Cancer groups offer guidance on musculoskeletal adverse events related to checkpoint inhibitors

Recently released guidelines from two major cancer organizations have provided some of the most comprehensive guidance to date on management of musculoskeletal side effects associated with cancer immunotherapy.

The guidelines, published in February, are a “sorely needed” reference point for the rheumatology community and others who will be encountering patients who experience immune-related adverse events (irAEs), according to Leonard H. Calabrese, DO , the R.J. Fasenmyer Chair of Clinical Immunology at the Cleveland Clinic in Ohio.

“They’re a good first start, given the fact that up until 4 or 5 months ago, there were no endorsed guidelines that included oncologists and rheumatologists,” Dr. Calabrese said of the guidelines, which were collaboratively developed and recently released by both the American Society of Clinical Oncology (ASCO) and the National Comprehensive Cancer Network (NCCN).

Rheumatologists can add value

“We talk a lot about rheumatologists being aware of these diseases, but it’s been pointed out by some oncologists that unless they’re really knowledgeable and can add considerably to the management, it doesn’t do any good just to be aware of it,” Dr. Calabrese explained. “You need to actually have some procedural knowledge.”

NCCN guidelines provide specific algorithms to guide management of myalgias/myositis and inflammatory arthritis, while the ASCO guidelines provide recommendations and discussion on management of inflammatory arthritis and myositis.

ASCO guidelines also describe a polymyalgia-like syndrome seen in some patients on immune checkpoint inhibitors that according to the guideline authors is characterized by pain, but not true muscle weakness.

In general, the guidelines endorse a stepwise approach, in which milder irAEs can be managed with conservative treatments and without the need to stop the immune checkpoint inhibitor therapy. In contrast, more serious side effects may require more intensive management and either temporary or permanent discontinuation of cancer immunotherapy.

One good example is NCCN’s take on managing inflammatory arthritis.

Mild cases of inflammatory arthritis can be treated with NSAIDs, low-dose prednisone, or intra-articular steroids with no need to stop immune checkpoint inhibitor treatment, according to NCCN guideline authors.

Moderate cases, by contrast, may require holding immunotherapy and treating with prednisone. A rheumatology consult by week 4 is “strongly recommended” if the immune arthritis doesn’t improve, the authors added.

Severe cases may warrant permanent discontinuation of immunotherapy and treatment with methylprednisolone/prednisone, infliximab, or tocilizumab, they added. If the irAE doesn’t improve after 2 weeks, a rheumatology consult should be considered for additional disease-modifying antirheumatic drugs, including methotrexate, leflunomide, or sulfasalazine.

irAEs on the rise

These guidelines are particularly useful for rheumatologists to familiarize themselves with the six Food and Drug Administration–approved immune checkpoint inhibitors, their spectrum of side effects, and how oncologists use the severity of presentation to guide therapy, according to Laura Cappelli, MD .

“The treatment of irAEs can’t be done in a vacuum,” said Dr. Cappelli, a rheumatologist at Johns Hopkins University, Baltimore. “It is definitely a multidisciplinary endeavor, so it’s important to know the perspective of the oncologist when making the treatment decisions.”

Understanding irAEs will be increasingly important for rheumatologist as the use of immune checkpoint inhibitors continues to increase, said Dr. Cappelli, who has started a research program at Johns Hopkins to evaluate the rheumatologic adverse effects of these therapies.

Dr. Cappelli said her division sees at least one suspected irAE case per week, most commonly the immune arthritis associated with checkpoint inhibitor therapy.

Likewise, Dr. Calabrese said he is already seeing approximately two new referrals per week for adverse events related to these relatively new therapies.

“It’s far outstripped our notion of what we thought we would be doing,” he said in an interview.

Systems have been set up to encourage interprofessional collaborations, he added, including a “virtual referral clinic” where advanced practitioners working with oncologists communicate with advanced practitioners in each of the specialty areas that are most frequently consulted in order to help facilitate care and triage patients.

In addition, a monthly irAE tumor board was set up to include only cases that have manifest autoimmune or autoinflammatory complications.

“We have a growing group of people who come to this from each area involved, whether it be nephrology, neurology, ophthalmology, gastroenterology, rheumatology, or something else,” Dr. Calabrese said. “That’s been a great learning experience for all of us to talk about these adverse events in real time.”

Critical need for guidance

These guidelines meet a growing need to help practicing clinicians identify and best manage immune-related adverse events, according to Bryan J. Schneider, MD , of the University of Michigan Comprehensive Cancer Center, and vice chair of the NCCN Panel on Management of Immunotherapy-Related Toxicities.

“The mechanism of action of these anticancer therapies is so much different from anything that we’re used to,” Dr. Schneider said in an interview.

“We’re experienced with chemotherapy, and we are very comfortable with the side effects,” he said. “The immunotherapy story is just an entirely different world because, as I tell patients, the therapies aren’t directly damaging cancer cells like chemotherapy. Instead, they are helping the immune system to identify the cancer cells as abnormal and mount an assault. Proteins on cancer cells may suppress the immune response and these therapies effectively ‘release these brakes’ so the immune system can attack.”

Rheumatologists and those with particular expertise in rheumatologic side effects participated in the development of the ASCO and NCCN guidelines. They include Maria E. Suarez-Almazor, MD, PhD , chief of rheumatology and clinical immunology at the University of Texas MD Anderson Cancer Center, Houston, who served on the ASCO expert panel; Jarushka Naidoo, MBBCh , from the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, provided expertise in the rheumatologic side effects that were considered by the NCCN panel, according to Dr. Schneider.

Rheumatologist input also informed another set of recommendations on immune checkpoint inhibitor toxicities published several months before the ASCO and NCCN guidelines. The working group for the September 2017 guidelines from the Society for Immunotherapy of Cancer (doi: 10.1186/s40425-017-0300-z ) included Dr. Suarez-Almazor, as well as Clifton O. Bingham III, MD, director of the Johns Hopkins Arthritis Center.

Vigilance required

Checkpoint inhibitors have been approved by the FDA to treat a variety of cancers, including melanoma, lung cancer, and Hodgkin lymphoma, as well as lung, liver, kidney, and bladder cancers.

Clinicians managing patients on checkpoint inhibitors should always be vigilant because irAE symptoms can be subtle, according to Julie Brahmer, MD , of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins in Baltimore.

“Everyone has to work as a team, which includes being educated on possible side effects to immunotherapy prior to prescribing it,” said Dr. Brahmer, chair of the ASCO panel and vice chair of the NCCN panel that developed the guidelines.

The guidelines were published Feb. 14 in two documents that are similar in content, but different in format. The ASCO guideline was published in the Journal of Clinical Oncology (doi: 10.1200/JCO.2017.77.6385 ) and the NCCN Clinical Practice Guidelines in Oncology were posted on the NCCN website .

While the first edition of the guidelines focus specifically on immune checkpoint inhibitors, an update anticipated for 2019 will include guidance on chimeric antigen receptor (CAR) T cell therapy, which is associated with several important side effects, notably cytokine release syndrome.


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