The aml Hub website uses a third-party service provided by Google that dynamically translates web content. Translations are machine generated, so may not be an exact or complete translation, and the aml Hub cannot guarantee the accuracy of translated content. The aml and its employees will not be liable for any direct, indirect, or consequential damages (even if foreseeable) resulting from use of the Google Translate feature. For further support with Google Translate, visit Google Translate Help.
The AML Hub is an independent medical education platform, sponsored by Astellas, Daiichi Sankyo, Johnson & Johnson, Kura Oncology and Syndax, and has been supported through educational grants from Bristol Myers Squibb and the Hippocrate Conference Institute, an association of the Servier Group. The funders are allowed no direct influence on our content. The levels of sponsorship listed are reflective of the amount of funding given. View funders.
Now you can support HCPs in making informed decisions for their patients
Your contribution helps us continuously deliver expertly curated content to HCPs worldwide. You will also have the opportunity to make a content suggestion for consideration and receive updates on the impact contributions are making to our content.
Find out moreCreate an account and access these new features:
Bookmark content to read later
Select your specific areas of interest
View aml content recommended for you
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 into 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 CAR T 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.
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
Characteristics EBMT recommendations CommentAge 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 yearsPrevious 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 leukapheresisALL, 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)
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 infusionTable 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 |
||
Prior to Apheresis | EBMT recommendations | Comment |
---|---|---|
ECOG performance status score | ECOG ≤ 2 | At the 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 the 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/LHematocrit > 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; 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 ALCCC, 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
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; ECGCAR T, chimeric antigen receptor; CMV, cytomegalovirus; CRP, C-reactive protein; EBV, Epstein-Barr virus; FBC, full blood count; IV, intravenous; LDL, lactate dehydrogenase
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, chimeric antigen receptor; FBC, full blood count; NPA, naso-pharyngeal aspirate; LTFU, long-term follow-up; PB, peripheral blood; PCR, polymerase chain reaction |
|||
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 |
References
Please indicate your level of agreement with the following statements:
The content was clear and easy to understand
The content addressed the learning objectives
The content was relevant to my practice
I will change my clinical practice as a result of this content