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Old 12-04-2016, 01:24 AM
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Default Collateral Damage of Immunotherapy

By MATT RICHTEL

A New York Times story about the collateral damage of immunotherapy.

As Chuck Peal lay in a Waterbury, Conn., emergency room one Sunday in early September, doctors furiously tried to make sense of his symptoms. Mr. Peal, 61, appeared to be dying, and they were not sure why.

He slipped in and out of consciousness, his blood pressure plummeted, his potassium levels soared and his blood sugar spiked to 10 times the normal level. A doctor suspected a heart attack, but uncertainty left him urgently researching the situation on his phone.

This was not a heart attack. Mr. Peal’s body was attacking itself, a severe reaction by his immune system that was a side effect of a seemingly miraculous cancer treatment aimed at saving his life.

In the seven weeks prior, doctors at Yale had combated Mr. Peal’s melanoma with two of the most promising drugs in cancer treatment today. These medicines work by stimulating the immune system to attack cancer as ferociously as it does other threats, like viruses and bacteria.

These so-called immunotherapy drugs have been hailed as a breakthrough in cancer treatment, attracting billions of research dollars and offering new hope to patients out of options. But as their use grows, doctors are finding that they pose serious risks that stem from the very thing that makes them effective. An unleashed immune system can attack healthy, vital organs: notably the bowel, the liver and the lungs, but also the kidneys, the adrenal and pituitary glands, the pancreas and, in rare cases, the heart.

Doctors at Yale believe immunotherapy is causing a new type of acute-onset diabetes, with at least 17 cases there so far, Mr. Peal’s among them. In cancer clinics around the world, and in drug trials, myriad other side effects are showing up. Studies are finding that severe reactions occur nearly 20 percent of the time with certain drugs, and in more than half of patients when some drugs are used in combination.

[url]https://www.ncbi.nlm.nih.gov/pubmed/20147741

[url]https://www.ncbi.nlm.nih.gov/pubmed/25891304

Another recent paper found that 30 percent of patients experienced “interesting, rare or unexpected side effects,” with a quarter of the reactions described as severe, life-threatening or requiring hospitalization. Some patients have died, including five in recent months in clinical trials of a new immunotherapy drug being tested by Juno Therapeutics Inc.

[url]https://www.ncbi.nlm.nih.gov/pubmed/27085692

The upshot, oncologists and immunologists say, is that the medical field must be more vigilant as these drugs soar in popularity. And they say more research is needed into who is likely to have reactions and how to treat them.

“We are playing with fire,” said Dr. John Timmerman, an oncologist and immunotherapy researcher at the University of California, Los Angeles, who recently lost a patient to side effects. The woman’s immunotherapy drugs had successfully “melted away” her cancer, he said, but some weeks later, she got cold and flulike symptoms and died in the emergency room from an inflammatory response that Dr. Timmerman described as “a mass riot, an uprising” of her immune system.

“We’ve heard about immunotherapy as God’s gift, the chosen elixir, the cure for cancer,” he said. “We haven’t heard much about the collateral damage.”

Despite the warnings, physicians like Dr. Timmerman remain hugely supportive of drugs that are saving the lives of people who would otherwise die. Far better to cope with diabetes, hepatitis or arthritis, the thinking goes, than to die. Most reactions are not nearly so bad and are treatable.

The rub, doctors and researchers say, is that the medical system — from front-line nurses to oncologists to emergency rooms — is too often caught off guard. This is happening for a number of reasons: The drugs are new, so many side effects just have not been seen. Symptoms appear at random, sometimes months after treatment, and can initially seem innocuous. Finally, oncologists are now trying to treat patients with a combination of two or more immunotherapy drugs, hoping for more effective treatment but sometimes getting amplified risks.

In the meantime, these drugs are moving from academic centers into cancer clinics across the country, where oncologists in smaller cities most likely have less experience with the side effects.

And with lives to be saved and billions of dollars to be made — $250,000 or more is the list price for a year of some regimens — not enough research has been done into the risks of the new therapies, said William Murphy, a professor of dermatology at the University of California, Davis, who reviews immunotherapy-related grants for the government.

It is “a massively understudied area,” Dr. Murphy said, adding: “The No. 1 priority is anti-tumor effects. Everything else, however severe, is considered the price worth paying.”

Caught in the middle are patients like Mr. Peal, whose stories show the delicacy of tinkering with the immune system. It may hold the keys to curing cancer if it can be at once stoked and tamed.

Real Promise, and Real Risks

Mr. Peal, bespectacled and lean, was dealing with melanoma that had spread to his lungs in June 2015 when he saw a Yale oncologist, Dr. Harriet Kluger. In the past, a patient like him would have been given little chance.

“We’d sit the patient down and say, ‘I’m really sorry, the median life expectancy is nine months. Get your affairs in order,’” said Dr. Kluger, who runs immunotherapy clinical trials focusing on skin and kidney cancer.

Now she could offer Mr. Peal hope. Consider: One study co-authored by Dr. Kluger found positive responses in more than 40 percent of advanced melanoma patients when they used a combination of two major immunotherapy drugs, nivolumab and ipilimumab.

Other research, however, shows that the promise comes with real risks. A 2015 paper in The New England Journal of Medicine showed that use of these drugs carried a risk of side effects that were severe, required hospitalization or were life-threatening 54 percent of the time.

[url]https://www.ncbi.nlm.nih.gov/pubmed/25891304

“It’s at least that high, at least,” Dr. Kluger said. But, she noted, most of the side effects are manageable through immune suppression, such as with steroids.

The effectiveness of immunotherapy drugs and their side effects are intimately bound by the same biological mechanisms.

Called checkpoint inhibitors, the drugs work by essentially reversing a trick that cancer plays on the immune system: The cancer cells send nefarious signals to immune-system cells that cause them to stand down. Cancer is turning on the immune system’s brake.

There is a valuable reason the brake exists: It can shut down the body’s powerful defenders so that they do not inadvertently attack the body itself. Cancer is taking advantage of this key survival mechanism.

When an immunotherapy drug turns the brake off, the immune system can sometimes shrink tumors in mere days.

Mr. Peal, an engineering technician who tests the performance of helicopter parts, started taking nivolumab and ipilimumab on July 8. Dr. Kluger told him he might feel drowsy or nauseated, or he could get a rash. A rash indeed struck with a vengeance on Aug. 30: red welts from his knees to his waist. On Sept. 1, a Thursday, he visited Dr. Kluger’s office, where he was given a steroid.

The next day, he had a fever, nausea and was “dying of thirst — like beyond being in the desert,” he said. He threw up everything. His girlfriend, Jo-ann Keating, called Dr. Kluger’s office, and an on-call doctor prescribed an antinausea drug. Later, Ms. Keating called back to say it was not working, and he was prescribed a second antinausea drug. By Sunday morning, Mr. Peal, unable to move, took an ambulance to the emergency room.

In his wallet, he kept an information card published by Bristol-Myers Squibb. It lists dozens of risks, including that the therapy “can cause serious side effects in many parts of your body, which can lead to death.” Mr. Peal’s family told the emergency room doctor about the treatment, Ms. Keating recalled.

“The doctor kept on saying he was on chemotherapy,” she said. “I said, ‘They’re calling it immunotherapy.’ He went on his phone and started looking for information.”

But even Dr. Kluger’s experienced team, which answered the distressed phone calls that weekend, was caught off guard and did not react immediately to the symptoms.

“It took us by surprise. He looked absolutely fine on Friday,” Dr. Kluger said. Part of the problem, she thinks, is that Mr. Peal was relatively new to the clinic, and so she and her staff members did not have the experience with him to accurately assess his symptoms. “It also happened very quickly. It spiraled within hours.”
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Old 12-04-2016, 01:29 AM
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Ultimately, Mr. Peal spent 24 days in the hospital, where trouble mounted. First his pancreas failed, then his bowels inflamed and his kidneys became dysfunctional, and “to top it off, he has a fever of 103 for which we can’t find a source,” Dr. Kluger said in an interview during the crisis. She was trying to figure it out and had emailed other experts around the country to see if they had ever had a patient with this combination of acute immune reactions. No one had seen it before.

The pancreas problem was particularly noteworthy. Mr. Peal’s is among a growing number of such cases that have led a Yale endocrinologist, Dr. Kevan Herold, an authority on autoimmunity, to conclude that he is seeing a new form of Type 1 diabetes. Typically, the peak age of onset of Type 1 diabetes is 6 to 12, and it involves the immune system’s destroying, bit by bit, the cells in the pancreas that make the insulin needed to metabolize sugar into energy.

But this is different: Patients are 50 or older and are losing insulin production all at once, including in one case of an 83-year-old. Dr. Herold said he was hearing similar stories from peers around the country. “A single case like this is uncommon,” he said. “As an aggregate, it’s unheard-of.”

Another case at Yale involved Colleen Platt, 65, a real estate agent from Torrington, Conn., who was being treated by Dr. Kluger for late-stage kidney cancer. Ms. Platt opted for a clinical trial involving two immunotherapy drugs, atezolizumab and a second drug that Dr. Kluger declined to name because the trial is continuing.

Days after the second treatment in November 2014, Ms. Platt started feeling dizzy and numb and was vomiting water. She went to Dr. Kluger’s office, where they did lab tests that “were so profoundly abnormal, we thought this was lab error,” Dr. Kluger recounted. “We thought the machine was messed up.”

The tests were right. Like Mr. Peal, Ms. Platt had gone into diabetic ketoacidosis, a condition in which her body, desperate to compensate for energy it was missing when her pancreas shut down, created a flux of acid that could keep her functioning in the short term, at the risk of gravely harming organs throughout her body. Outside the emergency room, while a chaplain visited Ms. Platt to comfort her, Dr. Kluger called the drug company to report the extraordinary reaction.

Today, like Mr. Peal, Ms. Platt takes multiple insulin shots each day, and still her sugar level fluctuates wildly. On the other hand, immunotherapy has largely beaten her cancer. In fact, after consulting with other doctors and one of the drug companies, Dr. Kluger recommended Ms. Platt continue with treatment, which she did.

“Her pancreas isn’t coming back,” Dr. Kluger said, referring to the diabetic effects of immunotherapy. “She has her life.”

Mr. Peal — who, like Ms. Platt, agreed to let Dr. Kluger and Dr. Herold discuss his case — feels the trade-off will be well worth it. In fact, on Friday, he got the results from a scan taken the day before and learned that immunotherapy had eliminated two of his cancer lesions and shrunk two others. “I can deal with diabetes,” he said, “if I can beat melanoma.”

‘Nature of the Beast’

Evidence of these challenges is decades old.

In the mid-1990s, Matthew Krummel, a young immunology graduate student known as Max, worked at a lab at the University of California, Berkeley, that would become one of the most influential in the development of immunotherapy. The lab was run by Dr. James Allison, who, along with Dr. Krummel, published a seminal paper in 1995 showing that they could eliminate tumors in mice by turning off a brake on the immune system.

But the lab got less attention for a related experiment: The skin of some mice treated this way turned from black to white. They had lost their pigmentation, a result of the immune system’s attacking the cells that make melanin. The startling change was not life-threatening but indicated the power of tinkering with the immune system.

[url]https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2195583/

This discovery was novel but not particularly celebrated compared with the promise of curing cancer, Dr. Krummel recalled. The skin study “was kind of a footnote,” he said.

Then came the TeGenero tragedy in 2006.

TeGenero Immuno Therapeutics designed a drug to stimulate the immune system to fight leukemia. At Northwick Park Hospital in London, a Phase 1 trial took place, with six healthy patients getting the drug. Within hours, all suffered multiorgan failure.

The devastating results tempered the enthusiasm and suggested that more work needed to be done in advance of human trials. But enthusiasm came roaring back. Part of the reason was that, ultimately, the autoimmune reactions were seen not only as an acceptable cost of these drugs but as evidence they were working.

“It’s the nature of the beast,” said Martin Bachmann, a professor and immunologist at the Jenner Institute, which is affiliated with Oxford University. “I’m not sure you can get rid of the side effects — it’s really what you want.”

Chemotherapy, too, has side effects, but Dr. Kluger prefers immunotherapy’s trade-offs because the drugs may offer enduring control of cancer without the need for continued treatment. So she is joining others looking to address largely unanswered questions: Who is likely to be at risk, can the side effects be recognized before turning dangerous, and how should they be treated?

In June, Dr. Kluger and Dr. Herold submitted a grant proposal to the National Institutes of Health to study whether they could predict which patients would develop these symptoms. They based the proposal on a hypothesis that some patients have a biology or a genetic background that might make them more likely to have side effects. The proposal has not yet been funded.

Thus far, only a modicum of work has been done on these questions. Several studies found that older mice were more susceptible than younger mice to autoimmune reactions; another study, also in mice, found that obese subjects were more likely to have adverse effects.

“Old or fat mice were literally dead within hours,” said Dr. Murphy, the professor at Davis who believes too little is being done. He is well positioned to see the trends: In the past year, he sat on eight government grant review committees focused on immunotherapy, and he said only three out of 500 research proposals he reviewed focused on the toxicity side of immunotherapy.

Part of the problem, he said, is that the drug companies that are driving research prefer working with labs that support trials’ moving quickly. As a result, Dr. Murphy said, human trials are advancing faster than the background research can be done.

Hoping to push access to lifesaving drugs, the Food and Drug Administration has a “breakthrough therapy designation” that allows faster approval. Since 2012, the agency has granted breakthrough designation about 110 times, almost a quarter of them for immunotherapy.

“When people talk about moonshots, they’re talking about curing cancer, but it has to look at the whole picture,” Dr. Murphy said.

With so much momentum pushing for a cure, the emphasis from researchers and front-line oncologists is on more vigilance about the side effects. Dr. Timmerman, from U.C.L.A., said he wished he had seen the signs of trouble in his patient, who survived cancer only to die in the emergency room after exhibiting seemingly modest flulike symptoms.

“If we had only known the power we had unleashed that was causing such a toll on her organ system, we might have saved her,” he said.

“You have to manage this hour by hour,” he added. “Minute by minute.”

Citation: New York Science Times: Immune System, Unleashed by Cancer Therapies, Can Attack Organs. Dec. 4, 2016
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Old 01-28-2017, 09:15 PM
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Default Immunotherapy May Need To Have Its Own Value Model

ClinicalOncology News
Current Practice
January 26, 2017

National Harbor, Md.—Immunotherapy has been a game changer for the oncology field, but typical models used to assess the value of cancer treatments don’t take into account the unique characteristics of this therapy, according to experts at the 2016 annual meeting of the Society for Immunotherapy of Cancer (SITC).

The average release price of a new therapeutic agent in oncology “is north of $10,000 a month,” Peter P. Yu, MD, the physician-in-chief of the Hartford HealthCare Cancer Institute, in Hartford, Conn., told attendees at the SITC meeting. There are multiple models to assess the value of a cancer treatment, including the American Society of Clinical Oncology’s Value Framework, the European Society of Medical Oncology’s Magnitude of Clinical Benefit Scale (ESMO-MCBS), the National Comprehensive Cancer Network Evidence Blocks, Memorial Sloan Kettering Cancer Center’s Drug Abacus, and the Institute for Clinical and Economic Review Value Assessment Framework, Dr. Yu said. While they all look at cost, effectiveness and population health impact, none are perfect to apply to immunotherapy or are really easy to use, he said. However, he noted that they could be used as a basis to develop a new value framework for immunotherapy.

Models Underestimate Benefits, Overestimate Toxicity, Cost

These models, when applied to immunotherapy, tend to overestimate the impact of acute but reversible toxicities, as well as the costs of treatment, and underestimate the benefits of long-term survival and treatment-free survival, according to Michael B. Atkins, MD, the deputy director of Georgetown University Medical Center’s Lombardi Comprehensive Cancer Center, in Washington, D.C.

With respect to overestimating toxicity, Dr. Atkins said that while approximately 50% of patients getting the nivolumab-ipilimumab combination develop serious immune toxicities involving the skin liver, colon or endocrine organs, approximately 80% of adverse events resolve in four to six weeks with immune-modulating treatments such as steroids. In addition, he said, these side effects do not interfere with ultimate response to therapy.

The models also overestimate the costs of immunotherapy, according to Dr. Atkins. The costs, he argued, should be amortized over the longer horizons of benefit, taking into account the absence of the need for subsequent therapies in patients who achieve remission. In addition, many patients receiving immunotherapy are being overtreated, he said, noting that effective immunotherapy should do its job within a maximum of six to 12 months. “The benefits of activating the immune system persist long after the treatment stops, so we shouldn’t be so afraid of stopping treatment,” Dr. Atkins said. Any residual disease after a year of immunotherapy should be biopsied to see if it’s actually cancer, and resected. In addition, he noted, immunotherapy combinations may actually be less expensive than single agents if they work faster. Cost-cutting approaches include avoiding immunotherapy/nonimmunotherapy combinations that don’t clearly indicate which therapy is benefiting the patient or that don’t allow for cessation of treatment, and, whenever possible, using biomarkers to help select the right drug or combination therapy for the right patient.

The models also underestimate the benefits of immunotherapy not only for patients and their families but for society, he added. The annual benefit of curing just 1% more cancers is estimated to be $500 billion, he said.

The hallmark of immunotherapy, Dr. Atkins said, is the “tail of the [Kaplan-Meier survival] curve,” referring to long-term survival. In melanoma over the past few years, survival rates have increased from 10% to 20% with ipilimumab (Yervoy, Bristol-Myers Squibb) treatment, to 35% to 40% with anti–PD-1 [programmed cell death protein 1] agents, to potentially higher than 50% with combination ipilimumab/nivolumab (Opdivo, Bristol-Myers Squibb), Dr. Atkins noted. This “means melanoma—a disease that had a median survival of six to nine months in 2011—now has no median survival,” he said.

Immunotherapy, along with targeted therapy, also has helped transform the treatment of lung cancer over the past 10 to 15 years, said Roy S. Herbst, MD, PhD, a professor of medicine and chief of medical oncology at Yale Cancer Center, in New Haven, Conn. “Are we curing people?” he asked. “I think we’re getting pretty close.”

He described the findings of the KEYNOTE-024 trial presented at the ESMO 2016 Congress (N Engl J Med 2016 Oct 8. [Epub ahead of print], PMID: 27718847), which demonstrated significant progression-free and overall survival benefits for patients with advanced lung cancer and high programmed death ligand 1 (PD-L1), expression taking pembrolizumab (Keytruda, Merck) compared with those taking platinum chemotherapy. These findings have “changed the way we think about lung cancer,” Dr. Herbst said.

Anti–PD-1 agents are effective for several other cancers, Dr. Atkins said, noting, “We probably have had no single treatment that was so broadly relevant in oncology.”

Patient-Reported Outcomes

In addition to incorporating the benefits shown via these positive clinical trial results, good value frameworks have to include patient-reported outcomes (PROs), according to Heather S. Jim, PhD, an associate member at Moffitt Cancer Center and Research Institute, in Tampa, Fla., and Adam P. Dicker, MD, PhD, a senior vice president and chair of radiation oncology, and a professor of radiation oncology, pharmacology and experimental therapeutics at Thomas Jefferson University, in Philadelphia, who also spoke at the SITC meeting. PROs can help show clinical benefit in reducing disease-related symptoms, provide more accurate estimates of toxicity, enhance value frameworks, help model treatment costs and help improve symptom management, they said. The National Cancer Institute has developed the PRO-Common Terminology Criteria for Adverse Events (PRO-CTCAE), offering a menu of symptoms such as rash, fatigue or itching to select clinical trials or targeted therapies that are more useful for immunotherapy than measures like the EQ-5D health-related quality of life questionnaire.

In the CheckMate 025 trial, a Phase III study of nivolumab versus everolimus (Afinitor, Novartis) in previously treated patients with advanced or metastatic renal cell carcinoma, investigators included a measure of kidney cancer–specific symptomatology, Dr. Jim said. Symptoms in patients taking nivolumab showed improvements as soon as four weeks into treatment, she said, and continued through two years of follow-up data, “showing that not only could nivolumab improve overall survival but could improve the quality of survival,” she said, noting that this information is “important not only for patients but also for regulatory agencies and payors.”

Using PROs in Assessing Cost of Toxicity

A study from Moffitt investigators, presented at the 2016 annual meeting of the American Society of Clinical Oncology, used PROs to model treatment toxicity costs. They looked at patients treated with ipilimumab, nivolumab and pembrolizumab and estimated patient toxicity from billing records. Then they searched public databases to estimate the added costs of these toxicities to the total cost of treatment, determining among other findings that colitis adds about $8,500 and fever adds $3,300, increasing the costs of ipilimumab by 6%, nivolumab by 18% and pembrolizumab by 16%. “These toxicities really do have costs, and it’s important to model those in the value frameworks so patients have an idea of how much out-of-pocket costs they might incur,” Dr. Jim said.

PROs also can help improve symptom management, which can help patients stay on treatment longer with potential survivor benefits, she added. In a recent clinical trial, 766 patients treated with chemotherapy for metastatic breast, genitourinary, gynecologic or lung cancer filled out tablet-based questionnaires about their symptoms (J Clin Oncol 2016;34[24]:2925-2934, PMID: 27247218). The program’s software triggered email alerts to nurses when patients reported severe or significantly worsening symptoms for common conditions in the PRO-CTCAE, and the nurses reached out to these patients to offer help in managing the symptoms. Of the patients receiving this intervention, 34% demonstrated improved quality of life compared with 18% of those receiving usual care; 21% of those in the intervention group had clinically significant improvements in quality of life compared with 11% in usual care. Patients receiving interventions also had fewer ER visits at one year and spent more median months on chemotherapy.

Technology such as smartphone applications or activity trackers may offer ways to better monitor PROs, Dr. Dicker said. “There’s a lot that happens between patient visits that’s not always being captured. We also appreciate white coat syndrome—patients may not want to report toxicities because they want to stay on therapy.”

ClinicalOncology News Karen Blum January 26, 2017.

[url]http://www.clinicaloncology.com/Current-Practice/Article/01-17/Immunotherapy-May-Need-To-Have-Its-Own-Value-Model/40164
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Old 08-17-2017, 11:28 PM
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Default Immunotherapy and the Heart: A Concern for Lung Cancer Patients

MedPage Today
June 1, 2017

David Hermel, M.D.
Internal Medicine Resident Physician
University of Southern California
Los Angeles, CA

Immune checkpoint inhibitors (ICIs) have significantly increased overall survival (OS) and have led to durable responses in subsets of patients with multiple tumor types. While these immunomodulating agents have relatively mild side effects when compared with those for conventional chemotherapeutics, they can frequently cause manageable immune-related adverse effects, including colitis, endocrinopathies, and pneumonitis. In addition, as this article highlights, a small percentage of patients can develop cardiotoxicity as a result of ICI treatment. A handful of case reports and data from clinical trials provide evidence for potential cardiotoxicity -- including conditions like autoimmune myocarditis, pericarditis, Takotsubo cardiomyopathy, heart failure, and myocardial fibrosis -- following ICI administration. While most of these patients had pre-existing cardiac disease and clinically improved with corticosteroids, this article addresses the need for prompt diagnosis and effective management strategies for these rare patients with cardiotoxicity following ICI treatment.

Every lung cancer therapy has the potential for an adverse event, including those involving immune checkpoint modulating antibodies. Although immune checkpoint inhibitors are generally well tolerated compared with conventional cytotoxic chemotherapies, immune-related adverse events (irAEs) -- including cardiotoxic incidents -- are an issue.

The key for lung cancer specialists is to recognize and manage these immune-related adverse events as soon as possible, but that may be easier said than done. First, published data on cardiotoxicities in lung cancer patients undergoing immunotherapy are fairly sparse. Second, immunotherapy packaging is currently of little assistance when it comes to monitoring for cardiotoxic adverse events, said Aarti Asnani, MD, a cardiologist at Massachusetts General Hospital in Boston.

"At present, there are no specific guidelines for echocardiographic monitoring or management of cardiovascular toxicities included in the package inserts for ipilimumab [Yervoy], pembrolizumab [Keytruda], or nivolumab [Opdivo]," she wrote in a recent expert analysis for the American College of Cardiology.

But lessons from cardiotoxicities documented in other cancers can certainly provide useful lessons, most notably heart-related adverse events during treatment for melanoma.

In general, potential heart-related adverse events from immunotherapy are myocardial fibrosis, myocarditis, and acute heart failure, which have been reported among patients treated with programmed cell death protein-1 (PD-1) pathway immunotherapy, noted Lucie Heinzerling, MD, MPH, of University Hospital Erlangen in Germany, and colleagues.

Heinzerling's group offered case studies of cardiotoxicity associated with PD1 blocking and CTLA4 immunotherapy. For example, a 68-year-old man with a past medical history of clinically asymptomatic dilated cardiomyopathy and alcohol abuse was diagnosed with metastatic BRAF wild-type melanoma metastatic to the lymph nodes and small bowel, and treated with four doses of ipilimumab between July and September 2011. About 1 month after the last dose, he developed dyspnea upon exertion along with upper and lower extremity edema. He was hospitalized for exacerbation of the heart failure in November 2011. An echocardiogram showed enlargement of the left ventricle with an ejection fraction (EF) of 46%, thickening of the mitral valve, severe mitral regurgitation, and mild to moderate tricuspid regurgitation with severe pulmonary hypertension.

The patient underwent a battery of tests that ruled out coronary artery disease and acute myocarditis. At one point, the treating physicians suspected that the etiology may have been due to alcohol abuse, but a repeat echocardiogram in December 2011 performed after strict abstinence from alcohol showed worsened EF (25% to 30%).

After immunotherapy was completed, imaging-based restaging showed clear, progressive disease. The patient's subsequent cancer treatment was complicated by multiple hospitalizations due to recurrent cellulitis. He was eventually treated with temozolomide (Temodar) chemotherapy and, over the course of 18 months, had long-term disease stabilization and remained alive more than 5 years post-diagnosis.

"While an association of heart failure exacerbation and treatment with ipilimumab was not definitively established, the close temporal relation, absence of clear other exacerbating etiologies, and long-term survival of the patient suggest an immune-mediated etiology triggered by ipilimumab as the most likely culprit of the heart failure," the researchers stated.

Like many of the patients in the case studies, this man already had pre-existing cardiac conditions, and that is important to bear in mind -- these patients should be closely monitored for deterioration of heart function while undergoing therapy, the authors advised.

Pinpointing these immune-related adverse events will lead to easier management, according to Jeryl Villadolid, PharmD, and Asim Amin, MD, PhD, both of Levine Cancer Institute in Charlotte, N.C.

"Prompt recognition and initiation of appropriate management, usually in the form of immunosuppression, usually results in complete reversibility, but failing to do so can lead to severe toxicity or even death."

Villadolid and Amin stressed that immunotherapy is not chemotherapy and, as such, adverse events observed with immunotherapy have a completely different underlying mechanism compared with chemotherapy-induced toxicity.

"The irAEs can present in an insidious and unpredictable fashion; therefore, the clinical team, as well as the patient, have to be educated and aware of the potential toxicities so that they are reported early, generate an appropriate level of suspicion, and prompt investigation."

Although the current experience with adverse cardiovascular events related to immunotherapy is limited to a handful of patients in clinical trials as well as in case reports, an awareness of cardiac toxicities will be necessary as the indications for immune checkpoint inhibitors continue to expand, Asnani pointed out.

In the meantime, more research will focus on cardiotoxicity in patients undergoing cancer treatment, including immunotherapy. Lori Minasian, MD, deputy director of the National Cancer Institute (NCI) Division of Cancer Prevention, observed that "many different forms of cancer treatment -- chemotherapy agents, radiation, immunotherapy agents, and targeted agents -- alone and together can result in cardiac adverse effects."

In an NCI cardiotoxicity resource article, Minasian noted that "NCI is working with the National Heart, Lung and Blood Institute to support research that will help us better understand the risk factors and ways to reduce or prevent both the short-term effects and the late effects that can compromise survivorship."

Citation: Immunotherapy and the Heart: A Concern for Lung Ca Patients by Shalmali Pal Contributing Editor, MedPage Today June 1, 2017
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