Severe platelet dysfunction in NHL patients receiving ibrutinib is absent in patients receiving acalabrutinib

Abstract

The Bruton tyrosine kinase (Btk) inhibitor ibrutinib induces platelet dysfunction and causes increased risk of bleeding. Off-target inhibition of Tec is believed to contribute to platelet dysfunction and other side effects of ibrutinib. The second-generation Btk inhibitor acalabrutinib was developed with improved specificity for Btk over Tec. We investigated platelet function in patients with non-Hodgkin lymphoma (NHL) receiving ibrutinib or acalabrutinib by aggregometry and by measuring thrombus formation on collagen under arterial shear. Both patient groups had similarly dysfunctional aggregation responses to collagen and collagen-related peptide, and comparison with mechanistic experiments in which platelets from healthy donors were treated with the Btk inhibitors suggested that both drugs inhibit platelet Btk and Tec at physiological concentrations. Only ibrutinib caused dysfunctional thrombus formation, whereas size and morphology of thrombi following acalabrutinib treatment were of normal size and morphology. We found that ibrutinib but not acalabrutinib inhibited Src family kinases, which have a critical role in platelet adhesion to collagen that is likely to underpin unstable thrombus formation observed in ibrutinib patients. We found that platelet function was enhanced by increasing levels of von Willebrand factor (VWF) and factor VIII (FVIII) ex vivo by addition of intermediate purity FVIII (Haemate P) to blood from patients, resulting in consistently larger thrombi. We conclude that acalabrutinib avoids major platelet dysfunction associated with ibrutinib therapy, and platelet function may be enhanced in patients with B-cell NHL by increasing plasma VWF and FVIII.

Itraconazole Increases Ibrutinib Exposure 10‐Fold and Reduces Interindividual Variation—A Potentially Beneficial Drug‐Drug Interaction

“…27 Inhibition of other kinases than BTK has been suggested to be involved in some of these adverse effects, such as inhibitory effect on platelet function. 28 Based on our present results, the concomitant use of currently available 70-mg and 140-mg capsules of ibrutinib with itraconazole or other strong CYP3A4 inhibitors increases ibrutinib exposure to a higher level than what is observed when the usual 420-mg or 560-mg daily doses are taken without CYP3A4 inhibitors. Such a high exposure could increase the risk of concentration-dependent adverse effects and lead to discontinuation of the treatment and potentially affect clinical outcomes.…”

Relative Selectivity of Covalent Inhibitors Requires Assessment of Inactivation Kinetics and Cellular Occupancy: A Case Study of Ibrutinib and Acalabrutinib

“…Although clinical data were still being accumulated, an earlier hypothesis based on kinase affinity data proposed that acalabrutinib might lead to lower bleeding rates because of its higher selectivity for BTK relative to TEC (Byrd et al, 2016;Barf et al, 2017;Awan et al, 2019). However, when properly adjusted for clinical exposure, covalent binding mechanism, and enzymatic activity, our data and those of other groups (Bye et al, 2017) now indicate that ibrutinib and acalabrutinib have similar selectivity between BTK and TEC. This similar selectivity is consistent with a recent study suggesting that platelet inhibition and potential hemorrhagic risk predicted by in vitro closure time are likelyclass effects across five BTK inhibitors: ibrutinib, zanubrutinib, acalabrutinib, tirabrutinib, and evobrutinib (Denzinger et al, 2019).…”

Mantle cell lymphoma: 2019 update on the diagnosis, pathogenesis, prognostication, and management

“…Acalabrutinib is a covalent inhibitor of C481S in the ATP binding pocket of BTK with a short half‐life. Acalabrutinib and its major metabolite ACP‐5862 have limited off‐target kinase activity, inhibiting only two kinases [ErbB4] and the BMX gene in chromosome X. Acalabrutinib preserves Src family kinase (collagen to platelet adhesion) activity and thus avoids the unstable platelet thrombus formation seen with ibrutinib therapy . These mechanisms potentially explain why the risk of bleeding and atrial fibrillation is significantly more minimal with acalabrutinib compared to ibrutinib.…”