Archive January 2019

Let’s jump forward and assume your dog does have Cancer. Cancer treatments for dogs are very experimental, costs thousands of dollars, and will probably just make your dog miserable during their last days. Prednisone would at least finally confirm if it’s allergy related or not, something actually curable, which is why the vet wants to try. Regardless usually only Universities with vet schools have real Cancer expertsequipment for pets, so that’s where you should be planning a trip to if you really want to head down that road.

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Flonase (Fluticasone Propionate Nasal Spray) – updated on RxList

<h1>Flonase (Fluticasone Propionate Nasal Spray) – updated on RxList</h1>

Flonase (Fluticasone Propionate Nasal Spray) – updated on RxList

3.8 2.8
Other adverse reactions with FLONASE Nasal Spray observed with an incidence less than or equal to 3% but greater than or equal to 1% and more common than with placebo included: blood in nasal mucus , runny nose, abdominal pain, diarrhea, fever, flu-like symptoms, aches and pains, dizziness, and bronchitis . Postmarketing Experience
In addition to adverse events reported from clinical trials, the following adverse events have been identified during postapproval use of intranasal fluticasone propionate. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These events have been chosen for inclusion due to either their seriousness, frequency of reporting, or causal connection to fluticasone propionate or a combination of these factors. General Disorders and Administration Site Conditions
Hypersensitivity reactions, including angioedema , skin rash, edema of the face and tongue, pruritus , urticaria , bronchospasm, wheezing , dyspnea , and anaphylaxis /anaphylactoid reactions, which in rare instances were severe. Ear and Labyrinth Disorders
Alteration or loss of sense of taste and/or smell and, rarely, nasal septal perforation, nasal ulcer, sore throat, throat irritation and dryness, cough, hoarseness , and voice changes. Eye Disorders
Dryness and irritation, conjunctivitis , blurred vision, glaucoma, increased intraocular pressure , and cataracts.
Cases of growth suppression have been reported for intranasal corticosteroids, including FLONASE [see WARNINGS AND PRECAUTIONS ]. Drug Interactions DRUG INTERACTIONS Inhibitors Of Cytochrome P450 3A4
Fluticasone propionate is a substrate of CYP3A4. The use of strong CYP3A4 inhibitors (e.g., ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, ketoconazole, telithromycin, conivaptan, lopinavir, nefazodone, voriconazole) with FLONASE Nasal Spray is not recommended because increased systemic corticosteroid adverse effects may occur. Ritonavir
A drug interaction trial with fluticasone propionate aqueous nasal spray in healthy subjects has shown that ritonavir (a strong CYP3A4 inhibitor) can significantly increase plasma fluticasone propionate exposure, resulting in significantly reduced serum cortisol concentrations [see CLINICAL PHARMACOLOGY ]. During postmarketing use, there have been reports of clinically significant drug interactions in patients receiving fluticasone propionate products, including FLONASE, with ritonavir, resulting in systemic corticosteroid effects including Cushing’s syndrome and adrenal suppression. Ketoconazole
Coadministration of orally inhaled fluticasone propionate (1,000 mcg) and ketoconazole (200 mg once daily) resulted in a 1.9-fold increase in plasma fluticasone propionate exposure and a 45% decrease in plasma cortisol area under the curve (AUC), but had no effect on urinary excretion of cortisol. Warnings & Precautions
Included as part of the PRECAUTIONS section. PRECAUTIONS Local Nasal Effects Epistaxis
In clinical trials of 2 to 26 weeks’ duration, epistaxis was observed more frequently in subjects treated with FLONASE Nasal Spray than those who received placebo [see ADVERSE REACTIONS ]. Nasal Ulceration
Postmarketing cases of nasal ulceration have been reported in patients treated with FLONASE Nasal Spray [see ADVERSE REACTIONS ]. Candida Infection
In clinical trials with fluticasone propionate administered intranasally, the development of localized infections of the nose and pharynx with Candida albicans has occurred. When such an infection develops, it may require treatment with appropriate local therapy and discontinuation of FLONASE Nasal Spray. Patients using FLONASE Nasal Spray over several months or longer should be examined periodically for evidence of Candida infection or other signs of adverse effects on the nasal mucosa . Nasal Septal Perforation
Postmarketing cases of nasal septal perforation have been reported in patients treated with FLONASE Nasal Spray [see ADVERSE REACTIONS ]. Impaired Wound Healing
Because of the inhibitory effect of corticosteroids on wound healing, patients who have experienced recent nasal ulcers, nasal surgery, or nasal trauma should avoid using FLONASE Nasal Spray until healing has occurred. Glaucoma And Cataracts
Use of intranasal and inhaled corticosteroids may result in the development of glaucoma and/or cataracts. Therefore, close monitoring is warranted in patients with a change in vision or with a history of increased intraocular pressure , glaucoma, and/or cataracts. Hypersensitivity Reactions including Anaphylaxis
Hypersensitivity reactions (e.g., anaphylaxis , angioedema , urticaria , contact dermatitis , and rash) have been reported after administration of FLONASE Nasal Spray. Discontinue FLONASE
Nasal Spray if such reactions occur [see CONTRAINDICATIONS ]. Rarely, immediate hypersensitivity reactions may occur after the administration of FLONASE Nasal Spray. Immunosuppression
Persons who are using drugs that suppress the immune system are more susceptible to infections than healthy individuals. Chickenpox and measles , for example, can have a more serious or even fatal course in susceptible children or adults using corticosteroids. In such children or adults who have not had these diseases or been properly immunized, particular care should be taken to avoid exposure. How the dose, route, and duration of corticosteroid administration affect the risk of developing a disseminated infection is not known. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known. If a patient is exposed to chickenpox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated. If a patient is exposed to measles, prophylaxis with pooled intramuscular immunoglobulin ( IG ) may be indicated. (See the complete prescribing information for VZIG and IG. ) If chickenpox develops, treatment with antiviral agents may be considered.
Intranasal corticosteroids should be used with caution, if at all, in patients with active or quiescent tuberculous infections of the respiratory tract; systemic fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex. Hypercorticism And Adrenal Suppression
When intranasal corticosteroids are used at higher than recommended dosages or in susceptible individuals at recommended dosages, systemic corticosteroid effects such as hypercorticism and adrenal suppression may appear. If such changes occur, the dosage of FLONASE Nasal Spray should be discontinued slowly consistent with accepted procedures for discontinuing oral corticosteroid therapy.
The replacement of a systemic corticosteroid with a topical corticosteroid can be accompanied by signs of adrenal insufficiency. In addition, some patients may experience symptoms of corticosteroid withdrawal (e.g., joint and/or muscular pain, lassitude , depression). Patients previously treated for prolonged periods with systemic corticosteroids and transferred to topical corticosteroids should be carefully monitored for acute adrenal insufficiency in response to stress . In patients who have asthma or other clinical conditions requiring long-term systemic corticosteroid treatment, rapid decreases in systemic corticosteroid dosages may cause a severe exacerbation of their symptoms. Drug Interactions With Strong Cytochrome P450 3A4 Inhibitors
The use of strong cytochrome P450 3A4 (CYP3A4) inhibitors (e.g., ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, ketoconazole, telithromycin, conivaptan, lopinavir, nefazodone, voriconazole) with FLONASE Nasal Spray is not recommended because increased systemic corticosteroid adverse effects may occur [see DRUG INTERACTIONS , CLINICAL PHARMACOLOGY ]. Effect On Growth
Intranasal corticosteroids may cause a reduction in growth velocity when administered to pediatric patients [see Use in Specific Populations ]. Monitor the growth routinely of pediatric patients receiving FLONASE Nasal Spray. To minimize the systemic effects of intranasal corticosteroids, including FLONASE Nasal Spray, titrate each patient’s dose to the lowest dosage that effectively controls his/her symptoms [see DOSAGE AND ADMINISTRATION , Use In Specific Populations ]. Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling ( PATIENT INFORMATION and Instructions for Use ). Local Nasal Effects
Inform patients that treatment with FLONASE Nasal Spray may lead to adverse reactions, which include epistaxis and nasal ulceration. Candida infection may also occur with treatment with FLONASE Nasal Spray. In addition, FLONASE Nasal Spray has been associated with nasal septal perforation and impaired wound healing. Patients who have experienced recent nasal ulcers, nasal surgery, or nasal trauma should not use FLONASE Nasal Spray until healing has occurred [see WARNINGS AND PRECAUTIONS ]. Glaucoma and Cataracts
Inform patients that glaucoma and cataracts are associated with nasal and inhaled corticosteroid use. Advise patients to notify their healthcare providers if a change in vision is noted while using FLONASE Nasal Spray [see WARNINGS AND PRECAUTIONS ]. Hypersensitivity Reactions, including Anaphylaxis
Inform patients that hypersensitivity reactions, including anaphylaxis, angioedema, urticaria, contact dermatitis , and rash, may occur after administration of FLONASE Nasal Spray. If such reactions occur, patients should discontinue use of FLONASE Nasal Spray [see WARNINGS AND PRECAUTIONS ]. Immunosuppression
Warn patients who are on immunosuppressant doses of corticosteroids to avoid exposure to chickenpox or measles and if they are exposed to consult their healthcare provider without delay. Inform patients of potential worsening of existing tuberculosis ; fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex [see WARNINGS AND PRECAUTIONS ]. Reduced Growth Velocity
Advise parents that FLONASE Nasal Spray may cause a reduction in growth velocity when administered to pediatric patients. Physicians should closely follow the growth of children and adolescents taking corticosteroids by any route [see WARNINGS AND PRECAUTIONS , Pediatric Use ]. Use Daily for Best Effect
Inform patients that they should use FLONASE Nasal Spray on a regular basis. FLONASE Nasal Spray, like other corticosteroids, does not have an immediate effect on rhinitis symptoms. Maximum benefit may not be reached for several days. Patients should not increase the prescribed dosage but should contact their healthcare providers if symptoms do not improve or if the condition worsens. Keep Spray Out of Eyes and Mouth
Inform patients to avoid spraying FLONASE Nasal Spray in their eyes and mouth. Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of Fertility
Fluticasone propionate demonstrated no tumorigenic potential in mice at oral doses up to 1,000 mcg/kg (approximately 20 times the MRHDID in adults and approximately 10 times the MRHDID in children on a mcg/m² basis) for 78 weeks or in rats at inhalation doses up to 57 mcg/kg (approximately 2 times the MRHDID in adults and approximately equivalent to the MRHDID in children on a mcg/m² basis) for 104 weeks.
Fluticasone propionate did not induce gene mutation in prokaryotic or eukaryotic cells in vitro . No significant clastogenic effect was seen in cultured human peripheral lymphocytes in vitro or in the mouse micronucleus test.
No evidence of impairment of fertility was observed in male and female rats at subcutaneous doses up to 50 mcg/kg (approximately 2 times the MRHDID in adults on a mcg/m² basis). Prostate weight was significantly reduced at a subcutaneous dose of 50 mcg/kg. Clinical Studies Perennial Nonallergic Rhinitis
Three randomized, double-blind, parallel-group, vehicle placebo-controlled trials were conducted in 1,191 subjects to investigate regular use of FLONASE Nasal Spray in subjects with perennial nonallergic rhinitis. These trials evaluated subject-rated total nasal symptom scores (TNSS) that included nasal obstruction, postnasal drip , rhinorrhea in subjects treated for 28 days of double-blind therapy and in 1 of the 3 trials for 6 months of open-label treatment. Two of these trials demonstrated that subjects treated with FLONASE Nasal Spray (100 mcg twice daily) exhibited statistically significant decreases in TNSS compared with subjects treated with vehicle. Use In Specific Populations Pregnancy Teratogenic Effects
Pregnancy Category C . There are no adequate and well-controlled trials with FLONASE Nasal Spray in pregnant women. Corticosteroids have been shown to be teratogenic in laboratory animals when administered systemically at relatively low dosage levels. Because animal reproduction studies are not always predictive of human response, FLONASE Nasal Spray should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Women should be advised to contact their physicians if they become pregnant while taking FLONASE Nasal Spray.
Mice and rats at fluticasone propionate doses approximately 1 and 4 times, respectively, the maximum recommended human daily intranasal dose (MRHDID) for adults (on a mg/m² basis at maternal subcutaneous doses of 45 and 100 mcg/kg/day, respectively) showed fetal toxicity characteristic of potent corticosteroid compounds, including embryonic growth retardation, omphalocele , cleft palate , and retarded cranial ossification . No teratogenicity was seen in rats at doses up to 3 times the MRHDID (on a mg/m² basis at maternal inhalation doses up to 68.7 mcg/kg/day).
In rabbits, fetal weight reduction and cleft palate were observed at a fluticasone propionate dose approximately 0.3 times the MRHDID for adults (on a mg/m² basis at a maternal subcutaneous dose of 4 mcg/kg/day). However, no teratogenic effects were reported at fluticasone propionate doses up to approximately 20 times the MRHDID for adults (on a mg/m² basis at a maternal oral dose up to 300 mcg/kg/day). No fluticasone propionate was detected in the plasma in this study, consistent with the established low bioavailability following oral administration [see CLINICAL PHARMACOLOGY ].
Fluticasone propionate crossed the placenta following subcutaneous administration to mice and rats and oral administration to rabbits.
Experience with oral corticosteroids since their introduction in pharmacologic, as opposed to physiologic , doses suggests that rodents are more prone to teratogenic effects from corticosteroids than humans. In addition, because there is a natural increase in corticosteroid production during pregnancy, most women will require a lower exogenous corticosteroid dose and many will not need corticosteroid treatment during pregnancy. Nonteratogenic Effects
Hypoadrenalism may occur in infants born of mothers receiving corticosteroids during pregnancy. Such infants should be carefully monitored. Nursing Mothers
It is not known whether fluticasone propionate is excreted in human breast milk. However, other corticosteroids have been detected in human milk. Subcutaneous administration to lactating rats of tritiated fluticasone propionate at a dose approximately 0.4 times the MRHDID for adults on a mg/m² basis resulted in measurable radioactivity in milk.
Since there are no data from controlled trials on the use of intranasal FLONASE Nasal Spray by nursing mothers, caution should be exercised when FLONASE Nasal Spray is administered to a nursing woman. Pediatric Use
The safety and effectiveness of FLONASE Nasal Spray in children aged 4 years and older have been established [see ADVERSE REACTIONS , CLINICAL PHARMACOLOGY ].Six hundred fifty (650) subjects aged 4 to 11 years and 440 subjects aged 12 to 17 years were studied in US clinical trials with fluticasone propionate nasal spray. The safety and effectiveness of FLONASE Nasal Spray in children younger than 4 years have not been established. Effects on Growth
Controlled clinical trials have shown that intranasal corticosteroids may cause a reduction in growth velocity when administered to pediatric patients. This effect was observed in the absence of laboratory evidence of hypothalamic- pituitary -adrenal (HPA) axis suppression, suggesting that growth velocity is a more sensitive indicator of systemic corticosteroid exposure in pediatric patients than some commonly used tests of HPA axis function. The long-term effects of this reduction in growth velocity associated with intranasal corticosteroids, including the impact on final adult height, are unknown. The potential for “catch-up” growth following discontinuation of treatment with intranasal corticosteroids has not been adequately studied. The growth of pediatric patients receiving intranasal corticosteroids, including FLONASE Nasal Spray, should be monitored routinely (e.g., via stadiometry). The potential growth effects of prolonged treatment should be weighed against the clinical benefits obtained and the risks associated with alternative therapies. To minimize the systemic effects of intranasal corticosteroids, including FLONASE Nasal Spray, each patient’s dosage should be titrated to the lowest dosage that effectively controls his/her symptoms.
A 1-year placebo-controlled trial was conducted in 150 pediatric subjects (aged 3 to 9 years) to assess the effect of FLONASE Nasal Spray (single daily dose of 200 mcg) on growth velocity. From the primary population receiving FLONASE Nasal Spray (n = 56) and placebo (n = 52), the point estimate for growth velocity with FLONASE Nasal Spray was 0.14 cm/year lower than placebo (95% CI: -0.54, 0.27 cm/year). Thus, no statistically significant effect on growth was noted compared with placebo. No evidence of clinically relevant changes in HPA axis function or bone mineral density was observed as assessed by 12-hour urinary cortisol excretion and dual-energy x-ray absorptiometry, respectively.
The potential for FLONASE Nasal Spray to cause growth suppression in susceptible patients or when given at higher than recommended dosages cannot be ruled out. Geriatric Use
A limited number of subjects aged 65 years and older (n = 129) or 75 years and older (n = 11) have been treated with FLONASE Nasal Spray in clinical trials. While the number of subjects is too small to permit separate analysis of efficacy and safety, the adverse reactions reported in this population were similar to those reported by younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Hepatic Impairment
Formal pharmacokinetic trials using FLONASE Nasal Spray have not been conducted in subjects with hepatic impairment. Since fluticasone propionate is predominantly cleared by hepatic metabolism , impairment of liver function may lead to accumulation of fluticasone propionate in plasma. Therefore, patients with hepatic disease should be closely monitored. Renal Impairment
Formal pharmacokinetic trials using FLONASE Nasal Spray have not been conducted in subjects with renal impairment. Overdosage & Contraindications OVERDOSE
Chronic overdosage may result in signs/symptoms of hypercorticism (see PRECAUTIONS ). Intranasal administration of 2 mg (10 times the recommended dose) of fluticasone propionate twice daily for 7 days to healthy human volunteers was well tolerated. Single oral doses up to 16 mg have been studied in human volunteers with no acute toxic effects reported. Repeat oral doses up to 80 mg daily for 10 days in volunteers and repeat oral doses up to 10 mg daily for 14 days in patients were well tolerated. Adverse reactions were of mild or moderate severity, and incidences were similar in active and placebo treatment groups. Acute overdosage with this dosage form is unlikely since 1 bottle of FLONASE (fluticasone propionate) Nasal Spray contains approximately 8 mg of fluticasone propionate.
The oral and subcutaneous median lethal doses in mice and rats were >1,000 mg/kg (>20,000 and >41,000 times, respectively, the maximum recommended daily intranasal dose in adults and >10,000 and >20,000 times, respectively, the maximum recommended daily intranasal dose in children on a mg/m 2 basis). CONTRAINDICATIONS
FLONASE (fluticasone propionate) Nasal Spray is contraindicated in patients with a hypersensitivity to any of its ingredients. Clinical Pharmacology CLINICAL PHARMACOLOGY Mechanism Of Action
Fluticasone propionate is a synthetic trifluorinated corticosteroid with anti-inflammatory activity. Fluticasone propionate has been shown in vitro to exhibit a binding affinity for the human glucocorticoid receptor that is 18 times that of dexamethasone , almost twice that of beclomethasone-17-monopropionate ( BMP ), the active metabolite of beclomethasone dipropionate, and over 3 times that of budesonide. Data from the McKenzie vasoconstrictor assay in man are consistent with these results. The clinical significance of these findings is unknown.
The precise mechanism through which fluticasone propionate affects rhinitis symptoms is not known. Corticosteroids have been shown to have a wide range of effects on multiple cell types (e.g., mast cells, eosinophils, neutrophils, macrophages, lymphocytes) and mediators (e.g., histamine , eicosanoids, leukotrienes, cytokines) involved in inflammation. In 7 trials in adults, FLONASE Nasal Spray has decreased nasal mucosal eosinophils in 66% of patients (35% for placebo) and basophils in 39% of patients (28% for placebo). The direct relationship of these findings to long-term symptom relief is not known. Pharmacodynamics HPA Axis Effect
The potential systemic effects of FLONASE Nasal Spray on the HPA axis were evaluated. FLONASE Nasal Spray given as 200 mcg once daily or 400 mcg twice daily was compared with placebo or oral prednisone 7.5 or 15 mg given in the morning. FLONASE Nasal Spray at either dosage for 4 weeks did not affect the adrenal response to 6-hour cosyntropin stimulation, while both dosages of oral prednisone significantly reduced the response to cosyntropin. Cardiac Electrophysiology
A study specifically designed to evaluate the effect of FLONASE on the QT interval has not been conducted. Pharmacokinetics
The activity of FLONASE Nasal Spray is due to the parent drug, fluticasone propionate. Due to the low bioavailability by the intranasal route, the majority of the pharmacokinetic data was obtained via other routes of administration. Absorption
Indirect calculations indicate that fluticasone propionate delivered by the intranasal route has an absolute bioavailability averaging less than 2%. Trials using oral dosing of labeled and unlabeled drug have demonstrated that the oral systemic bioavailability of fluticasone propionate is negligible ( < 1%), primarily due to incomplete absorption and presystemic metabolism in the gut and liver. After intranasal treatment of patients with rhinitis for 3 weeks, fluticasone propionate plasma concentrations were above the level of detection (50 pg/mL) only when recommended doses were exceeded and then only in occasional samples at low plasma levels. Distribution
Following intravenous administration, the initial disposition phase for fluticasone propionate was rapid and consistent with its high lipid solubility and tissue binding. The volume of distribution averaged 4.2 L/kg.
The percentage of fluticasone propionate bound to human plasma proteins averaged 99%. Fluticasone propionate is weakly and reversibly bound to erythrocytes and is not significantly bound to human transcortin. Elimination
Following intravenous dosing, fluticasone propionate showed polyexponential kinetics and had a terminal elimination half-life of approximately 7.8 hours. The total blood clearance of fluticasone propionate is high (average: 1,093 mL/min), with renal clearance accounting for less than 0.02% of the total.
Metabolism : The only circulating metabolite detected in man is the 17β-carboxylic acid derivative of fluticasone propionate, which is formed through the CYP3A4 pathway. This metabolite had less affinity (approximately 1/2,000) than the parent drug for the glucocorticoid receptor of human lung cytosol in vitro and negligible pharmacological activity in animal studies. Other metabolites detected in vitro using cultured human hepatoma cells have not been detected in man.
Excretion : Less than 5% of a radiolabeled oral dose was excreted in the urine as metabolites, with the remainder excreted in the feces as parent drug and metabolites. Special Populations
Fluticasone propionate nasal spray was not studied in any special populations, and no gender-specific pharmacokinetic data have been obtained. Drug Interactions
Inhibitors of Cytochrome P450 3A4: Ritonavir : Fluticasone propionate is a substrate of CYP3A4. Coadministration of fluticasone propionate and the strong CYP3A4 inhibitor, ritonavir, is not recommended based upon a multiple-dose, crossover drug interaction trial in 18 healthy subjects. Fluticasone propionate aqueous nasal spray (200 mcg once daily) was coadministered for 7 days with ritonavir (100 mg twice daily). Plasma fluticasone propionate concentrations following fluticasone propionate aqueous nasal spray alone were undetectable ( < 10 pg/mL) in most subjects, and when concentrations were detectable, peak levels (Cmax) averaged 11.9 pg/mL (range: 10.8 to 14.1 pg/mL) and AUC(0-τ) averaged 8.43 pg•h/mL (range: 4.2 to 18.8 pg•h/mL). Fluticasone propionate Cmax and AUC(0-τ) increased to 318 pg/mL (range: 110 to 648 pg/mL) and 3,102.6 pg•h/mL (range: 1,207.1 to 5,662.0 pg•h/mL), respectively, after coadministration of ritonavir with fluticasone propionate aqueous nasal spray. This significant increase in plasma fluticasone propionate exposure resulted in a significant decrease (86%) in serum cortisol AUC.
Ketoconazole : Coadministration of orally inhaled fluticasone propionate (1,000 mcg) and ketoconazole (200 mg once daily) resulted in a 1.9-fold increase in plasma fluticasone propionate exposure and a 45% decrease in plasma cortisol AUC, but had no effect on urinary excretion of cortisol.
Erythromycin : In a multiple-dose drug interaction study, coadministration of orally inhaled fluticasone propionate (500 mcg twice daily) and erythromycin (333 mg 3 times daily) did not affect fluticasone propionate pharmacokinetics. Medication Guide

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Supraclavical fat pads | Polymyalgia Rheumatica and GCA | Bones, joints and muscles | Community | Patient

<h1>Supraclavical fat pads | Polymyalgia Rheumatica and GCA | Bones, joints and muscles | Community | Patient</h1>

Supraclavical fat pads | Polymyalgia Rheumatica and GCA | Bones, joints and muscles | Community | Patient

Visit to my GP today to check on tingling numbness in hands feet and face — apparently it’s a side effect of PMR and/or prednisone, and nothing more serious. But I mentioned also a soft swelling above my collarbone — he’s ordered an urgent scan of my neck, which made me a little worried. Fast forward, and I’ve been Dr Googling, and I think it could be supraclavical fat pads, another side effect of taking prednisone — does anyone else have experience of this?
I thought that starting off on 10mg last September I might escape some of the side effects, and am still so grateful for the pain relief I have, I wonder how those on higher doses cope….
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Olaparib and Durvalumab to Treat Patients With Metastatic Triple Negative Breast Cancer

<h1>Olaparib and Durvalumab to Treat Patients With Metastatic Triple Negative Breast Cancer</h1>

Olaparib and Durvalumab to Treat Patients With Metastatic Triple Negative Breast Cancer

You have reached the maximum number of saved studies (100). Please remove one or more studies before adding more. Olaparib and Durvalumab to Treat Patients With Metastatic Triple Negative Breast Cancer The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. ClinicalTrials.gov Identifier: NCT03801369 First Posted : January 11, 2019 Last Update Posted : January 11, 2019 Oregon Health and Science University Information provided by (Responsible Party): Zahi Mitri, OHSU Knight Cancer Institute Study Details Study Description Go to Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information Brief Summary: This phase II study assesses the efficacy of the combination of olaparib and durvalumab in the treatment of patients with metastatic triple negative breast cancer (TNBC). Olabparib may stop growth of tumors cells by inhibiting some of the enzymes (ADP ribose polymerase (PARP)) needed for cell growth. Durvalumab, a monoclonal antibody, inhibits the growth and spread of tumors by stimulating the patient’s antitumor immune response. Giving olaparib and durvalumab together may provide an effective method to treat patients with metastatic triple negative breast cancer. Condition or disease Intervention/treatment Phase Metastatic Triple Negative Breast Cancer Breast Cancer ER-Negative PR-Negative HER2-Negative Breast Cancer ER-Negative PR-Negative HER2-Negative Breast Neoplasms Triple-Negative Breast Cancer Triple Negative Breast Cancer Triple-Negative Breast Neoplasm Drug: Olaparib Biological: Durvalumib I. Assess overall response to treatment SECONDARY OBJECTIVES: I. Assess participant benefit from treatment II. Determine the time to disease progression following response to study therapy III. Determine time to first disease progression or death of participants enrolled on the study IV. Determine survival of participants enrolled on the study V. Assess safety and tolerability of the proposed therapy EXPLORATORY OBJECTIVES: I. Examine response rates depending on tumor characteristics II. Identify predictive biomarkers of sensitivity to therapy III. Identify emerging mechanism of resistance to therapy IV. Determine changes in tumor cells induced by PARP inhibitors OUTLINE: This is an open-label, single-arm phase II study of olaparib and durvalumab. Participants with biopsy proven TNBC will undergo a pre-treatment biopsy, after which they will receive a 4 week, single cycle, induction treatment of olaparib (oral, twice a day). At the 4 week mark, participants will then undergo a repeat on-treatment biopsy, following which durvalumab will be administered (IV over 1 hr) every 4 weeks, in addition to olaparib. Treatment courses repeat every 28 days for 12 cycles. At the completion of all on-study procedures, participants will be considered off-treatment and will be followed every 6 months for disease and survival outcomes up to 1 year. Participants will be asked to submit an optional tumor biopsy in the event of disease progression. Study Design Go to
Treatment Official Title: A Phase II, Open Label, Study of Olaparib and Durvalumab (MEDI4736) in Patients With Metastatic Triple Negative Breast Cancer Actual Study Start Date : Arms and Interventions Go to
Intervention/treatment Experimental: Treatment (Olaparib and Durvalumab) Participants receive a 4 week, single cycle, induction treatment of olaparib (oral, twice a day). At the 4 week mark, participants will then undergo a repeat on-treatment biopsy, following which durvalumib will be administered (IV over 1 hr) every 4 weeks, in addition to olaparib. Treatment courses repeat every 28 days for 12 cycles in the absence of disease progression or unacceptable toxicity. Drug: Olaparib Given PO (Orally) 300 mg twice daily, for 4 weeks (induction) then every 28 days for up to 12 cycles Biological: Durvalumib Given IV (infusion), 1500 mg over 1 hr starting at 4 weeks (following induction) and repeating every 4 weeks for up to 12 cycles. Other Name: MEDI4736 Outcome Measures Go to Primary Outcome Measures : Objective Response Rate (ORR) [ Time Frame: Up to 6 months post treatment ] Using the efficacy analysis set, the estimate of ORR will be measured and reported with 95% exact confidence interval. Participants who achieve a complete response (CR) or a partial response (Pr) on the current protocol will be qualified as achieving a response, and will count towards the ORR measurement. Secondary Outcome Measures : Incidence of grade 3+ acute toxicity per Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.0 [ Time Frame: Up to 3 months post treatment ] Incidence will be determined for participants with TNBC that received at least one dose of olaparib and/or durvalumab. The 95% confidence interval will be reported with the point estimate of toxicity rate Clinical benefit rate (CBR) for olaparib in combination with durvalumab [ Time Frame: Up to 6 months post treatment ] An estimate of CBR will be measured and reported with 95% exact confidence interval. Participants who achieve a CR, Pr, or stable disease (SD) for at least 6 months on the current protocol will be qualified as deriving benefit from therapy, and will count towards the CBR measurement. Progression-free survival (PFS) for olaparib in combination with durvalumab [ Time Frame: Up to 1 year post treatment ] PFS is defined as the time from first treatment with olaparib (i.e., cycle 1 day 1) to the first of either recurrence or relapse (anywhere in the body), or death at time of last follow-up at 12-months. The estimated distribution of the PFS will be plotted using Kaplan Meier curves and reported with median survival and 95% confidence intervals if available Overall survival (OS) olaparib in combination with durvalumab [ Time Frame: Up to 1 year post treatment ] OS is defined as the time from first treatment with olaparib (i.e., Day 1) to the date of death or last follow-up at 12 months. The estimated distribution of the OS will be plotted using Kaplan Meier curves and reported with median survival and 95% confidence intervals if available. Duration of response (DOR) for olaparib in combination with durvalumab [ Time Frame: Up to 6 months post treatment ] The duration of overall response is measured from the time measurement criteria are met for CR or Pr (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented taking as reference for progressive disease the smallest measurements recorded since the treatment started. The duration of overall CR is measured from the time measurement criteria are first met for CR until the first date that progressive disease is objectively documented. If a participant dies, irrespective of cause, without documentation of recurrent or progressive disease beforehand, then the date of death will be used to denote the response end date. Eligibility Criteria Go to Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information Information from the National Library of Medicine
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies. Ages Eligible for Study: 18 Years and older (Adult, Older Adult) Sexes Eligible for Study: Ability to understand and the willingness to sign a written informed consent document. Participants are >= 18 years old at time of informed consent. Metastatic TNBC, as defined by: ER and PR negative as defined as ER < 10% and PR < 10% by immunohistochemistry according to American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines for hormone receptor testing HER2 non-amplified per ASCO/CAP guidelines, defined as: IHC score 0/1+ IHC 2+ and in situ hybridization (ISH) non-amplified with a ratio of HER2 to CEP17 < 2.0, and if reported, average HER2 gene copy number <4 signals/cells; or ISH non-amplified with a ratio of HER2 to CEP17 <2.0, and if reported, average HER2 gene copy number < 4 signals/cells Participants must have at least one measurable site of disease as defined by RECIST v1.1 that is amendable to biopsy. Prior therapies for metastatic breast cancer Frontline patients who have not received prior systemic therapy for metastatic breast cancer are eligible. Patients who have received <= 2 prior chemotherapy regimens for metastatic breast cancer are eligible. Participants must have fully recovered from the acute toxic effects of all prior treatment to grade 1 or less, except alopecia and =16 weeks. Participant must have Eastern Cooperative Oncology Group (ECOG) performance status = 10.0 g/dL with no blood transfusion in the past 28 days Absolute neutrophil count (ANC) >= 1.5 x 109/L Platelet count >= 100 x 109/L Total bilirubin <= 1.5 x institutional upper limit of normal (ULN) Aspartate aminotransferase (AST) (Serum Glutamic Oxaloacetic Transaminase (SGOT)) / Alanine aminotransferase (ALT) (Serum Glutamic Pyruvate Transaminase (SGPT)) <= 2.5 x institutional upper limit of normal unless liver metastases are present in which case they must be = 51 mL/min using the Cockcroft-Gault equation or based on a 24 hour urine test: Estimated creatinine clearance = (140-age [years]) x weight (kg) (x F) serum creatinine (mg/dL) x 72; where F=0.85 for females and F=1 for males. Female participants of childbearing potential must have a negative urine or serum pregnancy test within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. Female participants of childbearing potential agree to use adequate methods of contraception starting with the first dose of study therapy through 60 days after the last dose of study therapy. Participants of childbearing potential are those who are not proven postmenopausal. Postmenopausal is defined as: Amenorrheic for 1 year or more following cessation of exogenous hormonal treatments Luteinizing hormone (LH) and Follicle stimulating hormone (FSH) levels in the post menopausal range for women under 50 Radiation-induced oophorectomy with last menses > 1 year ago Chemotherapy-induced menopause with > 1 year interval since last menses Surgical sterilisation (bilateral oophorectomy or hysterectomy) Male participants must agree to use an adequate method of contraception starting with the first dose of study therapy through 60 days after the last dose of study therapy. Participants must not have received live vaccines within 30 days prior to the first dose of immunotherapy. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, chicken pox, shingles, yellow fever, rabies, BCG, and typhoid (oral) vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed. Patients, if enrolled, should not receive live vaccine whilst receiving immunotherapy and up to 30 days after the last dose of immunotherapy Exclusion Criteria: Currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigation device within 4 weeks of first dose of treatment. a. Individuals in the follow-up phase of a prior investigational study may participate as long as it has been 4 weeks since last dose of the previous investigational agent of device. Participants with germline BRCA mutated TNBC will be excluded Other malignancy unless curatively treated with no evidence of disease for >= 5 years except: adequately treated non-melanoma skin cancer, curatively treated in situ cancer of the cervix, ductal carcinoma in situ (DCIS), Stage 1, grade 1 endometrial carcinoma. Participants with a history of localized triple negative breast cancer may be eligible, provided they completed their adjuvant chemotherapy more than three years prior to registration, and that the participant remains free of recurrent or metastatic disease Participants with myelodysplastic syndrome/acute myeloid leukemia or with features suggestive of MDS/AML. Participant received prior chemotherapy or any other targeted therapies within the past 28, or radiation (except for palliative reasons) within the past 3 weeks, prior to going on-study. Participants with known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are stable [without evidence of progression by imaging (confirmed by CT scan if CT used at prior imaging, or confirmed by MRI if MRI was used at prior imaging) for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline], have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability. Participants unable to swallow orally administered medication and participants with gastrointestinal disorders likely to interfere with absorption of the study medication Participants with visceral crisis defined as severe organ dysfunction as assessed by signs and symptoms, laboratory studies, and rapid progression of disease. Active infection requiring systemic antibiotic therapy. Participants requiring systemic antibiotics for infection must have completed therapy before treatment is initiated. Participants considered a poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active, uncontrolled infection. Examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 3 months) myocardial infarction, uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava syndrome, extensive interstitial bilateral lung disease on High Resolution Computed Tomography (HRCT) scan or any psychiatric illness/social situation that prohibits obtaining informed consent. Resting ECG indicating uncontrolled, potentially reversible cardiac conditions, as judged by the investigator (e.g., unstable ischemia, uncontrolled symptomatic arrhythmia, congestive heart failure, QTcF prolongation >500 ms, electrolyte disturbances, etc.), or participants with congenital long QT syndrome Participants with a history of hypersensitivity reactions to study agent or their excipients. Participant is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit through 120 days after the last dose of trial treatment. Involvement in the planning and/or conduct of the study Judgment by the investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions and requirements. DRUG-SPECIFIC EXCLUSION CRITERIA: Durvalumab Participant has evidence of interstitial lung disease or active non-infectious pneumonitis. Major surgery within 2 weeks of starting study treatment and participants must have recovered from any effects of any major surgery Note: Local surgery of isolated lesions for palliative intent is acceptable per investigator discretion. Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and TB testing in line with local practice), hepatitis B (known positive HBV surface antigen (HBsAg) result), hepatitis C, or human immunodeficiency virus (positive HIV 1/2 antibodies). Participants with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Participants positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA. History of active primary immunodeficiency Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab, with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid. The following are exceptions to this criterion: Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular injection) Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication) Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g., colitis or Crohn’s disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves’ disease, rheumatoid arthritis, hypophysitis, uveitis, etc.]). The following are exceptions to this criterion: Participants with vitiligo or alopecia Participants with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement Any chronic skin condition that does not require systemic therapy Participants without active disease in the last 5 years may be included but only after consultation with the study physician Participants with celiac disease controlled by diet alone History of allogenic bone marrow transplant or double umbilical cord blood transplantation Contacts and Locations Go to Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information Information from the National Library of Medicine
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03801369 Locations

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Checkpoint inhibition and rheumatic events: ‘Many more questions than answers’

<h1>Checkpoint inhibition and rheumatic events: ‘Many more questions than answers’</h1>

Checkpoint inhibition and rheumatic events: ‘Many more questions than answers’

Checkpoint inhibition and rheumatic events: ‘Many more questions than answers’ HemOnc Today, January 10, 2019 Add Click here to manage your alerts .
It may seem silly to use Whac-A-Mole to illustrate a key challenge in cancer treatment.
But the popular arcade game’s basic premise — use a mallet to knock one mole back into its hole, only to have another pop up a split-second later — is a fitting comparison to the immune-related adverse events that can arise during treatment with checkpoint inhibitors.
Checkpoint inhibition — the foundation of the immunotherapy revolution in oncology — targets checkpoints, or regulators, that inhibit or stimulate the immune system’s actions. Tumors use these checkpoints to protect themselves from immune system attack.
This modality has greatly improved outcomes for patients with advanced malignancies. However, it has been associated with an array of complex autoimmune and systemic inflammatory reactions, including rheumatologic manifestations.
Although it may not be surprising that drugs that boost the immune system can contribute to rheumatologic disorders, these conditions can persist for several years after checkpoint inhibition stops. Cassandra Calabrese
“As one would imagine, with their increased use, more patients are going to develop immune-related adverse events (irAEs),” Cassandra Calabrese, DO, rheumatologist in the department of rheumatologic and immunologic disease at Cleveland Clinic, told HemOnc Today . “[Clinicians] must be able to recognize rheumatic irAEs as a complication of checkpoint inhibitors and be aware that many clinical syndromes have been described, including inflammatory arthritis, polymyalgia rheumatica, sicca syndrome, myositis and others. We must do our best to keep up with this quickly growing field, as it has already presented many challenges.” Epidemiology
Seven checkpoint inhibitors — including anti-PD-1, anti-PD-L1 and anti-CTLA-4 agents — are approved in the United States for treatment of several malignancies. These include melanoma or other skin cancers, lung cancer, genitourinary cancers and Hodgkin lymphoma.
Approvals of anti-OX40 and anti-TIM-3 monoclonal antibodies, as well as inhibitors of other immunologic checkpoints, are anticipated in the near future.
This will require greater understanding of the frequency and severity of complications, as well as optimal management strategies, Calabrese said.
Treatment of moderate to severe rheumatologic irAEs often requires use of corticosteroid immunosuppression, as well as interruption or discontinuation of checkpoint inhibitor therapy.
However, rheumatologic irAEs have been reported less consistently than other types.
In some cases, the infrequency of rheumatologic irAEs makes them difficult for oncologists to identify. In other cases, providers’ lack of recognition of musculoskeletal symptoms and the likelihood that these events will not be life-threatening likely contribute to variable reporting. Identification and accurate diagnosis of patients with rheumatologic immune-related adverse events — particularly those with arthritis — is an urgent clinical need, according to Anne R. Bass, MD. “We are just beginning to define these arthritides because they are so heterogeneous,” she said. “If you see five different patients, you might see five different phenotypes.” Source: Hospital for Special Surgery.
“We are really just getting a handle on the epidemiology,” Anne R. Bass, MD, professor of clinical medicine at Weill Cornell Medicine, told HemOnc Today . “The problem is that we see these cases, but don’t always know the denominator.”
Richter and colleagues used a database of all patients who received any immune checkpoint inhibitor at Mayo Clinic in Minnesota between Jan. 1, 2011, and March 1, 2018, to assess the prevalence, clinical presentation and management of rheumatologic irAEs.
The study — which many experts consider the first key data set in the field — included 1,293 patients who received a checkpoint inhibitor, 43 (3.3%) of whom were clinically diagnosed with rheumatologic irAEs.
An analysis of those 43 patients, plus another 18 with rheumatologic irAEs who received immune checkpoint inhibitor therapy elsewhere, showed clinical syndromes included inflammatory arthritis (n = 34), myopathy (n = 10) and 17 other rheumatic syndromes.
Most cases of inflammatory arthritis were polyarticular. Twenty-six (76%) of these patients required glucocorticoids, and mean treatment duration was 18 weeks. Five patients (14.7%) received disease-modifying drugs and three (9%) required discontinuation of immune checkpoint inhibitor therapy.
All patients who developed myopathy received glucocorticoids for a mean duration of 15 weeks; two patients died and nine (90%) required permanent immune checkpoint inhibitor discontinuation.
The other rheumatologic syndromes included vasculitis, connective tissue diseases, polymyalgia rheumatica-like syndrome and flared pre-existing rheumatic disease. The majority (71%) of these patients received immunosuppressive therapy and 12% required immune checkpoint inhibitor discontinuation.
Laura C. Cappelli, MD, MHS, assistant professor of medicine at Johns Hopkins School of Medicine, and colleagues systematically reviewed published literature on musculoskeletal and rheumatologic irAEs to improve understanding of their prevalence and clinical characteristics.
They searched the Medline and CENTRAL databases for articles that reported rheumatic and musculoskeletal irAEs secondary to immune checkpoint inhibitor treatment.
Researchers determined arthralgia (prevalence, 7% to 43%) and myalgia (prevalence, 2% to 20%) are commonly reported in this patient population, but there is greater uncertainty regarding the prevalence of other rheumatologic irAEs, including inflammatory arthritis, vasculitis and sicca syndrome. Laura C. Cappelli
“We still lack strong epidemiologic data, but rheumatologic irAEs like inflammatory arthritis can be seen in up to 7% of patients treated with certain checkpoint inhibitors,” Cappelli told HemOnc Today . “Other rheumatologic irAEs like myositis occur [among] less than 1% of patients.” ‘Considerable uncertainty’
Identification and accurate diagnosis of patients with rheumatologic irAEs — particularly those with arthritis — is an urgent clinical need, Bass said.
“We are just beginning to define these arthritides because they are so heterogeneous,” she said. “If you see five different patients, you might see five different phenotypes.”
Underlying genetics and environmental exposures may contribute to the heterogeneity in this population, Bass said.
“In our patients, around 20% or 25% present with what looks like rheumatoid arthritis, with both large joints and small joints affected,” she said, noting that only some of them are seropositive. “Another 20% have polymyalgia rheumatica, which causes achy shoulders and hips. Then there is a group who have large joint arthritis — usually the knees, hips, wrists and/or shoulders. We don’t see this pattern of arthritis outside of the immunotherapy context.”
Beyond these manifestations, there are rare reports of psoriatic arthritis, scleroderma and vasculitis.
Myositis is relatively common, whereas dermatomyositis and lupus — diseases that are driven by interferon — are very rare.
Some patients may have a disease susceptibility that is unmasked by immunotherapy, whereas others may have an immunotherapy-specific condition.
“There are just a lot of uncertainties right now,” Bass said.
Bass estimated that 5% of patients treated with checkpoint inhibitors develop arthritis, but approximately 20% experience joint pain.
“Many of these cases are missed by oncologists for two reasons,” Bass said. “[First], they don’t pay as much attention to joint pain as a rheumatologist would, and [second], because steroids used for other adverse events mask joint pain.”
A key concern is that oncologists do not typically recognize the difference between arthritis, arthralgia and polymyalgia syndromes, according to Maria E. Suarez-Almazor, MD, PhD, deputy department chair and distinguished professor in the department of general internal medicine and chief of the section of rheumatology and clinical immunology at The University of Texas MD Anderson Cancer Center. Maria E. Suarez-Almazor
“Reports vary greatly across trials, possibly because of differences in musculoskeletal adverse events characterizations,” Suarez-Almazor told HemOnc Today . “When we talk about these rheumatic syndromes, there are three primary presentations: arthritis/arthralgia, polymyalgia and myositis.
“Myositis is obviously the scariest, because it is acute and can be life-threatening,” she added. “Admittedly, myositis probably occurs in less than 1% of patients, but we are very concerned about it because patients can also develop myocarditis, a potentially fatal complication.”
Calabrese highlighted another concern.
“What is felt to be weakness from myositis may be the result of progressive intracranial metastasis,” she said.
Key considerations include whether immunotherapy is administered as primary or adjuvant treatment, how a patient responds to oncologic therapy, whether there are alternatives for oncologic treatment, and their life expectancy, Suarez-Almazor said.
“These drugs have not been widely used in patients with limited cancer yet, but that could change,” she said. “Also, new drugs and new combinations will likely come on board, so that will also change the landscape.” Making the diagnosis
The ability to accurately diagnose rheumatologic irAEs can be challenging, Calabrese said.
“This is a very heterogeneous patient population, with many patients having received chemotherapy, radiation and/or surgery prior to checkpoint inhibitor therapy, and they may have progression of their tumor at the time of evaluation,” she said. “It is important to keep other etiologies on the differential when evaluating a patient for rheumatic irAEs.”
It also is important to note that rheumatologic irAEs described thus far frequently have atypical features compared with de novo disease, Calabrese said.
“For example, they may lack characteristic autoantibodies or require higher doses of prednisone than would be expected,” she said. “Also, unlike all other irAEs to date, rheumatic manifestations appear to be the only irAE with inflammation that persists, even despite discontinuation of the checkpoint inhibitor.”
The potential that rheumatologic irAEs will persist — even for several years after checkpoint inhibitor therapy has been stopped — is a major concern for clinicians.
“We have patients who are 3 years out from receiving immune checkpoint inhibitors who continue to have issues with inflammatory arthritis,” Cappelli said.
Although strides have been made, there is still considerable room for improvement in terms of accurate and timely diagnosis, she added.
“It is still a problem for oncology and other nonrheumatology providers,” Cappelli said. “There is a knowledge gap in the range of rheumatologic irAEs like polymyalgia rheumatica, myositis, vasculitis and inflammatory arthritis.”
Musculoskeletal examination is not taught in depth in all medical training programs, Cappelli said. This makes it difficult for providers to determine if joints are swollen, warm or have a decreased range of motion when evaluating for inflammatory arthritis.
“In the area of myositis, sometimes routine labs will show an elevated aspartate aminotransferase, which can come from muscle in the setting of myositis, but clinicians may go down the path of investigating liver pathology,” she said.
Referral to a rheumatologist at the first sign of any such syndrome is essential, Suarez-Almazor said.
“Not only will a rheumatologist be able to make a diagnosis, but they will be familiar with the medications necessary to treat these patients,” she said. “We have seen that these syndromes are different from other immune-related arthritis in that they sometimes can have an insidious onset and can linger for weeks or months, even after discontinuing immunotherapy.” Treatment complications
A lack of understanding in the clinical community about the potential complications that can arise during treatment of rheumatologic irAEs compounds the challenge of caring for these patients.
“The main challenge in managing patients with rheumatologic irAEs is the lack of evidence-based medicine to guide treatment,” Cappelli said. “IrAEs are a relatively new clinical issue, and more research is needed to determine the most effective and safe treatments. The concern in treating irAEs is that immunosuppression may undermine the tumor immunologic response and have a negative impact on cancer progression.” Uma Thanarajasingam
For this reason, communication between oncologists and rheumatologists is key.
“Rheumatologists understand better than oncologists how aggressive we can be,” Uma Thanarajasingam, MD, PhD, of Mayo Clinic in Rochester, Minnesota, told HemOnc Today . “[However], any time we go beyond prednisone, we have to partner with oncologists to see how much damage we might be doing to the immune system.
“We have to understand the status of the underlying cancer and whether the patient is responding really well to checkpoint inhibitor therapy, even if they are having a great deal of arthritic pain,” Thanarajasingam added. “Sometimes we have to take a hiatus from the treatment we are using, or switch courses.”
The nature of a particular malignancy and the patient’s prognosis, as well as how immunosuppressive therapy may affect a patient, also must be taken into account, Bass said.
For example, Merkel cell carcinoma is immunologically sensitive and occurs primarily among immune-suppressed individuals. Treating immune-related adverse events experienced by a patient with this malignancy may be much riskier than doing so for a patient who has melanoma.
“You have to understand that the treatment approach for every patient and every tumor is different,” Bass said. “I would love to be able to offer concrete recommendations that always apply. The key is [for oncologists and rheumatologists] to work together … and [with] the patient to discuss risks and benefits, and to learn from each other.”
A small but growing area of research focuses on specific drug-drug interactions.
During a presentation at Congress of Clinical Rheumatology in 2018, Ami A. Shah, MD, MHS — associate professor of medicine at Johns Hopkins University School of Medicine — said current evidence indicates corticosteroids and short-term tumor necrosis factor inhibitor use may be tolerable without affecting melanoma responses to both the anti-CTLA-4 antibody ipilimumab (Yervoy, Bristol-Myers Squibb) and the PD-1 checkpoint inhibitor nivolumab (Opdivo, Bristol-Myers Squibb).
“These interactions are still quite an unknown area,” Thanarajasingam said. “We get a sense that certain combinations may have more or less toxicity than others.”
As use of these agents expands into other malignancies, the challenges likely will be compounded, Thanarajasingam said.
“Because these drugs were first approved in melanoma, the toxicities reported in that type of cancer are greatest,” she said. “As usage expands, it will be interesting to see how the toxicity profile changes. For example, lymphoma is a completely different type of cancer, and the immune cells are part of the cancer, so what are the implications for adverse events? It’s still such a new area, so it’s hard to say.” ASCO guidelines
In 2018, ASCO and National Comprehensive Cancer Network released a clinical practice guideline for management of irAEs among patients receiving checkpoint inhibitor therapy.
A multidisciplinary, multiorganizational panel of experts performed a systematic review of publications on immune checkpoint inhibitor therapy from 2000 through 2017.
The resulting guideline — published in Journal of Clinical Oncology — provided detailed recommendations for organ-specific management of several types of irAEs, including those that affect the skin, nervous system, lungs, musculoskeletal system and cardiovascular system.
“With rapidly increasing use of immune checkpoint inhibitors, it is imperative that clinicians are knowledgeable about their unique toxicity profiles,” Clifford A. Hudis, MD, FASCO, FACP, CEO of ASCO, said when the guidelines were released. “These new guidelines … will help our community continue to provide the highest quality of care to all patients as they incorporate these agents into routine care.”
General guidelines for irAEs are as follows: Grade 1 — Immune checkpoint inhibitor therapy should be continued with close monitoring for patients, with the exception of those who develop certain neurologic, hematologic or cardiac toxicities. Grade 2 — Immune checkpoint inhibition may be suspended and then resumed if symptoms revert to grade 1 or less. In these cases, corticosteroids may be administered. Grade 3 — Most cases warrant suspension of immune checkpoint inhibition and initiation of high-dose corticosteroids (prednisone or methyl-prednisolone dosed at 1 mg/kg to 2 mg/kg daily). Corticosteroids should be tapered over a minimum 4 weeks to 6 weeks. Infliximab (Remicade, Janssen) or other immunosuppressive therapy may be required for certain refractory cases. Grade 4 — Permanent discontinuation of immune checkpoint inhibitor therapy is recommended, with the exception of endocrinopathies that have been controlled by hormone replacement.
The guideline panel also issued recommendations based on specific rheumatic irAEs, such as inflammatory arthritis, myositis and polymyalgia-like syndrome.
“Despite the often-durable clinical benefits of the immune checkpoint blockade therapy, [immune checkpoint inhibitor] use is associated with a spectrum of adverse effects related to the mechanism of action that is quite different from other systemic therapies, such as cytotoxic chemotherapy,” guideline co-author Julie R. Brahmer, MD, co-director of the upper aerodigestive department within the Bloomberg Kimmel Institute for Cancer Immunotherapy and professor of oncology at Johns Hopkins, and colleagues wrote.“The adverse effects can affect multiple organs of the body … and there should be a high level of suspicion that any changes are treatment-related.
“The ability to influence immune response even after discontinuation of the immunotherapeutic agent is a unique feature and important education point for patients and their caregivers,” Brahmer and colleagues added. “As such, patients should be encouraged to alert all health care providers that they are receiving or have received an immunotherapeutic agent and to report any changes in health status to each provider.”
The take-home message of ASCO’s guideline is the need for increased awareness and importance of addressing these adverse events promptly.
“[Clinicians] need to understand that there is a place they can turn for information about these events, whether it is the guidelines or other experts who are familiar with them,” Thanarajasingam told HemOnc Today .
This increases the likelihood that basic interventions will be employed early in the course of irAEs, Bass said.
“What I have learned from caring for patients with immunotherapy-induced arthritis is that it often becomes chronic, so it is important to start early with steroid-sparing agents,” she said. Communication is key
Even with the guidelines in place, much uncertainty remains.
“At this point, there are so many more questions than answers,” Calabrese said. “We have much to learn about risk factors, biomarkers, pathogenesis and optimal treatment of rheumatic irAEs, as well as the impact that treatment for irAEs may have on cancer outcomes.”
Consequently, collaboration between oncologists and rheumatologists is essential.
“Communication is the most important thing to successfully care for patients with rheumatologic irAEs,” Cappelli said. “The oncologist and rheumatologist must reach consensus about ways to manage each patient.
“We contact the patient’s oncologist on the day of their clinic visit to us so we can confirm the plan,” she said. “It is also important for the patient to be aware of the role each physician plays in their care. Often patients ask us about plans for their cancer therapy and we need to remind them that their oncologist will guide their cancer treatment and we will manage their side effects, in collaboration with their oncologist.”
A cautious approach is appropriate, Calabrese said.
“If there are symptoms of grade 2 or higher based on [Common Terminology Criteria for Adverse Events] grading, they should be referred to a rheumatologist,” she said. “Long-term management of these patients requires multidisciplinary care that addresses the patients’ rheumatic manifestations while at the same time treating their cancer.”
The multidisciplinary care may need to extend beyond oncologists and rheumatologists, Suarez-Almazor said.
“We need to promptly recognize when others need to be involved — for instance cardiologists when suspecting myocarditis,” she said. “The benefits and harms of therapies need to be understood quickly, along with how the various therapies are interacting with each other.”
Despite the challenges associated with diagnosing and treating rheumatologic irAEs, many in the field consider it an opportunity to improve the knowledge base and ultimately improve outcomes.
“We have to take every opportunity to learn, because we are going to see more and more of these patients,” Bass said. “It is critical that we have people who understand and can manage these patients and the problems they confront.
“In most cases of rheumatoid arthritis, the development of antibodies to disease onset can usually be 3 to 5 years,” she added. “[Among patients who receive immunotherapy], we are seeing arthritis develop within 3 to 4 months of starting treatment. This means we can study this disease and biomarkers over a shorter period of time, and they will likely teach us something about rheumatic diseases that we see in other contexts.”
It also is important for members of the oncology care team to have mechanisms in place to identify and manage these rapidly developing conditions, Suarez-Almazor said.
“Many of these are patients who cannot wait to be seen by a rheumatologist for weeks or months, as decisions about their cancer treatment are critical,” she said. – by Rob Volansky References:
Brahmer JR, et al. J Clin Oncol . 2018;doi:10.1200/JCO.2017.77.6385.
Cappelli LC, et al. Arthritis Care Res . 2018;doi:10.1002/acr.23177.
Johnson DH, et al. J Immunother Cancer . 2018;doi:10.1186/s40425-018-0412-0.
Kapiteijn E. Abstract SP0097. Presented at: EULAR Annual Congress; June 13-16, 2018; Amsterdam.
Moseley KF, et al. J Immunother Cancer . 2018;doi:10.1186/s40425-018-0417-8.
Richter MD, et al. Arthritis Rheumatol . 2018;doi:10.1002/art.40745.
Shah A. Cancer, immunotherapy and autoimmune syndromes: Rheumatic consequences of checkpoint inhibitors; Presented at: Congress of Clinical Rheumatology; May 17-20, 2018; Destin, Fla. For more information:
Anne R. Bass, MD, can be reached at Hospital for Special Surgery, 535 E. 70th St., New York, NY 10021; email: .
Cassandra Calabrese, DO, can be reached at Cleveland Clinic, 9500 Euclid Ave., Desk A50, Cleveland, OH 44195; email: .
Laura C. Cappelli, MD, MHS, can be reached at Johns Hopkins Medicine, 5501 Hopkins Bayview Circle, Suite 1B1, Baltimore, MD 21224; email: .
Maria E. Suarez-Almazor, MD, PhD, can be reached at The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd. #437, Houston, TX 77030; email: .
Uma Thanarajasingam, MD, PhD, can be reached at Mayo Clinic, 200 First St. SW, Rochester, MN 55905; email: . Disclosures: Cappelli reports research funding from Bristol-Myers Squibb, as well as consultant roles with Regeneron and Sanofi. Bass, Calabrese, Suarez-Almazor and Thanarajasingam report no relevant financial disclosures.
It may seem silly to use Whac-A-Mole to illustrate a key challenge in cancer treatment.
But the popular arcade game’s basic premise — use a mallet to knock one mole back into its hole, only to have another pop up a split-second later — is a fitting comparison to the immune-related adverse events that can arise during treatment with checkpoint inhibitors.
Checkpoint inhibition — the foundation of the immunotherapy revolution in oncology — targets checkpoints, or regulators, that inhibit or stimulate the immune system’s actions. Tumors use these checkpoints to protect themselves from immune system attack.
This modality has greatly improved outcomes for patients with advanced malignancies. However, it has been associated with an array of complex autoimmune and systemic inflammatory reactions, including rheumatologic manifestations.
Although it may not be surprising that drugs that boost the immune system can contribute to rheumatologic disorders, these conditions can persist for several years after checkpoint inhibition stops. Cassandra Calabrese
“As one would imagine, with their increased use, more patients are going to develop immune-related adverse events (irAEs),” Cassandra Calabrese, DO, rheumatologist in the department of rheumatologic and immunologic disease at Cleveland Clinic, told HemOnc Today . “[Clinicians] must be able to recognize rheumatic irAEs as a complication of checkpoint inhibitors and be aware that many clinical syndromes have been described, including inflammatory arthritis, polymyalgia rheumatica, sicca syndrome, myositis and others. We must do our best to keep up with this quickly growing field, as it has already presented many challenges.” Epidemiology
Seven checkpoint inhibitors — including anti-PD-1, anti-PD-L1 and anti-CTLA-4 agents — are approved in the United States for treatment of several malignancies. These include melanoma or other skin cancers, lung cancer, genitourinary cancers and Hodgkin lymphoma.
Approvals of anti-OX40 and anti-TIM-3 monoclonal antibodies, as well as inhibitors of other immunologic checkpoints, are anticipated in the near future.
This will require greater understanding of the frequency and severity of complications, as well as optimal management strategies, Calabrese said.
Treatment of moderate to severe rheumatologic irAEs often requires use of corticosteroid immunosuppression, as well as interruption or discontinuation of checkpoint inhibitor therapy.
However, rheumatologic irAEs have been reported less consistently than other types.
In some cases, the infrequency of rheumatologic irAEs makes them difficult for oncologists to identify. In other cases, providers’ lack of recognition of musculoskeletal symptoms and the likelihood that these events will not be life-threatening likely contribute to variable reporting. Identification and accurate diagnosis of patients with rheumatologic immune-related adverse events — particularly those with arthritis — is an urgent clinical need, according to Anne R. Bass, MD. “We are just beginning to define these arthritides because they are so heterogeneous,” she said. “If you see five different patients, you might see five different phenotypes.” Source: Hospital for Special Surgery.
“We are really just getting a handle on the epidemiology,” Anne R. Bass, MD, professor of clinical medicine at Weill Cornell Medicine, told HemOnc Today . “The problem is that we see these cases, but don’t always know the denominator.” PAGE BREAK
Richter and colleagues used a database of all patients who received any immune checkpoint inhibitor at Mayo Clinic in Minnesota between Jan. 1, 2011, and March 1, 2018, to assess the prevalence, clinical presentation and management of rheumatologic irAEs.
The study — which many experts consider the first key data set in the field — included 1,293 patients who received a checkpoint inhibitor, 43 (3.3%) of whom were clinically diagnosed with rheumatologic irAEs.
An analysis of those 43 patients, plus another 18 with rheumatologic irAEs who received immune checkpoint inhibitor therapy elsewhere, showed clinical syndromes included inflammatory arthritis (n = 34), myopathy (n = 10) and 17 other rheumatic syndromes.
Most cases of inflammatory arthritis were polyarticular. Twenty-six (76%) of these patients required glucocorticoids, and mean treatment duration was 18 weeks. Five patients (14.7%) received disease-modifying drugs and three (9%) required discontinuation of immune checkpoint inhibitor therapy.
All patients who developed myopathy received glucocorticoids for a mean duration of 15 weeks; two patients died and nine (90%) required permanent immune checkpoint inhibitor discontinuation.
The other rheumatologic syndromes included vasculitis, connective tissue diseases, polymyalgia rheumatica-like syndrome and flared pre-existing rheumatic disease. The majority (71%) of these patients received immunosuppressive therapy and 12% required immune checkpoint inhibitor discontinuation.
Laura C. Cappelli, MD, MHS, assistant professor of medicine at Johns Hopkins School of Medicine, and colleagues systematically reviewed published literature on musculoskeletal and rheumatologic irAEs to improve understanding of their prevalence and clinical characteristics.
They searched the Medline and CENTRAL databases for articles that reported rheumatic and musculoskeletal irAEs secondary to immune checkpoint inhibitor treatment.
Researchers determined arthralgia (prevalence, 7% to 43%) and myalgia (prevalence, 2% to 20%) are commonly reported in this patient population, but there is greater uncertainty regarding the prevalence of other rheumatologic irAEs, including inflammatory arthritis, vasculitis and sicca syndrome. Laura C. Cappelli
“We still lack strong epidemiologic data, but rheumatologic irAEs like inflammatory arthritis can be seen in up to 7% of patients treated with certain checkpoint inhibitors,” Cappelli told HemOnc Today . “Other rheumatologic irAEs like myositis occur [among] less than 1% of patients.” ‘Considerable uncertainty’
Identification and accurate diagnosis of patients with rheumatologic irAEs — particularly those with arthritis — is an urgent clinical need, Bass said.
“We are just beginning to define these arthritides because they are so heterogeneous,” she said. “If you see five different patients, you might see five different phenotypes.”
Underlying genetics and environmental exposures may contribute to the heterogeneity in this population, Bass said. PAGE BREAK
“In our patients, around 20% or 25% present with what looks like rheumatoid arthritis, with both large joints and small joints affected,” she said, noting that only some of them are seropositive. “Another 20% have polymyalgia rheumatica, which causes achy shoulders and hips. Then there is a group who have large joint arthritis — usually the knees, hips, wrists and/or shoulders. We don’t see this pattern of arthritis outside of the immunotherapy context.”
Beyond these manifestations, there are rare reports of psoriatic arthritis, scleroderma and vasculitis.
Myositis is relatively common, whereas dermatomyositis and lupus — diseases that are driven by interferon — are very rare.
Some patients may have a disease susceptibility that is unmasked by immunotherapy, whereas others may have an immunotherapy-specific condition.
“There are just a lot of uncertainties right now,” Bass said.
Bass estimated that 5% of patients treated with checkpoint inhibitors develop arthritis, but approximately 20% experience joint pain.
“Many of these cases are missed by oncologists for two reasons,” Bass said. “[First], they don’t pay as much attention to joint pain as a rheumatologist would, and [second], because steroids used for other adverse events mask joint pain.”
A key concern is that oncologists do not typically recognize the difference between arthritis, arthralgia and polymyalgia syndromes, according to Maria E. Suarez-Almazor, MD, PhD, deputy department chair and distinguished professor in the department of general internal medicine and chief of the section of rheumatology and clinical immunology at The University of Texas MD Anderson Cancer Center. Maria E. Suarez-Almazor
“Reports vary greatly across trials, possibly because of differences in musculoskeletal adverse events characterizations,” Suarez-Almazor told HemOnc Today . “When we talk about these rheumatic syndromes, there are three primary presentations: arthritis/arthralgia, polymyalgia and myositis.
“Myositis is obviously the scariest, because it is acute and can be life-threatening,” she added. “Admittedly, myositis probably occurs in less than 1% of patients, but we are very concerned about it because patients can also develop myocarditis, a potentially fatal complication.”
Calabrese highlighted another concern.
“What is felt to be weakness from myositis may be the result of progressive intracranial metastasis,” she said.
Key considerations include whether immunotherapy is administered as primary or adjuvant treatment, how a patient responds to oncologic therapy, whether there are alternatives for oncologic treatment, and their life expectancy, Suarez-Almazor said.
“These drugs have not been widely used in patients with limited cancer yet, but that could change,” she said. “Also, new drugs and new combinations will likely come on board, so that will also change the landscape.” PAGE BREAK Making the diagnosis
The ability to accurately diagnose rheumatologic irAEs can be challenging, Calabrese said.
“This is a very heterogeneous patient population, with many patients having received chemotherapy, radiation and/or surgery prior to checkpoint inhibitor therapy, and they may have progression of their tumor at the time of evaluation,” she said. “It is important to keep other etiologies on the differential when evaluating a patient for rheumatic irAEs.”
It also is important to note that rheumatologic irAEs described thus far frequently have atypical features compared with de novo disease, Calabrese said.
“For example, they may lack characteristic autoantibodies or require higher doses of prednisone than would be expected,” she said. “Also, unlike all other irAEs to date, rheumatic manifestations appear to be the only irAE with inflammation that persists, even despite discontinuation of the checkpoint inhibitor.”
The potential that rheumatologic irAEs will persist — even for several years after checkpoint inhibitor therapy has been stopped — is a major concern for clinicians.
“We have patients who are 3 years out from receiving immune checkpoint inhibitors who continue to have issues with inflammatory arthritis,” Cappelli said.
Although strides have been made, there is still considerable room for improvement in terms of accurate and timely diagnosis, she added.
“It is still a problem for oncology and other nonrheumatology providers,” Cappelli said. “There is a knowledge gap in the range of rheumatologic irAEs like polymyalgia rheumatica, myositis, vasculitis and inflammatory arthritis.”
Musculoskeletal examination is not taught in depth in all medical training programs, Cappelli said. This makes it difficult for providers to determine if joints are swollen, warm or have a decreased range of motion when evaluating for inflammatory arthritis.
“In the area of myositis, sometimes routine labs will show an elevated aspartate aminotransferase, which can come from muscle in the setting of myositis, but clinicians may go down the path of investigating liver pathology,” she said.
Referral to a rheumatologist at the first sign of any such syndrome is essential, Suarez-Almazor said.
“Not only will a rheumatologist be able to make a diagnosis, but they will be familiar with the medications necessary to treat these patients,” she said. “We have seen that these syndromes are different from other immune-related arthritis in that they sometimes can have an insidious onset and can linger for weeks or months, even after discontinuing immunotherapy.” Treatment complications
A lack of understanding in the clinical community about the potential complications that can arise during treatment of rheumatologic irAEs compounds the challenge of caring for these patients. PAGE BREAK
“The main challenge in managing patients with rheumatologic irAEs is the lack of evidence-based medicine to guide treatment,” Cappelli said. “IrAEs are a relatively new clinical issue, and more research is needed to determine the most effective and safe treatments. The concern in treating irAEs is that immunosuppression may undermine the tumor immunologic response and have a negative impact on cancer progression.” Uma Thanarajasingam
For this reason, communication between oncologists and rheumatologists is key.
“Rheumatologists understand better than oncologists how aggressive we can be,” Uma Thanarajasingam, MD, PhD, of Mayo Clinic in Rochester, Minnesota, told HemOnc Today . “[However], any time we go beyond prednisone, we have to partner with oncologists to see how much damage we might be doing to the immune system.
“We have to understand the status of the underlying cancer and whether the patient is responding really well to checkpoint inhibitor therapy, even if they are having a great deal of arthritic pain,” Thanarajasingam added. “Sometimes we have to take a hiatus from the treatment we are using, or switch courses.”
The nature of a particular malignancy and the patient’s prognosis, as well as how immunosuppressive therapy may affect a patient, also must be taken into account, Bass said.
For example, Merkel cell carcinoma is immunologically sensitive and occurs primarily among immune-suppressed individuals. Treating immune-related adverse events experienced by a patient with this malignancy may be much riskier than doing so for a patient who has melanoma.
“You have to understand that the treatment approach for every patient and every tumor is different,” Bass said. “I would love to be able to offer concrete recommendations that always apply. The key is [for oncologists and rheumatologists] to work together … and [with] the patient to discuss risks and benefits, and to learn from each other.”
A small but growing area of research focuses on specific drug-drug interactions.
During a presentation at Congress of Clinical Rheumatology in 2018, Ami A. Shah, MD, MHS — associate professor of medicine at Johns Hopkins University School of Medicine — said current evidence indicates corticosteroids and short-term tumor necrosis factor inhibitor use may be tolerable without affecting melanoma responses to both the anti-CTLA-4 antibody ipilimumab (Yervoy, Bristol-Myers Squibb) and the PD-1 checkpoint inhibitor nivolumab (Opdivo, Bristol-Myers Squibb).
“These interactions are still quite an unknown area,” Thanarajasingam said. “We get a sense that certain combinations may have more or less toxicity than others.”
As use of these agents expands into other malignancies, the challenges likely will be compounded, Thanarajasingam said. PAGE BREAK
“Because these drugs were first approved in melanoma, the toxicities reported in that type of cancer are greatest,” she said. “As usage expands, it will be interesting to see how the toxicity profile changes. For example, lymphoma is a completely different type of cancer, and the immune cells are part of the cancer, so what are the implications for adverse events? It’s still such a new area, so it’s hard to say.” ASCO guidelines
In 2018, ASCO and National Comprehensive Cancer Network released a clinical practice guideline for management of irAEs among patients receiving checkpoint inhibitor therapy.
A multidisciplinary, multiorganizational panel of experts performed a systematic review of publications on immune checkpoint inhibitor therapy from 2000 through 2017.
The resulting guideline — published in Journal of Clinical Oncology — provided detailed recommendations for organ-specific management of several types of irAEs, including those that affect the skin, nervous system, lungs, musculoskeletal system and cardiovascular system.
“With rapidly increasing use of immune checkpoint inhibitors, it is imperative that clinicians are knowledgeable about their unique toxicity profiles,” Clifford A. Hudis, MD, FASCO, FACP, CEO of ASCO, said when the guidelines were released. “These new guidelines … will help our community continue to provide the highest quality of care to all patients as they incorporate these agents into routine care.”
General guidelines for irAEs are as follows: Grade 1 — Immune checkpoint inhibitor therapy should be continued with close monitoring for patients, with the exception of those who develop certain neurologic, hematologic or cardiac toxicities. Grade 2 — Immune checkpoint inhibition may be suspended and then resumed if symptoms revert to grade 1 or less. In these cases, corticosteroids may be administered. Grade 3 — Most cases warrant suspension of immune checkpoint inhibition and initiation of high-dose corticosteroids (prednisone or methyl-prednisolone dosed at 1 mg/kg to 2 mg/kg daily). Corticosteroids should be tapered over a minimum 4 weeks to 6 weeks. Infliximab (Remicade, Janssen) or other immunosuppressive therapy may be required for certain refractory cases. Grade 4 — Permanent discontinuation of immune checkpoint inhibitor therapy is recommended, with the exception of endocrinopathies that have been controlled by hormone replacement.
The guideline panel also issued recommendations based on specific rheumatic irAEs, such as inflammatory arthritis, myositis and polymyalgia-like syndrome.
“Despite the often-durable clinical benefits of the immune checkpoint blockade therapy, [immune checkpoint inhibitor] use is associated with a spectrum of adverse effects related to the mechanism of action that is quite different from other systemic therapies, such as cytotoxic chemotherapy,” guideline co-author Julie R. Brahmer, MD, co-director of the upper aerodigestive department within the Bloomberg Kimmel Institute for Cancer Immunotherapy and professor of oncology at Johns Hopkins, and colleagues wrote. “The adverse effects can affect multiple organs of the body … and there should be a high level of suspicion that any changes are treatment-related. PAGE BREAK
“The ability to influence immune response even after discontinuation of the immunotherapeutic agent is a unique feature and important education point for patients and their caregivers,” Brahmer and colleagues added. “As such, patients should be encouraged to alert all health care providers that they are receiving or have received an immunotherapeutic agent and to report any changes in health status to each provider.”
The take-home message of ASCO’s guideline is the need for increased awareness and importance of addressing these adverse events promptly.
“[Clinicians] need to understand that there is a place they can turn for information about these events, whether it is the guidelines or other experts who are familiar with them,” Thanarajasingam told HemOnc Today .
This increases the likelihood that basic interventions will be employed early in the course of irAEs, Bass said.
“What I have learned from caring for patients with immunotherapy-induced arthritis is that it often becomes chronic, so it is important to start early with steroid-sparing agents,” she said. Communication is key
Even with the guidelines in place, much uncertainty remains.
“At this point, there are so many more questions than answers,” Calabrese said. “We have much to learn about risk factors, biomarkers, pathogenesis and optimal treatment of rheumatic irAEs, as well as the impact that treatment for irAEs may have on cancer outcomes.”
Consequently, collaboration between oncologists and rheumatologists is essential.
“Communication is the most important thing to successfully care for patients with rheumatologic irAEs,” Cappelli said. “The oncologist and rheumatologist must reach consensus about ways to manage each patient.
“We contact the patient’s oncologist on the day of their clinic visit to us so we can confirm the plan,” she said. “It is also important for the patient to be aware of the role each physician plays in their care. Often patients ask us about plans for their cancer therapy and we need to remind them that their oncologist will guide their cancer treatment and we will manage their side effects, in collaboration with their oncologist.”
A cautious approach is appropriate, Calabrese said.
“If there are symptoms of grade 2 or higher based on [Common Terminology Criteria for Adverse Events] grading, they should be referred to a rheumatologist,” she said. “Long-term management of these patients requires multidisciplinary care that addresses the patients’ rheumatic manifestations while at the same time treating their cancer.”
The multidisciplinary care may need to extend beyond oncologists and rheumatologists, Suarez-Almazor said.
“We need to promptly recognize when others need to be involved — for instance cardiologists when suspecting myocarditis,” she said. “The benefits and harms of therapies need to be understood quickly, along with how the various therapies are interacting with each other.” PAGE BREAK
Despite the challenges associated with diagnosing and treating rheumatologic irAEs, many in the field consider it an opportunity to improve the knowledge base and ultimately improve outcomes.
“We have to take every opportunity to learn, because we are going to see more and more of these patients,” Bass said. “It is critical that we have people who understand and can manage these patients and the problems they confront.
“In most cases of rheumatoid arthritis, the development of antibodies to disease onset can usually be 3 to 5 years,” she added. “[Among patients who receive immunotherapy], we are seeing arthritis develop within 3 to 4 months of starting treatment. This means we can study this disease and biomarkers over a shorter period of time, and they will likely teach us something about rheumatic diseases that we see in other contexts.”
It also is important for members of the oncology care team to have mechanisms in place to identify and manage these rapidly developing conditions, Suarez-Almazor said.
“Many of these are patients who cannot wait to be seen by a rheumatologist for weeks or months, as decisions about their cancer treatment are critical,” she said. – by Rob Volansky References:
Brahmer JR, et al. J Clin Oncol . 2018;doi:10.1200/JCO.2017.77.6385.
Cappelli LC, et al. Arthritis Care Res . 2018;doi:10.1002/acr.23177.
Johnson DH, et al. J Immunother Cancer . 2018;doi:10.1186/s40425-018-0412-0.
Kapiteijn E. Abstract SP0097. Presented at: EULAR Annual Congress; June 13-16, 2018; Amsterdam.
Moseley KF, et al. J Immunother Cancer . 2018;doi:10.1186/s40425-018-0417-8.
Richter MD, et al. Arthritis Rheumatol . 2018;doi:10.1002/art.40745.
Shah A. Cancer, immunotherapy and autoimmune syndromes: Rheumatic consequences of checkpoint inhibitors; Presented at: Congress of Clinical Rheumatology; May 17-20, 2018; Destin, Fla. For more information:
Anne R. Bass, MD, can be reached at Hospital for Special Surgery, 535 E. 70th St., New York, NY 10021; email: .
Cassandra Calabrese, DO, can be reached at Cleveland Clinic, 9500 Euclid Ave., Desk A50, Cleveland, OH 44195; email: .
Laura C. Cappelli, MD, MHS, can be reached at Johns Hopkins Medicine, 5501 Hopkins Bayview Circle, Suite 1B1, Baltimore, MD 21224; email: .
Maria E. Suarez-Almazor, MD, PhD, can be reached at The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd. #437, Houston, TX 77030; email: .
Uma Thanarajasingam, MD, PhD, can be reached at Mayo Clinic, 200 First St. SW, Rochester, MN 55905; email: . Disclosures: Cappelli reports research funding from Bristol-Myers Squibb, as well as consultant roles with Regeneron and Sanofi. Bass, Calabrese, Suarez-Almazor and Thanarajasingam report no relevant financial disclosures. Read Next

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