAS pathway mutations presents an opportunity to expand therapeutic options, likely to most benefit this patient population. As a paradigm, significant progress has been made in the management of BCR-ABL1-positive disease through these approaches, culminating in a promising chemotherapy-free protocol.47 Further dedicated clinical trials that include comprehensive genomic profiling of
References
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older adults, combined with targeted treatments and/or immunotherapy and a reduction in the traditional chemo- therapy backbone will be key to improving the dismal out- come of these patients.
Disclosures
TC was supported by grants from the NIHR Newcastle Bio- medical Research Centre and Bright Red. The UKALL14 and UKALL60+ trials were coordinated by the Cancer Research UK (CRUK) & UCL Cancer Trials Centre and funded by CRUK (C27995/A9609 and C27995/A13920, respectively). The UKALL60+ trial was also supported by an educational grant from Jazz Pharmaceuticals UK Ltd. This study was sup- ported by research grants from Cancer Research UK (AVM and AKF) and Blood Cancer UK (AVM and CJH).
Contributions
TC and AVM designed the study. TC, AVM, EB and EB col- lected and assembled the data. TC, AVM, EB, EB and SLR performed data analysis and interpretation. CJH and AVM were responsible for administrative support. AKF was chief investigator of the UKALL14 and UKALL60+ clinical trials. AAK, DL, EP, PP, LCH, BP, TM, AKM, CJR, NM, DIM, and AKF participated in recruitment of patients and provided study materials. TC and AVM developed the first drafts of the manuscript. All authors contributed to the review and amendments of the manuscript and approved the final ver- sion for submission.
Acknowledgments
The authors thank all the participating sites, local investi- gators and research teams for their ongoing participation in the study, together with patients who took part in these trials as well as their families. We acknowledge the input of all the scientists and technicians working in the adult ALL MRD laboratory based at UCL. We thank the member laboratories of the UK Cancer Cytogenetic Group for cyto- genetic data and material.
Data-sharing statement
The datasets generated or analyzed during the current study are available in the Online Supplementary Material or from the corresponding author on reasonable request.
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chromosomal abnormalities in childhood B-cell precursor acute lymphoblastic leukaemia: results from the UK Medical Research Council ALL97/99 randomised trial. Lancet Oncol. 2010;11(5):429-438.
5. Moorman AV, Harrison CJ, Buck GAN, et al. Karyotype is an independent prognostic factor in adult acute lymphoblastic
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