Abstract
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% and17% 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.
Publication types
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Clinical Trial, Phase III
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Comparative Study
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Randomized Controlled Trial
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Research Support, Non-U.S. Gov't
MeSH terms
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ADP-ribosyl Cyclase 1 / genetics
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Adult
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Aged
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Aged, 80 and over
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Antineoplastic Agents, Alkylating / therapeutic use
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Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
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Biomarkers, Tumor / genetics
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Chlorambucil / therapeutic use
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Chromosomes, Human, Pair 12 / genetics
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Cyclophosphamide / therapeutic use
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Education, Medical, Continuing
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Female
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Humans
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Immunoglobulin Heavy Chains / genetics
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Immunoglobulin Variable Region / genetics
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Incidence
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Leukemia, Lymphocytic, Chronic, B-Cell / drug therapy*
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Leukemia, Lymphocytic, Chronic, B-Cell / genetics*
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Leukemia, Lymphocytic, Chronic, B-Cell / mortality
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Male
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Membrane Glycoproteins / genetics
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Middle Aged
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Phosphoproteins / genetics*
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Prognosis
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RNA Splicing Factors
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Receptor, Notch1 / genetics*
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Ribonucleoprotein, U2 Small Nuclear / genetics*
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Risk Factors
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Trisomy / genetics
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Tumor Suppressor Protein p53 / genetics
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Vidarabine / analogs & derivatives
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Vidarabine / therapeutic use
Substances
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Antineoplastic Agents, Alkylating
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Biomarkers, Tumor
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Immunoglobulin Heavy Chains
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Immunoglobulin Variable Region
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Membrane Glycoproteins
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NOTCH1 protein, human
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Phosphoproteins
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RNA Splicing Factors
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Receptor, Notch1
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Ribonucleoprotein, U2 Small Nuclear
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SF3B1 protein, human
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TP53 protein, human
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Tumor Suppressor Protein p53
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Chlorambucil
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Cyclophosphamide
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CD38 protein, human
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ADP-ribosyl Cyclase 1
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Vidarabine
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fludarabine
Supplementary concepts
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Chromosome 12, 12p trisomy