What is a cytokine storm and how do doctors treat it?

What is a cytokine storm?
Cytokine release syndrome may occur as a reaction to immunotherapy drugs for cancer.

Some cancer treatments help the body’s immune system do a better job of attacking cancer cells, but they may also trigger an overwhelming immune system response that doesn’t know when to stop, creating potentially life-threatening side effects.

That response, called cytokine release syndrome (CRS) or a cytokine storm, has been associated with viral and bacterial infections, autoimmune disorders—even COVID-19. In recent decades, however, oncologists have had to reckon with this worrisome side effect in some forms of immunotherapy, an otherwise promising area of cancer treatment that empowers the body’s immune system to help it better recognize and destroy cancer cells.

CRS has been identified as a side effect in a number of T-cell-based immunotherapies, particularly those using chimeric antigen receptor (CAR) T-cells, treatments involving monoclonal antibodies such as checkpoint inhibitors, and those using bispecific antibodies. It’s also a common side effect of some allogeneic stem cell transplants, such as haploidentical hematopoietic stem cell transplant (haplo-HSCT).

As the field of immunotherapy continues to advance, so does scientists’ understanding of cytokine storms. This knowledge is resulting in therapies that may reduce or counter a CRS reaction without lessening the cancer-fighting effectiveness of the immunotherapeutic drugs.

“We're finding that there are good ways to intervene and stop cytokine release syndrome before it becomes dangerous,” says Leslie Popplewell, MD, Medical Director of Hematology and Blood and Marrow Transplant at City of Hope Cancer Center Atlanta. “At the beginning of CAR T-cell development, there was this idea that some of those interventions would kill the CAR T-cells or make them less effective, and we know now that that's really not the case.”

In this article, we’ll explore:

If you’ve been diagnosed with a blood cancer, such as leukemia, lymphoma or multiple myeloma, and have questions about your treatment plan, or if you’re interested in a second opinion on your diagnosis, call us or chat online with a member of our team.

What is a cytokine storm?

Cytokines are protein molecules that play an important role in stimulating immune system cells. The body makes them when exposed to infections as part of its inflammatory response. The molecules control the growth and activation of immune system cells and blood cells, acting as chemical messengers that tell the immune cells what to do and prompt the body to produce even more immune system cells.

Immunotherapy drugs also trigger cytokine releases. Scientists are still trying to understand why a release may become a cytokine storm in some patients and why they trigger such a hyperproduction of cytokines that a patient may experience organ failure or other serious side effects.

“No single definition of cytokine storm or the cytokine release syndrome is widely accepted, and there is disagreement about how these disorders differ from an appropriate inflammatory response,” said David C. Fajgenbaum, MD, and Carl H. June, MD, of the University of Pennsylvania in a December 2020 review article in the New England Journal of Medicine. “The line between a normal and a dysregulated response to a severe infection is blurry, especially considering that certain cytokines may be both helpful in controlling an infection and harmful to the host.”

A study published in March in the journal Cancer about the use of teclistamab (Tecvayli®) for the treatment of relapsed or refractory multiple myeloma found that 72 percent of the 165 patients treated experienced cytokine release syndrome. However, most had lower-grade, less-severe events, described as grade 1 or grade 2, while only one patient experienced a grade 3 event. None were fatal.

Most of the reactions to teclistamab’s T-cell-redirecting bispecific antibodies occurred shortly after the initial “step-up doses” were administered. The median onset of CRS occurred two days after treatment, and the side effects lasted, in the median range, for two days.

“This is not something that smolders for weeks and weeks,” Jeremy T. Larsen, MD, Hematologic Oncologist at City of Hope Cancer Center Phoenix, said in a Sept. 18 article in the journal Oncology. “These are a median duration of a couple of days and are reversible. This is not a manifestation that’s resulting in patients discontinuing therapy.”

Cytokine storm symptoms

CRS causes a variety of symptoms that doctors need to be on the lookout for, including:

  • High fever and chills
  • Trouble breathing
  • Severe nausea, vomiting, and/or diarrhea
  • Feeling dizzy or lightheaded
  • Headaches
  • Fast heartbeat
  • Feeling very tired
  • Muscle and/or joint pain

“Patients react with the same kind of symptoms that they would if they had an infection,” Dr. Popplewell says. “That can include minor things like body aches, and in general not feeling well, to high fevers. Fevers themselves are not necessarily dangerous, but having a high fever for number of days can lead to other problems.”

Respiratory symptoms are common in CRS and can range from a mild cough to acute respiratory distress syndrome. Potentially life-threatening complications may include cardiac dysfunction, neurologic toxicity and organ failure. In particular, a cytokine storm may damage to the lungs and kidneys.

“I've certainly seen patients who simply had severe cytokine release,” Dr. Popplewell says. “Detailed discussion of risks and benefits of this treatment are important.”

Before starting it is important to talk about the likelihood of reactions and what will be done to monitor the patient and what interventions are available. 

Cytokine storm treatment

Still, as the teclistamab study showed, CRS is often treatable and manageable if doctors pay attention to the clues and watch for early signs of CRS disease as soon as treatment starts. That’s why CAR T-cell therapy, for instance, is typically delivered in a hospital setting and not on an outpatient basis.

“The risk of cytokine release syndrome is  why it is so important for [CAR T-cell therapy] to be delivered in medical centers where all staff members are trained to recognize and respond to this complication,” Dr. Popplewell says.

Treatment options include immunosuppressive drugs such as steroids, or monoclonal antibodies like tocilizumab (Actemra®).

In the teclistamab study, tocilizumab reduced the risk of a subsequent CRS episode in patients receiving it. The study said 20 percent of those receiving tocilizumab didn’t have another CRS event, compared to 62.2 percent of those who didn’t receive the drug.

In the Oncology article, Dr. Larsen said he might observe patients who have light fevers for a few hours without giving tocilizumab, but he’d use the drug for patients with “bona fide fevers.” If the fever lasts, he may turn to steroids, which he also uses to manage cases of neurotoxicity, the second leading side effect in CAR T-cell patients.

“Neurotoxicity is something we don't really understand as well as we do cytokine release syndrome,” Dr. Popplewell says. “Patients can develop confusion and, in some cases, seizures after CAR T-cells are given. And that's why it’s critical to partner with neurologists who can help with diagnostic procedures and provide support. We give anti-seizure medication as a precaution. 

One area of treatment where more study is needed is the pre-emptive use of tocilizumab or steroids prior to CAR T-cell treatment or prior to CRS symptoms appearing.

A 2021 study in the Journal of Clinical Oncology showed that risk-adapted use of tocilizumab before CAR T-cell therapy in the treatment of CD19-positive relapsed or refractory B-cell acute lymphoblastic leukemia “resulted in a decrease in the expected incidence of grade 4 CRS.”

Dr. Popplewell says some centers may use tocilizumab or steroids prior to cytokine storm symptoms have a chance to develop in patients who are elderly or who doctors think will not tolerate a CRS reaction well.

Dr. Larsen would like to see more data before considering the prophylactic use of these immunosuppressants as a standard practice for CAR T-cell therapy. However, if such treatment is shown to reduce the frequency and severity of CRS, he said it may lead to shorter hospital stays and improved outcomes.

If you’ve been diagnosed with a blood cancer, such as leukemia, lymphoma or multiple myeloma, and have questions about your treatment plan, or if you’re interested in a second opinion on your diagnosis, call us or chat online with a member of our team.