PF373 IMPACT OF ATM ALTERATIONS ON CHRONIC LYMPHOCYTIC LEUKEMIA IN GENERAL PRACTICE IN THE AREA OF NEXT GENERATION SEQUENCING

• Published in: HemaSphere 2019-06, Vol.3 (S1), p.137-128
• Main Authors: Ganard, M., Houot, R., Henry, C., Boulland, M.‐L., Luycx, O., Norwood, J., Bareau, B., Grulois, I., Launay, V., Jacomy, D., Roussel, M., De Tayrac, M., De Guibert, S., Fest, T., Lamy, T., Pastoret, C.
• Format: Article
• Language: English
• ISSN: 2572-9241; 2572-9241
• DOI: 10.1097/01.HS9.0000559704.91403.c0

Background: Chronic Lymphocytic Leukemia (CLL) is characterized by a very heterogeneous clinical course. Del11q22–23 affecting ATM gene is the most common cytogenetic abnormality associated with poor prognosis. Clinical significance of ATM mutations, isolated or associated with del11q22–23, remains unclear specifically since the widespread use of new therapeutic agents. Aims: Evaluate frequency, associations and clinical significance of ATM alterations in a daily clinical practice cohort. Methods: We retrospectively analyzed a cohort of 268 CLL patients tested by NGS (Next Generation Sequencing) including ATM mutations in daily clinical practice. Results: We identified 50 different ATM mutations among 42 patients (15.7%) by NGS, including a majority of missense mutations and 35 del11q using FISH. Bi‐allelic ATM alterations (ATM mutation and del11q) were found in only 13 patients (37.5% of the del11q patients and 31% of the ATM mutated patients). All but 11 patients with ATM alterations received anti‐CD20 combined chemotherapy directly after NGS realization. ATM alterations had no significant impact on overall survival (OS) but significantly affected time to first treatment (TTFT) in univariate analysis (median of 2.4 years versus 6.1 years (p = 0.004)) (Figure 1A) as well as in multivariate analysis (HR 1.6 IC 95% 1–2.6 ‐ p = 0.023). ATM alterations also affected significantly the time to next treatment (TTNT) with a median time of 2.0 years versus non‐reached in the absence of ATM alteration (p = 0.003) (Figure 1B).Outcome in the bi‐allelic ATM alterations subgroup was particularly pejorative with a median TTNT of 5.5 months (IC 95% 4.8–6.2 months). In multivariate analysis, only ATM mutation had a significant impact on TTNT (HR 3.98 IC 95% 1.45–10.9 ‐ p = 0.008) even when BCR‐inhibitors were used. Summary/Conclusion: ATM alterations are frequent in CLL either at diagnosis or at relapse. They confer worse disease evolutionary profile and earlier relapses, especially in case of bi‐allelic inactivation or multiple‐hit profile. These findings emphasize the importance of integrating ATM gene in a targeted NGS panel to better characterize CLL patients while waiting availability ofnew therapeutic agents targeting ATM deficiency.