ATM mutations alone do not predict early treatment need in chronic lymphocytic leukemia, study finds microbiologystudy

In chronic lymphocytic leukemia (CLL), certain recurrent genetic alterations are known to influence disease progression and survival. One important abnormality is the loss of part of chromosome 11, del(11q), which is associated with a more aggressive disease course. However, it has remained unclear whether mutations in the ATM gene, which is also located in this region, have a similar impact.

In a study published in Leukemia involving 3,631 untreated CLL patients—collected from several European centers and coordinated by the European Research Initiative on CLL (ERIC) as part of the HARMONY Alliance—researchers from Karolinska Institutet explored the prognostic significance of ATM mutations, along with mutations in nine additional genes. Prognosis was measured based on time to first treatment (TTFT).

“To assess the impact of recurrent genetic alterations in CLL it is important to collect large numbers of patients to reach solid conclusions. Thanks to our large collaborative network across Europe, we were able to perform one of the largest studies of its kind,” says Larry Mansouri, senior researcher at the Department of Molecular Medicine and Surgery.

ATM mutations were identified in approximately 7% of patients and frequently co-occurred with del(11q). Among affected patients, the pattern of accompanying genetic abnormalities differed depending on the mutational status of the immunoglobulin heavy variable (IGHV) gene, a major prognostic marker in CLL.

Specifically, among patients carrying mutated IGHV genes (M-CLL), ATM mutations often co-occurred with mutations in the SF3B1 and NFKBIE genes while in contrast, in patients with unmutated IGHV genes (U-CLL), ATM mutations were largely mutually exclusive with TP53 mutations and trisomy 12.

Furthermore, patients with any ATM-related abnormalities (ATM mutations and/or del(11q)) experienced a significantly shorter TTFT. However, after adjusting for other genetic factors, only del(11q)—and not ATM mutations alone—emerged as an independent predictor of earlier need for treatment. This finding was particularly relevant in M-CLL patients, who typically have a more favorable prognosis.

“In short, our findings strengthen the role of del(11q)—and not ATM mutations alone—as a critical marker for higher risk of progression in patients with CLL. This insight can help doctors to improve risk stratification and personalize treatment decisions for patients,” says Birna Thorvaldsdottir, post-doc at the Department of Molecular Medicine and Surgery.