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<p>Despite the well-established adverse impact of del(11q) in chronic lymphocytic leukemia (CLL), the prognostic significance of somatic <i>ATM</i> mutations remains uncertain. We evaluated the effects of <i>ATM</i> aberrations (del(11q) and/or <i>ATM</i> 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. <i>ATM</i> mutations were present in 246 cases (6.8%), frequently co-occurring with del(11q) (112/246 cases, 45.5%). <i>ATM</i>-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 <i>SF3B1</i> and <i>NFKBIE</i> mutations, whereas U-CLL showed mutual exclusivity with trisomy 12 and <i>TP53</i> mutations. Isolated <i>ATM</i> mutations were rare, affecting 1.2% of Binet A patients and &lt;1% of M-CLL cases. While univariable analysis revealed shorter TTFT for Binet A patients with any <i>ATM</i> aberration compared to <i>ATM</i>-wildtype, multivariable analysis identified only del(11q), trisomy 12, <i>SF3B1</i>, and <i>EGR2</i> 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 <i>ATM</i> 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.</p>

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ATM aberrations in chronic lymphocytic leukemia: del(11q) rather than ATM mutations is an adverse-prognostic biomarker

  • 期刊论文

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  • 发表日期：

    2025年4月24日

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  • Birna Thorvaldsdottir,
  • Larry Mansouri,
  • Lesley-Ann Sutton,
  • Ferran Nadeu,
  • Manja Meggendorfer,
  • Helen Parker,
  • Christian Brieghel,
  • Stamatia Laidou,
  • Riccardo Moia,
  • Davide Rossi,
  • Jana Kotaskova,
  • Julio Delgado,
  • Ana E. Rodríguez-Vicente,
  • Rocío Benito,
  • Gian Matteo Rigolin,
  • Silvia Bonfiglio,
  • Lydia Scarfò,
  • Mattias Mattsson,
  • Zadie Davis,
  • Panagiotis Baliakas,
  • Inmaculada Rapado,
  • Fatima Miras,
  • Joaquín Martinez-Lopez,
  • Javier de la Serna,
  • Jesús María Hernández Rivas,
  • María José Larráyoz,
  • María José Calasanz,
  • Karin E. Smedby,
  • Blanca Espinet,
  • Anna Puiggros,
  • Lars Bullinger,
  • Francesc Bosch,
  • Bárbara Tazón-Vega,
  • Fanny Baran-Marszak,
  • David Oscier,
  • Florence Nguyen-Khac,
  • Thorsten Zenz,
  • Maria Jose Terol,
  • Antonio Cuneo,
  • María Hernández-Sánchez,
  • Sarka Pospisilova,
  • Gianluca Gaidano,
  • Carsten U. Niemann,
  • Elias Campo,
  • Jonathan C. Strefford,
  • Paolo Ghia,
  • Kostas Stamatopoulos,
  • Richard Rosenquist

摘要

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.