BTK inhibitors potently impair platelet aggregation as a class effect independent of BTK specificity or dose in CLL and MCL

Abstract

BTK inhibitors (BTKi) are established standards of care for chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL); however, their use has been associated with an increased risk of bleeding. We investigated whether BTKi impaired platelet aggregation and adhesion in a drug- or dose-dependent manner in patients with CLL and MCL who received ibrutinib, acalabrutinib, or pirtobrutinib. Treatment with BTKi significantly inhibited 2 µg/mL collagen-induced platelet aggregation (CIPA) by 82.1±7.3% (P < 0.0001) in maximum aggregation rates, with levels independent of BTK selectivity and the applied dose. This inhibitory effect was more potent than that of acetylsalicylic acid (aspirin, 100 mg daily) (P < 0.0001). BTKi did not significantly affect adenosine diphosphate- or ristocetin-induced aggregation. The first-generation BTKi ibrutinib but not the newer BTKi acalabrutinib or pirtobrutinib, impairs platelet adhesion, possibly owing to the different inhibitory profiles to SRC family kinases. Our findings have two clinical implications. First, because BTKi treatment inhibits CIPA as a class effect, independent of drug specificity or dose, measuring CIPA levels alone may not help physicians predict near-future bleeding complications. Although the sample size was small, our results suggest the potential of impaired platelet adhesion as a candidate biomarker for estimating bleeding risk in patients receiving BTKi. Second, in BTKi-treated patients requiring anti-platelet agents, BTKi dose reduction may be considered, irrespective of BTK selectivity of the drug or whether aspirin or a P2Y_¹² receptor inhibitor is used.