The outcomes and prognoses of patients diagnosed with chronic lymphocytic leukemia (CLL) vary, but prognostic factors and scoring systems can be used to help identify the individuals most likely to benefit from earlier or more aggressive treatment, experts say.

“There is a lot of variability in the pace of disease and in the complications that the disease may cause,” said Adrian Wiestner, MD, PhD, senior investigator at the National Institutes of Health (NIH). “About one-third of patients diagnosed with CLL may never require treatment.”

The approval of Bruton tyrosine kinase (BTK) and B-cell lymphoma 2 (BCL2) inhibitors has helped those who do require therapy achieve disease control, but whether these new drugs are curative remains an open question. “Again, while these treatments are effective for all patients in the short term, there is a great deal of variability in how long patients will benefit,” Dr Wiestner said.

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In an effort to identify the patients with CLL for whom treatment with the BTK inhibitor ibrutinib would be most advantageous, Dr Wiestner and colleagues developed and validated a 4-factor prognostic model. The investigators used a discovery dataset of 720 patients who received ibrutinib in phase 2 and 3 clinical trials.

Multivariable analysis of the data set and machine learning algorithms underscored 4 factors that were independently associated with inferior progression-free survival (PFS) and overall survival (OS): relapsed or refractory disease, the presence of a TP53 aberration, β-2 microglobulin of at least 5 mg/L, and lactate dehydrogenase greater than 250 U/L.

“Using these 4 factors, we were able to stratify patients into 3 groups by the number of risk factors present: low was 0 to 1 factor, intermediate was 2 factors, and high was 3 or 4 factors,” explained Inhye E. Ahn, MD, a staff clinician at the NIH and lead author of the study. “Using this very simple 4-factor model, we were able to show distinct progression-free and overall survival across 3 risk groups.”

The validation cohort included the 720 original patients plus 84 patients from a phase 2 trial that the investigators initiated at the NIH (the external validation cohort). Among all 804 patients, the 3-year PFS rate was 47% for the high-risk group, 74% for the intermediate-risk group, and 87% for the low-risk group (P <.0001). The 3-year OS rates were 63%, 83%, and 93% for the high-, intermediate-, and low-risk groups, respectively.

The model remained significant when applied to treatment-naive and relapsed/refractory cohorts, affirming the prognostic model’s clinical applicability.

“This data set is representative of the real world because clinical practice is a mix of patients who get ibrutinib — some as first-line therapy, and some who have had multiple prior regimens,” Dr Wiestner said.

Of note, when the study authors tested for BTK and/or PLCG2 mutation burden in the 84-patient external validation group, the aberrations were found more frequently in patients classified as high risk compared with those deemed low risk, “suggesting that the 4-factor model can [also] capture the subsequent risk of clonal evolution,” Dr Ahn observed.