Table 1 Summary of key recommendations for the use of CAR T cell therapy

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

Recommendations Level of evidence Grade
Providers are encouraged to adhere to product information labels and guidance from REMS programmes as they are approved by the FDA8 IV D
Patient selection should be based upon the indications approved by the FDA and the criteria used in pivotal studies and can be tailored on the basis of emerging information from each new product8,9,49 IV D
Consent should include descriptions of the risks and benefits associated with leukapheresis, lymphodepletion, CRS, CRES, bridging chemotherapy, intensive-care support (mechanical ventilation, dialysis, and inotropic support), and anti-IL-6 therapy38 IIA B
When appropriate, child assent should also be obtained; age-appropriate advance directives should be considered. Incorporation of child life and psychological services in assent discussions can be helpful44 IV D
Paediatric patients can require a leukapheresis catheter for cell collection. Close monitoring for hypotension, hypocalcaemia, and catheter-related pain is imperative during paediatric leukapheresis, particularly among infants and younger children who might not verbalize symptoms47,48 IIA B
We recommend the selection of cyclophosphamide–fludarabine regimens for lymphodepletion, with exceptions considered in cases of haemorrhagic cystitis and/or resistance to a prior cyclophosphamide-based regimen9,4664,78,79,80,81 IIA B
Given the potential for rapid clinical deterioration, if CAR T cell therapy is administered in an outpatient setting, a low threshold should be set for patient admission upon the development of a fever and/or signs or symptoms that are suggestive of CRS and/or CRES38 IIA B
On the basis of the published experience for tisagenlecleucel in paediatric and young adult patients with CD19+ relapsed and/or refractory B cell acute lymphoblastic leukaemia, considering inpatient admission for a minimum of 3–7 days following infusion is reasonable8,38 IIA B
CRS grading should be performed as outlined in Table 2 at least once every 12 hours and more often if a change is noted and/or concerns exist37 IIA B
Parent and/or caregiver concerns should be addressed because early signs or symptoms of CRS can be subtle and best recognized by those who know the child best98 III C
CRS should be suspected if at least one of the following four symptoms or signs is present during the CRS-risk period within the first 2 weeks following CAR T cell infusion: fever ≥38 °C; hypotension (for patients aged 1–10 years: systolic blood pressure <(70 + (2 × age in years)) mmHg; for those aged >10 years: SBP <90 mmHg); a change from baseline and/or reduced requirements for chronic anti-hypertensive medications); hypoxia with an arterial oxygen saturation of <90% on room air; or evidence of organ toxicity as determined by the most recent CTCAE grading system (version 5.0)99 and paediatric considerations as outlined in Table 2 (refs29,37,82) IIA C
High vigilance for sinus tachycardia as an early sign of CRS is recommended (on the basis of age-specific normal range or baseline values)103,104 IIA B
We recommend application of the PALICC at-risk P-ARDS criteria for the CRS grading of hypoxia100,101,102 IIA B
Acute kidney injury in children can be graded according to CTCAE using pRIFLE and KDIGO definitions of oliguria105,106 IIA B
Tocilizumab paediatric dosing: patients weighing <30 kg are dosed at 12 mg/kg, and those weighing ≥30 kg are dosed at 8 mg/kg (ref.109) IIA B
CAR T cell-related HLH and/or MAS have been shown to resolve following administration of anti-IL-6 therapy and corticosteroids, although refractory cases can require further therapy, including consideration of systemic and/or intrathecal therapy on the basis of HLH-2004 management guidelines or use of the IL-1 receptor antagonist anakinra; further research is needed in this area62,113,114 IIA C
We recommend that delirium screening using the CAPD tool116 (or the CARTOX-10 grading system37 for patients aged ≥12 years who have sufficient cognitive abilities) be performed at least twice per 24-hour period among admitted patients and at least daily among outpatients during the high-risk periods for CRES IIA C
Consideration should be given to a prospective collaboration with intensive-care registries, such as VPS, which could allow accurate data entry of cell-therapy variables into the CIBMTR registry (by cell-therapy programmes) with concurrent entry of intensive-care variables into an appropriate registry by paediatric critical care teams IV D
We strongly encourage consideration of QALYs for paediatric patients who might achieve long-term remission through this therapy and encourage all efforts to reduce the cost of care136,137,138,139,140 IV D
We recommend that CAR T cell programmes seek FACT IEC accreditation as a voluntary means of ensuring adherence to quality standards55 IV D
  1. Levels and grades of evidence have been assigned on the basis of the definitions proposed by Shekelle et al.40 (see Supplementary Table 1 for details). CAPD, Cornell Assessment of Pediatric Delirium; CAR, chimeric antigen receptor; CARTOX-10, CAR T Cell Therapy-Associated Toxicity 10-point assessment scale; CIBMTR, Center for International Blood and Marrow Transplant Research; CRES, CAR T cell-related encephalopathy syndrome; CRS, cytokine-release syndrome; CTCAE, Common Terminology Criteria for Adverse Events; FACT, Foundation for the Accreditation of Cellular Therapy; HLH, haemophagocytic lymphohistiocytosis; IEC, immune effector cell; KDIGO, Kidney Disease: Improving Global Outcomes; MAS, macrophage-activation syndrome; P-ARDS, paediatric acute respiratory distress syndrome; PALICC; Pediatric Acute Lung Injury Consensus Conference; pRIFLE, Pediatric Risk, Injury, Failure, Loss, End-Stage Renal Disease; QALYs, quality-adjusted life years; REMS, risk evaluation and mitigation strategy; SBP, systolic blood pressure; VPS, virtual paediatric intensive-care unit (PICU) Systems.