Neck, throat swelling may signal local CRS after CAR T-cell therapy
Study highlights need to watch for airway risk in blood cancer patients
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Local cytokine release syndrome (L-CRS) is a potentially underrecognized complication of CAR T-cell therapy for blood cancer that can appear as cervical angioedema, or swelling in the deeper layers of tissue in the neck or throat, a study suggests. The swelling may occur after a bodywide inflammatory response has already started.
Because it can affect the airways and may develop despite treatment for inflammation, this swelling is a potentially serious complication. The researchers said it requires prompt evaluation for possible airway involvement, along with corticosteroid treatment or a higher dose if patients are already receiving corticosteroids.
Local CRS may threaten airways after CAR T-cell therapy
The real-world study, “Local cytokine release syndrome with cervical angioedema following CAR-T cell therapy,” was published as a letter to the editor of Haematologica.
CAR T-cell therapy modifies a patient’s own immune T-cells in a lab so they can recognize and attack cancer cells. However, it can cause side effects resulting from an overactive immune response. The most notable side effects are cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS).
CRS is a bodywide inflammatory response caused by large amounts of proteins called cytokines, which signal inflammation. In ICANS, an overactive immune system affects the nervous system, leading to confusion and other symptoms. As CAR T-cell therapy is being used for more diseases, doctors are studying side effects that do not fit the usual CRS or ICANS categories.
One of those side effects is local CRS (L-CRS), in which cytokines are released locally. It mainly appears as cervical and laryngeal angioedema — swelling in the neck or throat, including the larynx, or voice box — and can become life-threatening if it narrows the airways and makes breathing difficult.
This study looked at patients who developed cervical or laryngeal angioedema after receiving CAR T-cell therapy. It included 173 patients treated between December 2020 and March 2025 for blood cancer at two hospitals. It also included a review of previously published cases to better understand the timing, symptoms, treatment, and outcomes of this side effect.
Study finds local CRS in 8 of 173 CAR T-cell recipients
Becaise there are no official diagnostic criteria for L-CRS, the researchers defined it as new swelling in the neck or throat after CAR T-cell therapy when pre-treatment scans had not shown enlarged lymph nodes in that area, infection and allergic reactions had been ruled out, and the swelling improved after treatment with corticosteroids. CRS and ICANS were diagnosed using international guidelines.
Most patients in the overall group had a type of blood cancer called diffuse large B-cell lymphoma, while others had different types of lymphoma or multiple myeloma, a cancer of plasma cells, a type of immune cell found in bone marrow. CAR T-cell therapy targeted proteins such as CD19 or BCMA found on the surface of cancer cells.
Of the 173 patients, eight (4.6%) developed L-CRS. These patients included four women and four men, ages 45 to 76 years, who had different types of blood cancer and had received different types of CAR T-cell therapy.
L-CRS began a median of four days after infusion of the CAR T-cell therapy and lasted three to six days. Patients typically developed swelling in the neck and under the jaw, sometimes in the face, and some had difficulty swallowing. One patient had swelling affecting the larynx, which caused breathing difficulty and narrowing of the airways.
All patients with L-CRS had systemic CRS, meaning they also experienced bodywide inflammation. CRS started earlier, usually within the first two days after CAR T-cell therapy, and was still ongoing in most patients when L-CRS developed. This suggests that L-CRS tends to occur later during an already overactive immune response. About two-thirds of patients also developed ICANS, usually during or as L-CRS was resolving.
All patients were treated with corticosteroids to reduce inflammation. More than half had already started corticosteroids for CRS, but still developed L-CRS, meaning the swelling could occur despite ongoing treatment. In several cases, doctors had to increase the corticosteroid dose or give additional doses when L-CRS developed.
Published cases also point to airway concerns
The study also reviewed 14 previously published cases, which showed similar symptoms and timing. These cases involved several blood cancers, including lymphoma, multiple myeloma, and B-cell acute lymphoblastic leukemia. In those cases, systemic CRS, or bodywide inflammation, was reported in all 14 patients, and some required emergency breathing support, such as intubation (placement of a breathing tube into the airway) or tracheostomy (surgery to create an airway through the neck).
In nearly all published cases, tocilizumab (marketed as Actemra among others) was used. Tocilizumab blocks receptors for interleukin-6 (IL-6), a key inflammatory cytokine involved in CRS, preventing IL-6 from signaling inflammation. However, L-CRS still developed despite tocilizumab treatment.
The researchers propose that L-CRS may develop because CAR T-cells accumulate in lymphoid tissue in the neck, such as lymph nodes and tonsils, triggering a strong inflammatory response. Lymphoid tissue is part of the immune system and contains immune cells, which may explain why the neck area is especially affected.
Another possible explanation is that L-CRS could involve other inflammatory pathways besides IL-6, such as interleukin-1 (IL-1), another cytokine involved in inflammation. In an animal model, blocking IL-1 prevented CRS and neurotoxicity, suggesting IL-1 may be worth studying as a possible treatment target for L-CRS.
While it is not common, “L-CRS is a clinically meaningful complication that warrants a standardized diagnostic approach,” the researchers wrote. “Clinically, early recognition of progressive neck swelling, even in patients already receiving tocilizumab or [corticosteroids], mandates immediate evaluation for potential airway involvement and steroid administration or dose escalation,” they concluded.
