title: The clinical significance of NOTCH1 and SF3B1 mutations in the UK LRF CLL4 trial.
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.
authors.affiliation: Department of Molecular Pathology, Royal Bournemouth Hospital, Bournemouth, United Kingdom.
authors.forename: David G
authors.initials: DG
authors.lastname: Oscier
authors.forename: Matthew J J
authors.initials: MJ
authors.lastname: Rose-Zerilli
authors.forename: Nils
authors.initials: N
authors.lastname: Winkelmann
authors.forename: David
authors.initials: D
authors.lastname: Gonzalez de Castro
authors.forename: Belen
authors.initials: B
authors.lastname: Gomez
authors.forename: Jade
authors.initials: J
authors.lastname: Forster
authors.forename: Helen
authors.initials: H
authors.lastname: Parker
authors.forename: Anton
authors.initials: A
authors.lastname: Parker
authors.forename: Anne
authors.initials: A
authors.lastname: Gardiner
authors.forename: Andrew
authors.initials: A
authors.lastname: Collins
authors.forename: Monica
authors.initials: M
authors.lastname: Else
authors.forename: Nicholas C P
authors.initials: NC
authors.lastname: Cross
authors.forename: Daniel
authors.initials: D
authors.lastname: Catovsky
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Strefford
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000235:genetics; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000235:genetics; D002699:Chlorambucil / Q000627:therapeutic use; D002881:Chromosomes, Human, Pair 12 / Q000235:genetics; D003520:Cyclophosphamide / Q000627:therapeutic use; D004502:Education, Medical, Continuing; D005260:Female; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D007135:Immunoglobulin Variable Region / Q000235:genetics; D015994:Incidence; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics; D008875:Middle Aged; D010750:Phosphoproteins / Q000235:genetics*; D011379:Prognosis; D000072260:RNA Splicing Factors; D051881:Receptor, Notch1 / Q000235:genetics*; D017413:Ribonucleoprotein, U2 Small Nuclear / Q000235:genetics*; D012307:Risk Factors; D014314:Trisomy / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D014740:Vidarabine / Q000031:analogs & derivatives / Q000627:therapeutic use
chemical_list: D018906:Antineoplastic Agents, Alkylating; D014408:Biomarkers, Tumor; D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region; D008562:Membrane Glycoproteins; C497761:NOTCH1 protein, human; D010750:Phosphoproteins; D000072260:RNA Splicing Factors; D051881:Receptor, Notch1; D017413:Ribonucleoprotein, U2 Small Nuclear; C112491:SF3B1 protein, human; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D002699:Chlorambucil; D003520:Cyclophosphamide; C498154:CD38 protein, human; D051997:ADP-ribosyl Cyclase 1; D014740:Vidarabine; C024352:fludarabine