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Ensuring center quality, proper patient selection and fair access to chimeric antigen receptor T-cell therapy: position statement of the Austrian CAR-T Cell Network

Ensuring center quality, proper patient selection and fair access to chimeric antigen receptor... special report memo (2020) 13:27–31 https://doi.org/10.1007/s12254-020-00582-4 Ensuring center quality, proper patient selection and fair access to chimeric antigen receptor T-cell therapy: position statement of the Austrian CAR-T Cell Network Hildegard T. Greinix · Andishe Attarbaschi · Michael Girschikofsky · Richard Greil · Wolfgang Holter · Peter Neumeister · Christina Peters · Andreas Petzer · Jakob Rudzki · Peter Schlenke · Clemens A. Schmitt · Wolfgang Schwinger · Dominik Wolf · Nina Worel · Ulrich Jaeger Received: 27 January 2020 / Accepted: 28 January 2020 / Published online: 20 February 2020 © The Author(s) 2020 Summary Chimeric antigen receptor T cells (CAR-T Keywords CAR-T cells · Position statement · cells) are a novel form of cellular immunotherapy for Network · Patient selection criteria · Infrastructure patients with hematologic and oncologic malignan- requirements cies. Known side effects of these approved cellular Abbreviations immunotherapies are cytokine release syndrome, im- ASCTR Austrian Stem Cell Transplant Registry mune-cell associated neurotoxicity syndrome, cytope- B-ALL B-cell acute lymphoblastic leukemia nias, infections and long-lasting B cell aplasia. Safe CAR-T Chimeric antigen receptor-T cell administration of CAR-T cell therapy requires thor- CD19 Cluster of differentiation 19 ough patient selection and patient care in qualified CRS Cytokine release syndrome CAR-T cell centers. DLBCL Diffuse large B cell lymphoma EBMT European Society for Blood and Marrow Transplantation All authors contributed equally to this work. Dr. J.Rudzki·Univ.Prof. Dr.D. Wolf This position paper has been endorsed by the Austrian Division of Hematology, Medical University Innsbruck, Society of Hematology and Medical Oncology (OEGHO). Anichstraße 35, 6020 Innsbruck, Austria Univ. Prof. Dr. P. Schlenke Electronic supplementary material The online version of Department of Blood Group Serology and this article (https://doi.org/10.1007/s12254-020-00582-4) Transfusion Medicine, Medical University Graz, contains supplementary material, which is available to Auenbruggerplatz 36, 8036 Graz, Austria authorized users. Univ.Prof.Dr.H.T. Greinix ()·Univ.Prof. Dr.P. Neumeister Univ.Prof.Dr.C. A.Schmitt Division of Hematology, Medical University Graz, Department of Internal Medicine 3—Hematology and Auenbruggerplatz 38, 8036 Graz, Austria Oncology, Kepler University Clinic, Linz, Austria hildegard.greinix@medunigraz.at Univ. Prof. Dr. W. Schwinger Univ. Prof. Dr. A. Attarbaschi · Univ. Prof. Dr. W. Holter · Division of Pediatric Hematology and Oncology, Medical Univ. Prof. Dr. C. Peters University Graz, Auenbruggerplatz 36, 8036 Graz, Austria St. Anna Children’s Hospital, Univ.Prof.Dr.N. Worel Kinderspitalgasse 6, 1090 Vienna, Austria Department of Blood Group Serology and Transfusion Dr.M. Girschikofsky ·Univ.Prof.Dr.A.Petzer Medicine, Medical University Vienna, Waehringer Guertel Department of Hematology with Stem Cell Transplantation, 18–20, 1090 Vienna, Austria Hemostaseology and Medical Oncology, Ordensklinikum Univ.Prof.Dr.U. Jaeger Linz Barmherzige Schwestern—Elisabethinen, Linz, Austria Division of Hematology, Medical University Vienna, Waehringer Guertel 18–20, 1090 Vienna, Austria Univ.Prof.Dr.R. Greil Third Department of Internal Medicine with Hematology, Medical Oncology, Hemostaseology, Infectious Diseases and Rheumatology, Paracelsus Medical University Salzburg, Salzburg, Austria K Position Statement on CAR-T cell therapy in Austria 27 special report EMA European Medicines Agency Retrospective analysis of predictive factors, product HSCT Hematopoietic stem cell transplantation differences (real world evidence) ICANS Immune-cell associated neurotoxicity syn- To create a network for clinical and basic studies drome  To avoid hospital tourism ICU Intensive care unit PMBCL Primary mediastinal B cell lymphoma The following criteria for patient selection and infras- SOPs Standard operating procedures tructure of CAR-T cell centers have been developed within the CAR-T cell platform of the Austrian Soci- ety of Hematology and Medical Oncology (OeGHO) Introduction including the prerequisites for quality-controlled ad- Chimeric antigen receptor T cells (CAR-T cells) are ministration of CAR-T cell therapy in Austria. At least a novel form of cellular immunotherapy for pa- yearly or in case of new scientific developments and tients with hematologic and oncologic malignan- approvals this position statement will be updated. cies. Thereby patients’ immune cells are harvested by The institution responsible for CAR-T cell therapy leukapheresis, genetically modified to selectively ex- has to have specialized knowledge on therapy of pa- press a tumor-specific surface receptor using a retro- tients with the malignancies to be treated, compe- viral or lentiviral vector, expanded ex vivo and then tency in cellular therapy including use of gene-mod- reinfused into the patients after proper quality con- ified cells and competency in intensive care to allow trol measures and administration of lymphodepleting treatment of severe complications. therapy [1]. These genetically modified T lymphocytes To guarantee therapeutic access for all Austrian pa- selectively recognize antigens on the surface of tumor tients CAR-T cell centers should be established that cells against which they are directed and eradicate have all these competencies and fulfill the necessary malignant cells after T cell activation [1]. structural requirements to be described in more detail So far, two commercial CAR-T cell products have in the following. been approved by the European Medicines Agency The requirements of regulatory authorities for the (EMA) which contain a CAR against CD19, a sur- currently available CAR-T cell products have to be es- face antigen of B-lymphocytes. Tisagenlecleucel tablished. Most importantly, quality measures neces- (Kymriah ) has been approved for therapy of chil- sary for qualification of centers and the qualification dren and young adults up to the age of 25 years with by itself have to be achieved prior to use of CAR-T B cell acute lymphoblastic leukemia (B-ALL) and for cells. adult patients with diffuse large B cell lymphoma All CAR-T cell centers have to fulfill the following (DLBCL); axicabtagen ciloleucel (Yescarta ) has been criteria regarding infrastructure, personal, and proce- approved for patients with DLBCL and primary medi- dures. The medical head is responsible for the coor- astinal large cell B cell lymphoma (PMBCL). Of note, dination and administration of CAR-T cell therapies. all patients have to have relapsed or refractory disease Within a center a well-organized, controlled, interdis- [2, 3]. ciplinary and multiprofessional cooperation has to be Known side effects of these approved cellular in place for administration of CAR-T cell products. immunotherapies are cytokine release syndrome (CRS), immune-cell associated neurotoxicity syn- Criteria for infrastructure of CAR-T cell centers drome (ICANS), cytopenias, infections and long- lasting B cell aplasia [4]. Incidence and severity of Medical expertise these side effects differ individually and between cell products. Life-threatening disease with multiorgan Personal has to have extensive experience in therapy failure and severe cerebral edema have been reported of the malignant disease to be treated with CAR-T from clinical studies. Therefore, safe administration cells, experience with clinical study participation and of CAR-T cell therapy requires thorough patient selec- administration of experimental therapies. tion and patient care in a qualified CAR-T cell center For documentation of extensive experience in cel- [5, 6]. lular therapy at a given center, first allogeneic and/or We reasoned that a network of all centers involved autologous hematopoietic stem cell transplantations in administration of CAR-T cells would be most suited (HSCT) had tobe reported tothe Austrian Stem Cell to achieve the following aims: Transplant Registry (ASCTR) and the European Society of Blood and Marrow Transplantation (EBMT) during Ensure fair access for all citizens to all products the last 3 years. Selection of patients with a high likelihood of re- Each CAR-T cell center needs to have extensive ex- sponse perience in intensive care of patients with hemato- To avoid unjustified hopes for individual patients logic and oncologic diseases including the availabil- who are likely NOT to respond ity of 24-hour endoscopy, bronchoscopy, invasive pul- Ensure wise use of resources monary support and renal replacement therapy. Fur- Country-wide registration and outcome control thermore, standard operating procedures (SOPs) for 28 Position Statement on CAR-T cell therapy in Austria K special report management of complications of CAR-T cell therapy Criteria for personnel have to be in place including the use and 24-hour availability of tocilizumab as requested by regulatory The involved medical personnel (physicians and nurs- authorities. An immediate transfer to and admission ing staff) has to be thoroughly trained and has to have at an intensive care unit (ICU) if necessary has to be documented experience in administration of cytotoxic established. and immunosuppressive agents as well as cryopre- served cells. The medical head and his/her deputy responsible Additional criteria for infrastructure for CAR-T cell therapy of adult patients have to be cer- Hygiene tified specialists for internal medicine and hematol- Prior to the infusion of CAR-T cells a lymphodepleting ogy/medical oncology. They must have at least 2 years chemotherapy is administered resulting in immuno- of professional experience in a unit treating patients suppression and side effects known from patients with with severe immunodeficiency and/or performing al- lymphoma and acute leukemia given similar thera- logeneic HSCT. pies. Following CAR-T cell therapies patients can ex- The medical head and his/her deputy responsible perience neutropenia and need appropriate support- for CAR-T cell therapy of children and adolescents un- ive care. If necessary, immediate contact isolation til the age of 18 years have to be certified specialists during hospital stay has to be available. for pediatric hematology and oncology. CAR-T cell therapies have to be administered in de- Certified medical specialists (Internal Medicine, fined hospital rooms according to regulatory require- Hematology and Medical Oncology for adults; pedi- ments and their approval concerning handling of ge- atrics, pediatric hematology and oncology) have to be netically modified microorganisms at a safety level 1 constantly available for inpatient and outpatient care according to Austrian gene technique legislation. of patients given CAR-T cell therapy. On weekends a physician on call has to be immediately available. Pharmacy/Tissue bank In view of the reported neurotoxicity of the cur- The responsible pharmacy/tissue bank has to be in- rently approved CAR-T cell products it is of utmost cluded into the CAR-T cell center to allow timely ful- importance to have qualified specialists of neurology fillment of all regulatory requirements. trained about the side effects of CAR-T cells as mem- bers of the CAR-T cell center available who can im- Waste disposal mediately participate in the interdisciplinary manage- All materials in contact with the CAR-T cell product or ment of patients both during inpatient as well as out- included in it have to be handled as potentially infec- patient stay. tious according to local regulatory requirements on biologic safety and have to be disposed accordingly. Unused CAR-T cells have to be handled according to Table 1 Criteria for patient selection (routine patients) local requirements on biology safety in accordance Major criteria with its product information. 1. Cardiac function EF >50% Outpatient care 2. Lung function SpO2 >91–92% at room air 3. ECOG PS 0–1 For outpatient care a physician of the CAR-T cell cen- ter has to be always available. It has to be guaran- 4. CNS No active/symptomatic involvement teed that the patients are seen in rooms equipped for No major neurologic disease as contraindica- the outpatient care of immunosuppressed individuals. tion The rooms have to allow separation of patients with 5. Infection No active or uncontrolled infection transmissible infections for diagnostic procedures and Minor criteria therapy. An appropriate infrastructure for administer- 6. ANC G/L ≥1.0 ing intravenous medication and transfusion of blood 7. ALC G/L >0.1–0.3 products has to be available. Furthermore, a physi- 8. NFP eGFR ≥60 mL/min/1.73 m cian of the CAR-T cell center who is able to care for 9. LFP S-ALT/AST <2.5 × ULN patients according to the SOPs defined by the CAR-T 10. LFP Total bilirubin <2.0 mg/dL cell platform should be always available for follow-up 11. Plt G/L ≥50–75 of treated patients. This includes also prophylaxis and 12. Hb g/dL >8.0 therapy of long-term side effects such as hypogamma- globulinemia, opportunistic infections and neurologic EF ejection fraction, SpO oxygen saturation, ECOG PS Eastern Cooper- ative Oncology Group Performance Score, CNS central nervous system, toxicities. ANC absolute neutrophil count, G/L giga/liter, eGFR glomerular filtration rate, S-ALT/AST serum alanin-aminotransferase/ serum aspartat-amino- transferase, ULN upper level normal, ALC absolute lymphocyte count, NFP renal function profile, LFP liver function profile, Plt platelets, g/dL g/dl, Hb Hemoglobin K Position Statement on CAR-T cell therapy in Austria 29 special report Fig. 1 Selection process for routine chimeric antigen re- lymphoma, PMBCL primary mediastinal B-cell lymphoma, ceptor T(CAR-T) cell patients. r/r DLBCL relapsed/refractory SCT stem cell transplantation, L line diffuse large B-cell lymphoma, tFL transformed follicular In case of transfer to an ICU it has to be guaranteed During each shift a qualified nurse who has at least that the patient is seen on a daily basis during rounds 12 months of fulltime work experience on a hema- by a specialist of hematology/medical oncology, in tologic–oncologic ward, with experience in adminis- case of patients below the age of 18 years a specialist tering chemotherapy to leukemia and lymphoma pa- of pediatric hematology/oncology. This specialist has tients and who has participated in the center’s internal to discuss the treatment strategy during the ICU stay. training program on CAR-T cell therapy has to lead the In addition, the following specialists have to be nursing team. available: Since patients will have to be transferred to ICUs Ophthalmology, head, neck and ear disease, cardi- the nursing staff of the ICU taking care of these pa- ology, laboratory medicine, microbiology (availability tients has to be trained as well. within 24 h), neurosurgery, psychiatry, radiology (CT scan and MRI) and urology. Criteria for work processes For nursing staff the following qualifications are Technical equipment necessary: The Head Nurse and her/his deputy on the pa- A specification and qualification of all processes, tient ward responsible for CAR-T cell recipients have equipment and materials used for harvest, labeling to have a diploma on nursing care with hemato- and storage of blood cells and genetically modified logic–oncologic qualifications or previous fulltime cells has to be in place. For harvest and processing employment for at least 36 months on a hemato- of leukocytes to be send to the CAR-T cell production logic–oncologic ward and have to participate in the facility an authorization of AGES has to be obtained. center’s internal training program on CAR-T cell ther- In case of use of nonapproved CAR-T cells an autho- apy. rization for production has to be in place. 30 Position Statement on CAR-T cell therapy in Austria K special report SOPs and Janssen. A. Attarbaschi is a consultant for Jazz Pharma- ceuticals and Novartis; travel and accommodation expenses A CAR-T cell center has to have written descriptions, were covered by Jazz Pharmaceuticals, Amgen and Pfizer. training on and documentation of clinical SOPs as M. Girschikofsky is a consultant for Celgene. C. Peters works well as documentation and reporting of side effects at the speakers bureau and advisory board for Novartis and in place. Amgen. A. Petzer received honoraria from Novartis, Gilead, SOPs have to be available for clinical, radiologic and Celgene and Janssen-Cilag; travel support from Gilead and Janssen-Cilag. J. Rudzki works at the speakers bureau for BMS/ serologic surveillance for early detection of CRS and Celgene, Roche, MSD, AstraZeneca, Amgen, Gilead and No- ICANS, transfer of patients to the ICU and manage- vartis; is on the advisory board for Roche, MSD, AstraZeneca, ment of CRS and neurotoxicity of all grades. Amgen, Gilead, Novartis and BMS/Celgene. N. Worel works at the speakers bureau for Novartis and Gilead; gets travel Plan for qualification support from Novartis and Celgene; is on the advisory board The existence and the continuous revision of a risk- for Novartis and Celgene. R. Greil, W. Holter, P. Neumeister, adapted qualification plan based on regulatory re- P. Schlenke,C.A.Schmitt, W. Schwingerand D. Wolf declare that they have no competing interests. quirements and the current state of science and in- cluding all central aspects of administration of CAR-T Open Access This article is licensed under a Creative Com- cells has to be in place. mons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in Quality assurance any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to Members of the CAR-T cell center should participate the Creative Commons licence, and indicate if changes were in quality assurance measures offered by national and made. The images or other third party material in this article international research institutions, pharmaceutical are included in the article’s Creative Commons licence, unless industry and regulatory authorities. indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and Tumor board and patient selection your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permis- Patients will be presented and discussed in tumor sion directly from the copyright holder. To view a copy of this boards according to the Austrian recommendations licence, visit http://creativecommons.org/licenses/by/4.0/. (OeSG, Onkologiebeirat) and requirements of local hospitals. A guidance document produced by the Austrian References CAR-T Cell Network for patient selection is provided 1. JuneCH,etal. CARTcellimmunotherapyforhumancancer. and will be updated regularly (Table 1 and Fig. 1). Sciene. 2018;359:1361–5. 2. EMA/462626/2018 (2018). https://www.ema.europa.eu/ Registry medicines/human/EPAR/kymriah. Accessed February 11, Documentation is requested by EMA as part of the ap- proval process for pharmaceutical companies. Cen- 3. EMA/52410/2020 (2018). https://www.ema.europa.eu/ ters must fulfill the requirements regarding person- medicines/human/EPAR/yescarta. Accessed February 11, nel and infrastructure for participation in the registry 2020. 4. Lee DW, Santomasso BD, Locke FL, et al. ASTCT consen- module for CAR-T cells of the ASCTR and the registry sus grading for cytokine release syndrome and neurologic of the EBMT. They have to insure timely documen- toxicity associated with immune effector cells. Biol Blood tation and reporting. Documentation of patient rele- MarrowTransplant. 2019;25(4):625–38. vant data and side effects should be financed by the 5. Hopfinger G, Jäger U, Worel N. JCAR-T cell therapy in producers of CAR-T cells. diffuse large B cell lymphoma: hype and hope. Hema- sphere. 2019;3(2):e185. https://doi.org/10.1097/HS9. Take Home Message 6. EHA Guidance document: The process of CAR-T cell ther- apy in Europe. Hemasphere. 2019 Aug 7;3(4):e280. https:// Qualified CAR-T cell centers with den fi ed infrastructure doi.org/10.1097/HS9.0000000000000280. eCollection2019 allow safe administration of CAR-T cell products. Aug. No abstract available. Immediate and long-term care of CAR-T cell recipi- Publisher’s Note Springer Nature remains neutral with regard ents by qualified medical staff has to be in place in every to jurisdictional claims in published maps and institutional CAR-T cell center. affiliations. A network of CAR-T cell centers will ensure proper patient selection and fair access. Funding Open access funding provided by Medical University 7 For latest news from interna- of Graz. tional oncology congresses see: Conflict of interest H.T. Greinix received honoraria for pre- http://www.springermedizin.at/ sentations at scientific meetings and consultancy from Cel- memo-inoncology gene, Novartis and Janssen. U. Jaeger declares honoraria and research grants from Novartis, Gilead, Celgene, Miltenyi K Position Statement on CAR-T cell therapy in Austria 31 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png memo - Magazine of European Medical Oncology Springer Journals

Ensuring center quality, proper patient selection and fair access to chimeric antigen receptor T-cell therapy: position statement of the Austrian CAR-T Cell Network

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special report memo (2020) 13:27–31 https://doi.org/10.1007/s12254-020-00582-4 Ensuring center quality, proper patient selection and fair access to chimeric antigen receptor T-cell therapy: position statement of the Austrian CAR-T Cell Network Hildegard T. Greinix · Andishe Attarbaschi · Michael Girschikofsky · Richard Greil · Wolfgang Holter · Peter Neumeister · Christina Peters · Andreas Petzer · Jakob Rudzki · Peter Schlenke · Clemens A. Schmitt · Wolfgang Schwinger · Dominik Wolf · Nina Worel · Ulrich Jaeger Received: 27 January 2020 / Accepted: 28 January 2020 / Published online: 20 February 2020 © The Author(s) 2020 Summary Chimeric antigen receptor T cells (CAR-T Keywords CAR-T cells · Position statement · cells) are a novel form of cellular immunotherapy for Network · Patient selection criteria · Infrastructure patients with hematologic and oncologic malignan- requirements cies. Known side effects of these approved cellular Abbreviations immunotherapies are cytokine release syndrome, im- ASCTR Austrian Stem Cell Transplant Registry mune-cell associated neurotoxicity syndrome, cytope- B-ALL B-cell acute lymphoblastic leukemia nias, infections and long-lasting B cell aplasia. Safe CAR-T Chimeric antigen receptor-T cell administration of CAR-T cell therapy requires thor- CD19 Cluster of differentiation 19 ough patient selection and patient care in qualified CRS Cytokine release syndrome CAR-T cell centers. DLBCL Diffuse large B cell lymphoma EBMT European Society for Blood and Marrow Transplantation All authors contributed equally to this work. Dr. J.Rudzki·Univ.Prof. Dr.D. Wolf This position paper has been endorsed by the Austrian Division of Hematology, Medical University Innsbruck, Society of Hematology and Medical Oncology (OEGHO). Anichstraße 35, 6020 Innsbruck, Austria Univ. Prof. Dr. P. Schlenke Electronic supplementary material The online version of Department of Blood Group Serology and this article (https://doi.org/10.1007/s12254-020-00582-4) Transfusion Medicine, Medical University Graz, contains supplementary material, which is available to Auenbruggerplatz 36, 8036 Graz, Austria authorized users. Univ.Prof.Dr.H.T. Greinix ()·Univ.Prof. Dr.P. Neumeister Univ.Prof.Dr.C. A.Schmitt Division of Hematology, Medical University Graz, Department of Internal Medicine 3—Hematology and Auenbruggerplatz 38, 8036 Graz, Austria Oncology, Kepler University Clinic, Linz, Austria hildegard.greinix@medunigraz.at Univ. Prof. Dr. W. Schwinger Univ. Prof. Dr. A. Attarbaschi · Univ. Prof. Dr. W. Holter · Division of Pediatric Hematology and Oncology, Medical Univ. Prof. Dr. C. Peters University Graz, Auenbruggerplatz 36, 8036 Graz, Austria St. Anna Children’s Hospital, Univ.Prof.Dr.N. Worel Kinderspitalgasse 6, 1090 Vienna, Austria Department of Blood Group Serology and Transfusion Dr.M. Girschikofsky ·Univ.Prof.Dr.A.Petzer Medicine, Medical University Vienna, Waehringer Guertel Department of Hematology with Stem Cell Transplantation, 18–20, 1090 Vienna, Austria Hemostaseology and Medical Oncology, Ordensklinikum Univ.Prof.Dr.U. Jaeger Linz Barmherzige Schwestern—Elisabethinen, Linz, Austria Division of Hematology, Medical University Vienna, Waehringer Guertel 18–20, 1090 Vienna, Austria Univ.Prof.Dr.R. Greil Third Department of Internal Medicine with Hematology, Medical Oncology, Hemostaseology, Infectious Diseases and Rheumatology, Paracelsus Medical University Salzburg, Salzburg, Austria K Position Statement on CAR-T cell therapy in Austria 27 special report EMA European Medicines Agency Retrospective analysis of predictive factors, product HSCT Hematopoietic stem cell transplantation differences (real world evidence) ICANS Immune-cell associated neurotoxicity syn- To create a network for clinical and basic studies drome  To avoid hospital tourism ICU Intensive care unit PMBCL Primary mediastinal B cell lymphoma The following criteria for patient selection and infras- SOPs Standard operating procedures tructure of CAR-T cell centers have been developed within the CAR-T cell platform of the Austrian Soci- ety of Hematology and Medical Oncology (OeGHO) Introduction including the prerequisites for quality-controlled ad- Chimeric antigen receptor T cells (CAR-T cells) are ministration of CAR-T cell therapy in Austria. At least a novel form of cellular immunotherapy for pa- yearly or in case of new scientific developments and tients with hematologic and oncologic malignan- approvals this position statement will be updated. cies. Thereby patients’ immune cells are harvested by The institution responsible for CAR-T cell therapy leukapheresis, genetically modified to selectively ex- has to have specialized knowledge on therapy of pa- press a tumor-specific surface receptor using a retro- tients with the malignancies to be treated, compe- viral or lentiviral vector, expanded ex vivo and then tency in cellular therapy including use of gene-mod- reinfused into the patients after proper quality con- ified cells and competency in intensive care to allow trol measures and administration of lymphodepleting treatment of severe complications. therapy [1]. These genetically modified T lymphocytes To guarantee therapeutic access for all Austrian pa- selectively recognize antigens on the surface of tumor tients CAR-T cell centers should be established that cells against which they are directed and eradicate have all these competencies and fulfill the necessary malignant cells after T cell activation [1]. structural requirements to be described in more detail So far, two commercial CAR-T cell products have in the following. been approved by the European Medicines Agency The requirements of regulatory authorities for the (EMA) which contain a CAR against CD19, a sur- currently available CAR-T cell products have to be es- face antigen of B-lymphocytes. Tisagenlecleucel tablished. Most importantly, quality measures neces- (Kymriah ) has been approved for therapy of chil- sary for qualification of centers and the qualification dren and young adults up to the age of 25 years with by itself have to be achieved prior to use of CAR-T B cell acute lymphoblastic leukemia (B-ALL) and for cells. adult patients with diffuse large B cell lymphoma All CAR-T cell centers have to fulfill the following (DLBCL); axicabtagen ciloleucel (Yescarta ) has been criteria regarding infrastructure, personal, and proce- approved for patients with DLBCL and primary medi- dures. The medical head is responsible for the coor- astinal large cell B cell lymphoma (PMBCL). Of note, dination and administration of CAR-T cell therapies. all patients have to have relapsed or refractory disease Within a center a well-organized, controlled, interdis- [2, 3]. ciplinary and multiprofessional cooperation has to be Known side effects of these approved cellular in place for administration of CAR-T cell products. immunotherapies are cytokine release syndrome (CRS), immune-cell associated neurotoxicity syn- Criteria for infrastructure of CAR-T cell centers drome (ICANS), cytopenias, infections and long- lasting B cell aplasia [4]. Incidence and severity of Medical expertise these side effects differ individually and between cell products. Life-threatening disease with multiorgan Personal has to have extensive experience in therapy failure and severe cerebral edema have been reported of the malignant disease to be treated with CAR-T from clinical studies. Therefore, safe administration cells, experience with clinical study participation and of CAR-T cell therapy requires thorough patient selec- administration of experimental therapies. tion and patient care in a qualified CAR-T cell center For documentation of extensive experience in cel- [5, 6]. lular therapy at a given center, first allogeneic and/or We reasoned that a network of all centers involved autologous hematopoietic stem cell transplantations in administration of CAR-T cells would be most suited (HSCT) had tobe reported tothe Austrian Stem Cell to achieve the following aims: Transplant Registry (ASCTR) and the European Society of Blood and Marrow Transplantation (EBMT) during Ensure fair access for all citizens to all products the last 3 years. Selection of patients with a high likelihood of re- Each CAR-T cell center needs to have extensive ex- sponse perience in intensive care of patients with hemato- To avoid unjustified hopes for individual patients logic and oncologic diseases including the availabil- who are likely NOT to respond ity of 24-hour endoscopy, bronchoscopy, invasive pul- Ensure wise use of resources monary support and renal replacement therapy. Fur- Country-wide registration and outcome control thermore, standard operating procedures (SOPs) for 28 Position Statement on CAR-T cell therapy in Austria K special report management of complications of CAR-T cell therapy Criteria for personnel have to be in place including the use and 24-hour availability of tocilizumab as requested by regulatory The involved medical personnel (physicians and nurs- authorities. An immediate transfer to and admission ing staff) has to be thoroughly trained and has to have at an intensive care unit (ICU) if necessary has to be documented experience in administration of cytotoxic established. and immunosuppressive agents as well as cryopre- served cells. The medical head and his/her deputy responsible Additional criteria for infrastructure for CAR-T cell therapy of adult patients have to be cer- Hygiene tified specialists for internal medicine and hematol- Prior to the infusion of CAR-T cells a lymphodepleting ogy/medical oncology. They must have at least 2 years chemotherapy is administered resulting in immuno- of professional experience in a unit treating patients suppression and side effects known from patients with with severe immunodeficiency and/or performing al- lymphoma and acute leukemia given similar thera- logeneic HSCT. pies. Following CAR-T cell therapies patients can ex- The medical head and his/her deputy responsible perience neutropenia and need appropriate support- for CAR-T cell therapy of children and adolescents un- ive care. If necessary, immediate contact isolation til the age of 18 years have to be certified specialists during hospital stay has to be available. for pediatric hematology and oncology. CAR-T cell therapies have to be administered in de- Certified medical specialists (Internal Medicine, fined hospital rooms according to regulatory require- Hematology and Medical Oncology for adults; pedi- ments and their approval concerning handling of ge- atrics, pediatric hematology and oncology) have to be netically modified microorganisms at a safety level 1 constantly available for inpatient and outpatient care according to Austrian gene technique legislation. of patients given CAR-T cell therapy. On weekends a physician on call has to be immediately available. Pharmacy/Tissue bank In view of the reported neurotoxicity of the cur- The responsible pharmacy/tissue bank has to be in- rently approved CAR-T cell products it is of utmost cluded into the CAR-T cell center to allow timely ful- importance to have qualified specialists of neurology fillment of all regulatory requirements. trained about the side effects of CAR-T cells as mem- bers of the CAR-T cell center available who can im- Waste disposal mediately participate in the interdisciplinary manage- All materials in contact with the CAR-T cell product or ment of patients both during inpatient as well as out- included in it have to be handled as potentially infec- patient stay. tious according to local regulatory requirements on biologic safety and have to be disposed accordingly. Unused CAR-T cells have to be handled according to Table 1 Criteria for patient selection (routine patients) local requirements on biology safety in accordance Major criteria with its product information. 1. Cardiac function EF >50% Outpatient care 2. Lung function SpO2 >91–92% at room air 3. ECOG PS 0–1 For outpatient care a physician of the CAR-T cell cen- ter has to be always available. It has to be guaran- 4. CNS No active/symptomatic involvement teed that the patients are seen in rooms equipped for No major neurologic disease as contraindica- the outpatient care of immunosuppressed individuals. tion The rooms have to allow separation of patients with 5. Infection No active or uncontrolled infection transmissible infections for diagnostic procedures and Minor criteria therapy. An appropriate infrastructure for administer- 6. ANC G/L ≥1.0 ing intravenous medication and transfusion of blood 7. ALC G/L >0.1–0.3 products has to be available. Furthermore, a physi- 8. NFP eGFR ≥60 mL/min/1.73 m cian of the CAR-T cell center who is able to care for 9. LFP S-ALT/AST <2.5 × ULN patients according to the SOPs defined by the CAR-T 10. LFP Total bilirubin <2.0 mg/dL cell platform should be always available for follow-up 11. Plt G/L ≥50–75 of treated patients. This includes also prophylaxis and 12. Hb g/dL >8.0 therapy of long-term side effects such as hypogamma- globulinemia, opportunistic infections and neurologic EF ejection fraction, SpO oxygen saturation, ECOG PS Eastern Cooper- ative Oncology Group Performance Score, CNS central nervous system, toxicities. ANC absolute neutrophil count, G/L giga/liter, eGFR glomerular filtration rate, S-ALT/AST serum alanin-aminotransferase/ serum aspartat-amino- transferase, ULN upper level normal, ALC absolute lymphocyte count, NFP renal function profile, LFP liver function profile, Plt platelets, g/dL g/dl, Hb Hemoglobin K Position Statement on CAR-T cell therapy in Austria 29 special report Fig. 1 Selection process for routine chimeric antigen re- lymphoma, PMBCL primary mediastinal B-cell lymphoma, ceptor T(CAR-T) cell patients. r/r DLBCL relapsed/refractory SCT stem cell transplantation, L line diffuse large B-cell lymphoma, tFL transformed follicular In case of transfer to an ICU it has to be guaranteed During each shift a qualified nurse who has at least that the patient is seen on a daily basis during rounds 12 months of fulltime work experience on a hema- by a specialist of hematology/medical oncology, in tologic–oncologic ward, with experience in adminis- case of patients below the age of 18 years a specialist tering chemotherapy to leukemia and lymphoma pa- of pediatric hematology/oncology. This specialist has tients and who has participated in the center’s internal to discuss the treatment strategy during the ICU stay. training program on CAR-T cell therapy has to lead the In addition, the following specialists have to be nursing team. available: Since patients will have to be transferred to ICUs Ophthalmology, head, neck and ear disease, cardi- the nursing staff of the ICU taking care of these pa- ology, laboratory medicine, microbiology (availability tients has to be trained as well. within 24 h), neurosurgery, psychiatry, radiology (CT scan and MRI) and urology. Criteria for work processes For nursing staff the following qualifications are Technical equipment necessary: The Head Nurse and her/his deputy on the pa- A specification and qualification of all processes, tient ward responsible for CAR-T cell recipients have equipment and materials used for harvest, labeling to have a diploma on nursing care with hemato- and storage of blood cells and genetically modified logic–oncologic qualifications or previous fulltime cells has to be in place. For harvest and processing employment for at least 36 months on a hemato- of leukocytes to be send to the CAR-T cell production logic–oncologic ward and have to participate in the facility an authorization of AGES has to be obtained. center’s internal training program on CAR-T cell ther- In case of use of nonapproved CAR-T cells an autho- apy. rization for production has to be in place. 30 Position Statement on CAR-T cell therapy in Austria K special report SOPs and Janssen. A. Attarbaschi is a consultant for Jazz Pharma- ceuticals and Novartis; travel and accommodation expenses A CAR-T cell center has to have written descriptions, were covered by Jazz Pharmaceuticals, Amgen and Pfizer. training on and documentation of clinical SOPs as M. Girschikofsky is a consultant for Celgene. C. Peters works well as documentation and reporting of side effects at the speakers bureau and advisory board for Novartis and in place. Amgen. A. Petzer received honoraria from Novartis, Gilead, SOPs have to be available for clinical, radiologic and Celgene and Janssen-Cilag; travel support from Gilead and Janssen-Cilag. J. Rudzki works at the speakers bureau for BMS/ serologic surveillance for early detection of CRS and Celgene, Roche, MSD, AstraZeneca, Amgen, Gilead and No- ICANS, transfer of patients to the ICU and manage- vartis; is on the advisory board for Roche, MSD, AstraZeneca, ment of CRS and neurotoxicity of all grades. Amgen, Gilead, Novartis and BMS/Celgene. N. Worel works at the speakers bureau for Novartis and Gilead; gets travel Plan for qualification support from Novartis and Celgene; is on the advisory board The existence and the continuous revision of a risk- for Novartis and Celgene. R. Greil, W. Holter, P. Neumeister, adapted qualification plan based on regulatory re- P. Schlenke,C.A.Schmitt, W. Schwingerand D. Wolf declare that they have no competing interests. quirements and the current state of science and in- cluding all central aspects of administration of CAR-T Open Access This article is licensed under a Creative Com- cells has to be in place. mons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in Quality assurance any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to Members of the CAR-T cell center should participate the Creative Commons licence, and indicate if changes were in quality assurance measures offered by national and made. The images or other third party material in this article international research institutions, pharmaceutical are included in the article’s Creative Commons licence, unless industry and regulatory authorities. indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and Tumor board and patient selection your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permis- Patients will be presented and discussed in tumor sion directly from the copyright holder. To view a copy of this boards according to the Austrian recommendations licence, visit http://creativecommons.org/licenses/by/4.0/. (OeSG, Onkologiebeirat) and requirements of local hospitals. A guidance document produced by the Austrian References CAR-T Cell Network for patient selection is provided 1. JuneCH,etal. CARTcellimmunotherapyforhumancancer. and will be updated regularly (Table 1 and Fig. 1). Sciene. 2018;359:1361–5. 2. EMA/462626/2018 (2018). https://www.ema.europa.eu/ Registry medicines/human/EPAR/kymriah. Accessed February 11, Documentation is requested by EMA as part of the ap- proval process for pharmaceutical companies. Cen- 3. EMA/52410/2020 (2018). https://www.ema.europa.eu/ ters must fulfill the requirements regarding person- medicines/human/EPAR/yescarta. Accessed February 11, nel and infrastructure for participation in the registry 2020. 4. Lee DW, Santomasso BD, Locke FL, et al. ASTCT consen- module for CAR-T cells of the ASCTR and the registry sus grading for cytokine release syndrome and neurologic of the EBMT. They have to insure timely documen- toxicity associated with immune effector cells. Biol Blood tation and reporting. Documentation of patient rele- MarrowTransplant. 2019;25(4):625–38. vant data and side effects should be financed by the 5. Hopfinger G, Jäger U, Worel N. JCAR-T cell therapy in producers of CAR-T cells. diffuse large B cell lymphoma: hype and hope. Hema- sphere. 2019;3(2):e185. https://doi.org/10.1097/HS9. Take Home Message 6. EHA Guidance document: The process of CAR-T cell ther- apy in Europe. Hemasphere. 2019 Aug 7;3(4):e280. https:// Qualified CAR-T cell centers with den fi ed infrastructure doi.org/10.1097/HS9.0000000000000280. eCollection2019 allow safe administration of CAR-T cell products. Aug. No abstract available. Immediate and long-term care of CAR-T cell recipi- Publisher’s Note Springer Nature remains neutral with regard ents by qualified medical staff has to be in place in every to jurisdictional claims in published maps and institutional CAR-T cell center. affiliations. A network of CAR-T cell centers will ensure proper patient selection and fair access. Funding Open access funding provided by Medical University 7 For latest news from interna- of Graz. tional oncology congresses see: Conflict of interest H.T. Greinix received honoraria for pre- http://www.springermedizin.at/ sentations at scientific meetings and consultancy from Cel- memo-inoncology gene, Novartis and Janssen. U. Jaeger declares honoraria and research grants from Novartis, Gilead, Celgene, Miltenyi K Position Statement on CAR-T cell therapy in Austria 31

Journal

memo - Magazine of European Medical OncologySpringer Journals

Published: Mar 20, 2020

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