Managing the Serious Side Effects of CAR T-Cell Therapies

While CAR T-cell therapies have been lauded for curing very advanced blood cancers in many patients, the treatment comes with serious risks, including dangerously high fevers and neurologic effects.

But clinical pharmacists can reduce their patients’ chances of developing serious side effects if they provide proper monitoring and management, said two speakers at a Dec. 5 session at the Midyear Clinical Meeting & Exhibition.

Charlene Kabel and Amanda Chron, pharmacists at Memorial Sloan Kettering Cancer Center, discussed a pharmacotherapy regimen they used on a patient who developed serious side effects from CAR T-cell treatment.

CAR T-cell therapies involve altering a patient’s T cells to produce proteins on their surface called chimeric antigen receptors, or CARS. Those genetically modified cells are infused back into the patient’s body, where they attack cancer cells.

“CAR T cells are considered a living drug, as they harness the patient’s immune cells to target and kill cancer cells,” said Kabel. “Activation and proliferation of CAR T cells has resulted in significant and durable killing of malignant cells.”

First approved in 2017, six therapies have received Food and Drug Administration (FDA) approval. The FDA recently made headlines when it announced an investigation into whether CAR T-cell therapies were causing rare, secondary cancers.

But a much more common condition following treatment is cytokine release syndrome (CRS). That’s when the infused CAR T cells flood the bloodstream with cytokines, which can cause dangerously high fevers and precipitous drops in blood pressure, according to the National Cancer Institute. It can be fatal.

“Now that CAR T-cell therapy has been in practice for just over six years, we have a pretty strong understanding of how to manage CRS,” said Chron. “And we know that it can be managed well with a high level of clinical surveillance, fluids, as well as vasopressors. These patients do require continuous monitoring.”

The first-line treatment for CRS is tocilizumab, which was initially used to treat inflammatory conditions like juvenile arthritis. Second-line options can vary by institution, said Chron, but primarily include steroids.

Chron discussed the case of a girl who in 2012 was the first pediatric patient to receive CAR T-cell treatment. However, after her infusion, her blood pressure dropped, and she developed a fever and shortness of breath.

Her lab work showed elevated IL-6, a cytokine secreted by T cells. At that time, IL-6 happened to be the only cytokine with an approved drug that blocked it, tocilizumab, which her team gave her.

“Remarkably, within hours, her reaction improved,” said Chron. Five years later, the FDA approved its use for CRS in adults and children ages 2 and up.

Another common concern with CAR T-cell therapies is that patients will develop neurologic effects known as immune effector cell–associated neurotoxicity syndrome, or ICANS. Symptoms include severe confusion, seizure-like activity, and impaired speech.

Depending on the severity of the patient’s symptoms, as well as the particular type of CAR T-cell therapy, clinicians can use dexamethasone and methylprednisolone, according to their presentation.

In their case study, the patient was treated with methylprednisolone for grade 3 ICANS. But his condition worsened hours later. Kabel then discussed efforts to manage his refractory ICANS, which included anakinra, another drug approved for rheumatoid arthritis.

Responding to a question from an audience member, Kable said she had recently had a rare case, a patient who had developed cranial nerve palsy after his CAR T-cell treatment.

“It’s very, very rare,” she said. “But it is a risk. Unfortunately, it’s not responsive to treatment. For (this patient), we are using steroids right now. It’s helping with his headache but not doing anything with the cranial nerve palsy, unfortunately.”

In addition to detailing treatment approaches for CRS and ICANS, the presenters also explained the tests used to gauge the severity of the conditions.