scholarly journals Real World Experience of the BTK Inhibitors. Comparing Cardiac, Vascular and Infectious Toxicities

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4509-4509
Author(s):  
Samip R Master ◽  
Poornima Ramadas ◽  
Richard Preston Mansour
Keyword(s):  
Atrial Fibrillation ◽  
Adverse Effects ◽  
Adverse Events ◽  
Real World ◽  
General Public ◽  
Cardiac Toxicity ◽  
Kinase Inhibitor ◽  
Vascular Toxicity ◽  
Bruton Tyrosine Kinase ◽  
Btk Inhibitors

Abstract Background: Cardiac and vascular toxicities are known complications on Bruton Tyrosine kinase inhibitor (BTKi)drugs. Ibrutinib, acalibrutinib and zanubrutinib are all approved BTKi drugs. We did a retrospective analysis on adverse effects (AE) of BTKi's that has been made available to public by the FDA. Methods: The FDA has made the data on AEs of various treatments available to general public through the FDA Adverse Events Reports System (FAERS) public dashboard. We investigated the infectious, cardiac and vascular AEs of various BTKi for the years 2019-2021. Results: The percentage of cardiac AE compared to total AEs reported for ibrutinib, acalibrutinib and zanubrutinib were 12%, 7.3% and 6.2% respectively. The most common cardiac toxicity was atrial fibrillation. The percentage of vascular AE compared to total AEs reported for ibrutinib, acalibrutinib and zanubrutinib were 8.2 %, 5.2 % and 3.9 % respectively. The most common vascular toxicity was hemorrhage. The percentage of infectious AE compared to total AEs reported for ibrutinib, acalibrutinib and zanubrutinib were 18.3%, 13.6% and 35.5% respectively. The most common vascular toxicity was pneumonia. Conclusions: Out of the reported cases of AEs to BTKis approved, ibrutinib have most and acalibrutinib have least cardiac AEs. Zanubrutinib has least vascular AEs. Out of the reported cases of AEs to BTKis approved, zanubrutinib have most infectious AEs. Disclosures Master: Blue Bird Bio: Current holder of individual stocks in a privately-held company.

Abstract 12978: Identification of Cardiovascular Adverse Effects Associated With Midostaurin - A WHO Pharmacovigilance Database Analysis

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Arrush Choudhary ◽  
Ali Manouchehri ◽  
Javid Moslehi ◽  
Joe-elie Salem
Keyword(s):  
Heart Failure ◽  
Atrial Fibrillation ◽  
Adverse Effects ◽  
Adverse Events ◽  
Kinase Inhibitor ◽  
Systemic Mastocytosis ◽  
Qt Prolongation ◽  
Reporting Odds Ratio ◽  
Pericardial Disease ◽  
Global Database

Introduction: Midostaurin is an oral multiple tyrosine kinase inhibitor (TKI) approved for treatment of acute myeloid leukemia and systemic mastocytosis. Clinical trials have shown efficacy of midostaurin with few adverse events. Although midostaurin does cause QT-prolongation, other associated cardiovascular complications are unknown. The purpose of this study is to identify and characterize cardiovascular adverse events associated with midostaurin. Methods: We used VigiBase, WHO's global database of individual case safety reports, to evaluate the association between midostaurin and cardiovascular adverse events using the reporting odds ratio (ROR) and the information component (IC). IC is an indicator value for disproportionate Bayesian reporting that compares observed and expected values to find associations between drugs and adverse events. IC 025 is the lower end of the IC 95% credibility interval and an IC 025 value of more than zero is deemed significant. Results: We identified 153 adverse cardiovascular events reported in patients who received midostaurin. Midostaurin treatment was associated with higher reporting of QT prolongation (48 cases, IC 025 4.15), heart failure (38 cases, IC 025 1.90), atrial fibrillation (20 cases, IC 025 1.53), and pericardial disease (12 cases, IC 025 1.23). A majority of these adverse events occurred within 50 days of midostaurin initiation with midostaurin being the only suspected culprit medication. Fatalities occurred in 8.7%, 43.2%, and 42.1% of cases of QT prolongation, heart failure, and atrial fibrillation, respectively. Conclusions: Midostaurin can lead to severe and sometimes fatal cardiac toxicities in a subset of patients. Baseline electrocardiograms and echocardiograms would be prudent in patients starting midostaurin to characterize and monitor these adverse effects.

Cardiac complications of CDK4/6 inhibitors for breast cancer.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e13038-e13038
Author(s):  
Samip R. Master
Keyword(s):  
Breast Cancer ◽  
Myocardial Infarction ◽  
Atrial Fibrillation ◽  
Adverse Reaction ◽  
Pericardial Effusion ◽  
Adverse Effects ◽  
Adverse Events ◽  
Cardiac Failure ◽  
Cardiac Toxicity ◽  
Cardiac Complications

e13038 Background: Cardiac toxicity has largely been underestimated toxicity of CDK4/6 inhibitors. We did a retrospective analysis of data made available to public by the FDA regarding the cardiac adverse effects of CDK 4/6 inhibitors. We used data from trastuumab for comparison purpose. Methods: The FDA has made the data on adverse effects of various treatments available to general public through the FDA Adverse Events Reports System (FAERS) public dashboard. We investigated the cardiac toxicities of CDK 4/6 inhibitor therapies available at FDERS for the years 2018-2019. Results: A total of 27,079 advere events(AE) from CDK4/6 inhibitors namely, ribociclib, palbociclib and abemaciclib were reported during the year 2018-2019. Out the total, 805 i.e. 2.9% were cardiac AEs. The most common reported cardiac AE were atrial fibrillation (121), myocardial infarction (190), cardiac failure (85) and pericardial effusion (70). As shown in the table, percentage of cardiac AE compared to total AE reported were 2.2%, 5.4%, 7.9% and 7.2% respectively for Palbociclib, Abemaciclib, Ribociclib and trastuzumab. Conclusions: Out of the reported cases of adverse reaction to CDK4/6 inhibitors, 2.9 % were cardio toxicities. The incidence of cardiac complications was higher in ribociclib, compared to Palbociclib and Abemaciclib. [Table: see text]

scholarly journals Targeting Bruton tyrosine kinase using non-covalent inhibitors in B cell malignancies

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Danling Gu ◽  
Hanning Tang ◽  
Jiazhu Wu ◽  
Jianyong Li ◽  
Yi Miao
Keyword(s):  
Adverse Events ◽  
Tyrosine Kinase ◽  
B Cell ◽  
Clinical Studies ◽  
Acquired Resistance ◽  
B Cell Malignancies ◽  
Bcr Signaling ◽  
Bruton Tyrosine Kinase ◽  
Covalent Inhibitors ◽  
Btk Inhibitors

AbstractB cell receptor (BCR) signaling is involved in the pathogenesis of B cell malignancies. Activation of BCR signaling promotes the survival and proliferation of malignant B cells. Bruton tyrosine kinase (BTK) is a key component of BCR signaling, establishing BTK as an important therapeutic target. Several covalent BTK inhibitors have shown remarkable efficacy in the treatment of B cell malignancies, especially chronic lymphocytic leukemia. However, acquired resistance to covalent BTK inhibitors is not rare in B cell malignancies. A major mechanism for the acquired resistance is the emergence of BTK cysteine 481 (C481)  mutations, which disrupt the binding of covalent BTK inhibitors. Additionally, adverse events due to the off-target inhibition of kinases other than BTK by covalent inhibitors are common. Alternative therapeutic options are needed if acquired resistance or intolerable adverse events occur. Non-covalent BTK inhibitors do not bind to C481, therefore providing a potentially effective option to patients with B cell malignancies, including those who have developed resistance to covalent BTK inhibitors. Preliminary clinical studies have suggested that non-covalent BTK inhibitors are effective and well-tolerated. In this review, we discussed the rationale for the use of non-covalent BTK inhibitors and the preclinical and clinical studies of non-covalent BTK inhibitors in B cell malignancies.

scholarly journals Short-term Adverse Events With BIC/FTC/TAF: Postmarketing Study

2020 ◽  
Vol 7 (9) ◽  
Author(s):  
Edwin Hayes ◽  
Caroline Derrick ◽  
Danielle Smalls ◽  
Hilary Smith ◽  
Nicole Kremer ◽  
...  
Keyword(s):  
African American ◽  
Adverse Effects ◽  
Adverse Events ◽  
Real World ◽  
Short Term ◽  
Real World Data ◽  
Southern Us ◽  
Virologic Control ◽  
Tenofovir Alafenamide ◽  
Loss Of Appetite

Abstract Bictegravir (BIC)/emtricitabine (FTC)/tenofovir alafenamide (TAF) was Food and Drug Administration approved in February 2018. The paucity of real-world data prompted this retrospective, observational evaluation of discontinuation rates, adverse effects, and virologic control. In a Southern US, predominantly African American overweight population, we found optimal virologic control and low discontinuation rates, with 4% discontinuing BIC/FTC/TAF due to rash, low platelets, loss of appetite, and insomnia.

scholarly journals Real world experience from 1000 patients. Preprocedural DOAC interruption impacts detectable DOAC serum levels but not adverse events after catheter ablation of atrial fibrillation

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
A Konstantinou ◽  
S Bordignon ◽  
T Tohoku ◽  
S Chen ◽  
F Bologna ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Adverse Events ◽  
Real World ◽  
Patient Characteristics ◽  
Af Ablation ◽  
Patient Profile ◽  
Significant Difference ◽  
Single Pill ◽  
Group A ◽  
Group B

Abstract Introduction Direct oral anticoagulation (DOAC) therapy represents the standard of care in patients with atrial fibrillation (AF) and increased stroke risk. In a real world setting withholding DOAC medication before elective AF ablation is considered to reduce procedural bleeding risks. The aim of this study was to determine the individual DOAC level prior to the ablation procedure, to identify predisposing factors affecting traceable DOAC levels and to screen for associated severe adverse events. Methods Between September 2016 and March 2019 blood samples were obtained from patients on DOAC before an elective AF ablation. Per institutional standard all patients have been instructed to pause DOAC medication prior ablation for one or two doses depending on the patient profile and type of medication. The time interval between ablation and last DOAC intake was calculated in hours. Patient characteristics, procedural data and in-hospital complications were noted from all patients. Results A total of 1000 patients (60% male, age: 68y, GFR 83.25: BMI: 28, CHADSVASC score 3) undergoing AF ablation were included. Two groups were defined. Group A (n=416, 41.6%): patients treated with “single pill” DOAC (Rivaroxaban (n=288, 28.8%) and Edoxaban (n=128, 12.8%)). Group B (n=584, 58.4%): patients treated with twice a day DOAC (Apixaban (n=505, 50.5%) and Dabigatran (n=79, 7.9%)). The only difference in patient characteristics was an increased prior bleeding history in group B. The DOAC pause was significantly longer in group A (mean 40h) compared to group B (mean 32h), p=0.026. In a total of 217 patients (21.7%) DOAC levels where traceable prior to AF ablation. Traceable DOAC levels were significantly more common in group B (n=144/584, 24.7%) compared to group A (n=73/416, 17.5%). Adverse events occurred in 5.7% of patients (0.4% stroke, 0.3% tamponade, 2.5% hematoma, 1.9% AV-fistel, 0.7% pseudoaneurysma). T-Test analysis showed no significant difference in the occurrence of adverse events between both groups. Conclusion Despite of interrupting DOACs before an elective AF ablation therapeutic substance levels can be detected in >20% of patients. The rate of adverse events was not different between “single pill” vs. twice a day DOAC intake. Funding Acknowledgement Type of funding source: None

scholarly journals Cerebral Invasive Aspergillosis in a Case of Chronic Lymphocytic Leukemia with Bruton Tyrosine Kinase Inhibitor

2021 ◽  
Vol 28 (1) ◽  
pp. 837-841
Author(s):  
Omar Alkharabsheh ◽  
Alhareth Alsayed ◽  
Diana M. Morlote ◽  
Amitkumar Mehta
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Tyrosine Kinase ◽  
Kinase Inhibitor ◽  
Fungal Infections ◽  
Case Reports ◽  
Invasive Fungal Infections ◽  
Lymphocytic Leukemia ◽  
High Morbidity ◽  
Bruton Tyrosine Kinase ◽  
Btk Inhibitors

Bruton tyrosine kinase (BTK) inhibitors have become an important therapy for untreated and previously treated patients with chronic lymphocytic leukemia (CLL). Despite improved outcomes, rare adverse events, such as invasive fungal infections, have been reported with the use of first-generation BTK inhibitors. Invasive fungal infections carry a high morbidity and mortality risk. There have been several case reports describing the association between aspergillosis and ibrutinib treatment, but none with acalabrutinib, to our knowledge. In this case report, we describe a patient with CLL who developed an intracranial Aspergillus fumigatus infection while receiving acalabrutinib.

Axitinib and avelumab (AA) as first-line treatment of metastatic renal cell carcinoma (mRCC): A real-world outcome review in the Northwest of England, United Kingdom.

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 294-294
Author(s):  
Jennifer Allison ◽  
Natalie Charnley ◽  
Robert Stevenson ◽  
Tom Waddell ◽  
Manon Rhys Pillai
Keyword(s):  
Adverse Events ◽  
Real World ◽  
Kinase Inhibitor ◽  
Checkpoint Inhibitor ◽  
Risk Scores ◽  
Published Data ◽  
Line Treatment ◽  
First Line ◽  
First Line Treatment

294 Background: The combination of the immune checkpoint inhibitor avelumab and VEGF-targeted, antiangiogenic tyrosine kinase inhibitor axitinib (AA) has demonstrated superior PFS and ORR compared to sunitinib in patients with mRCC and is an option for first line treatment across all IMDC risk scores. In this retrospective review we report our real world experience of this combination in three cancer centres in the Northwest of England. Methods: Treatment naïve mRCC patients receiving AA through the Early Access to Medicine Scheme at 3 cancer sites in the UK between May 2019 and July 2020 were identified. Primary outcomes of interest include overall response rate (ORR), adverse events (AEs) and preliminary survival observations. Results: A total of 44 patients were identified with a median follow up of 6.9 months (0.8-13.5 mo). Median age was 68 (48-81); 68% were male. The patients’ adult comorbidity evaluation score (ACE-27) was calculated: 0 = 43%, 1 = 30%, 2 = 7% and 3 = 20% . 45%, 48% and 7% of patients had favourable (F), intermediate (I) and poor (P) IMDC risk scores respectively. All had clear cell histology with 16% demonstrating sarcomatoid change. Most patients had undergone a nephrectomy (70%) and 36% had a single organ site of metastatic disease. ORR in the whole cohort was 60% (CR 5%, PR 55%, SD 25%, PD 2%, NE 13 %). Median time to first response was 2.6 months (0.6- 8.2mo). At time of data cut-off, 64% of patients remain on treatment (80% F, 48% I and 67% P). 14% of patients discontinued treatment due to disease progression while 22% stopped due to toxicity. The majority of patients (68%) continued axitinib at the starting dose of 5mg BD. Dose escalation of axitinib was possible in 9% patients while 23% needed a dose reduction due to toxicities. AEs were observed in 36 (82%) patients (G3 36%); the commonest being mucositis 30%; hypertension 23% (G3 11%); fatigue 25%; thyroid dysfunction 18%; diarrhoea 20% (G3 5%); hepatitis 20% (G3 11%). 9% of patients experienced an infusion reaction to avelumab. Overall, 9 (20%) patients received steroids for suspected immune related adverse events (irAEs); 6 (14%) were managed as G3≤ irAEs. 9 (20%) patients required inpatient admission due to AEs; 5 (11%) were associated with irAEs. Of the patients who discontinued AA treatment, 50% received subsequent therapy (12.5%, 75% and 12.5% receiving combination checkpoint inhibitor therapy, other VEFG TKi and TKi/MTOR combination respectively). 4 patients remain on active surveillance with no evidence of progression. Conclusions: Our early experience of AA in this real world setting reports comparable clinical responses to the published data. Treatment is well tolerated, with lower than expected levels of G3 or above AEs which is reassuring in a non-trial selected population. Follow-up is ongoing and updated efficacy and safety outcomes will be presented.

scholarly journals Ibrutinib-Mediated Atrial Fibrillation Attributable to Inhibition of C-Terminal Src Kinase

Circulation ◽  
2020 ◽  
Vol 142 (25) ◽  
pp. 2443-2455 ◽  
Author(s):  
Ling Xiao ◽  
Joe-Elie Salem ◽  
Sebastian Clauss ◽  
Alan Hanley ◽  
Aneesh Bapat ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Left Atrial ◽  
Kinase Inhibitor ◽  
Src Kinase ◽  
Reporting Odds Ratio ◽  
Left Atrial Enlargement ◽  
Bruton Tyrosine Kinase ◽  
Atrial Enlargement

Background: 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. Methods: 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. Results: 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; P <0.0001). Conclusions: These data identify Csk inhibition as the mechanism through which ibrutinib leads to AF. Registration: URL: https://ww.clinicaltrials.gov ; Unique identifier: NCT03530215.

scholarly journals Acalabrutinib: A Selective Bruton Tyrosine Kinase Inhibitor for the Treatment of B-Cell Malignancies

2021 ◽  
Vol 11 ◽  
Author(s):  
Hussein A. Abbas ◽  
William G. Wierda
Keyword(s):  
Adverse Events ◽  
Tyrosine Kinase ◽  
B Cell ◽  
Kinase Inhibitor ◽  
Progression Free Survival ◽  
Lymphocytic Leukemia ◽  
B Cell Malignancies ◽  
Bruton Tyrosine Kinase ◽  
Btk Inhibitor

Bruton tyrosine kinase (BTK) is a validated target for treatment of B-cell malignancies, and oral inhibitors of BTK have emerged as a standard of care for these diseases. Acalabrutinib is a second generation, highly selective, potent, covalent BTK inhibitor that exhibits minimal off-target activity in in vitro assays, providing the potential to improve tolerability over the first-in-class BTK inhibitor, ibrutinib. Acalabrutinib was approved for the treatment of relapsed/refractory mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL) in the US in 2017 and 2019, respectively. Acalabrutinib is also undergoing trials for other B-cell malignancies, both as monotherapy and in combinations. In this review, we discuss results from clinical trials evaluating the efficacy and safety of acalabrutinib in patients with CLL, MCL, and Waldenstrom’s macroglobulinemia. Recent phase 3 data showed that acalabrutinib improved progression-free survival (PFS) compared with rituximab plus idelalisib or rituximab plus bendamustine in patients with relapsed/refractory CLL, and acalabrutinib with or without obinutuzumab improved PFS compared with chlorambucil plus obinutuzumab in patients with treatment-naïve CLL. Overall, acalabrutinib had a tolerable safety profile, with most adverse events being grade 1/2 severity (most commonly headache and diarrhea) and a low rate of discontinuation due to adverse events.

P4800Estimated effect of NOACs compared to Vitamin K Antagonists in real-world atrial fibrillation patients: Data from FANTASIA Registry

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
M A Esteve Pastor ◽  
J M Rivera-Caravaca ◽  
V Roldan ◽  
I Roldan Rabadan ◽  
J Muniz ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Adverse Events ◽  
Vitamin K ◽  
Major Bleeding ◽  
Real World ◽  
Absolute Risk ◽  
Vitamin K Antagonists ◽  
Oral Anticoagulants ◽  
Stroke Rate ◽  
All Cause Mortality

Abstract Background Despite of the effectiveness and safety profile of Non-vitamin K Antagonists Oral Anticoagulants (NOACs) even in real-world (RW) Atrial Fibrillation (AF) patients, Vitamin K Antagonists (VKAs) have remained widely used in clinical practice worldwide but the comparison with acenocoumarol therapy in RW is unknown. Purpose To estimate the potential absolute benefit in clinical adverse events if the AF patients anticoagulated with VKA therapy had been treated with NOACs. Methods We analyzed anticoagulated AF patients who were prospectively recruited into the multicentre FANTASIIA registry. Patients were treated with VKAs for at least 6 months prior to inclusion. The estimation of clinical adverse events avoided was calculated applying absolute risk reductions, relative risk reductions and hazard ratios from the meta-analysis of RW use of NOACs relative to VKAs. Results We analyzed 1,470 patients under VKA therapy (mean age 74.1±9.5 years; 56.4% male). Stroke rate with acenocoumarol treatment was 0.88%/year. The estimated rates for stroke using NOACs would be 0.80%/year for Dabigatran 150 mg; 0.76%/year for Rivaroxaban and 0.74%/year for Apixaban instead of VKA. No significant differences were observed between the different NOACs and VKA in stroke rate. Major bleeding with acenocoumarol was 3.40%/year. The estimated rates for major bleeding using NOACs would be 2.75%/year for Dabigatran 150 mg; 3.37%/year for Rivaroxaban and 2.18%/year for Apixaban instead of VKA. Apixaban was the only NOAC that showed a significant estimated reduction rates (p=0.046). Finally, the all-cause mortality rate with acenocoumarol was 4.69%/year. The estimated rates of all-cause mortality using NOACs would be 3.28%/year for Dabigatran 150mg; 4.88%/year for Rivaroxaban and 2.67%/year for Apixaban. Dabigatran and Apixaban showed significant estimated reduction rates with the highest reduction with Apixaban (Table). Annual Rate reduction of adverse events Conclusion The absolute estimated effect of NOACs in the AF patients anticoagulated with VKA showed a significant reduction in adverse clinical events. Apixaban performed the highest estimated reduction in major bleeding and all-cause mortality in comparison with acenocoumarol.

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