A 4-factor prognostic model may help to identify patients with chronic lymphocytic leukemia (CLL) at risk of ibrutinib failure, according to research published in the Journal of Clinical Oncology.

As CLL is a “clonal expansion of mature B cells drive by constitutive activation of B-cell receptor (BCR) signaling,” previous studies suggest that the selective inhibition of BCR and BCL-2 protein may significantly improve outcomes in some patients with CLL compared with chemotherapy as a first-line therapy.

Ibrutinib, a Bruton tyrosine kinase inhibitor, is frequently used in the CLL setting, though drug resistance invariably evolves, with relapse occurring often with ibrutinib monotherapy.

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Identifying those at risk of relapse after ibrutinib therapy would improve treatment decision-making among patients with CLL. While there are existing prognostic indices, none specifically evaluate for criteria known to be linked with the evolution of ibrutinib resistance. In the present study, the researchers evaluated and validated the effectiveness of a 4-factor prognostic model among patients with CLL treated with ibrutinib.

Data from 804 patients were used: 541 in a training cohort, 179 in an internal validation cohort, and 84 in a National Institutes of Health external validation cohort. Overall, across cohorts, the median age was 68 years (range, 30-89), 65.4% of patients were men, 58.7% of patients had relapsed/refractory disease, 45.6% had a TP53 aberration, 58.2% had unmutated IGHV, and the median β-2 microglobulin level was 4.4 mg/L.

For the entire cohort, the median follow-up was 49.1 months. The variables associated with worse progression-free and overall survival were TP53 mutation, β-2 microglobulin levels of at least 5 mg/L, and lactate dehydrogenase levels greater than 250 U/L. A positive score for any of these variables added 1 point to the prognostic scale, with a highest possible score of 4. Low-risk disease was defined as 0 to 1 point, 2 points were classified as intermediate risk, and 3 and 4 point scores were classified as high risk.

The 3-year progression-free survival and overall survival rates were worse at higher scales across the cohorts: 47% (high risk), 74% (intermediate), and 87% (low risk; P = .0001) and 63% (high risk), 83% (intermediate), and 93% (low risk; P =.0001), respectively. These results were significant after adjusting for the relapsed/refractory vs treatment-naive disease.

“The proposed [4]-factor model enables informed clinical decision making and patient counseling and can provide a platform for the investigation of risk-adapted treatment approaches,” the authors wrote.

“In clinical practice, the score can help set expectations, guide the frequency of monitoring, and direct patients to risk-adapted treatment approaches on the basis of the predicted risk of early progression. In clinical trials, stratifying patients by risk score could more rapidly and clearly answer whether novel treatments improve outcomes for those patients in greatest need,” the investigators noted.

Disclosures: Some authors have declared affiliations with or received funding from the pharmaceutical industry. Please refer to the original study for a full list of disclosures.


Ahn IE, Tian X, Ipe D, et al. Prediction of outcome in patients with chronic lymphocytic leukemia treated with ibrutinib: development and validation of a four-factor prognostic model. J Clin Oncol. Published online October 7, 2020. doi:10.1200/JCO.20.00979