Journal
BLOOD
Volume 121, Issue 3, Pages 468-475Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2012-05-429282
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Funding
- Kay Kendall Leukemia Fund, Leukemia and Lymphoma Research, Cancer Research UK
- Wessex Medical Research
- Leukemia and Lymphoma Research
- Royal Marsden Hospital
- Institute of Cancer Research National Institute of Health Research Biomedical Research Center
- Dr Mildred Scheel Stiftung for Cancer Research (Bonn, Germany)
- Arbib Foundation
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NOTCH1 and SF3B1 mutations have been previously reported to have prognostic significance in chronic lymphocytic leukemia but to date they have not been validated in a prospective, controlled clinical trial. We have assessed the impact of these mutations in a cohort of 494 patients treated within the randomized phase 3 United Kingdom Leukaemia Research Fund Chronic Lymphocytic Leukemia 4 (UK LRF CCL4) trial that compared chlorambucil and fludarabine with and without cyclophosphamide in previously untreated patients. We investigated the relationship of mutations in NOTCH1 (exon 34) and SF3B1 (exon 14-16) to treatment response, survival and a panel of established biologic variables. NOTCH1 and SF3B1 mutations were found in 10% and 17% of patients, respectively. NOTCH1 mutations correlated with unmutated IGHV genes, trisomy 12, high CD38/ZAP-70 expression and were associated with reduced overall (median 54.8 vs 74.6 months, P = .02) and progression-free (median 22.0 vs 26.4 months, P = .02) survival. SF3B1 mutations were significantly associated with high CD38 expression and with shorter overall survival (median 54.3 vs 79.0 months, P <.001). Furthermore, multivariate analysis, including baseline clinical variables, treatment, and adverse prognostic factors demonstrated that although TP53 alterations remained the most informative marker of dismal survival in this cohort, NOTCH1 (HR 1.58, P = .03) and SF3B1 (HR 1.52, P = .01) mutations have added independent prognostic value. (Blood. 2013;121(3):468-475)
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