Tumor Mutational Load Can Help Fine-Tune Prognoses in CLL

Tumor mutational load (TML) appears to be a strong predictor of time to first treatment (TTT) in patients with newly diagnosed chronic lymphocytic leukemia (CLL) and high-count monoclonal B-cell lymphocytosis (HC MBL), according to a new study.

The research, published in The American Journal of Hematology,¹ suggests that early mutational screening of patients may lead to better risk stratification and predicting of TTT.

Most patients--about three-quarters--who are diagnosed with CLL will not require therapy for years, if ever. However, some patients progress rapidly. Those patients are also more likely to have frequent relapses. HC MBL precedes CLL, and about 1% to 5% of patients with HC MBL will see their CLL progress to the point of needing therapy each year. The trouble, according to corresponding authors Esteban Braggio, PhD, and Susan L. Slager, PhD, both of the Mayo Clinic, is predicting which patients will fall into that narrow category.

One solution to the problem has been the CLL International Prognostic Index (IPI), which stratifies patients into risk groups based on their likelihood of overall survival (OS) at 5 years and can also be used to calculate a patient’s likely TTT.

Braggio, Slager, and colleagues, however, wondered whether genetic mutations alone could predict TTT. In their study, the authors wrote that about 60 recurrently mutated genes have been found in patients with CLL.^2,3 Some of those mutations have already taken place during HC MBL, but most occur later in CLL, suggesting that TML might be linked with disease progression.

The investigators set up a study to find potential links between disease progression and individual recurrently mutated genes and/or total number of recurrently mutated CLL genes.

The team initiated a study of 557 patients who were newly diagnosed but had not yet received treatment for CLL (n = 445) and HC MBL (n = 112), and who had peripheral blood mononuclear cells available that were taken within 2 years of CLL or HC MBL diagnosis. All of the patients in the study were diagnosed between 2002 and 2016. A majority of patients were male, and the median ages of the patients with CLL and HC MBL were 61 and 66, respectively. The samples were placed into 3 cohorts, based on when the samples were sequenced. The first group to undergo sequencing became the discovery cohort; the others were the validation cohorts.

The investigators extracted DNA from the samples and sequenced the entire coding regions of the DNA’s somatically recurring mutated CLL genes.

Meanwhile, the team calculated the CLL-IPI score for each patient and noted the patients’ TTT and OS.

The data showed that patients with HC MBL had fewer genetic mutations than those with CLL. Among the CLL group, 301 patients (68%) had high-impact mutations; in the HC MBL group, 58 (52%) had high-impact mutations.

The investigators found that while CLL-IPI score correlated with TTT (HR, 2.25) and OS (HR, 2.28), TML also appeared to be predictive of TTT in both the CLL (HR, 1.41) and HC MBL (HR, 1.53) populations; the higher a patient’s TML, the shorter the patient’s TTT. However, the authors did not notice the same link between TML and OS; while a correlation was found in the discovery group, it was not replicated in the validation groups.

“Based on our study, those individuals within the low to intermediate CLL-IPI category who had TML of 2+ had a ~6-fold increased risk of progression requiring therapy,” wrote Braggio, Slager, and colleagues. “Interestingly, the incorporation of TML, in addition to other important prognostic factors, improved the discriminatory power of the CLL-IPI in this cohort with c-statistic of 0.76 for CLL, compared to the CLL-IPI alone (c = 0.74 in the new study versus c = 0.72 in a previous paper⁴).

In their discussion, the authors noted that the current protocol of re-assessing patients with CLL every 6 to 12 months can lead to high levels of anxiety in patients and might be considered outdated given significant prognostic advances made in recent decades.

The study marks the first time that investigators have been able to affirm the value of CLL-IPI scores in calculating TTT in HC MBL. The study also suggested that mutations in the SF3B1 gene were associated with shorter TTT (HR, 2.05; c = 0.75), which is significant because just 10% to 15% of patients with CLL have impactful mutations of the gene, the authors wrote. Although more study is needed, the investigators said that the study provides strong evidence that single genes might be important prognostic indicators.

In the meantime, the authors concluded that mutation evaluation could be an important step for newly-diagnosed patients.

“Performing a focused mutation panel evaluating recurrently mutated CLL genes among individuals with HC MBL and CLL at time of diagnosis may improve risk stratification and the ability to predict time to progression requiring therapy,” the authors concluded.

_References:

_{1. 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 [published online April 12, 2020]. Am J Hematol. doi: 10.1002/ajh.25831}

_{2. Puente XS, Beà S, Valdés-Mas R, et al. Non-coding recurrent mutations in chronic lymphocytic leukaemia. Nature. 2015;526:519-524. doi: 10.1038/nature14666}

_{3. Landau DA, Tausch E, Taylor-Weiner AN, et al. Mutations driving CLL and their evolution in progression and relapse. Nature. 2015;526:525-530. doi: 10.1038/nature15395}

_{4. Molica S, Giannarelli D, Levato L, Mirabelli R, Gentile M, Morabito F. Assessing time to first treatment in early chronic lymphocytic leukemia (CLL): a comparative performance analysis of five prognostic models with inclusion of CLL-international prognostic index (CLL-IPI). Leuk Lymphoma. 2017;58:1736-1739. doi: 10.1080/10428194.2016.1257791}