Heart Failure: Symptoms, Causes, and Types
These Genetic Risk Loci Associated With Varicose Veins Have Been Identified By Researchers
Varicose veins cause considerable suffering for more than cosmetic reasons. This disorder also poses health risks, sometimes severe ones. What is the most significant risk factor for varicose veins? What genetic risks do scientists associate with the disorder?
Researchers now have more answers than ever. Recent investigations have identified several genetic risk loci that predispose a person to the disorder. Knowing your risk helps you take the appropriate steps to protect your health.
What should you know if you have concerns? Here's what we know about the genes associated with varicose veins, the most significant risk factors and how you can reduce your chances of severe complications.
What Are Varicose Veins? Symptoms and CausesVaricose veins refer to veins close to your skin's surface that twist and become enlarged. As venous walls become damaged over time, they contort, causing uneven blood flow and a protruding appearance.
In most cases, varicose veins are benign, causing no more than cosmetic discomfort. However, in some cases, they can lead to severe complications, including deep vein thrombosis and pulmonary embolisms.1 These risks increase depending on your typical activities — for example, those who often take long-distance flights must take additional precautions to avoid DVT.
1. Symptoms of Varicose VeinsThe symptoms of varicose veins include the following:2
The two most severe complications of varicose veins are deep vein thrombosis and embolisms. Pulmonary embolisms are the most common, which occur when a blood clot becomes lodged in the lungs. Coronary thrombosis refers to a clot that navigates to the heart, where it can cause cardiac arrest. Venous thromboembolisms can become trapped in the veins and arteries of the legs. They can restrict blood and oxygen flow, leading to tissue damage.
Other complications of varicose veins include the following:3
Human beings are the only mammals whose blood pressure affects vein health because we are the only ones who consistently stand upright. Additionally, scientists have long associated vein disease with the following risk factors:4
However, a recent study went more in-depth to examine what specific genes predispose individuals to varicose veins.
1. What Genes Are Associated With Varicose Veins?According to Dr. Mohammad Reza Amini, director of Peripheral Arterial and Venous Disease Services at Loma Linda University, one of the best things you can do to protect your health is to understand your varicose veins and what factors affect them.5 What genes are associated with varicose veins?
Researchers recently analyzed data from the VA Million Veteran Program and other large, multi-ancestry biobanks. They included 49,765 individuals with varicose veins compared to 1,334,301 disease-free controls.
Using this sample, investigators used fine mapping via MR-MEGA, a statistical approach that performs a meta-regression to account for similarities in alleles to construct credible sets.6 They identified 70 varicose vein risk loci when including a single variable in a 99% credible set. 63 of these 70 loci shared an association with other traits, including increased weight, body mass index and hip circumference.
Researchers then analyzed whether these alleles were associated with specific tissues or bodily processes. They found a significant association between varicose veins and 20 diagnoses, 15 operations, five medications and treatments, 77 circulating proteins and 216 circulating metabolites. When testing was completed, investigators narrowed down 139 loci associated with varicose veins.
2. What Is the Most Significant Risk Factor of Varicose Veins?This research reveals multiple influences, including those you can control, such as what medication you take, and those you cannot, such as the levels of various proteins and metabolites in your bloodstream. While it may be impossible to pinpoint the exact combination that leads to disease manifestation in a given person, the most significant risk factor for varicose veins that you have some control over is your weight and activity level.
Here's where advice can get tricky, as you can be healthy even while carrying a few extra pounds.7 However, there's a difference between having sufficient fat reserves and morbid obesity. If losing weight through the traditional methods of cutting calories and increasing physical activity doesn't work, you should seek medical care. You may have another disorder, such as thyroid disease, complicating your efforts.
Holistic Tips for Living With Varicose VeinsYou can't do anything to change your genetic risk for varicose veins. However, you can address the most significant risk factor for varicose veins by making lifestyle changes. Other shifts can improve your comfort and prevent your condition from worsening.
1. Wear Compression GarmentsCompression garments help varicose veins by compensating for some of the extra distance your blood has to travel, thanks to your upright posture. They put additional pressure on your lower legs, helping your body propel blood back to your heart. It's especially important to wear such socks and hose on long-distance flights if you have varicose veins to decrease your risk of DVT.
2. Avoid Prolonged StandingA career as a checkout clerk might not be your best bet if you have varicose veins. Anything that involves prolonged standing in a stationary position can increase blood pooling.
However, remaining seated can also cause blood pooling, as many positions keep your feet much lower than your heart. Jobs that require you to walk, such as waiting tables, may suit you better than those that need you to remain still for extended periods.
3. Kick Up Your FeetWhen you sit, try to keep your feet closer to your heart level. You can do so by kicking them up using a stool or a reclining chair to provide the necessary elevation.
You might also find it helpful to prop your feet against the wall. Find one without pictures or artwork that might fall on you and scoot your backside as close to the wall as possible, extending your legs upward.
4. Move Your BodyRemaining sedentary can worsen varicose veins. Worse, it increases your risk of DVT, which can have fatal consequences — that's why they tell you to stand up and move around as often as possible during flights.8
Regular exercise improves circulation, which keeps your vein walls healthier and prevents them from future damage. While it won't get rid of existing varicose veins, adequate movement might prevent existing ones from getting worse.
5. Avoid SaltSalt pulls water into your blood vessels, increasing pressure. High blood pressure can damage vein and artery walls, making existing varicose veins worse and creating new ones.
6. Try an Anti-Inflammatory DietDamage to vein walls can occur due to ongoing systemic inflammation — meaning it affects every system in your body. This swelling causes veins to open larger. According to Dr. Amini, when this venodilation occurs, additional blood swells vessels, worsening symptoms.
While multiple factors can increase or decrease inflammation, altering your diet may make a significant difference. An anti-inflammatory diet entails avoiding the following substances that increase swelling:
Additionally, you should consume more of the following:
Remember, obesity and physical inactivity may be the most significant risk factors for varicose veins. Daily movement and an improved diet should allow you to maintain a healthy weight. Work with your doctor, if possible, to design a customized plan to drop excess pounds if necessary. The same approach won't work for everyone — consider factors such as existing health conditions, food preferences and your knowledge of self when designing your plan.
8. Stop SmokingNicotine causes damage to vein walls, which can spur new varicose veins to form. It also weakens blood vessels, making them lose their elasticity, which impairs their ability to pump blood back to the heart.
Medical Treatments for Varicose VeinsWhat are your options if your varicose veins impair your quality of life significantly enough to warrant intervention? Here are the current medical treatments for this disorder:9
Scientists are closer to discovering the precise causes of varicose veins. They've found what genes are associated with varicose veins and the most significant risk factor for the condition.
Understanding that you have a genetic risk for varicose veins lets you take proactive steps to safeguard your health. Monitor your weight and use the other holistic interventions above to manage your condition and prevent it from worsening.
References
Takeda's GAMMAGARD LIQUID® Approved By U.S. FDA For Adults With Chronic Inflammatory Demyelinating Polyneuropathy (CIDP)
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Eisai Furthers Oncology Research In Gastrointestinal Cancer Treatment With New Data At ASCO GI 2024
(MENAFN- PR Newswire) Longer-Term Efficacy and Safety Results from the Phase 3 LEAP-002 Trial Offer Additional Information About the First-Line Treatment of Patients with Unresectable Hepatocellular CarcinomaData on E7386 and Tasurgratinib (formerly E7090) Showcase Eisai's Pipeline and Commitment to Identifying Additional Approaches in Treating Cancer to Help Improve Outcomes for Patients
NUTLEY, N.J., Jan. 16, 2024 /PRNewswire/ -- Eisai announced today the presentation of gastrointestinal cancer research during the 2024 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium (#GI24), which is taking place in-person in San Francisco, California and virtually from January 18-20.
Notable findings from the LEAP ( Le nvatinib A nd P embrolizumab) clinical program include updated efficacy and safety results from the Phase 3 LEAP-002 trial, which evaluated lenvatinib (LENVIMA®), the orally available multiple receptor tyrosine kinase inhibitor (TKI) discovered by Eisai, plus pembrolizumab (KEYTRUDA®), Merck's anti-PD-1 therapy, versus lenvatinib monotherapy as a first-line treatment for patients with unresectable hepatocellular carcinoma (HCC) (NCT03713593 ; Abstract: #482).
"We look forward to convening in San Francisco to share longer-term efficacy and safety results from the Phase 3 LEAP-002 trial with the scientific community at ASCO GI 2024. We are proud of the role that LENVIMA monotherapy plays as a first-line treatment for patients with unresectable hepatocellular carcinoma, particularly as the global burden of liver cancer rises," said Dr. Takashi Owa, Chief Scientific Officer, Senior Vice President, Eisai Co., Ltd. "Our data at the symposiumillustrate Eisai's commitment to contribute to the understanding of gastrointestinal cancers with the aim of making a difference in the lives of patients and their families."
Additional data from Eisai's pipeline include results from a single-arm Phase 2 trial evaluating tasurgratinib (formerly E7090) as a treatment for patients with fibroblast growth factor receptor 2 (FGFR2) gene fusion positive cholangiocarcinoma (NCT04238715 ; Abstract: #471). Tasurgratinib, for which a marketing authorization application was submitted in Japan in December 2023, is an orally available selective TKI of FGFR1-3. An analysis of tumor biomarkers in patients with advanced HCC from a Phase 1b study of E7386,a CREB-binding protein (CBP) / β-catenin interaction inhibitor, in combination with lenvatinib, will also be presented (NCT04008797 ; Abstract: #535).
This release discusses investigational compounds and investigational uses for FDA-approved products. It is not intended to convey conclusions about efficacy and safety. There is no guarantee that any investigational compounds or investigational uses of FDA-approved products will successfully complete clinical development or gain FDA approval.
The list of notable Eisai presentations is included below. These abstracts will be made available via the ASCO website on Tuesday, January 16, 2024, at 5:00 PM EST (2:00 PM PST).
Cancer Type
Study/Compound
Abstract Title
Abstract Type & Details
LenvatinibPlus Pembrolizumab
Gastrointestinal Cancer
LEAP-002
Lenvatinib plus pembrolizumab versuslenvatinib alone as first-line therapy foradvanced hepatocellular carcinoma: longer-term efficacy and safety results from thephase 3 LEAP-002 study
Poster Session
Abstract #482
January 19, 2024
12:30-2:00 PM PST / 3:30-5:00 PM EST
Pipeline
Gastrointestinal Cancer
E7090
Pivotal single-arm, phase 2 trial oftasurgratinib for patients with fibroblastgrowth factor receptor-2 gene fusion-positivecholangiocarcinoma
Poster Session
Abstract #471
January 19, 2024
12:30-2:00 PM PST / 3:30-5:00 PM EST
Gastrointestinal Cancer
E7386
Analysis of tumor biomarkers in patients withadvanced hepatocellular carcinoma from aphase 1b study of E7386, a CREB-bindingprotein/β-catenin interaction inhibitor, incombination with lenvatinib
Poster Session
Abstract #535
January 19, 2024
12:30-2:00 PM PST / 3:30-5:00 PM EST
InMarch 2018, Eisai and Merck (known as MSD outsidethe United StatesandCanada), through an affiliate, entered into a strategic collaboration for the worldwide co-development and co-commercialization of lenvatinib, both as monotherapy and in combination with Merck's anti-PD-1 therapy, pembrolizumab.Eisai and Merck are studying the lenvatinib plus pembrolizumab combination through the LEAP clinical program in various tumor types across multiple clinical trials.
About Tasurgratinib Discovered in-house by Eisai's Tsukuba Research Laboratories, tasurgratinib (formerly E7090) is an orally available tyrosine kinase inhibitor that demonstrates selective inhibitory activity against fibroblast growth factor receptors (FGFR) FGFR1, FGFR2 and FGFR3. In preclinical studies, E7090 exhibited faster association and slower dissociation time from FGFR1 compared with other FGFR1 inhibitors and it exhibited selective antiproliferative activity against cancer cell lines harboring FGFR genetic abnormalities. Preclinical studies have also prolonged survival in mice with metastasized tumors in the lung. A Phase II clinical trial (Study 201) of E7090 is underway in Japan and China to evaluate efficacy and safety in patients with cholangiocarcinoma with FGFR2 gene fusion. A Phase I clinical trial of E7090 is also underway in Japan in patients with estrogen receptor-positive and HER2-negative breast cancer.
About E7386 E7386 is a selective inhibitor of the interaction between the cAMP response element-binding protein (CREB) binding protein (CBP) / β-catenin and a modulator of the Wnt / β-catenin signaling pathway. E7386 is thought to block the protein-protein interaction between a transcriptional co-activator, CBP and β-catenin, resulting in the inhibition of Wnt / β-catenin pathway-dependent gene expression. Since E7386 acts on the CBP / β-catenin transcription complex located at the most downstream of the Wnt signaling, it is expected to inhibit not only ligand-dependent activation but also activation caused by gene mutations in Wnt signaling factors such as adenomatous polyposis coli (APC) and β-catenin. E7386 is created through collaboration research between Eisai and PRISM BioLab Co., Ltd. (Headquarters: Kanagawa)
About LENVIMA® (lenvatinib) Capsules
LENVIMAis indicated:
LENVIMA, discovered and developed by Eisai, is a multiple receptor tyrosine kinase inhibitor that inhibits the kinase activities of vascular endothelial growth factor (VEGF) receptors VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4). LENVIMA inhibits other kinases that have been implicated in pathogenic angiogenesis, tumor growth, and cancer progression in addition to their normal cellular functions, including fibroblast growth factor (FGF) receptors FGFR1-4, the platelet derived growth factor receptor alpha (PDGFRα), KIT, and RET. Lenvatinib also exhibited antiproliferative activity in hepatocellular carcinoma cell lines dependent on activated FGFR signaling with a concurrent inhibition of FGF-receptor substrate 2α (FRS2α) phosphorylation. In syngeneic mouse tumor models, the combination of lenvatinib with an anti-PD-1 monoclonal antibody decreased tumor-associated macrophages, increased activated cytotoxic T cells, and demonstrated greater antitumor activity compared to either treatment alone. The combination of LENVIMA and everolimus showed increased anti-angiogenic and anti-tumor activity as demonstrated by decreased human endothelial cell proliferation, tube formation, and VEGF signaling in vitro and tumor volume in mouse xenograft models of human renal cell cancer greater than each drug alone.
Important Safety Information for LENVIMA
Warnings and Precautions
Hypertension. In DTC (differentiated thyroid cancer), hypertension occurred in 73% of patients on LENVIMA (44% grade 3-4). In RCC (renal cell carcinoma), hypertension occurred in 42% of patients on LENVIMA + everolimus (13% grade 3). Systolic blood pressure ≥160 mmHg occurred in 29% of patients, and 21% had diastolic blood pressure ≥100 mmHg. In HCC (hepatocellular carcinoma), hypertension occurred in 45% of LENVIMA-treated patients (24% grade 3). Grade 4 hypertension was not reported in HCC.
Serious complications of poorly controlled hypertension have been reported. Control blood pressure prior to initiation. Monitor blood pressure after 1 week, then every 2 weeks for the first 2 months, and then at least monthly thereafter during treatment. Withhold and resume at reduced dose when hypertension is controlled or permanently discontinue based on severity.
Cardiac Dysfunction. Serious and fatal cardiac dysfunction can occur with LENVIMA. Across clinical trials in 799 patients with DTC, RCC, and HCC, grade 3 or higher cardiac dysfunction occurred in 3% of LENVIMA-treated patients. Monitor for clinical symptoms or signs of cardiac dysfunction. Withhold and resume at reduced dose upon recovery or permanently discontinue based on severity.
Arterial Thromboembolic Events. Among patients receiving LENVIMA or LENVIMA + everolimus, arterial thromboembolic events of any severity occurred in 2% of patients in RCC and HCC and 5% in DTC. Grade 3-5 arterial thromboembolic events ranged from 2% to 3% across all clinical trials.
Among patients receiving LENVIMA with pembrolizumab, arterial thrombotic events of any severity occurred in 5% of patients in CLEAR, including myocardial infarction (3.4%) and cerebrovascular accident (2.3%).
Permanently discontinue following an arterial thrombotic event. The safety of resuming after an arterial thromboembolic event has not been established, and LENVIMA has not been studied in patients who have had an arterial thromboembolic event within the previous 6 months.
Hepatotoxicity. Across clinical studies enrolling 1327 LENVIMA-treated patients with malignancies other than HCC, serious hepatic adverse reactions occurred in 1.4% of patients. Fatal events, including hepatic failure, acute hepatitis, and hepatorenal syndrome, occurred in 0.5% of patients. In HCC, hepatic encephalopathy occurred in 8% of LENVIMA-treated patients (5% grade 3-5). Grade 3-5 hepatic failure occurred in 3% of LENVIMA-treated patients; 2% of patients discontinued LENVIMA due to hepatic encephalopathy, and 1% discontinued due to hepatic failure.
Monitor liver function prior to initiation, then every 2 weeks for the first 2 months, and at least monthly thereafter during treatment. Monitor patients with HCC closely for signs of hepatic failure, including hepatic encephalopathy. Withhold and resume at reduced dose upon recovery or permanently discontinue based on severity.
Renal Failure or Impairment. Serious including fatal renal failure or impairment can occur with LENVIMA. Renal impairment was reported in 14% and 7% of LENVIMA-treated patients in DTC and HCC, respectively. Grade 3-5 renal failure or impairment occurred in 3% of patients with DTC and 2% of patients with HCC, including 1 fatal event in each study. In RCC, renal impairment or renal failure was reported in 18% of LENVIMA + everolimus–treated patients (10% grade 3).
Initiate prompt management of diarrhea or dehydration/hypovolemia. Withhold and resume at reduced dose upon recovery or permanently discontinue for renal failure or impairment based on severity.
Proteinuria. In DTC and HCC, proteinuria was reported in 34% and 26% of LENVIMA-treated patients, respectively. Grade 3 proteinuria occurred in 11% and 6% in DTC and HCC, respectively. In RCC, proteinuria occurred in 31% of patients receiving LENVIMA + everolimus (8% grade 3). Monitor for proteinuria prior to initiation and periodically during treatment. If urine dipstick proteinuria ≥2+ is detected, obtain a 24-hour urine protein. Withhold and resume at reduced dose upon recovery or permanently discontinue based on severity.
Diarrhea. Of the 737 LENVIMA-treated patients in DTC and HCC, diarrhea occurred in 49% (6% grade 3). In RCC, diarrhea occurred in 81% of LENVIMA + everolimus–treated patients (19% grade 3). Diarrhea was the most frequent cause of dose interruption/reduction, and diarrhea recurred despite dose reduction. Promptly initiate management of diarrhea. Withhold and resume at reduced dose upon recovery or permanently discontinue based on severity.
Fistula Formation and Gastrointestinal Perforation. Of the 799 patients treated with LENVIMA or LENVIMA + everolimus in DTC, RCC, and HCC, fistula or gastrointestinal perforation occurred in 2%. Permanently discontinue in patients who develop gastrointestinal perforation of any severity or grade 3-4 fistula.
QT Interval Prolongation. In DTC, QT/QTc interval prolongation occurred in 9% of LENVIMA-treated patients and QT interval prolongation of >500 ms occurred in 2%. In RCC, QTc interval increases of >60 ms occurred in 11% of patients receiving LENVIMA + everolimus and QTc interval >500 ms occurred in 6%. In HCC, QTc interval increases of >60 ms occurred in 8% of LENVIMA-treated patients and QTc interval >500 ms occurred in 2%.
Monitor and correct electrolyte abnormalities at baseline and periodically during treatment. Monitor electrocardiograms in patients with congenital long QT syndrome, congestive heart failure, bradyarrhythmias, or those who are taking drugs known to prolong the QT interval, including Class Ia and III antiarrhythmics. Withhold and resume at reduced dose upon recovery based on severity.
Hypocalcemia. In DTC, grade 3-4 hypocalcemia occurred in 9% of LENVIMA-treated patients. In 65% of cases, hypocalcemia improved or resolved following calcium supplementation with or without dose interruption or dose reduction. In RCC, grade 3-4 hypocalcemia occurred in 6% of LENVIMA + everolimus–treated patients. In HCC, grade 3 hypocalcemia occurred in 0.8% of LENVIMA-treated patients. Monitor blood calcium levels at least monthly and replace calcium as necessary during treatment. Withhold and resume at reduced dose upon recovery or permanently discontinue depending on severity.
Reversible Posterior Leukoencephalopathy Syndrome (RPLS). Across clinical studies of 1823 patients who received LENVIMA as a single agent, RPLS occurred in 0.3%. Confirm diagnosis of RPLS with MRI. Withhold and resume at reduced dose upon recovery or permanently discontinue depending on severity and persistence of neurologic symptoms.
Hemorrhagic Events. Serious including fatal hemorrhagic events can occur with LENVIMA. In DTC, RCC, and HCC clinical trials, hemorrhagic events, of any grade, occurred in 29% of the 799 patients treated with LENVIMA as a single agent or in combination with everolimus. The most frequently reported hemorrhagic events (all grades and occurring in at least 5% of patients) were epistaxis and hematuria. In DTC, grade 3-5 hemorrhage occurred in 2% of LENVIMA-treated patients, including 1 fatal intracranial hemorrhage among 16 patients who received LENVIMA and had CNS metastases at baseline. In RCC, grade 3-5 hemorrhage occurred in 8% of LENVIMA + everolimus–treated patients, including 1 fatal cerebral hemorrhage. In HCC, grade 3-5 hemorrhage occurred in 5% of LENVIMA-treated patients, including 7 fatal hemorrhagic events. Serious tumor-related bleeds, including fatal hemorrhagic events, occurred in LENVIMA-treated patients in clinical trials and in the postmarketing setting. In postmarketing surveillance, serious and fatal carotid artery hemorrhages were seen more frequently in patients with anaplastic thyroid carcinoma (ATC) than other tumors. Safety and effectiveness of LENVIMA in patients with ATC have not been demonstrated in clinical trials.
Consider the risk of severe or fatal hemorrhage associated with tumor invasion or infiltration of major blood vessels (eg, carotid artery). Withhold and resume at reduced dose upon recovery or permanently discontinue based on severity.
Impairment of Thyroid Stimulating Hormone Suppression/Thyroid Dysfunction. LENVIMA impairs exogenous thyroid suppression. In DTC, 88% of patients had baseline thyroid stimulating hormone (TSH) level ≤0.5 mU/L. In patients with normal TSH at baseline, elevation of TSH level >0.5 mU/L was observed post baseline in 57% of LENVIMA-treated patients. In RCC and HCC, grade 1 or 2 hypothyroidism occurred in 24% of LENVIMA + everolimus–treated patients and 21% of LENVIMA-treated patients, respectively. In patients with normal or low TSH at baseline, elevation of TSH was observed post baseline in 70% of LENVIMA-treated patients in HCC and 60% of LENVIMA + everolimus–treated patients in RCC.
Monitor thyroid function prior to initiation and at least monthly during treatment. Treat hypothyroidism according to standard medical practice.
Impaired Wound Healing. Impaired wound healing has been reported in patients who received LENVIMA. Withhold LENVIMA for at least 1 week prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of LENVIMA after resolution of wound healing complications has not been established.
Osteonecrosis of the Jaw (ONJ).ONJ has been reported in patients receiving LENVIMA. Concomitant exposure to other risk factors, such as bisphosphonates, denosumab, dental disease, or invasive dental procedures, may increase the risk of ONJ.
Perform an oral examination prior to treatment with LENVIMA and periodically during LENVIMA treatment. Advise patients regarding good oral hygiene practices and to consider having preventive dentistry performed prior to treatment with LENVIMA and throughout treatment with LENVIMA.
Avoid invasive dental procedures, if possible, while on LENVIMA treatment, particularly in patients at higher risk. Withhold LENVIMA for at least 1 week prior to scheduled dental surgery or invasive dental procedures, if possible. For patients requiring invasive dental procedures, discontinuation of bisphosphonate treatment may reduce the risk of ONJ.
WithholdLENVIMA if ONJ develops and restart based on clinical judgement of adequate resolution.
Embryo-Fetal Toxicity. Based on its mechanism of action and data from animal reproduction studies, LENVIMA can cause fetal harm when administered to pregnant women. In animal reproduction studies, oral administration of lenvatinib during organogenesis at doses below the recommended clinical doses resulted in embryotoxicity, fetotoxicity, and teratogenicity in rats and rabbits. Advise pregnant women of the potential risk to a fetus and advise females of reproductive potential to use effective contraception during treatment with LENVIMA and for 30 days after the last dose.
Adverse Reactions In DTC, the most common adverse reactions (≥30%) observed in LENVIMA-treated patients were hypertension (73%), fatigue (67%), diarrhea (67%), arthralgia/myalgia (62%), decreased appetite (54%), decreased weight (51%), nausea (47%), stomatitis (41%), headache (38%), vomiting (36%), proteinuria (34%), palmar-plantar erythrodysesthesia syndrome (32%), abdominal pain (31%), and dysphonia (31%). The most common serious adverse reactions (≥2%) were pneumonia (4%), hypertension (3%), and dehydration (3%). Adverse reactions led to dose reductions in 68% of LENVIMA-treated patients; 18% discontinued LENVIMA. The most common adverse reactions (≥10%) resulting in dose reductions were hypertension (13%), proteinuria (11%), decreased appetite (10%), and diarrhea (10%); the most common adverse reactions (≥1%) resulting in discontinuation of LENVIMA were hypertension (1%) and asthenia (1%).
In RCC, the most common adverse reactions (≥20%) observed in LENVIMA + pembrolizumab-treated patients were fatigue (63%), diarrhea (62%), musculoskeletal pain (58%), hypothyroidism (57%), hypertension (56%), stomatitis (43%), decreased appetite (41%), rash (37%), nausea (36%), decreased weight (30%), dysphonia (30%), proteinuria (30%), palmar-plantar erythrodysesthesia syndrome (29%), abdominal pain (27%), hemorrhagic events (27%), vomiting (26%), constipation (25%), hepatotoxicity (25%), headache (23%), and acute kidney injury (21%). The most common serious adverse reactions (≥2%) were hemorrhagic events (5%), diarrhea (4%), hypertension (3%), myocardial infarction (3%), pneumonitis (3%), vomiting (3%), acute kidney injury (2%), adrenal insufficiency (2%), dyspnea (2%), and pneumonia (2%). Fatal adverse reactions occurred in 4.3% of patients receiving LENVIMA in combination with pembrolizumab, including cardio-respiratory arrest (0.9%), sepsis (0.9%), and one case (0.3%) each of arrhythmia, autoimmune hepatitis, dyspnea, hypertensive crisis, increased blood creatinine, multiple organ dysfunction syndrome, myasthenic syndrome, myocarditis, nephritis, pneumonitis, ruptured aneurysm and subarachnoid hemorrhage. Serious adverse reactions occurred in 51% of patients receiving LENVIMA and pembrolizumab. Serious adverse reactions in ≥2% of patients were hemorrhagic events (5%), diarrhea (4%), hypertension (3%), myocardial infarction (3%), pneumonitis (3%), vomiting (3%), acute kidney injury (2%), adrenal insufficiency (2%), dyspnea (2%), and pneumonia (2%). Permanent discontinuation of LENVIMA, pembrolizumab, or both due to an adverse reaction occurred in 37% of patients; 26% LENVIMA only, 29% pembrolizumab only, and 13% both drugs. The most common adverse reactions (≥2%) leading to permanent discontinuation of LENVIMA, pembrolizumab, or both were pneumonitis (3%), myocardial infarction (3%), hepatotoxicity (3%), acute kidney injury (3%), rash (3%), and diarrhea (2%). Dose interruptions of LENVIMA, pembrolizumab, or both due to an adverse reaction occurred in 78% of patients receiving LENVIMA in combination with pembrolizumab. LENVIMA was interrupted in 73% of patients and both drugs were interrupted in 39% of patients. LENVIMA was dose reduced in 69% of patients. The most common adverse reactions (≥5%) resulting in dose reduction or interruption of LENVIMA were diarrhea (26%), fatigue (18%), hypertension (17%), proteinuria (13%), decreased appetite (12%), palmar-plantar erythrodysesthesia (11%), nausea (9%), stomatitis (9%), musculoskeletal pain (8%), rash (8%), increased lipase (7%), abdominal pain (6%), and vomiting (6%), increased ALT (5%), and increased amylase (5%).
In RCC, the most common adverse reactions (≥30%) observed in LENVIMA + everolimus–treated patients were diarrhea (81%), fatigue (73%), arthralgia/myalgia (55%), decreased appetite (53%), vomiting (48%), nausea (45%), stomatitis (44%), hypertension (42%), peripheral edema (42%), cough (37%), abdominal pain (37%), dyspnea (35%), rash (35%), decreased weight (34%), hemorrhagic events (32%), and proteinuria (31%). The most common serious adverse reactions (≥5%) were renal failure (11%), dehydration (10%), anemia (6%), thrombocytopenia (5%), diarrhea (5%), vomiting (5%), and dyspnea (5%). Adverse reactions led to dose reductions or interruption in 89% of patients. The most common adverse reactions (≥5%) resulting in dose reductions were diarrhea (21%), fatigue (8%), thrombocytopenia (6%), vomiting (6%), nausea (5%), and proteinuria (5%). Treatment discontinuation due to an adverse reaction occurred in 29% of patients.
In HCC, the most common adverse reactions (≥20%) observed in LENVIMA-treated patients were hypertension (45%), fatigue (44%), diarrhea (39%), decreased appetite (34%), arthralgia/myalgia (31%), decreased weight (31%), abdominal pain (30%), palmar-plantar erythrodysesthesia syndrome (27%), proteinuria (26%), dysphonia (24%), hemorrhagic events (23%), hypothyroidism (21%), and nausea (20%). The most common serious adverse reactions (≥2%) were hepatic encephalopathy (5%), hepatic failure (3%), ascites (3%), and decreased appetite (2%). Adverse reactions led to dose reductions or interruption in 62% of patients. The most common adverse reactions (≥5%) resulting in dose reductions were fatigue (9%), decreased appetite (8%), diarrhea (8%), proteinuria (7%), hypertension (6%), and palmar-plantar erythrodysesthesia syndrome (5%). Treatment discontinuation due to an adverse reaction occurred in 20% of patients. The most common adverse reactions (≥1%) resulting in discontinuation of LENVIMA were fatigue (1%), hepatic encephalopathy (2%), hyperbilirubinemia (1%), and hepatic failure (1%).
In EC, the most common adverse reactions (≥20%) observed in LENVIMA and pembrolizumab–treated patients were hypothyroidism (67%), hypertension (67%), fatigue (58%), diarrhea (55%), musculoskeletal disorders (53%), nausea (49%), decreased appetite (44%), vomiting (37%), stomatitis (35%), decreased weight (34%), abdominal pain (34%), urinary tract infection (31%), proteinuria (29%), constipation (27%), headache (26%), hemorrhagic events (25%), palmar‐plantar erythrodysesthesia (23%), dysphonia (22%), and rash (20%). Fatal adverse reactions occurred in 4.7% of those treated with LENVIMA and pembrolizumab, including 2 cases of pneumonia, and 1 case of the following: acute kidney injury, acute myocardial infarction, colitis, decreased appetite, intestinal perforation, lower gastrointestinal hemorrhage, malignant gastrointestinal obstruction, multiple organ dysfunction syndrome, myelodysplastic syndrome, pulmonary embolism, and right ventricular dysfunction. Serious adverse reactions occurred in 50% of patients receiving LENVIMA and pembrolizumab. Serious adverse reactions with frequency ≥3% were hypertension (4.4%), and urinary tract infection (3.2%). Discontinuation of LENVIMA due to an adverse reaction occurred in 26% of patients. The most common (≥1%) adverse reactions leading to discontinuation of LENVIMA were hypertension (2%), asthenia (1.8%), diarrhea (1.2%), decreased appetite (1.2%), proteinuria (1.2%), and vomiting (1.2%). Dose reductions of LENVIMA due to adverse reactions occurred in 67% of patients. The most common (≥5%) adverse reactions resulting in dose reduction of LENVIMA were hypertension (18%), diarrhea (11%), palmar-plantar erythrodysesthesia syndrome (9%), proteinuria (7%), fatigue (7%), decreased appetite (6%), asthenia (5%), and weight decreased (5%). Dose interruptions of LENVIMA due to an adverse reaction occurred in 58% of these patients. The most common (≥2%) adverse reactions leading to interruption of LENVIMA were hypertension (11%), diarrhea (11%), proteinuria (6%), decreased appetite (5%), vomiting (5%), increased alanine aminotransferase (3.5%), fatigue (3.5%), nausea (3.5%), abdominal pain (2.9%), weight decreased (2.6%), urinary tract infection (2.6%), increased aspartate aminotransferase (2.3%), asthenia (2.3%), and palmar-plantar erythrodysesthesia (2%).
Use in Specific Populations Because of the potential
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