pci-32765 and Atrial-Fibrillation

The natural history of chronic lymphocytic leukemia (CLL) was dramatically improved by the introduction of ibrutinib, a Bruton's tyrosine kinase (BTK) inhibitor. In this review, we aimed to summarize and critically evaluate the association between first- and second-generation BTK inhibitors and the risk of atrial fibrillation (AF) and ventricular arrhythmias (VA).. Since the first clinical experience, the development of AF was observed as the result of off-target effects that likely combined with patient's predisposing risk factors and concomitant cardiac morbidities. More recently, both ibrutinib dose reduction and arrhythmia management allowed long-term treatment, with positive effects on progression-free survival and reduced all-cause mortality as well. Second-generation BTK inhibitors, acalabrutinib, and zanubrutinib have been tested and validated in CLL. A lower occurrence of AF as compared with ibrutinib has been found, although AF has always been a secondary endpoint of all studies that probed these agents.. For this reason, caution should be exercised before concluding that second-generation BTK inhibitors are safer than ibrutinib. Recent data on the effectiveness of ibrutinib over a follow-up of 8 years show a remarkable benefit on all-cause mortality, which is of great value also for interpreting the clinical impact of the few cases of VA and sudden cardiac death (SCD) reported for ibrutinib, independently of QT lengthening. Since a risk of VA and SCD has been recently reported also during treatment with second-generation BTK inhibitors, it appears that this risk, usually reaching its maximum size effect at long-term follow-up, likely denotes a class effect of BTK inhibitors.

Topics: Agammaglobulinaemia Tyrosine Kinase; Atrial Fibrillation; Death, Sudden, Cardiac; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Protein Kinase Inhibitors; Tachycardia, Ventricular; Tyrosine Kinase Inhibitors

Ibrutinib is a potent Bruton tyrosine kinase inhibitor and is an effective and well-tolerated treatment for a variety of lymphoid diseases. However, its use is associated with an increased incidence of atrial fibrillation ranging from 4% to 16%. New onset atrial fibrillation in cancer patients is associated with a significantly higher risk of heart failure and thromboembolism, even after adjusting for known risk factors. Ibrutinib also inhibits platelet activation and decisions regarding anticoagulation must be carefully weighed against this increased risk of bleeding. It is well-known that the anti-arrhythmic and antithrombotic strategy for atrial fibrillation related to ibrutinib has its own characteristics. Physicians should be familiar with the special management considerations imposed by this drug. Indeed, the co-prescription of therapy in combination with ibrutinib must be carefully weighed in view of its numerous drug interactions. We review the potential mechanisms and incidence of ibrutinib-associated atrial fibrillation.

Topics: Anticoagulants; Atrial Fibrillation; Humans; Piperidines; Pyrazoles; Pyrimidines

The use of ibrutinib is hampered by major bleeding events and atrial fibrillation. Speculating whether randomized controlled trials might underestimate the risk of adverse events in clinical practice, we conducted a systematic review and meta-analysis studying patients treated in any setting and indication. We systematically searched the literature using MEDLINE and EMBASE databases for case series, cohort studies, or randomized controlled trials and retrieved all data in parallel. Proportions of patients with adverse events were pooled in relevant subgroups using the binominal distribution and Freeman-Tukey double arcsine transformation. Among 2'537 records screened, 85 were finally included, comprising 7'317 patients. Methodological quality according to the Newcastle-Ottawa Scale was rated as moderate to poor with regard to bleeding events and atrial fibrillation; 106 studies were excluded because of missing data at all. Reported events varied substantially between 0 % and 78 % (any bleedings), 0 % and 25 % (major bleedings), and 0 % and 38 % (new-onset atrial fibrillation). Pooled estimates were 28 % (95 % confidence interval 22 %, 34 %), 3 % (2 %, 4 %), and 8 % respectively (7 %, 10 %). The risk of events was higher in studies with an older population, high ibrutinib dosage, thrombocytopenia, antithrombotic treatment, and retrospective studies. In conclusions, reporting of bleeding events and atrial fibrillation varied substantially among studies. These observations, in combination with the estimates obtained, suggest a relevant risk in clinical practice.

Topics: Adenine; Atrial Fibrillation; Humans; Piperidines; Pyrazoles; Pyrimidines; Retrospective Studies

The purpose of this review is to summarize the epidemiology, mechanisms, and management of cardiovascular complications of Bruton's Tyrosine Kinase inhibitors (BTKIs).. Ibrutinib increases the risk of atrial fibrillation, bleeding, and hypertension compared with non-BTKI therapies. The evidence to support an association between ibrutinib and other cardiovascular complications including ventricular tachyarrhythmias or cardiomyopathy is limited. Ibrutinib metabolism can be inhibited by some medications used to treat cardiovascular complications. The cardiovascular effects of more selective BTKIs, such as acalabrutinib, remain to be determined. Future research should address the mechanisms underlying the cardiovascular complications of BTKIs and how best to manage them. The risks and benefits of more selective BTKIs as compared with ibrutinib require further evaluation.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Atrial Fibrillation; Cardiotoxicity; Heart Failure; Hemorrhage; Humans; Hypertension; Piperidines; Protein Kinase Inhibitors; Tachycardia, Ventricular

Ibrutinib is a new first-line drug for treating chronic lymphocytic leukemia (CLL), and could change frontline treatment of CLL from traditional IV chemotherapy to oral targeted therapy. Lymphocytosis often worsens with initiation of ibrutinib, but typically resolves over 6 to 18 months. Though patients generally tolerate ibrutinib well, the drug can cause adverse reactions including hypertension, atrial fibrillation, bleeding, and infections such as fungal pneumonia.

Topics: Adenine; Administration, Oral; Antineoplastic Agents; Atrial Fibrillation; Hemorrhage; Humans; Hypertension; Leukemia, Lymphocytic, Chronic, B-Cell; Lung Diseases, Fungal; Lymphocytosis; Piperidines; Warfarin

Advances in the molecular biology of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and development of molecularly targeted therapies have resulted in treatment innovations. Therapeutic approaches for previously untreated CLL/SLL patients are changing from chemoimmunotherapy (CIT) to molecularly targeted drugs. The aim of therapy for CLL patients has been to control the disease; however, FCR (fludarabine, cyclophosphamide, rituximab) has improved outcomes and reduced the high incidence of undetectable minimum/measurable residual disease (MRD) in previously untreated CLL patients with no 17p deletion/TP53 disruption and mutated immunoglobulin heavy chain gene (IGHV). Patients achieving undetectable MRD in the bone marrow are expected to be cured. BTK inhibitors and BCL-2 inhibitors are effective for CLL/SLL patients. However, atrial fibrillation and bleeding are associated with the BTK inhibitor, ibrutinib, while tumor lysis syndrome is an adverse event (AE) of the BCL-2 inhibitor, venetoclax. Although these novel targeted drugs are very useful, they are also expensive. Emergence of resistant clones of CLL cells must also be addressed. Therefore, treatments of indefinite duration until progression have been replaced by fixed-duration treatments. This review introduces advances in the treatment of previously untreated CLL/SLL patients in Europe and the United States.

Topics: Adenine; Antineoplastic Combined Chemotherapy Protocols; Atrial Fibrillation; Bridged Bicyclo Compounds, Heterocyclic; Cyclophosphamide; Humans; Immunotherapy; Japan; Leukemia, Lymphocytic, Chronic, B-Cell; Molecular Targeted Therapy; Neoplasm, Residual; Piperidines; Pyrazoles; Pyrimidines; Rituximab; Sulfonamides; Vidarabine

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Antineoplastic Agents; Atrial Fibrillation; Benzamides; Central Nervous System Diseases; Clinical Trials as Topic; Febrile Neutropenia; Gastrointestinal Diseases; Gene Expression Regulation, Neoplastic; Humans; Multicenter Studies as Topic; Myeloid Differentiation Factor 88; Neoplasm Proteins; NF-kappa B; Piperidines; Progression-Free Survival; Protein Kinase Inhibitors; Pyrazines; Pyrazoles; Pyrimidines; Quality of Life; Receptors, CXCR4; Recurrence; Salvage Therapy; Signal Transduction; Treatment Outcome; Waldenstrom Macroglobulinemia

Chronic lymphocytic leukemia (CLL) therapy has changed dramatically with the introduction of several targeted therapeutics. Ibrutinib was the first approved for use in 2014 and now is used for initial and salvage therapy of CLL patients. With its widespread use in clinical practice, ibrutinib's common and uncommon adverse events reported less frequently in earlier clinical trials have been experienced more frequently in real-world practice. In particular, atrial fibrillation, bleeding, infections, and arthralgias have been reported. The management of ibrutinib's adverse events often cannot be generalized but must be individualized to the patient and their long-term risk of additional complications. When ibrutinib was initially developed, there were limited therapeutic alternatives for CLL, which often resulted in treating through the adverse events. At the present time, there are several effective alternative agents available, so transition to an alternative CLL directed therapy may be considered. Given the continued expansion of ibrutinib across many therapeutic areas, investigation of the pathogenesis of adverse events with this agent and also clinical trials examining therapeutic approaches for complications arising during therapy are needed. Herein, we provide strategies we use in real-world CLL clinical practice to address common adverse events associated with ibrutinib.

Topics: Adenine; Aged; Anti-Infective Agents; Anticoagulants; Arthralgia; Atrial Fibrillation; Drug Resistance, Neoplasm; Female; Hemorrhage; Humans; Infections; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Piperidines; Prognosis; Pyrazoles; Pyrimidines

Ibrutinib is an oral covalent inhibitor of Bruton's tyrosine kinase approved for the treatment of patients with chronic lymphocytic leukemia (CLL), mantle cell lymphoma and Waldenstrӧm's macroglobulinemia. Ibrutinib has an increased risk of atrial fibrillation but the mechanism is unknown, and hypertension may play a role in the pathogenesis of this adverse drug reaction.. We aimed to review the risk of hypertension and atrial fibrillation as adverse events associated with ibrutinib through a systematic review with meta-analysis of randomized controlled trials (RCTs) retrieved in December 2018 on MEDLINE, EMBASE, CENTRAL and ClinicalTrials.gov. The data were pooled using random-effects meta-analyses using the risk ratio (RR) with the 95% confidence interval (95%CI). The confidence on the pooled estimates was ascertained through the grading of recommendations assessment, development, and evaluation (GRADE) approach.. There were 8 eligible RCTs (2580 patients), all reporting safety data of interest. Ibrutinib was associated with a significant increase in the risk of hypertension with a RR of 2.82 (95%CI 1.52-5.23) with moderate quality evidence. Ibrutinib increased significantly the risk of atrial fibrillation with a RR of 4.69 (95%CI 2.17-7.64) with high quality evidence.. Ibrutinib was associated with significantly increased risks of both hypertension and atrial fibrillation.

Topics: Adenine; Atrial Fibrillation; Databases, Factual; Humans; Hypertension; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Mantle-Cell; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Randomized Controlled Trials as Topic; Risk

Bruton tyrosine kinase signaling (BTK) is critical step for B-cell development and immunoglobulin synthesis. Ibrutinib is an orally bioavailable bruton tyrosine kinase inhibitor (BTKi) and forms an irreversible covalent bound to BTK at the Cysteine-481 residue. Ibrutinib has been approved by FDA for the treatment of mantle cell lymphoma, chronic lymphocytic leukemia, Waldenstrom's macroglobulinemia, marginal zone lymphoma and chronic graft-versus-host disease in allogeneic stem cell transplantation. Ibrutinib is generally well tolerated drug with rapid and durable responses but has some side events. The most common side effects are diarrhea, upper respiratory tract infection, bleeding, fatigue and cardiac side effects. These events are generally mild (grade I-II). However atrial fibrillation (AF) and bleeding are important and may be grade III or higher side effects require strict monitoring. Here side effects of ibrutinib have been summarized and important considerations in the management of these adverse events have been reviewed.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Atrial Fibrillation; Drug-Related Side Effects and Adverse Reactions; Hemorrhage; Humans; Incidence; Leukemia; Lymphoma; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines

Ibrutinib is a Bruton's tyrosine kinase (BTK) inhibitor finding increasingly widespread use in non-Hodgkin lymphoma. Evidence of an increased risk of atrial fibrillation (AF) emerged in Phase III studies with a median incidence of approximately 6%. The mechanism remains unknown, but inhibition of a cardioprotective pathway has been proposed. Ibrutinib induces a platelet function defect, increasing the bleeding risk of anticoagulation for AF stroke prophylaxis. Multiple potential drug interactions are an added complication. In this review we examine the characteristics and management of the reported cases of AF with ibrutinib and where possible make recommendations. The evidence suggests dose reduction or temporary suspension of drug, are feasible alternative to discontinuation. The optimum choice of thromboprophylaxis has not been determined, but we propose the use of novel anticoagulants (NOACs) and avoidance of anti-platelet agents where possible. Further research and consensus guidelines are required.

Topics: Adenine; Anticoagulants; Antineoplastic Agents; Atrial Fibrillation; Clinical Trials as Topic; Disease Management; Drug Interactions; Hemorrhage; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, B-Cell; Piperidines; Platelet Aggregation Inhibitors; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Risk Factors; Severity of Illness Index

The development of bruton tyrosine kinase inhibitors (BTKi) has been a significant advancement in the treatment of chronic lymphocytic leukemia and related B-cell malignancies. As experience in using ibrutinib increased, the first drug to be licensed in its class, atrial fibrillation (AF) emerged as an important side effect. The intersection between BTKi therapy for B-cell malignancies and AF represents a complex area of management with scant evidence for guidance. Consideration needs to be taken regarding the interplay of increased bleeding risk versus thromboembolic complications of AF, drug interactions between ibrutinib and anticoagulants and antiarrhythmic agents, and the potential for other, as yet seldom reported cardiac side effects. This review describes the current knowledge regarding BTKi and potential pathophysiologic mechanisms of AF and discusses the management of BTKi-associated AF. Finally, a review of the second generation BTKi is provided and gaps in knowledge in this evolving field are highlighted.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Anticoagulants; Antineoplastic Agents; Atrial Fibrillation; Cardiotoxicity; Clinical Trials as Topic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Signal Transduction; Treatment Outcome

Ibrutinib is a transformative therapy for high-risk and relapsed refractory chronic lymphocytic leukemia (CLL) patients. In clinical trials in relatively healthy younger patients, ibrutinib has been well tolerated. As its use has become more widespread in the community, however, its full adverse event profile has emerged and proven more challenging than was initially anticipated. Reports of community-based use have estimated discontinuation rates as high as 40% in the first year of therapy. This article therefore reviews my approach to the evaluation and management of a CLL patient starting on ibrutinib, with the goal of minimizing and managing toxicity to maintain patients on ibrutinib. Key topics discussed include bleeding risk; cardiac complications, particularly atrial fibrillation; drug interactions; and infections.

Topics: Adenine; Aged; Aged, 80 and over; Atrial Fibrillation; Autoimmunity; Communicable Diseases; Disease Management; Drug Interactions; Exanthema; Female; Hemorrhage; Humans; Hypertension; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines

Ibrutinib is indicated in Europe for the treatment of several B-cell malignancies, including chronic lymphocytic leukaemia (CLL). However, despite the high efficacy and favourable toxicity profile of ibrutinib, recent data suggest that it is not always administered optimally in clinical practice, with an increased tendency for dose reduction and a higher frequency of discontinuation. An expert panel of European haematologists was convened to identify practical issues pertinent to physicians involved in the therapeutic management of ibrutinib-treated CLL patients and here we outline the findings. Practical management recommendations are given for treating patients with ibrutinib and clinical considerations for the management of adverse events (AEs) that can be associated with ibrutinib treatment are addressed. This article highlights that patients should be monitored for treatment emergent adverse events, most of which are mild, transient and generally occur early in therapy and that, even with more challenging AEs, patients can often be maintained on therapy with minimal disruption through careful management. The necessity to use the correct ibrutinib dose, along with increased awareness, vigilance, mitigation and management of AEs, are all recommended to maximise outcomes for CLL patients treated with ibrutinib.

Topics: Adenine; Anticoagulants; Antineoplastic Agents; Arthralgia; Atrial Fibrillation; Diabetes Mellitus, Type 1; Diarrhea; Drug Eruptions; Drug Interactions; Exanthema; Fatigue; Hemorrhage; Humans; Hypertension; Infections; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphocytosis; Medication Adherence; Myalgia; Piperidines; Platelet Aggregation Inhibitors; Pyrazoles; Pyrimidines; Treatment Outcome

The Bruton tyrosine kinase inhibitor ibrutinib (IB) has attained an important role in the treatment of patients with chronic lymphocytic leukaemia, mantle cell lymphoma, and Waldenström macroglobulinemia, significantly improving clinical outcomes. However, IB therapy has been associated with an increased risk of atrial fibrillation (AF) and bleeding. We report on the expert opinion that a group of Italian haematologists, cardiologists, and pharmacologists jointly released to improve the practical management of patients at risk for AF and bleeding during treatment with IB. A proper pretreatment assessment to identify patients who are at a higher risk, careful choice of concomitant drugs, regular monitoring, and multispecialist approach were characterized as the main principles of clinical management of these patients. For patients developing AF, anticoagulant and antiarrhythmic therapy must be guided by considerations about efficacy, safety, and risk of pharmacokinetic interactions with IB. For patients experiencing bleeding or requiring procedures that increase the risk of bleeding, considerations about platelet turnover, IB-related platelet dysfunctions, and bleeding worsening by concomitant anticoagulants or antiplatelet agents provide clues to manage bleeding. Overall, AF and bleeding are manageable clinical events in patients receiving IB, not requiring drug interruption in most cases. Preexisting AF should not represent an absolute contraindication to IB therapy. For each patient candidate for IB, strategies of risk assessment and mitigation may allow to exploit the life-saving effects of in chronic lymphocytic leukaemia and mantle cell lymphoma.

Topics: Adenine; Anti-Arrhythmia Agents; Anticoagulants; Atrial Fibrillation; Clinical Trials as Topic; Hematologic Neoplasms; Hemorrhage; Humans; Piperidines; Platelet Aggregation Inhibitors; Pyrazoles; Pyrimidines; Randomized Controlled Trials as Topic; Risk Factors

B cell signaling agents, including ibrutinib, idelalisib, and the BCL-2 inhibitor venetoclax have become an integral part of therapy for patients with non-Hodgkin's lymphomas. The toxicity profiles of these medications is distinct from chemoimmunotherapy. Here, we will review the mechanism of action of these drugs, their efficacy, and toxicity management.. Ibrutinib use is associated with increased risk of atrial fibrillation and bleeding which can be managed using dose interruptions and modifications. Patients on idelalisib require close clinical and frequent laboratory monitoring, particularly of liver function tests to ensure there are no serious adverse events. Monitoring for infections is important in patients on both idelalisib and ibrutinib. Venetoclax requires close clinical and laboratory monitoring to prevent significant tumor lysis. Targeted B cell receptor therapies each have unique side effect profiles which require careful clinical monitoring. As we continue to use these therapies, optimal management strategies will continue to be elucidated.

Topics: Adenine; Antineoplastic Agents; Atrial Fibrillation; B-Lymphocytes; Bridged Bicyclo Compounds, Heterocyclic; Hemorrhage; Humans; Lymphoma, Non-Hodgkin; Piperidines; Purines; Pyrazoles; Pyrimidines; Quinazolinones; Receptors, Antigen, B-Cell; Sulfonamides

Ibrutinib, a novel and potent Bruton tyrosine kinase inhibitor, is an effective and well-tolerated treatment for a variety of B-cell lymphomas. However, its use is associated with an increased incidence of atrial fibrillation (AF), ranging from 4% to 16%. We reviewed the original clinical trials that led to the approval of ibrutinib, as well as several other prospective and retrospective studies, to better appreciate the incidence of ibrutinib-associated AF. Based on 16 studies included in our analysis, the incidence of ibrutinib-associated AF was 5.77 per 100 person-years, which is much higher than rates previously reported with ibrutinib and compared with the general adult population. New onset AF in cancer patients is associated with a significantly higher risk of heart failure and thromboembolism, even after adjusting for known risk factors. In addition, ibrutinib poses unique challenges due to its interactions with many medications that are commonly used to manage AF. Ibrutinib also inhibits platelet activation and decisions regarding anticoagulation have to be carefully weighed against this increased risk of bleeding. Ibrutinib's interaction with calcium channel blockers, digoxin, amiodarone, and direct oral anticoagulants can result in either ibrutinib or other drug-related toxicity and careful selection and dose adjustment may be needed. Ibrutinib-associated AF can be a therapy-limiting side effect and physicians should be familiar with the special management considerations imposed by this agent. We review the potential mechanisms and incidence of ibrutinib-associated AF and propose an algorithm for its management.

Topics: Adenine; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Atrial Fibrillation; Female; Humans; Lymphoma, B-Cell; Male; Middle Aged; Piperidines; Pyrazoles; Pyrimidines; Young Adult

The management of AF represents a major challenge in patients with CLL, especially in elderly patients with multiple comorbidities who are representative of the majority of patients with CLL. This is especially complex in the case of ibrutinib. Many anticoagulants have potential for pharmacological interaction with ibrutinib, and ibrutinib itself has antiplatelet properties. Use of ibrutinib therapy in these patients mandates review and revision of the need for anticoagulation and best anticoagulant to use. Herein, we review the current knowledge of the metabolism of common anticoagulants and how they may interact with ibrutinib.

Topics: Adenine; Anticoagulants; Antineoplastic Agents; Atrial Fibrillation; Disease Management; Drug Interactions; Humans; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Risk Assessment; Stroke

The B-cell receptor (BCR) pathway plays an important role in the survival, proliferation and trafficking of cancer cells in a variety of B-cell malignancies. Recently, a number of agents have been developed to target various components of the BCR pathway. One such target is Bruton's tyrosine kinase (BTK), a Tec family kinase member found near the cell membrane that is involved in upstream BCR signaling. The biological function of BTK in several B-cell lymphoid malignancies has led to the development of the oral BTK inhibitor ibrutinib. In chronic lymphocytic leukemia (CLL), ibrutinib has demonstrated durable clinical responses in relapsed/refractory (R/R) patients, including those with the high-risk del(17p) cytogenetic abnormality. These findings have paved the way for trials evaluating ibrutinib in previously untreated CLL patients, and also in combination with chemoimmunotherapy or other novel agents. Durable clinical responses have also been demonstrated in mantle cell lymphoma (MCL) and Waldenström's macroglobulinemia (WM) patients treated with ibrutinib. Ibrutinib is generally well tolerated, although current follow-up remains short and patients of advanced age are more likely to discontinue treatment for toxicity. Treatment-specific side effects such as bleeding and atrial fibrillation may, at least partly, be related to off-target inhibition of non-BTK kinases. Studies evaluating other potential indications for BTK inhibition are ongoing, including in post-allogeneic hematopoietic stem cell transplant patients for whom ibrutinib may be effective in modulating graft-versus-host disease. Combination trials of ibrutinib with venetoclax, a Bcl-2 inhibitor, are underway and are supported by sound preclinical rationale. Several next-generation BTK inhibitors are under development with the goal of decreasing treatment-related toxicity and resistance.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Atrial Fibrillation; Drug Discovery; Graft vs Host Disease; Hemorrhage; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Mantle-Cell; Piperidines; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines; Signal Transduction

Clinical trials raised concern that ibrutinib may increase the risk of atrial fibrillation/flutter (Afib/Aflutter) and major bleeding. However, the association has not been statistically validated, and there is no consensus regarding optimal management of anticoagulation among patients receiving ibrutinib who develop Afib/Aflutter. We performed a systematic review and pooled analysis to precisely assess the risk of Afib/Aflutter and bleeding associated with ibrutinib treatment in patients with hematologic malignancies.. We searched PubMed, EMBASE, Cochrane Database, and meeting abstracts up to May 15, 2016, for randomized controlled trials comparing ibrutinib to chemotherapy, monoclonal antibody, or a combination. Primary outcomes were serious Afib/Aflutter and major bleeding. Secondary outcomes were all-grade Afib/Aflutter and bleeding. We calculated the Mantel-Haenszel risk ratio (RR) and estimated the effect of the treatments using a fixed-effects model.. Ibrutinib treatment was associated with a significantly higher incidence of serious Afib/Aflutter (3.03% vs. 0.80%, RR = 3.80, 95% confidence interval [CI] = 1.56-9.29, P = .003), all-grade Afib/Aflutter (8.18% vs. 0.93%, RR = 8.81, 95% CI = 2.70-28.75, P = .0003), and all-grade bleeding (4.85% vs. 1.55%, RR = 2.93, 95% CI = 1.14-7.52, P = .03) compared to control treatments. The observed between-treatment difference in major bleeding rates was not statistically significant (3.69% vs. 2.13%, RR = 1.72, 95% CI = 0.95-3.11, P = .07). The risk of these adverse events was not different between subgroups on the basis of pathology, treatment setting, dose, and duration of ibrutinib exposure.. The risks of Afib/Aflutter and all-grade bleeding were significantly higher in the ibrutinib group. These results indicate the need for vigilant monitoring while the patient is receiving ibrutinib therapy, and careful assessment of the risks and benefits of anticoagulation is required.

Topics: Adenine; Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal; Atrial Fibrillation; Disease Susceptibility; Female; Hemorrhage; Humans; Male; Middle Aged; Piperidines; Pyrazoles; Pyrimidines; Randomized Controlled Trials as Topic; Risk

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Animals; Atrial Fibrillation; Humans; Incidence; Leukemia; Lymphoma; Piperidines; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines

Inhibitors of the B cell receptor (BCR) represent an attractive therapeutic option for patients with chronic lymphocytic leukemia. Recently approved inhibitors of Bruton's tyrosine kinase (ibrutinib) and phosphatidylinositol 3-kinase (idelalisib), are promising agents because they are generally well tolerated and highly effective. These agents may be particularly important in the treatment of older patients who are less able to tolerate the myelosuppression (and infections) associated with chemoimmunotherapy. As a class of medications, BCR inhibitors have some unique side effects including redistribution lymphocytosis. Ibrutinib has specific toxicities including increased risk for bleeding and atrial fibrillation. Idelalisib also has some unique toxicities consisting of transaminitis, diarrhea and pneumonitis. Ongoing clinical trials are evaluating these agents in combination with antibodies, chemotherapy and other small molecules.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Age Factors; Atrial Fibrillation; Diarrhea; Hemorrhage; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphocytosis; Neoplasm Proteins; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Piperidines; Pneumonia; Protein-Tyrosine Kinases; Purines; Pyrazoles; Pyrimidines; Quinazolinones; Receptors, Antigen, B-Cell

Ibrutinib (Imbruvica™) is an irreversible, potent inhibitor of Bruton's tyrosine kinase (BTK). Over the last few years, ibrutinib has developed from a promising drug candidate to being approved by FDA for the treatment of three B cell malignancies, a truly remarkable feat. Few, if any medicines are monospecific and ibrutinib is no exception; already during ibrutinib's initial characterization, it was found that it could bind also to other kinases. In this review, we discuss the implications of such interactions, which go beyond the selective effect on BTK in B cell malignancies. In certain cases, the outcome of ibrutinib treatment likely results from the combined inhibition of BTK and other kinases, causing additive or synergistic, effects. Conversely, there are also examples when the clinical outcome seems unrelated to inhibition of BTK. Thus, more specifically, adverse effects such as enhanced bleeding or arrhythmias could potentially be explained by different interactions. We also predict that during long-term treatment bone homoeostasis might be affected due to the inhibition of osteoclasts. Moreover, the binding of ibrutinib to molecular targets other than BTK or effects on cells other than B cell-derived malignancies could be beneficial and result in new indications for clinical applications.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Animals; Atrial Fibrillation; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Mantle-Cell; Lymphoproliferative Disorders; Mice; Multiple Myeloma; Osteoclasts; Phosphorylation; Piperidines; Protein Binding; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines; Waldenstrom Macroglobulinemia

ELEVATE-RR demonstrated noninferior progression-free survival and lower incidence of key adverse events (AEs) with acalabrutinib vs ibrutinib in previously treated chronic lymphocytic leukemia. We further characterize AEs of acalabrutinib and ibrutinib via post hoc analysis. Overall and exposure-adjusted incidence rate was assessed for common Bruton tyrosine kinase inhibitor-associated AEs and for selected events of clinical interest (ECIs). AE burden scores based on previously published methodology were calculated for AEs overall and selected ECIs. Safety analyses included 529 patients (acalabrutinib, n = 266; ibrutinib, n = 263). Among common AEs, incidences of any-grade diarrhea, arthralgia, urinary tract infection, back pain, muscle spasms, and dyspepsia were higher with ibrutinib, with 1.5- to 4.1-fold higher exposure-adjusted incidence rates. Incidences of headache and cough were higher with acalabrutinib, with 1.6- and 1.2-fold higher exposure-adjusted incidence rate, respectively. Among ECIs, incidences of any-grade atrial fibrillation/flutter, hypertension, and bleeding were higher with ibrutinib, as were exposure-adjusted incidence rates (2.0-, 2.8-, and 1.6-fold, respectively); incidences of cardiac events overall (the Medical Dictionary for Regulatory Activities system organ class) and infections were similar between arms. Rate of discontinuation because of AEs was lower for acalabrutinib (hazard ratio, 0.62; 95% confidence interval, 0.41-0.93). AE burden score was higher for ibrutinib vs acalabrutinib overall and for the ECIs atrial fibrillation/flutter, hypertension, and bleeding. A limitation of this analysis is its open-label study design, which may influence the reporting of more subjective AEs. Overall, event-based analyses and AE burden scores demonstrated higher AE burden overall and specifically for atrial fibrillation, hypertension, and hemorrhage with ibrutinib vs acalabrutinib. This trial was registered at www.clinicaltrials.gov as #NCT02477696.

Topics: Atrial Fibrillation; Hemorrhage; Humans; Hypertension; Leukemia, Lymphocytic, Chronic, B-Cell; Protein Kinase Inhibitors

Ibrutinib has superior progression-free survival compared with bendamustine plus rituximab (BR) in older CLL patients, however, differences in treatment duration, six monthly BR cycles versus continuous ibrutinib, complicate adverse event (AE) comparisons. We introduce the AE burden score (AE

Topics: Adenine; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Atrial Fibrillation; Bendamustine Hydrochloride; Female; Follow-Up Studies; Humans; Hypertension; Infections; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Piperidines; Prognosis; Rituximab; Survival Rate

Ibrutinib, an inhibitor of Bruton's tyrosine kinase, and venetoclax, an inhibitor of B-cell lymphoma 2 protein, have been approved for patients with chronic lymphocytic leukemia (CLL). Preclinical investigations have indicated potential synergistic interaction of their combination.. We conducted an investigator-initiated phase 2 study of combined ibrutinib and venetoclax involving previously untreated high-risk and older patients with CLL. All patients had at least one of the following features: chromosome 17p deletion, mutated. A total of 80 patients were treated. The median age was 65 years (range, 26 to 83). A total of 30% of the patients were 70 years of age or older. Overall, 92% of the patients had unmutated. In this study, combined venetoclax and ibrutinib was an effective oral regimen for high-risk and older patients with CLL. (Funded by AbbVie and others; ClinicalTrials.gov number, NCT02756897.).

Topics: Adenine; Administration, Oral; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Atrial Fibrillation; Bridged Bicyclo Compounds, Heterocyclic; Female; Humans; Induction Chemotherapy; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphocyte Count; Male; Middle Aged; Mutation; Neoplasm, Residual; Neutropenia; Piperidines; Pyrazoles; Pyrimidines; Remission Induction; Sulfonamides

Ibrutinib, a first-in-class once-daily oral Bruton tyrosine kinase inhibitor indicated for chronic lymphocytic leukemia (CLL), is continued until progressive disease or unacceptable toxicity. We conducted an integrated safety analysis of single-agent ibrutinib from randomized phase 3 studies PCYC-1112 (RESONATE, n = 195) and PCYC-1115/1116 (RESONATE-2, n = 135), and examined longer-term safety separately in the phase 1b/2 PCYC-1102/1103 study (n = 94, 420 mg/d). In the integrated analysis (ibrutinib treatment up to 43 months), the most common adverse events (AEs) were primarily grade 1/2; diarrhea (n = 173, 52% any-grade; n = 15, 5% grade 3) and fatigue (n = 119, 36% any-grade; n = 10, 3% grade 3). The most common grade 3/4 AEs were neutropenia (n = 60, 18%) and pneumonia (n = 38, 12%). Over time, prevalence of AEs of interest (diarrhea, fatigue, grade ≥3 infection, bleeding, and neutropenia) trended down; prevalence of hypertension increased, but incidence decreased after year 1. AEs led to dose reductions in 42 (13%) patients and permanent discontinuations in 37 (11%); dose modifications due to AEs were most common during year 1 and decreased in frequency thereafter. The most common AEs (preferred term) contributing to discontinuation included pneumonia (n = 4), anemia (n = 3), and atrial fibrillation (n = 3). With long-term follow-up on PCYC-1102/1103 (ibrutinib treatment up to 67 months), grade 3/4 AEs were generally similar to those in the integrated analysis. Overall, AEs were primarily grade 1/2 and manageable during prolonged ibrutinib treatment in patients with CLL. These trials were registered at www.clinicaltrials.gov as #NCT01578707, #NCT01722487, #NCT01724346, #NCT01105247, and #NCT01109069.

Topics: Adenine; Adult; Aged; Aged, 80 and over; Anemia; Atrial Fibrillation; Diarrhea; Drug Tolerance; Fatigue; Female; Follow-Up Studies; Hemorrhage; Humans; Hypertension; Infections; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Neutropenia; Piperidines; Pneumonia; Prevalence; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Safety

Ibrutinib increases the risk of atrial fibrillation (AF) and is associated with bleeding tendencies. Reported rates of arrhythmia are variable in different studies. The aim of the current analysis was to evaluate the incidence of AF in a single-center cohort of patients.. This analysis was conducted at Hunter New England Local Health District, Australia between April 1, 2015 and June 30, 2017. We included all consecutive patients commenced on ibrutinib for hematological malignancies. Patients with a history of paroxysmal AF were excluded. The primary end point was incidence of AF. Time to diagnosis and management were secondary outcomes of interest.. A total of 24 patients (age 73 ± 9 years, males n = 16 [67%]) were commenced on ibrutinib treatment during the study period with chronic lymphocytic leukemia (n = 21, 88%) as the main indication. During a median follow-up of 12 months, four (17%) patients were diagnosed with AF with increasing age, duration of ibrutinib treatment as associations. The median time to AF diagnosis was 9 (interquartile range [IQR]: 7-18) months. All patients were managed with a rate control strategy with beta blockers as the preferred agents. Three (75%) patients were commenced on anticoagulation for stroke prevention. During a follow-up of 18 (IQR: 17-23) months following AF onset, one patient required hospitalization for AF. There were no bleeding complications reported.. In conclusion, this series noted a higher incidence of AF than previously reported. Oncologists and cardiologists need to be aware of the increased risk of AF in patients receiving ibrutinib.

Topics: Adenine; Aged; Aged, 80 and over; Atrial Fibrillation; Australia; Female; Hematologic Neoplasms; Hospitalization; Humans; Incidence; Male; Piperidines; Prognosis; Pyrazoles; Pyrimidines; Survival Rate

Single-agent ibrutinib has shown substantial activity in patients with relapsed Waldenström's macroglobulinemia, a rare form of B-cell lymphoma. We evaluated the effect of adding ibrutinib to rituximab in patients with this disease, both in those who had not received previous treatment and in those with disease recurrence.. We randomly assigned 150 symptomatic patients to receive ibrutinib plus rituximab or placebo plus rituximab. The primary end point was progression-free survival, as assessed by an independent review committee. Key secondary end points were response rates, sustained hematologic improvement from baseline, and safety. The mutational status of MYD88 and CXCR4 was assessed in bone marrow samples.. At 30 months, the progression-free survival rate was 82% with ibrutinib-rituximab versus 28% with placebo-rituximab (hazard ratio for progression or death, 0.20; P<0.001). The benefit in the ibrutinib-rituximab group over that in the placebo-rituximab group was independent of the MYD88 or CXCR4 genotype. The rate of major response was higher with ibrutinib-rituximab than with placebo-rituximab (72% vs. 32%, P<0.001). More patients had sustained increases in hemoglobin level with ibrutinib-rituximab than with placebo-rituximab (73% vs. 41%, P<0.001). The most common adverse events of any grade with ibrutinib-rituximab included infusion-related reactions, diarrhea, arthralgia, and nausea. Events of grade 3 or higher that occurred more frequently with ibrutinib-rituximab than with placebo-rituximab included atrial fibrillation (12% vs. 1%) and hypertension (13% vs. 4%); those that occurred less frequently included infusion reactions (1% vs. 16%) and any grade of IgM flare (8% vs. 47%). The major hemorrhage rate was the same in the two trial groups (4%).. Among patients with Waldenström's macroglobulinemia, the use of ibrutinib-rituximab resulted in significantly higher rates of progression-free survival than the use of placebo-rituximab, both among those who had received no previous treatment and among those with disease recurrence. Atrial fibrillation and hypertension were more common with ibrutinib-rituximab, whereas infusion reactions and IgM flare were more common with placebo-rituximab. (Funded by Pharmacyclics and Janssen Research and Development; ClinicalTrials.gov number, NCT02165397 .).

Topics: Adenine; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Atrial Fibrillation; Disease-Free Survival; Female; Hemoglobins; Humans; Immunoglobulin M; Infusions, Intravenous; Male; Middle Aged; Piperidines; Pyrazoles; Pyrimidines; Rituximab; Survival Analysis; Waldenstrom Macroglobulinemia

Ibrutinib is approved in the EU, USA, and other countries for patients with mantle cell lymphoma who received one previous therapy. In a previous phase 2 study with single-agent ibrutinib, the proportion of patients who achieved an objective response was 68%; 38 (34%) of 111 patients had transient lymphocytosis. We hypothesised that adding rituximab could target mantle cell lymphoma cells associated with redistribution lymphocytosis, leading to more potent antitumour activity.. Patients with a confirmed mantle cell lymphoma diagnosis (based on CD20-positive and cyclin D1-positive cells in tissue biopsy specimens), no upper limit on the number of previous treatments received, and an Eastern Cooperative Oncology Group performance status score of 2 or less were enrolled in this single-centre, open-label, phase 2 study. Patients received continuous oral ibrutinib (560 mg) daily until progressive disease or unacceptable toxic effects. Rituximab 375 mg/m(2) was given intravenously once per week for 4 weeks during cycle 1, then on day 1 of cycles 3-8, and thereafter once every other cycle up to 2 years. The primary endpoint was the proportion of patients who achieved an objective response in the intention-to-treat population and safety assessed in the as-treated population. The study is registered with ClinicalTrials.gov, number NCT01880567, and is still ongoing, but no longer accruing patients.. Between July 15, 2013, and June 30, 2014, 50 patients were enrolled. Median age was 67 years (range 45-86), and the median number of previous regimens was three (range 1-9). At a median follow-up of 16·5 months (IQR 12·09-19·28), 44 (88%, 95% CI 75·7-95·5) patients achieved an objective response, with 22 (44%, 30·0-58·7) patients achieving a complete response, and 22 (44%, 30·0-58·7) a partial response. The only grade 3 adverse event in >=10% of patients was atrial fibrillation, which was noted in six (12%) patients. Grade 4 diarrhoea and neutropenia occurred in one patient each. Adverse events led to discontinuation of therapy in five (10%) patients (atrial fibrillation in three [6%] patients, liver infection in one [2%], and bleeding in one [2%]). Two patients died while on-study from cardiac arrest and septic shock; the latter was deemed possibly related to treatment.. Ibrutinib combined with rituximab is active and well tolerated in patients with relapsed or refractory mantle cell lymphoma. Our results provide preliminary evidence for the activity of this combination in clinical practice. A phase 3 trial is warranted for more definitive data.. Pharmacyclics LLC, an AbbVie Company.

Topics: Adenine; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Atrial Fibrillation; Diarrhea; Epistaxis; Female; Follow-Up Studies; Humans; Intention to Treat Analysis; Lymphoma, Mantle-Cell; Male; Middle Aged; Neutropenia; Piperidines; Pyrazoles; Pyrimidines; Recurrence; Retreatment; Rituximab; Treatment Outcome

Most patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma relapse after initial therapy. Bendamustine plus rituximab is often used in the relapsed or refractory setting. We assessed the efficacy and safety of adding ibrutinib, an oral covalent inhibitor of Bruton's tyrosine kinase (BTK), to bendamustine plus rituximab in patients with previously treated chronic lymphocytic leukaemia or small lymphocytic lymphoma.. The HELIOS trial was an international, double-blind, placebo-controlled, phase 3 study in adult patients (≥18 years of age) who had active chronic lymphocytic leukaemia or small lymphocytic lymphoma with measurable lymph node disease (>1·5 cm) by CT scan, and had relapsed or refractory disease following one or more previous lines of systemic therapy consisting of at least two cycles of a chemotherapy-containing regimen, an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, and adequate bone marrow, liver, and kidney function. Patients with del(17p) were excluded because of known poor response to bendamustine plus rituximab. Patients who had received previous treatment with ibrutinib or other BTK inhibitors, refractory disease or relapse within 24 months with a previous bendamustine-containing regimen, or haemopoietic stem-cell transplant were also excluded. Patients were randomly assigned (1:1) by a web-based system to receive bendamustine plus rituximab given in cycles of 4 weeks' duration (bendamustine: 70 mg/m(2) intravenously on days 2-3 in cycle 1, and days 1-2 in cycles 2-6; rituximab: 375 mg/m(2) on day 1 of cycle 1, and 500 mg/m(2) on day 1 of cycles 2-6 for a maximum of six cycles) with either ibrutinib (420 mg daily orally) or placebo until disease progression or unacceptable toxicity. Patients were stratified according to whether they were refractory to purine analogues and by number of previous lines of therapy. The primary endpoint was independent review committee (IRC)-assessed progression-free survival. Crossover to ibrutinib was permitted for patients in the placebo group with IRC-confirmed disease progression. Analysis was by intention-to-treat and is continuing for further long-term follow-up. The trial is registered with ClinicalTrials.gov, number NCT01611090.. Between Sept 19, 2012, and Jan 21, 2014, 578 eligible patients were randomly assigned to ibrutinib or placebo in combination with bendamustine plus rituximab (289 in each group). The primary endpoint was met at the preplanned interim analysis (March 10, 2015). At a median follow-up of 17 months (IQR 13·7-20·7), progression-free survival was significantly improved in the ibrutinib group compared with the placebo group (not reached in the ibrutinib group (95% CI not evaluable) vs 13·3 months (11·3-13·9) in the placebo group (hazard ratio [HR] 0·203, 95% CI 0·150-0·276; p<0·0001). IRC-assessed progression-free survival at 18 months was 79% (95% CI 73-83) in the ibrutinib group and 24% (18-31) in the placebo group (HR 0·203, 95% CI 0·150-0·276; p<0·0001). The most frequent all-grade adverse events were neutropenia and nausea. 222 (77%) of 287 patients in the ibrutinib group and 212 (74%) of 287 patients in the placebo group reported grade 3-4 events; the most common grade 3-4 adverse events in both groups were neutropenia (154 [54%] in the ibrutinib group vs 145 [51%] in the placebo group) and thrombocytopenia (43 [15%] in each group). A safety profile similar to that previously reported with ibrutinib and bendamustine plus rituximab individually was noted.. In patients eligible for bendamustine plus rituximab, the addition of ibrutinib to this regimen results in significant improvements in outcome with no new safety signals identified from the combination and a manageable safety profile.. Janssen Research & Development.

Topics: Adenine; Adult; Aged; Aged, 80 and over; Anemia; Antineoplastic Combined Chemotherapy Protocols; Atrial Fibrillation; Bendamustine Hydrochloride; Disease Progression; Disease-Free Survival; Double-Blind Method; Female; Hemorrhage; Humans; Intention to Treat Analysis; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Nausea; Neutropenia; Piperidines; Pyrazoles; Pyrimidines; Retreatment; Rituximab; Thrombocytopenia

Topics: Adenine; Adult; Aged; Aged, 80 and over; Atrial Fibrillation; Female; Humans; Male; Middle Aged; Piperidines; Pyrazoles; Pyrimidines; Risk Factors; Time Factors; Waldenstrom Macroglobulinemia

Ibrutinib-associated atrial fibrillation (IRAF) emerged among the adverse events of major interests in ibrutinib-treated patients as real-world studies showed a higher incidence compared to clinical trials. We prospectively analyzed predictors of IRAF in 43 single-center consecutive patients affected by chronic lymphocytic leukemia that started therapy with ibrutinib between 2015 and 2017. Key secondary endpoints were to describe the management of IRAF and survival outcomes. During a median follow-up period of 52 months, we registered 45 CV events, with a total of 23 AF events in 13 patients (CI 30.0% (95% CI: 16.5-43.9)). Pre-existent cardiovascular risk factors, in particular hypertension, a previous history of AF and a high Shanafelt risk score emerged as predictors of IRAF. Baseline echocardiographic evaluation of left atrial (LA) dimensions confirmed to predict IRAF occurrence and cut-off values were identified in our cohort: 32 mm for LA diameter and 18 cm

Topics: Atrial Fibrillation; Follow-Up Studies; Humans; Piperidines; Prospective Studies

Data regarding the safety of co-administration of ibrutinib with anticoagulants in real-life settings are scarce. Using a nationwide database, we conducted a nested case-control study in a cohort of new users of ibrutinib to assess the risk of clinically relevant bleeding (CRB) associated with anticoagulation. Cases were patients with a diagnosis of CRB, defined as hospitalization with a diagnosis of bleeding. The date of CRB constituted the index date. Up to four controls were matched on sex, age at index date and duration of follow-up. The risk of CRB associated with anticoagulation in patients receiving ibrutinib was estimated using conditional logistic regression models, providing odds ratios (OR) adjusted for risk factors of bleeding. Among 614 cases and 2407 matched controls, the risk of CRB was significantly higher in patients receiving both ibrutinib and anticoagulants (adjusted OR [aOR] 2.54, confidence interval [CI] 95% [1.94; 3.32]). When considering anticoagulant class, aOR was 1.99 (CI 95% [1.19; 3.33]) for VKA, 2.48 (CI 95% [1.76; 3.47]) for direct oral anticoagulants and 3.40 (CI 95% [2.01; 5.75]) for parenteral anticoagulants. In conclusion, this study found a 2.5-fold increased risk of CRB in patients receiving both ibrutinib and anticoagulants in real-life settings, and similar aOR among oral anticoagulants.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Case-Control Studies; Hemorrhage; Humans; Piperidines

Ibrutinib treatment is associated with cardiovascular side effects, in particular atrial fibrillation (AF) and hypertension, as well as increased risk of bleeding. Here, we aimed at describing the incidence of these events during long-term follow-up in patients with chronic lymphocytic leukemia treated outside clinical trials as well as identifying clinical factors predictive of developing AF. Additionally, other reasons for treatment withdrawal were analyzed.. The study was retrospective, data were collected from medical records.. A total of 134 patients were identified. Median follow-up was 32 months (range 3-103) and median duration of ibrutinib treatment was 26 months (range 1-103). Of 110 patients with no prior history of AF, 24.5% were diagnosed during treatment. Newly diagnosed or worsening of pre-existing hypertension occurred in 15.7%. Sixty-six % of the patients experienced bleeding events, of which 7.5% grade 3-4. Treatment discontinuation and dose reduction occurred in 68% and 47% of the patients, respectively, mostly due to toxicity.. The incidence of AF was high and at a median follow-up of 2.5 years, two-thirds of the patients discontinued treatment mostly due to bleeding and infections. Treatment-related toxicity of any grade should be regarded as a concern of prolonged ibrutinib therapy.

Topics: Atrial Fibrillation; Hemorrhage; Humans; Hypertension; Incidence; Leukemia, Lymphocytic, Chronic, B-Cell; Protein Kinase Inhibitors; Retrospective Studies

Topics: Adenine; Atrial Fibrillation; Case-Control Studies; Heart Failure; Humans; Piperidines; Risk Factors

Atrial fibrillation (AF) is a recognized adverse consequence associated with all Bruton's tyrosine kinase inhibitors used to treat chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL); however, real-world time to discontinuation (TTD) and time to next treatment (TTNT) of CLL/SLL patients with a high baseline AF/stroke risk remain unknown.. Patients with CLL/SLL from a nationwide electronic health record-derived database (February 12, 2013-January 31, 2021) initiating first-line (1L) or second or later-line (2L+) treatment with ibrutinib or other regimens on or after February 12, 2014 (index date) were analyzed. Kaplan-Meier survival analysis was used to assess TTD and TTNT among all patients, patients with high AF risk (CHARGE-AF risk score ≥10.0%), and patients at high risk of stroke (CHA. In 1L/2L+, 2190/1851 patients received ibrutinib and 4388/4135, were treated with other regimens. Median TTD for ibrutinib was similar regardless of AF/stroke-related risk (1L: all patients, 15.7 months; high AF risk, 11.7 months; high stroke risk, 13.7 months; similar results in 2L+). Median TTNT was significantly longer for ibrutinib vs. other regimens (1L: not reached vs. 45.9 months; 2L+: not reached vs. 23.6 months; both P < .05), including among those with high AF/stroke risk. TTNT was similar between all patients and high-risk cohorts in 1L and 2L+ (all P > .05).. This study highlights that elevated baseline AF/stroke-related risk does not adversely impact TTD and TTNT outcomes associated with ibrutinib use. Additionally, TTNT was significantly longer for patients treated with ibrutinib vs. other regimens.

Topics: Atrial Fibrillation; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, B-Cell; Male; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Stroke

Background Ibrutinib and acalabrutinib are Bruton tyrosine kinase inhibitors used in the treatment of B-cell lymphoproliferative disorders. Ibrutinib is associated with new-onset atrial fibrillation. Cases of sinus bradycardia and sinus arrest have also been reported following ibrutinib treatment. Conversely, acalabrutinib is less arrhythmogenic. The basis for these different effects is unclear. Methods and Results The effects of ibrutinib and acalabrutinib on atrial electrophysiology were investigated in anesthetized mice using intracardiac electrophysiology, in isolated atrial preparations using high-resolution optical mapping, and in isolated atrial and sinoatrial node (SAN) myocytes using patch-clamping. Acute delivery of acalabrutinib did not affect atrial fibrillation susceptibility or other measures of atrial electrophysiology in mice in vivo. Optical mapping demonstrates that ibrutinib dose-dependently impaired atrial and SAN conduction and slowed beating rate. Acalabrutinib had no effect on atrial and SAN conduction or beating rate. In isolated atrial myocytes, ibrutinib reduced action potential upstroke velocity and Na

Topics: Action Potentials; Adenine; Animals; Arrhythmias, Cardiac; Atrial Fibrillation; Benzamides; Cardiac Electrophysiology; Mice; Myocytes, Cardiac; Piperidines; Pyrazines; Sinoatrial Node

Ibrutinib therapy is associated with an increased risk of atrial fibrillation (AF) in chronic lymphocytic leukemia (CLL). Risk assessment tools and outcomes of AF in these patients are not well described.. We performed a retrospective review of patients with CLL treated with ibrutinib at Mayo Clinic between October 2012 and November 2018.. Two hundred ninety-eight patients were identified with a median time on ibrutinib of 19 months (range 0.23-69.7 months). Fifty-one patients developed treatment-emergent AF; the risk of treatment-emergent AF at 6 months, 1 year, and 2 years was 9%, 12%, and 16%, respectively. The following were associated with an increased risk of treatment-emergent AF on multivariable analyses: past history of AF (hazard ratio [HR] 3.5, p = 0.0072) and heart failure (HR 3.4, p = 0.0028). Most patients are able to continue ibrutinib therapy (dose reduced in 43%). Development of treatment-emergent AF was associated with shorter event-free survival (EFS; HR 2.0, p = 0.02) and shorter overall survival (OS; HR 3.2, p = 0.001), after adjusting for age, prior treatment status, TP53 disruption, heart failure, valvular disease, and past history of AF.. Patient comorbidities, rather than CLL-related factors, predict risk of treatment-emergent AF in patients treated with ibrutinib. Although the vast majority of patients with treatment-emergent AF are able to continue ibrutinib (with dose reduction in 43%), treatment-emergent AF appears to be associated with worse outcomes, independent of other adverse prognostic factors.

Topics: Adenine; Adult; Aged; Aged, 80 and over; Atrial Fibrillation; Disease Management; Female; Follow-Up Studies; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Piperidines; Predictive Value of Tests; Progression-Free Survival; Protein Kinase Inhibitors; Retrospective Studies; Risk Factors; Treatment Outcome

Ibrutinib is the first clinically approved inhibitor of Bruton's tyrosine kinase, an essential enzyme for survival and proliferation of B cells by activating the B-cell receptor-signalling pathway. Ibrutinib has been shown to be highly effective in B-cell malignancies and is recommended in current international guidelines as a first-line and/or second-line treatment of chronic lymphocytic leukemia. The drug has a favorable tolerability and safety profile but the occurrence of specific side effects (e.g. atrial fibrillation, bleeding and hypertension). If atrial fibrillation is diagnosed, anticoagulant therapy may be required. Such patients receiving concomitant anticoagulation should be followed closely. DOAC is preferred over a VKA because of the lower risk of major bleeding events and because of the favorable stroke risk--benefit profile. Of all, Dabigatran offers the availability of an antidote and shows reduced potential for CYP3A4 interactions. We report the cases relating to three patients in concomitant therapy with Ibrutinib and Dabigatran.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Aged; Antithrombins; Atrial Fibrillation; Dabigatran; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Piperidines; Protein Kinase Inhibitors

Ibrutinib is associated with atrial fibrillation (AF), though echocardiographic predictors of AF have not been studied in this population. We sought to determine whether left atrial (LA) strain on transthoracic echocardiography could identify patients at risk for developing ibrutinib-related atrial fibrillation (IRAF).. We performed a retrospective review of 66 patients who had an echocardiogram prior to ibrutinib treatment. LA strain was measured with TOMTEC Imaging Systems, obtaining peak atrial longitudinal strain (PALS) and peak atrial contraction strain (PACS) on 4-chamber and 2-chamber views. Statistical analysis was performed with chi-square analysis, t test, or binomial regression analysis, with a P-value < .05 considered statistically significant.. Twenty-two patients developed IRAF (33%). Age at initiation of ibrutinib was significantly associated with IRAF (65.1 years vs 74.1 years, P = .002). Mean ibrutinib dose was lower among patients who developed IRAF (388.2 ± 121.7 vs 448.6 ± 88.4, P = .025). E/e' was significantly higher among patients who developed IRAF (11.5 vs 9.3, P = .04). PALS was significantly lower in patients who developed AF (30.3% vs 36.3%, P = .01). On multivariate regression analysis, age, PALS, and PACS were significantly associated with IRAF. On multivariate regression analysis, only PACS remained significantly associated with IRAF while accounting for age.. Age, ibrutinib dose, E/e', and PALS on pre-treatment echocardiogram were significantly associated with development of IRAF. On multivariate regression analyses, age, PALS, and PACS remained significantly associated with IRAF. Impaired LA mechanics add to the assessment of patients at risk for IRAF.

Topics: Adenine; Atrial Fibrillation; Heart Atria; Humans; Piperidines; Retrospective Studies; Risk Assessment

Ibrutinib is a novel drug used in haematological malignancies. Its use is associated with an increased risk of atrial fibrillation (AF), which, in turn, exposes patients to embolic risk, including stroke. Reducing this risk requires anticoagulant therapy which is a matter of concern in the context of the increased bleeding risk of patients with haematological malignancies. In this context the presence of thrombocytopenia related to haematological disorder, ibrutinib-anticoagulants and ibrutinib-platelets interactions contribute to the amplification of the problem. The correct assessment of the thrombosis vs. haemorrhage balance represents a significant challenge for the clinician. In this paper we discuss practical issues related to anticoagulation in patients treated with ibrutinib and incident AF.

Topics: Adenine; Anticoagulants; Antineoplastic Agents; Atrial Fibrillation; Hematologic Neoplasms; Hemorrhage; Humans; Piperidines; Risk Factors; Stroke; Thromboembolism

Ibrutinib is the first clinically approved inhibitor of Bruton's tyrosine kinase, an enzyme that is essential for survival and proliferation of B‑cells by activating the B‑cell receptor signalling pathway. Ibrutinib has been shown to be highly effective in B‑cell malignancies in clinical trials and is recommended in current international guidelines as a first and/or second line treatment of chronic lymphocytic leukemia. The drug has a favorable tolerability and safety profile but the occurrence of specific side effects (e.g. atrial fibrillation, bleeding and hypertension) may complicate or be of concern for doctors and patients considering the use of this treatment. In many cases, however, it is not necessary to withhold this effective therapy. In contrast, ibrutinib treatment can be initiated or continued, if certain recommendations are followed. The possibilities of prevention, diagnosis and management of specific clinical situations are discussed in detail and recommendations are derived, which should facilitate ibrutinib use.

Topics: Adenine; Atrial Fibrillation; Cardiovascular Diseases; Humans; Piperidines; Pyrazoles; Pyrimidines; Risk Factors

Atrial fibrillation (AF) occurs in up to 11% of cancer patients treated with ibrutinib. The pathophysiology of ibrutinib promoted AF is complicated, as there are multiple interactions involved; the detailed molecular mechanisms underlying this are still unclear. Here, we aimed to determine the electrophysiological and molecular mechanisms of burst-pacing-induced AF in ibrutinib-treated mice. The results indicated differentially expressed proteins in ibrutinib-treated mice, identified through proteomic analysis, were found to play a role in oxidative stress-related pathways. Finally, treatment with an inhibitor of NADPH oxidase (NOX) prevented and reversed AF development in ibrutinib-treated mice. It was showed that the related protein expression of reactive oxygen species (ROS) in the ibrutinib group was significantly increased, including NOX2, NOX4, p22-phox, XO and TGF-β protein expression. It was interesting that ibrutinib group also significantly increased the expression of ox-CaMKII, p-CaMKII (Thr-286) and p-RyR2 (Ser2814), causing enhanced abnormal sarcoplasmic reticulum (SR) Ca

Topics: Acetophenones; Adenine; Animals; Atrial Fibrillation; Calcium; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Disease Models, Animal; Humans; Male; Mice; Myocytes, Cardiac; Piperidines; Protein Interaction Maps; Proteomics; Reactive Oxygen Species; Sarcoplasmic Reticulum; Signal Transduction

Topics: Adenine; Anticoagulants; Atrial Fibrillation; Dabigatran; Humans; Piperidines; Plasma; Stroke; Treatment Outcome

Ibrutinib is a Bruton tyrosine kinase inhibitor with remarkable efficacy against B-cell cancers. Ibrutinib also increases the risk of atrial fibrillation (AF), which remains poorly understood.. We performed electrophysiology studies on mice treated with ibrutinib to assess inducibility of AF. Chemoproteomic analysis of cardiac lysates identified candidate ibrutinib targets, which were further evaluated in genetic mouse models and additional pharmacological experiments. The pharmacovigilance database, VigiBase, was queried to determine whether drug inhibition of an identified candidate kinase was associated with increased reporting of AF.. We demonstrate that treatment of mice with ibrutinib for 4 weeks results in inducible AF, left atrial enlargement, myocardial fibrosis, and inflammation. This effect was reproduced in mice lacking Bruton tyrosine kinase, but not in mice treated with 4 weeks of acalabrutinib, a more specific Bruton tyrosine kinase inhibitor, demonstrating that AF is an off-target side effect. Chemoproteomic profiling identified a short list of candidate kinases that was narrowed by additional experimentation leaving CSK (C-terminal Src kinase) as the strongest candidate for ibrutinib-induced AF. Cardiac-specific Csk knockout in mice led to increased AF, left atrial enlargement, fibrosis, and inflammation, phenocopying ibrutinib treatment. Disproportionality analyses in VigiBase confirmed increased reporting of AF associated with kinase inhibitors blocking Csk versus non-Csk inhibitors, with a reporting odds ratio of 8.0 (95% CI, 7.3-8.7;. These data identify Csk inhibition as the mechanism through which ibrutinib leads to AF. Registration: URL: https://ww.clinicaltrials.gov; Unique identifier: NCT03530215.

Topics: Action Potentials; Adenine; Agammaglobulinaemia Tyrosine Kinase; Animals; Antineoplastic Agents; Atrial Fibrillation; Atrial Function, Left; CSK Tyrosine-Protein Kinase; Databases, Genetic; Heart Atria; Heart Rate; Humans; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Inbred CBA; Mice, Knockout; Piperidines; Protein Kinase Inhibitors; Risk Assessment; Risk Factors

Topics: Adenine; Atrial Fibrillation; Australia; Humans; Piperidines; Pyrazoles; Pyrimidines

Topics: Adenine; Atrial Fibrillation; Humans; Neoplasms; Piperidines; Pyrazoles; Pyrimidines

Ibrutinib is a drug used in several lymphohyperplastic diseases. Its use is associated with an increased risk of atrial fibrillation. New-onset atrial fibrillation in this setting is a true challenge as several antiarrhythmic drugs are not indicated and long-term anticoagulation has several limitations. Herein, we describe our experience in treating a 55-year-old patient receiving ibrutinib who presented with new-onset atrial fibrillation and borderline arterial pressure. Since first-line therapies, electrical cardioversion and ablation, could not be performed, rhythm control with intravenous administration of amiodarone was attempted and led to prompt sinus rhythm restoration. We discuss the therapeutic challenges related to sinus rhythm restoration and anticoagulation in this group of atrial fibrillation patients.

Topics: Adenine; Amiodarone; Anti-Arrhythmia Agents; Atrial Fibrillation; Humans; Male; Middle Aged; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines

Topics: Adenine; Aged; Atrial Fibrillation; Comorbidity; Electrocardiography; Female; Heart Failure; Humans; Incidence; Kaplan-Meier Estimate; Male; Middle Aged; Neoplasms; Patient Outcome Assessment; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Retrospective Studies; Risk Factors

Ibrutinib is a novel antitumor drug that targets Bruton tyrosine kinase for treatment of chronic lymphocytic leukemia. Atrial fibrillation (AF) occurs in 5%-9% of patients during treatment, but the underlying mechanisms remain unclear.. The purpose of this study was to develop a mouse model of ibrutinib-induced AF and investigate its proarrhythmic mechanisms.. In C57BI/6 mice in the ibrutinib and control groups, ibrutinib (25 mg/kg/d) or vehicle (hydroxypropy1-β-cyclodextrin), respectively, was administered orally for 4 weeks. Transesophageal burst stimulation then was used to induced AF. To evaluate the underlying mechanism of AF, cardiac echocardiography was performed. Ca. Compared with the control group, the ibrutinib group showed (1) a higher incidence and longer duration of AF with transesophageal burst stimulation; (2) increased left atrial mass, as indicated by echocardiography; (3) significant myocardial fibrosis in the left atrium on Masson trichrome staining; (4) Ca. The present study established a mouse model of AF by oral administration of ibrutinib for 4 weeks. The arrhythmogenic mechanisms underlying this model likely are associated with structural remodeling and Ca

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Animals; Antineoplastic Agents; Atrial Fibrillation; Atrial Remodeling; Calcium; Calcium Signaling; Disease Models, Animal; Echocardiography; Heart Atria; Leukemia, Lymphocytic, Chronic, B-Cell; Mice; Myocytes, Cardiac; Piperidines; Pyrazoles; Pyrimidines

Ibrutinib (IB) is an oral Bruton's tyrosine kinase (BTK) inhibitor that has demonstrated benefit in B cell cancers, but is associated with a dramatic increase in atrial fibrillation (AF). We employed cell-specific differentiation protocols and optical mapping to investigate the effects of IB and other tyrosine kinase inhibitors (TKIs) on the voltage and calcium transients of atrial and ventricular human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs). IB demonstrated direct cell-specific effects on atrial hPSC-CMs that would be predicted to predispose to AF. Second-generation BTK inhibitors did not have the same effect. Furthermore, IB exposure was associated with differential chamber-specific regulation of a number of regulatory pathways including the receptor tyrosine kinase pathway, which may be implicated in the pathogenesis of AF. Our study is the first to demonstrate cell-type-specific toxicity in hPSC-derived atrial and ventricular cardiomyocytes, which reliably reproduces the clinical cardiotoxicity observed.

Topics: Adenine; Atrial Fibrillation; Cardiotoxicity; Cell Differentiation; Cells, Cultured; Heart; Heart Atria; Heart Ventricles; Humans; Myocardium; Myocytes, Cardiac; Organ Specificity; Piperidines; Pluripotent Stem Cells; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines

There is increasing evidence that rates of atrial arrhythmias (AA), specifically atrial fibrillation and flutter are elevated in patients treated with the tyrosine kinase inhibitor, ibrutinib; however, the exact risk of ibrutinib-associated AA is not definitively established. We conducted a retrospective study of 137 patients diagnosed with B-cell malignancies treated with ibrutinib compared with 106 patients treated with chemotherapy for the same cancers in order to quantify the rates and risk of AA in a "real-world" sample of cancer patients. Fisher's exact test was used to evaluate for any statistically significant differences between groups. Logistic regression was used to generate odds ratios, adjusting for potential confounders. Incidence of AA was 14% (n = 17) in ibrutinib-treated patients compared with 3% (n = 3) in patients treated with chemotherapy (p = 0.009). Ibrutinib-treated patients were significantly older (mean age 67 vs 63 years, p = 0.003); however, there were no other significant differences in baseline characteristics. Ibrutinib use, age, hypertension, and previous use of ACE inhibitors, angiotensin receptor blocker use, β blocker use, and aspirin use were independently associated with incident arrhythmias. In multivariable analysis, patients treated with ibrutinib were associated with a 5-fold increased risk of developing AA (odds ratio = 5.18, 95% confidence interval 1.42 to 18.89). In conclusion, the rates and risk of AA are higher in patients treated with ibrutinib compared with chemotherapy, and this study provides strong evidence that ibrutinib itself is an independent risk factor for the development of incident AA.

Topics: Adenine; Age Factors; Aged; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antineoplastic Agents; Aspirin; Atrial Fibrillation; Atrial Flutter; Female; Humans; Hypertension; Incidence; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Mantle-Cell; Male; Middle Aged; Multivariate Analysis; Piperidines; Platelet Aggregation Inhibitors; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Risk Factors; Waldenstrom Macroglobulinemia

Results from several recent studies in chronic lymphocytic leukemia (CLL) have demonstrated an association between ibrutinib exposure and the development of atrial fibrillation, estimated incidence of 11% with long-term follow up. This is a common cause of ibrutinib discontinuation. Risk factors for atrial fibrillation include advanced age, hypertension (HTN), mitral valve disease (MVD), left atrial remodeling, coronary artery disease (CAD) and risk factors for cardiovascular dysfunction We conducted a retrospective case control study using the presence of left atrial abnormality identified on pre-ibrutinib EKGs, defined as either (1) Lead II-bifed p wave, with 40 mcsec between peaks for ≥ 2.5 mm wide ≥ 100 msec in duration, (2) Lead V1-biphasic P wave with terminal portion ≥ 40 msec in duration or terminal portion ≥ 1 mm deep or (3) PR interval ≥ 200 msec (intra-atrial conduction delay) as a predictor for development of atrial fibrillation. 183 consecutively CLL patients treated with ibrutinib were identified. 44 patients met inclusion criteria (20 cases, 24 controls). 20 (11.3%) of patients developed atrial fibrillation. Left atrial enlargement was identified as a significant predictor of development of atrial fibrillation (OR 9.1, 95% CI 2.2-37.3, p=0.02). Age, baseline HTN, CAD, diabetes, age and sex were not significant predictors. Area under the ROC curve for the model was estimated to be 75%. LAA identified by EKG is a moderately specific and sensitive finding that can identify patients at increased risk for this toxicity.

Topics: Adenine; Aged; Antineoplastic Agents; Atrial Fibrillation; Case-Control Studies; Electrocardiography; Follow-Up Studies; Heart Atria; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Piperidines; Pyrazoles; Pyrimidines; Retrospective Studies; Risk Factors

Atrial fibrillation is a side effect of ibrutinib, an irreversible inhibitor of Bruton tyrosine kinase used for treatment of B-cell lymphoproliferative disorders. We determined if single (2 or 10 mg/kg), or chronic (14 days) oral ibrutinib followed by 24-hour washout conferred susceptibility to electrically induced arrhythmias in 1-month-old male C57BL/6 mice. A single higher dose of ibrutinib increased arrhythmia inducibility. There was no inducibility difference after chronic dosing with washout. This suggests that high serum drug levels might be responsible for the proarrhythmic effect of ibrutinib and that an altered dosing strategy might mitigate the side effects.

Topics: Adenine; Animals; Atrial Fibrillation; Disease Models, Animal; Disease Susceptibility; Dose-Response Relationship, Drug; Electrocardiography; Male; Mice; Mice, Inbred C57BL; Piperidines; Pulse Therapy, Drug; Pyrazoles; Pyrimidines; Random Allocation; Reference Values; Risk Assessment; Ventricular Fibrillation

Ibrutinib is an oral irreversible inhibitor of Bruton's tyrosine kinase, indicated for the treatment of chronic lymphocytic leukaemia. The drug is generally well tolerated; however, not infrequent side effects are reported, with the major two being bleeding and ibrutinib-related atrial fibrillation. Atrial fibrillation pathogenesis in this setting is not completely clear, and no prospective studies have evaluated the impact of previous cardiologic history and baseline characteristics.. We prospectively performed cardiologic assessment in 43 CLL patients before starting ibrutinib therapy. Cardiologic workup included comorbidity collection and electrocardiographic and echocardiographic baseline evaluation.. After a median observation of 8 months, seven patients developed atrial fibrillation (16.3%). Cases developing atrial fibrillation were all elderly males (p = 0.04), and mostly with a history of previous arterial hypertension (p = 0.009). Atrial fibrillation occurrence also correlated with the presence of one or more pre-existent cardiologic comorbidities (p = 0.03), with a higher atrial fibrillation risk score (calculated with comorbidities and cardiologic risk factor evaluation p < 0.001), and with higher left atrial diameter (p = 0.02) and area (p = 0.03) by echocardiography. The occurrence of atrial fibrillation was managed after an integrated cardio-oncologic evaluation: anticoagulation was started in 4 (57.1%) patients and beta-blockers or amiodarone in 5 (71.4%). One patient underwent electric cardioversion and another patient pacemaker positioning to normalise heart rate in order to continue ibrutinib.. Our data show that echocardiography is a highly informative and reproducible tool that should be included in pre-treatment workup for patients who are candidates for ibrutinib therapy.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Aged; Aged, 80 and over; Atrial Fibrillation; Echocardiography; Female; Hemorrhage; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Piperidines; Prospective Studies; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines; Reproducibility of Results

Topics: Adenine; Aged; Aged, 80 and over; Atrial Fibrillation; Dabigatran; Female; Humans; Lymphoproliferative Disorders; Piperidines; Pyrazoles; Pyrimidines

Ibrutinib, an irreversible inhibitor of Bruton tyrosine kinase (BTK), is a novel drug that has shown significant efficacy and survival benefit for treatment of various B-cell malignancies. The primary objective of the present study was to investigate the efficacy of ibrutinib therapy in various B-cell malignancies in the general community. The secondary objectives included studying the adverse effects, ibrutinib-induced peripheral lymphocytosis, and effect on immunoglobulin levels.. The present study was a retrospective observational cohort analysis conducted at Abington Jefferson Health. The clinical response was determined from the hematologist's assessment and evaluated independently using the response criteria for each B-cell malignancy. Adverse effects were graded according to the Common Terminology Criteria for Adverse Events, version 4.0. The Wilcoxon signed-rank test was used to compare immunoglobulin levels before and after ibrutinib. Forty five patients with B-cell malignancies and receiving ibrutinib therapy were eligible.. Ibrutinib is a highly effective and tolerable drug for B-cell malignancies in the general community. In contrast to the previously reported rate of 5% to 7%, we observed a higher rate (11%) of atrial fibrillation, which might have resulted from the smaller sample size in the present study and the multiple comorbidities. Nonetheless, this treatment-limiting side effect requires further elucidation. Paradoxical lymphocytosis at the outset of therapy was a common and benign finding. In conjunction with the reported trials, the IgG levels decreased in the first year of continued therapy. However, the IgA levels did not increase, even after 2 years of therapy.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Aged; Aged, 80 and over; Atrial Fibrillation; B-Lymphocytes; Disease-Free Survival; Female; Humans; Immunoglobulin G; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphocytosis; Male; Middle Aged; Piperidines; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines; Retrospective Studies; Treatment Outcome; Waldenstrom Macroglobulinemia

Although preliminary data suggests that ibrutinib may increase risk of atrial fibrillation (AF), the incidence of AF in a general cohort of chronic lymphocytic leukemia (CLL) patients is unknown. We evaluated the prevalence of AF at CLL diagnosis and incidence of AF during follow-up in 2444 patients with newly diagnosed CLL. A prior history of AF was present at CLL diagnosis in 148 (6.1%). Among the 2292 patients without history of AF, 139 (6.1%) developed incident AF during follow-up (incidence approximately 1%/year). Older age (p < .0001), male sex (p = .01), valvular heart disease (p = .001), and hypertension (p = .04) were associated with risk of incident AF on multivariate analysis. A predictive model for developing incident AF constructed from these factors stratified patients into 4 groups with 10-year rates of incident AF ranging from 4% to 33% (p < .0001). This information provides context for interpreting rates of AF in CLL patients treated with novel therapies.

Topics: Adenine; Adult; Aged; Aged, 80 and over; Atrial Fibrillation; Comorbidity; Female; Humans; Incidence; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Neoplasm Staging; Piperidines; Prevalence; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Risk Factors; Young Adult

Topics: Adenine; Aged; Amiodarone; Atrial Fibrillation; Cytochrome P-450 CYP3A Inhibitors; Drug Interactions; Heart Failure; Humans; Male; Piperidines; Pyrazoles; Pyrimidines; Syndrome

Topics: Adenine; Aged; Aged, 80 and over; Atrial Fibrillation; Female; Follow-Up Studies; Humans; Incidence; Lymphoma, Mantle-Cell; Male; Piperidines; Pyrazoles; Pyrimidines; Recurrence; Retrospective Studies; Treatment Outcome

Topics: Adenine; Anticoagulants; Atrial Fibrillation; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Piperidines; Pyrazoles; Pyrimidines; Risk Factors; Stroke; Warfarin

Atrial fibrillation (AF) occurs in 5-9% of patients treated with ibrutinib for chronic lymphocytic leukaemia (CLL); the clinical consequences and optimal management are unclear. We retrospectively studied 56 CLL patients who received ibrutinib and developed AF. Median time to onset was 3·8 months. AF was persistent in 35/56 (62%) cases despite treatment. Clinical consequences included: three episodes of severe cardiac failure (one fatal) and one stroke; eight non-thrombocytopenic patients (14%) experienced severe bleeding adverse events. Altogether, ibrutinib was permanently discontinued in 26/56 cases (46%). Data to guide optimal management are lacking and clinical practice guidelines are urgently needed.

Topics: Adenine; Aged; Aged, 80 and over; Antineoplastic Agents; Atrial Fibrillation; Disease Management; Female; Hemorrhage; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Retrospective Studies

Topics: Adenine; Algorithms; Antineoplastic Agents; Atrial Fibrillation; Humans; Piperidines; Pyrazoles; Pyrimidines

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Animals; Animals, Newborn; Atrial Fibrillation; Gene Expression Regulation, Enzymologic; Humans; Infant, Newborn; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Mantle-Cell; Myocytes, Cardiac; Phosphatidylinositol 3-Kinases; Piperidines; Protein-Tyrosine Kinases; Proto-Oncogene Proteins c-akt; Pyrazoles; Pyrimidines; Rats; Risk Factors; Signal Transduction