The mutational landscape of chronic lymphocytic leukemia and its impact on prognosis and treatment

被引:75
作者
Gaidano, Gianluca [1 ]
Rossi, Davide [2 ,3 ]
机构
[1] Univ Piemonte Orientale, Div Hematol, Dept Translat Med, Via Solaroli 17, I-28100 Novara, Italy
[2] Oncol Inst Southern Switzerland, Hematol, Bellinzona, Switzerland
[3] Inst Oncol Res, Bellinzona, Switzerland
基金
瑞士国家科学基金会;
关键词
PREVIOUSLY UNTREATED PATIENTS; SF3B1; MUTATIONS; OPEN-LABEL; NOTCH1; CLL-IPI; CLINICAL IMPACT; TREATMENT-NAIVE; GENE-MUTATIONS; FREE SURVIVAL; 17P DELETION;
D O I
10.1182/asheducation-2017.1.329
中图分类号
G40 [教育学];
学科分类号
040101 ; 120403 ;
摘要
The typical genome of chronic lymphocytic leukemia (CLL) carries similar to 2000 molecular lesions. Few mutations recur across patients at a frequency >5%, whereas a large number of biologically and clinically uncharacterized genes are mutated at lower frequency. Approximately 80% of CLL patients carry at least 1 of 4 common chromosomal alterations, namely deletion 1 3q14, deletion 11q22-23, deletion 17p12, and trisomy 12. Knowledge of the CLL genome has translated into the availability of molecular biomarkers for prognosis and treatment prediction. Prognostic biomarkers do not affect treatment choice, and can be integrated into, prognostic scores that are based on both clinical and biological variables. Molecular predictive biomarkers affect treatment choice, and currently include TP53 disruption by mutation and/or deletion and IGHV mutation status. TP53 disruption by gene mutation and/or deletion associates with chemoimmunotherapy failure and mandates treatment with innovative drugs, including ibrutinib, idelalisib, or venetoclax. The mutation status of IGHVgenes represents a predictive biomarker for identifying patients that may benefit the most from chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab. Assessment of these biomarkers at the time of treatment requirement is recommended by most current guidelines for CLL management Other molecular predictors are under investigation, but their application in clinical practice is premature.
引用
收藏
页码:329 / 337
页数:9
相关论文
共 73 条
[1]   Gene mutations in chronic lymphocytic leukemia [J].
Amin, Nisar A. ;
Malek, Sami N. .
SEMINARS IN ONCOLOGY, 2016, 43 (02) :215-221
[2]   The BCL2 selective inhibitor venetoclax induces rapid onset apoptosis of CLL cells in patients via a TP53-independent mechanism [J].
Anderson, Mary Ann ;
Deng, Jing ;
Seymour, John F. ;
Tam, Constantine ;
Kim, Su Young ;
Fein, Joshua ;
Yu, Lijian ;
Brown, Jennifer R. ;
Westerman, David ;
Si, Eric G. ;
Majewski, Ian J. ;
Segal, David ;
Enschede, Sari L. Heitner ;
Huang, David C. S. ;
Davids, Matthew S. ;
Letai, Anthony ;
Roberts, Andrew W. .
BLOOD, 2016, 127 (25) :3215-3224
[3]  
[Anonymous], 2016, BLOOD
[4]  
[Anonymous], BIOMED RES INT
[5]  
[Anonymous], 2015, LEUKEMIA, DOI DOI 10.1038/leu.2014.196
[6]  
[Anonymous], ASH
[7]   Biomarker: Predictive or Prognostic? [J].
Ballman, Karla V. .
JOURNAL OF CLINICAL ONCOLOGY, 2015, 33 (33) :3968-+
[8]   Ibrutinib as Initial Therapy for Patients with Chronic Lymphocytic Leukemia [J].
Burger, J. A. ;
Tedeschi, A. ;
Barr, P. M. ;
Robak, T. ;
Owen, C. ;
Ghia, P. ;
Bairey, O. ;
Hillmen, P. ;
Bartlett, N. L. ;
Li, J. ;
Simpson, D. ;
Grosicki, S. ;
Devereux, S. ;
McCarthy, H. ;
Coutre, S. ;
Quach, H. ;
Gaidano, G. ;
Maslyak, Z. ;
Stevens, D. A. ;
Janssens, A. ;
Offner, F. ;
Mayer, J. ;
O'Dwyer, M. ;
Hellmann, A. ;
Schuh, A. ;
Siddiqi, T. ;
Polliack, A. ;
Tam, C. S. ;
Suri, D. ;
Cheng, M. ;
Clow, F. ;
Styles, L. ;
James, D. F. ;
Kipps, T. J. ;
Keating, Michael ;
Jen, Jie ;
Jindra, Pavel ;
Simkovic, Martin ;
Braester, Andrei ;
Ruchlemer, Rosa ;
Foa, Roberto ;
Semenzato, Gianpietro ;
Hawkins, Timothy ;
Atanasio, Carolina Moreno ;
Demirkan, Fatih ;
Kaynar, Leylagul ;
Pylypenko, Halyna ;
Fox, Christopher ;
Thirman, Michael ;
Campbell, Philip .
NEW ENGLAND JOURNAL OF MEDICINE, 2015, 373 (25) :2425-2437
[9]   Three-year follow-up of treatment-naive and previously treated patients with CLL and SLL receiving single-agent ibrutinib [J].
Byrd, John C. ;
Furman, Richard R. ;
Coutre, Steven E. ;
Burger, Jan A. ;
Blum, Kristie A. ;
Coleman, Morton ;
Wierda, William G. ;
Jones, Jeffrey A. ;
Zhao, Weiqiang ;
Heerema, Nyla A. ;
Johnson, Amy J. ;
Shaw, Yun ;
Bilotti, Elizabeth ;
Zhou, Cathy ;
James, Danelle F. ;
O'Brien, Susan .
BLOOD, 2015, 125 (16) :2497-2506
[10]   IGHV3-21 Gene Frequency in a Swedish Cohort of Patients With Newly Diagnosed Chronic Lymphocytic Leukemia [J].
Cahill, Nicola ;
Sutton, Lesley-Ann ;
Jansson, Mattias ;
Murray, Fiona ;
Mansouri, Larry ;
Gunnarsson, Rebeqa ;
Ryan, Fergus ;
Smedby, Karin E. ;
Geisler, Christian ;
Juliusson, Gunnar ;
Rosenquist, Richard .
CLINICAL LYMPHOMA MYELOMA & LEUKEMIA, 2012, 12 (03) :201-206