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The clinical significance of NOTCH1 and SF3B1 mutations in the UK LRF CLL4 trial

The clinical significance of NOTCH1 and SF3B1 mutations in the UK LRF CLL4 trial
The clinical significance of NOTCH1 and SF3B1 mutations in the UK LRF CLL4 trial
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.
0006-4971
468-475
Oscier, D.G.
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Rose-Zerilli, M.J.J.
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Winkelmann, N.
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de Castro, D.G.
37896832-99be-45ba-af41-db8096d4c99b
Gomez, B.
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Forster, J.
794b78dc-c6d5-43bb-8283-a60f29da55f1
Parker, Helen
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Parker, A.
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Gardiner, A.
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Collins, Andrew
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Else, M.
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Cross, N.C.P.
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Catovsky, D.
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Strefford, J.C.
3782b392-f080-42bf-bdca-8aa5d6ca532f
Oscier, D.G.
c2620a1d-25bb-48f7-9651-f5d023636381
Rose-Zerilli, M.J.J.
08b3afa4-dbc2-4c0d-a852-2a9f33431199
Winkelmann, N.
d8fec0ee-fd74-4ef1-83bb-9f7407a53a4e
de Castro, D.G.
37896832-99be-45ba-af41-db8096d4c99b
Gomez, B.
0dcf7f14-8bff-47a7-9266-c89b5e42b946
Forster, J.
794b78dc-c6d5-43bb-8283-a60f29da55f1
Parker, Helen
33e0cd81-d45f-49bc-9539-09345d79d895
Parker, A.
2060d83a-15d6-444c-82f3-a0e4e549dcaa
Gardiner, A.
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Collins, Andrew
7daa83eb-0b21-43b2-af1a-e38fb36e2a64
Else, M.
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Cross, N.C.P.
f87650da-b908-4a34-b31b-d62c5f186fe4
Catovsky, D.
8f2e75e5-9762-456e-b60b-1fd34a67ba82
Strefford, J.C.
3782b392-f080-42bf-bdca-8aa5d6ca532f

Oscier, D.G., Rose-Zerilli, M.J.J., Winkelmann, N., de Castro, D.G., Gomez, B., Forster, J., Parker, Helen, Parker, A., Gardiner, A., Collins, Andrew, Else, M., Cross, N.C.P., Catovsky, D. and Strefford, J.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)

Record type: Article

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.

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e-pub ahead of print date: 18 October 2012
Published date: 17 January 2013
Organisations: Cancer Sciences, Human Development & Health

Identifiers

Local EPrints ID: 350602
URI: http://eprints.soton.ac.uk/id/eprint/350602
ISSN: 0006-4971
PURE UUID: 028e552d-ccad-4b93-891a-6dccb9217bd8
ORCID for M.J.J. Rose-Zerilli: ORCID iD orcid.org/0000-0002-1064-5350
ORCID for Helen Parker: ORCID iD orcid.org/0000-0001-8308-9781
ORCID for Andrew Collins: ORCID iD orcid.org/0000-0001-7108-0771
ORCID for N.C.P. Cross: ORCID iD orcid.org/0000-0001-5481-2555
ORCID for J.C. Strefford: ORCID iD orcid.org/0000-0002-0972-2881

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Date deposited: 04 Apr 2013 10:32
Last modified: 28 Oct 2023 02:02

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Contributors

Author: D.G. Oscier
Author: N. Winkelmann
Author: D.G. de Castro
Author: B. Gomez
Author: J. Forster
Author: Helen Parker ORCID iD
Author: A. Parker
Author: A. Gardiner
Author: Andrew Collins ORCID iD
Author: M. Else
Author: N.C.P. Cross ORCID iD
Author: D. Catovsky
Author: J.C. Strefford ORCID iD

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