83 results on '"Rejeski, K"'
Search Results
2. Analyse der Diskordanz bildgebender Response Kriterien bei Lymphomen unter CAR-T-Zell-Therapie
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Winkelmann, M, additional, Rejeski, K, additional, Unterrainer, M, additional, Schmidt, C, additional, Dekorsy, F, additional, Bartenstein, P, additional, Ricke, J, additional, Bergwelt-Baildon, M, additional, Subklewe, M, additional, and Kunz, W, additional
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- 2023
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3. Immune effector cell–associated hematotoxicity: EHA/EBMT consensus grading and best practice recommendations
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Rejeski, K, Subklewe, M, Aljurf, M, Bachy, E, Balduzzi, A, Barba, P, Bruno, B, Benjamin, R, Carrabba, M, Chabannon, C, Ciceri, F, Corradini, P, Delgado, J, Di Blasi, R, Greco, R, Houot, R, Iacoboni, G, Jaeger, U, Kersten, M, Mielke, S, Nagler, A, Onida, F, Peric, Z, Roddie, C, Ruggeri, A, Sanchez-Guijo, F, Sánchez-Ortega, I, Schneidawind, D, Schubert, M, Snowden, J, Thieblemont, C, Topp, M, Zinzani, P, Gribben, J, Bonini, C, Sureda Balari, A, Yakoub-Agha, I, Rejeski, Kai, Subklewe, Marion, Aljurf, Mahmoud, Bachy, Emmanuel, Balduzzi, Adriana Cristina, Barba, Pere, Bruno, Benedetto, Benjamin, Reuben, Carrabba, Matteo Giovanni, Chabannon, Christian, Ciceri, Fabio, Corradini, Paolo, Delgado, Julio, Di Blasi, Roberta, Greco, Raffaella, Houot, Roch, Iacoboni, Gloria, Jaeger, Ulrich, Kersten, Marie José, Mielke, Stephan, Nagler, Arnon, Onida, Francesco, Peric, Zinaida, Roddie, Claire, Ruggeri, Annalisa, Sanchez-Guijo, Fermin M, Sánchez-Ortega, Isabel, Schneidawind, Dominik, Schubert, Maria-Luisa, Snowden, John, Thieblemont, Catherine, Topp, Max S, Zinzani, Pierluigi Luigi, Gribben, John G, Bonini, Chiara, Sureda Balari, Anna, Yakoub-Agha, Ibrahim, Rejeski, K, Subklewe, M, Aljurf, M, Bachy, E, Balduzzi, A, Barba, P, Bruno, B, Benjamin, R, Carrabba, M, Chabannon, C, Ciceri, F, Corradini, P, Delgado, J, Di Blasi, R, Greco, R, Houot, R, Iacoboni, G, Jaeger, U, Kersten, M, Mielke, S, Nagler, A, Onida, F, Peric, Z, Roddie, C, Ruggeri, A, Sanchez-Guijo, F, Sánchez-Ortega, I, Schneidawind, D, Schubert, M, Snowden, J, Thieblemont, C, Topp, M, Zinzani, P, Gribben, J, Bonini, C, Sureda Balari, A, Yakoub-Agha, I, Rejeski, Kai, Subklewe, Marion, Aljurf, Mahmoud, Bachy, Emmanuel, Balduzzi, Adriana Cristina, Barba, Pere, Bruno, Benedetto, Benjamin, Reuben, Carrabba, Matteo Giovanni, Chabannon, Christian, Ciceri, Fabio, Corradini, Paolo, Delgado, Julio, Di Blasi, Roberta, Greco, Raffaella, Houot, Roch, Iacoboni, Gloria, Jaeger, Ulrich, Kersten, Marie José, Mielke, Stephan, Nagler, Arnon, Onida, Francesco, Peric, Zinaida, Roddie, Claire, Ruggeri, Annalisa, Sanchez-Guijo, Fermin M, Sánchez-Ortega, Isabel, Schneidawind, Dominik, Schubert, Maria-Luisa, Snowden, John, Thieblemont, Catherine, Topp, Max S, Zinzani, Pierluigi Luigi, Gribben, John G, Bonini, Chiara, Sureda Balari, Anna, and Yakoub-Agha, Ibrahim
- Abstract
Hematological toxicity is the most common adverse event after chimeric antigen receptor (CAR) T-cell therapy. Cytopenias can be profound and long-lasting and can predispose for severe infectious complications. In a recent worldwide survey, we demonstrated that there remains considerable heterogeneity in regard to current practice patterns. Here, we sought to build consensus on the grading and management of immune effector cell–associated hematotoxicity (ICAHT) after CAR T-cell therapy. For this purpose, a joint effort between the European Society for Blood and Marrow Transplantation (EBMT) and the European Hematology Association (EHA) involved an international panel of 36 CAR T-cell experts who met in a series of virtual conferences, culminating in a 2-day meeting in Lille, France. On the basis of these deliberations, best practice recommendations were developed. For the grading of ICAHT, a classification system based on depth and duration of neutropenia was developed for early (day 0-30) and late (after day +30) cytopenia. Detailed recommendations on risk factors, available preinfusion scoring systems (eg, CAR-HEMATOTOX score), and diagnostic workup are provided. A further section focuses on identifying hemophagocytosis in the context of severe hematotoxicity. Finally, we review current evidence and provide consensus recommendations for the management of ICAHT, including growth factor support, anti-infectious prophylaxis, transfusions, autologous hematopoietic stem cell boost, and allogeneic hematopoietic cell transplantation. In conclusion, we propose ICAHT as a novel toxicity category after immune effector cell therapy, provide a framework for its grading, review literature on risk factors, and outline expert recommendations for the diagnostic workup and short- and long-term management.
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- 2023
4. P1458: PATTERNS OF LONG-TERM HEMATOPOIETIC RECOVERY IMPACT SURVIVAL OUTCOMES AFTER CD19-DIRECTED CAR T-CELL THERAPY FOR R/R LBCL
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Rejeski, K., primary, Albanyan, O., additional, Iacoboni, G., additional, Bücklein, V., additional, Blumenberg, V., additional, Penack, O., additional, Bethge, W., additional, Völkl, S., additional, Perez, A., additional, Carpio, C., additional, Schmidt, C., additional, Müller, N., additional, Reid, K., additional, Faramand, R., additional, Davila, M., additional, Bullinger, L., additional, Locke, F., additional, von Bergwelt-Baildon, M., additional, Mackensen, A., additional, Barba, P., additional, Jain, M., additional, and Subklewe, M., additional
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- 2022
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5. P1445: MYTCELL®: AN INTERACTIVE SMARTPHONE APPLICATION FOR CARS AND BITES INCREASES GUIDELINE ACCESSIBILITY AND REDUCES TIME TO APPLY EVIDENCE-BASED PATIENT CARE
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Blumenberg, V., primary, Siegmund, L., additional, Frölich, L., additional, Rejeski, K., additional, Warm, M., additional, Hildebrand, F., additional, Schmidt, C., additional, von Bergwelt, M., additional, Bücklein, V., additional, and Subklewe, M., additional
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- 2022
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6. P1438: PROCALCITONIN IS ELEVATED IN SEVERE INFECTIONS AFTER CD19 CAR-T IN R/R B-NHL AND ENABLES DISCRIMINATION OF EARLY INFECTIONS FROM CRS – PARTICULARLY IN COMBINATION WITH THE CAR-HEMATOTOX SCORE
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Rejeski, K., primary, Blumenberg, V., additional, Hildebrand, F., additional, Frölich, L., additional, Karschnia, P., additional, Dreyling, M., additional, von Bergwelt-Baildon, M., additional, Schmidt, C., additional, Subklewe, M., additional, and Bücklein, V., additional
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- 2022
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7. P1447: INFERIOR OUTCOMES OF EU VS. US PATIENTS WITH RELAPSED/REFRACTORY LARGE B-CELL LYMPHOMA AFTER CD19 CAR T-CELL THERAPY ARE IMPACTED BY BASELINE RISK FACTORS AND CAR PRODUCT CHOICE
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Bücklein, V., primary, Perez, A., additional, Iacoboni, G., additional, Rejeski, K., additional, Holtick, U., additional, Penack, O., additional, Kharboutli, S., additional, Blumenberg, V., additional, Ackermann, J., additional, Frölich, L., additional, Johnson, G., additional, Patel, K., additional, Arciola, B., additional, Schmidt, C., additional, Albanyan, O., additional, Gödel, P., additional, Hoster, E., additional, Bullinger, L., additional, Mackensen, A., additional, Locke, F., additional, von Bergwelt, M., additional, Barba, P., additional, Jain, M. D., additional, and Subklewe, M., additional
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- 2022
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8. PB2210: FAVORABLE OUTCOME AFTER SECOND CD19 CAR T INFUSION OF AN IDENTICAL PRODUCT: HOST ENVIRONMENT AND DISEASE CHARACTERISTICS DETERMINE THE OUTCOME OF TREATMENT
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Frölich, L., primary, Blumenberg, V., additional, Rejeski, K., additional, Schmidt, C., additional, Winkelmann, M., additional, Schöberl, F., additional, von Baumgarten, L., additional, Kunz, W., additional, Bücklein, V., additional, and Subklewe, M., additional
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- 2022
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9. Safety and feasibility of stem cell boost as a salvage therapy for severe hematotoxicity after CD19 CAR T-cell therapy
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Rejeski K, Burchert A, Iacoboni G, Sesques P, Fransecky L, Bucklein V, Trenker C, Hernani R, Naumann R, Schafer J, Blumenberg V, Schmidt C, Sohlbach K, von Bergwelt-Baildon M, Bachy E, Barba P, and Subklewe M
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- 2022
10. EXTRANODAL DISEASE IS ASSOCIATED WITH SHORTER PROGRESSION‐FREE SURVIVAL AFTER CD19‐CAR T‐CELL THERAPY FOR RELAPSED/REFRACTORY DIFFUSE LARGE B‐CELL LYMPHOMA
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Bücklein, V., primary, Blumenberg, V., additional, Ackermann, J., additional, Frölich, L., additional, Winkelmann, M., additional, Schmidt, C., additional, Rejeski, K., additional, Ruzicka, M., additional, Müller, N., additional, von Baumgarten, L., additional, Schöberl, F., additional, Hildebrandt, M., additional, Humpe, A., additional, Kunz, W., additional, Hoster, E., additional, von Bergwelt, M., additional, and Subklewe, M., additional
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- 2021
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11. CAR‐HEMATOTOX: A DISCRIMINATIVE MODEL FOR CAR T‐CELL RELATED HEMATOTOXICITY IN RELAPSED/REFRACTORY LARGE B‐CELL LYMPHOMA
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Rejeski, K., primary, Perez, A., additional, Sesques, P., additional, Berger, C., additional, Jentzsch, L., additional, Mougiakakos, D., additional, Frölich, L., additional, Ackermann, J., additional, Bücklein, V., additional, Blumenberg, V., additional, Schmidt, C., additional, Jallades, L., additional, Fehse, B., additional, Faul, C., additional, Karschnia, P., additional, Weigert, O., additional, Dreyling, M., additional, Hoster, E., additional, Locke, F., additional, Bergwelt‐Baildon, M., additional, Mackensen, A., additional, Bethge, W., additional, Ayuk, F., additional, Bachy, E., additional, Salles, G., additional, Jain, M., additional, and Subklewe, M., additional
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- 2021
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12. P07.01 CD19 CAR T-cells for relapsed/refractory diffuse large B-cell Lymphoma: real-world data from LMU Munich
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Bücklein, V, primary, Blumenberg, V, additional, Schmidt, C, additional, Rejeski, K, additional, Ruzicka, M, additional, Müller, N, additional, Reischer, A, additional, von Baumgarten, L, additional, Völkl, A, additional, Wagner, B, additional, Humpe, A, additional, Tischer, J, additional, Stemmler, H, additional, von Bergwelt, M, additional, and Subklewe, M, additional
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- 2020
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13. Charakterisierung des International Metabolic Prognostic Index (IMPI) und seiner Komponenten im Rahmen der CAR-T-Zell-Behandlung von Lymphomen.
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Winkelmann, M, Blumenberg, V, Rejeski, K, Bücklein, V, Schmidt, C, Dekorsy, F, Bartenstein, P, Ricke, J, Subklewe, M, and Kunz, W
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- 2024
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14. Reasons for Discordance Among Imaging‐based Response Criteria In Lymphoma Patients Receiving CAR T‐cell Therapy.
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Winkelmann, M., Blumenberg, V., Rejeski, K., Buecklein, V., Schmidt, C., Dekorsy, F., Bartenstein, P., Ricke, J., von Bergwelt‐Baildon, M., Subklewe, M., and Kunz, W.
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LYMPHOMAS ,T cells - Abstract
Overall response was determined based on Lugano criteria, Cheson criteria, response evaluation criteria in lymphoma (RECIL) and lymphoma response to immunomodulatory therapy criteria (LYRIC). Reasons for Discordance Among Imaging-based Response Criteria In Lymphoma Patients Receiving CAR T-cell Therapy B Introduction: b Chimeric antigen receptor T cell therapy (CART) has emerged as an effective cell-based immunotherapy using patient-derived T cells. [Extracted from the article]
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- 2023
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15. Modification of Lugano Criteria by Pre‐Infusion Tumor Kinetics Improves Early Survival Prediction for Lymphoma Patients Under Chimeric Antigen Receptor T‐Cell Therapy.
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Kunz, W. G., Blumenberg, V., Rejeski, K., Buecklein, V. L., Schmidt, C., Dekorsy, F. J., Bartenstein, P., Ricke, J., von Bergwelt‐Baildon, M., Subklewe, M., and Winkelmann, M.
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CHIMERIC antigen receptors ,T cells ,LYMPHOMAS - Abstract
Modification of Lugano Criteria by Pre-Infusion Tumor Kinetics Improves Early Survival Prediction for Lymphoma Patients Under Chimeric Antigen Receptor T-Cell Therapy PD TGR SP pre-to-post-BL DECR sp exhibited similar OS to patients classified as SD, while PD TGR SP pre-to-post-BL INCR sp had significantly shorter OS (65 days vs. 471 days; Figure 1C; I p i < 0.001). B Purpose: b Chimeric antigen receptor T-cell therapy (CART) is effective for patients with refractory or relapsed (r/r) lymphoma with prolongation of survival. [Extracted from the article]
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- 2023
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16. SEVERE HEMATOLOGICAL TOXICITY FOLLOWING CD19 CAR‐T FOR RELAPSED/REFRACTORY LBCL IS ASSOCIATED WITH SUPPRESSIVE IMMUNE DYSREGULATION AND LIMITED CAR‐T EXPANSION.
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Rejeski, K., Perez, A., Iacoboni, G., Blumenberg, V., Bücklein, V. L., Völkl, S., Penack, O., Albanyan, O., Petrera, A., Reid, K., Faramand, R., Davila, M. L., von Bergwelt‐Baildon, M., Locke, F. L., Bethge, W., Bullinger, L., Mackensen, A., Barba, P., Jain, M. D., and Subklewe, M.
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CD19 antigen ,LIFE sciences - Abstract
When comparing CAR-T expansion among phenotypes, "intermittent" patients displayed the greatest CAR T-cell expansion over time (Figure 1A). SEVERE HEMATOLOGICAL TOXICITY FOLLOWING CD19 CAR-T FOR RELAPSED/REFRACTORY LBCL IS ASSOCIATED WITH SUPPRESSIVE IMMUNE DYSREGULATION AND LIMITED CAR-T EXPANSION B Background: b Hematological toxicity represents the most frequent high-grade toxicity of CD19 CAR-T, but remains poorly understood. [Extracted from the article]
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- 2023
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17. 22 MUTATIONS IN SRSF2 IDENTIFIED IN MYELODYSPLASIA AFFECT RNA BINDING AFFINITY, SPECIFICITY, AND SPLICING
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Liang, Y., primary, Daubner, G., additional, Tebaldi, T., additional, Li, Y., additional, Stefani, G., additional, Taylor, A., additional, Maziarz, J., additional, Rejeski, K., additional, Vasic, R., additional, Modis, Y., additional, Allain, F.H.T., additional, and Halene, S., additional
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- 2015
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18. Identifying Early Infections in the Setting of CRS With Routine and Exploratory Serum Proteomics and the HT10 Score Following CD19 CAR-T for Relapsed/Refractory B-NHL
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Kai Rejeski, Viktoria Blumenberg, Gloria Iacoboni, Lucia Lopez-Corral, Soraya Kharboutli, Rafael Hernani, Agnese Petrera, Niklas Müller, Friederike Hildebrand, Lisa Frölich, Philipp Karschnia, Christian Schmidt, David M. Cordas dos Santos, José Luis Piñana, Fabian Müller, Ana Africa Martin, Martin Dreyling, Michael von Bergwelt-Baildon, Pere Barba, Marion Subklewe, Veit L. Bücklein, Institut Català de la Salut, [Rejeski K, Blumenberg V] Department of Medicine III – Hematology/Oncology, University Hospital, LMU Munich, Germany. Laboratory for Translational Cancer Immunology, LMU Gene Center, Munich, Germany. German Cancer Consortium (DKTK), Munich Site, and German Cancer Research Center, Heidelberg, Germany. Bavarian Cancer Research Center (BZKF), Partner Sites Munich and Erlangen, Germany. [Iacoboni G, Barba P] Servei d’Hematologia, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Departament of Medicina, Universitat Autònoma of Barcelona, Bellaterra, Spain. [Lopez-Corral L] Hematology Department, Hospital Clínico Universitario de Salamanca, IBSAL, CIBERONC, Salamanca, Spain. Centro de Investigación del Cáncer-IBMCC, Salamanca, Spain. [Kharboutli S] Bavarian Cancer Research Center (BZKF), Partner Sites Munich and Erlangen, Germany. Department of Internal Medicine 5, Hematology and Oncology, Friedrich-Alexander-Universität Erlangen-Nürnberg and University Hospital Erlangen, Germany. [Hernani R] Hematology Department, Hospital Clínico Universitario, INCLIVA Research Institute, Valencia, Spain, and Vall d'Hebron Barcelona Hospital Campus
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Cèl·lules T - Receptors ,Neoplasms::Neoplasms by Histologic Type::Lymphoma::Lymphoma, Non-Hodgkin::Lymphoma, B-Cell::Lymphoma, Large B-Cell, Diffuse [DISEASES] ,aminoácidos, péptidos y proteínas::proteínas::proteínas de membranas::receptores de superficie celular::receptores artificiales::receptores de antígenos quiméricos [COMPUESTOS QUÍMICOS Y DROGAS] ,neoplasias::neoplasias por tipo histológico::linfoma::linfoma no Hodgkin::linfoma de células B::linfoma de células B grandes difuso [ENFERMEDADES] ,Cèl·lules B - Tumors - Tractament ,Cells::Blood Cells::Leukocytes::Leukocytes, Mononuclear::Lymphocytes::T-Lymphocytes [ANATOMY] ,Other subheadings::/therapy [Other subheadings] ,Hematology ,Amino Acids, Peptides, and Proteins::Proteins::Membrane Proteins::Receptors, Cell Surface::Receptors, Artificial::Receptors, Chimeric Antigen [CHEMICALS AND DRUGS] ,Otros calificadores::/terapia [Otros calificadores] ,células::células sanguíneas::leucocitos::leucocitos mononucleares::linfocitos::linfocitos T [ANATOMÍA] - Abstract
Infections; Serum proteomics Infeccions; Proteòmica sèrica Infecciones; Proteómica sérica Early fever after chimeric antigen receptor T-cell (CAR-T) therapy can reflect both an infection or cytokine release syndrome (CRS). Identifying early infections in the setting of CRS and neutropenia represents an unresolved clinical challenge. In this retrospective observational analysis, early fever events (day 0–30) were characterized as infection versus CRS in 62 patients treated with standard-of-care CD19.CAR-T for relapsed/refractory B-cell non-Hodgkin lymphoma. Routine serum inflammatory markers (C-reactive protein [CRP], interleukin-6 [IL-6], procalcitonin [PCT]) were recorded daily. Exploratory plasma proteomics were performed longitudinally in 52 patients using a multiplex proximity extension assay (Olink proteomics). Compared with the CRSonly cohort, we noted increased event-day IL-6 (median 2243 versus 64 pg/mL, P = 0.03) and particularly high PCT levels (median 1.6 versus 0.3 µg/L, P < 0.0001) in the patients that developed severe infections. For PCT, an optimal discriminatory threshold of 1.5 µg/L was established (area under the receiver operating characteristic curve [AUCROC] = 0.78). Next, we incorporated day-of-fever PCT levels with the patient-individual CAR-HEMATOTOX score. In a multicenter validation cohort (n = 125), we confirmed the discriminatory capacity of this so-called HT10 score for early infections at first fever (AUCROC = 0.87, P < 0.0001, sens. 86%, spec. 86%). Additionally, Olink proteomics revealed pronounced immune dysregulation and endothelial dysfunction in patients with severe infections as evidenced by an increased ANGPT2/1 ratio and an altered CD40/CD40L-axis. In conclusion, the high discriminatory capacity of the HT10 score for infections highlights the advantage of dynamic risk assessment and supports the incorporation of PCT into routine inflammatory panels. Candidate markers from Olink proteomics may further refine risk-stratification. If validated prospectively, the score will enable risk-adapted decisions on antibiotic use. This work was supported by a grant within the Gilead Research Scholar Program (to KR, MS). Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) research grant provided within the Sonderforschungbereich SFB-TRR 388/1 2021 – 452881907, and DFG research grant 451580403 (to MS). The work was further supported by the Bavarian Elite Graduate Training Network (to MS), the Wilhelm-Sander Stiftung (to MS, project no. 2018.087.1), the Else-Kröner-Fresenius Stiftung (to MS), and the Bavarian Center for Cancer Research (BZKF). KR received a fellowship from the School of Oncology of the German Cancer Consortium (DKTK). KR, VB, and VLB were funded by the Else Kröner Forschungskolleg (EKFK) within the Munich Clinician Scientist Program (MCSP).
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- 2023
19. The CAR-HEMATOTOX risk-stratifies patients for severe infections and disease progression after CD19 CAR-T in R/R LBCL
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Kai Rejeski, Ariel Perez, Gloria Iacoboni, Olaf Penack, Veit Bücklein, Liv Jentzsch, Dimitrios Mougiakakos, Grace Johnson, Brian Arciola, Cecilia Carpio, Viktoria Blumenberg, Eva Hoster, Lars Bullinger, Frederick L Locke, Michael von Bergwelt-Baildon, Andreas Mackensen, Wolfgang Bethge, Pere Barba, Michael D Jain, Marion Subklewe, Institut Català de la Salut, [Rejeski K] Department of Medicine III, Hematology and Oncology, University Hospital, LMU Munich, Munich, Germany. Laboratory for Translational Cancer Immunology, LMU Gene Center, Munich, Germany. German Cancer Consortium (DKTK) Munich Site, and German Cancer Research Center, Heidelberg, Germany. [Perez A] Department of Blood and Marrow Transplant and Cellular Immunotherapy, Moffitt Cancer Center, Tampa, Florida, USA. Blood & Marrow Transplant Program, Miami Cancer Institute, Miami, Florida, USA. [Iacoboni G, Carpio C, Barba P] Servei d’Hematologia, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Departament de Medicina, Universitat Autònoma of Barcelona, Bellaterra, Spain. [Penack O] Department of Hematology, Oncology and Tumorimmunology, Charité Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany. German Cancer Consortium (DKTK) Berlin Site, and German Cancer Research Center, Heidelberg, Germany. [Bücklein V] Department of Medicine III, Hematology and Oncology, University Hospital, LMU Munich, Munich, Germany. Laboratory for Translational Cancer Immunology, LMU Gene Center, Munich, Germany. [Jentzsch L] Department of Hematology, Oncology, Clinical Immunology and Rheumatology, University Hospital Tübingen, Tübingen, Germany, and Vall d'Hebron Barcelona Hospital Campus
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Cancer Research ,Antígens CD - Immunologia ,Antigens, CD19 ,Immunology ,Immunoteràpia ,Cèl·lules B - Tumors - Tractament ,factores biológicos::antígenos::antígenos de superficie::antígenos de diferenciación::antígenos CD::antígenos CD19 [COMPUESTOS QUÍMICOS Y DROGAS] ,Therapeutics::Biological Therapy::Immunomodulation::Immunotherapy::Immunization::Immunization, Passive::Adoptive Transfer::Immunotherapy, Adoptive [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT] ,Immunotherapy, Adoptive ,terapéutica::terapia biológica::inmunomodulación::inmunoterapia::inmunización::inmunización pasiva::transferencia adoptiva::inmunoterapia adoptiva [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS] ,enfermedades hematológicas y linfáticas::enfermedades linfáticas::trastornos linfoproliferativos::linfoma::linfoma no Hodgkin::linfoma de células B::linfoma de células B grandes difuso [ENFERMEDADES] ,Humans ,Immunology and Allergy ,ddc:610 ,Biological Factors::Antigens::Antigens, Surface::Antigens, Differentiation::Antigens, CD::Antigens, CD19 [CHEMICALS AND DRUGS] ,Otros calificadores::/terapia [Otros calificadores] ,Retrospective Studies ,Pharmacology ,Hemic and Lymphatic Diseases::Lymphatic Diseases::Lymphoproliferative Disorders::Lymphoma::Lymphoma, Non-Hodgkin::Lymphoma, B-Cell::Lymphoma, Large B-Cell, Diffuse [DISEASES] ,Receptors, Chimeric Antigen ,Other subheadings::/therapy [Other subheadings] ,Oncology ,Disease Progression ,Molecular Medicine ,Lymphoma, Large B-Cell, Diffuse ,Neoplasm Recurrence, Local - Abstract
Hematologic neoplasms; Receptors; Chimeric antigen Neoplasias hematológicas; Receptores; Antígeno quimérico Neoplàsies hematològiques; Receptors; Antigen quimèric Background CD19-directed chimeric antigen receptor T-cell therapy (CAR-T) represents a promising treatment modality for an increasing number of B-cell malignancies. However, prolonged cytopenias and infections substantially contribute to the toxicity burden of CAR-T. The recently developed CAR-HEMATOTOX (HT) score—composed of five pre-lymphodepletion variables (eg, absolute neutrophil count, platelet count, hemoglobin, C-reactive protein, ferritin)—enables risk stratification of hematological toxicity. Methods In this multicenter retrospective analysis, we characterized early infection events (days 0–90) and clinical outcomes in 248 patients receiving standard-of-care CD19 CAR-T for relapsed/refractory large B-cell lymphoma. This included a derivation cohort (cohort A, 179 patients) and a second independent validation cohort (cohort B, 69 patients). Cumulative incidence curves were calculated for all-grade, grade ≥3, and specific infection subtypes. Clinical outcomes were studied via Kaplan-Meier estimates. Results In a multivariate analysis adjusted for other baseline features, the HT score identified patients at high risk for severe infections (adjusted HR 6.4, 95% CI 3.1 to 13.1). HThigh patients more frequently developed severe infections (40% vs 8%, p
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- 2022
20. Second primary malignancies after CAR T-cell therapy: A systematic review and meta-analysis of 5,517 lymphoma and myeloma patients.
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Tix T, Alhomoud M, Shouval R, Cliff ERS, Perales MA, Cordas Dos Santos DM, and Rejeski K
- Abstract
Purpose: CAR T-cell therapy is a potent immunotherapy for hematologic malignancies, but patients can develop long-term adverse events including second primary malignancies (SPMs) that impact morbidity and mortality. To delineate the frequency and subtypes of SPMs following CAR-T in lymphoma and myeloma, we performed a systematic review and meta-analysis., Design: A literature search was conducted in the MEDLINE, Embase, and CENTRAL (Cochrane) databases. Following extraction of SPM cases and assignment of malignant origin, we analyzed SPM point estimates using random effect models., Results: We identified 326 SPMs across 5,517 patients from 18 clinical trials (CT) and 7 real-world studies (RWS). With a median follow-up of 21.7 months, the overall SPM point estimate was 5.8% (95%CI 4.7-7.2). SPM estimates were associated with treatment setting (CT>RWS), duration of follow-up, and number of prior treatment lines, which were each confirmed as independent study-level risk factors of SPM in a meta-regression model. A subgroup meta-analysis of the four trials that randomized CAR-T versus standard-of-care revealed a similar risk of SPM with either treatment strategy (p=0.92). In a distribution analysis of SPM subtypes, hematologic malignancies were the most common (37%), followed by solid tumors (27%) and non-melanoma skin cancers (16%). T-cell malignancies represented a small minority of events (1.5%). We noted disease- and product-specific variations in SPM distribution., Conclusions: These data raise awareness of SPM as a clinically relevant long-term adverse event in patients receiving CAR T-cell therapy. However, our findings do not indicate that SPM frequency is higher with CAR-T versus previous standard-of-care strategies.
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- 2024
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21. A systematic review and meta-analysis of nonrelapse mortality after CAR T cell therapy.
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Cordas Dos Santos DM, Tix T, Shouval R, Gafter-Gvili A, Alberge JB, Cliff ERS, Theurich S, von Bergwelt-Baildon M, Ghobrial IM, Subklewe M, Perales MA, and Rejeski K
- Subjects
- Humans, Receptors, Chimeric Antigen immunology, Lymphoma therapy, Lymphoma immunology, Lymphoma mortality, Biological Products, Immunotherapy, Adoptive adverse effects, Immunotherapy, Adoptive methods, Multiple Myeloma therapy, Multiple Myeloma immunology, Multiple Myeloma mortality
- Abstract
Although chimeric antigen receptor (CAR) T cell therapy represents a transformative immunotherapy, it is also associated with distinct toxicities that contribute to morbidity and mortality. In this systematic review and meta-analysis, we searched MEDLINE, Embase and CINAHL (Cochrane) for reports of nonrelapse mortality (NRM) after CAR T cell therapy in lymphoma and multiple myeloma up to March 2024. After extraction of causes and numbers of death, we analyzed NRM point estimates using random-effect models. We identified 7,604 patients across 18 clinical trials and 28 real-world studies. NRM point estimates varied across disease entities and were highest in patients with mantle-cell lymphoma (10.6%), followed by multiple myeloma (8.0%), large B cell lymphoma (6.1%) and indolent lymphoma (5.7%). Entity-specific meta-regression models for large B cell lymphoma and multiple myeloma revealed that axicabtagene ciloleucel and ciltacabtagene autoleucel were independently associated with increased NRM point estimates, respectively. Of 574 reported nonrelapse deaths, over half were attributed to infections (50.9%), followed by other malignancies (7.8%) and cardiovascular/respiratory events (7.3%). Conversely, the CAR T cell-specific side effects, immune effector cell-associated neurotoxicity syndrome/neurotoxicity, cytokine release syndrome and hemophagocytic lymphohistiocytosis, represented only a minority of nonrelapse deaths (cumulatively 11.5%). Our findings underline the critical importance of infectious complications after CAR T cell therapy and support the comprehensive reporting of NRM, including specific causes and long-term outcomes., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)
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- 2024
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22. Novel prognostic scoring systems for severe CRS and ICANS after anti-CD19 CAR T cells in large B-cell lymphoma.
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Sesques P, Kirkwood AA, Kwon M, Rejeski K, Jain MD, Di Blasi R, Brisou G, Gros FX, le Bras F, Bories P, Choquet S, Rubio MT, Iacoboni G, O'Reilly M, Casasnovas RO, Bay JO, Mohty M, Joris M, Abraham J, Castilla Llorente C, Loschi M, Carras S, Chauchet A, La Rochelle LD, Hermine O, Guidez S, Cony-Makhoul P, Fogarty P, Le Gouill S, Morschhauser F, Gastinne T, Cartron G, Subklewe M, Locke FL, Sanderson R, Barba P, Houot R, and Bachy E
- Subjects
- Humans, Male, Female, Middle Aged, Prognosis, Aged, Adult, Neurotoxicity Syndromes etiology, Biological Products therapeutic use, Biological Products adverse effects, France, Aged, 80 and over, Receptors, Antigen, T-Cell, Immunotherapy, Adoptive adverse effects, Immunotherapy, Adoptive methods, Antigens, CD19 immunology, Lymphoma, Large B-Cell, Diffuse therapy, Lymphoma, Large B-Cell, Diffuse immunology, Cytokine Release Syndrome etiology
- Abstract
Autologous anti-CD19 chimeric antigen receptor (CAR) T cells are now used in routine practice for relapsed/refractory (R/R) large B-cell lymphoma (LBCL). Severe (grade ≥ 3) cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity (ICANS) are still the most concerning acute toxicities leading to frequent intensive care unit (ICU) admission, prolonging hospitalization, and adding significant cost to treatment. We report on the incidence of CRS and ICANS and the outcomes in a large cohort of 925 patients with LBCL treated with axicabtagene ciloleucel (axi-cel) or tisagenlecleucel (tisa-cel) in France based on patient data captured through the DESCAR-T registry. CRS of any grade occurred in 778 patients (84.1%), with 74 patients (8.0%) with grade 3 CRS or higher, while ICANS of any grade occurred in 375 patients (40.5%), with 112 patients (12.1%) with grade ≥ 3 ICANS. Based on the parameters selected by multivariable analyses, two independent prognostic scoring systems (PSS) were derived, one for grade ≥ 3 CRS and one for grade ≥ 3 ICANS. CRS-PSS included bulky disease, a platelet count < 150 G/L, a C-reactive protein (CRP) level > 30 mg/L and no bridging therapy or stable or progressive disease (SD/PD) after bridging. Patients with a CRS-PSS score > 2 had significantly higher risk to develop grade ≥ 3 CRS. ICANS-PSS included female sex, low level of platelets (< 150 G/L), use of axi-cel and no bridging therapy or SD/PD after bridging. Patients with a CRS-PSS score > 2 had significantly higher risk to develop grade ≥ 3 ICANS. Both scores were externally validated in international cohorts of patients treated with tisa-cel or axi-cel., (© 2024. The Author(s).)
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- 2024
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23. Development and validation of an automated computational approach to grade immune effector cell-associated hematotoxicity.
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Liang EC, Rejeski K, Fei T, Albittar A, Huang JJ, Portuguese AJ, Wu Q, Raj S, Subklewe M, Shouval R, and Gauthier J
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- Humans, Immunotherapy, Adoptive methods, Immunotherapy, Adoptive adverse effects
- Abstract
Hematologic toxicity frequently complicates chimeric antigen receptor (CAR) T-cell therapy, resulting in significant morbidity and mortality. In an effort to standardize reporting, the European Hematology Association (EHA) and European Society of Blood and Marrow Transplantation (EBMT) devised the immune effector cell-associated hematotoxicity (ICAHT) grading system, distinguishing between early (day 0-30) and late (after day +30) events based on neutropenia depth and duration. However, manual implementation of ICAHT grading criteria is time-consuming and susceptible to subjectivity and error. To address these challenges, we introduce a novel computational approach, utilizing the R programming language, to automate early and late ICAHT grading. Given the complexities of early ICAHT grading, we benchmarked our approach both manually and computationally in two independent cohorts totaling 1251 patients. Our computational approach offers significant implications by streamlining grading processes, reducing manual time and effort, and promoting standardization across varied clinical settings. We provide this tool to the scientific community alongside a comprehensive implementation guide, fostering its widespread adoption and enhancing reporting consistency for ICAHT., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)
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- 2024
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24. Subsequent Malignancies After CD19-Targeted Chimeric Antigen Receptor T Cells in Patients With Lymphoma.
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Lorenc R, Shouval R, Flynn JR, Devlin SM, Saldia A, De Abia AL, De Lapuerta MC, Tomas AA, Cassanello G, Leslie LA, Rejeski K, Lin RJ, Scordo M, Shah GL, Palomba ML, Salles G, Park J, Giralt SA, Perales MA, Ip A, and Dahi PB
- Subjects
- Humans, Male, Female, Middle Aged, Aged, Adult, Retrospective Studies, Neoplasms, Second Primary immunology, Neoplasms, Second Primary epidemiology, Young Adult, Aged, 80 and over, Immunotherapy, Adoptive adverse effects, Receptors, Chimeric Antigen immunology, Antigens, CD19 immunology
- Abstract
Chimeric antigen receptor (CAR) T cells are an established treatment for B cell non-Hodgkin lymphomas (B-NHL). With the remarkable success in improving survival, understanding the late effects of CAR T cell therapy is becoming more relevant. The aim of this study is to determine the incidence of subsequent malignancies in adult patients with B-NHL. We retrospectively studied 355 patients from 2 different medical centers treated with four different CAR T cell products from 2016 to 2022. The overall cumulative incidence for subsequent malignancies at 36 months was 14% (95% CI: 9.2%, 19%). Subsequent malignancies were grouped into 3 primary categories: solid tumor, hematologic malignancy, and dermatologic malignancy with cumulative incidences at 36 months of 6.1% (95% CI: 3.1%-10%), 4.5% (95% CI: 2.1%-8.1%) and 4.2% (95% CI: 2.1%-7.5%) respectively. Notably, no cases of T cell malignancies were observed. In univariable analysis, increasing age was associated with higher risk for subsequent malignancy. While the overall benefits of CAR T products continue to outweigh their potential risks, more studies and longer follow ups are needed to further demonstrate the risks, patterns, and molecular pathways that lead to the development of subsequent malignancies., (Copyright © 2024 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)
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- 2024
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25. Efficacy and safety of bendamustine-containing bridging therapy in R/R LBCL patients receiving CD19 CAR T-cells.
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Iacoboni G, Sánchez-Salinas MA, Rejeski K, Martín-López AÁ, Kwon M, Navarro V, Jalowiec KA, Hernani R, Reguera-Ortega JL, Gallur L, Blumenberg V, Herrero-García M, Roddie C, Benzaquén A, Delgado-Serrano J, Bailén R, Carpio C, Amat P, López-Corral L, Martín-Martín L, Bastos M, Subklewe M, O'Reilly M, and Barba P
- Abstract
Bridging therapy (BT) after leukapheresis is required in most relapsed/refractory (R/R) large B-cell lymphoma (LBCL) patients receiving chimeric antigen receptor (CAR) T cells. Bendamustine-containing regimens are a potential BT option. We aimed to assess if this agent had a negative impact on CAR-T outcomes when it was administered as BT. We included R/R LBCL patients from six centers who received systemic BT after leukapheresis from February 2019 to September 2022; patients who only received steroids or had pre-apheresis bendamustine exposure were excluded. Patients were divided into two BT groups, with and without bendamustine. Separate safety and efficacy analyses were carried out for axi-cel and tisa-cel. Of 243 patients who received BT, bendamustine (benda) was included in 62 (26%). There was a higher rate of BT progressors in the non-benda group (62% vs. 45%, p = 0.02). Concerning CAR-T efficacy, complete responses were comparable for benda versus non-benda BT cohorts with axi-cel (70% vs. 53%, p = 0.12) and tisa-cel (44% vs. 36%, p = 0.70). Also, 12-month progression-free and overall survival were not significantly different between BT groups with axi-cel (56% vs. 43% and 71% vs. 63%) and tisa-cel (25% vs. 26% and 52% vs. 48%); there were no differences when BT response was considered. CAR T-cell expansion for each construct was similar between BT groups. Regarding safety, CRS G ≥3 (6% vs. 6%, p = 0.79), ICANS G ≥3 (15% vs. 17%, p = 0.68), severe infections, and neutropenia post-infusion were comparable among BT regimens. BT with bendamustine-containing regimens is safe for patients requiring disease control during CAR T-cell manufacturing., Competing Interests: Gloria Iacoboni: Consultancy and Honoraria: Novartis, Roche, Kite/Gilead, Bristol‐Myers Squibb, Abbvie, Janssen, Sandoz, Miltenyi, AstraZeneca. Mario A. Sánchez‐Salinas Honoraria for presentations: Kite. Support for attending meetings: Takeda. Kai Rejeski: Kite/Gilead: Research Funding, Consultancy, Honoraria and travel support; Novartis: Honoraria; BMS/Celgene: Consultancy, Honoraria; Pierre‐Fabre: travel support. Mi Kwon Consulting and lectures: Gilead, Jazz, Pfizer. Katarzyna A. Jalowiec Honoraria: Kite/Gilead. Rafael Hernani: Research: Gilead. Travel support: Gilead. Honoraria: Gilead, Janssen, MSD, Celgene, Novartis. Viktoria Blumenberg: BMS/Celgene: Research Funding; Kite/Gilead: Consultancy, Honoraria, Research Funding; Janssen: Research Funding, Honoraria; Novartis: Research Funding, Honoraria; Roche: Consultancy, Research Funding; Takeda: Research Funding. Claire Roddie: Honoraria from Kite/Gilead, Novartis, BMS, Amgen. Javier Delgado‐Serrano: Honoraria from Kite‐Gilead, Novartis, Bristol Myers Squibb, Janssen. Rebeca Bailén: Speaker and travel: Kite. Cecilia Carpio: Regeneron: Consultancy/Advisory, BMS: Consultancy/Advisory, Takeda: Consultancy/Advisory/Honoraria, Novartis: Honoraria. Marion Subklewe: receives industry research support from Amgen, Bristol‐Myers Squibb/Celgene, Gilead, Janssen, Miltenyi Biotec, Morphosys, Novartis, Roche, Seattle Genetics, and Takeda, and serves as a consultant/advisor to AvenCell, CDR‐Life, Ichnos Sciences, Incyte Biosciences, Janssen, Molecular Partners, and Takeda. She serves on the speakers' bureau at Amgen, AstraZeneca, BMS/Celgene, Gilead, GSK, Janssen, Novartis, Pfizer, Roche, and Takeda. Maeve O'Reilly: Honoraria from Kite, Novartis, Janssen. Advisory boards Kite and Autolus. Travel grant Kite and Novartis. Pere Barba: Allogene: Honoraria; Amgen: Honoraria; BMS: Honoraria; Kite/Gilead: Honoraria; Janssen: Honoraria; Jazz Pharmaceuticals: Honoraria; Miltenyi: Honoraria; Novartis: Honoraria; Nektar: Honoraria., (© 2024 The Author(s). HemaSphere published by John Wiley & Sons Ltd on behalf of European Hematology Association.)
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- 2024
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26. T-Cell Malignant Neoplasms After Chimeric Antigen Receptor T-Cell Therapy.
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Storgard R, Rejeski K, Perales MA, Goldman A, and Shouval R
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- Humans, T-Lymphocytes immunology, Male, Female, Immunotherapy, Adoptive adverse effects, Immunotherapy, Adoptive methods, Receptors, Chimeric Antigen immunology
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- 2024
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27. Immune effector cell-associated haematotoxicity after CAR T-cell therapy: from mechanism to management.
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Rejeski K, Jain MD, Shah NN, Perales MA, and Subklewe M
- Subjects
- Humans, Receptors, Chimeric Antigen immunology, Granulocyte Colony-Stimulating Factor therapeutic use, T-Lymphocytes immunology, Hematologic Diseases therapy, Hematologic Diseases etiology, Immunotherapy, Adoptive adverse effects, Immunotherapy, Adoptive methods
- Abstract
Genetically engineered chimeric antigen receptor (CAR) T cells have become an effective treatment option for several advanced B-cell malignancies. Haematological side-effects, classified in 2023 as immune effector cell-associated haematotoxicity (ICAHT), are very common and can predispose for clinically relevant infections. As haematopoietic reconstitution after CAR T-cell therapy differs from chemotherapy-associated myelosuppression, a novel classification system for early and late ICAHT has been introduced. Furthermore, a risk stratification score named CAR-HEMATOTOX has been developed to identify candidates at high risk of ICAHT, thereby enabling risk-based interventional strategies. Therapeutically, growth factor support with granulocyte colony-stimulating factor (G-CSF) is the mainstay of treatment, with haematopoietic stem cell (HSC) boosts available for patients who are refractory to G-CSF (if available). Although the underlying pathophysiology remains poorly understood, translational studies from the past 3 years suggest that CAR T-cell-induced inflammation and baseline haematopoietic function are key contributors to prolonged cytopenia. In this Review, we provide an overview of the spectrum of haematological toxicities after CAR T-cell therapy and offer perspectives on future translational and clinical developments., Competing Interests: Declaration of interests KR reports research funding from Kite/Gilead; consultancy fees from Kite/Gilead and Bristol-Myers Squibb/Celgene; honoraria from Kite/Gilead, Novartis, and Bristol-Myers Squibb/Celgene; and travel support from Kite/Gilead and Pierre-Fabre. MDJ reports research funding from Kite/Gilead, Loxo@Lilly, and Incyte and consultancy fees from Kite/Gilead, Novartis, and Myeloid Therapeutics. NNS reports research funding from Lentigen, VOR Bio, and CARGO therapeutics and has participated in Advisory Boards (no honoraria) for Sobi, Allogene, invoX, ImmunoACT, and VOR. M-AP reports honoraria from Adicet, Allogene, Allovir, Caribou Biosciences, Celgene, Bristol-Myers Squibb, Equilium, Exevir, ImmPACT Bio, Incyte, Karyopharm, Kite/Gilead, Merck, Miltenyi Biotec, MorphoSys, Nektar Therapeutics, Novartis, Omeros, OrcaBio, Sanofi, Syncopation, VectivBio AG, and Vor Biopharmal; serves on data safety and monitoring boards for Cidara Therapeutics, Medigene, and Sellas Life Sciences; serves on the scientific advisory board of NexImmune; has ownership interests in NexImmune, Omeros, and OrcaBio; and has received institutional research support for clinical trials from Allogene, Incyte, Kite/Gilead, Miltenyi Biotec, Nektar Therapeutics, and Novartis. MS reports research funding from Morphosys, Novartis, Seattle Genetics, AMGEN, Kite/Gilead, and Roche AG; consultancy fees from Novartis, Janssen, AMGEN, Celgene, Kite/Gilead, and Roche AG; and honoraria from AMGEN, Celgene, and Kite/Gilead., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)
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- 2024
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28. Applying the EHA/EBMT grading for ICAHT after CAR-T: comparative incidence and association with infections and mortality.
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Rejeski K, Wang Y, Hansen DK, Iacoboni G, Bachy E, Bansal R, Penack O, Müller F, Bethge W, Munoz J, Mohty R, Bücklein VL, Barba P, Locke FL, Lin Y, Jain MD, and Subklewe M
- Subjects
- Humans, Adult, Incidence, Adaptor Proteins, Signal Transducing, Receptors, Chimeric Antigen, Cytopenia, Neutropenia, Lymphoma, Mantle-Cell, Multiple Myeloma therapy
- Abstract
Abstract: Cytopenias represent the most common side effect of CAR T-cell therapy (CAR-T) and can predispose for severe infectious complications. Current grading systems, such as the Common Terminology Criteria for Adverse Events (CTCAE), neither reflect the unique quality of post-CAR-T neutrophil recovery, nor do they reflect the inherent risk of infections due to protracted neutropenia. For this reason, a novel EHA/EBMT consensus grading was recently developed for Immune Effector Cell-Associated HematoToxicity (ICAHT). In this multicenter, observational study, we applied the grading system to a large real-world cohort of 549 patients treated with BCMA- or CD19-directed CAR-T for refractory B-cell malignancies (112 multiple myeloma [MM], 334 large B-cell lymphoma [LBCL], 103 mantle cell lymphoma [MCL]) and examined the clinical sequelae of severe (≥3°) ICAHT. The ICAHT grading was strongly associated with the cumulative duration of severe neutropenia (r = 0.92, P < .0001), the presence of multilineage cytopenias, and the use of platelet and red blood cell transfusions. We noted an increased rate of severe ICAHT in patients with MCL vs those with LBCL and MM (28% vs 23% vs 15%). Severe ICAHT was associated with a higher rate of severe infections (49% vs 13%, P < .0001), increased nonrelapse mortality (14% vs 4%, P < .0001), and inferior survival outcomes (1-year progression-free survival: 35% vs 51%, 1-year overall survival: 52% vs 73%, both P < .0001). Importantly, the ICAHT grading demonstrated superior capacity to predict severe infections compared with the CTCAE grading (c-index 0.73 vs 0.55, P < .0001 vs nonsignificant). Taken together, these data highlight the clinical relevance of the novel grading system and support the reporting of ICAHT severity in clinical trials evaluating CAR-T therapies., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
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- 2024
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29. Comparative performance of scFv-based anti-BCMA CAR formats for improved T cell therapy in multiple myeloma.
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Stock S, Fertig L, Gottschlich A, Dörr J, Märkl F, Majed L, Menkhoff VD, Grünmeier R, Rejeski K, Cordas Dos Santos DM, Theurich S, von Bergwelt-Baildon M, Endres S, Subklewe M, and Kobold S
- Subjects
- Humans, B-Cell Maturation Antigen, Antibodies, CD28 Antigens, Cell- and Tissue-Based Therapy, Multiple Myeloma therapy
- Abstract
In multiple myeloma (MM), B cell maturation antigen (BCMA)-directed CAR T cells have emerged as a novel therapy with potential for long-term disease control. Anti-BCMA CAR T cells with a CD8-based transmembrane (TM) and CD137 (41BB) as intracellular costimulatory domain are in routine clinical use. As the CAR construct architecture can differentially impact performance and efficacy, the optimal construction of a BCMA-targeting CAR remains to be elucidated. Here, we hypothesized that varying the constituents of the CAR structure known to impact performance could shed light on how to improve established anti-BCMA CAR constructs. CD8TM.41BBIC-based anti-BCMA CAR vectors with either a long linker or a short linker between the light and heavy scFv chain, CD28TM.41BBIC-based and CD28TM.CD28IC-based anti-BCMA CAR vector systems were used in primary human T cells. MM cell lines were used as target cells. The short linker anti-BCMA CAR demonstrated higher cytokine production, whereas in vitro cytotoxicity, T cell differentiation upon activation and proliferation were superior for the CD28TM.CD28IC-based CAR. While CD28TM.CD28IC-based CAR T cells killed MM cells faster, the persistence of 41BBIC-based constructs was superior in vivo. While CD28 and 41BB costimulation come with different in vitro and in vivo advantages, this did not translate into a superior outcome for either tested model. In conclusion, this study showcases the need to study the influence of different CAR architectures based on an identical scFv individually. It indicates that current scFv-based anti-BCMA CAR with clinical utility may already be at their functional optimum regarding the known structural variations of the scFv linker., (© 2024. The Author(s).)
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- 2024
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30. Navigating the prognostic role of transfusions after CAR-T.
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Alhomoud M and Rejeski K
- Subjects
- Humans, Prognosis, Immunotherapy, Adoptive adverse effects, Blood Transfusion, Receptors, Chimeric Antigen, Lymphoma, B-Cell
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- 2024
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31. Baseline Serum Inflammatory Proteins Predict Poor CAR T Outcomes in Diffuse Large B-cell Lymphoma.
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Faramand RG, Lee SB, Jain MD, Cao B, Wang X, Rejeski K, Subklewe M, Fahrmann JF, Saini NY, Hanash SM, Kang YP, Chang D, Rodriguez PC, Dean EA, Nishihori T, Shah BD, Lazaryan A, Chavez J, Khimani F, Pinilla-Ibarz JA, Dam M, Reid KM, Corallo SA, Menges M, Hidalgo Vargas M, Mandula JK, Holliday BA, Bachmeier CA, Speth K, Song Q, Mattie M, Locke FL, and Davila ML
- Subjects
- Humans, Adaptor Proteins, Signal Transducing, Antigens, CD19 therapeutic use, Blood Proteins, C-Reactive Protein, Ferritins, Receptors, Chimeric Antigen therapeutic use, Lymphoma, Large B-Cell, Diffuse therapy, Hematologic Neoplasms
- Abstract
A subset of patients with diffuse large B-cell lymphoma (DLBCL) treated with CD19 chimeric antigen receptor (CAR) T-cell therapy have poor clinical outcomes. We report serum proteins associated with severe immune-mediated toxicities and inferior clinical responses in 146 patients with DLBCL treated with axicabtagene ciloleucel. We develop a simple stratification based on pre-lymphodepletion C reactive protein (CRP) and ferritin to classify patients into low-, intermediate-, and high-risk groups. We observe that patients in the high-risk category were more likely to develop grade ≥3 toxicities and had inferior overall and progression-free survival. We sought to validate our findings with two independent international cohorts demonstrating that patients classified as low-risk have excellent efficacy and safety outcomes. Based on routine and readily available laboratory tests that can be obtained prior to lymphodepleting chemotherapy, this simple risk stratification can inform patient selection for CAR T-cell therapy., Significance: CAR T-cell therapy has changed the treatment paradigm for patients with relapsed/refractory hematologic malignancies. Despite encouraging efficacy, a subset of patients have poor clinical outcomes. We show that a simple clinically applicable model using pre-lymphodepletion CRP and ferritin can identify patients at high risk of poor outcomes. This article is featured in Selected Articles from This Issue, p. 80., (©2024 The Authors; Published by the American Association for Cancer Research.)
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- 2024
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32. Recent Bendamustine Treatment Before Apheresis Has a Negative Impact on Outcomes in Patients With Large B-Cell Lymphoma Receiving Chimeric Antigen Receptor T-Cell Therapy.
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Iacoboni G, Navarro V, Martín-López AÁ, Rejeski K, Kwon M, Jalowiec KA, Amat P, Reguera-Ortega JL, Gallur L, Blumenberg V, Gutiérrez-Herrero S, Roddie C, Benzaquén A, Delgado-Serrano J, Sánchez-Salinas MA, Bailén R, Carpio C, López-Corral L, Hernani R, Bastos M, O'Reilly M, Martín-Martín L, Subklewe M, and Barba P
- Subjects
- Humans, Bendamustine Hydrochloride adverse effects, Immunotherapy, Adoptive adverse effects, Antigens, CD19, Cell- and Tissue-Based Therapy, Receptors, Chimeric Antigen, Blood Component Removal, Lymphoma, Large B-Cell, Diffuse
- Abstract
Purpose: Approximately 30%-40% of patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL) infused with CD19-targeted chimeric antigen receptor (CAR) T cells achieve durable responses. Consensus guidelines suggest avoiding bendamustine before apheresis, but specific data in this setting are lacking. We report distinct outcomes after CAR T-cell therapy according to previous bendamustine exposure., Methods: The study included CAR T-cell recipients from seven European sites. Safety, efficacy, and CAR T-cell expansion kinetics were analyzed according to preapheresis bendamustine exposure. Additional studies on the impact of the washout period and bendamustine dose were performed. Inverse probability treatment weighting (IPTW) and propensity score matching (PSM) analyses were carried out for all efficacy comparisons between bendamustine-exposed and bendamustine-naïve patients., Results: The study included 439 patients with R/R LBCL infused with CD19-targeted commercial CAR T cells, of whom 80 had received bendamustine before apheresis. Exposed patients had significantly lower CD3
+ cells and platelets at apheresis. These patients had a lower overall response rate (ORR, 53% v 72%; P < .01), a shorter progression-free survival (PFS, 3.1 v 6.2 months; P = .04), and overall survival (OS, 10.3 v 23.5 months; P = .01) in comparison with the bendamustine-naïve group. Following adjustment methods for baseline variables, these differences were mitigated. Focusing on the impact of bendamustine washout before apheresis, those with recent (<9 months) exposure (N = 42) displayed a lower ORR (40% v 72%; P < .01), shorter PFS (1.3 v 6.2 months; P < .01), and OS (4.6 v 23.5 months; P < .01) in comparison with bendamustine-naïve patients. These differences remained significant after IPTW and PSM analysis. Conversely, the cumulative dose of bendamustine before apheresis did not affect CAR-T efficacy outcomes., Conclusion: Recent bendamustine exposure before apheresis was associated with negative treatment outcomes after CD19-targeted CAR T-cell therapy and should be therefore avoided in CAR T-cell candidates.- Published
- 2024
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33. Predictive value of pre-infusion tumor growth rate for the occurrence and severity of CRS and ICANS in lymphoma under CAR T-cell therapy.
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Winkelmann M, Blumenberg V, Rejeski K, Quell C, Bücklein VL, Ingenerf M, Unterrainer M, Schmidt C, Dekorsy FJ, Bartenstein P, Ricke J, von Bergwelt-Baildon M, Subklewe M, and Kunz WG
- Subjects
- Humans, Female, Middle Aged, Male, Cytokine Release Syndrome, Immunotherapy, Adoptive, Lymphocytes, Lymphoma, Neoplasms therapy
- Abstract
Chimeric antigen receptor T-cell therapy (CART) can be administered outpatient yet requires management of potential side effects such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). The pre-infusion tumor burden is associated with CRS, yet there is no data on the relevance of pre-infusion tumor growth rate (TGR). Our objective was to investigate TGR for the occurrence and severity of CRS and ICANS. Consecutive patients with available pre-baseline and baseline (BL) imaging before CART were included. TGR was determined as both absolute (abs) and percentage change (%) of Lugano criteria-based tumor burden in relation to days between exams. CRS and ICANS were graded according to ASTCT consensus criteria. Clinical metadata was collected including the international prognostic index (IPI), patient age, ECOG performance status, and LDH. Sixty-two patients were included (median age: 62 years, 40% female). The median pre-BL TGR [abs] and pre-BL TGR [%] was 7.5 mm
2 /d and 30.9%/d. Pre-BL TGR [abs] and pre-BL TGR [%] displayed a very weak positive correlation with the grade of CRS (r[abs] = 0.14 and r[%] = 0.13) and no correlation with ICANS (r[abs] = - 0.06 and r[%] = - 0.07). There was a weak positive correlation between grade of CRS and grade of ICANS (r = 0.35; p = 0.005) whereas there was no significant correlation of CRS or ICANS to any other of the examined parameters. The pre-infusion TGR before CART was weakly associated with the occurrence of CRS, but not the severity, whereas there were no significant differences in the prediction of ICANS. There was no added information when compared to pre-infusion tumor burden alone. Outpatient planning and toxicity management should not be influenced by the pre-infusion TGR., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)- Published
- 2024
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34. Recognizing, defining, and managing CAR-T hematologic toxicities.
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Rejeski K, Subklewe M, and Locke FL
- Subjects
- Humans, Receptors, Antigen, T-Cell genetics, Immunotherapy, Adoptive adverse effects, Cytokine Release Syndrome diagnosis, Cytokine Release Syndrome etiology, Cytokine Release Syndrome therapy, Granulocyte Colony-Stimulating Factor, Receptors, Chimeric Antigen genetics, Multiple Myeloma drug therapy
- Abstract
Autologous CAR-T cell therapy (CAR-T) has improved outcomes for patients with B-cell malignancies. It is associated with the well-described canonical toxicities cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), which may be abrogated by corticosteroids and the anti-IL6 receptor antagonist tocilizumab. Practitioners and researchers should be aware of additional toxicities. Here we review current understanding and management of hematologic toxicities after CAR-T, including cytopenias, coagulopathies, bleeding and clotting events, hemophagocytic-lymphohistiocytosis, and tumor lysis syndrome. We pay particular attention to cytopenias, recently termed immune effector cell-associated hematological toxicity (ICAHT). While the "H" is silent, hematotoxicity is not: ICAHT has the highest cumulative incidence of all immune adverse events following CAR-T. Early cytopenia (day 0-30) is closely linked to lymphodepleting chemotherapy and CRS-related inflammatory stressors. Late ICAHT (after day 30) can present either with or without antecedent count recovery (e.g., "intermittent" vs "aplastic" phenotype), and requires careful evaluation and management strategies. Growth factor support is the mainstay of treatment, with recent evidence demonstrating safety and feasibility of early granulocyte colony-stimulating factor (G-CSF) (e.g., within week 1). In G-CSF refractory cases, autologous stem cell boosts represent a promising treatment avenue, if available. The CAR-HEMATOTOX scoring system, validated for use across lymphoid malignancies (B-NHL, multiple myeloma), enables pretherapeutic risk assessment and presents the potential for risk-adapted management. Recent expert panels have led to diagnostic scoring criteria, severity grading systems, and management strategies for both ICAHT and the recently termed immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS), now clarified and defined as a distinct entity from CRS., (Copyright © 2023 by The American Society of Hematology.)
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- 2023
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35. Neurotoxicity and management of primary and secondary central nervous system lymphoma after adoptive immunotherapy with CD19-directed chimeric antigen receptor T-cells.
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Karschnia P, Arrillaga-Romany IC, Eichler A, Forst DA, Gerstner E, Jordan JT, Ly I, Plotkin SR, Wang N, Martinez-Lage M, Winter SF, Tonn JC, Rejeski K, von Baumgarten L, Cahill DP, Nahed BV, Shankar GM, Abramson JS, Barnes JA, El-Jawahri A, Hochberg EP, Johnson PC, Soumerai JD, Takvorian RW, Chen YB, Frigault MJ, and Dietrich J
- Subjects
- Humans, Immunotherapy, Adoptive adverse effects, C-Reactive Protein, Retrospective Studies, Central Nervous System, T-Lymphocytes, Receptors, Chimeric Antigen, Lymphoma therapy, Central Nervous System Neoplasms therapy, Neurotoxicity Syndromes etiology, Neurotoxicity Syndromes therapy
- Abstract
Background: Chimeric antigen receptor (CAR) T-cells targeting CD19 have been established as a leading engineered T-cell therapy for B-cell lymphomas; however, data for patients with central nervous system (CNS) involvement are limited., Methods: We retrospectively report on CNS-specific toxicities, management, and CNS response of 45 consecutive CAR T-cell transfusions for patients with active CNS lymphoma at the Massachusetts General Hospital over a 5-year period., Results: Our cohort includes 17 patients with primary CNS lymphoma (PCNSL; 1 patient with 2 CAR T-cell transfusions) and 27 patients with secondary CNS lymphoma (SCNSL). Mild ICANS (grade 1-2) was observed after 19/45 transfusions (42.2%) and severe immune effector cell-associated neurotoxicity syndrome (ICANS) (grade 3-4) after 7/45 transfusions (15.6%). A larger increase in C-reactive protein (CRP) levels and higher rates of ICANS were detected in SCNSL. Early fever and baseline C-reactive protein levels were associated with ICANS occurrence. CNS response was seen in 31 cases (68.9%), including a complete response of CNS disease in 18 cases (40.0%) which lasted for a median of 11.4 ± 4.5 months. Dexamethasone dose at time of lymphodepletion (but not at or after CAR T-cell transfusion) was associated with an increased risk for CNS progression (hazard ratios [HR] per mg/d: 1.16, P = .031). If bridging therapy was warranted, the use of ibrutinib translated into favorable CNS-progression-free survival (5 vs. 1 month, HR 0.28, CI 0.1-0.7; P = .010)., Conclusions: CAR T-cells exhibit promising antitumor effects and a favorable safety profile in CNS lymphoma. Further evaluation of the role of bridging regimens and corticosteroids is warranted., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
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- 2023
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36. Early quantification of anti-CD19 CAR T cells by flow cytometry predicts response in R/R DLBCL.
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Blumenberg V, Busch G, Baumann S, Jitschin R, Iacoboni G, Gallur L, Iraola-Truchuelo J, Hoster E, Winkelmann M, Hellwig K, Schmidt C, Frölich L, Tast B, Hildebrand F, Rejeski K, Dekorsy F, Schmidkonz C, Bäuerle T, Kunz WG, Mougiakakos D, Müller F, von Bergwelt-Baildon M, Barba P, Bücklein VL, Mackensen A, Völkl S, and Subklewe M
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- Flow Cytometry, Receptors, Antigen, T-Cell genetics, T-Lymphocytes
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- 2023
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37. Infections after chimeric antigen receptor (CAR)-T-cell therapy for hematologic malignancies.
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Kampouri E, Little JS, Rejeski K, Manuel O, Hammond SP, and Hill JA
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- Humans, B-Cell Maturation Antigen, Cell- and Tissue-Based Therapy, Receptors, Chimeric Antigen, Hematologic Neoplasms therapy, Cytomegalovirus Infections
- Abstract
Background: Chimeric antigen receptor (CAR)-T-cell therapies have revolutionized the management of acute lymphoblastic leukemia, non-Hodgkin lymphoma, and multiple myeloma but come at the price of unique toxicities, including cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, and long-term "on-target off-tumor" effects., Methods: All of these factors increase infection risk in an already highly immunocompromised patient population. Indeed, infectious complications represent the key determinant of non-relapse mortality after CAR-T cells. The temporal distribution of these risk factors shapes different infection patterns early versus late post-CAR-T-cell infusion. Furthermore, due to the expression of their targets on B lineage cells at different stages of differentiation, CD19, and B-cell maturation antigen (BCMA) CAR-T cells induce distinct immune deficits that could require different prevention strategies. Infection incidence is the highest during the first month post-infusion and subsequently decreases thereafter. However, infections remain relatively common even a year after infusion., Results: Bacterial infections predominate early after CD19, while a more equal distribution between bacterial and viral causes is seen after BCMA CAR-T-cell therapy, and fungal infections are universally rare. Cytomegalovirus (CMV) and other herpesviruses are increasingly breported, but whether routine monitoring is warranted for all, or a subgroup of patients, remains to be determined. Clinical practices vary substantially between centers, and many areas of uncertainty remain, including CMV monitoring, antibacterial and antifungal prophylaxis and duration, use of immunoglobulin replacement therapy, and timing of vaccination., Conclusion: Risk stratification tools are available and may help distinguish between infectious and non-infectious causes of fever post-infusion and predict severe infections. These tools need prospective validation, and their integration in clinical practice needs to be systematically studied., (© 2023 The Authors. Transplant Infectious Disease published by Wiley Periodicals LLC.)
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- 2023
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38. The CAR-HEMATOTOX score identifies patients at high risk for hematological toxicity, infectious complications, and poor treatment outcomes following brexucabtagene autoleucel for relapsed or refractory MCL.
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Rejeski K, Wang Y, Albanyan O, Munoz J, Sesques P, Iacoboni G, Lopez-Corral L, Ries I, Bücklein VL, Mohty R, Dreyling M, Baluch A, Shah B, Locke FL, Hess G, Barba P, Bachy E, Lin Y, Subklewe M, and Jain MD
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- Humans, Adult, Treatment Outcome, Immunotherapy, Adoptive, Progression-Free Survival, Lymphoma, Mantle-Cell drug therapy, Neutropenia
- Abstract
CD19-directed CAR T-cell therapy with brexucabtagene autoleucel (brexu-cel) has substantially improved treatment outcomes for patients with relapsed/refractory mantle cell lymphoma (r/r MCL). Prolonged cytopenias and infections represent common and clinically relevant side effects. In this multicenter observational study, we describe cytopenias and infections in 103 r/r MCL patients receiving brexu-cel. Furthermore, we report associations between the baseline CAR-HEMATOTOX (HT) score and toxicity events, non-relapse mortality (NRM), and progression-free/overall survival (PFS/OS). At lymphodepletion, 56 patients were HT
low (score 0-1) while 47 patients were HThigh (score ≥2). The HThigh cohort exhibited prolonged neutropenia (median 14 vs. 6 days, p < .001) and an increased rate of severe infections (30% vs. 5%, p = .001). Overall, 1-year NRM was 10.4%, primarily attributed to infections, and differed by baseline HT score (high vs. low: 17% vs. 4.6%, p = .04). HThigh patients experienced inferior 90-day complete response rate (68% vs. 93%, p = .002), PFS (median 9 months vs. not-reached, p < .0001), and OS (median 26 months vs. not-reached, p < .0001). Multivariable analyses showed that high HT scores were independently associated with severe hematotoxicity, infections, and poor PFS/OS. In conclusion, infections and hematotoxicity are common after brexu-cel and contribute to NRM. The baseline HT score identified patients at increased risk of poor treatment outcomes., (© 2023 The Authors. American Journal of Hematology published by Wiley Periodicals LLC.)- Published
- 2023
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39. Functional connectivity MRI provides an imaging correlate for chimeric antigen receptor T-cell-associated neurotoxicity.
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Stoecklein S, Wunderlich S, Papazov B, Winkelmann M, Kunz WG, Mueller K, Ernst K, Stoecklein VM, Blumenberg V, Karschnia P, Bücklein VL, Rejeski K, Schmidt C, von Bergwelt-Baildon M, Tonn JC, Ricke J, Liu H, Remi J, Subklewe M, von Baumgarten L, and Schoeberl F
- Abstract
Background: Treatment of hematological malignancies with chimeric antigen receptor modified T cells (CART) is highly efficient, but often limited by an immune effector cell-associated neurotoxicity syndrome (ICANS). As conventional MRI is often unremarkable during ICANS, we aimed to examine whether resting-state functional MRI (rsfMRI) is suitable to depict and quantify brain network alterations underlying ICANS in the individual patient., Methods: The dysconnectivity index (DCI) based on rsfMRI was longitudinally assessed in systemic lymphoma patients and 1 melanoma patient during ICANS and before or after clinical resolution of ICANS., Results: Seven lymphoma patients and 1 melanoma patient (19-77 years; 2 female) were included. DCI was significantly increased during ICANS with normalization after recovery ( P = .0039). Higher ICANS grades were significantly correlated with increased DCI scores ( r = 0.7807; P = .0222). DCI increase was most prominent in the inferior frontal gyrus and the frontal operculum (ie, Broca's area) and in the posterior parts of the superior temporal gyrus and the temporoparietal junction (ie, Wernicke's area) of the language-dominant hemisphere, thus reflecting the major clinical symptoms of nonfluent dysphasia and dyspraxia., Conclusions: RsfMRI-based DCI might be suitable to directly quantify the severity of ICANS in individual patients undergoing CAR T-transfusion. Besides ICANS, DCI seems a promising diagnostic tool to quantify functional brain network alterations during encephalopathies of different etiologies, in general., Competing Interests: S.S., S.W., B.P., M.W., W.G.K., K.M., K.E., V.M.S., V.B., P.K., V.L.B., K.R., C.S., M.v. B.-B., J.R., H.L., J.Re., M.S., and L.v.B. report no competing interests. J.C.T. reports research grants from Novocure and Munich Surgical Imaging, both not related to this study. F.S. has received an honorarium from Gilead for an advisory board meeting, which was not related to this study., (© The Author(s) 2023. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)
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- 2023
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40. Neurologic toxicities following adoptive immunotherapy with BCMA-directed CAR T cells.
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Karschnia P, Miller KC, Yee AJ, Rejeski K, Johnson PC, Raje N, Frigault MJ, and Dietrich J
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- Humans, Immunotherapy, Adoptive adverse effects, B-Cell Maturation Antigen, T-Lymphocytes, Receptors, Chimeric Antigen, Multiple Myeloma
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- 2023
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41. Modification of Lugano criteria by pre-infusion tumor kinetics improves early survival prediction for patients with lymphoma under chimeric antigen receptor T-cell therapy.
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Winkelmann M, Blumenberg V, Rejeski K, Quell C, Bücklein V, Ingenerf M, Unterrainer M, Schmidt C, Dekorsy FJ, Bartenstein P, Ricke J, von Bergwelt-Baildon M, Subklewe M, and Kunz WG
- Subjects
- Humans, Positron-Emission Tomography, Progression-Free Survival, Cell- and Tissue-Based Therapy, Receptors, Chimeric Antigen, Lymphoma
- Abstract
Background: Chimeric antigen receptor T-cell therapy (CART) is effective for patients with refractory or relapsed lymphoma with prolongation of survival. We aimed to improve the prediction of Lugano criteria for overall survival (OS) at 30-day follow-up (FU1) by including the pre-infusion tumor growth rate (TGR
pre-BL ) and its early change to 30-day FU1 imaging (TGRpost-BL )., Methods: Consecutive patients with pre-baseline (pre-BL), baseline (BL) and FU1 imaging with CT or positron emission tomography/CT before CART were included. TGR was defined as change of Lugano criteria-based tumor burden between pre-BL, BL and FU1 examinations in relation to days between imaging examinations. Overall response and progression-free survival were determined based on Lugano criteria. Proportional Cox regression analysis studied association of TGR with OS. For survival analysis, OS was analyzed using Kaplan-Meier survival curves., Results: Fifty-nine out of 81 patients met the inclusion criteria. At 30-day FU1 8 patients (13.6%) had a complete response (CR), 25 patients (42.4%) a partial response (PR), 15 patients (25.4%) a stable disease (SD), and 11 patients (18.6%) a progressive disease (PD) according to CT-based Lugano criteria. The median TGRpre-BL was -0.6 mm2 /day, 24.4 mm2 /day, -5.1 mm2 /day, and 18.6 mm2 /day and the median TGRpost-BL was -16.7 mm2 /day, -102.0 mm2 /day, -19.8 mm2 /day and 8.5 mm2 /day in CR, PR, SD, and PD patients, respectively. PD patients could be subclassified into a cohort with an increase in TGR (7 of 11 patients (64%), PD TGRpre-to-post-BL INCR ) and a cohort with a decrease in TGR (4 of 11 patients (36%), PD TGRpre-to-post-BL DECR ) from pre-BL to post-BL. PD TGRpre-to-post-BL DECR patients exhibited similar OS to patients classified as SD, while PD TGRpre-to-post-BL INCR patients had significantly shorter OS (65 days vs 471 days, p<0.001)., Conclusion: In the context of CART, the additional use of TGRpre-BL and its change to TGRpost-BL determined at 30-day FU1 showed better OS prognostication for patients with overall PD according to Lugano criteria. Therefore, this modification of the Lugano classification should be explored as a potential novel imaging biomarker of early response and should be validated prospectively in future studies., Competing Interests: Competing interests: VBl: BMS/Celgene: Research Funding; Kite/Gilead: Consultancy, Honoraria, Research Funding; Janssen: Research Funding, Honoraria; Novartis: Research Funding, Honoraria,; Roche: Research Funding; Takeda: Research Funding. KR: Kite/Gilead: Research Funding; Kite/Gilead: Travel Support; Novartis: Honoraria. VBü: Amgen: Honoraria; Celgene/BMS: Research Funding; Kite/Gilead: Research Funding, Honoraria; Novartis: Honoraria; Pfizer: Honoraria. CS: Kite/Gilead: Travel Support. MvB-B: Astellas: Consultancy, Research Funding and Honoraria; BMS: Consultancy, Research Funding and Honoraria; Kite/Gilead: Consultancy, Research Funding and Honoraria; Miltenyi: Consultancy, Research Funding and Honoraria; Mologen: Consultancy, Research Funding and Honoraria; MSD Sharp & Dohme: Consultancy, Research Funding and Honoraria; Novartis: Consultancy, Research Funding and Honoraria; Roche: Consultancy, Research Funding and Honoraria. MS: Amgen: Research Funding, Speakers Bureau; AstraZeneca: Speakers Bureau; Aven Cell: Consultancy, BMS/Celgene: Research Funding, Speakers Bureau; CDR-Life: Consultancy, Gilead: Research Funding, Speakers Bureau; GSK: Speakers Bureau; Ichnos Sciences: Consultancy; Incyte Biosciences: Consultancy; Janssen: Research Funding, Consultancy, Speakers Bureau; Miltenyi Biotec: Research Funding, Consultancy; Morphosys: Research Funding; Molecular Partners: Consultancy; Novartis: Research Funding, Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Roche: Research Funding, Speakers Bureau; Seattle Genetics: Research Funding; Takeda: Research Funding, Consultancy, Speakers Bureau. WGK: Bristol Myers Squibb: Advisor. The remaining authors declare no competing financial interests. None of the mentioned conflicts of interest were related to financing of the content of this manuscript., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)- Published
- 2023
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42. Real-world results of CAR T-cell therapy for large B-cell lymphoma with CNS involvement: a GLA/DRST study.
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Ayuk F, Gagelmann N, von Tresckow B, Wulf G, Rejeski K, Stelljes M, Penack O, Baldus CD, Kröger N, Bethge W, and Dreger P
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- Humans, Immunotherapy, Adoptive methods, Lymphoma, Large B-Cell, Diffuse therapy, Lymphoma, Large B-Cell, Diffuse pathology, Central Nervous System Neoplasms therapy
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- 2023
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43. Severe hematotoxicity after CD19 CAR-T therapy is associated with suppressive immune dysregulation and limited CAR-T expansion.
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Rejeski K, Perez A, Iacoboni G, Blumenberg V, Bücklein VL, Völkl S, Penack O, Albanyan O, Stock S, Müller F, Karschnia P, Petrera A, Reid K, Faramand R, Davila ML, Modi K, Dean EA, Bachmeier C, von Bergwelt-Baildon M, Locke FL, Bethge W, Bullinger L, Mackensen A, Barba P, Jain MD, and Subklewe M
- Subjects
- Humans, Adaptor Proteins, Signal Transducing, Antigens, CD19, Cell Cycle, Immunotherapy, Adoptive adverse effects, Receptors, Chimeric Antigen
- Abstract
Prolonged cytopenias after chimeric antigen receptor (CAR) T cell therapy are a significant clinical problem and the underlying pathophysiology remains poorly understood. Here, we investigated how (CAR) T cell expansion dynamics and serum proteomics affect neutrophil recovery phenotypes after CD19-directed CAR T cell therapy. Survival favored patients with "intermittent" neutrophil recovery (e.g., recurrent neutrophil dips) compared to either "quick" or "aplastic" recovery. While intermittent patients displayed increased CAR T cell expansion, aplastic patients exhibited an unfavorable relationship between expansion and tumor burden. Proteomics of patient serum collected at baseline and in the first month after CAR-T therapy revealed higher markers of endothelial dysfunction, inflammatory cytokines, macrophage activation, and T cell suppression in the aplastic phenotype group. Prolonged neutrophil aplasia thus occurs in patients with systemic immune dysregulation at baseline with subsequently impaired CAR-T expansion and myeloid-related inflammatory changes. The association between neutrophil recovery and survival outcomes highlights critical interactions between host hematopoiesis and the immune state stimulated by CAR-T infusion.
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- 2023
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44. Immune effector cell-associated hematotoxicity: EHA/EBMT consensus grading and best practice recommendations.
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Rejeski K, Subklewe M, Aljurf M, Bachy E, Balduzzi A, Barba P, Bruno B, Benjamin R, Carrabba MG, Chabannon C, Ciceri F, Corradini P, Delgado J, Di Blasi R, Greco R, Houot R, Iacoboni G, Jäger U, Kersten MJ, Mielke S, Nagler A, Onida F, Peric Z, Roddie C, Ruggeri A, Sánchez-Guijo F, Sánchez-Ortega I, Schneidawind D, Schubert ML, Snowden JA, Thieblemont C, Topp M, Zinzani PL, Gribben JG, Bonini C, Sureda A, and Yakoub-Agha I
- Subjects
- Consensus, Immunotherapy, Adoptive, Immunologic Factors, Hematopoietic Stem Cell Transplantation, Hematology
- Abstract
Hematological toxicity is the most common adverse event after chimeric antigen receptor (CAR) T-cell therapy. Cytopenias can be profound and long-lasting and can predispose for severe infectious complications. In a recent worldwide survey, we demonstrated that there remains considerable heterogeneity in regard to current practice patterns. Here, we sought to build consensus on the grading and management of immune effector cell-associated hematotoxicity (ICAHT) after CAR T-cell therapy. For this purpose, a joint effort between the European Society for Blood and Marrow Transplantation (EBMT) and the European Hematology Association (EHA) involved an international panel of 36 CAR T-cell experts who met in a series of virtual conferences, culminating in a 2-day meeting in Lille, France. On the basis of these deliberations, best practice recommendations were developed. For the grading of ICAHT, a classification system based on depth and duration of neutropenia was developed for early (day 0-30) and late (after day +30) cytopenia. Detailed recommendations on risk factors, available preinfusion scoring systems (eg, CAR-HEMATOTOX score), and diagnostic workup are provided. A further section focuses on identifying hemophagocytosis in the context of severe hematotoxicity. Finally, we review current evidence and provide consensus recommendations for the management of ICAHT, including growth factor support, anti-infectious prophylaxis, transfusions, autologous hematopoietic stem cell boost, and allogeneic hematopoietic cell transplantation. In conclusion, we propose ICAHT as a novel toxicity category after immune effector cell therapy, provide a framework for its grading, review literature on risk factors, and outline expert recommendations for the diagnostic workup and short- and long-term management., (© 2023 by The American Society of Hematology.)
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- 2023
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45. Prognostic value of pre-infusion tumor growth rate for patients with lymphoma receiving chimeric antigen receptor T-cell therapy.
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Winkelmann M, Blumenberg V, Rejeski K, Quell C, Bücklein VL, Ingenerf M, Unterrainer M, Schmidt C, Dekorsy FJ, Bartenstein P, Ricke J, von Bergwelt-Baildon M, Subklewe M, and Kunz WG
- Subjects
- Humans, Prognosis, Fluorodeoxyglucose F18, Cell- and Tissue-Based Therapy, Retrospective Studies, Receptors, Chimeric Antigen, Neoplasms, Lymphoma
- Abstract
Background Aims: Chimeric antigen receptor T-cell therapy (CART) prolongs survival for patients with refractory or relapsed lymphoma, yet its efficacy is affected by the tumor burden. The relevance of tumor kinetics before infusion is unknown. We aimed to study the prognostic value of the pre-infusion tumor growth rate (TGR
pre-BL ) for progression-free (PFS) and overall survival (OS)., Methods: Consecutive patients with available pre-baseline (pre-BL) and baseline (BL) computed tomography or positron emission tomography/computed tomography scan before CART were included. TGR was determined as change of Lugano criteria-based tumor burden between pre-BL, BL and follow-up examinations (FU) in relation to days between imaging exams. Overall response rate (ORR), depth or response (DoR) and PFS were determined based on Lugano criteria. Multivariate regression analysis studied association of TGR with ORR and DoR. Proportional Cox regression analysis studied association of TGR with PFS and OS., Results: In total, 62 patients met the inclusion criteria. The median TGRpre-BL was 7.5 mm2 /d (interquartile range -14.6 mm2 /d to 48.7 mm2 /d); TGRpre-BL was positive (TGRpre-BL POS ) in 58% of patients and negative (TGRpre-BL NEG , indicating tumor shrinkage) in 42% of patients. Patients who were TGRpre-BL POS had a 90-day (FU2) ORR of 62%, a DoR of -86% and a median PFS of 124 days. Patients who were TGRpre-BL NEG had a 90-day ORR of 44%, DoR of -47% and a median PFS of 105 days. ORR and DoR were not associated with slower TGR (P = 0.751, P = 0.198). Patients with an increase of TGR from pre-BL over BL to 30-day FU (FU1) ≥100% (TGRpre-BL-to-FU1≥100% ) showed a significant association with shorter median PFS (31 days versus 343 days, P = 0.002) and shorter median OS after CART (93 days versus not reached, P < 0.001), compared with patients with TGRpre-BL-to-FU1<100% ., Conclusions: In the context of CART, differences in pre-infusion tumor kinetics showed minor differences in ORR, DoR, PFS and OS, whereas the change of the TGR from pre-BL to 30-day FU significantly stratified PFS and OS. In this patient population of refractory or relapsed lymphomas, TGR is readily available based on pre-BL imaging, and its change throughout CART should be explored as a potential novel imaging biomarker of early response., Competing Interests: Declaration of Interest Statement VB: BMS/Celgene: research funding; Kite/Gilead: consultancy, honoraria, research funding; Janssen: research funding, honoraria; Novartis: research funding, honoraria; Roche: research funding; Takeda: research funding. KR: Kite/Gilead: research funding; Kite/Gilead: travel support; Novartis: honoraria. VLB: Amgen: honoraria; Celgene/BMS: research funding; Kite/Gilead: research funding, honoraria; Novartis: honoraria; Pfizer: honoraria. CS: Kite/Gilead: travel support. MvB: Astellas: consultancy, research funding and honoraria; BMS: consultancy, research funding and honoraria; Kite/Gilead: consultancy, research funding and honoraria; Miltenyi: consultancy, research funding and honoraria; Mologen: consultancy, research funding and honoraria; MSD Sharp & Dohme: consultancy, research funding and honoraria; Novartis: consultancy, research funding and honoraria; Roche: consultancy, research funding and honoraria. M.S.: Amgen: research funding, speakers bureau; Astra Zeneca: speakers bureau; Aven Cell: consultancy, BMS/Celgene: research funding, speakers bureau; CDR-Life: consultancy, Gilead: research funding, speakers bureau; GSK: speakers bureau; Ichnos Sciences: consultancy; Incyte Biosciences: consultancy; Janssen: research funding, consultancy, speakers bureau; Miltenyi Biotec: research funding, consultancy; Morphosys: research funding; Molecular Partners: consultancy; Novartis: research funding, consultancy, speakers bureau; Pfizer: consultancy, speakers bureau; Roche: research funding, speakers bureau; Seattle Genetics: research funding; Takeda: research funding, consultancy, speakers bureau. WGK: Bristol Myers Squibb: advisor. The remaining authors declare no competing financial interests. None of the mentioned conflicts of interest were related to financing of the content of this manuscript., (Copyright © 2023 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.)- Published
- 2023
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46. The CAR-HEMATOTOX score as a prognostic model of toxicity and response in patients receiving BCMA-directed CAR-T for relapsed/refractory multiple myeloma.
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Rejeski K, Hansen DK, Bansal R, Sesques P, Ailawadhi S, Logue JM, Bräunlein E, Cordas Dos Santos DM, Freeman CL, Alsina M, Theurich S, Wang Y, Krackhardt AM, Locke FL, Bachy E, Jain MD, Lin Y, and Subklewe M
- Subjects
- Humans, B-Cell Maturation Antigen, Prognosis, Retrospective Studies, Immunotherapy, Adoptive, Multiple Myeloma drug therapy, Receptors, Chimeric Antigen therapeutic use
- Abstract
Background: BCMA-directed CAR T-cell therapy (CAR-T) has altered the treatment landscape of relapsed/refractory (r/r) multiple myeloma, but is hampered by unique side effects that can lengthen hospital stays and increase morbidity. Hematological toxicity (e.g. profound and prolonged cytopenias) represents the most common grade ≥ 3 toxicity and can predispose for severe infectious complications. Here, we examined the utility of the CAR-HEMATOTOX (HT) score to predict toxicity and survival outcomes in patients receiving standard-of-care idecabtagene vicleucel and ciltacabtagene autoleucel., Methods: Data were retrospectively collected from 113 r/r multiple myeloma patients treated between April 2021 and July 2022 across six international CAR-T centers. The HT score-composed of factors related to hematopoietic reserve and baseline inflammatory state-was determined prior to lymphodepleting chemotherapy., Results: At lymphodepletion, 63 patients were HT
low (score 0-1) and 50 patients were HThigh (score ≥ 2). Compared to their HTlow counterparts, HThigh patients displayed prolonged severe neutropenia (median 9 vs. 3 days, p < 0.001), an increased severe infection rate (40% vs. 5%, p < 0.001), and more severe ICANS (grade ≥ 3: 16% vs. 0%, p < 0.001). One-year non-relapse mortality was higher in the HThigh group (13% vs. 2%, p = 0.019) and was predominantly attributable to fatal infections. Response rates according to IMWG criteria were higher in HTlow patients (≥ VGPR: 70% vs. 44%, p = 0.01). Conversely, HThigh patients exhibited inferior progression-free (median 5 vs. 15 months, p < 0.001) and overall survival (median 10.5 months vs. not reached, p < 0.001)., Conclusions: These data highlight the prognostic utility of the CAR-HEMATOTOX score for both toxicity and treatment response in multiple myeloma patients receiving BCMA-directed CAR-T. The score may guide toxicity management (e.g. anti-infective prophylaxis, early G-CSF, stem cell boost) and help to identify suitable CAR-T candidates., (© 2023. The Author(s).)- Published
- 2023
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47. Inferior Outcomes of EU Versus US Patients Treated With CD19 CAR-T for Relapsed/Refractory Large B-cell Lymphoma: Association With Differences in Tumor Burden, Systemic Inflammation, Bridging Therapy Utilization, and CAR-T Product Use.
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Bücklein V, Perez A, Rejeski K, Iacoboni G, Jurinovic V, Holtick U, Penack O, Kharboutli S, Blumenberg V, Ackermann J, Frölich L, Johnson G, Patel K, Arciola B, Mhaskar R, Wood A, Schmidt C, Albanyan O, Gödel P, Hoster E, Bullinger L, Mackensen A, Locke F, von Bergwelt M, Barba P, Subklewe M, and Jain MD
- Abstract
Real-world evidence suggests a trend toward inferior survival of patients receiving CD19 chimeric antigen receptor (CAR) T-cell therapy in Europe (EU) and with tisagenlecleucel. The underlying logistic, patient- and disease-related reasons for these discrepancies remain poorly understood. In this multicenter retrospective observational study, we studied the patient-individual journey from CAR-T indication to infusion, baseline features, and survival outcomes in 374 patients treated with tisagenlecleucel (tisa-cel) or axicabtagene-ciloleucel (axi-cel) in EU and the United States (US). Compared with US patients, EU patients had prolonged indication-to-infusion intervals (66 versus 50 d; P < 0.001) and more commonly received intermediary therapies (holding and/or bridging therapy, 94% in EU versus 74% in US; P < 0.001). Baseline lactate dehydrogenase (LDH) (median 321 versus 271 U/L; P = 0.02) and ferritin levels (675 versus 425 ng/mL; P = 0.004) were significantly elevated in the EU cohort. Overall, we observed inferior survival in EU patients (median progression-free survival [PFS] 3.1 versus 9.2 months in US; P < 0.001) and with tisa-cel (3.2 versus 9.2 months with axi-cel; P < 0.001). On multivariate Lasso modeling, nonresponse to bridging, elevated ferritin, and increased C-reactive protein represented independent risks for treatment failure. Weighing these variables into a patient-individual risk balancer (high risk [HR] balancer), we found higher levels in EU versus US and tisa-cel versus axi-cel cohorts. Notably, superior PFS with axi-cel was exclusively evident in patients at low risk for progression (according to the HR balancer), but not in high-risk patients. These data demonstrate that inferior survival outcomes in EU patients are associated with longer time-to-infusion intervals, higher tumor burden/LDH levels, increased systemic inflammatory markers, and CAR-T product use., Competing Interests: VB: Amgen: Honoraria; Celgene: Research Funding; Pfizer: Honoraria; Kite/Gilead: Research Funding, Honoraria; Novartis: Honoraria. KR: Kite/Gilead: Research Funding and travel support. Novartis: Honoraria. GI: Consultancy and Honoraria: Novartis, Roche, Kite/Gilead, Bristol-Myers Squibb, Abbvie, Janssen, Sandoz, Miltenyi. UH: Consultancy and Honoraria: Amgen, BMS/Celgene, CSL Behring, GSK, Janssen, Kite/Gilead, Novartis, Sanofi. OP: Honoraria or travel support: Gilead, Jazz, MSD, Novartis, Pfizer and Therakos. Research support: Incyte and Priothera. Consultancy: Equillium Bio, Jazz, Gilead, Novartis, MSD, Omeros, Priothera, Shionogi and SOBI. SK: Celgene/Bristol-Myers Squib: Honoraria. V Blumenberg: Novartis: Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Celgene: Research Funding; Janssen: Research Funding. PG: Travel support: Gilead. LB: Honoraria: Novartis, Celgene/BMS, Astellas, Gilead, Abbvie, Jazz Pharmaceuticals, Pfizer, Janssen; Consultancy: Novartis, Celgene/BMS, Gilead, Abbvie, Jazz Pharmaceuticals, Pfizer, Janssen; Research Funding: Jazz Pharmaceuticals, Bayer Oncology. AM: Honoraria: Novartis, Kite/Gilead, Celgene/BMS, Miltenyi Biomedicine. FL: has a scientific advisory role with Kite, a Gilead Company, Novartis, Celgene/Bristol-Myers Squibb, GammaDelta Therapeutics, Wugen, Amgen, Calibr, and Allogene; is a consultant with grant options for Cellular Biomedicine Group, Inc.; and receives research support from Kite, a Gilead Company, Novartis, and Allogene; and reports that his institution holds unlicensed patents in his name in the field of cellular immunotherapy. MvB: Consultancy, Research Funding and Honoraria: MSD Sharp & Dohme, Novartis, Roche, Kite/Gilead, Bristol-Myers Squibb, Astellas, Mologen, and Miltenyi. PB: declares having received honoraria from Amgen, BMS, Gilead, Incyte, Miltenyi Biotec, Novartis and Pfizer not related with the present article. MS: Morphosys: Research Funding; Novartis: Consultancy, Research Funding; Janssen: Consultancy; Seattle Genetics: Research Funding; AMGEN: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Kite/Gilead: Consultancy, Honoraria, Research Funding; Roche AG: Consultancy, Research Funding. MDJ: Kite/Gilead: Consultancy/Advisory, Novartis: Consultancy/Advisory, BMS: Consultancy/Advisory, Takeda: Consultancy/Advisory. All the other authors have no conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Hematology Association.)
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- 2023
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48. Mechanisms of Resistance and Treatment of Relapse after CAR T-cell Therapy for Large B-cell Lymphoma and Multiple Myeloma.
- Author
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Rejeski K, Jain MD, and Smith EL
- Subjects
- Humans, Immunotherapy, Adoptive, Neoplasm Recurrence, Local, Multiple Myeloma genetics, Multiple Myeloma therapy, Receptors, Chimeric Antigen genetics, Lymphoma, Large B-Cell, Diffuse therapy
- Abstract
Although chimeric antigen receptor (CAR) T cell therapy (CAR-T) has altered the treatment landscape for relapsed/refractory B cell malignancies and multiple myeloma, only a minority of patients attain long-term disease remission. The underlying reasons for CAR-T resistance are multifaceted and can be broadly divided into host-related, tumor-intrinsic, microenvironmental and macroenvironmental, and CAR-T-related factors. Emerging host-related determinants of response to CAR-T relate to gut microbiome composition, intact hematopoietic function, body composition, and physical reserve. Emerging tumor-intrinsic resistance mechanisms include complex genomic alterations and mutations to immunomodulatory genes. Furthermore, the extent of systemic inflammation prior to CAR-T is a potent biomarker of response and reflects a proinflammatory tumor micromilieu characterized by infiltration of myeloid-derived suppressor cells and regulatory T cell populations. The tumor and its surrounding micromilieu also can shape the response of the host to CAR-T infusion and the subsequent expansion and persistence of CAR T cells, a prerequisite for efficient eradication of tumor cells. Here, focusing on both large B cell lymphoma and multiple myeloma, we review resistance mechanisms, explore therapeutic avenues to overcome resistance to CAR-T, and discuss the management of patients who relapse after CAR-T., (Copyright © 2023 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)
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- 2023
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49. Influence of Adipose Tissue Distribution, Sarcopenia, and Nutritional Status on Clinical Outcomes After CD19 CAR T-cell Therapy.
- Author
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Rejeski K, Cordas Dos Santos DM, Parker NH, Bücklein VL, Winkelmann M, Jhaveri KS, Liu L, Trinkner P, Günther S, Karschnia P, Blumenberg V, Schmidt C, Kunz WG, von Bergwelt-Baildon M, Jain MD, Theurich S, and Subklewe M
- Subjects
- Humans, Immunotherapy, Adoptive methods, Tissue Distribution, Neoplasm Recurrence, Local, Antigens, CD19, Receptors, Chimeric Antigen, Sarcopenia etiology, Sarcopenia therapy, Lymphoma, B-Cell
- Abstract
Although CD19-directed chimeric antigen receptor T-cell therapy (CD19.CAR-T) has proven clinical efficacy for multiple refractory B-cell malignancies, over 50% of patients ultimately relapse. Recent evidence has underlined the critical role of the host in determining treatment responses. In this retrospective observational study of 106 patients with relapsed/refractory large B-cell lymphoma receiving standard-of-care CD19.CAR-T, we analyzed the impact of immunometabolic host features and detailed body composition measurements on post-CAR T clinical outcomes. We extracted muscle and adipose tissue distributions from prelymphodepletion CT images and assessed laboratory-based immuno-nutritional scores. Early responders displayed increased total abdominal adipose tissue deposits (TAT: 336 mm3 vs. 266 mm3, P = 0.008) and favorable immuno-nutritional scores compared to nonresponding patients. On univariate Cox regression analysis, visceral fat distribution, sarcopenia, and nutritional indices significantly impacted both progression-free (PFS) and overall survival (OS). Patients with a low skeletal muscle index (SMI; e.g.<34.5), a sarcopenia indicator, exhibited poor clinical outcomes (mOS 3.0 months vs. 17.6 months, log-rank P = 0.0026). Prognostically adverse immuno-nutritional scores were linked to inferior survival [low PNI: HROS, 6.31; 95% confidence interval (CI), 3.35-11.90; P < 0.001]. In a multivariable analysis adjusting for baseline Eastern Cooperative Oncology Group performance status, C-reactive protein, and lactate dehydrogenase, increased TAT was independently associated with improved clinical outcomes (adjusted HROS, 0.27; 95% CI, 0.08-0.90; P = 0.03). We noted particularly favorable treatment outcomes in patients with both increased abdominal fat and muscle mass (TAThigh/SMIhigh: 1-year PFS 50%, 1-year OS 83%). These real-world data provide evidence for a role of body composition and immuno-nutritional status in the context of CD19.CAR-T and suggest that the obesity paradox may extend to modern T cell-based immunotherapies. See related Spotlight by Nawas and Scordo, p. 704., (©2023 The Authors; Published by the American Association for Cancer Research.)
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- 2023
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50. Staging of lymphoma under chimeric antigen receptor T-cell therapy: reasons for discordance among imaging response criteria.
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Winkelmann M, Blumenberg V, Rejeski K, Bücklein VL, Ingenerf M, Unterrainer M, Schmidt C, Dekorsy FJ, Bartenstein P, Ricke J, von Bergwelt-Baildon M, Subklewe M, and Kunz WG
- Subjects
- Humans, Diagnostic Imaging, Cell- and Tissue-Based Therapy, Receptors, Chimeric Antigen, Lymphoma diagnostic imaging, Lymphoma therapy
- Abstract
Background: Chimeric antigen receptor T-cell therapy (CART) prolongs survival for patients with refractory or relapsed lymphoma. Discrepancies among different response criteria for lymphoma under CART were recently shown. Our objective was to evaluate reasons for discordance among different response criteria and their relation to overall survival., Methods: Consecutive patients with baseline and follow-up imaging at 30 (FU1) and 90 days (FU2) after CART were included. Overall response was determined based on Lugano, Cheson, response evaluation criteria in lymphoma (RECIL) and lymphoma response to immunomodulatory therapy criteria (LYRIC). Overall response rate (ORR) and rates of progressive disease (PD) were determined. For each criterion reasons for PD were analyzed in detail., Results: 41 patients were included. ORR was 68%, 68%, 63%, and 68% at FU2 by Lugano, Cheson, RECIL, and LYRIC, respectively. PD rates differed among criteria with 32% by Lugano, 27% by Cheson, 17% by RECIL, and 17% by LYRIC. Dominant reasons for PD according to Lugano were target lesion (TL) progression (84.6%), new appearing lesions (NL; 53.8%), non-TL progression (27.3%), and progressive metabolic disease (PMD; 15.4%). Deviations among the criteria for defining PD were largely explained by PMD of preexisting lesions that are defined as PD only by Lugano and non-TL progression, which is not defined as PD by RECIL and in some cases classified as indeterminate response by LYRIC., Conclusions: Following CART, lymphoma response criteria show differences in imaging endpoints, especially in defining PD. The response criteria must be considered when interpreting imaging endpoints and outcomes from clinical trials., (© 2023. The Author(s).)
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- 2023
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