Acalabrutinib in Patients With Chronic Lymphocytic Leukemia With Direct Oral Anticoagulation (CICERO)

Study Overview
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Brief Summary
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The goal of CICERO is to investigate the clinical outcome with a particular focus on prospective data on safety using acalabrutinib (+/- obinutuzumab) in CLL patients receiving co-medication with DOACs (edoxaban, rivaroxaban, dabigatran, apixaban) irrespective of treatment line.

Detailed Description
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The non-interventional study (NIS) CICERO will collect real-world data to explore acalabrutinib (+/- obinutuzumab) in adult CLL patients (irrespective of treatment line) who receive co-medication with DOACs. The primary focus of the study is to investigate the incidence proportion of bleeding events. Due to the mostly elderly CLL patient population, CLL patients often suffer from multiple cardiovascular comorbidities including atrial fibrillation (AF), deep vein thrombosis (DVT) or pulmonary embolism (PE) which make anticoagulation mandatory. Up to now, no systematic and prospective evaluation on interactions of BTKis and DOACs has been conducted. In Order to assess bleeding events, a questionnaire will be used to document if bleeding events occurred in-between visits in routine care. Patients will be asked at each visit if distinct events occurred in the time between the last visit until the current visit and discuss the questionnaire with the physician to determine of any (S)AE occurred until end of acalabrutinib treatment.

Official Title
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A Non-interventional, Prospective, Open-label, Observational Study Evaluating the Effectiveness and Safety of Acalabrutinib (Calquence®) in Patients With Chronic Lymphocytic Leukemia (CLL) Receiving Direct Oral Anticoagulation (DOAC).

Conditions
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CLL

Intervention / Treatment
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* Drug: Calquence
* Drug: Calquence


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 18 years of age or older Patients with chronic lymphocytic leukemia (CLL) and decision for treatment with acalabrutinib (+/- obinutuzumab) according to current SmPC as assessed by the treating physician or already started treatment with acalabrutinib (+/- obinutuzumab) according to current SmPC no longer than 6 weeks ago Other concomitant disease resulting in medical need of or already under treatment with direct oral anticoagulant (DOAC) treatment with edoxaban (Lixiana®) or rivaroxaban (Xarelto®) or dabigatran (Pradaxa®) or apixaban (Eliquis®) according to the respective current SmPC. Eastern Cooperative Oncology Group (ECOG) performance status 0-2 Signed, written informed consent. Exclusion Criteria: Combination of acalabrutinib with other substances than obinutuzumab for CLL treatment Participation in an interventional clinical trial with acalabrutinib

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| first-line therapy<br>Patients enrolled for first-line acalabrutinib (+/- obinutuzumab). | Drug: Calquence<br>* acalabrutinib (+/- obinutuzumab) according to Calquence® SmPC.<br>|
| later-line therapy<br>Pre-treated patients enrolled for later-line acalbrutinib therapy. | Drug: Calquence<br>* acalabrutinib according to Calquence® SmPC.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence proportion of patients with major bleeding event according to Schulman et al. | Bleeding event is defined as major according to Schulmann et al., if it is fatal (contributes to death) and/or symptomatic in a critical area or organ (such as intracranial, intraspinal, intraocular, retroperitoneal, intraarticular or pericardial, or intramuscular with compartment syndrome) and/or causing a decrease in hemoglobin of 2 g/dL (1.24 mmol/l) or more or requires a transfusion of 2 or more units of whole blood or red blood cells. Incidence proportion (cumulative incidence) is calculated as the number of patients with bleeding event while on treatment (+30 days safety follow-up), divided by the number of patients in the full analysis population. | Baseline until end of acalabrutinib treatment (+ 30 days safety follow-up); up to 30 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence proportion of clinically relevant non-major (CRNM) bleeding events | CRNM bleeding is defined as bleeding that does not meet the criteria for major bleeding according to Schulman et al. but is associated with the need for medical intervention and/or personal contact with a physician and/or hospitalization or increase in level of care. | Baseline, up to 30 months | 
| Major (according to Schulman et al.) and/or CRNM bleeding events. | Incidence proportion of major (according to Schulman et al.) and/or CRNM bleeding events. | Baseline, up to 30 months | 
| Any bleeding event. | Incidence proportion of any bleeding event. | Baseline, up to 30 months | 
| Incidence proportion of major bleeding according to Ghia et al. | Major bleeding according to Ghia et al. is defined as any serious OR grade ≥3 hemorrhage OR central nervous system (CNS) hemorrhage of any grade, excluding immune thrombocytopenic purpura. | Baseline, up to 30 months | 
| Time to first Occurrence of major bleeding events | Time to first occurrence of major (according to Schulman et al.) bleeding events. | Baseline, up to 30 months | 
| Incidence proportion of central nervous system (CNS) bleeding events | Frequencies of patients with CNS bleeding events. | Baseline, up to 30 months | 
| Patient safety regarding mortality | Mortality from all causes during acalabrutinib therapy. | Baseline, up to 30 months | 
| Patient safety in terms of interactions with effectiveness of DOAC | Rate of any new or recurrent ischemic stroke or arterial systemic embolism or venous thromboembolic events. | Baseline, up to 30 months | 
| VTE (venous thromboembolism)-related death | Incidence proportion of VTE-related death. | Baseline, up to 30 months | 
| Overall response rate (ORR) | ORR is defined as proportion of patients with any response (partial or complete remission) overall. | Baseline, up to 30 months | 
| Progression-free survival (PFS) | Time from start of acalabrutinib to occurrence of progressive disease or death from any cause, whichever comes first. | Baseline, up to 30 months | 
| Overall survival (OS) | OS is defined as time from first administration of acalabrutinib to death from any cause. | Baseline, up to 30 months | 
| Therapy decision making | Frequencies of parameters affecting therapy choice. | Baseline | 
| Previous therapies | Frequencies and percentages of previous therapies | Baseline | 
| Acalabrutinib (+/- obinutuzumab) treatment: Duration | Analysis of treatment duration of acalabrutinib using descriptive statistics. | Baseline, up to 30 months | 
| Acalabrutinib (+/- obinutuzumab) treatment: Dose intensity | Analysis of dose intensity of acalabrutinib treatment with reference to the SmPC (absolute and relative) using descriptive statistics. | Baseline, up to 30 months | 
| Obinutuzumab treatment: Duration | Analysis of treatment duration of obinutuzumab using descriptive statistics | Baseline, up to 30 months | 
| Reasons for end of treatment of obinutuzumab | Frequencies and percentages of reasons for end of obinutuzumab treatment. | Baseline, up to 30 months | 
| Types of DOAC | Type of DOAC used (edoxaban, rivaroxaban, dabigatran and apixaban). | Baseline, up to 30 months | 
| Reasons for DOAC treatment | Frequencies and precentages of reasons for DOAC treatment. | Baseline, up to 30 months | 
| DOAC treatment: Duration | Analysis of DOAC treatment duration using descriptive statistics. | Baseline, up to 30 months | 
| DOAC treatment: Dose modifications | Frequencies and percentages of dose modifications of DOAC treatment. | Baseline, up to 30 months | 
| DOAC treatment: Reasons for dose modifications | Frequencies and percentages of reasons for dose modifications of DOAC treatment. | Baseline, up to 30 months | 
| DOAC treatment: Reasons for end of treatment | Frequencies and percentages of reasons for end of DOAC treatment. | Baseline, up to 30 months | 
| Time from onset to DOAC to start of acalabrutinib | Assessment of time from onset of DOAC to start of acalabrutinib therapy using descriptive statistics. | Baseline, up to 30 months | 
| Concomitant medication | Frequency of concomitant medication other than DOAC. | Baseline, up to 30 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CLL, Acalabrutinib (+/- Obinutuzumab), DOAC