TML Helps Predict Time to Treatment in CLL and Its Precursor, Study Shows

Tumor mutational load (TML) can be used as a prognostic indicator in patients with chronic lymphocytic leukemia (CLL) and high-count monoclonal B-cell lymphocytosis (HC MBL), according to a new study.

The findings suggest that performing a focused mutation panel on recurrently mutated CLL genes could help risk-stratify patients and more accurately predict time to treatment (TTT).

Most patients who are newly diagnosed with CLL do not require therapy for a number of years, but some patients will require therapy right away. CLL’s precursor, HC MBL, will progress to CLL at a rate of 1-5% per year, but it can be difficult to predict how soon an individual patient will progress.

In hopes of better predicting patient progression, investigators from the Mayo Clinic conducted a study to analyze the total number of recurrently mutated CLL genes (TML) and the individually mutated genes beyond the CLL international prognostic index (CLL-IPI) in newly diagnosed patients with CLL and HC MBL.

To do so, they recruited 557 patients, 445 of whom had CLL and the remainder of whom had HC MBL, and sequenced 59 genes in the patients. Their goal was to identify links with TTT, adjusted for CLL and sex.

The authors found that TML correlated with shorter TTT. Among patients with low/intermediate risk, the link was even stronger when patients were stratified by CLL-IPI. Their results are published in the American Journal of Hematology.

“Overall, 80% of low/intermediate CLL-IPI cases with 2 or more mutational genes progressed to require therapy within 5 years,” corresponding author Esteban Braggio, PhD, and colleagues, wrote.

Among those without mutations, only 24% of patients required therapy within 5 years. TML also predicted shorter TTT among the 112 patients with HC MBL.

Braggio and colleagues noted that the current paradigm means patients who are newly diagnosed have to face months or years of uncertainty.

“Current recommendations are to follow these patients in the clinic every 6 to 12 months to look for evidence of disease progression (“watch and wait” strategy),” authors wrote. “Although this approach is evidence-based, it can lead to significant anxiety and distress in a significant number of patients.”

The investigators said their study aligns with earlier research suggesting TML has an important prognostic value. They said this fact could be used to help recruit patients with shorter TTT for early intervention clinical trials.

For patients with HC MBL, the authors noted that many patients will remain asymptomatic, while others will progress to active leukemia.

“Our results provide, for the first time, evidence that both CLL-IPI and TML are useful prognostic factors for TTT in pre-malignant, HC MBL phase,” they wrote.

The authors noted that CLL is a heterogenous disease, marked by the presence of around 60 genes mutated in 1 to 15% of patients each.

Braggio and colleagues said they found “interesting” associations between single genes and TTT in patients with low to intermediate risk CLL-IPI.

“These results need further validation but provide strong evidence that single genes are important prognostic factors for TTT in CLL with low to intermediate risk CLL-IPI,” they said.

In the meantime, focused mutation panels could be used to evaluate TML in patients with both HC MBL and CLL, and the insights derived from such analyses could provide meaningful insights for clinicians and patients.

Reference:

Kleinstern G, O'Brien DR, Li X, et al. Tumor mutational load predicts time to first treatment in chronic lymphocytic leukemia (CLL) and monoclonal B-cell lymphocytosis beyond the CLL international prognostic index. Am J Hematol. 2020;95(8):906-917. doi:10