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 2nd 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
ALL, acute lymphoblastic leukemia; allo-HCT, allogeneic hematopoietic cell transplantation; BiTE, bispecific monoclonal antibodies; CAR, chimeric antigen receptor; CNS, central nervous system; DLBCL, diffuse large B-cell lymphoma; EBMT, European Society for Blood And Marrow Transplantation; ECOG, Eastern Cooperative Oncology Group; GvHD, graft-versus-host disease; NHL, non-Hodgkin lymphoma; SPC, summary of product characteristics |
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Characteristics |
EBMT recommendations |
Comment |
Age limit |
||
NHL |
No upper age limit |
Decision should be based on physical condition rather than age |
ALL |
Follow SPC |
Ability to collect sufficient cells by apheresis can be a limiting factor in infants and small children |
ECOG performance status |
>2 not recommended |
Prognosis may be better if the decline in performance status is due to active disease |
History of malignancy |
Absence of history of malignancy other than carcinoma in situ unless disease-free and off therapy for at least three years |
|
Previous treatment | ||
Prior allo-HCT |
Not a contra-indication |
Active GvHD is listed as a reason to delay treatment with axicabtagene ciloleucel or tisagenlecleucel |
Prior CD19-directed therapy/anti-CD3 BiTE antibodies |
Not a contra-indication |
|
Previous CAR T-cell therapy |
Not a contra-indication |
Further CAR T therapy outside of clinical trials is to be avoided |
Current systemic immunosuppressive treatment |
Contra-indication |
Intermittent topical, inhaled or intranasal corticosteroids are allowed |
History of autoimmune disease |
Not recommended in active autoimmune disease resulting in end-organ injury or requiring systemic immunosuppression or systemic disease-modifying agents within the last two years |
Individualized risk-benefit assessment required |
Existing or suspected fungal, bacterial, viral, or other infection |
Relative contra-indication; individualized risk-benefit assessment required
|
Active infection should be controlled and on treatment prior to leukapheresis |
Screening laboratory tests and imaging
- The minimum required patient eligibility assessments are shown in Table 2
Table 2. Minimum required tests for patient eligibility
ALL, acute lymphoblastic leukemia; ANC, absolute neutrophil count; CAR, chimeric antigen receptor; CNS, central nervous system; EBMT, European Society for Blood And Marrow Transplantation; LVEF, left ventricular ejection fraction; MRI, magnetic resonance imaging; NHL, non-Hodgkin Lymphoma; SPC, summary of product characteristics; ULN, upper limit of normal *Leukapheresis material for tisagenlecleucel manufacturing will not be accepted from patients with a positive test for active HBV, HCV or HIV (SPC) |
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Test methods |
EBMT recommendations |
Comment |
Disease confirmation |
Histology only for NHL Immunophenotyping for ALL |
|
Hematology |
||
Hematology |
ANC >1.0x109/L |
Evidence of adequate bone marrow reserve |
Chemistry |
||
Bilirubin |
<34umol/L; higher limit acceptable (< 43umol/L) with Gilbert’s syndrome |
No trial data regarding patients outside of these parameters |
AST/ALT |
<5x ULN |
Attempt to identify causes e.g. active infections |
Creatinine clearance |
>30ml/min |
Caution is required in patients with CrCl of <60ml/min |
Virology |
||
Hepatitis B* |
To be done within 30 days of leukapheresis and results must be available at the time of collection and shipment |
As per national guidelines |
Hepatitis C* |
To be done within 30 days of leukapheresis and results must be available at the time of collection and shipment |
As per national guidelines |
HIV* |
To be done within 30 days of leukapheresis and results must be available at the time of collection and shipment |
Tisagenlecleucel is using a lentiviral vector whereas axicabtagene ciloleucel uses a retroviral vector |
Other work-up |
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Cardiac function |
LVEF >40%; assess for pericardial effusion by echocardiography; ECG |
Work-up of effusions required to identify causes |
CNS imaging |
MRI not required except in those with a history of CNS disease or current neurological symptoms of concern |
A baseline MRI can be helpful, should severe neurological toxicities arise |
Lumbar puncture |
Lumbar puncture not required except in those with a history ofCNS disease or current neurological symptoms of concern |
|
Fertility |
Must have a negative serum or urine pregnancy test |
Test must be repeated and confirmed negative within eight days of the CAR T-cell cell infusion |
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
ALC, absolute lymphocyte count; ANC, absolute neutrophil count; ECOG, Eastern Cooperative Oncology Group; EBMT, European Society for Blood And Marrow Transplantation; FBC, full blood count; HIV, human immunodeficiency virus; HTLV, human T-cell lymphotropic virus; NAT, nucleic acid testing; SPC, summary of product characteristics |
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Prior to Apheresis
|
EBMT recommendations |
Comment |
ECOG performance status score |
ECOG ≤2 |
At discretion of apheresis practitioner |
Days after last chemotherapy |
Allow for recovery from cytotoxic chemotherapy |
Need for marrow recovery from prior chemotherapy |
Days off corticosteroids |
Ideally, seven days to minimize effect on lymphocyte collection |
Physiological replacement doses of hydrocortisone permitted |
Blood tests |
||
Hepatitis B, hepatitis C, HIV, syphilis, and HTLV |
To be done within 30 days of leukapheresis and results must be available at the time of collection and shipment |
NAT is not necessary if all serological testing is negative |
C-reactive protein |
Recommended to assess for ongoing infection |
Eligibility for apheresis will need to be decided on a case-by-case basis in the instance of active infection |
Standard electrolytes and renal function |
Required |
Apheresis may predispose to electrolyte imbalance and limit fluid tolerance |
Blood values required for optimal apheresis performance |
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Hemoglobin |
Hemoglobin >80g/L Hematocrit >0.24 |
To establish a good interface during collection |
ANC |
>1.0x109/L |
Consistent with recovery from prior chemotherapy |
ALC |
>0.2x109/L |
Higher count required in small children. Of note, 0.2x109/L CD3+ count is the minimum threshold |
Platelet count |
>30x109/L |
|
FBC |
To be repeated at the end of the apheresis procedure |
Apheresis can remove >30% of circulating platelets |
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 7th 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
ALC, absolute lymphocyte count; CAR, chimeric antigen receptor; EBMT, European Society for Blood And Marrow Transplantation; LD, lymphodepletion; SPC, summary of product characteristics; WBC, white blood cell count |
|
EBMT recommendations |
|
CAR T-cell product |
LD conditioning should only be administered following receipt of CAR T product on site |
Clinical conditions |
Active infections must be excluded or under control before starting LD conditioning |
WBC |
Administer LD conditioning to all patients regardless of WBC or ALC |
Table 5. Routine laboratory testing prior to LD conditioning
CC, creatinine clearance; EBMT, European Society for Blood and Marrow Transplantation; ECG, electrocardiogram; LD, lymphodepletion; LVFE, left ventricular ejection fraction; SPC, summary of product characteristics; ULN, upper limit of normal |
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Test methods |
EBMT recommendations |
Comment |
Chemistry |
||
C-reactive protein and/or fibrinogen level |
Required to rule out ongoing infection |
Active infection must be excluded or under control before starting LD |
Bilirubin |
<34umol/L; higher limit acceptable (>43umol/L) with Gilbert’s syndrome |
No trial data regarding patients outside of these parameters |
AST/ALT |
<5xULN |
Attempt to identify causes e.g. active infections |
CC |
>30 ml/min |
Modify drug doses according to CC |
Other work-up |
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Cardiac function |
Repeat cardiac investigations if clinically indicated |
LVEF >40%; assess for pericardial effusion by echocardiography; ECG |
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
Always |
Often |
Sometimes |
Rarely |
Never |
|
Eye contact with caregiver |
0 |
1 |
2 |
3 |
4 |
Purposeful actions |
0 |
1 |
2 |
3 |
4 |
Aware of their surroundings |
0 |
1 |
2 |
3 |
4 |
Being restless |
4 |
3 |
2 |
1 |
0 |
Being inconsolable |
4 |
3 |
2 |
1 |
0 |
Being underactive |
4 |
3 |
2 |
1 |
0 |
Slow response to interactions |
4 |
3 |
2 |
1 |
0 |
Communicating needs and wants |
4 |
3 |
2 |
0 |
0 |
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
CAR T, chimeric antigen receptor; CMV, cytomegalovirus; CRP, C-reactive protein; EBV, Epstein-Barr virus; FBC, full blood count; IV, intravenous; LDL, lactate dehydrogenase |
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Test |
Purpose |
Frequency |
Comment |
FBC, biochemistry panel, LDH, fibrinogen, CRP |
Standard follow-up |
At every visit and as clinically indicated |
|
CMV, EBV, adenovirus |
Viral reactivation |
As clinically indicated |
|
Quantitative immunoglobulins or serum protein electrophoresis |
Immune reconstitution |
Monthly |
Consider IV immunoglobulins |
Peripheral blood immunophenotyping: CD3/4/8/16+56/19+ |
Immune recovery |
Once monthly for first three months, thrice monthly thereafter in first year |
Guide to anti-infective prophylaxis |
CAR T monitoring where kits are available for routine monitoring of anti-CD19 CAR T |
CAR T persistence |
Peripheral blood flow cytometry or transgene by molecular methods as clinically indicated |
Not recommended by CAR T manufacturers |
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
CAR, chimeric antigen receptor; FBC, full blood count; NPA, naso-pharyngeal aspirate; LTFU, long-term follow-up; PB, peripheral blood; PCR, polymerase chain reaction |
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Test |
Purpose |
Frequency |
Comment |
FBC, biochemistry panel |
Standard follow-up |
At every visit |
|
Viral infection (PB PCR, NPA) |
Viral reactivation |
As clinically indicated |
|
Quantitative immunoglobulins with or without serum protein electrophoresis |
Immune reconstitution |
At every visit |
|
Peripheral blood immunophenotyping |
Immune reconstitution |
Every second visit |
Discontinuation following normalization |
CAR T monitoring where kits are available for routine monitoring of anti-CD19 CAR T |
CAR T persistence |
Every visit |
Discontinuation when absent for two consecutive tests |
Endocrine function |
Standard follow-up |
As clinically indicated |
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