Biallelic ATM inactivation significantly reduces survival in patients treated on the United Kingdom Leukemia Research Fund Chronic Lymphocytic Leukemia 4 trial.

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.

• Authors: Anna Skowronska, Anton Parker, Gulshanara Ahmed, Ceri Oldreive, Zadie Davis, Sue Richards, Martin Dyer, Estella Matutes, David Gonzalez, A Malcolm R Taylor, Paul Moss, Peter Thomas, David Oscier, Tatjana Stankovic
• Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 30 Issue 36 Pg. 4524-32 (Dec 20 2012) ISSN: 1527-7755 [Electronic] United States
• PMID: 23091097 (Publication Type: Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Cell Cycle Proteins
• DNA-Binding Proteins
• Tumor Suppressor Proteins
• Chlorambucil
• Cyclophosphamide
• ATM protein, human
• Ataxia Telangiectasia Mutated Proteins
• Protein Serine-Threonine Kinases
• Vidarabine
• fludarabine

Topics

• Aged
• Alleles
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Ataxia Telangiectasia Mutated Proteins
• Cell Cycle Proteins (genetics)
• Chlorambucil (therapeutic use)
• Cyclophosphamide (administration & dosage)
• DNA-Binding Proteins (genetics)
• Disease Progression
• Disease-Free Survival
• Female
• Gene Expression Regulation, Enzymologic
• Gene Expression Regulation, Leukemic
• Gene Silencing
• Humans
• Leukemia, Lymphocytic, Chronic, B-Cell (drug therapy, enzymology, genetics)
• Male
• Middle Aged
• Mutation
• Prognosis
• Prospective Studies
• Protein Serine-Threonine Kinases (genetics)
• Survival Analysis
• Tumor Suppressor Proteins (genetics)
• United Kingdom
• Vidarabine (administration & dosage, analogs & derivatives, therapeutic use)