The chimeric antigen receptor-intensive care unit (CAR-ICU) initiative: Surveying intensive care unit practices in the management of CAR T-cell associated toxicities
Introduction
Chimeric antigen receptor (CAR) T-cell therapy has proven to be a promising area in cancer treatment. Durable remissions in up to 50% of patients have been demonstrated in relapsed refractory acute lymphoblastic leukemia (ALL), large B-cell lymphoma, mantle cell lymphoma and most recently in multiple myeloma [[1], [2], [3], [4], [5], [6]]. Toxicities associated with CAR T-cell therapy, particularly cytokine release syndrome (CRS) and Immune Effector Cell Associated Neurotoxicity Syndrome (ICANS), are reversible but can be associated with significant morbidity, with up to 47% of patients requiring Intensive Care Unit (ICU) admission [1,2,4,7,8]. CRS presents as a range of clinical symptoms including fever to hypoxia and/or hypotension which can progress to circulatory shock, acute respiratory failure and multi-organ failure [[9], [10], [11]]. ICANS is a complex syndrome characterized by varying degrees of encephalopathy, dysgraphia, aphasia, seizures, motor deficits and, in severe cases status epilepticus and cerebral edema [9,10,12]. Numerous guidelines for grading and management of these toxicities exist [1,7,9,10,[13], [14], [15], [16]], and a recent consensus has achieved some homogeneity in grading of CRS and ICANS across centers [9].
Despite the high acuity of illness observed with CRS and ICANS, there is limited data and consensus in management of critically ill patients with CAR T-cell therapy toxicities. Current treatment recommendations of grade 3 and 4 toxicities are based on clinical experience and extrapolation of practices and guidelines from other causes of critical illness (e.g. sepsis) [13]. It is unclear how these practices and interventions in the ICU affect the outcomes of this patient population, where the cause of CRS and ICANS is different from common causes of shock, respiratory failure and encephalopathy. In order to improve ICU care, data driven interventions are necessary.
In an effort to address these knowledge gaps, we created a working group of critical care, hematology-oncology and infectious disease specialists from 11 centers in the United States (US) called the CAR-ICU initiative. Our focus is to conduct research on monitoring and management strategies to improve the care of critically ill patients following CAR T-cell therapy. In order to optimize the care of these patients, we must first understand current practices in the ICU management of CAR mediated toxicities. Utilizing a survey, we assessed the structure and practices of care for CAR patients in different ICUs. Our results, reported here, identified areas for further research into novel interventional strategies that could improve patient outcomes.
Section snippets
Materials and methods
This study was conducted in accordance with the amended Declaration of Helsinki. Local institutional review boards or independent ethics committees approved the protocol; the study was approved by the Institutional Review Board (PA19–0289) at MD Anderson Cancer Center (MDACC). This survey was developed and reviewed by a multidisciplinary group of physician and pharmacy experts in CAR T-cell toxicity assessment and treatment. The survey was distributed electronically through REDCap hosted by
Results
All 11 hospitals (100%) completed the survey. Participating centers included: MD Anderson Cancer Center, Memorial Sloan Kettering Cancer Center, Seattle Cancer Care Alliance/University of Washington Medical Center, Massachusetts General Hospital, Barnes Jewish Hospital, National Institutes of Health Clinical Center, Mayo Clinic, Roswell Park Comprehensive Cancer Center, University of Miami Cancer Center, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital and Cleveland
Specifics of CAR T-cell products
The type of CAR products used at each institution varied (Table 1). Nine centers (82%) were using commercial products: axicabtagene ciloleucel and/or tisagenlecleucel. Ongoing protocols from pharmaceutical companies were being studied at 9 centers (82%); 4 centers (36%) had products created at their institution. Three of the 11 centers (27%) had experience using all 4 different types of products. In addition to treating patients with CAR T-cells, 7 centers (64%) were also treating patients with
Criteria for ICU admission
The ASTCT grading for CRS and ICANS was used to assess criteria for ICU admission across centers (Table 2) [9]. Eight centers (73%) admitted patients with grade 1 and 2 CRS for close monitoring. One institution admitted all patients being infused with CARs to the ICU because of no available intermediate care unit to monitor these patients. Patients requiring vasopressors, continuous renal replacement therapy (CRRT), high flow nasal cannula (HFNC), bilevel positive airway pressure ventilation
CAR toxicities and management
Assessment of practices specific to the treatment of CAR related toxicities was determined by evaluating the use of tocilizumab, siltuximab, anakinra and corticosteroids (Table 3). Use of tocilizumab, was similar amongst institutions and limited to CRS, or neurotoxicity with accompanying CRS symptoms (n = 9; 82%). Siltuximab, utilized in 6 centers (55%), was reserved for patients with grade 3–4 CRS refractory to tocilizumab. Anakinra was used in 6 centers (55%) and commonly for refractory grade
Interventions in the intensive care unit
Interventions for hemodynamic support were similar between all institutions. All centers used norepinephrine as the first vasopressor agent for grade 3 CRS but some variability was observed when choosing a second and third vasopressor (Table 2). Choice of intravenous fluids for resuscitation and assessment of volume responsiveness varied widely between institutions (Table 2). Seven centers (64%) routinely perform echocardiograms once shock occurs during CRS. Non-cardiogenic pulmonary edema was
Discussion
Our survey showed that participating centers in the CAR-ICU initiative use similar ICU admission criteria for neurotoxicity but not for CRS. Practices for vasopressor administration, neurotoxicity monitoring, utilization of EEG, prophylactic AEDs and tocilizumab use were comparable. In contrast, fluid resuscitation, respiratory support, methods of surveillance and management of cerebral edema, corticosteroid and other anti-cytokine therapies varied within centers. Our survey identified areas of
Conclusion
The CAR-ICU initiative survey revealed important similarities as well as differences in the management of CAR patients in select ICUs across the US. The variability in practices created opportunities for possible future collaborative investigations. Continuing this initiative will help us gather baseline data on critically ill CAR patients and better design interventions that could help improve outcomes of this complex patient population.
Guarantor
CG had full access to the data and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Author's contributions
CG, ARTB and SSN designed, reviewed and edited the study and survey prior to its distribution. ARTB, CG, SSN contacted the centers to participate in the CAR-ICU initiative and distributed the survey. CG, ARTB, SMP, PR, BH, CJT, KP, YL, HPM, MVM, MJF, JNB, JA, AD, AB, CM, RSS, after discussing with co-authors within their institution, provided the answers to the survey according to practices within their institution and provided clarification if requested by CG. CG, ARTB, SMP, PR, CJT, KP, YL,
Declaration of Competing Interest
CG, ARBT, CM, MMH, PR, AD, AD, EM, JA, JNB, MVM, NNS, JLN, KP, RSS, SSK, SMP, HPM, AGM, ASA have no conflict of interest to declare.
BH: has received research funding from Kite Pharmaceuticals. Have also served as a consultant to Juno, Novartis and Kite Pharmaceuticals.
CJT: receives research funding from Juno Therapeutics and Nektar Therapeutics; is a Scientific Advisory Board member for Precision Biosciences, Eureka Therapeutics, Caribou Biosciences, Myeloid Therapeutics, T-CURX, and Arsenal
Acknowledgements
CG, ARTB, SSN, BH, MH, CJT, LY, MVM, MJF, JNB, NNS, JK, AB, EM, RSS and Dr. Philip McCarthy from Roswell Park Comprehensive Cancer Center had input within their institution in the creation of treatment guidelines for the management of complications associate to CAR T-cells. We'd like to acknowledge the CARTOX committee at MDACC for their work in the monitoring and creation of guidelines of CAR patients within the institution. MD Anderson Cancer Center, Memorial Sloan-Kettering Cancer Center,
Funding
This study was supported in part by the National Institutes of Health through Cancer Center Support Grant P30CA016672 and in part by the Intramural Research Program of the NIH Clinical Center and NHLBI respectively.
Disclaimer
The findings and conclusions in this study are those of the authors and do not necessarily represent the official position of the National Institutes of Health.
Research data will be available only after review and approval by the Institutional Review Board at MD Anderson Cancer Center.
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