EBMT and JACIE recommendations for the management of CAR T-cell therapy

To date, two chimeric antigen receptor (CAR) T-cell-based therapies have been approved for a number of hematological malignancies in USA and Europe, axicabtagene ciloleucel and tisagenlecleucel.^1,2 Despite the targeted nature of CAR T-cell therapies, life-threatening toxicities are still associated with their use. The main CAR T-cell-associated complications have been divided in to three broad categories. Short-term, medium-term and long-term follow-up (LTFU) complications are referred to as those occurring between day(s) zero and 28, 28 and 100 or 100 plus after CAR T-cell infusion, respectively. The necessary precautions required for a successful CAR T-cell regimen are complex, and the need for routine guidelines has become apparent.³

In December 2018, the Practice Harmonisation and Guidelines Subcommittee of the Chronic Malignancies Working Party (CMWP) of the European Society for Blood and Marrow Transplantation (EBMT) proposed a project to define practical clinical recommendations on the management of adults and children undergoing autologous CAR T-cell therapy. The EBMT board accepted the proposal and Ibrahim Yakoub-Agha, Lille University Hospital, Lille, FR, presented a summary of the first EBMT and Joint Accreditation Committee of ISCT and EBMT (JACIE) recommendations at the 2^nd European CAR T-Cell Meeting, Sitges, ES.^3,4 The guidelines are based on survey responses from active CART centers and a literature review performed by the authors. They aim to provide recommendations for individuals involved in the administration of CAR T therapies and act as a useful resource for other stakeholders, such as pharmacists and health service administrators. We hereby provide a comprehensive summary of these published guidelines.

Patient eligibility

• Eligibility (Table 1) for CAR T-cell therapy must be decided at a multi-disciplinary team meeting in a designated CAR T center

Table 1. EBMT CAR T-cell therapy eligibility criteria

Screening laboratory tests and imaging

• The minimum required patient eligibility assessments are shown in Table 2

Table 2. Minimum required tests for patient eligibility

Minimum required laboratory tests before apheresis

• Prior to the guidelines, regulations were based on the donor-recipient relationship irrespective of the intended use
• The novel guidelines regarding the necessary procedures prior to apheresis are given in Table 3

Table 3. Apheresis checklist

Performing leukapheresis

• Leukapheresis must be coordinated with the manufacturing company prior to start date confirmation
• A pre-existing quality management system (QMS) must be confirmed prior to leukapheresis
  • The QMS must comply with the 7^th edition of the FACT-JACIE standards for hematopoietic cellular therapies or FACT standards for immune effector cells
• Identification of infectious disease markers in peripheral blood, sterility testing, and hemocytometry should be carried out on the day-of-collection

Bridging therapy

• Although the ideal bridging therapy regimen is disease- and patient-specific, there are a number of uniform factors for consideration:

• Patients receiving chemotherapy will be at risk of developing cytokine release syndrome (CRS), encephalopathy or tumor lysis syndrome following lymphodepletion (LD)
• Bridging therapy should not induce infections, bleeding or organ dysfunction that could interfere with LD and CAR T-cell infusion
• Immunotherapeutic drugs with a longer half-life may interfere with the expansion or persistence of the infused CAR T-cells
• Bridging therapy should be given after leukapheresis to prevent interference with T-cell therapy
• Frequent monitoring of patients after leukapheresis as well as during and following bridging therapy at specialist centers is compulsory

LD conditioning

• Factors to consider prior to LD conditioning are shown in Table 4
• Factors requiring laboratory testing prior to LD conditioning are shown in Table 5

Table 4. Considerations prior to LD conditioning

Table 5. Routine laboratory testing prior to LD conditioning

CAR T- cell infusion

• CAR T-cell infusion should be carried out using a transfusion filter set with a 50-200μm pore size
• Fluid infusion sets and transfusion sets with leukocyte depletion filters should not be used
• Pre-medication to prevent adverse reactions is acceptable, however, corticosteroids must be avoided as they may damage the CAR T product
• Concurrent medication must not be given during CAR T-cell infusion
• Patients must be assessed before the onset of CAR T product thawing, and CAR T-cell infusion may be delayed in the case of:
  • Active infection
  • Cardiac arrhythmia not controlled with medical management
  • Hypotension requiring vasopressor support
  • Non-hematologic organ dysfunction
  • Significant worsening of the clinical condition since the start of LD

Management of short-term complications

• Patients must be able to access a trained coordinator 24 hours a day, seven days a week
• 14 days of hospitalization following CAR T-cell therapy
• Patients must be located within 60 minutes of the treating unit following hospital discharge until day 28 following CAR T infusion
• Anti-infective prophylaxis following CAR T-cell therapy is infection-dependent

CRS and neurotoxicity

• As the most common complications following CAR T-cell infusion, CRS and neurotoxicity must be monitored daily using both behavioral observations and laboratory testing methods
• First- and second-line treatment for severe cases of CRS are tocilizumab plus corticosteroids and siltuximab respectively
• Daily writings tests following CAR T-cell infusion should be used to detect incipient immune effector cell-associated neurotoxicity syndrome (ICANS)
• Cross-sectional imaging, electroencephalography, and cerebrospinal fluid examination should be used in the management of patients with severe neurotoxicity
• Anti-epileptic prophylaxis is only recommended in patients with a history of seizures or central nervous system disease
• ICANS severity has been associated with the severity and early onset of CRS
• The American Society for Transplantation and Cellular Therapy (ASTCT) consensus panel replaced the CARTOX scoring system with the ICE score
• Table 6 illustrates the measures for screening delirium in children
• CRP and ferritin levels should be monitored daily as they are indicative of CRS and neurotoxicity development

Table 6. Encephalopathy assessment in children < 12 years

 Management of medium-term complications

• The guidelines for testing and managing medium-term complications are shown in Table 7

Table 7. Management of medium-term complications

LTFU

• The clinic should routinely measure cardiovascular, gastrointestinal, liver, respiratory, endocrine, reproductive and bone health, disease status, further treatments, infections, immunological status, new cancers, autoimmunity and neurological and psychological status
• To address the uncertainty surrounding long-term effects of CAR T-cell therapy the guidelines in Table 8 have been put in place

Table 8. Tests to be performed at the LTFU clinic

Conclusions:

• Until now, management of patients receiving CAR T-cell therapy has been clinical trial-, location- and product-specific
• The novel guidelines provide the first routine measures to enhance global uniformity of CAR T-cell therapy