The clinical significance of NOTCH1 and SF3B1 mutations in the UK LRF CLL4 trial
Oscier, David G., Rose-Zerilli, Matthew J.J., Winkelmann, Nils, Gonzalez de Castro, David, Gomez, Belen, Forster, Jade, Parker, Helen, Parker, Anton, Gardiner, Anne, Collins, Andrew, Else, Monica, Cross, Nicholas C.P., Catovsky, Daniel and Strefford, Jonathan C. (2013) The clinical significance of NOTCH1 and SF3B1 mutations in the UK LRF CLL4 trial. Blood, 121, (3), 468-475. (doi:10.1182/blood-2012-05-429282). (PMID:23086750).
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Description/Abstract
NOTCH1 and SF3B1 mutations have been previously reported to have prognostic significance in CLL 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 III UK LRF CLL4 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 biological 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 74.6mths, P=0.02) and progression-free
(median 22.0 vs. 26.4mths, P=0.02) survival. SF3B1 mutations were significantly associated with high CD38
expression and with shorter overall survival (median 54.3 vs. 79.0mths, P<0.001). Furthermore, multivariate
analysis, including baseline clinical variables, treatment and adverse prognostic factors demonstrated that while
TP53 alterations remained the most informative marker of dismal survival in this cohort, NOTCH1 (HR 1.58, P=0.03)
and SF3B1 (HR 1.52, P=0.01) mutations have added independent prognostic value.
| Item Type: | Article |
|---|---|
| ISSNs: | 0006-4971 (print) 1528-0020 (electronic) |
| Subjects: | Q Science > QH Natural history > QH426 Genetics |
| Divisions: | Faculty of Medicine > Cancer Sciences Faculty of Medicine > Human Development and Health |
| Item ID: | 344499 |
| Date Deposited: | 23 Oct 2012 13:20 |
| Last Modified: | 26 Apr 2013 07:21 |
| Contributors: | Oscier, David G. (Author) Rose-Zerilli, Matthew J.J. (Author) Winkelmann, Nils (Author) Gonzalez de Castro, David (Author) Gomez, Belen (Author) Forster, Jade (Author) Parker, Helen (Author) Parker, Anton (Author) Gardiner, Anne (Author) Collins, Andrew (Author) Else, Monica (Author) Cross, Nicholas C.P. (Author) Catovsky, Daniel (Author) Strefford, Jonathan C. (Author) |
| Date: | January 2013 |
| Status: | Published |
| URI: | http://eprints.soton.ac.uk/id/eprint/344499 |
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