Abstract:Background: Therapy with irreversible Bruton's tyrosine kinase inhibitor ibrutinib in chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) is associated with bleeding. Objectives: To propose the predictive markers of such bleeding, as well as mechanisms responsible for decreased bleeding at later therapy stages. Patients/Methods: We investigate platelet functional activity in 50 CLL and 16 MCL patients on ibrutinib using flow cytometry and light transmission aggregometry. Results: Prior to treatme… Show more
“…The highest risk of haemorrhage occurs in the first months of treatment, suggesting that both disease and treatment-related factors influence the severity of this AE (Ysebaert et al, 2014;Lipsky et al, 2015;Brown et al, 2019;Dmitrieva et al, 2020). Furthermore, patients with B-cell malignancies have an intrinsic risk of bleeding (Gifkins et al, 2015).…”
Section: Increased Risk For Bleedings Under Btki Treatmentmentioning
confidence: 99%
“…Low-grade bleeding events are usually not associated with thrombocytopenia, suggesting an impaired platelet function as the cause of the AE as reviewed (Berglöf et al, 2015). However, Dmitrieva et al (2020) investigated the platelet function in 50 CLL and 16 MCL patients and their results suggest that ibrutinibdependent bleeding in CLL patients requires a setting of three mechanisms. Most important was a decreased platelet count prior ibrutinib treatment.…”
Section: Increased Risk For Bleedings Under Btki Treatmentmentioning
The cytoplasmic protein-tyrosine kinase BTK plays an essential role for differentiation and survival of B-lineage cells and, hence, represents a suitable drug target. The number of BTK inhibitors (BTKis) in the clinic has increased considerably and currently amounts to at least 22. First-in-class was ibrutinib, an irreversible binder forming a covalent bond to a cysteine in the catalytic region of the kinase, for which we have identified 228 active trials listed at ClinicalTrials.gov. Next-generation inhibitors, acalabrutinib and zanubrutinib, are approved both in the United States and in Europe, and zanubrutinib also in China, while tirabrutinib is currently only registered in Japan. In most cases, these compounds have been used for the treatment of B-lymphocyte tumors. However, an increasing number of trials instead addresses autoimmunity and inflammation in multiple sclerosis, rheumatoid arthritis, pemphigus and systemic lupus erythematosus with the use of either irreversibly binding inhibitors, e.g., evobrutinib and tolebrutinib, or reversibly binding inhibitors, like fenebrutinib. Adverse effects (AEs) have predominantly implicated inhibition of other kinases with a BTKi-binding cysteine in their catalytic domain. Analysis of the reported AEs suggests that ibrutinib-associated atrial fibrillation is caused by binding to ERBB2/HER2 and ERBB4/HER4. However, the binding pattern of BTKis to various additional kinases does not correlate with the common assumption that skin manifestations and diarrhoeas are off-target effects related to EGF receptor inhibition. Moreover, dermatological toxicities, diarrhoea, bleedings and invasive fungal infections often develop early after BTKi treatment initiation and subsequently subside. Conversely, cardiovascular AEs, like hypertension and various forms of heart disease, often persist.
“…The highest risk of haemorrhage occurs in the first months of treatment, suggesting that both disease and treatment-related factors influence the severity of this AE (Ysebaert et al, 2014;Lipsky et al, 2015;Brown et al, 2019;Dmitrieva et al, 2020). Furthermore, patients with B-cell malignancies have an intrinsic risk of bleeding (Gifkins et al, 2015).…”
Section: Increased Risk For Bleedings Under Btki Treatmentmentioning
confidence: 99%
“…Low-grade bleeding events are usually not associated with thrombocytopenia, suggesting an impaired platelet function as the cause of the AE as reviewed (Berglöf et al, 2015). However, Dmitrieva et al (2020) investigated the platelet function in 50 CLL and 16 MCL patients and their results suggest that ibrutinibdependent bleeding in CLL patients requires a setting of three mechanisms. Most important was a decreased platelet count prior ibrutinib treatment.…”
Section: Increased Risk For Bleedings Under Btki Treatmentmentioning
The cytoplasmic protein-tyrosine kinase BTK plays an essential role for differentiation and survival of B-lineage cells and, hence, represents a suitable drug target. The number of BTK inhibitors (BTKis) in the clinic has increased considerably and currently amounts to at least 22. First-in-class was ibrutinib, an irreversible binder forming a covalent bond to a cysteine in the catalytic region of the kinase, for which we have identified 228 active trials listed at ClinicalTrials.gov. Next-generation inhibitors, acalabrutinib and zanubrutinib, are approved both in the United States and in Europe, and zanubrutinib also in China, while tirabrutinib is currently only registered in Japan. In most cases, these compounds have been used for the treatment of B-lymphocyte tumors. However, an increasing number of trials instead addresses autoimmunity and inflammation in multiple sclerosis, rheumatoid arthritis, pemphigus and systemic lupus erythematosus with the use of either irreversibly binding inhibitors, e.g., evobrutinib and tolebrutinib, or reversibly binding inhibitors, like fenebrutinib. Adverse effects (AEs) have predominantly implicated inhibition of other kinases with a BTKi-binding cysteine in their catalytic domain. Analysis of the reported AEs suggests that ibrutinib-associated atrial fibrillation is caused by binding to ERBB2/HER2 and ERBB4/HER4. However, the binding pattern of BTKis to various additional kinases does not correlate with the common assumption that skin manifestations and diarrhoeas are off-target effects related to EGF receptor inhibition. Moreover, dermatological toxicities, diarrhoea, bleedings and invasive fungal infections often develop early after BTKi treatment initiation and subsequently subside. Conversely, cardiovascular AEs, like hypertension and various forms of heart disease, often persist.
“…83,84 Ibrutinib treatment further reduced procoagulant platelet formation upon strong stimulation, which was already reduced in patients with chronic lymphocytic leukemia which could also contribute to the development of bleeding. 85 On the other hand, recent study suggests that procoagulant platelets are upregulated by desmopressin and may play a role in its mechanism of action of desmopressin. 86 Another study 87 showed the ability of procoagulant platelets to bind factor VIIa and promote factor X activation by it, which may be a mechanism of action of recombinant-activated factor VII.…”
Section: Generation Of Procoagulant Platelets In Patientsmentioning
During the past decades, it has been increasingly recognized that the major function of accelerating membrane-dependent reactions of blood coagulation is predominantly implemented by a subset of activated platelets. These procoagulant platelets (also called collagen- and thrombin-activated or COAT, coated, necrotic, although there could be subtle differences between these definitions) are uniquely characterized by both procoagulant activity and, at the same time, inactivated integrins and profibrinolytic properties. The mechanisms of their generation both in vitro and in situ have been increasingly becoming clear, suggesting unique and multidirectional roles in hemostasis and thrombosis. In this mini-review, we shall highlight the existing concepts and challenges in this field.
“…Consideration of bleeding risk is therefore increasingly needed in oncological practice. In this edition of the journal, Dmitrieva and colleagues explore the timing of bleeding risk and platelet dysfunction in lymphoproliferative disorders treated with the first‐in‐class Bruton's tyrosine kinase (BTK) inhibitor ibrutinib 3 …”
Section: Figurementioning
confidence: 99%
“…Dmitrieva and colleagues examined platelet dysfunction over time during ibrutinib treatment 3 . They found that platelet function decreased following initiation of ibrutinib, but then improved in concert with disease response.…”
Background: Platelets have critical roles in preventing blood loss following injury, promoting wound healing, and in fighting infection through innate immune defense strategies. Key Results: Deficiencies in platelet number or function either as a result of disease, as a consequence of therapy, or both can lead to dramatic and potentially fatal consequences. Conclusions and Inferences: With the advent of new therapeutics targeting pathways within hematological malignant cells that are also important for platelet function, monitoring the state of a patient's haemostasis system is now an important clinical consideration.
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