pci-32765 and Drug-Related-Side-Effects-and-Adverse-Reactions

Ibrutinib is a highly effective drug for patients with chronic lymphocytic leukemia (CLL), and is well tolerated even by older patients and those unfit to receive conventional immuno-chemotherapy.. The occurrence of adverse events was revealed as a major cause of ibrutinib failure in the real-world. Ibrutinib-induced lymphocytosis carries the risk of an untimely interruption of therapy because it may be misinterpreted as disease progression. In addition, drug interactions can worsen ibrutinib-associated toxicities by increasing the plasma concentration of ibrutinib. In this review, we present a case of major hemorrhage and atrial fibrillation (AF) during ibrutinib use and summarize the adverse events associated with ibrutinib. Furthermore, the practical management of ibrutinib-associated toxicities was covered with reference to a drug interaction mechanism.. Clinicians should examine the prescribed drugs prior to ibrutinib initiation and carefully monitor toxicities while taking ibrutinib. A reduced dose of ibrutinib with the concurrent use of CYP3A inhibitors such as antifungal agents could be an attractive strategy to reduce toxicities and may confer financial benefits. Reducing unexpected toxicities is as significant as achieving treatment response in the era of life-long therapy with ibrutinib in patients with CLL.

Topics: Adenine; Aged; COVID-19; Disease Management; Drug Interactions; Drug-Related Side Effects and Adverse Reactions; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Piperidines; Protein Kinase Inhibitors

Ibrutinib is a first-in-class, highly potent Bruton tyrosine kinase inhibitor which has become standard of care for patients with chronic lymphocytic leukaemia and other lymphoproliferative disorders. It requires indefinite administration which places emphasis on toxicity and long-term tolerance.. Extensive use of ibrutinib in studies and clinical practice has better defined its full toxicity profile which has made its use more challenging than initially foreseen. In particular, dysrhythmias, bleeding, infections and constitutional symptoms have been reported and can result in dose reduction or discontinuation of ibrutinib. Herein, we review the common as well as rare but important toxicities and discuss approach and management on a practical level. We also highlight that patients should be regularly monitored for adverse events and proactively treated to minimise side effects and avoid disruption.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Antineoplastic Agents; Drug-Related Side Effects and Adverse Reactions; Humans; Piperidines; Protein Kinase Inhibitors; Risk Assessment; Risk Factors; Treatment Outcome

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

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Antineoplastic Agents; Disease Management; Drug Interactions; Drug-Related Side Effects and Adverse Reactions; Humans; Incidence; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, B-Cell; Piperidines; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Purines; Pyrazoles; Pyrimidines; Quinazolinones; Severity of Illness Index

P110-γ and -δ act in lymphocytes chemotaxis, presenting distinct, nonredundant roles in B- and T-cell migration and adhesion to stromal cells. Moreover, phosphoinositide-3-kinase-γ inhibition contributes to regulate macrophage polarization inhibiting cancer growth. Duvelisib (IPI-145) is an oral first-in-class, dual phosphoinositide-3-kinase inhibitor targeting p110-δ/γ exerting its activity in preclinical studies across different prognostic groups. In a large Phase III study, duvelisib showed superior progression-free survival and overall response rate compared with ofatumumab, thus leading to its approval for relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma. Immune-related effects are the main reason for treatment suspension, thus affecting survival benefit. Nevertheless, the correct management of adverse events, eventually including dose modification, allows patients to remain on treatment. In conclusion, duvelisib represents a promising treatment in chronic lymphocytic leukemia and a salvage therapy after ibrutinib.

Topics: Adenine; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Class I Phosphatidylinositol 3-Kinases; Drug Evaluation; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Isoquinolines; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Piperidines; Prognosis; Purines; Pyrazoles; Pyrimidines; Salvage Therapy

Observation (watch and wait) is the standard of care for patients with asymptomatic Binet stage A chronic lymphocytic leukemia (CLL). However, the clinical course of these patients is very heterogeneous with some patients requiring treatment rather soon and others not progressing for ages. The clinical staging does not reflect this high variability of the clinical course of CLL. Published data demonstrate that the comprehensive use of several risk factors dramatically improves the accuracy of prognostication independent of clinical stage. The treatment of CLL underwent considerable changes with the introduction of kinase-inhibitors, including ibrutinib, an orally administered, well-tolerated and potent inhibitor of Bruton's tyrosine kinase. This is the first prospective, multicenter, placebo-controlled, double-blind, Phase III study to compare efficacy and safety of ibrutinib to a watch-and-wait approach in Binet stage A CLL with risk of disease progression defined by the comprehensive CLL score.

Topics: Adenine; Adult; Aged; Aged, 80 and over; Disease Progression; Disease-Free Survival; Double-Blind Method; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Neoplasm Staging; Piperidines; Pyrazoles; Pyrimidines; Risk

We describe a case vision-threatening sclerouveitis as a probable adverse drug reaction to ibrutinib.. Case report.. Ibrutinib is an inhibitor of Bruton's kinase which has shown success in the treatment of hematological malignancies such as chronic lymphocytic leukemia. Despite being generally well tolerated, recent studies have implicated ibrutinib in several adverse events affecting organs such as the heart, intestines, and the eyes. We present the case of a patient who developed severe sclerouveitis after approximately one year of ibrutinib therapy, and suggest this is a probable adverse drug reaction associated with ibrutinib in accordance with the Naranjo algorithm, highlighting the importance of prompt management of ocular symptoms in these patients.

Topics: Adenine; Drug-Related Side Effects and Adverse Reactions; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Uveitis

Topics: Adenine; Aged; Arm; Drug-Related Side Effects and Adverse Reactions; Humans; Lymphedema; Male; Piperidines; Skin

There are limited data on treatment patterns, adverse events (AEs), and economic burden in younger, commercially insured patients treated for mantle cell lymphoma (MCL).. Adults with ≥1 treatment for MCL between 1 November 2013-31 December 2017 were identified from IQVIA Real-World Data Adjudicated Claims-US; index date was first treatment. Patients carried ≥1 MCL diagnosis, were newly treated, and were enrolled continuously for ≥12 months prior to and ≥30 days following index. Patients receiving the four most common MCL regimens were included. Measures included frequency of incident AEs, resource use, and costs overall and by number of AEs. Adjusted logistic regression and generalized linear modeling evaluated risk of hospitalization and all-cause costs per patient per month (PPPM).. Two thousand five hundred and nine treated patients had a drug-specific code and were classified to a specific treatment regimen. Of those patients, 1785 patients received at least one of the four most commonly used MCL regimens (R-CHOP, rituximab monotherapy, B-R, and ibrutinib) at some point over follow-up (median 23 months). R-CHOP was the most common regimen observed in the first line (26%), followed by rituximab monotherapy (19%), B-R (15%), and ibrutinib (5%). The median age was 57 years; median Charlson Comorbidity Index was 0. Among patients receiving the four most common regimens, 63% of patients experienced ≥1 incident AE (R-CHOP 77%, B-R 58%, and ibrutinib 52%). An increasing number of incident AEs was associated with increased hospitalization risk (odds ratio = 2.4; 95% Confidence Interval [CI] 2.1-2.7) and increased mean costs PPPM (cost ratio = 1.1; 95% CI 1.1-1.2).. This is the largest study describing treatment patterns and clinical and economic impact of MCL treatment. The most common regimens were R-CHOP, rituximab monotherapy, B-R, and ibrutinib. The majority of treated patients experienced at least one incident AE, with hospitalization risk and all-cause costs increasing as the number of AEs increased.

Topics: Adenine; Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Cost of Illness; Cyclophosphamide; Doxorubicin; Drug-Related Side Effects and Adverse Reactions; Female; Follow-Up Studies; Health Care Costs; Health Care Rationing; Hospitalization; Humans; Incidence; Insurance, Health; Lymphoma, Mantle-Cell; Male; Middle Aged; Piperidines; Practice Patterns, Physicians'; Prednisone; Pyrazoles; Pyrimidines; Retrospective Studies; Rituximab; Treatment Outcome; United States; Vincristine; Young Adult

Clinical trials that led to ibrutinib's approval for the treatment of chronic lymphocytic leukemia showed that its side effects differ from those of traditional chemotherapy. Reasons for discontinuation in clinical practice have not been adequately studied. We conducted a retrospective analysis of chronic lymphocytic leukemia patients treated with ibrutinib either commercially or on clinical trials. We aimed to compare the type and frequency of toxicities reported in either setting, assess discontinuation rates, and evaluate outcomes. This multicenter, retrospective analysis included ibrutinib-treated chronic lymphocytic leukemia patients at nine United States cancer centers or from the Connect® Chronic Lymphocytic Leukemia Registry. We examined demographics, dosing, discontinuation rates and reasons, toxicities, and outcomes. The primary endpoint was progression-free survival. Six hundred sixteen ibrutinib-treated patients were identified. A total of 546 (88%) patients were treated with the commercial drug. Clinical trial patients were younger (mean age 58

Topics: Adenine; Adult; Aged; Aged, 80 and over; Disease Progression; Drug-Related Side Effects and Adverse Reactions; Female; Follow-Up Studies; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Piperidines; Prognosis; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Retrospective Studies; Survival Rate

Most patients with chronic lymphocytic leukemia (CLL) present with multiple comorbidities. Although comorbidities negatively affect outcomes for patients treated with chemoimmunotherapy, their impact on patients who receive targeted therapies is unknown.. This multicenter, retrospective analysis evaluated the significance of comorbidities, as assessed by the Cumulative Illness Rating Scale (CIRS), among patients with CLL treated with ibrutinib.. One hundred forty-five patients received ibrutinib (80% in a relapsed/refractory setting). A high burden of comorbidities (CIRS score ≥ 7) was associated with inferior median event-free survival (EFS; 24 vs 37 months; P = .003) and 2-year overall survival (OS; 79% vs 100%; P = .005). In an adjusted Cox model, both EFS and OS worsened with an incremental increase in the CIRS score. Furthermore, comorbidities were associated with an increased risk of ibrutinib dose reduction and therapy discontinuation. CIRS was predictive in both frontline and relapsed CLL, regardless of patient age.. Comorbidities portend a poor prognosis among patients with CLL treated with ibrutinib. Prospective studies are needed to optimize the treatment of patients with CLL who have comorbidities. Cancer 2018. © 2018 American Cancer Society.

Topics: Adenine; Aged; Aged, 80 and over; Comorbidity; Drug-Related Side Effects and Adverse Reactions; Electronic Health Records; Female; Humans; Immunotherapy; Kaplan-Meier Estimate; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Neoplasm Recurrence, Local; Piperidines; Progression-Free Survival; Pyrazoles; Pyrimidines; Treatment Outcome

Ibrutinib is a Bruton tyrosine kinase inhibitor and is approved for the treatment of patients with chronic lymphocytic leukemia (CLL) in frontline and relapsed/refractory settings. The authors previously reported poor outcomes for patients who discontinued ibrutinib; however, long-term outcomes were not reported.. Data from 320 patients who received ibrutinib on clinical studies between 2010 and 2015 at The University of Texas MD Anderson Cancer Center were retrospectively analyzed.. Long-term outcomes among patients with CLL after they discontinued ibrutinib were analyzed. Ninety of 320 patients (28%) who were treated on ibrutinib-based regimens discontinued ibrutinib. Of these, 80 had relapsed/refractory disease, and 10 were treatment-naive. The median time to discontinuation was 15 months (range, 1.2-54 months). After a median follow-up of 38 months after starting ibrutinib, 40 patients (44%) remained alive. Major reasons for ibrutinib discontinuation were intolerance (n = 29; 32%), miscellaneous (n = 28; 31%), progression (n = 19; 21%), and Richter transformation (RT) (n = 9; 10%). The median survival according to the reason for discontinuation was 33 months for ibrutinib intolerance, 11 months for miscellaneous causes, 16 months for progressive CLL, and 2 months for RT. Among the 19 patients who had progressive CLL, 42% responded to subsequent therapy.. Ibrutinib discontinuation was observed during therapy. Patients with CLL who had disease transformation had especially poor outcomes, whereas those who developed progressive disease during ibrutinib therapy had a median survival of <1.5 years. Survival was associated with the reason for discontinuation; patients who had progressive CLL had better survival compared with those who had disease transformation. Effective salvage strategies for patients with CLL who progress on ibrutinib therapy is of critical importance. Cancer 2017;123:2268-2273. © 2017 American Cancer Society.

Topics: Adenine; Adult; Aged; Aged, 80 and over; Deprescriptions; Disease Progression; Drug-Related Side Effects and Adverse Reactions; Female; Follow-Up Studies; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Retrospective Studies; Survival Rate