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Researchers Provide Management Recommendations for CRS, Other Toxicities of CAR T

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While chimeric antigen receptor (CAR) T-cell therapy has offered a new option and improved outcomes for patients with advanced hematologic malignancies, the treatment approach has been associated with toxicities such as cytokine release syndrome (CRS), neurotoxicity, and hematotoxicity.

As chimeric antigen receptor (CAR) T-cell therapy continues to be used in hematologic malignancies and be explored in solid tumors, researchers of a new paper have provided recommendations for the prevention and management of toxicities associated with the technology.

While CAR T-cell therapy has offered a new option and improved outcomes for patients with advanced hematologic malignancies, including multiple myeloma and B-acute lymphoblastic leukemia, who have progressed or relapsed after multiple lines of therapy, the treatment approach has been associated with toxicities such as cytokine release syndrome (CRS), neurotoxicity, and hematotoxicity.

“There is an exponential growth in research into new biomarkers and novel CAR-T constructs, which are designed to improve persistence and response with a better toxicity profile. This will extend CAR-T therapy to other hematological malignancies or solid tumors,” explained the researchers.“As living drugs, CAR-T cells are associated with potentially life-threatening immunological toxicities, which frequently need a multidisciplinary team approach, including intensive care unit and neurology specialists.”

Of the most documented toxicities associated with CAR T-cell therapy is CRS, which generally occurs within the first week following CAR T-cell infusion. Strategies for treating CRS typically begins with tocilizumab, with corticosteroids being reserved for use in cases where patients are refractory to the interleukin-6 blocker or in cases of concomitant immune effector cell-associated neurotoxicity syndrome (ICANS), another frequently documented toxicity associated with CAR T-cell treatment.

The researchers of the study, based on former and current recommendations, suggest tocilizumab initiation in cases of grade ≥2 CRS, with a second dose administered if needed. For concomitant ICANS, the group recommends a short duration of corticosteroids when using tocilizumab, as corticosteroids are recommended the frontline treatment option for ICANS. In cases of CRS where patients are refractory to tocilizumab, the researchers recommend initiating a new line with corticosteroids. For ICANs not responding to corticosteroids, anakinra, and IL-1 receptor antagonist, is recommended.

Several clinical trials are underway assessing new approaches to treating patients refractory to tocilizumab and corticosteroids, including siltuximab and extracorporeal cytokine adsorption added to CRS treatment.

“To date, CRS and ICANS are the most frequent and concerning toxicities after CAR-T therapy. Treatment of these immunotoxicities with corticosteroids, tocilizumab or other immunosuppressive agents also increases the risk for cytopenias and infections,” explained the researchers. “Therefore, it is crucial to recognize the risk factors for CAR-T associated-toxicities, as well as to implement adequate therapeutic and prophylactic strategies, without affecting the efficacy of CAR-T lymphocytes.”

In cases of cytopenias, CD34+ selected-stem cell boost has been assessed for patients who have undergone allogeneic stem cell transplant and in patients with cryopreserved CD34+ cells. While the use of and the best time to start granulocyte colony-stimulating factor (G-CSF) is still being debated, the researchers recommended G-CSF stimulation within a week of CAR T-cell infusion, unless there severe infection is documented, in which case, a risk-benefit analysis should be performed.

According to the group, there is no clear association between G-CSF use and higher grades of immunotoxicity, unlike with GM-CSF. The researchers flagged that there are no randomized studies on the early use of G-CSF. Data from 2 retrospective studies showed shorter duration of hospitalization associated with early use of G-CSF, although no differences in the severity of neutropenia or infection rates within 30 days of CAR T-cell infusion.

Reference

Hernani R, Benzaquén A, Solano C. Toxicities following CAR-T therapy for hematological malignancies. Cancer Treat Rev. Published online October 26, 2022. doi:10.1016/j.ctrv.2022.102479

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