Editor: Deborah Sesok-Pizzini, MD, MBA, professor, Department of Clinical Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, and chief, Division of Transfusion Medicine, Children’s Hospital of Philadelphia.
Chimeric antigen receptor T-cell therapy assessment and management of toxicities
In August, the FDA approved the gene therapy Kymriah (tisagenlecleucel) for pediatric and young adult patients with a form of acute lymphoblastic leukemia. Chimeric antigen receptor (CAR) T-cell therapy is a breakthrough in the treatment of leukemia and lymphoma, but it is associated with unique acute toxicities, such as cytokine-release syndrome and CAR-T-cell-related encephalopathy syndrome. While intensive monitoring and prompt management of toxicities is essential to minimizing related morbidity and mortality, algorithms to accurately and consistently grade and manage the toxicities are lacking. To address this problem, the authors formed a CAR-T-cell-therapy-associated toxicity (CARTOX) working group comprising investigators from multiple institutions and medical disciplines who have experience treating patients receiving CAR-T-cell therapy. The authors described algorithms for monitoring, grading, and managing the acute toxicities that may occur in patients treated with CAR-T-cell therapy. Reactions to such therapy may be severe or even fatal. The most commonly observed toxicity was cytokine-release syndrome, which ranges from low-grade constitutional symptoms to a high-grade syndrome associated with multiorgan dysfunction or, rarely, haemophagocytic lymphohistiocytosis. These reactions are due to an escalated immune response in the CAR-T-cell recipient. The second most common toxicity is CAR-T-cell-related encephalopathy syndrome, a reaction that may lead to fatal cerebral edema. The authors recommend hospitalization with monitoring for at least seven days after CAR-T-cell infusion. Monitoring consists, in part, of daily blood counts with differential, complete metabolic profiling, and coagulation profiling, as well as measurement of C-reactive protein and ferritin levels daily, starting on the day of infusion. Assessment and grading of cytokine-release syndrome and CAR-T-cell-related encephalopathy syndrome is also important. Due to the risk of severe reactions with CAR-T-cell therapy, the FDA restricts the use of tisagenlecleucel to certified centers. The centers are required to have personnel trained in prescribing, dispensing, and administering the therapy, as well as recognizing and managing cytokine-release syndrome and other neurological events. The newly developed recommendations can serve as a guideline for assessing and managing the toxicities associated with CAR-T-cell therapy and, potentially, other gene therapies that may cause similar acute toxicities.
Neelapu SS, Tummala S, Kebriaei P, et al. Chimeric antigen receptor T-cell therapy—assessment and management of toxicities [published online ahead of print September 19, 2017]. Nat Rev/Clin Oncol. doi:10.1038/nrclinonc.2017.148.
Correspondence: Dr. Sattva S. Neelapu at sneelapu@mdanderson.org
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Impact of age of red cells on transfusion and outcomes in critically ill adults
The question of whether the duration of red cell storage affects mortality after transfusion in critically ill adults has been debated widely. Two recent trials, the Age of Blood Evaluation (ABLE) and Informing Fresh Versus Old Red Cell Management (INFORM) trials, showed no significant differences in outcome between patients who received fresher red cells and those who received older red cells. The authors designed the Standard Issue Transfusion Versus Fresher Red-Cell Use in Intensive Care (TRANSFUSE) trial to compare the effects of the freshest available red cells with those of standard-issue (oldest available) red cells in 5,000 high-risk critically ill patients. They hypothesized that administering the freshest available red cells would result in lower 90-day all-cause mortality than administering standard-issue red cells. The authors’ multicenter, randomized, double-blind, parallel-group trial was conducted in 59 hospital intensive care units in five countries: Australia, New Zealand, Ireland, Finland, and Saudi Arabia. The primary analysis involved 4,919 patients 18 years of age or older who had an anticipated ICU stay of at least 24 hours. Among the 2,457 patients in the short-term storage group, the mean red cell storage duration was 11.8 days. Among the 2,462 patients in the long-term storage group, the mean red cell storage duration was 22.4 days. At 90 days, there were 610 deaths in the short-term storage group and 594 in the long-term storage group, and the absolute risk difference was 0.7 percentage points (P = 0.57). The authors concluded that there were no significant differences in 90-day mortality according to the duration of red cell storage. Only a nominal difference in febrile nonhemolytic transfusion reactions was observed, with reactions occurring more frequently in the short-term storage group. The clinical significance of this finding was uncertain. With regard to primary or secondary outcomes, the authors concluded that there was no benefit, either overall or in most subgroups, to transfusing the freshest available red cells. This supports the current practice of transfusing patients with the oldest blood available.
Cooper DJ, McQuilten ZK, Nichol A, et al. Age of red cells for transfusion and outcomes in critically ill adults. N Engl J Med. 2017:e1–e10. doi:10.1056/NEJMoa1707572.
Correspondence: Dr. James Cooper at jamie.cooper@monash.edu