Scope
This guidance discusses the management of acute, early onset CAR-T cell therapy side effects, focusing on the most common immune effector cell (IEC) associated toxicities.
This guidance aims to standardise the management of acute CAR-T cell therapy side effects across CAR-T cell therapy treatment centres.
This guidance does not cover:
- management of non-IEC associated toxicities, for example, those associated with lymphodepleting therapy, tumour lysis syndrome or infections
- management of late onset CAR-T cell therapy side effects
- management of paediatric or adolescent patients
- Supportive medicines guidance for adults on CAR-T cell therapy (SPS page)
Clinical trials
This guidance supports the use of licensed CAR-T cell therapy products. Principles can be applied to CAR-T cell therapy clinical trials, but the clinical trial protocol must always be followed.
Recommended treatment pathways may not be applicable within the clinical trial setting and should be discussed with the trial Sponsor.
Introduction to CAR-T cell therapy side effects
CAR-T cell therapy is a type of IEC therapy. There are a range of unique toxicities associated with these therapies.
Patients receiving CAR-T cell therapy treatment may experience a variety of side effects, including IEC associated toxicities like cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Patients can also experience side effects related to lymphodepleting chemotherapy, tumour lysis syndrome and infections.
IEC toxicities can be divided into:
- acute or early onset (occurring within 30 days of infusion)
- late onset (occurring greater than 30 days after infusion)
Accurate assessment and prompt recognition and treatment of these side effects is essential as there is a high morbidity and mortality risk if treatment is delayed or suboptimal.
The incidence of CRS and ICANS varies between products and indications and can be found in the SmPC of each product.
Cytokine release syndrome (CRS)
CRS is the most common acute side effect of CAR-T cell therapy. Symptoms range from mild to life-threatening multi-organ failure.
It generally occurs within the first week after therapy although it can occur later.
Diagnosis and management of cytokine release syndrome (CRS) (SPS page) provides further information on the management of CRS.
Immune effector cell associated neurotoxicity syndrome (ICANS)
ICANS is another serious acute side effect. Symptom severity can vary from language disturbance, impaired handwriting, confusion and agitation to cerebral oedema and death.
It generally occurs within the first month after therapy although it can occur later.
Diagnosis and management of ICANS (SPS page) providers further information on the management of ICANS.
Immune effector cell – hyperinflammatory syndrome (IEC-HS)
IEC-HS is a rare, but very severe side effect that can occur after IEC therapy, characterised by prolonged immune activation. It overlaps with secondary haemophagocytic lymphohistiocytosis (HLH).
IEC-HS should be managed in line with the American Society for Transplantation and Cellular Therapy (ASTCT) IEC-HS consensus recommendations.
Emerging toxicities
Additional toxicities are emerging as experience with CAR-T cell therapy grows. These should be managed in line with emerging guidelines as they become available.
For a full overview of side effects and incidence, refer to the SmPC for each of the licensed CAR-T cell therapy products.
Monitoring
Regularly monitor for signs and symptoms of IEC toxicities in CAR-T cell therapy is required. It should be performed in line with the individual product SmPC, and national service specification.
Patients with suspected CRS or ICANS are at risk of rapid deterioration and may require organ support. More frequent monitoring allows for prompt intervention and treatment.
Alert the ICU team of any patient with suspected CRS or ICANS, regardless of NEWS2 score. This enables prompt transfer to ICU if required. Patients may be referred earlier to ICU than the recommended NEWS2 thresholds and triggers.
Uncertainty over the diagnosis or appropriate management of a patient, should be immediately escalated to the attending consultant.
Closely monitor patients until discharge, or as specified in the individual product SmPC, even after the resolution of symptoms.
Upon discharge, inform patients and their carers about the risk of delayed side effects and the management plan.
Toxicity grading systems
All UK CAR-T centres have adopted the ASTCT consensus grading system for IEC toxicities. These consensus toxicity definitions and grading criteria enable objective clinical grading and clear characterisation of the severity of toxicity that informs clinical management of IEC toxicities.
How this guidance has been produced
This guidance has been developed in collaboration with haematology consultants and pharmacists from CAR-T cell therapy treatment centres across the UK. It reflects current practice within the UK and is based on published literature and growing experience of product safety since the CAR-T programme began.
Some recommendations may differ from the current SmPC for each of the licensed CAR-T products.
This guidance is published and maintained by the Pharmacy ATMP Network UK (PAN UK).