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