Chronic lymphocytic leukemia (CLL), a cancer of B-cell lymphocytes, is the most common type of leukemia in adults. Ibrutinib is a potent, small molecule inhibitor of BTK that has revolutionized the treatment approach of CLL patients. A major cause of morbidity in patients treated with ibrutinib is atrial fibrillation that represents a high risk for cardioembolic stroke and systemic embolism. Treatment and prevention of cardioembolic stroke and systemic embolism of atrial fibrillation pose a clinical challenge in balancing thrombosis and bleeding risks in patients taking ibrutinib, a drug that is associated with an anti-aggregant effect. Very limited data and conflicting opinions are available about the use of direct-acting oral anticoagulants (DOACS) or other anticoagulants/antiaggregant agents in the ibrutinib-treated population. At present, recommendations about the use or not of DOACS are not supported by studies including representative cohorts of patients treated with these agents. The primary endpoints of this multicenter, observational, retrospective/prospective study are to define the rate of thromboembolic events and severe bleeding events in CLL patients who develop atrial fibrillation while on ibrutinib and receive anticoagulation with DOACS or other anticoagulants/ antiaggregant treatment. Secondary endpoints will describe the clinical and biologic characteristics of CLL patients requiring anticoagulation due to atrial fibrillation, the type of DOACS (Rivaroxaban, Apixaban, Edoxaban, Dabigatran) or other anticoagulants/antiaggregant treatment (Low-molecular-weight heparin, aspirin, clopidogrel, etc) used in this patient population. We will also analyze the reasons for anticoagulant discontinuation, the management of anticoagulant treatment, and the survival probability of CLL patients treated with anticoagulants and ibrutinib.
Ibrutinib is an oral Bruton tyrosine kinase (BTK) inhibitor that has recently revolutionized the treatment and improved the patient outcome of chronic lymphocytic leukemia (CLL), the most common leukemia in adults, and other B-cell chronic malignancies.
Atrial fibrillation, a frequent off-target effect of ibrutinib, represents challenges in the clinical management of CLL patients.
The majority of patients with CLL who develop atrial fibrillation and require anticoagulant therapy to prevent ischaemic stroke. Their anticoagulation is challenging due to the concomitant anti-aggregant effect of ibrutinib and the associated bleeding risk under antithrombotic therapy. International and national treatment guidelines had an important role in helping clinicians to safely administer ibrutinib. However, there is no general agreements regarding the type of antithrombotic therapy in patients treated with ibrutinib. Concerns about bleeding associated with the combination of ibrutinib plus anticoagulants led many authors to recommend ibrutinib discontinuation in patients with atrial fibrillation. Some authors stated that direct-acting oral anticoagulants (DOACs), apixaban, and rivaroxaban, are appropriate options for concomitant use with ibrutinib. However, this recommendation is based on a pharmacokinetic rationale only. Some experts recommended low starting doses of DOACs but this strategy has not been tested to account for increased bleeding risks in patients while using ibrutinib therapy at full therapeutic doses.
In conclusion, a not irrelevant proportion of patients treated with ibrutinib develop atrial fibrillation and require anticoagulant therapy. At present no therapeutic recommendations regarding the optimal anticoagulant treatment are based on clinical data, in particular, data deriving from real-life studies. Data about the efficacy and safety of DOACS, or other anticoagulant/ antiaggregant treatments, treated with ibrutinib are of great importance in evaluating the risk/benefit ratio of these different treatment approaches in CLL patients with atrial fibrillation who receive ibrutinib