Acute life-threatening toxicity from CAR T-cell therapy
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WHAT’S NEW IN INTENSIVE CARE
Acute life‑threatening toxicity from CAR T‑cell therapy Elie Azoulay* , Michael Darmon and Sandrine Valade © 2020 Springer-Verlag GmbH Germany, part of Springer Nature
Chimeric antigen receptor (CAR) T-cell therapy is an effective adoptive cell treatment that constitutes a powerful new class of therapeutic agents to treat patients with B‐cell leukemia and lymphoma [1]. It uses patient’s T lymphocytes harvested through cytapheresis and manipulated ex vivo to express specific antigens before infusion back to the patient. Although the clinical responses are beyond expectations, CAR T-cells also frequently produce life-threatening acute toxicities [2], chiefly the cytokine-release syndrome (CRS) and neurotoxicity (Fig. 1). Tumor lysis syndrome that has been reported in up to 5% of the patients in the first trials, is not discussed in this short article. Obviously, in these high risk immunocompromised patients with altered B cell and T cell response and frequent neutropenia, sepsis should be ruled out and treated empirically. In this what’s new paper, we have listed the top ten tips to manage critically ill CAR T-cell recipients.
Learning from oncology Many ICU specialists are used to manage the toxicity of checkpoint inhibitors that allow the potentiation of T-cell specific immune responses against tumor cells. Uncontrolled multi-organ immune-related adverse events occur rarely with checkpoint inhibitors [3], but life-threatening toxicity affects 1% of the treated patients [4] and management share common points with CAR T-cell-related toxicity. Namely, (1) early resuscitation; (2) careful clinical examination to assess severity and rule out infection; (3) empirical antibiotics; (4) close collaboration with oncologists and hematologists and (5) anti-inflammatory therapy, mostly relying on steroids.
*Correspondence: [email protected] Médecine Intensive Et Réanimation, APHP, Hôpital Saint‑Louis, Paris Diderot Sorbonne University, Paris, France
CAR T‑cell Therapy: the miracle from adoptive immunotherapy Currently, two types of anti-CD19 CAR T-cell therapies (tisagenlecleucel and axicabtagene-ciloleucel) are available for B malignancies. Impressive short and longer term outcomes have been reported [5–7]. CAR T-cells recipients are patients refractory to several lines of chemotherapy, and sometimes stem cell transplantation. Yet, more than half the patients have progression-free survival at 1 year [5–7] and longer term survival is close to 50%, most particularly with the second generation CARs [8]. Rule out sepsis Unsurprisingly, CAR T-cell recipients are at high risk of sepsis. In a study including 133 patients, Hill et al. reported infectious episodes within 28 days after infusion in 23% of the patients (1.19/100 days) [9]. A second study reported that 22/53 patients (42%) presented with infections within 30 days after infusion [10]. Most infections are diagnosed within 10 days after CAR-T cells infusion (median 6 days). Severe CRS was independently associated with infection [9]
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