9515-Article Text-70471-1-10-20200725

GUIDELINE ARTICLE
Management of adults and children Ferrata Storti Foundation

undergoing chimeric antigen receptor 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 2018
Ibrahim Yakoub-Agha, Christian Chabannon, Peter Bader, Grzegorz W.
1 2 3 Volume 105(2):297-316
Basak,4 Halvard Bonig,5 Fabio Ciceri,6 Selim Corbacioglu,7 Rafael F. Duarte,8
Hermann Einsele,9 Michael Hudecek,9 Marie José Kersten,10 Ulrike Köhl,11
Jürgen Kuball,12 Stephan Mielke,13 Mohamad Mohty,14 John Murray,15 Arnon
Nagler,16 Stephen Robinson,17 Riccardo Saccardi,18 Fermin Sanchez-Guijo,19
John A. Snowden,20 Micha Srour,21 Jan Styczynski,22 Alvaro Urbano-Ispizua,23
Patrick J. Hayden24 and Nicolaus Kröger25
1
CHU de Lille, LIRIC, INSERM U995, Université de Lille, Lille, France; 2Institut Paoli-
Calmettes & Module Biothérapies, INSERM CBT-1409, Centre d’Investigations Cliniques
de Marseille, Marseille, France; 3Clinic for Children and Adolescents, University Children's
Hospital, Frankfurt, Germany; 4Department of Hematology, Oncology and Internal
Medicine, Medical University of Warsaw, Warsaw, Poland; 5Institute for Transfusion
Medicine and Immunohematology of Goethe University and German Red Cross Blood
Service, Frankfurt, Germany; 6Università Vita-Salute San Raffaele, IRCCS Ospedale San
Raffaele, Milan, Italy; 7Department of Pediatric Hematology, Oncology and Stem Cell
Transplantation, University Hospital of Regensburg, Regensburg, Germany; 8Hospital
Universitario Puerta de Hierro Majadahonda, Madrid, Spain; 9Medizinische Klinikund
Poliklinik II, Universitätsklinikum Würzburg, Würzburg, Germany; 10Department of
Hematology, Amsterdam UMC, University of Amsterdam, Cancer Center Amsterdam and
LYMMCARE, Amsterdam, the Netherlands; 11Fraunhofer Institute for Cellular Therapeutics
and Immunology (IZI) and Institute of Clinical Immunology, University of Leipzig, Leipzig as
well as Institute for Cellular Therapeutics, Hannover Medical School, Hannover, Germany; Correspondence:
12
Department of Hematology and Laboratory of Translational Immunology, University
Medical Center Utrecht, Utrecht, the Netherlands; 13Department of Laboratory
PATRICK J. HAYDEN
Medicine/Department of Cell Therapy and Allogeneic Stem Cell Transplantation (CAST),
[email protected]
Karolinska Institutet and University Hospital, Stockholm, Sweden; 14Hôpital Saint-Antoine,
AP-HP, Sorbonne Université, INSERM UMRS 938, Paris, France; 15Christie Hospital NHS
Trust, Manchester, UK; 16The Chaim Sheba Medical Center, Tel-Hashomer, Affiliated with
Received: June 16, 2019.
the Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel; 17University Hospitals Accepted: November 19, 2019.
Bristol NHS Foundation Trust, Bristol, UK; 18Hematology Department, Careggi University
Hospital, Florence, Italy; 19IBSAL-Hospital Universitario de Salamanca, CIC, Universidad de
Pre-published: November 21, 2019.
Salamanca, Salamanca, Spain; 20Department of Haematology, Sheffield Teaching
Hospitals NHS Foundation Trust, Sheffield, UK; 21Service des Maladies du Sang, CHU de
Lille, Lille, France; 22Department of Pediatric Hematology and Oncology, Collegium
doi:10.3324/haematol.2019.229781
Medicum, Nicolaus Copernicus University Torun, Bydgoszcz, Poland; 23Department of
Hematology, ICMHO, Hospital Clínic de Barcelona, Barcelona, Spain; 24Department. of
Check the online version for the most updated
Hematology, Trinity College Dublin, St. James’s Hospital, Dublin, Ireland and 25Department
information on this article, online supplements,
of Stem Cell Transplantation, University Medical Center Hamburg, Hamburg, Germany
and information on authorship & disclosures:
www.haematologica.org/content/105/2/297
ABSTRACT
©2020 Ferrata Storti Foundation
C
himeric antigen receptor (CAR) T cells are a novel class of anti-can- Material published in Haematologica is covered by copyright.
All rights are reserved to the Ferrata Storti Foundation. Use of
cer therapy in which autologous or allogeneic T cells are engineered published material is allowed under the following terms and
to express a CAR targeting a membrane antigen. In Europe, tisagen- conditions:
lecleucel (KymriahTM) is approved for the treatment of refractory/relapsed https://creativecommons.org/licenses/by-nc/4.0/legalcode.
Copies of published material are allowed for personal or inter-
acute lymphoblastic leukemia in children and young adults as well as nal use. Sharing published material for non-commercial pur-
relapsed/refractory diffuse large B-cell lymphoma, while axicabtagene poses is subject to the following conditions:
ciloleucel (YescartaTM) is approved for the treatment of relapsed/refractory https://creativecommons.org/licenses/by-nc/4.0/legalcode,
sect. 3. Reproducing and sharing published material for com-
high-grade B-cell lymphoma and primary mediastinal B-cell lymphoma. mercial purposes is not allowed without permission in writing
Both agents are genetically engineered autologous T cells targeting CD19. from the publisher.
These practical recommendations, prepared under the auspices of the
European Society of Blood and Marrow Transplantation, relate to patient
haematologica | 2020; 105(2) 297

I. Yakoub-Agha et al.
care and supply chain management under the following headings: patient eligibility, screening laboratory
tests and imaging and work-up prior to leukapheresis, how to perform leukapheresis, bridging therapy, lym-
phodepleting conditioning, product receipt and thawing, infusion of CAR T cells, short-term complications
including cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, antibiotic
prophylaxis, medium-term complications including cytopenias and B-cell aplasia, nursing and psychological
support for patients, long-term follow-up, post-authorization safety surveillance, and regulatory issues.
These recommendations are not prescriptive and are intended as guidance in the use of this novel therapeu-
tic class.
Introduction ing scientists, nurses and physicians, and close collabora-

tion with a range of other specialists, especially intensive
The first experimental attempts to engineer T cells to care unit staff and the neurology/neuroimaging services,
express chimeric antigen receptors (CAR) were performed is required.11,12
30 years ago.1,2 The ultimate goal was to produce function- As CAR T cells represent a novel class of therapy and as
al, high-affinity, CAR T cells in which the T-cell receptor is both of the currently available products have only been
re-directed towards a tumor antigen of choice.3 Following evaluated in phase II studies to date, close post-marketing
refinements in the signaling properties of a CAR within the surveillance is mandatory. The EMA has endorsed the use
context of a T cell, development progressed rapidly from of the European Blood and Marrow Transplantation
the laboratory to clinical trials and CAR T cells targeting (EBMT) registry for the collection of 15-year follow-up
CD19 now represent a novel and promising therapy for data on treated patients in order to ensure that evaluation
patients with refractory/relapsed B-cell malignancies of the efficacy and safety of commercially available CAR
including acute lymphoblastic leukemia (ALL) and diffuse T cells continues on an ongoing basis. The Center for
large B-cell lymphoma (DLBCL).3-7 CAR T cells are also International Blood and Marrow Transplant Research
being assessed as treatment for other hematologic diseases (CIBMTR) fulfills a similar function in the United States
such as multiple myeloma and acute myeloid leukemia as of America (USA). The newly updated EBMT Registry
well as for solid tumors.5,8-10 Cellular Therapy form is designed to capture the efficacy
Tisagenlecleucel (KymriahTM, previously CTL019, and side-effects of modern cellular therapies and to pro-
Novartis, Basel, Switzerland) consists of autologous CAR vide the required post-marketing surveillance through
T cells genetically modified ex vivo using a lentiviral vec- Post-Authorization Safety Surveillance (PASS) and other
tor encoding an anti-CD19 CAR that includes a domain studies. The main objective for professionals in the field
of the 4-1BB co-stimulatory molecule. It is indicated for is to evaluate how these innovative treatments compare
the treatment of children and young adults up to the age with the alternative therapeutic options and current stan-
of 25 years with relapsed/refractory B-ALL and was dards-of-care. Phase III studies are underway.13
approved by the Food and Drug Administration (FDA) on The clinical use of CAR T cells is early in its evolution
30th August, 2017. It was subsequently FDA-approved on and it is, as yet, unclear whether CAR T-cell therapy con-
May 1st, 2018 for the treatment of adult patients with stitutes a definitive treatment or whether disease cure
relapsed or refractory large B-cell lymphoma after two or will require further immunologically based consolidation
more lines of systemic therapy, including DLBCL not oth- such as allogeneic stem cell transplantation, especially for
erwise specified, high-grade B-cell lymphoma and ALL. In trials on the use of CAR T-cell therapy in DLBCL,
DLBCL arising from follicular lymphoma. The European long-term disease control is observed in up to 50% of
Medicines Agency (EMA) approved similar indications on patients. As some of these patients may be cured, allo-
August 22nd, 2018. geneic transplantation as consolidation may not be neces-
Axicabtagene ciloleucel, (YescartaTM, previously KTE- sary.14-16 This issue can only be resolved with longer fol-
C19, Gilead, USA) is an autologous CAR T-cell product low-up.
which has been genetically modified ex vivo using a retro- Research areas include dual antigen targeting to counter
viral vector encoding an antibody fragment targeting one of the most common resistance mechanisms, which
CD19 and an intracellular domain including the CD28 co- is loss of the targeted antigen, the inclusion of safety
stimulatory molecule. It was FDA-approved on October switches such as suicide genes in order to mitigate side-
18th, 2017 for the treatment of adult patients with effects when they occur, ‘off the shelf’ allogeneic CAR T
relapsed or refractory large B-cell lymphoma after two or products, the refinement of co-stimulatory domains to
more lines of systemic therapy, including DLBCL not oth- enhance persistence and avoid immune escape, and the
erwise specified, primary mediastinal large B-cell lym- use of non-viral vectors and semi-automated on-site pro-
phoma, high grade B-cell lymphoma, and DLBCL arising duction to simplify the manufacturing process.
from follicular lymphoma. The EMA approved its use in Although this field will inevitably change over the com-
relapsed or refractory DLBCL and primary mediastinal ing years, these first EBMT guidelines on CAR T cells are
large B-cell lymphoma after two or more lines of systemic intended to provide practical, clinically relevant recom-
therapy, on August 23rd, 2018. mendations for hematologists and other cancer specialists
While CAR T cells are rationally designed, targeted and their teams involved in the administration of CAR T-
therapies, they nevertheless frequently induce life-threat- cell therapies, especially the commercially available prod-
ening toxicities that can be mitigated by planning and ucts. These guidelines may also be a useful resource for
proper hospital organization. Comprehensive training other stakeholders such as pharmacists or health service
should be provided to all categories of personnel includ- administrators involved in the planning and delivery of
298 haematologica | 2020; 105(2)

Management of patients undergoing CAR T-cell therapy
CAR T-cell therapies, given the complexity of their pro- Directives was required. Although a number of argu-
duction and administration and their high cost. ments, including manufacturing of Advanced Therapy
Medicinal Products, were brought forward in favor of
revising the directives, no formal decision has yet been
Methodology made.
The current rules are solely based on the donor-recipient
The Practice Harmonization and Guidelines subcom- relationship, whether autologous or allogeneic, and do not
mittee of the Chronic Malignancies Working Party of the address the intended use of the collected material. As a
EBMT proposed the project in December 2018. The consequence, the same requirements apply both to the
EBMT Board accepted the proposal and worked with collection of mononuclear cells for stem cell transplanta-
experts in the field to produce practical clinical recommen- tion and when procuring the starting material for the man-
dations on the management of adults and children under- ufacture of Advanced Therapy Medicinal Products, unless
going autologous CAR T-cell therapy. A survey was sent the Marketing Authorization Holder stipulates specific
to centers active in this field to solicit feedback on current additional requirements.
approaches to the topics covered in these guidelines.17 Cross-border shipment of the collected cell product
Their responses (41 of 50 centers) along with a literature requires compliance with national regulations both in the
review and assessment of both the licensing study proto- country of origin and in the country of destination.
cols and the summaries of product characteristics (SPC) of Obtaining authorization to export human autologous-
the commercially available CAR T-cell products inform derived elements will require knowledge of the patient’s
these recommendations. Finally, three teleconferences viral serology.
were held in preparation for a 2-day workshop that took Table 3 presents a checklist that should be verified
place in Lille on 4th-5th April, 2019. before starting the leukapheresis procedure.
These recommendations are intended to reflect current
best practice in this novel and rapidly moving field and to
support clinicians and other healthcare professionals in How to perform leukapheresis
delivering consistent, high-quality care. They principally
apply to the CAR T-cell therapies that are currently com- Scheduling of leukapheresis must be coordinated with
mercially available for the treatment of hematologic the pharmaceutical company as lack of manufacturing
malignancies. Given the absence of randomized trial evi- capacity is currently one of the bottlenecks in the avail-
dence in this field, a decision was made not to grade these ability of CAR T-cell therapies.20 Confirmation of an
recommendations. They therefore represent the consen- agreed manufacturing slot is therefore mandatory prior to
sus view of the authors. deciding on a date for apheresis. With technical advances
When patients are receiving CAR T-cell therapies in and more patients likely to become candidates for these
clinical trials, physicians should follow the relevant trial treatments in the coming years, limitations in the capacity
protocols. The management of disease relapse following of collection centers are likely to become a challenge.
CAR T-cell therapy is outside the scope of these recom- Any of the commercially available leukapheresis devices
mendations. are, in principle, suitable for apheresis. While companies
may suggest preferences for devices or systems, local
Patient eligibility for chimeric antigen receptor experience, local permits and the regulatory approval sta-
tus of individual devices and systems should guide the
T-cell therapy selection of technology. Technically, unmobilized leuka-
The decision to treat a patient with CAR T cells therapy pheresis is most similar to apheresis for off-line extracor-
should be made collectively at a multidisciplinary team poreal photopheresis or for the collection of allogeneic
meeting in a designated center for CAR T-cell therapy. The mononuclear cells intended for post-transplant
patients’ medical history and physical condition are impor- immunotherapy (donor lymphocyte infusions); no specific
tant factors in determining their suitability for treatment. apheresis protocols have so far been proposed by cell
Trial eligibility criteria and EBMT recommendations are processor manufacturers or by the CAR T-cell manufactur-
shown in Table 1. ers. Proof of proper validation and maintenance of equip-
ment and established training processes for personnel
operating or supervising the use of cell processors are key
Screening laboratory tests and imaging elements required by the Marketing Authorization
Holders in order to qualify and onboard sites that are
Table 2 summarizes a recommended minimum set of authorized to collect cells for CAR T-cell manufacturing.
tests that should be performed at screening in order to Prior accreditation in compliance with the 7th edition of
assess organ function and patient eligibility. the Foundation for the Accreditation of Cellular Therapy
(FACT) - Joint Accreditation Committee of the
International Society for Cell Therapy and EBMT (JACIE)
Work-up prior to apheresis Standards for Hematopoietic Cellular Therapies or the
FACT Standards for Immune Effector Cells confirms the
The current set of rules that apply to human tissue and presence of a pre-existing Quality Management System,
cell procurement in the European Union derives from the although additional requirements are often identified,
Tissue and Cell Directives published in 2004 (2004/23/EC) including those from pharmaceutical providers and health
and 2006 (2006/17/EC; 2006/86/EC). The European Union service commissioners.21
Commission recently convened a stakeholder meeting to Further information on the technical aspects of aphere-
examine whether revision of the Tissue and Cell sis is provided in the Online Supplement.

Table 1. Eligibility criteria for the selection of patients for clinical trials.
Characteristics ELIANA JULIET ZUMA-1 EBMT Comment
(ALL KymriahTM) (DLBCL KymriahTM) (High-grade B-cell recommendations
NHL YescartaTM)
Age limit (NHL) N/A ≥18 years ≥18 years No upper age limit Decision should be
based on physical
SPC - No data are available SPC - No data are available condition rather than age
on children < 18 years of age on children <
18 years of age
Age limit (ALL) ‘Age 3 years at the time N/A N/A Follow SPC Ability to collect sufficient
of screening to age 21 years cells by apheresis can be
at the time of initial diagnosis’ a limiting factor in infants
and small children
SPC- up to 25 years of age
ECOG PS Karnofsky (age ≥16 years) or ECOG PS ECOG PS >2 not recommended Prognosis may be
Performance Status Lansky (age <16 years) of either of 0 or 1 Note, however, less poor if the decline
PS ≥50 at screening 0 or 1 at screening that real-world data with in PS is due to
YescartaTM included patients active disease
with ECOG PS >218
History of malignancy No prior malignancy, except No previous or concurrent No history of malignancy Absence of history of
carcinoma in situ of the malignancy except other than nonmelanoma malignancy other than
skin or cervix treated adequately treated skin cancer or carcinoma carcinoma in situ
with curative intent and BCC or SCC, in situ in situ (e.g. cervix, bladder, (e.g. cervix, bladder,
with no evidence of cancer of the breast breast) or follicular breast) unless disease-
active disease or cervix treated and without lymphoma unless disease free and off therapy
recurrence for 3 years, free for at least for at least 3 years
primary malignancy resected 3 years
and in remission for more
than 5 years
Prior allo-HCT Not excluded; however, Excluded Excluded Not a contraindication Active GvHD is listed
excluded if grade II-IV acute as a reason to delay
or extensive chronic GvHD treatment in the
KymriahTM and
YescartaTM SPC
Prior anti-CD19/anti-CD3 Excluded Excluded Excluded if prior Not a contraindication
BiTE antibodies or Not a contraindication CD19 targeted therapy
any other CD19 therapy as per SPC
Previous CAR T-cell therapy Not applicable in trials Not applicable in trials Excluded Not a contraindication Further CAR T-cell
Not in SPC Not in SPC therapy outside of
clinical trials is
to be avoided
History of autoimmune Not an exclusion Not an exclusion Not an exclusion Not recommended Individualized risk-benefit
disease criterion criterion criterion in active autoimmune assessment required
disease resulting in
end-organ injury or
requiring systemic
immunosuppression
or systemic disease-modifying
agents within the last
2 years
Current systemic Any GvHD therapy must Any immunosuppressive Any immunosuppressive Contraindication Intermittent topical,
immunosuppressive be stopped more than medication must be medication must be inhaled or intranasal
treatment 4 weeks prior to stopped more than stopped more than corticosteroids are
enrollment to confirm 4 weeks prior to 4 weeks prior to allowed
that GvHD recurrence enrollment enrollment
is not observed
Existing or suspected Active or latent HBV Uncontrolled active or Known history of HIV, Relative contra-indication; Active infection
fungal, bacterial, viral, or HCV (test latent HBV HBV (HepBs Ag positive) individualized should be controlled
or other infection within 8 weeks or active HCV; or HCV (anti-HCV); risk-benefit and on treatment
of screening) or any Uncontrolled acute life- Clinically significant active assessment required prior to leukapheresis
uncontrolled infection threatening bacterial, infection, or currently receiving
at screening viral or fungal infection IV antibiotics or within
(e.g. blood cultures positive 7 days of enrollment
<72 h prior to screening)
continued on the next page

continued from the previous page
History of CNS disease CNS involvement by Active CNS involvement Subjects with detectable Relative Caution required as
malignancy defined as by malignancy CSF malignant contra indication; higher risk of
CNS-3 as per NCCN guidelines excluded cells, or brain individualized risk- neurological toxicity
excluded; however, those metastases, or with benefit assessment
with history of effectively history of CSF malignant required19
treated CNS disease cells or brain metastases
were eligible excluded
ALL: acute lymphoblastic leukemia; DLBCL: diffuse large B-cell lymphoma; NHL: non-Hodgkin lymphoma; EBMT: European Society for Blood and Marrow Transplantation; N/A: not available; SPC:
summary of product characteristics; ECOG: Eastern Cooperative Oncology Group; PS: performance status; BCC: basal cell carcinoma;SCC: squamous cell carcinoma; allo-HCT: allogeneic
hematopoietic cell transplantation; GvHD: graft-versus-host disease; BiTE: bispecific monoclonal antibodies; CAR: chimeric antigen receptor; HBV: hepatitis B virus; HCV: hepatitis C virus; HIV:
human immunodeficiency virus; CNS: central nervous system; NCCN: National Comprehensive Cancer Network.
Table 2. The minimum required tests.

Test methods Trials and/or SPC EBMT recommendations Comment
Disease Histology only for NHL
confirmation Immunophenotyping for ALL
Hematology
Hematology 9
ANC >1.0x10 /L in NHL trials ANC >1.0x109/L Evidence of adequate bone marrow reserve
Chemistry
Bilirubin <26-34 mmol/L <34 mmol/L; higher limit No trial data regarding patients outside
acceptable (<43 mmol/L) of these parameters
with Gilbert syndrome
AST/ALT <5xULN <5x ULN Attempt to identify causes e.g. active infections
Creatinine clearance Age- and gender-dependent > 30 mL/min Caution is required in patients with CrCl of <60 mL/min
cut-offs for ELIANA trial,
> 60 mL/min/1.73m2 (JULIET)
Virology
Hepatitis B* Active or latent hepatitis B (test within 8 Mandatory in some countries. As per national guidelines
weeks of screening) To be done within 30 days of Serology/molecular testing
(ELIANA, JULIET) leukapheresis and results must be
available at the time of collection
and shipment
Hepatitis C* Active hepatitis C (test within 8 weeks of screening) Mandatory in some countries. As per national guidelines
(ELIANA, JULIET) To be done within 30 days Serology/molecular testing
of leukapheresis and results must be
and shipment
HIV* HIV positive test within 8 weeks Mandatory in some countries. KymriahTM is using a lentiviral vector
of screening - ineligible for CAR T trials To be done within 30 days of whereas YescartaTM uses
leukapheresis and results must be a retroviral vector
and shipment
Other work-up
Cardiac function Hemodynamically stable and LVEF >45% LVEF >40%; Work-up of effusions required to
confirmed by echocardiogram assess for pericardial effusion identify causes
or MUGA scan; Patients with by echocardiography; ECG
cardiac involvement by NHL were
excluded from some trials
CNS imaging ZUMA-1 trial required an MRI MRI not required except in A baseline MRI can be helpful, should severe
of the brain to confirm there was those with a history of CNS disease neurological toxicities arise
no evidence of lymphoma or current neurological symptoms
of concern
Lumbar puncture Patients with active CNS disease Lumbar puncture not required
were excluded from trials except in those with a history of CNS
disease or current neurological symptoms
of concern
Fertility Females of childbearing potential must Females of childbearing potential Test must be repeated and confirmed negative
have a negative serum or urine pregnancy must have a negative serum or urine within 8 days of the CAR T-cell infusion
test within 48 h of infusion (ELIANA) pregnancy test
SPC: summary of product characteristics; EBMT: European Society for Blood and Marrow Transplantation; NHL: non-Hodgkin lymphoma; ALL: acute lymphoblastic leukemia; ANC: absolute neu-
trophil count; AST: aspartate aminotransferase: ALT: alanine aminotransferase; ULN: upper limit of normal; CrCl: creatinine clearance; HIV: human immunodeficiency virus; CAR: chimeric antigen
receptor; LVEF: left ventricular ejection fraction; MUGA: multiple-gated acquisition; MRI: magnetic resonance imaging; CNS: central nervous system. *Leukapheresis material for KymriahTM manu-
facturing will not be accepted from patients with a positive test for active hepatitis B virus, hepatitis C virus or HIV (SPC)

Only one of the commercial CAR T-cell manufacturers EMA requirements.22 Accredited and validated testing
– Novartis – currently requires cryopreservation of the methods must be used. In addition to testing for infectious
mononuclear cells on site. It is stipulated that the white disease markers in peripheral blood samples on the day of
blood cell count should be adjusted to 1.0 (0.5-2.0) collection, reasonable quality control should include steril-
x108/mL, that an approved (approved by the company and ity testing as well as some hemocytometric parameters
local regulators) cryoprotectant be added slowly and that (white blood cell count, hematocrit, CD3+, and viable
the cells be frozen in controlled-rate freezers prior to stor- CD45+ counts). Sampling of the collected cell product
age in vapor phase liquid nitrogen. To produce KymriahTM, must follow the manufacturer’s requirements so as not to
Novartis will accept cells that have been harvested within compromise downstream processing steps, while also
the preceding 18 months and cryopreserved with appro- complying with local manufacturing authorizations.
priate quality management surveillance. Whether autolo- Depending on the disease burden, it may be possible to
gous blood mononuclear cells intended for CAR T-cell arrange for leukapheresis before starting salvage
manufacturing should be prospectively collected and cry- chemotherapy to treat disease relapse. There is evidence
opreserved in selected patients at high risk of relapse is that cumulative chemotherapy exposure adversely affects
already under debate. The other commercial manufactur- the quality of circulating T cells. Although apheresis can
ers will collect fresh apheresis product packed in their be performed in patients with absolute lymphocyte
own specified shipping containers. Until shipping, these counts as low as 0.1x109/L, the likelihood of reaching the
apheresis products are stored refrigerated (2-8°C). target number of autologous lymphocytes and successful-
Manufacturers’ requirements for quality control are cur- ly manufacturing the drug product is higher in individuals
rently very limited and may be exceeded by local require- with absolute lymphocyte counts exceeding 0.5x109/L. In
ments. There may also be differences between FDA and addition, the choice of salvage therapy (chemotherapy,
Table 3. Checklist prior to apheresis.

Prior to apheresis Trials/SPC EBMT recommendations Comment
ECOG PS score Not specified ECOG PS score ≤2 At discretion of apheresis practitioner
Days after last chemotherapy Allow for recovery from cytotoxic Need for marrow recovery from prior
chemotherapy chemotherapy
Days off corticosteroids Three (KymriahTM) Ideally, 7 days to A shorter period of as few as 3 days
to 7 (YescartaTM) days minimize effect on lymphocyte was considered acceptable
off or on no more than collection by Kansagra et al.12
prednisolone 5 mg equivalent Physiological replacement doses of
hydrocortisone permitted
Mandatory blood tests

Hepatitis B, hepatitis C, Mandatory for all trials Mandatory in some countries. Only serological testing is required; nucleic
HIV, syphilis, and HTLV To be done within 30 days of acid testing is not necessary if all
leukapheresis and results must serological testing is negative
be available at the time of collection
and shipment
Blood tests to ascertain suitability for apheresis
C-reactive protein Recommended to assess for In patients with active infection, eligibility for
ongoing infection apheresis will need to be decided on
a case-by-case basis
Standard electrolytes and renal function Required Apheresis may predispose to electrolyte imbalance
and limited fluid tolerance
Blood values required for optimal apheresis performance

Hemoglobin Hemoglobin >80 g/L To establish a good interface during collection
Hematocrit >0.24
Absolute neutrophil count >1.0x109/L Consistent with recovery from
prior chemotherapy
Absolute lymphocyte count > 0.2x109/L* Higher count required in small children.
Of note, 0.2x109/L CD3+ count is the minimum threshold
Platelet count > 30x109/L Transfuse as required
Full blood count To be repeated at the end of Apheresis can remove more than
apheresis procedure 30% of circulating platelets
SPC: summary of product characteristics; EBMT: European Society for Blood and Marrow Transplantation; ECOG PS: Eastern Cooperative Oncology Group Performance Status; HIV: human
immunodeficiency virus; HTLV: human T-lymphotropic virus. *This threshold specifically applies to count recovery following corticosteroid therapy where an absolute lymphocyte count
>0.2 is a surrogate marker of corticosteroid washout.

serotherapy and radiotherapy) may adversely affect sub- time for the CAR T cells is expected to be short.
sequent attempts at leukapheresis and washout periods Importantly, certain agents, especially immunotherapeutic
need to be considered. drugs with a longer half-life, may interfere with the
Table 4 provides recommendations on washout periods expansion or persistence of the infused CAR T cells and
following various salvage treatments before starting should be avoided. Examples include alemtuzumab, dara-
leukapheresis. In addition, it should be noted that prior tumumab, checkpoint inhibitors and brentuximab
use of blinatumomab is not a contraindication to anti- vedotin.
CD19 CAR T-cell therapy.23 When choosing bridging therapy for lymphoma
patients, factors to be considered include the prior
response to chemotherapy and chemo-immunotherapy,
Bridging therapy the overall tumor burden and the distribution and sites of
tumor involvement. Options include parenteral agents
Bridging therapy refers to the administration of anti- such as rituximab, gemcitabine, oxaliplatin, bendamustine
cancer drugs including chemotherapy to maintain disease or pixantrone; oral chemotherapy regimens e.g. variants of
control during the period between lymphocyte collection prednisolone, etoposide, procarbazine, and cyclophos-
and the final administration of the CAR T-cell product.16 phamide (PEP-C), or oral cyclophosphamide 100 mg once
This time window may be longer than anticipated for daily; novel targeted therapies such as lenalidomide or
logistical reasons, sometimes but not always related to ibrutinib; high-dose corticosteroids e.g. dexamethasone
manufacturing, and will be specifically monitored through 40 mg for 4 days or high-dose methylprednisolone,
EBMT Registry collection of ‘real world’ data. repeated as needed; or radiotherapy to symptomatic or
The goal of bridging therapy is to prevent clinically sig- large masses.24,25
nificant disease progression leading to impaired organ In ALL, the risk of CRS has been found to correlate with
function or any other complications that might prevent the leukemic blast burden at the time of the CAR T-cell
the patient proceeding with lymphodepletion and receiv- infusion. Bridging chemotherapy is therefore especially
ing the CAR T cells. It is also hoped that treatment of rap- important in ALL and the chosen agents are typically
idly proliferating disease will establish a balanced in vivo drawn from known B-ALL chemotherapy regimens
target-effector ratio to allow for effective CAR T-cell although doses are often reduced to lower the risk of
adoptive immunotherapy. In brief, the aim is not so much infectious complications and organ dysfunction.5,26 Novel
to achieve disease remission as to establish adequate dis- and targeted agents, for example, tyrosine kinase
ease control prior to the CAR T-cell infusion. inhibitors and monoclonal antibodies, may also be used
The optimal bridging therapy for any individual will although it is important to consider whether the agent is
depend on disease- and patient-specific factors. However, capable of inducing a rapid response and whether the
clinicians should bear in mind that patients receiving therapy might interact with subsequent lymphodepleting
chemotherapeutic agents, either alone or in combination, and CAR T-cell therapy. Whatever treatment is chosen,
will subsequently receive lymphodepleting therapy and bridging therapy should only be given after leukapheresis
will be at risk of specific CAR T-cell-related complications so that the quality of the CAR T-cell product is not affect-
such as cytokine release syndrome (CRS), encephalopathy ed. The patient can be monitored after leukapheresis and
and tumor lysis syndrome. Bridging therapy should there- during and following bridging chemotherapy either at the
fore ideally not induce major complications, such as infec- treating center or at the referring center provided that
tions, bleeding or any organ dysfunction that might inter- there are clear lines of communication between the cen-
fere with the planned lymphodepleting therapy and CAR ters regarding the choice of any treatments and the man-
T-cell infusion. Bridging therapy can be omitted in the agement of any complications. Frequent monitoring,
presence of stable, low burden disease if the turn-around including laboratory testing and imaging, is mandatory in
Table 4. Wash-out period before leukapheresis (adapted from Kansagra et al.12).

Type of therapy SPC EBMT recommendations Comments
Allo-HCT No guidance Patients should be off immunosuppression A minimum of 1 month is recommended
and GvHD-free
Donor lymphocyte infusion No guidance 4 weeks 6 to 8 weeks may be safer to rule out any GvHD
High-dose chemotherapy No guidance 3-4 weeks depending on Recovery from cytopenias is required
the intensity of the chemotherapy
CNS-directed therapy No guidance 1 week
Short-acting cytotoxic/ No guidance 3 days Recovery from cytopenias is required
anti-proliferative drugs
Systemic corticosteroids No guidance Ideally, 7 days to minimise any A shorter period of as few as 3 days
effect on lymphocyte collection was considered acceptable by Kansagra et al.12
Regardless of timing, an ALC>0.2 x109/L is preferable
given the likely effect of recent corticosteroids
on lymphocyte quality
SPC: summary of product characteristics; EBMT: European Society for Blood and Marrow Transplantation; Allo-HCT: allogeneic hematopoietic cell transplantation; GvHD: graft-versus-host
disease; CNS: central nervous system; ALC: absolute lymphocyte count.

order to prevent or rapidly treat complications that might The designated receiving laboratory will receive advance
arise while awaiting the arrival of the CAR T-cell product. notice from the manufacturer and the product will be
delivered in a sealed liquid nitrogen dewar (vacuum flask).
Upon receipt, the seals of the dewar are inspected for
Lymphodepleting conditioning breaches; seals are broken, if applicable; the temperature
log is read out; and the product is inspected for bag integri-
The use of lymphodepleting (LD) conditioning prior to ty and identity according to the label; the bag in its cassette
the CAR T-cell infusion creates a ‘favorable’ environment is subsequently transferred to a liquid nitrogen storage con-
for CAR T-cell expansion and survival in vivo, probably by tainer until it is brought to the bedside. The company-spe-
eliminating regulatory T cells.27 In addition, it can lead to cific product receipt documentation must be completed;
the upregulation of tumor immunogenicity and improve personnel authorized to handle products are provided with
disease control.28 Furthermore, there are data demonstrat- specific and detailed training from the relevant manufac-
ing that LD conditioning works to promote homeostatic turer. When the ward is ready to receive the product, the
proliferation of adoptively transferred T cells via increases cassette is transferred to a laboratory dewar and this is
in the pro-survival/proliferation cytokines, interleukin transported to the ward.
(IL)-7 and IL-15, and in conjunction with a lack of compe- In some countries, the use of water baths, carefully cali-
tition with wildtype T cells.29-31 brated to 35-37°C, remains acceptable; use of an automat-
Many drugs have been used for LD conditioning included thawing device is preferable. Representative examples
ing cyclophosphamide, fludarabine, pentostatin and ben- of such devices are the SaharaTM (Sarstedt) and
damustine as well as total body irradiation.32 In a clinical PlasmathermTM (Barkey) devices. While the thawing of
trial involving 30 patients with B-ALL at the Fred CAR T cells is, in principle, the same as for cryopreserved
Hutchinson Cancer Research Center, fludarabine and hematopoietic progenitor cells collected by apheresis, the
cyclophosphamide was associated with superior CAR T- much smaller volumes of CAR T-cell products only require
cell persistence and better disease-free survival when com- very short thawing times. We recommend that thawing
pared to single-agent cyclophosphamide or cyclophos- times be established locally with similarly-sized mock
phamide in combination with etoposide.33,34 Fludarabine- products, ideally with mononuclear cell suspensions in
cyclophosphamide is the most widely used LD condition- protein-saline-dimethylsulfoxide freezing buffer and test-
ing regimen.35,36 ing of post-thaw viability, but at a minimum, with protein-
LD conditioning is usually administered on a 3-to-5 day saline-dimethylsulfoxide buffer without cells and observa-
schedule prior to the infusion of the CAR T cells. If the tion of the time until the buffer assumes the slushy consis-
center does not have established policies and infrastruc- tency of a ready-to-spike cryo product. If thawing is con-
ture to allow for safe outpatient-based administration, ducted in a water bath, the spike ports that protrude out of
hospitalization is recommended during this period to the water must be carefully massaged to ensure that they
ensure close monitoring and optimal hydration. thaw in synchrony with the rest of the product. The spike
Items to consider before starting LD conditioning are ports of the thawed product are uncapped, disinfected and
shown in Table 5A. aseptically spiked with the transfusion set, the air trap is
Laboratory tests to review before starting LD condition- filled completely with the cell suspension (no falling drops,
ing are shown in Table 5B. as this shears cells) and air is evacuated from the infusion
If there is a long delay (in general, more than 3 weeks) line. The individual responsible for the thawing and prepa-
between completing LD conditioning and the subsequent ration of the infusion varies between countries and health
CAR T-cell infusion, and the white blood cell count is care systems. We propose that the decision as to who is
>1.0x109/L, then consideration should be given to re-treat- responsible should be primarily based on competence,
ing the patient with LD chemotherapy prior to adminis- meaning that those individuals who normally thaw autol-
tration of the CAR T cells. ogous transplants are likely best qualified. On this basis,
pharmacy, processing facility and clinical transplant staff
are all acceptable candidates and bedside thawing is prefer-
Product receipt and thawing able.
The currently licensed CAR T-cell products are delivered

frozen and must be maintained at very low temperatures Infusion of chimeric antigen receptor T cells
during shipping, receipt and temporary storage until they
are thawed immediately prior to use. Hospitals have adopt- Before starting to thaw the CAR T-cell product, the
ed different approaches to product receipt, taking into patient should be assessed. Some factors to consider are
account local organizational and regulatory issues. The unit shown in Table 6. A transfusion set is required for the
receiving the CAR T-cell products will need to have suitable administration of the cells. In general, a typical transfusion
storage containers and facilities for genetically manipulated filter set with 50-200 mm pore size is used; this is, in fact,
material; depending on national legislation, a storage site mandatory in some countries. Importantly, fluid infusion
may need regulatory approval as gene therapy medicinal sets are not suitable because of the sub-micrometer bacte-
products are also genetically modified organisms.21 As the rial filters. Transfusion sets with leukocyte-depletion fil-
manufacturing companies use differently sized cryostorage ters are also unacceptable. It should be noted that the
cassettes, custom-made cryo racks, at least one for each manufacturers recommend the use of non-filtered tubing
company, must be obtained. A storage site with secured sets although our recommendations, and some local regu-
access and an adequate number of trained staff licensed to latory requirements, deviate from this approach.
work with biohazards and liquid nitrogen are required, both Pre-medication to prevent adverse reactions is reason-
at the hospital pharmacy and at the cell processing facility. able with the important exception of corticosteroids

Table 5A. Checklist before starting the conditioning.

SPCs EBMT recommendations Comments
CAR T-cell product The availability of the CAR T-cell product LD conditioning should only be Exceptional situations may necessitate
must be confirmed prior to starting administered following receipt of the administration of LD conditioning
the LD conditioning product on site following confirmation of successful
production but prior to arrival
Clinical conditions Active infections must be excluded Patient has to be able to tolerate
or under control before starting LD conditioning
LD conditioning
WBC LD conditioning should be administered Administer LD conditioning to all Some investigators have suggested that
before the KymriahTM infusion unless patients regardless of WBC or ALC patients with low ALC (<0.1x109/L)
the WBC count within 1 week of may not require LD as these patients
the infusion is ≤1.0x109/L are already “lymphodepleted”
SPC: summary of product characteristics; EBMT: European Society for Blood and Marrow Transplantation; CAR: chimeric antigen receptor; LD: lymphodepletion; WBC: white
blood cell count; ALC: absolute lymphocyte count.
Table 5B. Checklist of laboratory tests prior to conditioning.

Test methods Trials and SPC EBMT recommendations Comment
Chemistry
C-reactive protein and/or Required to rule out ongoing infection LD is contraindicated in patients
fibrinogen level with active infection. Active
infection must be excluded or
under control before starting LD
Bilirubin <26-34 mmol/L <34 mmol/L; higher limit No trial data regarding patients
acceptable (>43 mmol/L) outside of these parameters
with Gilbert syndrome
AST/ALT <5xULN <5xULN Attempt to identify causes e.g.
active infections
Creatinine clearance > 30 mL/min Modify drugs doses according to
creatinine clearance
Other work-up
Cardiac function Repeat cardiac investigations only if LVEF >40%;
clinically indicated (e.g. cardiotoxic assess for pericardial effusion by
bridging chemotherapy) echocardiography; ECG
SPC: summary of product characteristics; EBMT: European Society for Blood and Marrow Transplantation; AST: aspartate aminotransferase: ALT: alanine aminotransferase; LD: lym-
phodepletion; ULN: upper limit of normal; LVEF: left ventricular ejection fraction; ECG: electrocardiogram.
which may damage the CAR T-cell product; typically, as CRS and neurotoxicity, which generally occur within
paracetamol derivatives and antihistamines, such as chlor- 14 and 28 days of the CAR T-cell infusion, respectively.11,36-
pheniramine or diphenhydramine, are used. Individual 38
LD conditioning may also contribute to the cytopenias.
guidelines are provided by the manufacturers.
The product is aseptically connected to the port of a Hospitalization
central venous catheter. The line to be used for the CAR Some centers have established policies and infrastructure
T-cell infusion must be clearly designated; as with blood that allow for the safe administration of CAR T cells on an
and stem cell products, no concurrent medication may be outpatient, ambulatory care basis. However, for ambulato-
given during the CAR T-cell infusion. Infusion should ry care to work, clear protocols, staffing and training need
begin as rapidly after spiking as possible, but no later than to be in place so that patients are able to access a coordina-
30 min thereafter. The small volumes and cell numbers tor on a 24/7 basis. Centers must also be able to provide
allow for rapid (less than 30 min) drip infusion of the cell both immediate review and the emergency admission of
suspension. The infusion bag and set should be disposed patients under the care of experienced staff. As such
of as a biohazard and genetically modified organism arrangements are not currently available in most European
waste in compliance with institutional policies and coun- centers, we recommend that patients are admitted to hos-
try-specific regulations. Transfusion of the low-volume pital during the early post-infusion period unless high-level
CAR T-cell product is typically uneventful. ambulatory care and rapid re-admission pathways are
already well established, as in centers already providing
Short-term complications and management: ambulatory hematopoietic cell transplantation (HCT).
Table 7 summarizes our recommendations relating to the
infusion to day +28 first 28 days following the CAR T-cell infusion. These are in
The rapid in vivo proliferation of CAR T cells may be line with a number of clinical trial protocols and the recom-
associated with potentially life-threatening toxicities such mendations of scientific societies.21,39

Tumor lysis syndrome and the release of commensal organisms resulting in peri-
CAR T-cell therapy can result in the rapid destruction of tonitis.43
tumor cells and therapy-associated adverse events includ-
ing tumor lysis syndrome.40-42 Standard hospital protocols Infections
should apply. Tumor lysis in certain locations (gut, biliary Active infections should be fully treated and under con-
tree, lungs, genitourinary tract) may lead to perforation trol prior to the administration of LD conditioning and the
Table 6. Checklist and pre-medication before chimeric antigen receptor T-cell infusion.
SPC EBMT recommendations Comment
Active infection Reasons to delay treatment: Contraindication CAR T-cell infusion should be delayed
active uncontrolled infection until the infection has been
(KymriahTM and YescartaTM) successfully treated or controlled
Cardiac arrhythmia Reasons to delay treatment: unresolved Cardiologist opinion is required Specific individualized risk-benefit
not controlled with SAR (esp. pulmonary reactions, cardiac assessment required
medical management reactions or hypotension) from preceding
chemotherapies (KymriahTM and YescartaTM)
Hypotension requiring See above Contraindication CAR T-cell infusion should be delayed
vasopressor support until the hypotension has been fully
treated
New-onset or worsening Work-up is needed to identify Specific individualized risk-benefit
of another non-hematologic the cause assessment required
organ dysfunction ≥ grade 3
Significant worsening Reasons to delay treatment: Work-up is needed to identify Specific individualized risk-benefit
of the clinical condition significant clinical worsening of leukemia the cause assessment required
since start of LD burden or lymphoma following LD
chemotherapy (KymriahTM)
Pre-medication ‘It is recommended that patients As per SPC
be pre-medicated with paracetamol
and diphenhydramine or another H1
antihistamine within approximately
30 to 60 minutes prior to KymriahTM infusion’
‘Paracetamol given orally and
diphenhydramine or chlorpheniramine
intravenous or oral (or equivalent)
approximately 1 hour before YescartaTM
infusion is recommended’
Concomitant medication Corticosteroids should NOT be used As per SPC
prior to or around the time of
the infusion except in case of a
life-threatening emergency
SPC: summary of product characteristics; EBMT: European Society for Blood and Marrow Transplantation; CAR: chimeric antigen receptor; SAR: severe adverse reaction; LD:
lymphodepletion.
Table 7. Recommendations regarding the first month after chimeric antigen receptor T-cell infusion.
Period SPC and protocols EBMT recommendations Comments
Day 0 to day Some protocols require 5-14 days Ideally, 14 days hospitalization Shorter hospitalization periods
+14 post-infusion hospitalization after the infusion as well as outpatient follow-up are
possible in centers that can provide
24/7 contact with immediate availability
of specialist inpatient care. Patients
must be located within 30 min
of the center
From hospital discharge Some protocols require Patients must be located within CRS and, in particular, ICANS
to day +28 post-infusion that patients be located within 60 min of the treating unit can occur after the patient
30 to 60 min of the center or a well-equipped center* has left the hospital.
The continuous presence of a caregiver In addition, life-threatening
who is educated to recognize complications may occur
the signs and symptoms of CRS and during this period e.g. septic
ICANS is required shock in neutropenic patients
SPC: summary of product characteristics; CRS: cytokine release syndrome; ICANS: immune effector cell-associated neurotoxicity syndrome. * Centers competent to manage such
complications.

infusion of CAR T-cell products, especially given the likely and, sometimes, corticosteroids. Tocilizumab should be
cytokine-driven exacerbation of inflammatory processes. administered no more than four times during one episode
The presence of fever should prompt blood and urine cul- of CRS. Siltuximab (monoclonal antibody against IL-6)
tures, a chest radiograph, and, depending on symptoms, can be used as a second-line treatment (Figure 1).
respiratory viral screening, cytomegalovirus and Epstein- An algorithm outlining the management of CRS is
Barr virus nucleic acid testing, computed tomography shown in Figure 1.
imaging, lumbar puncture, and/or brain magnetic reso-
nance imaging. Empiric antimicrobial therapy based on Neurological toxicity
symptoms and institutional protocols should not be The neurological toxicity seen in CAR T-cell recipients,
delayed based on the presumption of CRS and clinicians previously called CAR-related encephalopathy syndrome
should consider the prior duration of neutropenia.43 (CRES), has recently been termed immune effector cell-
To reduce the time from recognition of suspected sepsis associated neurotoxicity syndrome (ICANS).38 This is the
to treatment with antimicrobial medications, institutions second most common adverse event following CAR T-cell
may consider the use of patient group directives or condi- infusion and its incidence has been reported at rates vary-
tional orders. These orders allow nursing staff to respond ing from 12% to 55%. In a recent study of 100 patients,
rapidly to signs and symptoms of infection, an example the median time-to-onset of the first neurological symp-
being the automatic administration of specific intravenous toms was 6 days (range, 1-34 days) after the CAR T-cell
antibiotics following the detection of a fever. infusion.57 The duration of symptoms is generally
between 2 and 9 days although late complications may
Cytokine release syndrome occur.11,38,57 In general, it develops either at the same time
CRS is a form of systemic inflammatory response fol- as or following resolution of CRS. Deterioration in hand-
lowing the infusion of CAR T cells. However, CRS has writing has been shown to be an early predictor of central
also been described following the administration of vari- neurotoxicity. Therefore, daily writing tests over the first
ous monoclonal antibodies including bi-specific antibod- months following the CAR T-cell infusion can be used as
ies and anti-lymphocyte globulin and as a complication of a simple tool to detect incipient ICANS.
haploidentical transplantation.44-48 CRS is the most com- The spectrum of symptoms and signs is non-specific,
mon complication after CAR T-cell therapy. Depending on ranging from confusion, headaches, tremors, hallucina-
the type of CAR T-cell therapy, the disease characteristics tions and abnormal movements to seizures, papilloedema
and the grading system which has been used, the reported and coma. Any neurological symptom occurring after the
incidence has ranged from 30-100% and for CRS grade 3 CAR T-cell infusion must therefore be considered as CAR
or 4 from 10-30%.49 T-related until proven otherwise. However, the ASTCT
The activation of CAR T cells is the triggering event of consensus panel recommended excluding non-specific
CRS. This leads to the release of effector cytokines such as symptoms such as headache, tremor, myoclonus, asterix-
interferon-g, tumor necrosis factor-α and IL-2. These mol- is, and hallucinations as they are usually managed symp-
ecules are, in turn, capable of activating the tomatically and do not generally trigger specific interven-
monocyte/macrophage system and inducing the produc- tions.
tion of a broad spectrum of pro-inflammatory cytokines Severe cases have been reported, occasionally leading to
(including IL-1, IL-6, IL-10, interferon g and monocyte death, due to multifocal hemorrhage, cerebral edema and
chemoattractant protein-1) leading to a raised level of C- laminar cortical necrosis. The severity is correlated with
reactive protein and sometimes hyperferritinemia. In pre- the increase in specific biomarkers such as C-reactive pro-
clinical models (humanized immunodeficient mice), it has tein, ferritin and IL-6.11,58-60 Close monitoring of patients
been shown that human monocytes are the main source using validated nursing tools is necessary to identify early
of IL-1 and IL-6 during CRS. The syndrome can be pre- manifestations of neurotoxicity. This requires serial cogni-
vented by monocyte depletion or by blocking the IL-6 tive testing.
receptor with tocilizumab. Tocilizumab does not, howev- Rapid access to neurological expertise is needed. Cross-
er, protect mice against late lethal neurotoxicity character- sectional imaging (computed tomography, magnetic reso-
ized by meningeal inflammation. In contrast, an anti-IL-1 nance imaging), electroencephalography, and cerebro-
receptor antagonist (anakinra) appeared to prevent CRS spinal fluid examination may all be required in the man-
and neurotoxicity in animal models.36,50,51 agement of these complex patients. Anti-epileptic prophy-
Severe CRS shares clinical features with macrophage laxis with agents such as levetiracetam is not routinely
activation syndrome, including fever, hyperferritinemia recommended except in patients with a history of seizures
and multi-organ dysfunction. CRS usually occurs between or central nervous system disease.
1 and 14 days after the CAR T-cell infusion and can last Pre-existing neurological comorbidities may be a risk
from 1 to 10 days.11,52 Its severity is variable and is evalu- factor for the development of ICANS. Disease-associated
ated according to a novel grading scale recently proposed factors include ALL, tumor burden, history of meningeal
by an American Society for Transplantation and Cellular involvement and prior central nervous system-directed
Therapy (ASTCT) consensus panel.38 Rare but fatal cases therapies.11,58-60 The intensity of ICANS has been correlated
with neurological involvement have been reported in the with the depth of lymphopenia and the homeostatic
literature.11 Risk factors for CRS include tumor burden, the expansion of CAR T cells. Moreover, the severity of
presence of active infection at the time of the infusion, the ICANS has also been found to be associated with the
dose of infused CAR T cells, the type of CAR T-cell con- severity and early onset of CRS as measured by the extent
struct and the choice of LD regimen.37,53-55 of fever within 36 h of the infusion, hemodynamic insta-
The treatment for severe cases, in addition to sympto- bility, tachypnea and hypoalbuminemia reflecting loss of
matic measures, consists of the administration of vascular integrity and capillary leakage.
tocilizumab (a monoclonal antibody against IL-6 receptor) The CARTOX scoring system was updated by the

ASTCT consensus panel and has been replaced by the Antibiotic prophylaxis
Immune Effector Cell-Associated Encephalopathy (ICE)
score shown in Table 8.38 A different assessment tool for The combined effect of prior treatments
screening delirium in children, adapted from Traube et al., (immunochemotherapy and/or autologous or allogeneic
is shown in Table 9.61 HCT, bridging chemotherapy administered after leuk-
apheresis and LD conditioning) all increase the risk of
Laboratory monitoring of cytokine release syndrome opportunistic infections in patients receiving CAR T-cell
and neurotoxicity therapy. Approximately one-third of patients have pro-
In addition to routine daily hematology and chemistry longed neutropenia (beyond day +30) and up to 20% of
laboratory tests, C-reactive protein and ferritin levels are patients have neutropenia lasting more than 90 days. B-
of use in the monitoring of patients developing CRS and cell depletion and hypogammaglobulinemia are additional
neurotoxicity. Although assaying IL-6 or other cytokine risk factors for infections.15,16,63,64
levels is theoretically interesting, cytokine testing is not After CRS and ICANS, infections are one of the most
routinely performed in most centers at present. common side effects of CAR T-cell therapy. Most infec-
Atypical lymphocytes that can mimic blasts are not tions are seen within the first 30 days and are bacterial,
uncommon at the peak of CAR T-cell expansion and can and to a lesser extent, respiratory viral infections. Invasive
be found in the peripheral blood, bone marrow, and even fungal infections are rare and are mostly observed in ALL
the cerebrospinal fluid of patients treated with these ther- patients who have undergone prior allogeneic stem cell
apies. Flow cytometry can be used to exclude relapse. transplantation.65
Repeating microbiological testing and imaging to rule out CAR T-cell recipients, like patients undergoing allogene-
infection is recommended in febrile patients. ic HCT, are at increased risk of a range of infections at the
Figure 1. Management of cytokine release syndrome. Adapted from Yakoub-Agha et al.56 CPAP: continuous positive airway pressure: BiPAP: biphasic positive airway
pressure; ICU: intensive care unit; CRS: cytokine release syndrome.

different stages of their treatment course and appropriate are infectious issues specific to CAR T-cell therapy. Table
antimicrobial prophylaxis is required. In general, centers 10 summarizes recommendations for prophylaxis against
performing allogeneic HCT will be familiar with the care the most common infections.
of such patients and there is, as yet, no evidence that there There is no evidence to suggest that cytomegalovirus,
Table 8. Immune Effector Cell-Associated Encephalopathy (ICE) score to neurological toxicity assess. Adapted from Lee et al.38
Test Points
Orientation: orientation to year, month, city, hospital 4
Naming: ability to name three objects (e.g. table, television, pillow) 3
Following commands: ability to follow simple commands (e.g. “smile” or “open your mouth”) 1
Writing: ability to write a standard sentence (e.g. “Happy to have my family around”) 1
Attention: ability to count backwards from 100 by 10 1
Table 9. Cornell Assessment of Pediatric Delirium (CAPD) to assess encephalopathy in children <12 years. Adapted from Traube et al.61
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 1 0
Table 10. Anti-infective prophylaxis after chimeric antigen receptor T-cell therapy.
Trials EBMT recommendation Comment
Neutropenia G-CSF should be used according to G-CSF to shorten duration of neutropenia Avoid if patient has CRS or ICANS
published guidelines from 14 days post-infusion There are theoretical concerns
can be considered regarding macrophage activation
Antibacterial prophylaxis Not recommended Not recommended* Can be considered in case of prolonged
neutropenia and should be based
on local guidelines e.g. with levofloxacin
or ciprofloxacin
Anti-viral Subjects should receive prophylaxis for Valaciclovir 500 mg bid or Start from LD conditioning until 1 year
prophylaxis infection with herpes virus, according aciclovir 800 mg bd post-CAR T-cell infusion and/or until
to NCCN guidelines or standard CD4+ count >0.2x109/L
institutional practice
Anti-pneumocystis Subjects should receive prophylaxis for Co-trimoxazole Can be started later depending on
prophylaxis infection with Pneumocystis pneumonia, 480 mg once daily center guidelines.
according to NCCN guidelines or standard or 960 mg three times each week In case of co-trimoxazole allergy,
institutional practice To start from LD conditioning pentamidine inhalation (300 mg once
until 1 year post-CAR T-cell every month), dapsone 100 mg
infusion and/or until CD4+count daily or atovaquone 1500 mg once
>0.2x109/L daily are other agents to consider
Systemic anti-fungal Subjects should receive prophylaxis Not recommended routinely; In patients with prior allo-HCT, prior invasive
prophylaxis for fungal infections according however, consider in patients with aspergillosis and those receiving
to NCCN guidelines or standard prolonged neutropenia and corticosteroids, posaconazole
institutional practice on corticosteroids prophylaxis should be considered
IV immunoglobulins Gammaglobulin will be administered Routine in children, consider in adults Clinical evidence does not support
for hypogammaglobulinaemia who have had infections with encapsulated routine use in adults following allo-HCT
according to institutional guidelines. organisms
At a minimum, trough IgG levels should
be kept above 400 mg/dL, especially in the
setting of infection
EBMT: European Society for Blood and Marrow Transplantation; G-CSF: granulocyte colony stimulating factor; CRS: cytokine release syndrome: ICANS: immune effector cell-asso-
ciated neurotoxicity syndrome; NCCN: National Comprehensive Cancer Network; LD: lymphodepleting conditioning; IV: intravenous; IgG: immunoglobulin G; allo-HCT: allogene-
ic hematopoietic cell transplantation. *In patients with neutropenic fever, empiric treatment with broad spectrum antibiotics is strongly recommended.

Epstein-Barr virus or adenoviruses are significant clinical detection of flow cytometry, whereas CTL019 remained
problems after CAR T-cell therapy. Little is known regard- detectable by means of quantitative polymerase chain
ing the risk of hepatitis B and C virus reactivation as reaction analysis.42 B-cell aplasia can therefore serve as a
patients with these infections were specifically excluded marker for monitoring CD19-specific CAR T-cell activity
from the trials. It is not possible to provide recommenda- over time.42,67
tions regarding the use of CAR T-cell therapy in patients Persistent B-cell lymphopenia is associated with sino-
with human immunodeficiency virus infection as seropos- pulmonary infections, notably with encapsulated bacteria;
itive individuals were also excluded. The pharmaceutical consideration can be given to vaccination although there is
companies may, however, manufacture a drug product for no evidence and immunoglobulin levels should be moni-
a patient positive for hepatitis B, hepatitis C or human tored.43 It has therefore been standard practice in pediatric
immunodeficiency virus if the viral load is below the level centers to administer empiric immunoglobulin replace-
of detection following treatment. For patients with a his- ment following the administration of CAR T cells.
tory of hepatitis B infection, prophylaxis with tenofovir is Children with B-cell aplasia should receive immunoglobu-
recommended.66 lin replacement to maintain IgG levels according to insti-
tutional guidelines for IgG substitution (i.e. ≥500mg/dL).42
In some cases, this may be a long-term requirement.
Medium-term complications and management: There is no consensus regarding systematic supplemen-
tation in adults who have been shown to have long-lived
day +28 to day +100 CD19-negative plasma cells that continue to confer
Potential toxicities during this period include delayed humoral immunity in patients who were successfully
tumor lysis syndrome, delayed hemophagocytic lympho- treated with CAR T cells targeting CD19. Nevertheless,
histiocytosis/macrophage activation syndrome and CRS, intravenous immunoglobulin replacement is recommend-
B-cell aplasia, hypogammaglobulinemia, graft-versus-host ed in patients with hypogammaglobulinemia and recur-
disease (GvHD), and infections. Neutropenia, thrombocy- rent infections with encapsulated bacteria. Patients may
topenia and anemia are common but generally resolve transition to home-administered subcutaneous
slowly over several months. Growth factor support may immunoglobulins after 6 months.
be indicated in the early stages.
Table 11 summarizes tests to be performed during this Graft-versus-host disease
period and their recommended frequency. Donor-derived CAR T cells may rarely trigger GvHD if
harvested from, and then returned to, patients who have
Delayed macrophage activation syndrome and cytokine undergone allogeneic HCT. Current evidence suggests
release syndrome that the risk of inducing GvHD with the use of donor-
In the experience of CAR T-cell therapy for ALL, CRS derived CAR T cells is low.68-70 However, vigilance is
typically occurred between 1 and 14 days after the CAR T- required as this complication is potentially severe and life-
cell infusion, whereas in patients with chronic lymphocyt- threatening. If suspected, GvHD should be diagnosed and
ic leukemia, CRS usually occurred later, between 14 and managed using standard protocols, balancing the potential
21 days after the infusion.42 Regardless of the timing, benefit of introducing systemic immunosuppression
delayed macrophage activation syndrome and CRS are against its effect on anti-tumor CAR T-cell function.
managed using standard approaches.
Infections
B-cell aplasia and hypogammaglobulinemia Beyond 30 days, viral infections predominate including
B-cell aplasia is an almost universal on-target, off-tumor respiratory viral infections, cytomegalovirus viremia and
toxicity and results in hypogammaglobulinemia. It occurs pneumonia. Later infections may reflect prolonged
in all responding patients and can persist for several years. immunoglobulin deficiency (up to 46% at day 90) as well
This absence of CD19-positive cells correlated with func- as lymphopenia.71 Severe co-infections with CRS include
tional persistence of CTL019 cells below the limits of respiratory virus infections (some nosocomial),
Table 11. Monitoring of patients during medium-term follow-up.

Test Purpose Frequency Comment
FBC, biochemistry panel, Standard follow-up At every visit and as clinically indicated
LDH, fibrinogen, CRP
CMV, EBV, adenovirus Viral reactivation As clinically indicated
Quantitative immunoglobulins Immune reconstitution Monthly Consider IV immunoglobulins
or serum protein electrophoresis
Peripheral blood Immune recovery Once monthly for first 3 months, Guide to anti-infective prophylaxis
immunophenotyping – three monthly thereafter in first year
CD3/4/8/16+56/19+
CAR T-cell monitoring where CAR T-cell persistence Peripheral blood flow cytometry or Not recommended by CAR
kits are available for routine transgene by molecular methods as T-cell manufacturers
monitoring of anti-CD19 CAR T cells clinically indicated
FBC: full blood count; LDH: lactate dehydrogenase; CRP: C-reactive protein; CMV: cytomegalovirus; EBV; Epstein-Barr virus; IV: intravenous; CAR: chimeric antigen receptor.

cytomegalovirus, human herpes virus-6 or Epstein-Barr All patients must be informed of the potential risks and
viremia, Clostridium difficile colitis, cholangitis, and viral the precautions that they need to take, as described in the
encephalitis.67,72-74 relevant product patient information leaflet. They may
also receive further written information, according to local
Nursing and psychological support of patients practice, in the form of a patient information booklet or
CAR T cells are generally being administered in a small leaflet. This should include information and education on
number of regional specialist centers to which patients are the symptoms of CRS and serious neurological adverse
referred from general hospitals. Patients who are treated reactions, the need to report any symptoms immediately
with CAR T cells may therefore experience high levels of to their treating physician and the need to remain in close
anxiety due to their new environment as well as their proximity to the center in which the CAR T cells were
prognosis. Many will be socially isolated and at a signifi- administered for at least 4 weeks following the infusion.
cant distance from their established support networks. Patients must be advised to keep their Patient Advice
The role of the clinical nurse specialist is vital to the suc- Card with them at all times and to show it to any health-
cess of the procedure as well as providing essential bed- care professional they encounter, especially if they are
side support. Referral to local counselling/psychology admitted to another hospital. Patients are advised not to
services should be offered to these patients when appro- drive for 8 weeks after the infusion and only after resolu-
priate. tion of any neurological symptoms. This is due to the risk
Patients who are being treated on an outpatient basis of delayed neurological toxicity. It is also preferable to
and their caregivers should receive comprehensive educa- have a responsible adult such as a parent, spouse or other
tion on the symptoms of CRS and neurotoxicity and caregiver available during the first 3 months following the
patients should attend the treating hospital without delay infusion. A reliable, consistent and well-informed caregiv-
in the event that they begin to feel unwell. On discharge, er is essential.
they should be instructed to remain within 1 hour’s travel
of the treating hospital for at least 4 weeks following the
infusion, during which time a caregiver should always be
present. If the patient lives further away, then alternative Long-term follow-up from day +100 onwards –
accommodation, such as a local hotel or apartment, will ‘late effects’
be required. Independently of whether the patient is living Little is known about the long-term effects of CAR T-
at home or lodging in a local apartment, ambulatory care cell therapy. Only a small cohort of patients has been fol-
arrangements for rapid re-admission should be well estab- lowed for more than 2 years. The main identified compli-
lished. cations are prolonged cytopenias and hypogammaglobu-
Table 12. Recommended minimum frequency of attendance at centers for monitoring for late effects after chimeric antigen receptor T-cell ther-
apy.
Post CAR-T Stable patients Complications Disease monitoring Comment
Day +100 to 1 year Three-monthly As clinically indicated Frequency of visits Patients who proceed to
required is disease-specific and subsequent allo-HCT, cytotoxic
monitoring could be performed therapy and/or immune effector
One year to 15 years Annually by CAR T-cell center or cell therapy should be followed
referring clinician as per Majhail et al. 201275
CAR: chimeric antigen receptor; allo-HCT: allogeneic hematopoietic cell transplantation
Table 13. Recommended tests to be performed at long-term follow-up clinics.

Test Purpose Frequency Comment
Full blood count, biochemistry panel Standard follow-up At every visit
Viral infection (PB PCR, NPA) Viral reactivation As clinically indicated
Quantitative immunoglobulins Immune reconstitution At every visit
± serum protein electrophoresis
Peripheral blood immunophenotyping Immune reconstitution Every second visit No longer required following
– CD3/4/8/16+56/19* normalization
CAR T-cell monitoring where kits are CAR T-cell persistence Every visit. However, no longer Testing for CAR T-cell persistence
available for routine monitoring required when absent for two is not standard. Checking for B-cell
of anti-CD19 CAR T* consecutive tests depletion as a surrogate marker
is an option
Endocrine function and other Standard follow-up As clinically indicated
standard late effects testing
appropriate to age
PB: peripheral blood; PCR: polymerase chain reaction; NPA: naso-pharyngeal aspirate; CAR: chimeric antigen receptor. *Equivalent test methods for other immune effector cells
as they become available

Figure 2. Management of chimeric antigen receptor T-cell-related neurological toxicity. Adapted from Cornillon et al.62 ICE. Immune effector cell-associated
encephalopathy; CAPD: Cornell Assessment of Pediatric Delirium; EEG: electroencephalography; ICU: intensive care unit; IV: intravenous; ICANS: effector cell-associ-
ated neurotoxicity syndrome; MRI: magnetic resonance imaging; LP: lumbar puncture; CRS: cytokine release syndrome; IL1R: interleukin-1 receptor; IL-6: interleukin
6.
linemia. There are also more theoretical concerns about ity for CAR T-cell administration, disease-specific special-
the risk of secondary malignancies and both neurological ists, long-term follow-up nursing staff, data managers and
and autoimmune diseases. clinical trial staff.
It should be recognized that all patients will have been Long-term follow-up clinics may be incorporated into
treated previously with multiple anti-cancer therapies, local arrangements for generic allogeneic HCT ‘late effects’
some having also undergone allogeneic HCT. Some clinics with other allogeneic HCT patients, although dedi-
patients may receive CAR T-cell treatment at overseas cated clinics for the late effects of CAR T-cell therapy can
centers and may then return to a CAR T-cell therapy or be developed if a critical mass of survivors is reached.
HCT center. There is a duty-of-care on all CAR T-cell- The clinic should systematically monitor for the follow-
administering centers to arrange for appropriate local fol- ing outcomes: (i) disease status – remission, minimal resid-
low-up. In cases of geographical transition, formal com- ual disease, relapse, management of relapse, death, (ii) fur-
munication, including discharge correspondence and other ther treatments administered after CAR T-cell therapy,
clinical material such as imaging files, should be provided including allogeneic HCT and other immune effector cell
to new healthcare providers. therapy/Advanced Therapy Medicinal Products; (iii) late
Protocols and policies (standard operating procedures) effects – for stable patients in ongoing remission, 3-
for long-term follow-up will need to be put in place. These monthly monitoring for the first year, annually thereafter
should cover shared care and out-reach arrangements and or as clinically appropriate; (iv) infections, (v) immunolog-
should be based on service level agreements between ical status – cell markers, immunoglobulins, including
CAR T-cell centers and referring centers. CAR T-cell persistence; (vi) new cancers, including sec-
Multidisciplinary teams dealing with CAR T-cell thera- ondary myeloid diseases; (vii) new autoimmunity and
pies should arrange for long-term follow-up of treated autoimmune diseases; (viii) endocrine, reproductive and
patients in order to capture disease status and the late bone health (including growth and development in chil-
effects of CAR T-cell and prior treatments. The multidisci- dren and young adult patients); (ix) neurological status
plinary team should include a physician with responsibil- (including recovery from ICANS); (x) psychological status

and quality of life; (xi) cardiovascular status, including CIBMTR to develop common data collection policies so
echocardiographic assessments and risk factors for cardio- the prospect of robust global datasets on the efficacy and
vascular disease, such as ‘metabolic syndrome’; (xii) respi- safety of CAR T-cell therapies is on the horizon.
ratory status; and (xiii) gastrointestinal and hepatic status. It is expected that patients receiving CAR T-cell thera-
The role of vaccination following CAR T-cell therapy pies in both investigator-led and pharma-sponsored trials
remains unclear. Until further evidence is available, no might also have their follow-up data collected in the
specific recommendation can be made. This is, in particu- EBMT registry. In order to address concerns that pharma-
lar, a problem with small children who might not yet have ceutical companies may have about the confidentiality of
completed their basic immunization schedule and who commercially sensitive clinical data, trial data reported to
therefore need close follow-up. the EBMT registry can be embargoed until investigating
In view of long-term B-cell depletion, the advisability of centers decide to make such data accessible to the public.
vaccination and adherence to the standard recommended Early data collection might also create a virtuous circle
national schedules needs to be evaluated for each individ- whereby knowledge of increased activity might help
ual based on the history of infections and laboratory those lobbying for an improved infrastructure for CAR T-
assessments of cellular and humoral immunity.75 If vac- cell therapies across Europe in terms of funding opportu-
cines are given, specific antibody responses should be nities, regulatory frameworks, and, ultimately, commer-
assessed. cial drug approval. EMA approval for the use of the EBMT
registry also places certain responsibilities on the EBMT.
As a formal data controller, the EBMT will need to guar-
Post-authorization safety surveillance antee a fair and transparent mode of data sharing in order
to improve the assessment of the many different agents
As tisagenlecleucel (KymriahTM) and axicabta- and ultimately to improve our knowledge on how best to
geneciloleucel (YescartaTM) are the first agents in a novel use CAR T-cell therapies.
class of therapies based on the genetic modification of
autologous T cells using viral vectors, the EMA and the
FDA have made marketing approval conditional on 15- JACIE and regulatory issues
year post-authorization safety surveillance (PASS). At an
EMA-sponsored stakeholder workshop on how to best FACT-JACIE standards were initially developed for the
capture the long-term side effects of different CAR T-cell accreditation of HCT programs.78,79 The current 7th edition
products over the next 15 years, it was felt that the report- of the standards also covers immune effector cells (IEC) to
ing of CAR T-cell safety and efficacy in one European reg- accommodate the rapidly evolving field of cellular thera-
istry would avoid the creation of data silos and would py, mainly, although not exclusively, genetically modified
allow for the risks and benefits of the different agents to cells, such as CAR T cells. FACT-JACIE standards do not
be transparently compared on a common platform. Such a cover the manufacturing of CAR T cells but do include the
registry would also set an excellent example as to how supply chain and handover of responsibilities when the
public registries can not only improve patient care but also product is provided by a third party. Specific clauses in the
help to support affordable health care.76 In March 2019, standards detail the following requirements, among oth-
the EBMT received a qualification opinion from the EMA ers: the need for the appropriate recognition of side effects
which found the cellular therapy module of the EBMT related to the infusion of IEC, a policy for the rapid esca-
registry to be fit-for-purpose for the regulatory overseeing lation of care in critically ill patients, the availability of
of pharmaco-epidemiological studies concerning CAR T- specific drugs for CRS and other complications and a
cell therapy.77 labeling system to guarantee both the identification and
A modified version of the MED-A cell therapy form will traceability of the product from the collection to the man-
be used for CAR T cells and other academic- or industry- ufacturer and back to the clinical unit. In all involved areas,
manufactured cell therapies. The data submission time there is the need for evidence of adequate staffing and
points are day 0, day +100, 6 months, and annually there- training, satisfactory levels of competency, validated pro-
after. This module has already proven to be effective in cedures and efficient communication. Documentation is
capturing basic data sets on academic and commercial available at www.jacie.org.
CAR T-cell infusions, although the EMA has requested During the introductory phase of developing CAR T cells,
additional safeguards during data capture for regulatory some centers received ‘focused’ site visits for IEC.
purposes. However, the current minimal data set request- However, now that the 7th edition of the standards is well
ed by the EMA for commercial products does not require established, inspection of IEC standards should be routinely
detailed product information such as CD4 and CD8 ratios incorporated within standard JACIE site visits, particularly
or transduction efficiencies, as companies consider these as there is much dependency on the wider accreditation
to be sensitive proprietary information. Agreed access to a requirements of the HCT program i.e., clinical, apheresis,
more detailed data set regarding products being evaluated pharmacy and processing laboratory service, along with
in clinical trials might benefit all those working in the quality management system requirements. In fact, in the
CAR T-cell research field. current 7th edition, only 2% and 6% of items are specifically
In the USA, the FDA has implemented product-specific related to either IEC or HCT, respectively, and 92% of the
Risk Evaluation and Mitigation Strategy (REMS) pro- items are common to all forms of cellular therapy.
grams. In parallel, the National Cancer Institute-funded In addition to JACIE, the complexity of the clinical
Moonshot Initiative program called Cellular management of patients receiving CAR T-cell therapy has
Immunotherapy Data Resource, awarded to the CIBMTR led to competent authorities and other regulatory bodies
in October 2018, will allow for the collection of real-world in some European countries requiring the administration
data. In recent years, the EBMT has worked with the of CAR T cells and other IEC within the context of an

accredited allogeneic HCT program, where established therefore potentially outside mainstream transplant prac-
facilities, staffing and expertise can support most aspects tice, there are a number of possible routes. First, there may
of the CAR T-cell pathway. Regardless, the logistical be referral to an accredited HCT program, where shared
impact of IEC administration within a HCT program has care arrangements can be easily accommodated within
to be carefully planned; an implementation plan aimed at the quality management systems and service level agree-
meeting all accreditation and other regulatory requirements. This is a model that already applies to occasional
ments, while engaging all professionals, services and infra- HCT in solid tumors, such as germ cell tumors, where
structure, is essential. Before starting, an assessment of the patients are referred back at a mutually agreed, often early,
number of eligible patients and likely resource require- stage after transplantation for ongoing care by the refer-
ments will usually have to be reviewed by the competent ring medical or clinical oncologists.
authorities and other regulators, as well as by funding An alternative strategy would be to undertake inde-
bodies. As mandated by the EMA, the pharmaceutical pendent IEC accreditation specifically for CAR T-cell and
manufacturers also have their own requirements and rou- other IEC therapies. This would have to be an individual
tinely inspect facilities before a CAR T-cell program is decision, based on the number of patients undergoing
commenced. therapy in a given center, as to whether the establishment
The EBMT and JACIE expect that most CAR T-cell of a functional quality system and other generic measures
activity in Europe will be delivered by experienced allo- were justified just for CAR T-cell or other IEC therapy.
geneic HCT centers and, ultimately, as the accreditation The EBMT and JACIE are currently evaluating the
cycles of centers roll through to the 7th edition of the stan- demand and feasibility of this approach, which has been
dards, the IEC standards will be covered at routine allo- adopted by FACT.
geneic HCT re-accreditation inspections. For the minority Currently, the general recommendation from the EBMT
of centers that undertake CAR T-cell therapy outside of an and JACIE is that CAR T cells and other IEC are best deliv-
accredited allogeneic HCT program, there are a number of ered within the framework of an accredited HCT program,
options. Given that CAR T-cell therapy is presently used whether allogeneic or autologous, with shared care poli-
predominantly in B-cell non-Hodgkin lymphoma, there is cies and service level agreements incorporated into the
the possibility of achieving the IEC standards as part of quality systems of the HCT program. Importantly, JACIE
the accreditation covering autologous HCT, given that also provides a robust method to ensure that programs
referral for autologous HCT is common in lymphoma meet the quality and other requirements for mandatory
practice. The same considerations could also apply to long-term data submission to the EBMT registry, as well as
myeloma specialists working outside of allogeneic HCT potential benchmarking of survival outcomes.
programs, as IEC accreditation standards could be aligned
to autologous HCT activity or referral routes routinely Acknowledgments
established in every myeloma service. The authors would like to thank all respondents to the interna-
In the event of CAR T-cell or related therapies becoming tional survey on the management of patients receiving CAR T-cell
more broadly applicable to non-hematologic cancers and therapy.
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GUIDELINE ARTICLE

Management of adults and children Ferrata Storti Foundation

haematologica | 2020; 105(2) 297

Introduction ing scientists, nurses and physicians, and close collabora-

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continued from the previous page

Table 2. The minimum required tests.

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Table 3. Checklist prior to apheresis.

Mandatory blood tests

Blood values required for optimal apheresis performance

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Table 4. Wash-out period before leukapheresis (adapted from Kansagra et al.12).

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The currently licensed CAR T-cell products are delivered

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Table 5A. Checklist before starting the conditioning.

Table 5B. Checklist of laboratory tests prior to conditioning.

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Table 11. Monitoring of patients during medium-term follow-up.

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Table 13. Recommended tests to be performed at long-term follow-up clinics.

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References Transl Med. 2018;66(2):62-64. Transl Med. 2018;10(436).

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2019;134(11):860-866. Blood. 2019;133(15):1652-1663. et al. CAR T cell-induced cytokine release

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