*Follow that CAR!* - A prospective observational cohort study on CAR T-cell therapy for B-cell malignancies in the Netherlands

Chimeric Antigen Receptor T-cell (CAR T) therapy is a unique form of cellular
immunotherapy using autologous genetically modified T cells that express a
synthetic receptor (the **CAR**) combining the specificity of a monoclonal
antibody for a specific tumor surface antigen with the cytolytic power and
capacity for immune surveillance of a T cell. CAR T-cell therapy revolutionized
the field of hemato-oncology and is becoming an increasingly important part of
standard of care. For decades, attempts at improvement of the poor prognosis of
relapsed/refractory B-cell malignancies with new treatment regimens have been
disappointing. Based on high response rates and prolonged progression-free
survival in pivotal phase 1/2 trials different CAR T-cell products are FDA and
EMA approved. Three CAR T-cell products for relapsed or refractory (R/R)
diffuse Large B-cell lymphoma (DLBCL) are FDA approved; axicabtagene ciloleucel
(axi-cel) (Yescarta® in 2017), tisagenlecleucel (tisa-cel) (Kymriah® in 2017)
and lisocabtagene maraleucel (liso-cel in 2021). Axi-cel and tisa-cel are also
EMA approved since 2018. In the Netherlands, the *Zorginstituut
Nederland* (ZIN) has until now only approved the product axi-cel for the
treatment of R/R DLBCL (May 2020). Tisa-cel (Kymriah®) is also FDA and EMA
approved for the treatment of R/R B-cell Acute Lymphoblastic Leukemia (B-ALL)
in children and adults up to and including 24 years of age, since 2017 and 2018
respectively. In the Netherlands, ZIN has also approved tisa-cel for treatment
of R/R B-ALL in children and adults up to and including 24 years of age
(December 2018). Additionally, the FDA has granted accelerated approval of
brexucabtagene autoleucel (brexu-cel, Tecartus®) in 2020 for treatment of R/R
mantel cell lymphoma (MCL) and EMA has granted a conditional marketing
authorization. It is expected that many more CAR T-cell products will be
approved in the foreseeable future. Despite the hopeful response rates,
challenges remain.

• To set up a national prospective observational cohort study of patients who
have a hematological B-cell malignancy and are referred to the national CAR
T-cell tumorboard for evaluation of eligibility for treatment with CAR T-cell
therapy and to follow them from time of referral until 30 years follow-up or
death.
o To prospectively collect accurate data on medical history,
comorbidities, medication use, disease characteristics, baseline clinical
parameters, laboratory results, imaging results, pathology results, CAR T
tumorboard evaluation outcomes, treatment outcomes, treatment related adverse
events, (new) interventions and treatment strategies and patient reported
outcome and experience measures.
o To facilitate the evaluation of quality of standard of care in this
patient population in the Netherlands.
o To serve as a continuous basis for a large variety of research purposes
regarding CAR T-cell therapy in the Netherlands including:
* Efficacy and safety studies
* Prognostic and predictive studies
* Biological studies
* Health technology assessment studies
* Evaluation studies of patient reported outcome measures
(PROMs, to measure a.o. quality of life, psycho-social functioning and side
effects) and patient reported experience measures
(PREMs, to measure a.o. quality of care).
* Studies on evaluation and development of education materials
for patients and their relatives and healthcare professionals.
* Studies to compare new interventions in a target population
according to the Trials within Cohorts Design (TwiCs)

A prospective national multicentre observational cohort study.

Extension to the study design:
As the study initiation was delayed due to organizational and legal constraints
and some participating centers were not able to include patients before May
2024, not all patients referred to the Dutch CAR T-cell tumorboard can be asked
informed consent before they received CAR T-cell therapy. In order to be able
to still include all referred patients from establishment of the CAR T-cell
tumorboard as soon as CAR T-cell therapy became available outside clinical
trials in the Netherlands, we will also allow that informed consent is asked
after screening for CAR T-cell infusion for patients treated with CAR T-cell
therapy up to and including December 31st 2024. Subsequently, after signing
the informed consent, prospective data collection will follow. In order to have
the same information for all included patients available for analyses, the data
until informed consent was signed will also be collected but then
retrospectively. However, due to the aggressive disease course some patients
referred to the CAR T-cell tumorboard have already deceased before obtaining
informed consent. To avoid selection bias we need to include these patients.
For this subcohort retrospective data collection is allowed on the ground of
general no-objection.

Since this is an observational study there are no additional risks associated
with participation. Clinical parameters will be collected during routine care
and derived from medical charts. If patients also give their consent on
collecting PROMs and PREMs through validated questionnaires, patients will be
informed about the extra time effort to complete these questionnaires. A
possible advantage is that the answers to these questions can directly be
shared with the treating healthcare professional to improve patient-centered
care, if sharing this information is desired by the patient.
If a patient gives informed consent to be approached for future studies
including studies on experimental treatment strategies according to the TwiCs
design, they will be informed that their data may be used for comparative
evaluation of safety and effectiveness of these new treatment strategies. They
are also informed about the possibility that they may be randomly selected to
being offered an experimental treatment strategy. If they are selected for this
experimental treatment strategy they will receive separate information and will
have to give separate informed consent. Patients will always have the option to
choose the standard of care treatment strategy. Patients are informed about the
fact that if they are not selected for a certain experimental treatment
strategy, and therefore are part of the control arm, they will not be informed
about this and may be (temporarily) ineligible for some future other
experimental treatment strategies within this cohort, without knowing. However,
in any instance, standard, evidence-based treatments will never be withheld
from patients. Also, patients within the Follow that CAR project may still
participate in other research such as traditional RCTs.