Frailty predicts treatment-related toxicity and discontinuation in older adults with chronic lymphocytic leukemia treated with BTK and BCL-2 inhibitors: Findings from a prospective single-center cohort study.

Introduction: Chronic lymphocytic leukemia (CLL) particularly impacts older adults with multiple comorbidities. The advent of targeted therapies has improved outcomes, but challenges related to treatment adherence and drug interactions persist. Assessment of frailty is recommended to tailor treatment, though its application in clinical settings is often limited due to its complexity. This study aimed to investigate the predictive value of frailty regarding treatment toxicity and discontinuation in older patients with CLL treated with targeted therapies.

Materials And Methods: This prospective cohort study involved 82 older adults with CLL (≥65 years) treated with Bruton's tyrosine kinase inhibitors (BTKi) or BCL-2 inhibitors (BCL-2i) from November 2018 to February 2024. Patients were assessed by the Canadian Study of Health and Aging (CSHA) Clinical Frailty Scale (CFS) within a week before starting treatment. Demographics, CLL characteristics, comorbidities, and treatment-related adverse events were collected. Statistical analyses included receiver operating characteristic (ROC) curve analysis to determine the optimal cut-off for predicting treatment discontinuation due to toxicity.

Results: The median age of patients was 75 years. Most patients (90.2 %) were at Binet stage B/C, with 14.6 % having 17p deletion and 17.1 % TP53 mutations. Overall, 46 patients experienced treatment-related toxicity. The ROC curve analysis showed that the best cut-off for predicting treatment-related toxicity was a CSHA CFS >3. The accuracy was fair, with an area under the curve (AUC) of 0.695 (95 % CI 0.55-0.84; P = 0.02), sensitivity = 85 % and specificity = 53 %. Patients with a score > 3 experienced higher rates of treatment discontinuation (28.6 %) compared to those with a score ≤ 3 (12.5 %; P < 0.05). Other factors such as polypharmacy, cumulative illness rating, and comorbidity indices did not significantly affect treatment discontinuation rates.

Discussion: The CSHA CFS is a feasible tool for identifying older adults with CLL at higher risk of treatment toxicity and discontinuation. Patients with a CFS >3 had a significantly higher likelihood of treatment interruption due to adverse effects. Therefore, CSHA CFS can aid in stratifying patients and optimizing therapeutic strategies. Further validation in multicenter studies is warranted to confirm these results and explore the potential for adjusting treatment dosages based on frailty assessments in the era of targeted therapies.