Background: A significant proportion of patients (pts) with Chronic Lymphocytic Leukemia (CLL) have cardiovascular comorbidities requiring treatment with direct oral anti-coagulants (DOAC). However, Bruton's tyrosine kinase inhibitors (BTKi) are associated with an increased risk of bleeding events, caused by the inhibition of platelet coagulation, a BTKi class effect. Additionally, there is an elevated risk of bleeding events in pts taking DOAC and in CLL pts. Given the need for safe and effective treatment options for CLL pts in real-world, the CICERO study assesses the incidence of bleeding events in pts treated with the BTKi acalabrutinib (acala) +/- obinutuzumab (obi) and requiring co-medication with DOAC in routine clinical practice in Germany.

Methods: In this ongoing, prospective, non-interventional study, eligible pts have CLL, ECOG Performance status (ECOG PS) ≤2, are either treatment-naïve or pre-treated, receive acala +/- obi according to summary of product characteristics (SmPC) in a routine setting, and have required treatment with DOAC since before the start of treatment with acala. Informed consent was obtained from all pts. Pts were observed until treatment with either acala or DOAC was discontinued. Bleeding events were categorized into major or non-major according to definitions by Schulman et al. (J Thromb Haemost 2005), Ghia et al. (J Clin Oncol 2020) or based on the criteria for clinically relevant non-major bleeding (CRNMB; Kaatz et al., J Thromb Haemost 2015).

Results:From 06/2022 to 03/2025, 45 pts were enrolled in 15 sites in Germany. Herein, we present the results of a safety interim analysis of CICERO, data base cut (DBC) 06/30/2025. Of N=43 evaluable pts, median age was 81 years (range: 61-88), 69.8% were male and 23.3, 44.2 or 32.6% of pts had an ECOG PS of 0, 1 or 2, respectively. Comorbidities were frequent with a Charlson Comorbidity Index (CCI) of 1 in 14.0% and of ≥2 in 46.5% of pts. The main reason for DOAC use was atrial fibrillation (AF, 37.2%), followed by venous thrombosis (18.6%), non-valvular AF (7.0%), deep venous thrombosis (7.0%), and others (25.6%). Most pts received either Apixaban® (39.5%), Edoxaban® (30.2%) or Rivaroxaban® (27.9%). Of the pts tested, 65.1% had a high-risk mutation and/or cytogenetic aberration. Median time from diagnosis of CLL to treatment start with acala was 5.0 years (range 0-24.4).

Major bleeding events according to Schulman et al. were reported for 4.7% of pts. 14.0% of pts had one or more CRNMB event, but none of these had any major bleeding event. Major bleeding events according to Ghia et al. were reported for 7.0% of pts. There were no pts with central nervous system (CNS) bleeding events neither any deaths related to venous thromboembolic events (VTE) or bleeding events. 48.8% of pts had any bleeding event, mainly hematoma, contusion or epistaxis. Median treatment duration with acala was 6.9 months (range: 0.4-30.8). Obi was received by 6 pts only (14.0%). 65.1 % of pts were still on treatment with acala at the time of DBC and a mean relative dose intensity of 81.2% was reached. 46.5% did not require a treatment modification, 39.5% of pts had a dose reduction, treatment was interrupted in 34.9% of pts and had to be discontinued in 2.3% of pts. 25.6% of pts had a treatment modification due to an (S)AE unrelated to acala and 18.6% of pts had a treatment modification due to an (S)AE associated with acala. 9.3% of pts had a treatment modification due to administrative reasons and 20.9% due to others. The most common reason for end of treatment (EOT) with acala were (S)AE, in 20.9% of pts.

Most pts (81.4%) did not require treatment modification of DOAC. The dose of DOAC was reduced in 9.3% of pts and treatment was interrupted in 9.3% of pts. The most common reasons for treatment modification were (S)AE, unrelated to study medication (11.6%) and others (9.3%).

Conclusion:In a cohort of elderly and comorbid CLL pts, the CICERO study demonstrated the feasibility of acala +/- obi in pts receiving DOAC in real-world. The rate of major bleeding events according to Ghia et al. did not dramatically increase compared to the pivotal studies (7.0% vs 4.5% in Byrd et al. 2021 vs 3% major bleeding events in Ghia et al. 2022) given the advanced age (median age: 66 vs 68 vs 81 years) and the requirement for DOAC of pts in CICERO. Future analyses will further describe safety and the effectiveness of acala +/- obi + DOAC in this fragile cohort.

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2025
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