Biallelic ATM Inactivation Significantly Reduces Survival in Chronic Lymphocytic Leukemia Patients Treated with Alkylating Agent/Purine Analogue Therapy: Results From the UKCLL4 Trial

Abstract 467^FN2

The Ataxia Telangiectasia Mutated (ATM) gene located at 11q23 plays a central role in DNA damage response. Deletion of 11q23 occurs in approximately 20–30% chronic lymphocytic leukemia (CLL) cases and in 30% of these exhibit mutations in their remaining ATM allele. A smaller proportion of CLL tumours exhibit the presence of ATM mutations in the absence of 11q deletion. We have previously shown that ATM mutations are associated with a shorter overall survival from diagnosis and treatment free survival (TFS) in an unselected CLL cohort. Furthermore, several prospective and retrospective studies, including the UKCLL4 trial, show an inferior overall survival and progression free survival after therapy (OS and PFS) in cases with an 11q deletion treated with alkylating agents and/or purine analogues.

The entire ATM coding region was screened for sequence changes using high-performance liquid chromatography and sequencing and known polymorphisms excluded. Screening was performed on 238/777 cases enrolled in the UKCLL4 trial, including all available cases with 11q deletions, with the remaining cases being randomly selected. Other than significant enrichment for patients with 11q deletion (p<0.0001) and a reduction in cases with trisomy 12 (p=0.019), the cohort did not differ from the other 539 patients in the trail.

ATM mutations were detected in 35/238(14.7%) cases and no cases with biallelic mutations were observed. In 224 patients 11q deletion and ATM mutation data were available; 49(22%) had an 11q deletion only, 16 (7%) an ATM mutation only, 18 (8%) an ATM mutation plus an 11q deletion and 141 (63%) exhibited both ATM alleles wild type. Apart from an association with 11q deletion (p=0.001), ATM mutations were associated with advanced stage of disease (p=0.01) but not with any other variable.

Overall response rate (ORR), PFS and OS were analysed in 188 cases with no detected TP53 mutation or 17p deletion.

Compared to ATM wild type cases (ORR=99/109, 91%), 11q deletion alone (ORR=28/38, 74%) and ATM mutation plus 11q deletion (ORR=8/15, 53%) were both associated with reduced ORR, independent of treatment arm (HR= 0.24; 95% CI 0.09 to 0.69; p= 0.007 and HR= 0.09; 95% CI, 0.02 to 0.36; p= 0.001 respectively), whereas ATM mutation alone (ORR=13/15, 87%) was not (p=0.46).

In univariate analysis, cases with ATM mutation plus 11q deletion showed significantly reduced PFS (median, 9.2 months) compared to cases with ATM wild type (32.1 months), 11q deletion alone (17.2 months) and ATM mutation alone (37.1 months) (all p<0.003). The difference in PFS between 11q deletion alone and ATM wild type was also significant (p=0.002), whereas between ATM mutation alone and ATM wild type it was not (p=0.98). Similarly, OS for cases with ATM mutation plus 11q deletion was significantly reduced (median, 43.5 months) compared to cases with ATM wild type (89.4 months) and ATM mutation alone (88.9 months) (p=0.001 and 0.036 respectively) and again, the difference between 11q deletion alone (54.4 months) and ATM wild type was significant (p=0.001), whereas between ATM mutation alone and ATM wild type it was not (p=0.63).

In multivariate analysis, including the combined ATM mutation and 11q deletion scoring, treatment arm, IGVH mutational status, age, gender and disease stage as covariates. Compared to ATM wild type cases, the presence of deletion 11q alone or of ATM mutation plus 11q deletion was independently associated with significantly increased risk of progression after therapy (Hazard ratio (HR) 1.86, 95% CI 1.23–2.75, p=0.002 and HR 4.11, 95% CI 2.33–7.27, p<0.001 respectively) where as the presence of ATM mutation alone was not.

Further univariate analysis showed that while cases with TP53 mutation and 17p deletion had significantly reduced PFS (median 3.4 months) compared to cases with ATM mutation plus 11q deletion (9.2 months) and those with monoalleic TP53 abnormality (6.7 months), the difference in between cases with ATM mutation plus 11q deletion and those with monoalleic TP53 abnormality was not significant (p=0.53).

Our results suggest that ATM mutations influence CLL progression under treatment with purine analogues and alkylating agents, independently of other established prognostic markers and that ATM status should be considered before such treatments. It remains to be determined whether ATM mutations have equal impact on patients' response to immunochemotherapy.