Past medical history, active comorbidities and concomitant medications, and therapy selection
| Nonwarfarin anticoagulant and/or single antiplatelet therapy |
| Although bleeding risk appears lower with acalabrutinib or zanubrutinib than ibrutinib, major bleeding still occurs in 3%-5% of patients.10,11,50 Bleeding risk is increased with coadministration of a nonwarfarin anticoagulant or antiplatelet therapy, which influences treatment selection toward Ven-O, but the absolute difference in major bleeding risk is low (<1%-2%) and a second-generation cBTKi remains a reasonable option.10,50 It is also important to clarify the indication for anticoagulation/antiplatelet therapy, and whether its continued use is needed. |
| Warfarin anticoagulant |
| Our recommendation against concomitant warfarin with cBTKi comes from early phase 1 trials of ibrutinib, which reported subdural hematomas in patients receiving warfarin, leading subsequent trials to exclude concomitant warfarin.51 When a cBTKi is being considered in a patient on warfarin, which we consider a contraindication, use of an alternative anticoagulant is often acceptable, and even preferable for many indications. |
| Dual antiplatelet therapy |
| Data regarding safety of concurrent dual antiplatelet therapy and cBTKi is limited, as dual antiplatelet therapy use was very rare in cBTKi trials. However, major bleeding risk may already be increased up to approximately twofold with dual antiplatelet therapy vs aspirin, without addition of a cBTKi, which leads to additional antiplatelet effect.52 Therefore, we strongly recommend Ven-O over a cBTKi in patients on dual antiplatelet therapy. |
| Bleeding history |
| A history of major bleeding who have ongoing risk, eg, because of an underlying bleeding disorder or uncontrolled bleeding source, have generally been excluded from clinical trials of cBTKis. Therefore, we strongly recommend use of Ven-O over a cBTKi in these patients.22-34,42-44 Preexisting bruising or petechiae alone does not predict major bleeding and should not influence treatment selection. |
| AF history |
| AF risk is lower with acalabrutinib or zanubrutinib than ibrutinib (2% vs 9% cumulative incidence at 12 mo).42-44,53 Patients with persistent or paroxysmal AF may be safely treated with a second-generation cBTKi, although this can occasionally precipitate recurrent AF, and use of anticoagulation or antiplatelet therapy for AF stroke reduction increases bleeding risk. |
| Ventricular arrhythmia history |
| Ventricular arrhythmias are very rare, 6-8 per 1000 person-years with ibrutinib, and occurring less frequently with acalabrutinib or zanubrutinib.54-56 Risk factors for cBTKi-related ventricular arrhythmias are largely unknown, and ventricular arrhythmias can occur in patients without known cardiac disease. We strongly recommend against cBTKi use in patients with a history of ventricular arrhythmias unless the underlying cause is addressed. |
| Hypertension |
| Hypertension does not influence our treatment selection toward Ven-O or a cBTKi, in part because acalabrutinib has a lower incidence of hypertension compared with ibrutinib, making it an appealing cBTKi option for patients with uncontrolled or difficult-to-manage hypertension.42,44 |
| Heart failure |
| Heart failure is not a single disease and can have heterogeneous clinical manifestations, each interacting differently with treatment risks. For example, although the presence of volume overload may complicate intravenous fluid administration for Ven-treated patients with higher risk of tumor lysis syndrome, this short-term risk may be preferred as baseline heart failure increases cardiovascular risks associated with BTKis. |
| Nonwarfarin anticoagulant and/or single antiplatelet therapy |
| Although bleeding risk appears lower with acalabrutinib or zanubrutinib than ibrutinib, major bleeding still occurs in 3%-5% of patients.10,11,50 Bleeding risk is increased with coadministration of a nonwarfarin anticoagulant or antiplatelet therapy, which influences treatment selection toward Ven-O, but the absolute difference in major bleeding risk is low (<1%-2%) and a second-generation cBTKi remains a reasonable option.10,50 It is also important to clarify the indication for anticoagulation/antiplatelet therapy, and whether its continued use is needed. |
| Warfarin anticoagulant |
| Our recommendation against concomitant warfarin with cBTKi comes from early phase 1 trials of ibrutinib, which reported subdural hematomas in patients receiving warfarin, leading subsequent trials to exclude concomitant warfarin.51 When a cBTKi is being considered in a patient on warfarin, which we consider a contraindication, use of an alternative anticoagulant is often acceptable, and even preferable for many indications. |
| Dual antiplatelet therapy |
| Data regarding safety of concurrent dual antiplatelet therapy and cBTKi is limited, as dual antiplatelet therapy use was very rare in cBTKi trials. However, major bleeding risk may already be increased up to approximately twofold with dual antiplatelet therapy vs aspirin, without addition of a cBTKi, which leads to additional antiplatelet effect.52 Therefore, we strongly recommend Ven-O over a cBTKi in patients on dual antiplatelet therapy. |
| Bleeding history |
| A history of major bleeding who have ongoing risk, eg, because of an underlying bleeding disorder or uncontrolled bleeding source, have generally been excluded from clinical trials of cBTKis. Therefore, we strongly recommend use of Ven-O over a cBTKi in these patients.22-34,42-44 Preexisting bruising or petechiae alone does not predict major bleeding and should not influence treatment selection. |
| AF history |
| AF risk is lower with acalabrutinib or zanubrutinib than ibrutinib (2% vs 9% cumulative incidence at 12 mo).42-44,53 Patients with persistent or paroxysmal AF may be safely treated with a second-generation cBTKi, although this can occasionally precipitate recurrent AF, and use of anticoagulation or antiplatelet therapy for AF stroke reduction increases bleeding risk. |
| Ventricular arrhythmia history |
| Ventricular arrhythmias are very rare, 6-8 per 1000 person-years with ibrutinib, and occurring less frequently with acalabrutinib or zanubrutinib.54-56 Risk factors for cBTKi-related ventricular arrhythmias are largely unknown, and ventricular arrhythmias can occur in patients without known cardiac disease. We strongly recommend against cBTKi use in patients with a history of ventricular arrhythmias unless the underlying cause is addressed. |
| Hypertension |
| Hypertension does not influence our treatment selection toward Ven-O or a cBTKi, in part because acalabrutinib has a lower incidence of hypertension compared with ibrutinib, making it an appealing cBTKi option for patients with uncontrolled or difficult-to-manage hypertension.42,44 |
| Heart failure |
| Heart failure is not a single disease and can have heterogeneous clinical manifestations, each interacting differently with treatment risks. For example, although the presence of volume overload may complicate intravenous fluid administration for Ven-treated patients with higher risk of tumor lysis syndrome, this short-term risk may be preferred as baseline heart failure increases cardiovascular risks associated with BTKis. |