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Background and Importance The use of Bruton’s tyrosine kinase inhibitors (BTKi) and BCL2 inhibitors (BCL2i) has revolutionised chronic lymphocytic leukaemia (CLL) treatment. CLL typically occurs in older patients, who have comorbidities and multiple medications in therapy and consequently potential clinically significant drug-drug interactions (DDI), which may have adverse effects on outcomes.Aim and Objectives The aim of the study is to assess comorbidity and polytherapy in CLL patients treated with BTKi and BCL2i. Another aim is to determine potential clinically significant DDIs of these drugs.Material and Methods A single-centre study was conducted over a 2-month period. The pharmacist obtained medication history. Data on comorbidities were obtained from medical records. The Cumulative Illness Rating Scale (CIRS) was calculated for each subject. Medication use was divided into the following categories: low drug use (< 5 medications), polytherapy (5-9 medications) and excessive polytherapy (≥ 10 medications). DDIs were analysed using the UpToDate Lexidrug.Results The study included 59 subjects receiving ibrutinib (40.7%), acalabrutinib (30.5%), zanubrutinib (3.4%) or venetoclax (25.4%). 91.5% of them had at least one comorbidity and the median number of comorbidities was three. High comorbidity burden (CIRS ≥ 7) was found in 45.7% of patients. The most common comorbidity was arterial hypertension (54.2%), which was severe according to CIRS scale (value 3) in 25.4% of subjects. The median number of medications per patient was seven. Polytherapy was identified in 45.8% of subjects, and excessive polytherapy in 33.9%. At least one potential clinically significant DDI of BTKi was identified in 70.5% of patients, predominantly (95.7%) of significance level C. The most common consequence of BTKi DDIs was an increased risk of bleeding, recorded in 65.9% of patients taking BTKi. The most common interactants in those interactions were nonsteroidal anti-inflammatory drugs, followed by antiplatelet drugs, selective serotonin reuptake inhibitors and anticoagulants. At least one potential clinically significant DDI involving venetoclax was identified in 26.7% of patients, of which the majority (71.4%) were interactions with antidiabetic agents of significance level C, as venetoclax may decrease their therapeutic effects.Conclusion and Relevance The incidence of polytherapy and DDIs is significant and should be regularly analysed in prescribed pharmacotherapy of CLL patients treated with targeted therapy.Conflict of Interest No conflict of interest