Treatment Options for Elderly/Unfit Patients with Chronic Lymphocytic Leukemia in the Era of Targeted Drugs: A Comprehensive Review

Abstract

Chronic lymphocytic leukemia (CLL) incidence increases with age reaching 37.9/100,000 in patients over 85 years. Although there is no standardized geriatric tool specifically validated for CLL, a correct framing of the fitness status is of critical importance to individualize treatment strategies. Based on the evidence available to date, frontline chemoimmunotherapy has an increasingly narrowing application, being eligible for candidacy only in elderly fit patients without or with minimal geriatric syndromes. On the other hand, treatment with BCR inhibitors, monotherapy, or in combination with anti-CD20 antibodies (e.g., obinutuzumab), must be preferred both for frontline and relapsed CLL not only in unfit patients, but also in fit patients with unmutated IGHV or harboring del(17p) and/or TP53 mutations/deletions. Second-generation inhibitors (e.g., acalabrutinib, zanubrutinib, pirtobrutinib) are novel compounds that, due to their better safety profile and different specificity, will help physicians overcome some of the safety issues and treatment resistances. In the era of targeted therapies, treatment decisions in elderly and/or unfit patients with CLL must be a balance between efficacy and safety, carefully evaluating comorbidities and geriatric syndromes to ensure the best approach to improve both quality of life and life expectancy.

Relative dose intensity of obinutuzumab-chlorambucil in chronic lymphocytic leukemia: a multicenter Italian study

“… 13-15 Studies in which ECOG PS showed a negative impact included more unfit and, on average, older patients, whereas a higher CIRS showed an impact in younger and fit patients, independently of the treatment received. 16 Our results align with this observation, considering that our cohort includes exclusively unfit patients, almost all of whom are older than 65 years.…”

Evidence-Based Management of Chronic Lymphocytic Leukemia: Consensus Statements from the Gulf Region

“…In clinical trials, when considering patients with comorbidities, fitness is assessed based on CIRS and creatinine clearance, calculated by Cockcroft-Gault [59,60]. CIRS allocates a severity level specific to each system from 0 to 4, depending on the impairment, while creatinine clearance provides a precise assessment of renal impairment [61,62]. CIRS assesses comorbidities in different organ systems by rating 13 body systems on a fivepoint pathophysiology severity scale [63].…”

The Five “Ws” of Frailty Assessment and Chronic Lymphocytic Leukemia: Who, What, Where, Why, and When

“…In the preceding era, age was firmly established as an unfavorable predictor [20][21][22][23]. However, the influence of age on prognosis with targeted therapies seems to be less pronounced, at least in clinical trials [24][25][26][27][28].…”