Introduction: Chronic lymphocytic leukemia (CLL) is a common haematological neoplasm in elderly patients (pts), with a median age at diagnosis of 70 years. The therapeutic landscape of CLL has changed radically in the recent years, thanks to target agents such as BTKi and BCL-2 inhibitors, that have improved outcomes. Despite offering therapeutic options even to pts considered ineligible for chemoimmunotherapy (CIT) regimes due to fitness, performance status and treatment-related logistics, their use in elderly pts raises concerns regarding tolerance and toxicity. During the CIT era, the concept of suitability was assessed using the comorbidity indices (CIRS, CIRS-G, CLL-CI), the ECOG-PS and the caregiver's needs; today, in the target era, it remains highly debated. Current guidelines emphasize the importance of pts fitness and comorbidities (Eichhorst B, 2024); however, the systematic implementation and standardization of practical geriatric and fitness assessment tools in clinical practice are inconsistent. A geriatric assessment could help to personalize treatment by identifying the most vulnerable individuals.

Methods: We conducted with the support of the Geriatric Unit, at Fondazione Policlinico A. Gemelli (FPG), a pilot observational study, from June 2023 to March 2025, involving CLL pts over 65 years old, treated with BTKi and/or BCL-2 inhibitors alone or with anti-CD20 monoclonal antibody. A multidimensional geriatric assessment, using validated oncogeriatric tools, was applied, including CLL-CI (Gordon, 2021), Chair Stand Test (CST) (Guralnik JM, 1995, Cesari M,2009), polypharmacy (> 5 active principles), Mini-Cog test (Borson S, 2003, McCarten J, 2011), and caregiver support. A score was given for each tool. The primary endpoint assessed the association between the score, based on these 5 items, and treatment-related toxicities (grade ≥2 per CTCAE v5.0). The secondary endpoint evaluated whether any of the 5 items had a stronger association with toxicity and if the score changed when reassessed after 6 months.

Results: During the study period, 39 CLL pts were enrolled (28 males and 11 females), with a median age of 75 years (70-80). Concerning biological features, IGHV was unmutated in 16/26 (60%) pts. Del17 was present in 3/28 (11%). TP53 was mutated in 4/24 (16%). Thirty-two pts started therapy: 21 were treatment naïve and 11 were relapsed/refractory. Treatments included ibrutinib (6), acalabrutinib (13), zanubrutinib (5), venetoclax (4), venetoclax - obinutuzumab (2), and venetoclax - rituximab (2). The main comorbidities were hypertension, ischemic cardiomyopathy, heart failure, atrial fibrillation, renal failure, diabetes, thyroidopathy, chronic gastropathy. The median creatinine clearance (CrCl) was 53 ml/min (45-61). Only two pts started treatment with ibrutinib at reduced dosage. Fitness evaluation was carried out in all pts using the comorbidity indices and validated oncogeriatric tools. The median CIRS and CIRS-G score were 5 (IQR: 4-7) and 2 (IQR: 1.6-2), respectively. Males showed a significantly higher CIRS-G scores (2, IQR 1.66-2; p=0.046). In the cohort, 8% had an ECOG-PS score ≥2. The median multidimensional oncogeriatric assessment was 2.5 (IQR: 1-4), with higher rates in women (3 vs 2; IQR 2-4 vs 1-4; p=0.6). The median polypharmacy score was 4 (1-10). Out of the pts, 11% and 41% presented functional (CST) and cognitive (Mini-Cog) impairment, respectively, without significant gender differences. Nevertheless, CST was poorer in females (p=0.07). A caregiver was present in 30% of pts (9/30). The median CLL-CI was 1 (IQR: 1-2). Ten pts discontinued treatment due to toxicity, and four required dose reductions. Pts needing treatment modifications had a higher median oncogeriatric assessment (3 vs 2). We re-evaluated 10 pts 6 months after beginning treatment, using the same oncogeriatric tools: 3 improved, 3 remained stable, and 4 worsened.

Discussion: Pts with reduced treatment tolerance had a higher median oncogeriatric score, showing a possible correlation between the assessment and treatment toxicity. CIRS-G and physical function appeared particularly relevant.

Conclusion: Preliminary data from this pilot study support multidimensional geriatric assessment in elderly CLL pts, as it may be useful to identify pts at risk of toxicity and to personalize treatments. Larger studies are needed to confirm these findings and validate a score for assessing elderly pts fitness in this target era.

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2025
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