Despite the well-established adverse impact of del(11q) in chronic lymphocytic leukemia (CLL), the prognostic significance of somatic ATM mutations remains uncertain. We evaluated the effects of ATM aberrations (del(11q) and/or ATM mutations) on time-to-first-treatment (TTFT) in 3631 untreated patients with CLL, in the context of IGHV gene mutational status and mutations in nine CLL-related genes. ATM mutations were present in 246 cases (6.8%), frequently co-occurring with del(11q) (112/246 cases, 45.5%). ATM-mutated patients displayed a different spectrum of genetic abnormalities when comparing IGHV-mutated (M-CLL) and unmutated (U-CLL) cases: M-CLL was enriched for SF3B1 and NFKBIE mutations, whereas U-CLL showed mutual exclusivity with trisomy 12 and TP53 mutations. Isolated ATM mutations were rare, affecting 1.2% of Binet A patients and <1% of M-CLL cases. While univariable analysis revealed shorter TTFT for Binet A patients with any ATM aberration compared to ATM-wildtype, multivariable analysis identified only del(11q), trisomy 12, SF3B1, and EGR2 mutations as independent prognosticators of shorter TTFT among Binet A patients and within M-CLL and U-CLL subgroups. These findings highlight del(11q), and not ATM mutations, as a key biomarker of increased risk of early progression and need for therapy, particularly in otherwise indolent M-CLL, providing insights into risk-stratification and therapeutic decision-making.

Cancer Genomics School for Cancer Sciences Faculty of Medicine University of Southampton Southampton UK

Cancer Research Center CSIC University of Salamanca Salamanca Spain

Central European Institute of Technology Masaryk University Brno Czech Republic

Centre for Research and Technology Hellas Institute of Applied Biosciences Thessaloniki Greece

Centro de Investigación Biomédica en Red de Cáncer Madrid Spain

Clinic of Hematology Oncology Institute of Southern Switzerland Ente Ospedaliero Cantonale Bellinzona Switzerland

Clinical Epidemiology Division Department of Medicine Solna Karolinska Institutet Stockholm Sweden

Clinical Genetics and Genomics Karolinska University Hospital Solna Sweden

Department of Biochemistry and Molecular Biology Pharmacy School Universidad Complutense de Madrid Madrid Spain

Department of Clinical Medicine University of Copenhagen Copenhagen Denmark

Department of Hematology Danish Cancer Institute Copenhagen Denmark

Department of Hematology Hospital Universitari Vall d'Hebron Department of Medicine Universitat Autònoma de Barcelona Barcelona Spain

Department of Hematology INCLIVA Research Insitute University of Valencia Valencia Spain

Department of Hematology Oncology and Cancer Immunology Charité Universitätsmedizin Berlin corporate member of Freie Universität Berlin Hum boldt Universität zu Berlin Berlin Germany

Department of Hematology Rigshospitalet Copenhagen University Hospital Copenhagen Denmark

Department of Hematology University Hospital of Salamanca Salamanca Spain

Department of Immunology Genetics and Pathology Uppsala University Uppsala Sweden

Department of Internal Medicine Hematology and Oncology University Hospital Brno Brno Czech Republic

Department of Molecular Medicine and Surgery Karolinska Institutet Stockholm Sweden

Department of Oncology and Haematology University Hospital and University of Zurich Zurich Switzerland

Division of Hematology Department of Translational Medicine University of Eastern Piedmont Novara Italy

Faculty of Medicine Masaryk University Brno Czech Republic

Hematological Diseases Laboratory CIMA LAB Diagnostics University of Navarra 31008 Pamplona Spain IdiSNA Navarra Institute for Health Research 31008 Pamplona Spain

Hematology Department of Medical Sciences University of Ferrara Ferrara Italy

Hospital Clínic of Barcelona Barcelona Spain

Hospital Universitario 12 Octubre Madrid Spain

Institut d'Investigacions Biomèdiques August Pi 1 Sunyer Barcelona Spain

Instituto de Investigación Biomédica Salamanca Spain

IRCCS Ospedale San Raffaele Milano Italy

Laboratory of Experimental Hematology Institute of Oncology Research Universita' della Svizzera Italiana Bellinzona Switzerland

MLL Munich Leukemia Laboratory Munich Germany

Molecular Cytogenetics Laboratory Pathology Department Hospital del Mar and Translational Research on Hematological Neoplasms Group Hospital del Mar Research Institute Barcelona Spain

Molecular Pathology Department University Hospitals Dorset Bournemouth UK

Service d'hématologie biologique Hôpital Avicenne Assistance Publique des Hôpitaux de Paris Bobigny France Bobigny France

Sorbonne Université Service d'Hématologie Biologique Hôpital Pitié Salpêtrière APHP Paris France

Spanish National Cancer Research Madrid Spain

Università Vita Salute San Raffaele Milano Italy

Universitat de Barcelona Barcelona Spain

Zobrazit více v PubMed

Lee J-H, Paull TT. Cellular functions of the protein kinase ATM and their relevance to human disease. Nat Rev Mol Cell Biol. 2021;22:796–814. PubMed

Puente XS, Beà S, Valdés-Mas R, Villamor N, Gutiérrez-Abril J, Martín-Subero JI, et al. Non-coding recurrent mutations in chronic lymphocytic leukaemia. Nature. 2015;526:519–24. PubMed

Landau DA, Tausch E, Taylor-Weiner AN, Stewart C, Reiter JG, Bahlo J, et al. Mutations driving CLL and their evolution in progression and relapse. Nature. 2015;526:525–30. PubMed PMC

Nadeu F, Delgado J, Royo C, Baumann T, Stankovic T, Pinyol M, et al. Clinical impact of clonal and subclonal TP53, SF3B1, BIRC3, NOTCH1, and ATM mutations in chronic lymphocytic leukemia. Blood. 2016;127:2122–30. PubMed PMC

Knisbacher BA, Lin Z, Hahn CK, Nadeu F, Duran-Ferrer M, Stevenson KE, et al. Molecular map of chronic lymphocytic leukemia and its impact on outcome. Nat Genet. 2022;54:1664–74. PubMed PMC

Robbe P, Ridout KE, Vavoulis DV, Dréau H, Kinnersley B, Denny N, et al. Whole-genome sequencing of chronic lymphocytic leukemia identifies subgroups with distinct biological and clinical features. Nat Genet. 2022;54:1675–89. PubMed PMC

Skowronska A, Parker A, Ahmed G, Oldreive C, Davis Z, Richards S, et al. Biallelic ATM inactivation significantly reduces survival in patients treated on the United Kingdom Leukemia Research Fund Chronic Lymphocytic Leukemia 4 trial. J Clin Oncol. 2012;30:4524–32. PubMed

Gunnarsson R, Isaksson A, Mansouri M, Goransson H, Jansson M, Cahill N, et al. Large but not small copy-number alterations correlate to high-risk genomic aberrations and survival in chronic lymphocytic leukemia: a high-resolution genomic screening of newly diagnosed patients. Leukemia. 2010;24:211–5. PubMed

Gunnarsson R, Mansouri L, Isaksson A, Göransson H, Cahill N, Jansson M, et al. Array-based genomic screening at diagnosis and during follow-up in chronic lymphocytic leukemia. Haematologica. 2011;96:1161–9. PubMed PMC

Goy J, Gillan TL, Bruyere H, Huang SJT, Hrynchak M, Karsan A, et al. Chronic lymphocytic leukemia patients with deletion 11q have a short time to requirement of first-line therapy, but long overall survival: results of a population-based cohort in British Columbia, Canada. Clin Lymphoma Myeloma Leuk. 2017;17:382–9. PubMed

Dohner H, Stilgenbauer S, Benner A, Leupolt E, Krober A, Bullinger L, et al. Genomic aberrations and survival in chronic lymphocytic leukemia. N. Engl J Med. 2000;343:1910–6. PubMed

Van Dyke DL, Werner L, Rassenti LZ, Neuberg D, Ghia E, Heerema NA, et al. The Dohner fluorescence in situ hybridization prognostic classification of chronic lymphocytic leukaemia (CLL): The CLL Research Consortium experience. Br J Haematol. 2016;173:105–13. PubMed PMC

Dohner H, Stilgenbauer S, James MR, Benner A, Weilguni T, Bentz M, et al. 11q deletions identify a new subset of B-cell chronic lymphocytic leukemia characterized by extensive nodal involvement and inferior prognosis. Blood. 1997;89:2516–22. PubMed

Stilgenbauer S, Bullinger L, Lichter P, Dohner H. Genetics of chronic lymphocytic leukemia: genomic aberrations and V(H) gene mutation status in pathogenesis and clinical course. Leukemia. 2002;16:993–1007. PubMed

Stankovic T, Skowronska A. The role of ATM mutations and 11q deletions in disease progression in chronic lymphocytic leukemia. Leuk Lymphoma. 2014;55:1227–39. PubMed

Wierda WG, O’Brien S, Wang X, Faderl S, Ferrajoli A, Do KA, et al. Multivariable model for time to first treatment in patients with chronic lymphocytic leukemia. J Clin Oncol. 2011;29:4088. PubMed PMC

Blakemore SJ, Clifford R, Parker H, Antoniou P, Stec-Dziedzic E, Larrayoz M, et al. Clinical significance of TP53, BIRC3, ATM and MAPK-ERK genes in chronic lymphocytic leukaemia: data from the randomised UK LRF CLL4 trial. Leukemia. 2020;34:1760–74. PubMed PMC

Austen B, Powell JE, Alvi A, Edwards I, Hooper L, Starczynski J, et al. Mutations in the ATM gene lead to impaired overall and treatment-free survival that is independent of IGVH mutation status in patients with B-CLL. Blood. 2005;106:3175–82. PubMed

Nadeu F, Clot G, Delgado J, Martín-García D, Baumann T, Salaverria I, et al. Clinical impact of the subclonal architecture and mutational complexity in chronic lymphocytic leukemia. Leukemia. 2018;32:645–53. PubMed PMC

Nguyen‐Khac F, Baron M, Guièze R, Feugier P, Fayault A, Raynaud S, et al. Prognostic impact of genetic abnormalities in 536 first‐line chronic lymphocytic leukaemia patients without 17p deletion treated with chemoimmunotherapy in two prospective trials: Focus on IGHV‐mutated subgroups (a FILO study). Br J Haematol. 2024;205:495–502. PubMed

Hu B, Patel KP, Chen HC, Wang X, Luthra R, Routbort MJ, et al. Association of gene mutations with time-to-first treatment in 384 treatment-naive chronic lymphocytic leukaemia patients. Br J Haematol. 2019;187:307–18. PubMed

Mansouri L, Thorvaldsdottir B, Sutton LA, Karakatsoulis G, Meggendorfer M, Parker H, et al. Different prognostic impact of recurrent gene mutations in chronic lymphocytic leukemia depending on IGHV gene somatic hypermutation status: a study by ERIC in HARMONY. Leukemia. 2023;37:339–47. PubMed PMC

Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Döhner H, et al. iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL. Blood. 2018;131:2745–60. PubMed

Chen S, Francioli LC, Goodrich JK, Collins RL, Kanai M, Wang Q, et al. A genomic mutational constraint map using variation in 76,156 human genomes. Nature. 2023;625:92–100. PubMed PMC

Landrum MJ, Lee JM, Riley GR, Jang W, Rubinstein WS, Church DM, et al. ClinVar: Public archive of relationships among sequence variation and human phenotype. Nucleic Acids Res. 2014;42:D980–D985. PubMed PMC

Chakravarty D, Gao J, Phillips S, Kundra R, Zhang H, Wang J, et al. OncoKB: a precision oncology knowledge base. JCO Precis Oncol. 2017;2017:1–16. PubMed PMC

Suehnholz SP, Nissan MH, Zhang H, Kundra R, Nandakumar S, Lu C, et al. Quantifying the expanding landscape of clinical actionability for patients with cancer. Cancer Discov. 2024;14:49–65. PubMed PMC

Cheng J, Novati G, Pan J, Bycroft C, Žemgulytė A, Applebaum T, et al. Accurate proteome-wide missense variant effect prediction with AlphaMissense. Science. 2023;381:eadg7492. PubMed

Sc HubacHM, Maass T, Nazaretyan L, Röner S, Tin KirCHerM. CADD v1.7: using protein language models, regulatory CNNs and other nucleotide-level scores to improve genome-wide v ar iant predictions. Nucleic Acids Res. 2024;52:1143–54. PubMed PMC

Lampson BL, Gupta A, Tyekucheva S, Mashima K, Petráčková A, Wang Z, et al. Rare germline ATM variants influence the development of chronic lymphocytic leukemia. J Clin Oncol. 2023;41:1116–28. PubMed PMC

Tiao G, Improgo MR, Kasar S, Poh W, Kamburov A, Landau DA, et al. Rare germline variants in ATM are associated with chronic lymphocytic leukemia. Leukemia. 2017;31:2244–7. PubMed PMC

Rosenquist R, Ghia P, Hadzidimitriou A, Sutton L-A, Agathangelidis A, Baliakas P, et al. Immunoglobulin gene sequence analysis in chronic lymphocytic leukemia: updated ERIC recommendations. Leukemia. 2017;31:1477–81. PubMed PMC

Agathangelidis A, Chatzidimitriou A, Chatzikonstantinou T, Tresoldi C, Davis Z, Giudicelli V, et al. Immunoglobulin gene sequence analysis in chronic lymphocytic leukemia: the 2022 update of the recommendations by ERIC, the European Research Initiative on CLL. Leukemia. 2022;36:1961. PubMed PMC

R Core Team. R: A language and environment for statistical computing. 2024. https://www.R-project.org/ (accessed 31 Oct2024).

Posit team. RStudio: Integrated Development Environment for R. 2024. http://www.posit.co/ (accessed 31 Oct2024).

Mayakonda A, Lin DC, Assenov Y, Plass C, Koeffler HP. Maftools: efficient and comprehensive analysis of somatic variants in cancer. Genome Res. 2018;28:1747–56. PubMed PMC

Edelmann J, Holzmann K, Miller F, Winkler D, Bühler A, Zenz T, et al. High-resolution genomic profiling of chronic lymphocytic leukemia reveals new recurrent genomic alterations. Blood. 2012;120:4783–94. PubMed

Barone G, Groom A, Reiman A, Srinivasan V, Byrd PJ, Taylor AMR. Modeling ATM mutant proteins from missense changes confirms retained kinase activity. Hum Mutat. 2009;30:1222–30. PubMed

Navrkalova V, Sebejova L, Zemanova J, Kminkova J, Kubesova B, Malcikova J, et al. ATM mutations uniformly lead to ATM dysfunction in chronic lymphocytic leukemia: application of functional test using doxorubicin. Haematologica. 2013;98:1124–31. PubMed PMC

Austen B, Skowronska A, Baker C, Powell JE, Gardiner A, Oscier D, et al. Mutation status of the residual ATM allele is an important determinant of the cellular response to chemotherapy and survival in patients with chronic lymphocytic leukemia containing an 11q deletion. J Clin Oncol. 2007;25:5448–57. PubMed

Yin S, Gambe RG, Sun J, Martinez AZ, Cartun ZJ, Regis FFD, et al. A murine model of chronic lymphocytic leukemia based on B cell-restricted expression of Sf3b1 mutation and Atm deletion. Cancer Cell. 2019;35:283–296.e5. PubMed PMC

Zenz T, Krober A, Scherer K, Habe S, Buhler A, Benner A, et al. Monoallelic TP53 inactivation is associated with poor prognosis in chronic lymphocytic leukemia: results from a detailed genetic characterization with long-term follow-up. Blood. 2008;112:3322–9. PubMed

Chatzikonstantinou T, Scarfò L, Karakatsoulis G, Minga E, Chamou D, Iacoboni G, et al. Other malignancies in the history of CLL: an international multicenter study conducted by ERIC, the European Research Initiative on CLL, in HARMONY. EClinicalMedicine. 2023;65:102307. PubMed PMC

Parikh SA, Rabe KG, Kay NE, Call TG, Ding W, Schwager SM, et al. Chronic lymphocytic leukemia in young (≤ 55 years) patients: a comprehensive analysis of prognostic factors and outcomes. Haematologica. 2014;99:140–7. PubMed PMC

Schlosser P, Schiwitza A, Klaus J, Hieke-Schulz S, vel Szic KS, Duyster J, et al. Conditional survival to assess prognosis in patients with chronic lymphocytic leukemia. Ann Hematol. 2024;103:1613–22. PubMed PMC

Kipps TJ, Fraser G, Coutre SE, Brown JR, Barrientos JC, Barr PM, et al. Long-term studies assessing outcomes of ibrutinib therapy in patients with Del(11q) Chronic lymphocytic leukemia. Clin Lymphoma Myeloma Leuk. 2019;19:715–722.e6. PubMed

Burger JA, Barr PM, Robak T, Owen C, Ghia P, Tedeschi A, et al. Long-term efficacy and safety of first-line ibrutinib treatment for patients with CLL/SLL: 5 years of follow-up from the phase 3 RESONATE-2 study. Leukemia. 2020;34:787. PubMed PMC

Barr PM, Owen C, Robak T, Tedeschi A, Bairey O, Burger JA, et al. Up to 8-year follow-up from RESONATE-2: first-line ibrutinib treatment for patients with chronic lymphocytic leukemia. Blood Adv. 2022;6:3440. PubMed PMC

Seymour JF, Kipps TJ, Eichhorst BF, D’Rozario J, Owen CJ, Assouline S, et al. Enduring undetectable MRD and updated outcomes in relapsed/refractory CLL after fixed-duration venetoclax-rituximab. Blood. 2022;140:839. PubMed PMC