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Biallelic ATM inactivation significantly reduces survival in patients treated on the United Kingdom leukemia research fund chronic lymphocytic leukemia 4 trial

Biallelic ATM inactivation significantly reduces survival in patients treated on the United Kingdom leukemia research fund chronic lymphocytic leukemia 4 trial
Biallelic ATM inactivation significantly reduces survival in patients treated on the United Kingdom leukemia research fund chronic lymphocytic leukemia 4 trial
PURPOSE: The prognostic significance of ATM mutations in chronic lymphocytic leukemia (CLL) is unclear. We assessed their impact in the context of a prospective randomized trial.

PATIENTS AND METHODS: We analyzed the ATM gene in 224 patients treated on the Leukemia Research Fund Chronic Lymphocytic Leukemia 4 (LRF-CLL4) trial with chlorambucil or fludarabine with and without cyclophosphamide. ATM status was analyzed by denaturing high-performance liquid chromatography and was related to treatment response, survival, and the impact of TP53 alterations for the same patient cohort.

RESULTS: We identified 36 ATM mutations in 33 tumors, 16 with and 17 without 11q deletion. Mutations were associated with advanced disease stage and involvement of multiple lymphoid sites. Patients with both ATM mutation and 11q deletion showed significantly reduced progression-free survival (median, 7.4 months) compared with those with ATM wild type (28.6 months), 11q deletion alone (17.1 months), or ATM mutation alone (30.8 months), but survival was similar to that in patients with monoallelic (6.7 months) or biallelic (3.4 months) TP53 alterations. This effect was independent of treatment, immunoglobulin heavy chain variable gene (IGHV) status, age, sex, or disease stage. Overall survival for patients with biallelic ATM alterations was also significantly reduced compared with those with ATM wild type or ATM mutation alone (median, 42.2 v 85.5 v 77.6 months, respectively).

CONCLUSION: The combination of 11q deletion and ATM mutation in CLL is associated with significantly shorter progression-free and overall survival following first-line treatment with alkylating agents and purine analogs. Assessment of ATM mutation status in patients with 11q deletion may influence the choice of subsequent therapy.
1527-7755
4524-4532
Skowronska, A.
dc182eac-7036-4699-93a5-a2246c47a50b
Parker, A.
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Oldreive, C.
affb2eb8-6b9a-4296-a9e9-cbfbcb333eb7
Davis, Z.
b106965c-11bb-4133-98f0-540894dd11a9
Richards, S.
231c6be9-3769-47b3-ae97-06ea844e0448
Dyer, M.
9120bc76-cb33-4896-a9ab-f68872887097
Matutes, E.
1ede5543-9493-4b0b-8d9b-62315bdfd36b
Gonzalez, D.
edb9678f-6ae0-4fa2-b781-252749f64fe1
Taylor, A.M.
91d75d8e-90db-485b-bf6a-42c186d31b01
Moss, P.
c10e3fed-ba2e-43db-8324-b28f507b9dab
Thomas, P.
260a29e1-369d-4578-a3df-0e3ba5346608
Oscier, D.G.
c2620a1d-25bb-48f7-9651-f5d023636381
Stankovic, T.
29cba387-f7bd-4c78-a336-b0d8c117f82f
Skowronska, A.
dc182eac-7036-4699-93a5-a2246c47a50b
Parker, A.
2060d83a-15d6-444c-82f3-a0e4e549dcaa
Oldreive, C.
affb2eb8-6b9a-4296-a9e9-cbfbcb333eb7
Davis, Z.
b106965c-11bb-4133-98f0-540894dd11a9
Richards, S.
231c6be9-3769-47b3-ae97-06ea844e0448
Dyer, M.
9120bc76-cb33-4896-a9ab-f68872887097
Matutes, E.
1ede5543-9493-4b0b-8d9b-62315bdfd36b
Gonzalez, D.
edb9678f-6ae0-4fa2-b781-252749f64fe1
Taylor, A.M.
91d75d8e-90db-485b-bf6a-42c186d31b01
Moss, P.
c10e3fed-ba2e-43db-8324-b28f507b9dab
Thomas, P.
260a29e1-369d-4578-a3df-0e3ba5346608
Oscier, D.G.
c2620a1d-25bb-48f7-9651-f5d023636381
Stankovic, T.
29cba387-f7bd-4c78-a336-b0d8c117f82f

Skowronska, A., Parker, A., Oldreive, C., Davis, Z., Richards, S., Dyer, M., Matutes, E., Gonzalez, D., Taylor, A.M., Moss, P., Thomas, P., Oscier, D.G. and Stankovic, T. (2012) Biallelic ATM inactivation significantly reduces survival in patients treated on the United Kingdom leukemia research fund chronic lymphocytic leukemia 4 trial. Journal of Clinical Oncology, 30 (36), 4524-4532. (doi:10.1200/JCO.2011.41.0852). (PMID:23091097)

Record type: Article

Abstract

PURPOSE: The prognostic significance of ATM mutations in chronic lymphocytic leukemia (CLL) is unclear. We assessed their impact in the context of a prospective randomized trial.

PATIENTS AND METHODS: We analyzed the ATM gene in 224 patients treated on the Leukemia Research Fund Chronic Lymphocytic Leukemia 4 (LRF-CLL4) trial with chlorambucil or fludarabine with and without cyclophosphamide. ATM status was analyzed by denaturing high-performance liquid chromatography and was related to treatment response, survival, and the impact of TP53 alterations for the same patient cohort.

RESULTS: We identified 36 ATM mutations in 33 tumors, 16 with and 17 without 11q deletion. Mutations were associated with advanced disease stage and involvement of multiple lymphoid sites. Patients with both ATM mutation and 11q deletion showed significantly reduced progression-free survival (median, 7.4 months) compared with those with ATM wild type (28.6 months), 11q deletion alone (17.1 months), or ATM mutation alone (30.8 months), but survival was similar to that in patients with monoallelic (6.7 months) or biallelic (3.4 months) TP53 alterations. This effect was independent of treatment, immunoglobulin heavy chain variable gene (IGHV) status, age, sex, or disease stage. Overall survival for patients with biallelic ATM alterations was also significantly reduced compared with those with ATM wild type or ATM mutation alone (median, 42.2 v 85.5 v 77.6 months, respectively).

CONCLUSION: The combination of 11q deletion and ATM mutation in CLL is associated with significantly shorter progression-free and overall survival following first-line treatment with alkylating agents and purine analogs. Assessment of ATM mutation status in patients with 11q deletion may influence the choice of subsequent therapy.

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Published date: 20 December 2012
Organisations: Cancer Sciences

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Local EPrints ID: 352055
URI: https://eprints.soton.ac.uk/id/eprint/352055
ISSN: 1527-7755
PURE UUID: a2ad3dfe-1dfd-4b0d-9257-0fadc40c2b06

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Date deposited: 01 May 2013 13:44
Last modified: 18 Jul 2017 04:19

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Contributors

Author: A. Skowronska
Author: A. Parker
Author: C. Oldreive
Author: Z. Davis
Author: S. Richards
Author: M. Dyer
Author: E. Matutes
Author: D. Gonzalez
Author: A.M. Taylor
Author: P. Moss
Author: P. Thomas
Author: D.G. Oscier
Author: T. Stankovic

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