Management guidelines for paediatric patients receiving chimeric antigen receptor T cell therapy

Abstract

In 2017, an autologous chimeric antigen receptor (CAR) T cell therapy indicated for children and young adults with relapsed and/or refractory CD19 acute lymphoblastic leukaemia became the first gene therapy to be approved in the USA. This innovative form of cellular immunotherapy has been associated with remarkable response rates but is also associated with unique and often severe toxicities, which can lead to rapid cardiorespiratory and/or neurological deterioration. Multidisciplinary medical vigilance and the requisite health-care infrastructure are imperative to ensuring optimal patient outcomes, especially as these therapies transition from research protocols to standard care. Herein, authors representing the Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) Network Hematopoietic Stem Cell Transplantation (HSCT) Subgroup and the MD Anderson Cancer Center CAR T Cell Therapy-Associated Toxicity (CARTOX) Program have collaborated to provide comprehensive consensus guidelines on the care of children receiving CAR T cell therapy.

Mechanisms of resistance to CAR T cell therapy

“…No article on CAR T cell therapy would be complete without a discussion of the related toxicities, particularly CRS; however, several in-depth reviews of the current state-of-the-art knowledge and management of CAR T cell-related toxicities have been published in this journal and elsewhere over the past few years [136][137][138][139][140][141][142] . Notably, efforts are underway to establish uniform multicentre grading scales and, in this regard, the original CRS grading scale proposed by Lee et al 141 has now been updated and published as the American Society for Blood and Marrow Transplant consensus guidelines 143 .…”

Psychosocial care for children receiving chimeric antigen receptor (CAR) T‐cell therapy

“…Notably, mental status examination of the pediatric patient is highly dependent on the developmental stage of the child. Accordingly, the Cornell Assessment of Pediatric Delirium (CAPD) has been recommended as a tool to guide the diagnosis and grading of neurologic toxicity until more sensitive mechanisms are identified 6 . As symptoms of neurologic toxicity may develop and progress rapidly, systematic evaluation of cognitive function and neurologic symptoms at baseline and along the treatment trajectory is necessary and may lead to earlier identification and intervention 6,77 .…”

“…Engaging patients and caregivers in care can lead to decreased distress and improved quality of life 80,81 . Until the symptom experience of CAR T cells is better understood, we must heavily rely on partnership with the patient and the family as part of the care team 6 . This is especially important as some of the symptoms of CRS and neurotoxicity are subtle and best recognized by the parents and family caregivers 82 .…”

“…As the availability of CAR T‐cell therapy grows, there is an increasing need for standardization of care and recommendations specific to the unique challenges and opportunities accompanied by this novel therapeutic paradigm. We hope to use this hypothetical case presentation to provide an initial road map for navigating clinical and psychosocial practice scenarios for children and adolescents undergoing CAR T‐cell therapies, supplementing existing consensus statements with expert opinion specifically addressing interdisciplinary psychosocial support 6,7 …”

Chimeric antigen receptor T‐cell therapy in patients with neurologic comorbidities

“…The incidence of grade 3 or greater CRS has ranged anywhere from 13% to 47% in prospective studies and can be treated with the anti‐interleukin (IL)‐6 receptor antibody tocilizumab. The other major toxicity seen with CAR‐T therapy is neurotoxicity, also known as immune effector cell‐associated neurotoxicity syndrome (ICANS) or CAR‐T cell–related encephalopathy syndrome (CRES) . Symptoms are diverse and include headache, confusion, expressive aphasia, apraxia, and myoclonus and can progress to severe encephalopathy, including seizures, obtundation, and even rarely cerebral edema.…”