This article is more than 5 years old. Information may no longer be current.
Pediatric CAR T-cell therapy guidelines highlight need for interdisciplinary monitoring
Click Here to Manage Email Alerts
Children treated with chimeric antigen receptor T-cell therapy experience unique toxicities that require careful monitoring to prevent serious sequalae, according to new management guidelines.
An educated interdisciplinary team — including nurses, trainees, intensivists and cell therapists — is essential to identify early signs and symptoms of cytokine release syndrome (CRS) and chimeric antigen receptor (CAR)-T-cell-related encephalopathy syndrome (CRES), the two most common toxicities associated with CAR T-cell therapy.
In November 2017, the FDA approved tisagenlecleucel (Kymriah, Novartis) for the treatment of children with acute lymphoblastic leukemia.
“As this approval moved to standard of care in pediatrics, we though that it was important to have guidelines that would provide a universal framework for this and other products that may be approved,” Kris M. Mahadeo, MD, MPH, section chief and medical director of pediatric stem cell transplantation and cellular therapy at The University of Texas MD Anderson Cancer Center, told HemOnc Today. “We recognized that there wasn’t going to be a one-size-fits-all approach, but that we needed some sort of overarching infrastructure in place in order to have this therapy safely delivered across institutions, outside of the context of a clinical trial.”
Last year, researchers from MD Anderson Cancer Center published guidelines about the management of patients undergoing CAR T-cell therapy, focused primarily on adults.
Experts from the hematopoietic stem cell transplant subgroup of the Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) Network and the CAR T-cell Therapy-Associated Toxicity Program (CARTOX) at MD Anderson Cancer Center worked to create pediatric-focused guidelines, as recognition of toxicities among children may present subtly.
Managing CRS
One of the most important elements of the guidelines are the algorithms for grading and managing CRS and CRES, according to Mahadeo.
Both toxicities are graded between grade 1 and grade 4 depending on the severity of symptoms, and then are managed accordingly.
“The CRS and CRES tables provide a very detailed outline so that anyone — including nurses, intensivists, neurologists, fellows, and those in emergency and urgent care centers — can look at a child and use this tool to score them, which will allow for early recognition of these signs and symptoms and hopefully lead to early treatment,” Mahadeo said.
CRS is often defined by a rise in heart rate and fever. However, in pediatric patients, “normal” heart rate is defined based on age and can be influenced by the activity of the child or stranger anxiety. Additionally, children with a fever will have a high heart rate.
“In pediatrics, a child that is crying or a child that is moving a lot will also have an elevated heart rate, so it’s really important to determine the child’s baseline heart rate and take the whole thing into context,” Mahadeo said. “Having trained staff across institutions and across departments in pediatrics is important to ensure high vigilance to the fact that there are age-based norms.”
Managing CRES
It has been well established to use Common Terminology Criteria for Adverse Events v5.0 or other algorithms to assess for delirium or CRES among adults. However, these methods are not optimal for infants and young children, according to the guidelines.
In the adult CAR T-cell guidelines published last year, the authors recommended looking at changes in handwriting as an early sign of CRES, something that could not be applied to younger children.
For children, the new guidelines recommended using the Cornell Assessment of Pediatric Delirium (CAPD), which is a validated delirium screening tool for use among children and adolescents aged from birth to 21 years old.
“When you look at the early signs of CRES, you’re going to be relying on people who know the child best for their baseline,” Mahadeo said.
The CAPD test adds a point to a patient’s score if the parent or caregiver at the bedside has a concern about the child.
“We’re hoping these guidelines increase early detection of these toxicities, just because a lot of these signs and symptoms can be either missed or confused for something else,” Mahadeo said.
Patient selection, cell infusion
In addition to recommendations on the grading and management of toxicities, the guidelines included information on patient selection, bridging chemotherapy and postinfusion monitoring.
According to the guideline authors, the FDA approved indications should guide patient selection. However, emerging data could potentially expand eligible patients. Product information labels should dictate selection and treatment protocol.
Further, clinicians should consider active infections, graft-versus-host disease and active central nervous system pathology when selecting patients for treatment.
After leukapheresis for CAR T-cell production, bridging chemotherapy can be used while patients wait for infusion, according to the guidelines. Clinicians should carefully select a regimen to minimize toxicities, while maintaining disease control and preventing progression.
At the time of CAR T-cell infusion, patients should be free of uncontrolled infections or other contradictions, including active HCV or HIV infection, severe acute or chronic extensive GVHD, and pregnancy.
Patients can be monitored via inpatient or outpatient care after consideration of several factors, including toxicity profiles of the CAR T-cell product, institution protocol, availability of prompt care, presence of a responsible caregiver and clinical status of the patient, according to the guidelines.
Health system considerations
A significant motivation in writing these guidelines included setting up a framework for the management of CAR T-cell therapy as the FDA approved more agents, Mahadeo said.
The guideline authors recommend programs seek immune effector cell accreditation by the Foundation for the Accreditation of Cellular Therapy as a voluntary means of ensuring adherence to quality standards.
“To gain this accreditation, it helps make sure you’ve put into place the mechanisms to provide safe delivery of this type of care,” Mahadeo told HemOnc Today. “Specific clinical management decisions for specific products obviously will need to be adapted as each product is approved. However, if you’ve trained your staff on the principles of looking for CRS and CRES, you’ll already have the overarching structure in place.”
Additionally, coordination and education of parents and caregivers, nurses and clinicians will help ensure toxicities are caught early and managed appropriately.
“The more attention that you get to the subspecialists within pediatrics that are going to interface with these patients, the more we’ll learn about this as time goes by,” Mahadeo said. “The best part of the guidelines is the interdisciplinary approach.” – by Cassie Homer
For more information:
Kris M. Mahadeo, MD, MPH, can be reached at The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, Texas 77030; email: kmmahadeo@mdanderson.org.
Disclosures: Mahadeo reports no relevant financial disclosures. Please see the guidelines for all other authors’ relevant financial disclosures.
Click Here to Manage Email Alerts