Relapsed/refractory patients

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 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

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

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

Screening laboratory tests and imaging
  • The minimum required patient eligibility assessments are shown in Table 2

Table 2. Minimum required tests for patient eligibility

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

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 of

CNS 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

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)

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

 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

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

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

Performing leukapheresis
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

 

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

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

Table 5. Routine laboratory testing prior to LD conditioning

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

Cardiac function

Repeat cardiac investigations if clinically indicated

LVEF >40%; assess for pericardial effusion by echocardiography; ECG

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

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

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

CAR T, chimeric antigen receptor; CMV, cytomegalovirus; CRP, C-reactive protein; EBV, Epstein-Barr virus; FBC, full blood count; IV, intravenous; LDL, lactate dehydrogenase

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

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

 

CAR, chimeric antigen receptor; FBC, full blood count; NPA, naso-pharyngeal aspirate; LTFU, long-term follow-up; PB, peripheral blood; PCR, polymerase chain reaction

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
References
  1. YESCARTA (axicabtagene ciloleucel) FDA. https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/yescarta-axicabtagene-ciloleucel [Accessed on Feb 2020]
  2. KYMRIAH (tisagenlecleucel) FDA. https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/kymriah-tisagenlecleucel [Accessed on Feb 2020]
  3. Yakoub-Agha I. et al., Management of adults and children undergoing CAR t-cell therapy: best practice recommendations of the European Society for Blood and Marrow Transplantation (EBMT) and the Joint Accreditation Committee of ISCT and EBMT (JACIE). Haematologica. 2020 Jan 31;105 (2):297-316 DOI: 10.3324/haematol.2019.229781
  4. Yakoub-Agha I. Management of CAR-T Cell: EBMT/JACIE recommendations. Paper presented at: 2nd European CAR T Cell Meeting; Feb 01, 2020; Sitges, ES
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