September 20, 2017
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Guidelines address ‘unmet need’ for grading, management of CAR T-cell toxicities

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An expert panel of researchers — representing The University of Texas MD Anderson Cancer Center, Moffitt Cancer Center, Sylvester Comprehensive Cancer Center and Mayo Clinic —developed a new grading system for neurotoxic events associated with chimeric antigen receptor T-cell therapies, according to guidelines published in Nature Reviews Clinical Oncology.

Perspective from

The panel also provides recommendations for additional monitoring, grading and managing of other acute toxicities that can occur in patients treated with chimeric antigen receptor (CAR) T-cell therapies.

CAR T-cell therapy is a highly promising approach for leukemias and lymphomas and can potentially be curative for these patients,” Sattva S. Neelapu, MD, director of laboratory and translational research in the department of lymphoma/myeloma at MD Anderson, told HemOnc Today. “But [the therapies are] associated with unique toxicities that are unlike side effects observed with traditional chemotherapy or radiation therapy. If the toxicities are not recognized promptly or managed appropriately, they can be fatal. Therefore, physicians and other health care providers involved in the care of these patients need to be educated on how to recognize and manage these side effects.”

The panel wrote in the guidelines that “algorithms for accurate and consistent grading and management of the toxicities [associated with CAR T cells] are lacking.” In an effort to “address this unmet need,” the panel formed a CAR-T-cell-therapy-associated TOXicity (CARTOX) Working Group comprised of investigators experienced in treating patients with various CAR-T cell therapies.

“Previously, guidelines have been proposed for grading and [managing] cytokine-release syndrome, but not CAR-T-cell-related encephalopathy syndrome,” he said. “We have updated the grading and management guidelines for CRS based on additional experience we have gained using four different CAR T-cell products. In addition, we describe a new grading system for CRES and propose new guidelines for the management of CRES. These guidelines also provide information on the potential infrastructure required for implementation of this therapy at centers that have not previously had experience in administering CAR T-cell therapy.”

Neurological assessment

The CARTOX group developed a 10-point neurological assessment tool to help identify patients with CAR-T-cell-related encephalopathy syndrome.

The 10-point test asks a patient to name the year, month, city, hospital and president or prime minister of their home country (5 points), name three nearby objects (3 points), write a standard sentence and count backward from 100 in increments of 10. The tasks can be simplified depending on the education level of the patient. The panel recommends taking a baseline test prior to CAR-T cell infusion to ensure that follow-up assessments are reliable and consistent.

Additionally, the panel recommends that the 10-point neurological assessment be administered every 8 hours while a patient is hospitalized after CAR-T cell therapy.

Cytokine-release syndrome

The panel also issued a recommendation on the monitoring, grading and management of cytokine-release syndrome that can result from the use of CAR T cells.

“Given the pioneering work that has been done so far, the next step is to try to improve the efficacy, safety and delivery of these agents so more of our patients have access,” Hetty E. Carraway, MD, MBA, staff physician in hematologic oncology and blood disorders at Taussig Cancer Institute at Cleveland Clinic, told HemOnc Today. “There has been a great deal of discussion about toxicities — specifically cytokine-release syndrome — and for very good reason.”

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The panel recommends suspecting cytokine-release syndrome in a patient if at least one of the four following signs or symptoms develops within the first 3 weeks of therapy:

  • fever of, or greater than, 38°C;
  • hypotension with systolic blood pressure less than 90 mmHg;
  • hypoxia with an arterial oxygen saturation of less than 90% on room air; and
  • evidence of organ toxicity.

Physicians are recommended to determine a patient’s cytokine-release syndrome grade at least twice daily and at any time when a change in the patient’s status is observed.

Patients with a grade 1 cytokine-release syndrome should primarily be managed with supportive care, according to the panel. The use of maintenance IV fluids is recommended to keep patients well-hydrated, with special attention to fluid balance to avoid pulmonary vascular congestion.

Patients who present with grade 3 or grade 4 cytokine-release syndrome should be treated in the ICU to enable continuous monitoring and management of arrhythmias, hemodynamic shock, non-invasive positive pressure ventilation, and/or dialysis.

Managing toxicity

Carraway noted there is a great deal of concern with toxicities associated with CAR T cells.

“These toxicities do appear manageable, especially when this type of therapy is given in the appropriate setting with the necessary staff and support,” she said.

However, there is a bit of uncertainty on how readily available CAR-T cell therapies will be to patients outside the reach of major medical centers that are equipped to manage the administration of therapies and the potential resulting toxicities, according to Ryan D. Cassaday, MD, assistant professor in the division of hematology at University of Washington and assistant member in the clinical research division at Fred Hutchinson Cancer Research Center.

“We in the medical community will need to wrestle with these challenging topics as this story unfolds,” he told HemOnc Today. – by Ryan McDonald

Disclosures: Neelapu reports receiving research funding from BristolMyers Squibb, Celgene, Cellectis, Kite Pharma, Merck and Poseida Therapeutics. Additionally, Neelapu reports serving as a consultant and/or a scientific advisory board member for Celgene, Kite Pharma, Merck and Novartis. Carraway reports no relevant financial disclosures. Cassaday reports research support from Gilead, Incyte, Merck, Pfizer and Seattle Genetics, as well as consultant roles with Adaptive Biotechnologies, Amgen and Pfizer.