PAP programs breathe life into asthma/COPD care

PAPs Breathe Life Into Asthma/COPD Care

Patients with asthma and chronic obstructive pulmonary disease (COPD) who are enrolled in patient assistance programs (PAPs) for long-term medications are less likely to be hospitalized or visit the emergency department (ED), according to a study by Georgia pharmacists.

Looking at records from 56 patients with COPD or asthma at Piedmont Athens Regional Medical Center who obtained medication through a PAP from January 2018 through March 2019, researchers found that the number of cumulative ED visits decreased from 54 in the six months before PAP enrollment to seven in the six months after enrollment. Cumulative hospitalizations during the same time frame dropped from 13 to zero.

“Having access to the medication was a huge contributor” to the results, said lead author Brooke Gallman, PharmD, a PGY-1 resident at the 360-bed nonprofit hospital and referral center. “Most of these patients were not able to afford inhalers prior to enrolling in the program, so they were having a lot of exacerbations. Every hospital encounter that I included in this study was related to a COPD or asthma visit,” she said.

A lot of these patients were set up with primary care during the study period, which could be another factor contributing to the positive findings, she added.

The median amount billed per patient decreased from $4,683 before PAP enrollment to $0 (P<0.001), and the median hospital acquisition cost per person dropped

SMOFLIPID (lipid injectable emulsion), for intravenous use aluminum at greater than 4 to 5 mcg/kg/day can accumulate aluminum to levels BRIEF SUMMARY OF PRESCRIBING INFORMATION associated with central nervous system and bone toxicity. Tissue loading may occur at even lower rates of administration of PN products. This brief summary does not include all the information needed to use • Risk of Parenteral Nutrition-Associated Liver Disease (PNALD): PNALD has been SMOFlipid safely and effectively. Please see full prescribing information, reported in patients who receive PN for extended periods of time, especially including Boxed Warning for Smoflipid (lipid injectable emulsion), for preterm infants, and can present as cholestasis or steatohepatitis. The exact intravenous use at www.freseniuskabinutrition.com/products/smoflipid. etiology is unknown and is likely multifactorial. Intravenously administered phytosterols (plant sterols) contained in plant-derived lipid formulations have been associated with development of PNALD, although a causal relationship >(9505.!+,(;/0579,;,9405-(5;: has not been established. If SMOFlipid-treated patients develop liver test abnormalities, consider discontinuation or dose reduction. ‹+LH[OZPUWYL[LYTPUMHU[ZHM[LYPUM\ZPVUVMPU[YH]LUV\ZSPWPKLT\SZPVUZ • Hypertriglyceridemia: Impaired lipid metabolism with hypertriglyceridemia may

OH]LILLUYLWVY[LKPU[OLTLKPJHSSP[LYH[\YL occur in conditions such as inherited lipid disorders, obesity, diabetes mellitus, ‹(\[VWZ`ÄUKPUNZPUJS\KLKPU[YH]HZJ\SHYMH[HJJ\T\SH[PVUPU[OLS\UNZ and metabolic syndrome. ‹7YL[LYTPUMHU[ZHUKSV^IPY[O^LPNO[PUMHU[ZOH]LWVVYJSLHYHUJLVM • Monitoring/Laboratory Tests: Routinely monitor serum triglycerides, fluid

PU[YH]LUV\ZSPWPKLT\SZPVUHUKPUJYLHZLKMYLLMH[[`HJPKWSHZTHSL]LSZ and electrolyte status, blood glucose, liver and kidney function, blood count

MVSSV^PUNSPWPKLT\SZPVUPUM\ZPVU including platelets, and coagulation parameters throughout treatment. Monitoring patients for signs and symptoms of essential fatty acid deficiency INDICATIONS AND USAGE (EFAD) is recommended. SMOFlipid is indicated in adults as a source of calories and essential fatty acids for • Interference with Laboratory Tests: Content of vitamin K may counteract Piedmont Athens PAP Successes: parenteral nutrition (PN) when oral or enteral nutrition is not possible, insufficient, or contraindicated. Limitations of Use: The omega-6: omega-3 fatty acid ratio and Medium Chain Triglycerides in anticoagulant activity. The lipids contained in this emulsion may interfere with some laboratory blood tests (e.g., hemoglobin, lactate dehydrogenase [LDH], bilirubin, and oxygen saturation) if blood is sampled before lipids have cleared from the bloodstream. SMOFlipid have not been shown to improve clinical outcomes compared to other ADVERSE REACTIONS intravenous lipid emulsions. Cumulative ED visits decreased Most common adverse drug reactions >1% of patients who received SMOFlipid DOSAGE AND ADMINISTRATION from 54 to seven from clinical trials were nausea, vomiting, hyperglycemia, flatulence, pyrexia, Cumulative hospitalizations The recommended daily dosage in adults is 1 to 2 grams/kg per day and should not exceed 2.5 grams/kg per day. SMOFlipid 1000 mL is supplied as a Pharmacy Bulk abdominal pain, increased blood triglycerides, hypertension, sepsis, dyspepsia, urinary tract infection, anemia and device-related infection. dropped from 13 to zero Package for admixing only and is not for direct infusion. Prior to administration, Less common adverse reactions in ) 1% of patients who received SMOFlipid were transfer to a separate PN container. dyspnea, leukocytosis, diarrhea, pneumonia, cholestasis, dysgeusia, increased Median amount billed per patient decreased from $4,683 to $0 CONTRAINDICATIONS Known hypersensitivity to fish, egg, soybean, or peanut protein, or to any of the blood alkaline phosphatase, increased gamma-glutamyltransferase, increased C-reactive protein, tachycardia, liver function test abnormalities, headache, pruritis, dizziness, rash and thrombophlebitis. active ingredients or excipients. Median hospital acquisition cost per person dropped from $351 to $0 Severe hyperlipidemia or severe disorders of lipid metabolism with serum triglycerides > 1,000 mg/dL. The following adverse reactions have been identified during post-approval use of SMOFlipid in countries where it is registered. Infections and Infestations: infection. Respiratory, Thoracic and Mediastinal Disorders: dyspnea.

WARNINGS AND PRECAUTIONS

• Death in Preterm Infants: (see BLACK BOX WARNING) To report SUSPECTED ADVERSE REACTIONS, contact Fresenius Kabi USA, LLC, at 1-800-551-7176, option 5, or FDA at 1-800-FDA-1088 or • Hypersensitivity Reactions: SMOFlipid contains soybean oil, fish oil, and egg www.fda.gov/medwatch. phospholipids, which may cause hypersensitivity reactions. Cross reactions have been observed between soybean and peanut oil. Signs or symptoms DRUG INTERACTIONS of a hypersensitivity reaction may include: tachypnea, dyspnea, hypoxia, Coumarin and Coumarin Derivatives, Including Warfarin: Anticoagulant activity bronchospasm, tachycardia, hypotension, cyanosis, vomiting, nausea, headache, may be counteracted; monitor laboratory parameters. sweating, dizziness, altered mentation, flushing, rash, urticaria, erythema, pyrexia, or chills. If a hypersensitivity reaction occurs, stop infusion of SMOFlipid immediately and undertake appropriate treatment and supportive measures. USE IN SPECIFIC POPULATIONS • Pregnancy and Lactation: There are no available data on risks associated with SMOFlipid when used in pregnant or lactating women. • Risk of Catheter-Related Infections: Lipid emulsions, such as SMOFlipid, can support microbial growth and is an independent risk factor for the development of catheter-related bloodstream infections. The risk of infection is increased in • Pediatric Use: The safety and effectiveness of SMOFlipid have not been established in pediatric patients. patients with malnutrition-associated immunosuppression, long-term use and • Hepatic Impairment: Parenteral nutrition should be used with caution in patients poor maintenance of intravenous catheters, or immunosuppressive effects of with hepatic impairment. Hepatobiliary disorders are known to develop in some other concomitant conditions or drugs. patients without preexisting liver disease who receive PN, including cholestasis, • Fat Overload Syndrome: This is a rare condition that has been reported with intravenous lipid emulsions. A reduced or limited ability to metabolize lipids hepatic steatosis, fibrosis and cirrhosis (PN associated liver disease), possibly leading to hepatic failure. accompanied by prolonged plasma clearance may result in a syndrome OVERDOSE characterized by a sudden deterioration in the patient’s condition including fever, In the event of an overdose, fat overload syndrome may occur. Stop the SMOFlipid anemia, leukopenia, thrombocytopenia, coagulation disorders, hyperlipidemia, infusion until triglyceride levels have normalized. The effects are usually reversible fatty liver infiltration (hepatomegaly), deteriorating liver function, and central by stopping the lipid infusion. If medically appropriate, further intervention may be nervous system manifestations (e.g., coma). indicated. Lipids are not dialyzable from serum. • Refeeding Syndrome: Reintroducing calories and protein to severely undernourished patients with PN may result in the refeeding syndrome, characterized by the intracellular shift of potassium, phosphorus, and magnesium as the patient becomes anabolic. Thiamine deficiency and fluid retention may also develop. • Aluminum Toxicity: SMOFlipid contains no more than 25 mcg/L of aluminum.

During prolonged PN administration in patients with renal impairment, the 9,-,9,5*,:!  Vanek VW, et al. A.S.P.E.N. position paper: Clinical role for alternative intravenous aluminum levels in the patient may reach toxic levels. Preterm infants are at fat emulsions. Nutr Clin Pract. 2012;27(2):150-192.  Deckelbaum RJ, et al. Medium-chain versus greater risk because their kidneys are immature, and they require large amounts long-chain triacylglycerol emulsion hydrolysis by lipoprotein lipase and hepatic lipase: implications for of calcium and phosphate solutions, which contain aluminum. Patients with the mechanisms of lipase action. Biochemistry (Mosc). 1990;29(5):1136-1142. renal impairment, including preterm infants, who receive parenteral intakes of

Piedmont Athens PAP Successes:

Cumulative ED visits decreased from 54 to seven

Cumulative hospitalizations dropped from 13 to zero

Median amount billed per patient decreased from $4,683 to $0

Median hospital acquisition cost per person dropped from $351 to $0

from $351 to $0 (P=0.002), according to the study (No. 5) presented at the American College of Clinical Pharmacy’s 2020 virtual poster symposium.

“I knew there was a benefit for the patient; however, I wasn’t expecting to see that much of a monetary decrease as well as seeing ED visits decrease by almost 90% in these patients,” said Dr. Gallman, who added that a pharmacy buyer who is a certified pharmacy technician helps enroll patients in the PAP. “We were really happy with our results, and we think that it justifies continuing this program.”

Some Caveats

It would have been helpful to see patient medication compliance information before and after participation in the program to confirm the validity of the conclusions and learn whether the PAP provided medications or coupons, commented Mark Malesker, PharmD, a professor of pharmacy practice at Creighton University, in Omaha, Neb., who works with pulmonary critical care patients. He noted that it’s also unusual to put asthma and COPD patients together in one study, he said, because those populations tend to have different demographics. —Karen Blum

Immunotherapy Toxicities: Early Recognition, Management, And Concerns in the COVID-19 Pandemic

SAMANTHA SPENCER, PHARMD, BCPS

Clinical Assistant Professor University of Illinois at Chicago Drug Information Group Chicago, Illinois

mmune checkpoint inhibitors and adoptive cell transfer therapies have unlocked new avenues to treat cancer, but they are associated with immune-related adverse events (irAEs). Pharmacists can play an integral role in managing these irAEs and educating patients and other health care professionals about them.

The immune system recognizes tumors and eradicates cancerous cells through T cells and natural killer cells, 1 but to ensure that T cells do not autoreact to normal cells, the body has mechanisms that downregulate their activity as needed. 2 Checkpoint pathways regulate T cells to prevent autoimmunity through a process called peripheral tolerance. To evade detection by T cells, cancer cells hijack this mechanism. Checkpoint inhibitors enable the immune system to better recognize and eliminate cancerous cells that are evading the immune system this way. 2

Several checkpoint pathways regulate T cells, including the cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) and programmed death-1 (PD-1) pathways. 2 The CTLA pathway regulates the early stages of T-cell activation, and most expression is found in lymphoid tissue. In contrast, PD-1 regulates previously activated T cells in the later stages of the immune system response and is found mostly in peripheral tissues. Inhibition of CTLA-4 and PD-1—or its ligand, programmed death ligand-1 (PD-L1)— restores the immune system’s ability to respond to tumors. These pathways have been successfully targeted and have led to the approval of several checkpoint inhibitors (Table 1). 3-12

Adoptive cell transfer therapy is another approach that has been developed to increase the immune system’s ability to target tumors. 1 Specifically, in chimeric antigen receptor (CAR) T-cell therapy, T cells are harvested from a patient, genetically modified to express CARs, multiplied, and reinfused into the patient. Three such therapies are approved by the FDA: axicabtagene ciloleucel ( Yescarta, Kite) tisagenlecleucel ( Kymriah, Novartis), and brexucabtagene autoleucel ( Tecartus, Kite) (Table 1). All express a CAR with an anti-CD19 chain, which allows the modified T cells to recognize and eliminate CD19-expressing cells. 3,4,12

Checkpoint Inhibitors

Immune-Related Adverse Events

Due to their novel mechanism of action, checkpoint inhibitors are not associated with the traditional AEs seen with cytotoxic chemotherapy. 13 However, inhibition of CTLA-4, PD-1, and PD-L1 can lead to excessive immune system activation with upregulation of T-cell proinflammatory responses. 13-15 This activation of the immune system can result in irAEs. The exact mechanism of irAEs has not been elucidated fully, but it is hypothesized that T-cell activity, autoantibodies, and proinflammatory cytokines may contribute to their development. Dermatologic, gastrointestinal, endocrine, and pulmonary-related irAEs are the most common irAEs, but they can manifest in any organ system.

The CTLA-4 inhibitor ipilimumab ( Yervoy, Bristol-Myers Squibb) is associated with the highest rates of irAEs; 75% of patients will experience an irAE and one-fourth will have a high-grade irAE. 13,15 Dermatologic and gastrointestinal events have been reported most commonly. 13 Phase 3 trials of the PD-1/PD-L1 inhibitors reported lower rates, with no more than 30% of patients experiencing an irAE. 13,15 In patients receiving combination checkpoint inhibitor therapy (ie, nivolumab [Opdivo, Bristol-Myers Squibb] with ipilimumab), almost all experience an irAE (96%) and over half (59%) develop a high-grade irAE. The rates of irAEs also vary based on the underlying cancer, and for ipilimumab and pembrolizumab (Keytruda, Merck) the toxicity is dose dependent. Most irAEs experienced by patients receiving checkpoint inhibitors are mild to moderate, but severe events, including fatal ones, can occur with these agents.

Rash and pruritus are the most common dermatologic irAEs, and they typically present as a lowgrade reaction. 13 Dermatologic toxicities occur in approximately 30% to 40% of patients receiving PD-1/PD-L1 inhibitors and 50% of those receiving ipilimumab. 15 Patients with melanoma have been observed to experience more dermatologic irAEs than patients with other underlying cancers. 16 Diarrhea is another frequent irAE, with ipilimumab associated with the highest rates of occurrence (23%-41%). Additionally, colitis occurs in 7% to 16% of patients receiving ipilimumab and in 1% to 3% of patients receiving PD-1/PD-L1 inhibitors. Endocrine irAEs occur less frequently, but hypothyroidism,

hyperthyroidism, and hypophysitis have been reported most frequently among the endocrinopathies. Pneumonitis is rare (<1% with ipilimumab; 1%-3% with PD-1/PD-L1 inhibitors) but can lead to serious consequences. A number of additional irAEs have been reported, but many occur at a much lower incidence. The average onset of these irAEs varies, with dermatologic reactions presenting within 2 to 3 weeks and gastrointestinal, hepatic, and endocrine toxicities occurring after 2 to 3 months of therapy. 14,16 However, the range for onset is broad, with some irAEs taking up to 2 years to appear, 16 and they sometimes occur weeks or months after discontinuation of the medication. 14

Management of irAEs

Patients increasingly are presenting with irAEs outside of the oncology space. 14 Recognition of irAEs generally begins with a detailed medication history, including past medications because irAEs can occur even after discontinuation of a checkpoint inhibitor. A recent study reported that diarrhea was the most common irAE that led to patient presentation in an emergency department (ED). 17 Other irAEs frequently observed in the ED included colitis, pneumonitis, dermatitis, hypophysitis, and hepatitis.

Mild irAEs typically can be managed while the patient continues checkpoint inhibitor therapy, with a few exceptions. 13,17 More severe toxicities generally require discontinuation of therapy.

Corticosteroids are a cornerstone of irAE management and are recommended in the treatment of most reactions. 13,16 Thyroid-related irAEs are a notable exception; clinicians do not use corticosteroids as part of the management of thyroid-related irAEs, except in cases of severe hyperthyroidism that may progress to thyroid storm. 18 Guidance on steroid dosing can be found in clinical guidelines and the prescribing information for individual drugs. 5-13,18 Generally, higher corticosteroid doses are reserved for moderate and severe irAEs. 13 Additionally, the decision to use corticosteroids must consider patient-specific factors, such as

IMMUNOTHERAPY

continued from page 17

comorbid conditions, type and number of irAEs, concurrent immunosuppressive therapies, and the ability to tolerate corticosteroids.

Specific guidance on irAE management can be found in practice guidelines by the American Society of Clinical Oncology (ASCO) and National Comprehensive Cancer Network. 13,18 The ASCO guideline has detailed information about the grading and management of irAEs. 18 A few examples outlining the recognition and management of irAEs are presented in Table 2. 13,18 For high-grade toxicities, more aggressive management is needed and should be provided in conjunction with a specialist referral. 13,18

IrAEs Considerations With COVID-19

The novel 2019 coronavirus disease (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has introduced potential complications in patients with cancer. Particularly relevant to checkpoint inhibitor therapy is the overlap of symptoms of COVID-19 with immunerelated pneumonitis. 19 Appropriate recognition of symptoms is imperative to ensure patients receive optimal treatment. While the clinical presentation of COVID-19 still is being characterized, the most common symptoms are fever, cough, and dyspnea. 20 With pneumonitis, dyspnea and cough are common, with fever occurring less frequently. 19,21 Given these overlapping symptoms, it is critical for patients taking checkpoint inhibitors to quickly recognize and contact their health care provider about any of these core symptoms. COVID-19 testing and radiological findings can aid in the differential diagnosis to quickly determine the appropriate course of therapy and whether corticosteroids, which have a controversial role in COVID-19 treatment outside of severe cases, should be initiated.

CAR T-Cell Therapy

Cytokine Release Syndrome

Axicabtagene ciloleucel, brexucabtagene autoleucel, and tisagenlecleucel contain boxed warnings in their prescribing information and are only available through a Risk Evaluation and Mitigation Strategies (REMS) program to moderate the risks of therapy, including cytokine release syndrome (CRS). 3,4,22,23 Infusion of CAR T cells leads to a state of increased circulating proinflammatory cytokines coupled with suppression of anti-inflammatory cytokines. 1,24 This imbalance causes CRS and, specifically, the activation of interleukin (IL)-6 contributes to capillary leak syndrome. CRS presents as fever, myalgias, and malaise that can progress to potentially fatal or life-threatening manifestations, including hypoxia, pulmonary edema, hemodynamic instability, renal and/or hepatic dysfunction, and hemophagocytic lymphohistiocytosis/macrophage activation syndrome. 1,13

Almost all patients receiving axicabtagene ciloleucel (94%) had CRS (any grade) in its clinical trial. 3 Any grade of CRS was reported in 79% and 74% of patients receiving tisagenlecleucel for relapsed/refractory acute lymphoblastic leukemia and relapsed/refractory diffuse large B-cell lymphoma in clinical trials,

Table 1. FDA-Approved Immunotherapies

Class Drug

Checkpoint inhibitors

CTLA-4 inhibitor Ipilimumab (Yervoy, BristolMyers Squibb)

PD-1 inhibitor Cemiplimab (Libtayo, Regeneron)

Nivolumab (Opdivo, BristolMyers Squibb)

Pembrolizumab (Keytruda, Merck)

PD-L1 inhibitor Atezolizumab (Tecentriq, Genentech)

Avelumab (Bavencio, EMD Serono)

Durvalumab (Imfinzi, AstraZeneca)

Initial Approval Date Current FDA Indications a

2011 • CRC, metastatic or metastatic MSI-H • HCC • Melanoma • Metastatic NSCLC • RCC, advanced

2018 • Cutaneous SCC, metastatic or locally advanced

2014 • Classic Hodgkin lymphoma, relapsed • CRC, metastatic MSI-H • Esophageal SCC • HCC • HNSCC, recurrent or metastatic • Melanoma • NSCLC, metastatic • RCC, advanced • SCLC, metastatic • UCC, recurrent or metastatic

2014 • Cervical cancer, recurrent or metastatic • Classic Hodgkin lymphoma, refractory • CRC, MSI-H • Cutaneous SCC • Endometrial carcinoma, advanced • Esophageal cancer, recurrent or metastatic • Gastric cancer, recurrent or metastatic • HCC • HNSCC • Melanoma • Merkel cell carcinoma, recurrent or metastatic • MSI-H cancers, unresectable or metastatic • NSCLC • PMBCL, refractory • RCC, advanced • SCLC, metastatic • TMB-H solid tumors, unresectable or metastatic • UCC

2016 • Breast cancer, triple-negative • HCC, unresectable or metastatic • Melanoma • SCLC, extensive-stage • NSCLC, metastatic • UCC, locally advanced or metastatic

2017 • Merkel cell carcinoma, advanced • RCC, advanced • UCC, locally advanced or metastatic

2017 • NSCLC, unresectable stage III • SCLC, extensive-stage • UCC, advanced or metastatic

CAR T-cell therapy

CD-19 T-cell immunotherapy Axicabtagene ciloleucel (Yescarta, Kite) 2017 • B-cell lymphoma, relapsed or refractory

Brexucabtagene autoleucel 2020 • Mantle cell lymphoma, relapsed or refractory

Tisagenlecleucel (Kymriah, Novartis) 2017 • B-cell ALL, relapsed or refractory • Large B-cell lymphoma, relapsed or refractory

a As of August 3, 2020; see prescribing information for details on the specific place in therapy within these indications.

ALL, acute lymphoblastic leukemia; CAR, chimeric antigen receptor; CRC, colorectal cancer; HCC, hepatocellular carcinoma; HNSCC, head and neck squamous cell carcinoma; MSI-H, microsatellite instability-high; NSCLC, non-small cell lung cancer; PMBCL, primary mediastinal B-cell lymphoma; RCC, renal cell carcinoma; SCC, cutaneous squamous cell carcinoma; SCLC, small cell lung cancer, TMB-H, tumor mutational burden-high; UCC, urothelial carcinoma Based on references 3-12.

IMMUNOTHERAPY

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respectively. 4 Most often, CRS presents within 2 to 3 days after CAR T-cell infusion and persists for approximately a week. 13 However, patients should be monitored for signs and symptoms of CRS for 4 weeks after CAR T-cell therapy. 22,23

Management of CRS

Management of CRS is critically dependent on early recognition of symptoms to reduce the risk for a fatal outcome. 1 The IL-6 receptor antagonist tocilizumab (Actemra, Genentech) is an important component in treating CRS. 25 In an analysis of clinical trials for axicabtagene ciloleucel and tisagenlecleucel, 53% to 69% of patients with severe or life-threatening CRS resolved their fever and need for vasopressors within 14 days after 1 or 2 doses of tocilizumab. 26

For patients presenting with a fever not attributable to another cause, symptomatic management and administration of empirical antibiotics is appropriate. 13 For prolonged (>3 days) or higher-grade CRS (grade 2 or higher), tocilizumab is recommended. The dosing is 8 mg/kg (maximum, 800 mg) given via IV infusion over 1 hour. 13,25 For patients weighing less than 30 kg, a dose of 12 mg/kg should be used instead. 25 Tocilizumab can be repeated as needed every 8 hours, with a maximum of 3 doses in 24 hours or 4 doses overall. For grades 3 and 4, IV corticosteroids should be given with tocilizumab therapy. 13 Vasopressors and other therapies to manage hypotension and hypoxia also should be used when needed.

The Pharmacist’s Role

Pharmacists are in a unique position to educate providers and patients about potential AEs, recognition of symptoms, and management of immunotherapy toxicities. 27 Early recognition and management of irAEs is critical for patients. Patient education for checkpoint inhibitors should focus on potential signs and symptoms and encourage patients to report any concerning symptoms quickly. 28 Patterns of irAE incidence, including the type of irAE, prescribed checkpoint inhibitor, and underlying risk factors, should be considered. 27

In addition, as corticosteroids are a foundation of treatment, pharmacists can assist in initial prescribing and tapering strategies. Tapers should last at least 4 weeks but should be individualized, as patients with corticosteroid-refractory disease may require a longer taper (6-12 weeks). 27 There is no universal recommended tapering strategy, but the length of the taper is dependent on the severity and type of irAE. 29 During any tapering strategy, close monitoring is warranted because the irAE can rebound. In addition, to help mitigate the risk

Table 2. Management of Selected Low-Grade Immune-Related AEs

Toxicity Signs and Symptoms Other Considerations Management

Rash • Erythematous or maculopapular rash, frequently affecting the upper trunk • Pruritus • Vitiligo • Blistering, skin sloughing, and severe cutaneous irAEs (SJS, TENS) are treated more aggressively • Typically presents during the first 2 treatment cycles • Ipilimumab is associated with higher rates of dermatologic irAEs compared with

PD-1/PD-L1 inhibitors • Continue ICPi for grades 1 and 2; hold with higher grades • Topical emollients, topical corticosteroids, and oral antihistamines • For more moderate symptoms, higher potency topical corticosteroids may be needed • Consider initiating oral corticosteroids for moderate symptoms (prednisone 0.5-1 mg/kg/day until back to grade 1, then taper over 4-6 wk)

Diarrhea/ colitis • Watery diarrhea • Increase in stool count • Blood or mucus in stool • Abdominal pain, cramping • Typically presents 6 to 8 weeks after starting treatment • Ipilimumab is associated with higher rates of gastrointestinal irAEs compared with

PD-1/PD-L1 inhibitors • Consider holding ICPi with grade 1; hold with higher grades • Oral hydration and dietary changes • Loperamide for 2-3 d • Consider initiating oral corticosteroids for grade 2 (prednisone 1-2 mg/kg/day until back to grade 1, then taper over 4-6 wk)

Pneumonitis • Dyspnea, cough • Chest pain • Difficulty with breathing (grade 1 – asymptomatic) • Median time to onset is 2.5 months; earlier onset with combination therapy • PD-1/PD-L1 inhibitors are associated with higher rates of pulmonary irAEs compared with ipilimumab • Hold ICPi with evidence of pneumonitis progression • For grade 2, oral corticosteroids (prednisone 1-2 mg/kg/day, then taper over 4-6 wk) • Consider empirical antibiotics for corticosteroid AEs, gastrointestinal bleeding prophylaxis and Pneumocystis jirovecii prophylaxis should be considered. 15 For CAR T-cell therapies, detailed information on the management of CRS can be found in the REMS programs for axicabtagene ciloleucel, brexucabtagene autoleucel, and tisagenlecleucel. 22,23 Of note, hospitals that

Table 3. Key Education Points for Pharmacists

Pearls on Use of Corticosteroids for irAEs

• Prednisone is recommended if a patient can tolerate oral therapy; otherwise, IV methylprednisolone can be used. • Short-term use does not affect the antitumor efficacy of the checkpoint inhibitors. • Patients should expect some response within 48 to 72 hours of initiation; dose increases or additional immunosuppressive agents may be required if there is no initial response. • Once symptoms improve to a mild level (ie, grade 1), corticosteroids are tapered off over 4 to 6 weeks. • Consider prescribing a PPI for gastrointestinal prophylaxis during corticosteroid therapy. • For long-term immunosuppression (>30 mg prednisone for more than 3 weeks), consider PCP prophylaxis. • Monitor for AEs associated with corticosteroid therapy (eg, hyperglycemia, edema, anxiety, iatrogenic adrenal insufficiency).

Pearls on Use of Tocilizumab for CRS

• Tocilizumab is approved only for CAR

T-cell–induced CRS, not CRS mediated by other factors. • Hospitals and clinics that prescribe

CAR T-cell therapies must be certified through REMS programs and have immediate, on-site access to tocilizumab. • For CRS, tocilizumab should be administered as an IV infusion only. • Consider storing tocilizumab vials in a separate location from prefilled syringes that are intended for subcutaneous administration to reduce the risk for dispensing errors. • Through inhibition of IL-6, tocilizumab can induce cytochrome P450 activities, which can persist for several weeks after a dose; therefore, concomitant medications should be reviewed for potential monitoring or dose adjustments. • Patients with concomitant neurologic toxicity also will need corticosteroids, since tocilizumab has limited efficacy in treating neurologic symptoms.

AEs, adverse events; CAR, chimeric antigen receptor; CRS, cytokine release syndrome; IL-6, interleukin-6; PCP, Pneumocystis jirovecii prophylaxis; PPI, proton pump inhibitor; REMS, risk evaluation and mitigation strategies Based on references 1, 3, 4, 13, 15, 18, 25, and 30.

treat patients with CAR T-cell therapies must have 2 vials of tocilizumab on hand as part of the REMS program. Table 3 contains some key educational pearls for pharmacists about the use of corticosteroids and tocilizumab for irAE management. 1,3,4,13,15,18,25,30

In the setting of the COVID-19 pandemic, additional challenges have arisen in balancing the risks and benefits of starting or continuing immunotherapeutic agents in cancer patients. 21,31 Delivery of these agents requires contact with the health care system, and it is not known whether receipt of these agents affects the risk for contracting COVID-19 or its clinical course. For example, with FDA approval, extended-interval dosing strategies for checkpoint inhibitors (eg, pembrolizumab every 6 week administration) may be considered to limit patient exposure to health care environments. 32 For CAR T- cell therapies, it may be prudent to delay treatment if resources such as hospital and ICU capacity and tocilizumab availability are strained. 31 However, delaying treatment may not be realistic for many patients who need these therapies. 21,33 Treatment decisions should be Individualized and consider indications and therapy goals. It is important to keep patients who are starting or continuing treatment informed of potential risks and the need to promptly report any symptoms of cough, fever, or dyspnea.

Use of telemedicine also may help minimize exposure. 34 Regulations for telemedicine have been relaxed through federal packages, notably the Coronavirus Aid, Relief, and Economic Security (CARES) Act that expanded Medicare telehealth coverage. Several private payors also have expanded coverage of telemedicine as well. Given these expansions, pharmacists can contribute by encouraging telemedicine when appropriate and following up with patients to ensure that they have the knowledge and resources needed to navigate their health care during this pandemic.

Conclusion

The use of immunotherapeutic agents has increased dramatically over the past few years with the approval of additional agents and expansion of indications. 14 Thus, it is likely that more health care providers, including those in emergency medicine, will encounter patients with irAEs. Ultimately, timely recognition of irAEs and CRS is critical in managing the potential toxicities of immune checkpoint inhibitors and CAR T-cell therapies, respectively. 35 Patients should be educated to promptly report any symptoms of cough, fever, and dyspnea during the COVID-19 pandemic in particular. Early identification and prompt management reduce patient morbidity and mortality. The complexities of cancer treatment with immunotherapies make a multidisciplinary approach increasingly important, with pharmacists playing an integral role in optimizing the management of patients treated with these agents.

References

1. Dushenkov A, Jungsuwadee P. Chimeric antigen receptor T-cell therapy: foundational science and clinical knowledge for pharmacy practice. J Oncol Pharm Pract. 2019;25(5):1217-1225. 2. Buchbinder EI, Desai A. CTLA-4 and PD-1 pathways: similarities, differences, and implications of their inhibition. Am J Clin

Oncol. 2016;39(1):98-106. 3. Yescarta [package insert]. El Segundo, CA:

Kite Pharma Inc; 2020. 4. Kymriah [package insert]. East Hanover, NJ:

Novartis Pharmaceuticals Corp; 2018. 5. Yervoy [package insert]. Princeton, NJ:

Bristol-Myers Squibb Co; 2020. 6. Libtayo [package insert]. Regeneron

Pharmaceuticals Inc; 2020. 7. Opdivo [package insert]. Princeton, NJ:

Bristol-Myers Squibb Co; 2020. 8. Keytruda [package insert]. Whitehouse

Station, NJ: Merck Sharpe & Dohme Corp; 2020. 9. Tecentriq [package insert]. South San

Francisco, CA: Genentech Inc; 2020. 10. Bavencio [package insert]. Rockland, MD:

EMB Serono Inc; 2020. 11. Imfi nzi [package insert]. Wilmington, DE:

AstraZeneca Pharmaceuticals; 2020. 12. Tecartus [package insert]. Santa Monica, CA:

Kite Pharma Inc; 2020. 13. Management of immunotherapy-related toxicities. Version 2.2019. National

Comprehensive Cancer Network website. www.nccn.org/professionals/physician_gls/ pdf/immunotherapy.pdf. Updated December 16, 2019. Accessed August 3, 2020. 14. Hryniewicki AT, Wang C, Shatsky RA, et al.

Management of immune checkpoint inhibitor toxicities: a review and clinical guideline for emergency physicians. J Emerg Med. 2018;55(4):489-502. 15. Puzanov I, Diab A, Abdallah K, et al. Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group.

J Immunother Cancer. 2017;5(1):95. 16. Davies M, Duffi eld EA. Safety of checkpoint inhibitors for cancer treatment: strategies for patient monitoring and management of immune-mediated adverse events.

Immunotargets Ther. 2017;6:51-71. 17. El Majzoub I, Qdaisat A, Thein KZ, et al.

Adverse effects of immune checkpoint therapy in cancer patients visiting the emergency department of a comprehensive cancer center. Ann Emerg Med. 2019;73(1):79-87. 18. Brahmer JR, Lacchetti C, Schneider BJ, et al. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American

Society of Clinical Oncology clinical practice guideline. J Clin Oncol. 2018;36(17):1714-1768. 19. Russano M, Citarella F, Napolitano A, et al. COVID-19 pneumonia and immunerelated pneumonitis: critical issues on differential diagnosis, potential interactions, and management. Expert Opin Biol Ther. 2020;1-5. doi: 10.1080/14712598.2020.1789097 20. Burke RM, Killerby ME, Newton S, et al.

Symptom profi les of a convenience sample of patients with COVID-19 — United States,

January–April 2020. MMWR Morb Mortal

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COVID-19: current concern in cancer treatment. J Immunother Cancer. 2020;8(2):e000952. 22. FDA. Approved risk evaluation and mitigation strategies. Yescarta (axicabtagen ciloleucel) ) and Tecartus (brexucabtagene autoleucel). www.accessdata.fda.gov/Scripts/Cder/

Rems/index.cfm?event=IndvRemsDetails. page&REMS=375. Updated July 24, 2020.

Accessed August 3, 2020. 23. Novartis. Kymriah (tisagenlecleucel) suspension for IV infusion. Risk evaluation and mitigation strategy (REMS): cytokine release syndrome and neurological toxicities. www. accessdata.fda.gov/drugsatfda_docs/rems/

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Francisco, CA: Genentech Inc; 2020. 26. Le RQ, Li L, Yuan W, et al. FDA approval summary: tocilizumab for treatment of chimeric antigen receptor T cell-induced severe or life-threatening cytokine release syndrome. Oncologist. 2018;23(8):943-947. 27. MacDougall K. The pharmacist’s role in educating the health-care team about adverse effects of immune checkpoint inhibitors. American Society of Clinical

Oncology website. www.ascopost.com/ issues/may-25-2018/pharmacist-role-ineducating-the-health-care-team/. Published

May 25, 2018. Accessed August 3, 2020. 28. Wood LS, Moldawer NP, Lewis C. Immune checkpoint inhibitor therapy: key principles when educating patients. Clin J Oncol Nurs. 2019;23(3):271-280. 29. Bosworth T. Tapering protocols needed to manage checkpoint inhibitor AEs. www. clinicaloncology.com/Current-Practice/ Article/05-18/Tapering-ProtocolsNeeded-To-Manage-Checkpoint-InhibitorAEs-/48704. Published May 16, 2018. Accessed August 3, 2020.

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COVID-19 pandemic. Biol Blood Marrow

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34. Royce TJ, Sanoff HK, Rewari A. Telemedicine for cancer care in the time of COVID-19 [published online ahead of print July 16, 2020]. JAMA Oncol. doi: 10.1001/ jamaoncol.2020.2684

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Pract. 2019;25(4):954-960.

Dr. Spencer reported no relevant fi nancial relationships.

Biosimilars Windfall

continued from page 1

compromising outcomes, and it wouldn’t have been possible without the leadership of an advanced specialty pharmacy program and the insights that provides,” Dr. Pham said during the session, a one-day pre-conference workshop on health-system specialty pharmacy.

“As more and more biosimilars come out, that represents a huge opportunity to decrease costs and an additional value point specialty pharmacy can bring to your institution,” said David Mitchell, PharmD, the pharmacist manager of specialty operations at UC Davis Health. He praised the BMC researchers for focusing not only on the cost containment aspect of the biosimilar switch, but also the outcomes that were achieved with new biosimilar products.

PBMs Finding Similar Benefits

Major pharmacy benefit managers (PBMs) also have realized the value of biosimilar switches. In an initiative by Magellan Rx Specialty, biosimilar utilization significantly shifted from originator infliximab to a lower cost biosimilar formulation after implementation of a medical benefit drug management solution.

Using the program, which leverages a comprehensive management solution to shift utilization to lower cost biosimilar versions of infliximab for the treatment of autoimmune conditions such as rheumatoid arthritis and inflammatory bowel disease, health plans saw a shift in utilization of up to 86%. “This yielded a 34% cost savings, which is in line with what our expectations were given the cost difference between the brand and the biosimilars,” Steve Cutts, the senior vice president and general manager for Magellan Rx Specialty, told Specialty Pharmacy Continuum.

When a “softer” approach was used, requiring only that new patients be started on biosimilar infliximab, biosimilar uptake was still as high as 75%.

Although specific dollar savings were not available, recent data from Magellan Rx Management’s Medical Pharmacy Trend Report found that the originator infliximab is the most expensive drug on the medical benefit.

Improving Imatinib Adherence

BMC’s specialty pharmacy program also successfully improved adherence to imatinib (Gleevec, Novartis) among patients with chronic myeloid leukemia. Adherence is a key driver of treatment success for this agent, Dr. Pham explained. “Patients who are adherent have a 76.7% five-year event-free

survival rate, compared with just under 60% if you do not take the drug the right way,” he said, referring to results from a study in the American Journal of Hematology (2011;86[6]:471-474).

BMC’s specialty pharmacy set an adherence goal for its patients receiving imatinib of a proportion of days covered (PDC) of 90% or higher. “Among the patients we observed at BMC specialty pharmacy, the average PDC was 93.5%,” Dr. Pham said. However, he added, when they included patients using outside pharmacies, they “saw PDCs of 75% to 80%, and sometimes far lower.”

Patients who achieved 90% or better adherence as measured by PDC had significantly improved health care resource utilization compared with those whose average PDC fell below 90%, as measured by annual average inpatient visits (0.4 vs. 4.1), total inpatient days (1.8 vs. 14.8), average length of stay in days (1.3 vs. 4.5), outpatient visits (30.2 vs 41.7), and total average cost per year ($58,000 vs. $107,000) (unpublished data). “Our specialty pharmacy is among the top five strategic initiatives at Boston Medical Center, because it brings so much value to the health system overall and is one of the few financial, operational and clinical drivers of our health system’s service lines,” Dr. Pham said.

Underscoring the value of such initiatives, Dr. Mitchell told Specialty Pharmacy Continuum that “there are significant economic and outcomes opportunities associated with specialty pharmacy for an [integrated delivery network]. In 2010, when we were preparing to launch our specialty program, the University HealthSystem Consortium had valued the average academic medical center specialty pharmacy opportunity at about $200 million, and that was 10 years ago, so you can imagine what that’s grown to today.” —Gina Shaw

Dr. Pham reported no relevant fi nancial relationships. His co-authors Francis Farraye, MD, MSc, and Bhavesh Shah, RPh, reported fi nancial relationships with companies including Janssen, Merck and Pfi zer.

Health-system specialty pharmacies:

Lots of Data, but What Do Payors Want to Know?

Although health-system specialty Many other health-system specialty At West Virginia University Hospitals, were higher than those of most nearby pharmacies have access to an abunpharmacies that are drawing up outin Morgantown, a lack of payor clarity on pharmacies outside their system, showdance of clinical and dispensing data, comes-based contracts are likely to be the question of outcomes led Louis Sokos, ing “a better return on investment” for according to one expert who spoke durin the same boat, finding that payors do BS Pharm, MBA, the director of allied payors, he said. ing a session at the 2020 NASP Annual not always know what outcomes they health solutions, specialty pharmacy serOther health-system specialty pharMeeting & Expo Virtual Experience, want to have measured as part of a convices, to formulate what he believes is a macies should take similar initiative some pharmacies in outcomes-based tract, Dr. Schuessler said. “Is a cliniuniversally applicable equation. Specifiand articulate what they believe to be contracts continue to ask payors the cal outcome SVR [sustained virologic cally, he said, demonstrating the impact the value of their services, suggestsame question: What outcomes do they response] or is it days-to-therapy, or is of specialty pharmacies on both clinical ed session moderator Erin Hendrick, want to know about? it adherence?” he asked. outcomes and total cost of care for the the senior vice president of hospital

That’s the “million-dollar question,” Dr. Schuessler noted that his team health system is “a value proposition that strategy at Shields Health Solutions, Bryan Schuessler, PharmD, MS, the draws on a large pool of data from the I think any payor can see.” headquartered in Stoughton, Mass. director of home infusion and specialSaint Luke’s electronic medical record He stressed that health-system spe“We seem to have, as a collective, been ty pharmacy at Saint Luke’s Health system as well as dispensing and clinicialty providers have “to make sure we very reactive to the data that’s been System in Kansas City, Mo., said during cal documentation data from their retail manage our patients as efficiently as we requested of us,” she said. Instead, the session, a one-day pre-conference and specialty pharmacies. “We’re docucan and drive down costs overall … to Ms. Hendrick said, “I think there’s an workshop on health-system specialty menting all these things. We’re followmake sure we’re a player in this space.” opportunity for health systems to betpharmacy. “What is it that people really ing patients. We’re making notes. We’re For example, his specialty pharmacy ter define what we believe good spewant to see on that payor line? We’re collecting all this data, but … we’re still looked at a group of the health system’s cialty outcomes really are.” not sure from payor to payor what’s struggling to understand what [payors] patients receiving antiviral medicavaluable at this point.” want to see,” he said. tions and documented SVR rates that —David Wild

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