Page 186 - 2019_11 Resto del Mondo-web

Ferrata Storti Foundation
Haematologica 2019 Volume 104(11):2292-2299
Platelet Biology & its Disorders
Differences and similarities in the effects of ibrutinib and acalabrutinib on platelet functions
Jennifer Series,1,2 Cédric Garcia,2 Marie Levade,1,2 Julien Viaud,1 Pierre Sié,1,2 Loïc Ysebaert3,§ and Bernard Payrastre1,2,§
1Inserm, U1048 and Université Toulouse 3, Toulouse Cedex 04; 2Laboratoire d’Hématologie, CHU de Toulouse, Toulouse Cedex 04; 3Service d’Hématologie IUCT-Oncopôle, Toulouse Cedex 09, France
§These authors share senior authorship.
ABSTRACT
While efficient at treating B-cell malignancies, Bruton tyrosine kinase (BTK) inhibitors are consistently reported to increase the risk of bleeding. Analyzing platelet aggregation response to colla- gen in platelet-rich plasma allowed us to identify two groups in the healthy population characterized by low or high sensitivity to ibrutinib in vitro. Inhibition of drug efflux pumps induced a shift from ibrutinib low-sensitive platelets to high-sensitive ones. At a clinically relevant dose, acalabrutinib, a second-generation BTK inhibitor, did not affect maximal collagen-induced platelet aggregation in the ibrutinib low-sensitive group but did inhibit aggregation in a small fraction of the ibrutinib high-sensitive group. Consistently, acalabrutinib delayed aggregation, particularly in the ibrutinib high-sensitive group. In chronic lymphocytic leukemia patients, acalabruti- nib inhibited maximal platelet aggregation only in the ibrutinib high-sensi- tive group. Acalabrutinib inhibited collagen-induced tyrosine-753 phospho- rylation of phospholipase Cγ2 in both groups, but, in contrast to ibrutinib, did not affect Src-family kinases. Acalabrutinib affected thrombus growth under flow only in the ibrutinib high-sensitive group and potentiated the effect of cyclooxygenase and P2Y12 receptor blockers in both groups. Since the better profile of acalabrutinib was observed mainly in the ibrutinib low- sensitive group, replacement therapy in patients may not systematically reduce the risk of bleeding.
Introduction
Bruton tyrosine kinase (Btk) inhibitors are efficient therapeutic agents for the treat- ment of chronic lymphocytic leukemia (CLL), mantle-cell lymphoma and Waldenström macroglobulinemia.1-3 However, these drugs are recognized to increase the rate of bleeding in up to 50% of treated patients.4,5 Most bleeding events are of grade 1-2, and include spontaneous bruising, petechiae and hematomas, but, in 5% of patients, they are of grade 3 or higher.6-9 Such an incidence of bleeding warrants concerns, particularly during invasive procedures or surgery or when Btk inhibitors are associated with antithrombotic therapy.4,5
Several studies have now clearly shown that the first-in-class Btk inhibitor, ibru- tinib, causes platelet dysfunction in a significant proportion of treated patients. In vitro, in normal platelets, the drug has been shown to affect activation mechanisms downstream of the collagen receptor GPVI, GPIb and αIIbβ3 integrin.10-13 Btk and Tec are two members of the same family of tyrosine kinases involved in platelet activation, at least via their contribution to phospholipase Cγ2 (PLCγ2) phosphory- lation.14,15 Experimental mouse models of Btk invalidation have shown that Btk is involved in collagen/GPVI and von Willebrand factor/GPIb-IX-V-induced platelet activation.14,16 However, patients with X-linked agammaglobulinemia do not have a bleeding phenotype and their Btk-deficient platelets exhibit only a weak defect, suggesting compensation of Btk by Tec.14,17,18 Accordingly, invalidation of both Btk and Tec in mice was required to impair platelet responses evoked by GPVI agonists.15
Correspondence:
BERNARD PAYRASTRE
bernard.payrastre@inserm.fr
LOIC YSEBAERT
ysebaert.loic@iuct-oncopole.fr
Received: October 1, 2018. Accepted: February 28, 2019. Pre-published: February 28, 2019.
doi:10.3324/haematol.2018.207183
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/104/11/2292
©2019 Ferrata Storti Foundation
Material published in Haematologica is covered by copyright. All rights are reserved to the Ferrata Storti Foundation. Use of published material is allowed under the following terms and conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode. Copies of published material are allowed for personal or inter- nal use. Sharing published material for non-commercial pur- poses is subject to the following conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode, sect. 3. Reproducing and sharing published material for com- mercial purposes is not allowed without permission in writing from the publisher.
2292
haematologica | 2019; 104(11)
ARTICLE