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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.
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.”
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 Bristol‑Myers 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.
Perspective
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CAR T-cell therapies hold great promise as anticancer treatments. However, they also carry significant, potentially life-threatening risks, including cytokine release syndrome (CRS), CAR T-cell-related encephalopathy syndrome, and even hemophagocytic lymphohistiocytosis/macrophage activation syndrome. Additional challenges are faced in the delivery of this therapy beyond a select few, highly experienced academic medical centers. The CARTOX working group is to be commended for drafting comprehensive guidelines for the monitoring, grading and management of the serious risks that accompany this treatment.
This article provides an excellent “owner’s manual” for the identification and management of the most serious CAR T-cell toxicities. However, the trouble lies in the successful implementation of these guidelines, which may prove particularly difficult for inexperienced centers. Indeed, any missed diagnostic clues — no matter how subtle — or undue delays in management may have catastrophic consequences. Conversely, overzealous use of immunosuppressive therapies might, at least theoretically, compromise the efficacy of the CAR T cells.
It should be recognized that some education may be needed before many providers are facile with these guidelines, particularly use of the grading systems — such as the CARTOX-10 neurologic assessment, the modified Frisén scale for papilledema, and perhaps even the common terminology criteria for adverse events. Appropriate monitoring and management of any CAR T-cell toxicities will require a skilled multidisciplinary team, including nurses and subspecialty consultants — specifically, critical care and neurology. In addition, it is critical that interleukin-6 inhibitors be immediately available from the pharmacy, along with appropriate laboratory, imaging and electroencephalogram services.
These guidelines represent a vital resource for optimizing the management of CAR T-cell complications, especially for less experienced centers. As the authors note, new CAR T-cell targets and platforms may present new toxicities; revisions to these guidelines will undoubtedly be needed as the field continues to evolve.
Neelapu and colleagues have written an admirably comprehensive review of CRS and other toxicities of CAR T-cell therapy. The review points out salient characteristics of CRS, grading and suggestions for therapy. Key points that treating clinicians should be aware of include that CRS is an on-target toxicity of CAR T cells and worse in patients with high disease burden, including need for ICU-level support.
The vast majority of the experience comes from CD19 CAR studies with two costimulatory domains: 4-1BB — which includes CTL019/tisagenlecleucel and now JCAR17 (Juno Therapeutics) — and CD28, which includes JCAR15 (Juno Therapeutics), with academic studies at Memorial Sloan Kettering Cancer Center and NIH, and axicabtagene ciloleucel (KTE-C19, Kite Pharma). Tisagenlecleucel is FDA approved and axicabtagene ciloleucel is likely to be approved this year. 4-1BB and CD28 products can be similar regarding CRS, but seem to differ in neurotoxicity, with cerebral edema — including five fatal cases — associated with CD28 CARs.
It is important to point out that there are some areas where the review appears to exceed the data and experience currently available. To give several examples:
• The authors suggest that tocilizumab (Actemra, Genentech) or siltuximab (Sylvant, Janssen Biotech) are interchangeable for initial management of CRS. In the absence of data demonstrating this, using either drug first is not recommended. Physicians are better advised to use tocilizumab, now indicated for CRS, prior to using siltuximab, which we and others have reserved for third line after tocilizumab and steroids.
• The authors suggest that all patients should be admitted for observation at the time of infusion. In more than 150 patients infused at Children’s Hospital of Philadelphia over 5.5 years, we have not found this to be necessary. The initial presenting symptom of CRS — which precedes all other significant symptoms — is fever. Thus, infusion in the clinic followed by admission for fever has been safe in our extended patient experience. Patients with ALL with low disease burden can have minimal symptoms, so mandatory admission is not justified.
• The section on macrophage activation syndrome misses a central point, which is that it overlaps with CRS substantially. Most patients with grade 2 or higher CRS meet diagnostic criteria for macrophage activation syndrome, and early use of etoposide or intrathecal cytarabine is entirely speculative.
References:
Maude SL, et al. N Engl J Med. 2014;doi:10.1056/NEJMoa1407222.
Teachy DT, et al. Cancer Discov. 2016;doi:10.1158/2159-8290.CD-16-0040.
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