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Murphy D, Khan RB, Pinto SN, Metais JY, Gottschalk S, Naik S. Recurrent Immune-Effector Cell-Associated Neurotoxicity Syndrome With Atypical Manifestations after Tisagenlecleucel. Pediatr Blood Cancer 2025; 72:e31763. [PMID: 40320686 DOI: 10.1002/pbc.31763] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2025] [Revised: 04/12/2025] [Accepted: 04/16/2025] [Indexed: 05/24/2025]
Affiliation(s)
- Devin Murphy
- Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
| | - Raja B Khan
- Department of Pediatric Medicine, St Jude Children's Research Hospital, Memphis, Tennessee, USA
| | - Soniya N Pinto
- Department of Diagnostic Imaging, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
| | - Jean-Yves Metais
- Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
| | - Stephen Gottschalk
- Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
| | - Swati Naik
- Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
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2
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Palani HK, Arunachalam AK, Kulkarni U, Yasar M, Venkatraman A, Palanikumar S, Radhakrishnan RN, Solomon M, Rajasekaran A, Bankar A, Datari PVR, Selvarajan S, Korula A, Dash P, Schneider D, Wirthlin L, Abraham A, George B, Mathews V. Safety, efficacy and total cost of point-of-care manufactured anti-CD19 CAR-T cell therapy in India: VELCART trial. MOLECULAR THERAPY. ONCOLOGY 2025; 33:200977. [PMID: 40248244 PMCID: PMC12005290 DOI: 10.1016/j.omton.2025.200977] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 01/06/2025] [Revised: 03/11/2025] [Accepted: 03/21/2025] [Indexed: 04/19/2025]
Abstract
Decentralized or point-of-care (POC) manufacture of CAR-T cells is a potential strategy to improve accessibility and reduce cost and logistic challenges. A total of 10 relapsed/refractory patients (B cell acute lymphoblastic leukemia [B-ALL] N = 6, diffuse large B cell lymphoma [DLBCL] N = 4) were enrolled in this POC phase 1 study. Chimeric antigen receptor (CAR)-T cells were manufactured using the fully automated CliniMACS Prodigy system. The CAR-T cell products had a median 15-fold expansion with a median transduction rate of 38%. The immunophenotypic characterization indicates a significant increase in central memory and effector T cells. All the patients were infused with fresh CAR-T cells. Complete remission rates were 100% for B-ALL and 50% for DLBCL. At a median follow-up of 15 months, 8 of 10 patients remain without disease progression. Adverse events reported were cytokine release syndrome grade 2 or higher in 2 of 10 patients. None of the patients developed immune effector cell-associated neurotoxicity syndrome. Late hematological toxicity of grade 2 or higher was noted only in one patient. Evaluation of health care resource utilization demonstrates that the median cost was US$12,724, while the manufacturing cost was US$35,107. Our data highlight the safety, efficacy, low cost, and potential to enhance the accessibility of CAR-T cell therapy in low- and middle-income countries through a fully automated and closed manufacturing platform.
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Affiliation(s)
- Hamenth Kumar Palani
- Department of Haematology, Christian Medical College, Ranipet Campus, Vellore 632517, Tamil Nadu, India
| | - Arun Kumar Arunachalam
- Department of Haematology, Christian Medical College, Ranipet Campus, Vellore 632517, Tamil Nadu, India
| | - Uday Kulkarni
- Department of Haematology, Christian Medical College, Ranipet Campus, Vellore 632517, Tamil Nadu, India
| | - Mohammed Yasar
- Department of Haematology, Christian Medical College, Ranipet Campus, Vellore 632517, Tamil Nadu, India
| | - Arvind Venkatraman
- Department of Haematology, Christian Medical College, Ranipet Campus, Vellore 632517, Tamil Nadu, India
| | - Swathy Palanikumar
- Department of Haematology, Christian Medical College, Ranipet Campus, Vellore 632517, Tamil Nadu, India
| | | | - Majeela Solomon
- Department of Haematology, Christian Medical College, Ranipet Campus, Vellore 632517, Tamil Nadu, India
| | - Abirami Rajasekaran
- Department of Haematology, Christian Medical College, Ranipet Campus, Vellore 632517, Tamil Nadu, India
| | - Aniket Bankar
- Princess Margaret Cancer Center, University Avenue, Toronto, ON M5G2C1, Canada
| | | | - Sushil Selvarajan
- Department of Haematology, Christian Medical College, Ranipet Campus, Vellore 632517, Tamil Nadu, India
| | - Anu Korula
- Department of Haematology, Christian Medical College, Ranipet Campus, Vellore 632517, Tamil Nadu, India
| | - Pradyot Dash
- Lentigen Technology Inc., A Miltenyi Biotec Company, Gaithersburg, MD 20878, USA
| | - Dina Schneider
- Lentigen Technology Inc., A Miltenyi Biotec Company, Gaithersburg, MD 20878, USA
| | - Louisa Wirthlin
- Lentigen Technology Inc., A Miltenyi Biotec Company, Gaithersburg, MD 20878, USA
| | - Aby Abraham
- Department of Haematology, Christian Medical College, Ranipet Campus, Vellore 632517, Tamil Nadu, India
| | - Biju George
- Department of Haematology, Christian Medical College, Ranipet Campus, Vellore 632517, Tamil Nadu, India
| | - Vikram Mathews
- Department of Haematology, Christian Medical College, Ranipet Campus, Vellore 632517, Tamil Nadu, India
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3
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Locke FL, Siddiqi T, Jacobson CA, Nikiforow S, Ahmed S, Miklos DB, Lin Y, Lunning MA, Hill BT, Ghobadi A, Hu ZH, Hemmer MT, Zoratti MJ, Vunnum S, Tsang J, Spooner C, Smith H, Fu C, Patel A, Miao H, Shahani SA, Mirjah DL, Xu H, Pasquini MC. Impact of vein-to-vein time in patients with R/R LBCL treated with axicabtagene ciloleucel. Blood Adv 2025; 9:2663-2676. [PMID: 39883946 DOI: 10.1182/bloodadvances.2024013656] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2024] [Revised: 11/26/2024] [Accepted: 12/30/2024] [Indexed: 02/01/2025] Open
Abstract
ABSTRACT Chimeric antigen receptor (CAR) T-cell products axicabtagene ciloleucel (axi-cel), tisagenlecleucel (tisa-cel), and lisocabtagene maraleucel (liso-cel) are approved for relapsed/refractory (R/R) large B-cell lymphoma (LBCL). Emerging evidence indicates that delayed CAR T-cell infusion, including prolonged time from leukapheresis to infusion, known as vein-to-vein time (V2Vt), may adversely impact clinical outcomes. We conducted a systematic literature review (SLR) and meta-analysis to identify differences in V2Vt in patients with R/R LBCL treated with axi-cel, tisa-cel, or liso-cel. The impact of V2Vt (<28 days vs ≥28 to <40 days vs ≥40 days) on effectiveness and safety outcomes was evaluated in patients treated with axi-cel enrolled in a post-authorization safety study using the Center for International Blood and Marrow Transplant Research data. SLR and meta-analysis showed that patients treated with axi-cel had the shortest median V2Vt (30.6 days) compared with tisa-cel (48.4 days) or liso-cel (35.9 days). Real-world analysis of patients treated with axi-cel demonstrated that V2Vt ≥40 days was associated with significantly lower complete response rate than V2Vt <28 days (odds ratio [OR], 0.61) or ≥28 to <40 days (OR, 0.66) and significantly worse overall survival than V2Vt <28 days (hazard ratio [HR], 1.33) or ≥28 to <40 days (HR, 1.36). Higher prolonged thrombocytopenia rates were observed in patients with axi-cel V2Vt ≥28 to <40 days or ≥40 days compared with <28 days (OR, 1.44 or 1.95, respectively). Together, these results show the impact of V2Vt on patient outcomes with axi-cel therapy and that earlier infusion with CD19-CAR therapies may be beneficial.
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MESH Headings
- Humans
- Lymphoma, Large B-Cell, Diffuse/therapy
- Lymphoma, Large B-Cell, Diffuse/mortality
- Lymphoma, Large B-Cell, Diffuse/drug therapy
- Immunotherapy, Adoptive/methods
- Immunotherapy, Adoptive/adverse effects
- Antigens, CD19/therapeutic use
- Treatment Outcome
- Veins
- Time Factors
- Receptors, Chimeric Antigen
- Biological Products
- Receptors, Antigen, T-Cell
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Affiliation(s)
- Frederick L Locke
- Department of Blood and Marrow Transplant and Cellular Immunotherapy, Moffit Cancer Center, Tampa, FL
| | - Tanya Siddiqi
- Department of Hematology/HCT, City of Hope National Medical Center, Duarte, CA
| | - Caron A Jacobson
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
| | - Sarah Nikiforow
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
| | - Sairah Ahmed
- Department of Lymphoma - Myeloma, MD Anderson Cancer Center, Houston, TX
| | - David B Miklos
- Department of Medicine - Med/Blood and Marrow Transplantation, Stanford University School of Medicine, Stanford, CA
| | - Yi Lin
- Division of Hematology, Mayo Clinic, Rochester, MN
| | - Matthew A Lunning
- Division of Oncology and Hematology, Department of Internal Medicine, Fred & Pamela Buffett Cancer Center, Omaha, NE
| | - Brian T Hill
- Department of Hematology and Medical Oncology, Cleveland Clinic Taussig Cancer Institute, Cleveland, OH
| | - Armin Ghobadi
- Division of Oncology, Washington University School of Medicine, St. Louis, MO
| | | | | | | | | | | | | | | | | | - Anik Patel
- Kite, a Gilead Company, Santa Monica, CA
| | - Harry Miao
- Kite, a Gilead Company, Santa Monica, CA
| | | | | | - Hairong Xu
- Kite, a Gilead Company, Santa Monica, CA
| | - Marcelo C Pasquini
- Department of Hematology and Oncology - Medicine, Center for International Blood and Marrow Transplant Research, Milwaukee, WI
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Nagai Y, Hayakawa I, Sugawa M, Gocho Y, Sakaguchi H, Tomizawa D, Abe Y. Persistent Cognitive Dysfunction After Chimeric Antigen Receptor T-Cell Therapy in Adolescents and Young Adults. Pediatr Neurol 2025; 167:77-81. [PMID: 40228396 DOI: 10.1016/j.pediatrneurol.2025.03.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2023] [Revised: 02/29/2024] [Accepted: 03/15/2025] [Indexed: 04/16/2025]
Abstract
BACKGROUND Chimeric antigen receptor T-cell (CAR-T) therapy for hematological malignancies causes a neurological complication known as immune effector cell-associated neurotoxicity syndrome (ICANS). The precise neurocognitive pathology underlying ICANS remains incompletely described. The aim of this study is to elucidate that persistent cognitive dysfunction as potential neurotoxicity of CAR-T therapy. METHODS This was a single-center consecutive study of ICANS caused by CAR-T therapy for B-cell acute lymphoblastic leukemia. We determined the cognitive functions of all patients with ICANS at the onset of ICANS symptoms and followed them up in the neurology department thereafter. RESULTS Among the 10 CAR-T cases between 2020 and 2022, three patients had ICANS. None of the patients experienced seizures. Of the three patients, the preadolescent patient showed decreased levels of consciousness, tremors, and striatal signs without cognitive dysfunction. The other two adolescent and young adult patients presented with cognitive decline, short- and long-term memory loss, and emotional disturbances. Although the Immune Effector Cell-Associated Encephalopathy score remained low, the cognitive impairment was profound and disabling in both cases. The neurological status of all patients fully recovered to pre-CAR-T status within one month. CONCLUSIONS The findings in our cases indicate that persistent cognitive dysfunction may be a potentially under-recognized outcome of neurotoxicity due to CAR-T therapy for B-cell acute lymphoblastic leukemia in adolescents and young adults. Detailed neuropsychologic assessments may be beneficial for CAR-T therapy.
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Affiliation(s)
- Yusa Nagai
- Division of Neurology, National Center for Child Health and Development, Setagaya-ku, Tokyo, Japan.
| | - Itaru Hayakawa
- Division of Neurology, National Center for Child Health and Development, Setagaya-ku, Tokyo, Japan
| | - Masahiro Sugawa
- Children's Cancer Center, National Center for Child Health and Development, Setagaya-ku, Tokyo, Japan
| | - Yoshihiro Gocho
- Children's Cancer Center, National Center for Child Health and Development, Setagaya-ku, Tokyo, Japan
| | - Hirotoshi Sakaguchi
- Children's Cancer Center, National Center for Child Health and Development, Setagaya-ku, Tokyo, Japan
| | - Daisuke Tomizawa
- Children's Cancer Center, National Center for Child Health and Development, Setagaya-ku, Tokyo, Japan
| | - Yuichi Abe
- Division of Neurology, National Center for Child Health and Development, Setagaya-ku, Tokyo, Japan
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5
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Yao X, Wang H, Lei X, Yao S, Wang W, Yang J. Pre-infusion 18 F-FDG PET/CT for Prognostic and Toxicity Prediction in B-cell Non-Hodgkin Lymphoma Patients Undergoing Chimeric Antigen Receptor T-cell Therapy. Clin Nucl Med 2025; 50:501-507. [PMID: 40197422 DOI: 10.1097/rlu.0000000000005888] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2024] [Accepted: 03/05/2025] [Indexed: 04/10/2025]
Abstract
PURPOSE The aim of this study was to evaluate the value of 18 F-FDG PET/CT in predicting outcomes and toxicity for patients with B-cell non-Hodgkin lymphoma (B-NHL) who underwent chimeric antigen receptor T (CAR-T) cell therapy. METHODS This retrospective study included B-NHL patients who underwent CAR-T therapy and had pre-infusion 18 F-FDG PET/CT images. We recorded SUVmax, metabolic tumor volume (MTV), total lesion glycolysis (TLG), and various clinical and laboratory indexes. The primary endpoints were progression-free survival (PFS) and overall survival (OS). PFS and OS were estimated using the Kaplan-Meier method. In addition, we reported the correlation between PET/CT parameters and the objective response (OR), as well as cytokine release syndrome (CRS). RESULTS A total of 133 patients were enrolled in this study. The median follow-up duration was 20.8 months. SUVmax (with a cutoff value of 15.65) emerged as an independent metabolic parameter associated with PFS, OS, and OR. Patients with SUVmax ≥15.65 had a median PFS of 9.13 months (95% CI: 0.11-18.16), while the PFS for those with SUVmax<15.65 was not reached ( P =0.006). Furthermore, patients with SUVmax ≥15.65 exhibited significantly shorter average OS compared with those with SUVmax<15.65 (26.89 mo vs. 45.14 mo, P =0.010). In addition, the odds ratio for achieving an OR in patients with SUVmax ≥15.65 was found to be lower at 0.173 (95% CI: 0.056-0.539). Other factors associated with PFS included ECOG-PS, B symptoms, bulky mass, and extranodal sites, whereas IPI and LDH were associated with OS. Furthermore, SUVmax and Deauville scores showed a weak positive correlation with the occurrence of CRS. CONCLUSIONS The pretreatment PET/CT parameter SUVmax appears to be a promising predictive factor for efficacy and prognosis, as well as being associated with the occurrence of CRS. Consequently, we can conclude that this metabolic parameter from pretreatment PET/CT scans may serve as a valuable tool in guiding patient selection for CAR-T therapy and predicting potential side effects.
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Affiliation(s)
- Xilan Yao
- Department of Nuclear Medicine, Beijing Friendship Hospital of Capital Medical University
| | - Hongrong Wang
- Department of Nuclear Medicine, Beijing Boren Hospital
| | - Xiao Lei
- Department of Nuclear Medicine, Beijing Boren Hospital
| | - Shuang Yao
- Department of Nuclear Medicine, Beijing Fengtai You'anmen Hospital, Beijing, China
| | - Wei Wang
- Department of Nuclear Medicine, Beijing Friendship Hospital of Capital Medical University
| | - Jigang Yang
- Department of Nuclear Medicine, Beijing Friendship Hospital of Capital Medical University
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Jain MD, Abramson JS, Ansell SM. Easy as ABC: Managing Toxicities of Antibody-Drug Conjugates, Bispecific Antibodies, and CAR T-Cell Therapies. Am Soc Clin Oncol Educ Book 2025; 45:e473916. [PMID: 40294348 DOI: 10.1200/edbk-25-473916] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/30/2025]
Abstract
Antibody-drug conjugates (ADCs), bispecific antibodies that engage T cells (BsAbs), and chimeric antigen receptor (CAR) T cells are widely used standard-of-care therapies that have revolutionized the treatment of lymphoid and plasma cell malignancies. With recent regulatory approvals, these therapies are poised to also revolutionize the treatment of common solid tumors and become a part of the everyday lexicon, the ABCs, of the practicing oncologist. Drawing from experience in hematology, we review the early, late, and rare toxicities of ADCs, BsAbs, and CAR T cells and provide general principles for their management.
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7
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Zoref-Lorenz A, Rocco J, Schwartz DM, Jordan M. Recognizing and Managing Secondary Hemophagocytic Lymphohistiocytosis in Adults: A Practical Clinical Guide. Hematol Oncol Clin North Am 2025; 39:577-596. [PMID: 40222878 DOI: 10.1016/j.hoc.2025.02.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/15/2025]
Abstract
Secondary hemophagocytic lymphohistiocytosis (sHLH) is a life-threatening hyperinflammatory syndrome triggered by infections, malignancies, or rheumatologic conditions. Effective management requires identifying and treating the acute trigger while addressing underlying factors and calming the inflammatory response. Like sepsis, sHLH represents a cytokine storm resulting from diverse triggering events rather than a standalone diagnosis. This review synthesizes current literature and the authors' clinical experience to provide a comprehensive framework for diagnosing and managing sHLH, emphasizing the importance of tailored, trigger-specific interventions. Emerging diagnostic tools and therapeutic strategies and improved mechanistic understanding of sHLH hold promise for improving outcomes in this challenging condition.
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Affiliation(s)
- Adi Zoref-Lorenz
- Hematology Institute, Department of Medicine, Meir Medical Center, Tchernichovsky Street 59, Kfar Saba 4428164, Israel; Faculty of Medicine and Health Sciences, Tel Aviv University, Tel Aviv, Israel.
| | - Joseph Rocco
- Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, NIH Clinical Center Building 10, Room 11B-17 10 Center Drive, Bethesda, MD 20892, USA. https://twitter.com/JMRocco5
| | - Daniella M Schwartz
- Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Pittsburgh, 1551W Starzl Building, 200 Lothrop Street, Pittsburgh, PA 15213, USA. https://twitter.com/SchwartzLab9
| | - Michael Jordan
- Division of Immunobiology and Bone Marrow Transplant, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, 240 Albert Sabin Way, ML 7038, Cincinnati, OH 45229-3039, USA. https://twitter.com/Mjordanlab
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Lee JC, Johnson WT, Hines M, Shah NN. Immune Effector Cell-associated Hemophagocytic Lymphohistiocytosis-like Syndrome (IEC-HS). Hematol Oncol Clin North Am 2025; 39:617-643. [PMID: 40158936 DOI: 10.1016/j.hoc.2025.02.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/02/2025]
Abstract
Immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS) is a complication of adoptive cell therapy. Presenting with clinical manifestations of hyperinflammation and surrogate indicators of hyperinflammation such as elevations in serum ferritin and hepatic transaminases, decreasing cell counts, and hypofibrinogenemia, IEC-HS resembles primary and other forms of secondary hemophagocytic lymphohistiocytosis. Nonetheless, this is an iatrogenic complication resulting from the induction of hyperinflammatory pathways during T-cell-mediated anticancer targeting. Distinct from cytokine release syndrome, IEC-associated neurotoxicity syndrome, and IEC-associated hematotoxicity, IEC-HS can be life-threatening. Identification of IEC-HS, optimization of treatment strategies, and use of supportive care are critical to improving outcomes.
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Affiliation(s)
- Jerry C Lee
- Hematology, Blood and Marrow Transplantation, and Cellular Therapy Program, Division of Hematology/Oncology, Department of Medicine, University of California, UCSF Box 0345, 400 Parnassus Avenue, San Francisco, CA 94143, USA
| | - William T Johnson
- Lymphoma Service and Cellular Therapy Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Melissa Hines
- Division of Critical Care Medicine, Department of Pediatric Medicine, St. Jude Children's Research Hospital, MS #734262 Danny Thomas Place, Memphis, TN 38105, USA
| | - Nirali N Shah
- Pediatric Oncology Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), NIH, Bethesda, MD, USA.
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Chen DT, Goloubeva O, Rapoport AP, Dahiya S, Atanackovic D, Hardy N, Kocoglu M, Lutfi F, Alkhaldi H, Claiborne JP, Lee ST, Kline K, Law JY, Yared JA. CD19 CAR-T With Axicabtagene Ciloleucel in R/R Large B-Cell Lymphoma With/Without Prior Autologous Stem Cell Transplant. CLINICAL LYMPHOMA, MYELOMA & LEUKEMIA 2025; 25:432-439. [PMID: 39865000 DOI: 10.1016/j.clml.2024.12.019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/15/2024] [Revised: 12/24/2024] [Accepted: 12/28/2024] [Indexed: 01/28/2025]
Abstract
BACKGROUND Anti-CD19 CAR-T therapy has been a breakthrough in treatment of primary refractory or relapsed large B-cell lymphoma (r/r LBCL) and is poised to supplant previous second line of high dose chemotherapy and autologous stem cell transplantation (HDT/ASCT). However, in clinical practice, high risk patients with chemoimmunotherapy sensitive disease continue to receive salvage chemoimmunotherapy or cannot access CAR-T in a timely manner and thus may still proceed to HDT/ASCT. Little is known about clinical outcomes of CAR-T in patients who receive HDT/ASCT compared to those who are transplant-naïve. DESIGN We conducted a retrospective study of patients with r/r LBCL who previously underwent HDT/ASCT or were transplant-naïve (n = 97) and received axicabtagene ciloleucel after at least 2 prior therapy lines between 1/1/2018 to 12/31/2021. Primary endpoint was progression-free survival (PFS). Secondary endpoints were overall survival (OS), nonrelapse mortality (NRM), and cumulative incidence of relapse/progression. RESULTS 82 (84.5%) patients were transplant-naïve and 15 (15.5%) previously received HDT/ASCT. No differences were found in the incidence of high-grade cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome, length of hospital admission, or incidence of cytopenia at day 30. 90-day response, PFS, OS, cumulative incidence of relapse/progression, and NRM were not different. Factors that adversely affected outcomes were prior bridging therapy, elevated LDH or thrombocytopenia at time of lymphodepleting chemotherapy, and worse ECOG performance status. CONCLUSION Prior treatment with HDT/ASCT does not compromise the safety and efficacy of anti-CD19 CAR-T therapy, suggesting a continued role for HDT/ASCT in treatment of select patients with r/r DLBCL.
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MESH Headings
- Humans
- Male
- Female
- Middle Aged
- Lymphoma, Large B-Cell, Diffuse/therapy
- Lymphoma, Large B-Cell, Diffuse/mortality
- Lymphoma, Large B-Cell, Diffuse/drug therapy
- Immunotherapy, Adoptive/methods
- Retrospective Studies
- Antigens, CD19/immunology
- Antigens, CD19/therapeutic use
- Transplantation, Autologous/methods
- Aged
- Adult
- Hematopoietic Stem Cell Transplantation/methods
- Biological Products/therapeutic use
- Biological Products/pharmacology
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Affiliation(s)
- David T Chen
- Division of Hematology/Oncology, Department of Medicine, Greenebaum Comprehensive Cancer Center, University of Maryland Medical Center, University of Maryland School of Medicine, Baltimore, MD.
| | - Olga Goloubeva
- Department of Epidemiology and Public Health, Division of Biostatistics and Bioinformatics, University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD
| | - Aaron P Rapoport
- Transplantation & Cellular Therapy Program, Division of Hematology/Oncology, Department of Internal Medicine, Greenebaum Comprehensive Cancer Center, University of Maryland Medical Center, University of Maryland School of Medicine, Baltimore, MD
| | - Saurabh Dahiya
- Transplantation & Cellular Therapy Program, Division of Hematology/Oncology, Department of Internal Medicine, Greenebaum Comprehensive Cancer Center, University of Maryland Medical Center, University of Maryland School of Medicine, Baltimore, MD
| | - Djordje Atanackovic
- Transplantation & Cellular Therapy Program, Division of Hematology/Oncology, Department of Internal Medicine, Greenebaum Comprehensive Cancer Center, University of Maryland Medical Center, University of Maryland School of Medicine, Baltimore, MD
| | - Nancy Hardy
- Transplantation & Cellular Therapy Program, Division of Hematology/Oncology, Department of Internal Medicine, Greenebaum Comprehensive Cancer Center, University of Maryland Medical Center, University of Maryland School of Medicine, Baltimore, MD
| | - Mehmet Kocoglu
- Transplantation & Cellular Therapy Program, Division of Hematology/Oncology, Department of Internal Medicine, Greenebaum Comprehensive Cancer Center, University of Maryland Medical Center, University of Maryland School of Medicine, Baltimore, MD
| | - Forat Lutfi
- Transplantation & Cellular Therapy Program, Division of Hematology/Oncology, Department of Internal Medicine, Greenebaum Comprehensive Cancer Center, University of Maryland Medical Center, University of Maryland School of Medicine, Baltimore, MD
| | - Hanan Alkhaldi
- Transplantation & Cellular Therapy Program, Division of Hematology/Oncology, Department of Internal Medicine, Greenebaum Comprehensive Cancer Center, University of Maryland Medical Center, University of Maryland School of Medicine, Baltimore, MD
| | - John Preston Claiborne
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Seung Tae Lee
- Transplantation & Cellular Therapy Program, Division of Hematology/Oncology, Department of Internal Medicine, Greenebaum Comprehensive Cancer Center, University of Maryland Medical Center, University of Maryland School of Medicine, Baltimore, MD
| | - Kathryn Kline
- Transplantation & Cellular Therapy Program, Division of Hematology/Oncology, Department of Internal Medicine, Greenebaum Comprehensive Cancer Center, University of Maryland Medical Center, University of Maryland School of Medicine, Baltimore, MD
| | - Jennie Y Law
- Transplantation & Cellular Therapy Program, Division of Hematology/Oncology, Department of Internal Medicine, Greenebaum Comprehensive Cancer Center, University of Maryland Medical Center, University of Maryland School of Medicine, Baltimore, MD
| | - Jean A Yared
- Transplantation & Cellular Therapy Program, Division of Hematology/Oncology, Department of Internal Medicine, Greenebaum Comprehensive Cancer Center, University of Maryland Medical Center, University of Maryland School of Medicine, Baltimore, MD
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Irby D, Hibma J, Elmeliegy M, Wang D, Vandendries E, Poels K, Shtylla B, Williams JH. A Novel Two-Part Mixture Model for the Incidence and Time Course of Cytokine Release Syndrome After Elranatamab Dosing in Multiple Myeloma Patients. Clin Pharmacol Ther 2025; 117:1687-1695. [PMID: 39955765 PMCID: PMC12087694 DOI: 10.1002/cpt.3533] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2024] [Accepted: 12/02/2024] [Indexed: 02/18/2025]
Abstract
Cytokine release syndrome (CRS) is a common, acute adverse event associated with T-cell redirecting therapies such as bispecific antibodies (BsAbs). The nature of CRS events data makes it challenging to capture an unbiased exposure-response relationship with commonly used models. For example, simple logistic regression models cannot handle traditional time-varying exposure, and static exposure metrics chosen at early time points and with lower priming doses may underestimate the incidence of CRS. Therefore, more advanced modeling techniques are needed to adequately describe the time course of BsAb-induced CRS. Herein, we present a two-part mixture model that describes the population incidence and time course of CRS following various dose-priming regimens of elranatamab, a humanized BsAb that targets the B-cell maturation antigen on myeloma cells and CD3 on T cells, where the conditional time-evolution of CRS was described with a two-state (i.e., CRS-yes or no) Markov model. In the first part, increasing elranatamab exposure (maximum elranatamab concentration at first CRS event time (Cmax,event)) was associated with an increased CRS incidence probability. Similarly, in the second part, increased early elranatamab exposure (Cmax,D1) increased the predicted probability of CRS over time, whereas premedication including corticosteroids and IL-6 pathway inhibitors use demonstrated the opposite effect. This is the first reported application of a Markov model to describe the probability of CRS following BsAb therapy, and it successfully explained differences between different dose-priming regimens via clinically relevant covariates. This approach may be useful for the future clinical development of BsAbs.
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Affiliation(s)
- Donald Irby
- Pfizer Research and Development, Pfizer, Inc.San DiegoCaliforniaUSA
| | - Jennifer Hibma
- Pfizer Research and Development, Pfizer, Inc.San DiegoCaliforniaUSA
| | - Mohamed Elmeliegy
- Oncology Research and Development, Pfizer, Inc.San DiegoCaliforniaUSA
| | - Diane Wang
- Oncology Research and Development, Pfizer, Inc.San DiegoCaliforniaUSA
| | - Erik Vandendries
- Oncology Research and Development, Pfizer, Inc.CambridgeMassachusettsUSA
| | - Kamrine Poels
- Pfizer Research and Development, Pfizer, Inc.San DiegoCaliforniaUSA
| | - Blerta Shtylla
- Pfizer Research and Development, Pfizer, Inc.San DiegoCaliforniaUSA
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11
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Vetsika EK, Katsianou MA, Sarantis P, Palamaris K, Papavassiliou AG, Piperi C. Pediatric gliomas immunity challenges and immunotherapy advances. Cancer Lett 2025; 618:217640. [PMID: 40090572 DOI: 10.1016/j.canlet.2025.217640] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2025] [Revised: 03/11/2025] [Accepted: 03/12/2025] [Indexed: 03/18/2025]
Abstract
Pediatric gliomas, the most frequent brain tumors in children, are characterized by heterogeneity and a unique tumor immune microenvironment. They are categorized into different subtypes, including low-grade gliomas like pilocytic astrocytomas and high-grade gliomas such as diffuse midline gliomas and diffuse intrinsic pontine gliomas, each exhibiting distinct immunological profiles. The tumor immune microenvironment in pediatric gliomas is shaped by cellular and non-cellular components, including immune cells, cytokines, and the extracellular matrix, involved in tumor progression, immune evasion, and response to therapy. While pediatric low-grade gliomas often display an immunosuppressed microenvironment, high-grade gliomas are characterized by complex immune infiltrates and intricate immunosuppressive mechanisms. The blood-brain barrier further obscures immune cell recruitment and therapeutic delivery. Despite advances in understanding adult gliomas, the immunobiology of pediatric tumors is poorly investigated, with limited data on the interactions between glioma cells and immune populations such as T and natural killer cells, as well as tumor-associated macrophages. Herein, we provide an update of the current knowledge on tumor immune microenvironment interactions in pediatric gliomas, highlighting the immunosuppressive mechanisms and emerging immunotherapeutic strategies aiming at overcoming these barriers to improve clinical outcomes for affected children.
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Affiliation(s)
- Eleni-Kyriaki Vetsika
- Centre of New Biotechnologies and Precision Medicine (CNBPM), School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Maria A Katsianou
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Panagiotis Sarantis
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Kostas Palamaris
- First Department of Pathology, School of Medicine, National and Kapodistrian University of Athens, 10679, Athens, Greece
| | - Athanasios G Papavassiliou
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Christina Piperi
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
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12
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Westin J, Phillips TJ, Mehta A, Hoffmann MS, Gonzalez-Barca E, Thieblemont C, Bastos-Oreiro M, Greil R, Giebel S, Wei MC, Wang J, Bucher R, Sit J, Penuel E, Purev E, Yee DL, Bergua-Burgues JM. Mosunetuzumab plus Pola-CHP compared with Pola-R-CHP in previously untreated DLBCL: final results from a phase 2 study. Blood Adv 2025; 9:2461-2472. [PMID: 39908481 DOI: 10.1182/bloodadvances.2024014907] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2024] [Revised: 12/18/2024] [Accepted: 12/18/2024] [Indexed: 02/07/2025] Open
Abstract
ABSTRACT This phase 2 study evaluated mosunetuzumab plus cyclophosphamide, doxorubicin, prednisone, and polatuzumab vedotin (Pola-M-CHP) vs Pola-rituximab (R)-CHP for first-line treatment of diffuse large B-cell lymphoma. Patients were randomized 2:1 to receive 6 cycles of Pola-M-CHP or Pola-R-CHP on day 1 of each 21-day cycle. Mosunetuzumab was administered intravenously via step-up dosing during cycle 1 and at 30 mg on day 1 of subsequent cycles. The primary end point was independent review committee-assessed complete response (CR) rate by positron emission tomography-computed tomography. Overall, 62 patients were enrolled and received Pola-M-CHP (n = 40) or Pola-R-CHP (n = 22). CR rates were similar in both arms (72.5% with Pola-M-CHP vs 77.3% with Pola-R-CHP); the 24-month investigator-assessed progression-free survival rate was 70.8% (95% confidence interval [CI], 55.6-86.1) with Pola-M-CHP vs 81.8% (95% CI, 65.7-97.9) with Pola-R-CHP. The most common adverse event (AE) was cytokine release syndrome (68.4%; mostly grade 1 [52.6%], and primarily confined to cycle 1) with Pola-M-CHP and neutropenia/neutrophil count decreased (54.5%) with Pola-R-CHP. Neutropenia/neutrophil count decreased was the most frequently observed grade ≥3 AE in both arms (Pola-M-CHP, 36.8%; Pola-R-CHP, 22.7%). Rates of grade ≥3 AEs (86.8% vs 59.1%), serious AEs (63.2% vs 13.6%), and AEs leading to treatment discontinuation (13.2% vs 0%) were higher with Pola-M-CHP than Pola-R-CHP, respectively. Pharmacodynamic changes were supportive of mosunetuzumab's mechanism of action and its addition to the Pola-CHP combination. Pola-M-CHP, although an active combination, did not demonstrate a clinical benefit over Pola-R-CHP in this small study. This trial was registered at www.clinicaltrials.gov as #NCT03677141.
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MESH Headings
- Humans
- Lymphoma, Large B-Cell, Diffuse/drug therapy
- Lymphoma, Large B-Cell, Diffuse/mortality
- Male
- Female
- Middle Aged
- Antineoplastic Combined Chemotherapy Protocols/therapeutic use
- Antineoplastic Combined Chemotherapy Protocols/adverse effects
- Aged
- Adult
- Rituximab/administration & dosage
- Rituximab/adverse effects
- Rituximab/therapeutic use
- Doxorubicin/administration & dosage
- Doxorubicin/therapeutic use
- Doxorubicin/adverse effects
- Cyclophosphamide/administration & dosage
- Cyclophosphamide/therapeutic use
- Cyclophosphamide/adverse effects
- Treatment Outcome
- Aged, 80 and over
- Prednisone/administration & dosage
- Prednisone/therapeutic use
- Prednisone/adverse effects
- Antibodies, Monoclonal, Humanized/administration & dosage
- Antibodies, Monoclonal, Humanized/adverse effects
- Antibodies, Monoclonal, Humanized/therapeutic use
- Immunoconjugates/administration & dosage
- Immunoconjugates/adverse effects
- Immunoconjugates/therapeutic use
- Antibodies, Monoclonal
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Affiliation(s)
- Jason Westin
- Department of Lymphoma & Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Tycel J Phillips
- Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan, Ann Arbor, MI
| | - Amitkumar Mehta
- Division of Hematology and Oncology, The University of Alabama School of Medicine, Birmingham, AL
| | - Marc S Hoffmann
- Division of Hematologic Malignancies and Cellular Therapeutics, The University of Kansas Cancer Center, Kansas City, MO
| | - Eva Gonzalez-Barca
- Institut Català d'Oncologia Hospitalet, Institut de Investigació Biomédica de Bellvitge, Universitat de Barcelona, Barcelona, Spain
| | - Catherine Thieblemont
- Hemato-Oncology Department, Université Paris Cité, Paris, France
- Assistance Publique-Hôpitaux de Paris, Hôpital Saint Louis, Hemato-oncologie, Paris, France
- Hemato-Oncology Department, INSERM U1153, Hôpital Saint Louis, Paris, France
| | - Mariana Bastos-Oreiro
- Hematology Department, Gregorio Marañon Hospital, Gregorio Marañon Health Research Institute, Madrid, Spain
| | - Richard Greil
- Salzburg Cancer Research Institute-Center for Clinical Cancer and Immunology Trials, Cancer Cluster, Paracelsus Medical University, Salzburg, Austria
| | - Sebastian Giebel
- Department of Bone Marrow Transplantation and Onco-Hematology, Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice, Poland
| | | | - Jue Wang
- Genentech, Inc, South San Francisco, CA
| | | | - Jason Sit
- Genentech, Inc, South San Francisco, CA
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13
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Gu J, Li J, Xu Y, Zhang G, Xie J, Jia R, Chen W, Lu Z, Chang C, Wen H, Chang LJ, Ma H, Cai Q. Preliminary exploration of PSMA CAR-T combined with GD2 CAR-T for the treatment of refractory/relapsed gliomas. J Transl Med 2025; 23:591. [PMID: 40420236 DOI: 10.1186/s12967-025-06523-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2025] [Accepted: 04/21/2025] [Indexed: 05/28/2025] Open
Abstract
BACKGROUND This study aimed to investigate the safety and efficacy of fourth-generation combined PSMA and GD2-targeted chimeric antigen receptor (CAR)-T cells in the treatment of refractory/relapsed gliomas. METHOD This study employed a single-arm design, enrolling patients with confirmed refractory/relapsed gliomas at the Immuno-oncology Department of the Cancer Center at Clifford Hospital in Guangdong. Eligible patients received combined treatment with PSMA CAR-T and GD2 CAR-T cells via intravenous administration. The dose of reinfused CAR-T cells ranged from 1-5 × 10^6 cells/kg of body weight. RESULTS Six patients were included in the study, all of whom responded to the treatment. The overall response rate (ORR) was 50%, with three patients achieving complete response (CR) (50%) and three demonstrating stable disease (SD) (50%). The median progression-free survival (PFS) was 9.0 months (range, 1-56 months), and the median overall survival (OS) was 24.5 months (range, 13-63 months). Three patients (50%) developed cytokine release syndrome (CRS), all of which were classified as grade I CRS, and no patients experienced immune effector cell-associated neurotoxicity Syndrome (ICANS). CONCLUSION Combined PSMA CAR-T and GD2 CAR-T cell therapy demonstrated significant efficacy and good tolerability in the treatment of refractory/relapsed gliomas, without severe adverse reactions.
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Affiliation(s)
- Jinshan Gu
- Immuno-oncology department of the cancer center, 21 st Floor, Building 2, Guangdong Clifford Hospital, Hongfu Road, Panyu District, Guangzhou, 511400, China
| | - Jiasheng Li
- State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen University, Guangzhou, 510275, China
| | - Yang Xu
- State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen University, Guangzhou, 510275, China
| | - Ge Zhang
- Immuno-oncology department of the cancer center, 21 st Floor, Building 2, Guangdong Clifford Hospital, Hongfu Road, Panyu District, Guangzhou, 511400, China
| | - Jingyi Xie
- Immuno-oncology department of the cancer center, 21 st Floor, Building 2, Guangdong Clifford Hospital, Hongfu Road, Panyu District, Guangzhou, 511400, China
| | - Rui Jia
- Immuno-oncology department of the cancer center, 21 st Floor, Building 2, Guangdong Clifford Hospital, Hongfu Road, Panyu District, Guangzhou, 511400, China
| | - Wei Chen
- Immuno-oncology department of the cancer center, 21 st Floor, Building 2, Guangdong Clifford Hospital, Hongfu Road, Panyu District, Guangzhou, 511400, China
| | - Zhengfeng Lu
- Immuno-oncology department of the cancer center, 21 st Floor, Building 2, Guangdong Clifford Hospital, Hongfu Road, Panyu District, Guangzhou, 511400, China
| | - Chengwei Chang
- Shenzhen Geno-Immune Medical Institute, Shenzhen, Guangdong, China
| | - Haijun Wen
- State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen University, Guangzhou, 510275, China
| | - Lung-Ji Chang
- Shenzhen Geno-Immune Medical Institute, Shenzhen, Guangdong, China.
| | - Huajuan Ma
- Immuno-oncology department of the cancer center, 21 st Floor, Building 2, Guangdong Clifford Hospital, Hongfu Road, Panyu District, Guangzhou, 511400, China.
| | - Qichun Cai
- Immuno-oncology department of the cancer center, 21 st Floor, Building 2, Guangdong Clifford Hospital, Hongfu Road, Panyu District, Guangzhou, 511400, China.
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14
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Phina-Ziebin X, Bachy E, Gros FX, Di Blasi R, Herbaux C, Bay JO, Carras S, Bories P, Casasnovas O, Jardin F, Morschhauser F, Guffroy B, Mohty M, Gat E, Calvani J, Parrens MC, Poullot E, Traverse-Glehen A, Roulin L. Outcome of high-grade B-cell lymphoma compared with other large B-cell lymphoma after CAR-T rescue: a DESCAR-T LYSA study. Blood Adv 2025; 9:2500-2510. [PMID: 39874518 DOI: 10.1182/bloodadvances.2024014732] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2024] [Revised: 01/02/2025] [Accepted: 01/07/2025] [Indexed: 01/30/2025] Open
Abstract
ABSTRACT High-grade B-cell lymphoma (HGBL) with MYC and BCL2 and/or BCL6 rearrangements (double hit [HGBL-DH] or triple hit [HGBL-TH]) or not otherwise specified (HGBL-NOS) are considered to be more aggressive diseases among large B-cell lymphomas (LBCLs). CD19-targeting chimeric antigen receptor (CAR) T cells have changed the prognosis of chemoresistant LBCL. Clinical and pathological data of patients treated for relapsed/refractory LBCL or HGBL in third line or more, all characterized by fluorescence in situ hybridization, were collected from the French DESCAR-T registry. Between January 2018 and November 2022, a total of 228 patients were included across 14 centers, 73 with HGBL (28 HGBL-DH MYC-BCL2, 14 HGBL-TH, 8 HGBL-DH MYC-BCL6, and 23 HGBL-NOS) and 155 with non-HGBL. The median follow-up was 18.5 months (95% confidence interval [CI], 14.3-23.4) from the date of infusion. Progression-free survival and overall survival (OS) were not significantly different between HGBL and non-HGBL, at 3.2 months (95% CI, 2.8-6.0) vs 4.5 months (95% CI, 3.1-8.7; P = .103) and 15.4 months (95% CI, 5.6-32.4) vs 18.3 months (95% CI, 8.5 to not reached), respectively. From the date of eligibility, the median OS was inferior for patients with HGBL-TH/DH MYC-BCL2 at 6.6 months vs 18.5 months for HGBL-NOS vs 13.6 months for HGBL-DH MYC-BCL6 vs 11.8 months for LBCL (P = .037). However, patients who received infusion presented the same outcome. CAR T-cell therapy used in third line or more seems to overcome the poor prognosis of HGBL subtypes, especially in HGBL-TH/DH MYC-BCL2. This observation supports considering the potential benefit of using CAR T cells earlier in disease course.
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MESH Headings
- Humans
- Male
- Female
- Middle Aged
- Immunotherapy, Adoptive/methods
- Aged
- Lymphoma, Large B-Cell, Diffuse/therapy
- Lymphoma, Large B-Cell, Diffuse/mortality
- Lymphoma, Large B-Cell, Diffuse/pathology
- Adult
- Receptors, Chimeric Antigen
- Lymphoma, B-Cell/therapy
- Lymphoma, B-Cell/mortality
- Lymphoma, B-Cell/pathology
- Treatment Outcome
- Neoplasm Grading
- Prognosis
- Aged, 80 and over
- Proto-Oncogene Proteins c-bcl-6/genetics
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Affiliation(s)
- Xavier Phina-Ziebin
- Department of Lymphoid Hemopathy, Hemopathy Lymphoid Unit, Henri Mondor Hospital, Créteil, France
| | - Emmanuel Bachy
- Department of Hematology, Hospices Civils de Lyon, Pierre Bénite, France
| | | | | | - Charles Herbaux
- Department of Hematology, University Hospital of Montpellier, Montpellier, France
| | - Jacques Olivier Bay
- Department of Hematology, University Hospital of Clermont-Ferrand, Clermont-Ferrand, France
| | - Sylvain Carras
- Department of Hematology, University Hospital of Grenoble, Grenoble, France
| | - Pierre Bories
- Department of Hematology, Toulouse University Institute of Cancer-Oncopole, Toulouse, France
| | | | - Fabrice Jardin
- Department of Hematology, Centre Henri Becquerel, Rouen, France
| | - Franck Morschhauser
- Department of Hematology, Claude Huriez Hospital, Lille University Hospital, Lille, France
| | - Blandine Guffroy
- Department of Hematology, Institut de Cancérologie Strasbourg Europe, Strasbourg, France
| | - Mohamad Mohty
- Department of Hematology, Saint-Antoine Hospital, Sorbonne University, Paris, France
| | - Elodie Gat
- Department of Biostatistics, Institut Carnot CALYM, Lyon, France
| | - Julien Calvani
- Department of Pathology, Hôpital Saint Louis, Paris, France
| | | | - Elsa Poullot
- Department of Pathology, Henri Mondor Hospital, Créteil, France
| | - Alexandra Traverse-Glehen
- Department of Pathology, Hospices Civils de Lyon, Centre Hospitalier Lyon-Sud, Pierre-Bénite, France
| | - Louise Roulin
- Department of Lymphoid Hemopathy, Hemopathy Lymphoid Unit, Henri Mondor Hospital, Créteil, France
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15
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Park T, Jang S, Koh Y, Shin DY, Yoon SS, Lee CM, Jo HJ, Choe PG, Park WB, Kim NJ, Kang CK, Byun JM. Incidence and Characteristics of Infectious Complications in Multiple Myeloma Patients Treated With Bispecific Antibodies. J Korean Med Sci 2025; 40:e86. [PMID: 40425193 DOI: 10.3346/jkms.2025.40.e86] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2024] [Accepted: 11/14/2024] [Indexed: 05/29/2025] Open
Abstract
BACKGROUND Bispecific antibodies (BsAbs) are a new class of immunotherapeutic agents for patients with multiple myeloma (MM). Although this new class of drug is associated with good disease control, they are also associated with increased risk of infectious complications. Since endemic community-acquired and nosocomial infections vary across the globe, we conducted this study to report real-world data of infectious complications associated with BsAbs in Korean population. METHODS We retrospectively reviewed all MM patients who received BsAb therapy between January 2021 and January 2024 at Seoul National University Hospital. We identified 61 patients who underwent BsAb therapy at our center with median follow-up of 34 weeks (95% confidence interval, 25.85-55.85). Thirty-three patients (54%) received B-cell maturation antigen (BCMA)-targeting BsAb, and 30 (49%) received combination therapy. RESULTS Of the 61 patients, 39 (64%) had at least one episode of infection. A total of 69 infections affecting patient management occurred during the study period, 3% grade 1 infection, 8% grade 2, 72% grade 3, 8% grade 4 and 8% grade 5. The most common type of infection was lower respiratory tract infection (n = 32/69, 46%), followed by systemic infection (n = 21/69, 30%). Etiology wise, viral infections were most common (67%), followed by fungal infections (13%) and bacterial infections (10%). Among viral infections, cytomegalovirus (CMV) was most common. Patients treated with BCMA-targeting BsAb or combination therapy were associated with higher incidence of CMV reactivation and clinically significant CMV infection. CONCLUSION Particular pattern of infectious complications including CMV infection was noted in Korean patients. Identifying and determining the nature of infectious disease dynamics is becoming increasingly important for optimal resource allocation and shaping healthcare policies. In this regard, our first-in-Asian population study holds its value.
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Affiliation(s)
- Taekeun Park
- Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Sukjin Jang
- Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Youngil Koh
- Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
- Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Dong-Yeop Shin
- Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
- Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Sung-Soo Yoon
- Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
- Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Chan Mi Lee
- Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Hyeon Jae Jo
- Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Pyoeng Gyun Choe
- Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Wan Beom Park
- Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Nam Joong Kim
- Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Chang Kyung Kang
- Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea.
| | - Ja Min Byun
- Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
- Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.
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16
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Hanajiri R, Wakabayashi H, Ishigiwa K, Ohara F, Hirano S, Yokota H, Kuwano S, Furukawa K, Shimada K, Sato T, Terakura S, Kiyoi H. Robust CAR T-cell expansion and superior outcomes in DLBCL patients in complete response at infusion. Br J Haematol 2025. [PMID: 40415166 DOI: 10.1111/bjh.20186] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2025] [Accepted: 05/14/2025] [Indexed: 05/27/2025]
Abstract
Historically, the presence of measurable disease has been considered essential to stimulate CAR T-cell expansion and persistence. However, the kinetics of CAR T cells in patients achieving complete response (CR) before infusion remain poorly understood. This study aimed to evaluate the outcomes and CAR T-cell kinetics in relapsed/refractory diffuse large B-cell lymphoma (DLBCL) patients stratified by pre-infusion disease status. In this retrospective analysis of 87 patients treated at a single institution, 23 (26.4%) were in CR and 64 (73.6%) were in non-CR prior to CAR T-cell infusion. Patients in CR exhibited significantly better progression-free survival (PFS) and overall survival compared to non-CR patients. Peripheral blood CAR T-cell kinetics, including the proportion and absolute counts of CAR T cells, CD4+ CAR T cells and CD8+ CART cells, showed no significant differences between CR and non-CR groups. These findings were consistent across different CAR T-cell products, whether 4-1BB- or CD28-based. Moreover, an analysis of patients achieving complete metabolic response (CMR) by PET-CT confirmed comparable CAR T-cell expansion and persistence in both CMR and non-CMR patients. Our findings demonstrate that CAR T-cell therapy achieves robust expansion and favourable survival outcomes in CR patients, even in the absence of measurable disease.
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Affiliation(s)
- Ryo Hanajiri
- Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Hiroya Wakabayashi
- Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Kohei Ishigiwa
- Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Fumiya Ohara
- Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Shiho Hirano
- Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Hirofumi Yokota
- Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Shihomi Kuwano
- Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Katsuya Furukawa
- Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Kazuyuki Shimada
- Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Takahiko Sato
- Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Seitaro Terakura
- Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Hitoshi Kiyoi
- Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan
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17
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Ahmed SO, Fakih RE, Kharfan-Dabaja MA, Syed F, Mufti G, Chabannon C, Rondelli D, Mohty M, Ahmari AAA, Gauthier J, Ruella M, Perales MA, Hashmi S, Alfraih F, Ghorashian S, Alzahrani M, Abba Z, Koh M, Pasquini M, Ruggeri A, Garderet L, Albabtain A, Weisdorf D, Greinix H, Samarkandi H, Hamad N, Atsuta Y, Hamadani M, Hari P, Majhail NS, Greco R, Alzahrani H, Sureda A, Yakoub-Agha I, Alahmari AD, Niederwieser D, Aljurf M. Setting up a CAR-T Program: A Framework for Delivery from the Worldwide Network for Blood & Marrow Transplantation. Transplant Cell Ther 2025:S2666-6367(25)01196-0. [PMID: 40414351 DOI: 10.1016/j.jtct.2025.05.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2025] [Revised: 04/21/2025] [Accepted: 05/16/2025] [Indexed: 05/27/2025]
Abstract
Chimeric antigen receptor therapy (CAR-T therapy) is a genetically engineered cellular therapy that is currently integrated into the management of hematological malignancies. Institutions treating patients with CAR-T therapy need to establish a framework of delivery that covers all the main components of the patient journey including intake of patients into the program from referring centers, patient selection according to established eligibility criteria, apheresis, logistics, bridging therapy, infusion and post-infusion care. A CAR-T therapy program, with its unique requirements, needs to be delivered by a multidisciplinary team (MDT). Prior to the establishment of the program, a well-structured business plan should be developed with a clear financial and/or reimbursement model. Consideration should be given to the overall capacity and staffing requirements. Standard operating procedures and guidelines are vital for ensuring that quality standards are clearly defined and adhered to. Institutions should develop a research plan for CAR-T that may incorporate not only industry sponsored trials but also in-house CAR-T manufacture of investigational CAR-T constructs. This report presents recommendations from a group of international experts highlighting the priorities and considerations when developing a new CAR-T program.
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Affiliation(s)
- Syed Osman Ahmed
- King Faisal Specialist Hospital and Research Center, Riyadh, KSA
| | - Riad El Fakih
- King Faisal Specialist Hospital and Research Center, Riyadh, KSA; Alfaisal University School Of Medicine, Riyadh, KSA.
| | - Mohamed A Kharfan-Dabaja
- Division of Hematology-Oncology and Blood and Marrow Transplantation and Cellular Therapy Program, Mayo Clinic, Jacksonville, FL, USA
| | - Farhatullah Syed
- King Faisal Specialist Hospital and Research Center, Riyadh, KSA
| | - Ghulam Mufti
- Comprehensive Cancer Centre, School of Cancer & Pharmaceutical Sciences, Faculty of Life Sciences & Medicine, King's College London, London, United Kingdom
| | - Christian Chabannon
- Institut Paoli-Calmettes, Inserm CBT-1409 & Aix-Marseille Université, Marseille, France
| | - Damiano Rondelli
- University of Illinois Hospital & Health Sciences System, Chicago, Illinois, USA
| | - Mohamad Mohty
- Hôpital Pitié Salpêtrière, Sorbonne Université, Paris, France
| | - Ali A Al Ahmari
- King Faisal Specialist Hospital and Research Center, Riyadh, KSA
| | | | - Marco Ruella
- Division of Hematology/Oncology of the Dept. of Medicine of the University of Pennsylvania, Philadelphia, PA, USA
| | - Miguel-Angel Perales
- Adult Bone Marrow Transplant Service at Memorial Sloan Kettering Cancer Center in New York, NY, USA
| | - Shahrukh Hashmi
- Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN, USA; Department of Computer Vision, MBZ University of Artificial Intelligence, Abu Dhabi, UAE
| | - Feras Alfraih
- King Faisal Specialist Hospital and Research Center, Riyadh, KSA
| | - Sarah Ghorashian
- University College London, Transplant Immunol Grp, Dept Haematol, London NW3 2PF, UK
| | - Mohsen Alzahrani
- Division of Hematology/ Adult SCT and Cellular Therapy, King Abdulaziz Medical City, Ministry of National Guard Health Affairs, Riyadh, KSA
| | - Zubair Abba
- Mayo Clinic Comprehensive Cancer Center Laboratory Medicine and Pathology Location Jacksonville, Florida, USA
| | - Mickey Koh
- St. George's Hospital and Medical School, London, United Kingdom; Cell Therapy Facility, Blood Services Group, Health Sciences Authority, Singapore
| | - Marcelo Pasquini
- Division of Hematology/Oncology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | | | | | | | - Daniel Weisdorf
- Department of Medicine, Division of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, MN, USA
| | - Hildegard Greinix
- Division of Hematology, Department of Internal Medicine, Medical University of Graz, Austria
| | | | - Nada Hamad
- Australasian Bone Marrow Transplant Recipient Registry (ABMTRR), St. Vincent´s Hospital Sydney, Australia
| | - Yoshiko Atsuta
- Center for Hematopoietic Stem Cell Transplantation, Aichi Medical University Hospital, Nagakute, Japan
| | | | - Parameswaran Hari
- Froedtert Hospital and the Medical College of Wisconsin, Milwaukee, WI, USA
| | - Navneet S Majhail
- Sarah Cannon Transplant and Cellular Therapy Network, Sarah Cannon Cancer Network, Nashville, TN, USA
| | - Raffaella Greco
- Hematology and Bone Marrow Transplantation Unit, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milano, Italy
| | - Hazzaa Alzahrani
- King Faisal Specialist Hospital and Research Center, Riyadh, KSA
| | - Anna Sureda
- Hematology Department, Institut Català d'Oncologia-Hospitalet, IDIBELL, University of Barcelona, Barcelona, Spain
| | - Ibrahim Yakoub-Agha
- Centre Hospitalier Universitaire de Lille, Université de Lille, INSERM U1286, Lille, France
| | - Ali D Alahmari
- King Faisal Specialist Hospital and Research Center, Riyadh, KSA
| | - Dietger Niederwieser
- Division of Hematology and Medical Oncology, University of Leipzig, Leipzig, Germany
| | - Mahmoud Aljurf
- King Faisal Specialist Hospital and Research Center, Riyadh, KSA
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18
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Dai H, Xu S, Wang Z, Li Z, Cao J, Hu T, Zhou F. Quality of life and symptom burden among hematologic malignancy patients undergoing CAR-T therapy: a cross-sectional study. Sci Rep 2025; 15:17763. [PMID: 40404866 PMCID: PMC12098898 DOI: 10.1038/s41598-025-02720-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2025] [Accepted: 05/15/2025] [Indexed: 05/24/2025] Open
Abstract
Few studies have thoroughly evaluated the symptom burden and quality of life (QOL) among patients diagnosed with hematologic malignancies who underwent chimeric antigen receptor T-cell (CAR-T) therapy. In total, 97 eligible patients completed the Functional Assessment of Cancer Therapy generic scale (FACT-G) at week 4 after CAR-T cell infusion. We used the Common Terminology Criteria Adverse Events (CTCAE) to measure symptom burden of CAR-T patients during the same period. We studied factors associated with QOL using liner regression analysis. During the period of hospitalization after CAR-T treatment, the prevalence of self-reported symptoms among CAR-T patients was highest for fatigue (89.7%), followed by sleep disorders (79.4%) and decreased appetite (66.0%). And the mean score of FACT-G was 69.06 (SD = 13.88). Liner regression analysis showed that decreased appetite (β = -0.30, 95% CI = -7.48 to -1.83, P = 0.002), fatigue (β = -0.28, 95% CI = -7.23- -1.69, P = 0.002), nausea (β = -0.26, 95% CI = -10.50 to -2.16, P = 0.003) and a history of hematopoietic stem cell transplantation (HSCT) (β = -0.21, 95% CI = -13.38- -1.56, P = 0.014) were associated with poorer quality of life. The symptom burden experienced by patients undergoing CAR-T treatment is substantial during their hospitalization, and it is closely associated with a diminished quality of life. It is imperative for clinical medical staff to be attentive to the symptom burden of CAR-T patients and to enhance the effectiveness of symptom management interventions.
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Affiliation(s)
- Hongyuan Dai
- Department of Nursing, Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
- School of Nursing, Xuzhou Medical University, Jiangsu, China
| | - Shuya Xu
- School of Nursing, Xuzhou Medical University, Jiangsu, China
- Department of Medical Psychology, The School of Health Humanities, Peking University, Beijing, China
| | - Zengxiang Wang
- Department of Nursing, Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Zhenyu Li
- Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Jiangsu, China
| | - Jiang Cao
- Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Jiangsu, China
| | - Tingyu Hu
- Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Jiangsu, China.
| | - Fang Zhou
- School of Nursing, Xuzhou Medical University, Jiangsu, China.
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19
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Lin H, Case R, Wei KY, Eres I, Alba BM, Kaner J, Wu YC, Yamawaki TM, Mostafavi M, Zhou H, Ma H, Manzanillo P, Deng W. Characterization and comparative analysis of multifunctional natural killer cell engagers during antitumor responses. Cell Rep Med 2025; 6:102117. [PMID: 40318632 DOI: 10.1016/j.xcrm.2025.102117] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2024] [Revised: 12/18/2024] [Accepted: 04/10/2025] [Indexed: 05/07/2025]
Abstract
T cell engagers (TCEs) are transformational oncology therapies but are limited in use due to the induction of cytokine release syndrome (CRS). In comparison to T cells, natural killer (NK) cells produce fewer cytokines upon activation, leading to the exploration of NK cell engagers (NKCEs). However, why NK cells secrete fewer cytokines, such as tumor necrosis factor (TNF), and how NKCEs perform directly against TCEs remains unclear. Here, we report that relative to T cells, NK cells have reduced trafficking and processing of TNF. Systematic development and benchmarking studies show that NKCEs can be optimized to engage multiple activating receptors and incorporate interleukin (IL)-2, thereby increasing their potency and durability. Furthermore, comparative studies of NKCE, IL-2, and TCE therapy in animal tumor models reveal both common and distinct therapeutic benefits. Our results provide a blueprint for the development of multifunctional NKCEs, which may serve as an alternative to current TCE therapies.
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Affiliation(s)
- Hang Lin
- Amgen Research, South San Francisco, CA 94080, USA; Amgen R&D Postdoctoral Fellows Program, South San Francisco, CA 94080, USA
| | - Ryan Case
- Amgen Research, South San Francisco, CA 94080, USA
| | - Kathy Y Wei
- Amgen Research, South San Francisco, CA 94080, USA
| | - Ittai Eres
- Amgen Research, South San Francisco, CA 94080, USA
| | | | - Joelle Kaner
- Amgen Research, South San Francisco, CA 94080, USA
| | - Yen-Chi Wu
- Amgen Research, South San Francisco, CA 94080, USA
| | | | | | - Hong Zhou
- Amgen Research, South San Francisco, CA 94080, USA
| | - Hayley Ma
- Amgen Research, Thousand Oaks, CA 91320, USA
| | | | - Weiwen Deng
- Amgen Research, South San Francisco, CA 94080, USA.
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20
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Hushmandi K, Imani Fooladi AA, Reiter RJ, Farahani N, Liang L, Aref AR, Nabavi N, Alimohammadi M, Liu L, Sethi G. Next-generation immunotherapeutic approaches for blood cancers: Exploring the efficacy of CAR-T and cancer vaccines. Exp Hematol Oncol 2025; 14:75. [PMID: 40382583 DOI: 10.1186/s40164-025-00662-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2025] [Accepted: 04/25/2025] [Indexed: 05/20/2025] Open
Abstract
Recent advancements in immunotherapy, particularly Chimeric antigen receptor (CAR)-T cell therapy and cancer vaccines, have significantly transformed the treatment landscape for leukemia. CAR-T cell therapy, initially promising in hematologic cancers, faces notable obstacles in solid tumors due to the complex and immunosuppressive tumor microenvironment. Challenges include the heterogeneous immune profiles of tumors, variability in antigen expression, difficulties in therapeutic delivery, T cell exhaustion, and reduced cytotoxic activity at the tumor site. Additionally, the physical barriers within tumors and the immunological camouflage used by cancer cells further complicate treatment efficacy. To overcome these hurdles, ongoing research explores the synergistic potential of combining CAR-T cell therapy with cancer vaccines and other therapeutic strategies such as checkpoint inhibitors and cytokine therapy. This review describes the various immunotherapeutic approaches targeting leukemia, emphasizing the roles and interplay of cancer vaccines and CAR-T cell therapy. In addition, by discussing how these therapies individually and collectively contribute to tumor regression, this article aims to highlight innovative treatment paradigms that could enhance clinical outcomes for leukemia patients. This integrative approach promises to pave the way for more effective and durable treatment strategies in the oncology field. These combined immunotherapeutic strategies hold great promise for achieving more complete and lasting remissions in leukemia patients. Future research should prioritize optimizing treatment sequencing, personalizing therapeutic combinations based on individual patient and tumor characteristics, and developing novel strategies to enhance T cell persistence and function within the tumor microenvironment. Ultimately, these efforts will advance the development of more effective and less toxic immunotherapeutic interventions, offering new hope for patients battling this challenging disease.
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Affiliation(s)
- Kiavash Hushmandi
- Nephrology and Urology Research Center, Clinical Sciences Institute, Baqiyatallah University of Medical Sciences, Tehran, Islamic Republic of Iran.
| | - Abbas Ali Imani Fooladi
- Applied Microbiology Research Center, Biomedicine Technologies Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Russel J Reiter
- Department of Cell Systems and Anatomy, UT Health San Antonio, San Antonio, TX, 78229, USA
| | - Najma Farahani
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Liping Liang
- Guangzhou Key Laboratory of Digestive Diseases, Department of Gastroenterology and Hepatology, Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, 510180, China
| | - Amir Reza Aref
- Department of Vitro Vision, DeepkinetiX, Inc, Boston, MA, USA
| | | | - Mina Alimohammadi
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Le Liu
- Integrated Clinical Microecology Center, Shenzhen Hospital, Southern Medical University, Shenzhen, 518000, China.
- Department of Gastroenterology, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, China.
| | - Gautam Sethi
- Department of Pharmacology and NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore.
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21
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Dong MH, Mei ZC, Zhou LQ, Heming M, Xu LL, Liu YX, Pang XW, Chu YH, Cai SB, Ye H, Shang K, Xiao J, Meyer Zu Hörste G, Wang W, Qin C, Tian DS. Anti-BCMA CAR-T cell therapy in relapsed/refractory chronic inflammatory demyelinating polyneuropathy. MED 2025:100704. [PMID: 40425008 DOI: 10.1016/j.medj.2025.100704] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2025] [Revised: 04/14/2025] [Accepted: 04/29/2025] [Indexed: 05/29/2025]
Abstract
BACKGROUND Chronic inflammatory demyelinating polyneuropathy (CIDP) presents a significant therapeutic challenge, with up to 15% of patients being refractory to first-line treatments. METHODS Anti-B cell maturation antigen chimeric antigen receptor T (CAR-T) cell therapy was applied to two patients with highly relapsed and refractory CIDP, followed by safety and efficacy evaluation. Multi-omics analyses were performed on samples of peripheral blood mononuclear cells (PBMCs) collected before and after infusion. FINDINGS Both patients had no severe adverse events and achieved drug-free remission within 6 months post-CAR-T therapy. Patient 1 experienced disease recurrence 12 months post infusion following a severe infection of COVID-19, while patient 2 maintained remission over 24 months. Relapse was accompanied by reactivation of pathogenic B cells and recurrence of autoantibodies/peptides targeting axons or myelin. Metabolic reprogramming of B cells characterized by overglycolysis was linked to disease relapse, which could be modulated by regulatory factor X5. CONCLUSION This study demonstrates the safety and potential of anti-BCMA CAR-T cell therapy in treating refractory CIDP and provides insights into the molecular mechanisms underlying patient responses (ClinicalTrials.gov: NCT04561557). FUNDING Ministry of Science and Technology China Brain Initiative grant STI2030-Major Projects 2022ZD0204700 (to W.W.), National Natural Science Foundation of China grants 82371404 and 82071380 (to D.-S.T.) and 82471353 and 82271341 (to C.Q.), Knowledge Innovation Program of Wuhan Shuguang Project 2022020801020454 (to C.Q.), and Key Research and Development Program of Hubei Provincial Department of Science and Technology 2023BCB148 (to D.-S.T.). The clinical trial was funded by Nanjing IASO Biotechnology Co., Ltd.
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Affiliation(s)
- Ming-Hao Dong
- Department of Neurology, Tongji Hospital, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China; Hubei Key Laboratory of Neural Injury and Functional Reconstruction, Huazhong University of Science and Technology, Wuhan 430030, China; Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Zhi-Cheng Mei
- Department of Neurology, Tongji Hospital, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China; Hubei Key Laboratory of Neural Injury and Functional Reconstruction, Huazhong University of Science and Technology, Wuhan 430030, China; Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Luo-Qi Zhou
- Department of Neurology, Tongji Hospital, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China; Hubei Key Laboratory of Neural Injury and Functional Reconstruction, Huazhong University of Science and Technology, Wuhan 430030, China; Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Michael Heming
- Department of Neurology with Institute of Translational Neurology, University Hospital Münster, Münster, Germany
| | - Lu-Lu Xu
- Department of Neurology, Tongji Hospital, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China; Hubei Key Laboratory of Neural Injury and Functional Reconstruction, Huazhong University of Science and Technology, Wuhan 430030, China; Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Yu-Xin Liu
- Department of Neurology, Tongji Hospital, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China; Hubei Key Laboratory of Neural Injury and Functional Reconstruction, Huazhong University of Science and Technology, Wuhan 430030, China; Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Xiao-Wei Pang
- Department of Neurology, Tongji Hospital, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China; Hubei Key Laboratory of Neural Injury and Functional Reconstruction, Huazhong University of Science and Technology, Wuhan 430030, China; Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Yun-Hui Chu
- Department of Neurology, Tongji Hospital, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China; Hubei Key Laboratory of Neural Injury and Functional Reconstruction, Huazhong University of Science and Technology, Wuhan 430030, China; Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Song-Bai Cai
- Nanjing IASO Biotherapeutics Ltd., Nanjing, China
| | - Huan Ye
- Nanjing IASO Biotherapeutics Ltd., Nanjing, China
| | - Ke Shang
- Department of Neurology, Tongji Hospital, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China; Hubei Key Laboratory of Neural Injury and Functional Reconstruction, Huazhong University of Science and Technology, Wuhan 430030, China; Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Jun Xiao
- Department of Neurology, Tongji Hospital, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China; Hubei Key Laboratory of Neural Injury and Functional Reconstruction, Huazhong University of Science and Technology, Wuhan 430030, China; Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Gerd Meyer Zu Hörste
- Department of Neurology with Institute of Translational Neurology, University Hospital Münster, Münster, Germany.
| | - Wei Wang
- Department of Neurology, Tongji Hospital, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China; Hubei Key Laboratory of Neural Injury and Functional Reconstruction, Huazhong University of Science and Technology, Wuhan 430030, China; Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
| | - Chuan Qin
- Department of Neurology, Tongji Hospital, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China; Hubei Key Laboratory of Neural Injury and Functional Reconstruction, Huazhong University of Science and Technology, Wuhan 430030, China; Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
| | - Dai-Shi Tian
- Department of Neurology, Tongji Hospital, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China; Hubei Key Laboratory of Neural Injury and Functional Reconstruction, Huazhong University of Science and Technology, Wuhan 430030, China; Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
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22
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Moiseev I, Bondarenko S, Vlasova Y, Morozova E, Smirnova A, Epifanovskaya O, Zhogolev D, Chernishova D, Meliboev A, Khudayberdiev J, Mazing A, Lapin S, Kholopova I, Botina A, Baykov V, Popova M, Kosarev O, Kulagin A. Allogeneic hematopoietic cell transplantation with a combination of posttransplantation bendamustine and cyclophosphamide in refractory myeloid neoplasms. Cancer 2025; 131:e35893. [PMID: 40372957 DOI: 10.1002/cncr.35893] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2024] [Revised: 02/20/2025] [Accepted: 03/21/2025] [Indexed: 05/17/2025]
Abstract
BACKGROUND Prognosis after salvage allogeneic hematopoietic cell transplantation (HCT) in refractory myeloid malignant diseases is poor with no standard of care. METHODS A prospective single-arm study was conducted to evaluate if a combination of posttransplantation bendamustine and cyclophosphamide (PTBCy) facilitates augmented graft-vs-leukemia effect in this group of patients. The prospective study (NCT04943757) of HCT from all types of donors enrolled 50 patients with refractory myeloid neoplasms. RESULTS Cumulative incidence of engraftment was 88%; 76% had no measurable residual disease. Immune toxicity in the form of cytokine release syndrome was observed in 30%. Cumulative incidence of acute graft-vs-host disease (GVHD) Grade 2 through 4 was 20%. Cumulative incidence of moderate and severe chronic GVHD was 34%. Nonrelapse mortality was 20%. Relapse incidence was 62%, but median time to relapse was 245 days. Overall survival was 33% and event-free survival was 22%. In the multivariate analysis of event-free survival alternative donor (hazard ratio, 0.24; 95% CI, 0.11-0.52) and adverse genetic features (hazard ratio, 2.48; 95% CI, 1.26-4.88) were significant. PTBCy regimen was associated with unique immune reconstitution pattern with high levels of CD8+ effector memory T cells, PD-1L-positive monocytes, and granulocytes. CONCLUSIONS PTBCy GVHD prophylaxis is a promising approach for refractory myeloid neoplasms, which delays relapse after HCT and opens the window for posttransplant prophylaxis.
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Affiliation(s)
- Ivan Moiseev
- RM Gorbacheva Research Institute, Pavlov University, Saint Petersburg, Russia
| | - Sergey Bondarenko
- RM Gorbacheva Research Institute, Pavlov University, Saint Petersburg, Russia
| | - Yulia Vlasova
- RM Gorbacheva Research Institute, Pavlov University, Saint Petersburg, Russia
| | - Elena Morozova
- RM Gorbacheva Research Institute, Pavlov University, Saint Petersburg, Russia
| | - Anna Smirnova
- RM Gorbacheva Research Institute, Pavlov University, Saint Petersburg, Russia
| | - Olga Epifanovskaya
- RM Gorbacheva Research Institute, Pavlov University, Saint Petersburg, Russia
| | - Dmitrii Zhogolev
- RM Gorbacheva Research Institute, Pavlov University, Saint Petersburg, Russia
| | - Daria Chernishova
- RM Gorbacheva Research Institute, Pavlov University, Saint Petersburg, Russia
| | - Azamjon Meliboev
- RM Gorbacheva Research Institute, Pavlov University, Saint Petersburg, Russia
| | | | - Alexandra Mazing
- Molecular Medicine Center, Pavlov University, Saint Petersburg, Russia
| | - Sergey Lapin
- Molecular Medicine Center, Pavlov University, Saint Petersburg, Russia
| | - Irina Kholopova
- Molecular Medicine Center, Pavlov University, Saint Petersburg, Russia
| | - Anna Botina
- Faculty of pathology, Pavlov University, Saint Petersburg, Russia
| | - Vadim Baykov
- Faculty of pathology, Pavlov University, Saint Petersburg, Russia
| | - Marina Popova
- RM Gorbacheva Research Institute, Pavlov University, Saint Petersburg, Russia
| | - Oleg Kosarev
- RM Gorbacheva Research Institute, Pavlov University, Saint Petersburg, Russia
- Department of Informatics and Computer Technologies, St. Petersburg Mining University, Saint Petersburg, Russia
| | - Alexander Kulagin
- RM Gorbacheva Research Institute, Pavlov University, Saint Petersburg, Russia
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23
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Song KW, Lim M, Monje M. Complex neural-immune interactions shape glioma immunotherapy. Immunity 2025; 58:1140-1160. [PMID: 40324379 DOI: 10.1016/j.immuni.2025.04.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2025] [Revised: 04/14/2025] [Accepted: 04/15/2025] [Indexed: 05/07/2025]
Abstract
Rich neural-immune interactions in the central nervous system (CNS) shape its function and create a unique immunological microenvironment for immunotherapy in CNS malignancies. Far from the now-debunked concept of CNS "immune privilege," it is now understood that unique immunological niches and constant immune surveillance of the brain contribute in multifaceted ways to brain health and robustly influence immunotherapy approaches for CNS cancers. Challenges include immune-suppressive and neurotoxicity-promoting crosstalk between brain, immune, and tumor cells. Developing effective immunotherapies for cancers of the nervous system will require a deeper understanding of these neural-immune-malignant cell interactions. Here, we review progress and challenges in immunotherapy for gliomas of the brain and spinal cord in light of these unique neural-immune interactions and highlight future work needed to optimize promising immunotherapies for gliomas.
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Affiliation(s)
- Kun-Wei Song
- Department of Neurology and Neurological Sciences, Stanford University, Palo Alto, CA, USA
| | - Michael Lim
- Department of Neurosurgery, Stanford University, Palo Alto, CA, USA
| | - Michelle Monje
- Department of Neurology and Neurological Sciences, Stanford University, Palo Alto, CA, USA; Department of Neurosurgery, Stanford University, Palo Alto, CA, USA; Howard Hughes Medical Institute, Stanford University, Palo Alto, CA, USA.
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24
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Frigault MJ, Yao N, Berger TR, Wehrli M, Gallagher KME, Horick N, Graham CE, Jacobson CA, Chen YB, Leick MB, DeFilipp Z, El-Jawahri AR, Johnson PC, Dolaher M, Katsis K, Kim AI, Crombie J, Merryman RW, Cook D, Trailor M, Cho H, Jeffrey R, Shen R, Filosto S, Nater J, Getz G, Haradhvala NJ, Maus MV. Single-cell dynamics of breakthrough toxicities after anakinra prophylaxis for axicabtagene ciloleucel in lymphoma. Blood Adv 2025; 9:2122-2135. [PMID: 39928957 PMCID: PMC12051123 DOI: 10.1182/bloodadvances.2024015161] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Revised: 01/09/2025] [Accepted: 01/22/2025] [Indexed: 02/12/2025] Open
Abstract
ABSTRACT Chimeric antigen receptor (CAR) T-cell (CAR-T) therapy is limited by cytokine release syndrome (CRS) and neurotoxicity (NT). We sought to use once-daily prophylactic anakinra, an interleukin-1 (IL-1) receptor antagonist, to prevent CRS/NT that would require hospitalization (grade ≥2) in patients receiving axicabtagene ciloleucel for large-cell lymphoma, with the goal of facilitating outpatient therapy and management. Our study, in line with others, demonstrates that once-daily prophylactic anakinra is insufficient to prevent the development of toxicities that would require hospitalization in most patients. As part of the initial study design, we prospectively incorporated single-cell RNA sequencing to gain insight into the molecular immune signaling associated with breakthrough CRS and NT despite anakinra prophylaxis. In patients who developed breakthrough CRS or NT, we found that interferon gamma (IFN-γ) pathways and ligand-receptor activities were significantly enriched, as were cytokine levels of IFN-γ and CXCL10 in CD14+ monocytes. This correlated with increased IFN-γ and other cytokines in the peripheral blood. In infused CAR-T products, IL-4 and IL-10 anti-inflammatory pathways were negatively associated with grade ≥2 toxicities, regardless of anakinra treatment. These data identify IFN-γ as a potential key mechanism in CAR-T-associated toxicities, which is not inhibited by anakinra but may be otherwise targetable. This trial was registered at www.ClinicalTrials.gov as #NCT04150913.
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Affiliation(s)
- Matthew J. Frigault
- Cellular Immunotherapy Program, Department of Medicine, Massachusetts General Hospital Cancer Center, Boston, MA
- Cancer Program, The Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA
- Harvard Medical School, Boston, MA
| | - Ning Yao
- Harvard Medical School, Boston, MA
| | - Trisha R. Berger
- Cellular Immunotherapy Program, Department of Medicine, Massachusetts General Hospital Cancer Center, Boston, MA
| | - Marc Wehrli
- Cellular Immunotherapy Program, Department of Medicine, Massachusetts General Hospital Cancer Center, Boston, MA
- Cancer Program, The Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA
| | - Kathleen M. E. Gallagher
- Cellular Immunotherapy Program, Department of Medicine, Massachusetts General Hospital Cancer Center, Boston, MA
- Cancer Program, The Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA
| | - Nora Horick
- Cellular Immunotherapy Program, Department of Medicine, Massachusetts General Hospital Cancer Center, Boston, MA
- Cancer Program, The Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA
| | - Charlotte E. Graham
- Cellular Immunotherapy Program, Department of Medicine, Massachusetts General Hospital Cancer Center, Boston, MA
- Cancer Program, The Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA
| | - Caron A. Jacobson
- Cancer Program, The Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA
- Harvard Medical School, Boston, MA
- Dana-Farber Cancer Institute, Department of Hematology/Oncology, Boston, MA
| | - Yi-Bin Chen
- Cellular Immunotherapy Program, Department of Medicine, Massachusetts General Hospital Cancer Center, Boston, MA
- Cancer Program, The Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA
- Harvard Medical School, Boston, MA
| | - Mark B. Leick
- Cellular Immunotherapy Program, Department of Medicine, Massachusetts General Hospital Cancer Center, Boston, MA
- Cancer Program, The Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA
- Harvard Medical School, Boston, MA
| | - Zachariah DeFilipp
- Cellular Immunotherapy Program, Department of Medicine, Massachusetts General Hospital Cancer Center, Boston, MA
- Cancer Program, The Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA
- Harvard Medical School, Boston, MA
| | - Areej R. El-Jawahri
- Cellular Immunotherapy Program, Department of Medicine, Massachusetts General Hospital Cancer Center, Boston, MA
- Cancer Program, The Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA
- Harvard Medical School, Boston, MA
| | - P. Connor Johnson
- Cellular Immunotherapy Program, Department of Medicine, Massachusetts General Hospital Cancer Center, Boston, MA
- Cancer Program, The Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA
- Harvard Medical School, Boston, MA
| | - Maria Dolaher
- Cellular Immunotherapy Program, Department of Medicine, Massachusetts General Hospital Cancer Center, Boston, MA
| | - Katelin Katsis
- Cellular Immunotherapy Program, Department of Medicine, Massachusetts General Hospital Cancer Center, Boston, MA
| | - Austin I. Kim
- Harvard Medical School, Boston, MA
- Dana-Farber Cancer Institute, Department of Hematology/Oncology, Boston, MA
| | - Jennifer Crombie
- Harvard Medical School, Boston, MA
- Dana-Farber Cancer Institute, Department of Hematology/Oncology, Boston, MA
| | - Reid W. Merryman
- Harvard Medical School, Boston, MA
- Dana-Farber Cancer Institute, Department of Hematology/Oncology, Boston, MA
| | - Daniella Cook
- Cellular Immunotherapy Program, Department of Medicine, Massachusetts General Hospital Cancer Center, Boston, MA
| | - Michael Trailor
- Cellular Immunotherapy Program, Department of Medicine, Massachusetts General Hospital Cancer Center, Boston, MA
| | - Hana Cho
- Cellular Immunotherapy Program, Department of Medicine, Massachusetts General Hospital Cancer Center, Boston, MA
| | - Richard Jeffrey
- Cellular Immunotherapy Program, Department of Medicine, Massachusetts General Hospital Cancer Center, Boston, MA
| | - Rhine Shen
- Kite, a Gilead Company, Santa Monica, CA
| | | | | | - Gad Getz
- Cancer Program, The Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA
- Harvard Medical School, Boston, MA
| | | | - Marcela V. Maus
- Cellular Immunotherapy Program, Department of Medicine, Massachusetts General Hospital Cancer Center, Boston, MA
- Cancer Program, The Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA
- Harvard Medical School, Boston, MA
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25
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Freund BE, Feyissa AM, Betiku OE, Shar A, Drees C, Sherman W, Qin H, Britton JW, Barrios MS, Quinones-Hinojosa A, Tatum WO. Acute Symptomatic Seizures During CAR T-Cell Therapy for Hematologic Malignancies: Tri-Site Mayo Clinic Experience. Neurology 2025; 104:e213535. [PMID: 40215424 DOI: 10.1212/wnl.0000000000213535] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2024] [Accepted: 02/20/2025] [Indexed: 04/18/2025] Open
Abstract
BACKGROUND AND OBJECTIVES Chimeric antigen receptor T-cell (CAR T-cell) therapy is associated with neurotoxicity, which may include acute symptomatic seizures (ASySs). Specific risk factors and short-term and long-term outcomes of ASyS associated with CAR T-cell therapy have not been well investigated. METHODS This retrospective cohort study evaluated incidence and risk factors for ASyS during CAR T-cell therapy. We included patients treated at Mayo Clinic in Minnesota, Florida, and Arizona who underwent CAR T-cell therapy for hematologic malignancies from October 2019 to November 2023. Pretreatment demographics, clinical information, type of CAR T-cell therapy, neuroimaging, laboratories during treatment, and clinical features during admission were analyzed. Data on treatment and prevalence of seizures, EEG, and survival at the last follow-up were assessed. T-tests and nonparametric testing were performed on categorical and continuous data, respectively. Multivariable analysis was also performed. RESULTS We included 180 patients (mean age 62.3 years, 57.2% women) with 8 (4.4%) developing ASyS at a mean of 8.0 ± 5.3 days after therapy. Earlier onset of cytotoxic release syndrome (odds ratio [OR] 1.81, 95% CI 0.62-2.99, p = 0.007), higher grade immune effector cell-associated neurotoxicity syndrome (ICANS) (OR -1.43, 95% CI -1.86 to -1.00, p < 0.001), focal neurologic deficits (OR 7.15, 95% CI 1.60-32.14, p = 0.007), and cefepime (OR 0.58, 95% CI 0.51-0.65, p = 0.022) exposure were significantly associated with a higher risk of ASyS. A multivariable model accounting for age and sex fit best using the lowest minimum immune effector cell encephalopathy score and highest ICANS grade (R2 = 0.555, χ2 = 28.507, p < 0.001). ASyS was associated with death at the last follow-up (OR 0.48, 95% CI 0.41-0.56, p = 0.007), although short-term outcomes were not affected by ASyS. Nonprotocolized antiseizure medication (ASM) prophylaxis did not affect ASyS incidence. DISCUSSION This study suggests a low risk of ASyS because of CAR T-cell therapy, with certain risk factors that may be predictive of ASyS and lack of a definitive and direct association of ASyS with outcomes. The current approach to ASM prophylaxis should be reconsidered when ICANS is encountered. This study is limited by its retrospective nature and the use of ASM prophylaxis in all patients with ICANS, which requires further study to assess its necessity.
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Affiliation(s)
- Brin E Freund
- Department of Neurology, Mayo Clinic, Jacksonville, FL
| | | | | | - Andy Shar
- Virginia Commonwealth University, Richmond
| | | | - Wendy Sherman
- Department of Neurology, Mayo Clinic, Jacksonville, FL
| | - Hong Qin
- Department of Hematology and Oncology, Mayo Clinic, Jacksonville, FL
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26
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Andersen L, Quinn RJ, Difilippo H, Garfall AL, Porter DL, Meghani SH, Deng J. Long-Term Quality of Life, Cognitive Function, and Symptom Burden Among Chimeric Antigen Receptor T-Cell Recipients and Associated Cytokine Release Syndrome and Neurotoxicity. JCO Oncol Pract 2025:OP2400823. [PMID: 40359451 DOI: 10.1200/op-24-00823] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2024] [Revised: 02/22/2025] [Accepted: 04/08/2025] [Indexed: 05/15/2025] Open
Abstract
PURPOSE Immediate side effects after chimeric antigen receptor (CAR) T-cell therapy are well documented and include cytokine release syndrome (CRS) and immune effector-cell-associated neurotoxicity (ICANS). However, long-term patient-reported outcomes are understudied. Using a social determinants of health (SDoH) framework, we described the long-term health-related quality of life (HRQoL), cognitive function, and symptom burden of patients in sustained remission after CAR T-cell therapy and examined the relationship between acute CRS and ICANS and long-term cognitive function and symptom burden. METHODS This cross-sectional study included adults in remission after CAR T-cell therapy for multiple myeloma or B-cell lymphoma who were within 1-5 years post-treatment. We used bivariate analyses to measure associations between clinical and SDoH variables and long-term outcomes and linear regression to examine the relationship between ICANS and CRS toxicity and longer-term outcomes. RESULTS Participants (n = 58) were a median of 67 years of age (22-88), 72% had lymphoma, 28% had multiple myeloma, and they were a median of 2 years (1-4.7) post-CAR T-cell infusion. Most of the participants reported good HRQoL. Over one third of participants reported mild-to-moderate impairment in physical function, social roles and activities, or pain domains. Higher income and employment were significantly associated with better physical HRQoL (P < .05). Participants reported low symptom burden, with fatigue most commonly reported. Neither CRS nor ICANS toxicity predicted long-term cognitive function or symptom burden. CONCLUSION Patients in long-term remission after CAR T-cell therapy have good HRQoL and cognitive function with minimal symptom burden. Importantly, there was no relationship between CRS and ICANS and long-term symptom burden or cognitive function. Results support the long-term clinical benefit of CAR T-cell therapy.
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Affiliation(s)
- Lucy Andersen
- Biobehavioral Health Sciences, School of Nursing, University of Pennsylvania, Philadelphia, PA
- Johnson and Johnson Innovative Medicine, Raritan, NJ
| | - Ryan J Quinn
- Biobehavioral Health Sciences, School of Nursing, University of Pennsylvania, Philadelphia, PA
| | - Heather Difilippo
- Cell Therapy and Transplant Program, Abramson Cancer Center and Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Alfred L Garfall
- Cell Therapy and Transplant Program, Abramson Cancer Center and Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
- Division of Hematology and Oncology, Department of Medicine, University of Pennsylvania, Philadelphia, PA
| | - David L Porter
- Cell Therapy and Transplant Program, Abramson Cancer Center and Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
- Division of Hematology and Oncology, Department of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Salimah H Meghani
- Biobehavioral Health Sciences, School of Nursing, University of Pennsylvania, Philadelphia, PA
| | - Jie Deng
- Biobehavioral Health Sciences, School of Nursing, University of Pennsylvania, Philadelphia, PA
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27
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Wang Y, Chang C, Wang Z, Zhao J, Wang J. Efficacy and safety of blinatumomab in Chinese patients with relapsed/refractory B-cell acute lymphoblastic leukemia: a single-center retrospective study. Front Oncol 2025; 15:1587185. [PMID: 40421088 PMCID: PMC12104222 DOI: 10.3389/fonc.2025.1587185] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2025] [Accepted: 04/22/2025] [Indexed: 05/28/2025] Open
Abstract
Background Blinatumomab is a bispecific T-cell engager approved for the treatment of relapse/refractory B-cell acute lymphoblastic leukemia (R/R B-ALL). Most studies evaluating blinatumomab were conducted in Caucasian populations, with limited data available in Chinese patients. This retrospective study aims to evaluate the efficacy and safety of blinatumomab in Chinese patients with R/R B-ALL. Methods A total of 19 patients (10 males, 9 females) with a median age of 49 years (range: 9-66) who received blinatumomab treatment at the Aerospace Center Hospital between November 2021 and November 2024 were included. Rates of complete remission (CR) and minimal residual disease (MRD) response, 1-year overall survival (OS) and relapse-free survival (RFS), and adverse events were analyzed. Results The median number of blinatumomab cycles administered was 1 (range: 1-6). Twelve (80.0%, 95% confidence interval [CI]: 51.9-95.7) of the 15 patients with overt marrow disease achieved CR, with 8 achieving MRD negativity. Four patients with < 5% blast but positive MRD all sustained CR and achieved MRD negativity. The overall MRD response rate was 63.2% (12/19, 95%CI: 38.4-83.7). The 1-year overall survival (OS) and relapse-free survival (RFS) rates were 64.2% ± 12.1% and 73.3% ± 11.4%, respectively. MRD responders had significantly better OS compared to MRD non-responders (log-rank test, P = 0.023). Of the 16 patients with CR, 62.5% proceeded to allogeneic hematopoietic stem cell transplantation (allo-HSCT). The most frequent adverse event was cytokine release syndrome, which occurred in 11 patients (10 with grade 1-2 and 1 with grade 3 severity). Conclusion Blinatumomab is both effective and well-tolerated in Chinese patients with R/R B-ALL, achieving high rates of CR and MRD negativity and facilitating more patients' eligibility for allo-HSCT.
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Affiliation(s)
| | | | | | | | - Jingbo Wang
- Department of Hematology, Aerospace Center Hospital,
Beijing, China
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28
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Iida S, Sunami K, Ito S, Yuda J, Fujikawa E, Takamoto M, Aida K, Yamazaki H, Takahashi M, Ishida T. Phase 1 study of talquetamab, a humanized GPRC5D x CD3 bispecific antibody, in Japanese patients with relapsed/refractory MM. Int J Hematol 2025:10.1007/s12185-025-03991-5. [PMID: 40343678 DOI: 10.1007/s12185-025-03991-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2024] [Revised: 04/10/2025] [Accepted: 04/10/2025] [Indexed: 05/11/2025]
Abstract
The bispecific antibody talquetamab demonstrated substantial responses in heavily pretreated relapsed or refractory multiple myeloma (RRMM) in the global phase 1/2 MonumenTAL-1 study. This study, evaluated the safety and efficacy of talquetamab in Japanese patients with RRMM pretreated with a proteasome inhibitor, immunomodulatory drug, and anti-CD38 monoclonal antibody. The primary endpoints were frequency and type of treatment-emergent adverse events (TEAEs) and serious AEs including dose-limiting toxicity (DLT). The secondary endpoints were overall response (ORR; partial response or better), duration of, and time to response. At data cutoff, 15 patients had received subcutaneous talquetamab at three doses (Cohort 1: 135 µg/kg weekly [QW, n = 4]; Cohort 2: 400 µg/kg [QW, n = 5]; Cohort 3: 800 µg/kg [Q2W, n = 6]). No DLTs, deaths, or AE-related dose reductions/treatment discontinuation were observed. Common TEAEs were neutropenia (60.0%), lymphopenia (53.3%), and CRS (46.7%). TEAEs of clinical interest (all Grade ≤ 2) were dysgeusia, skin toxicity, nail disorder, and dry mouth. With an overall median follow-up of 9.0 months, the ORR was 60.0% (95% confidence interval 32.3%, 83.7%). Talquetamab showed substantial responses in Japanese patients with RRMM, consistent with the global MonumenTAL-1 study, supporting its potential as a new standard of care for Japanese RRMM patients.
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Affiliation(s)
- Shinsuke Iida
- Department of Hematology and Oncology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Kazutaka Sunami
- Department of Hematology, NHO Okayama Medical Center, Okayama, Japan
| | - Shigeki Ito
- Hematology and Oncology, Department of Internal Medicine, Iwate Medical University School of Medicine, Yahaba-Cho, Japan
| | - Junichiro Yuda
- Department of Hematology, National Cancer Center Hospital East, Kashiwa, Japan
| | | | | | | | | | | | - Tadao Ishida
- Department of Hematology, Japanese Red Cross Medical Center, Tokyo, Japan
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29
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Pasvolsky O, Dima D, Feng L, Dong W, Richards T, Davis JA, Afrough A, Vazquez-Martinez M, Sannareddy A, Goel U, Banerjee R, Khouri J, Cervoni F, Gaballa MR, Lieberman-Cribbin A, Rana MS, Julian K, Ferreri CJ, Shune L, DeJarnette S, Bhurtel E, Susanibar Adaniya S, Portuguese A, Hosoya H, Mikkilineni L, Kaur G, Rossi A, Herr MM, Schrum D, Lin C, Raza S, Lin Y, Midha S, Omar N, Atarsh S, McGuirk J, Sborov D, Voorhees P, Anwer F, Alsina M, Freeman C, Garfall AL, Razzo BM, Sidana S, Cowan AJ, Anderson LD, Hansen DK, Richard S, Patel KK, Lee HC, Grajales-Cruz A. Outcomes of elderly patients with relapsed refractory multiple myeloma (RRMM) treated with teclistamab: a multicenter study from the U.S. Multiple Myeloma Immunotherapy Consortium. Blood Cancer J 2025; 15:92. [PMID: 40346049 PMCID: PMC12064690 DOI: 10.1038/s41408-025-01297-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2024] [Revised: 04/23/2025] [Accepted: 04/28/2025] [Indexed: 05/11/2025] Open
Abstract
Teclistamab, a BCMA-directed bispecific antibody, received regulatory approval for relapsed/refractory multiple myeloma (RRMM) based on the MajesTEC-1 study. Despite the fact that myeloma is primarily a cancer of elderly adults, only 15% of MajesTEC-1 participants (n = 24) were ≥75 years old. In this multicenter retrospective study, we report real-world outcomes of a large cohort of older RRMM patients treated with teclistamab. Of 385 analyzed patients, 83 (22%) were in the older group (age ≥75) and 302 (78%) in the younger group (age <75). Compared to the younger group, the older group had less adverse baseline disease characteristics, including a lower incidence of high-risk cytogenetics (44.6% vs. 57.9%, p = 0.03) and extramedullary disease (22% vs. 40%, p = 0.02). There were no significant differences in rates of any-grade CRS (52% vs. 59%, p = 0.27), any-grade ICANS (19% vs. 13%, p = 0.12), and overall response rate (62% vs. 53%, p = 0.17) between the older and younger groups. In multivariable analysis, age was not significantly associated with survival outcomes. Our findings suggest that teclistamab is safe and efficacious in well-selected patients ≥75 years old, and advanced age alone should not preclude teclistamab administration.
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Affiliation(s)
| | - Danai Dima
- Fred Hutchinson Cancer Center, Seattle, WA, USA
- Cleveland Clinic Lerner College of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH, USA
| | - Lei Feng
- MD Anderson Cancer Center, Houston, TX, USA
| | - Wenli Dong
- MD Anderson Cancer Center, Houston, TX, USA
| | | | - James A Davis
- Medical University of South Carolina, Charleston, SC, USA
| | - Aimaz Afrough
- Myeloma, Waldenstrom's, and Amyloidosis Program, Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX, USA
| | | | - Aishwarya Sannareddy
- Myeloma, Waldenstrom's, and Amyloidosis Program, Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX, USA
| | - Utkarsh Goel
- Cleveland Clinic Lerner College of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH, USA
| | | | - Jack Khouri
- Cleveland Clinic Lerner College of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH, USA
| | | | | | | | | | - Kelley Julian
- Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA
| | - Christopher J Ferreri
- Atrium Health Levine Cancer Institute, Wake Forest University School of Medicine, Charlotte, NC, USA
| | - Leyla Shune
- University of Kansas Medical Center, Kansas City, KS, USA
| | | | | | - Sandra Susanibar Adaniya
- Abramson Cancer Center and Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | | | | | | | - Gurbakhash Kaur
- Myeloma, Waldenstrom's, and Amyloidosis Program, Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX, USA
| | | | - Megan M Herr
- Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | | | - Chenyu Lin
- Duke University Cancer Institute, Durham, NC, USA
| | - Shahzad Raza
- Cleveland Clinic Lerner College of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH, USA
| | - Yi Lin
- Division of Hematology, Mayo Clinic, Rochester, MN, USA
| | | | - Nadeem Omar
- Dana-Farber Cancer Institute, Boston, MA, USA
| | - Shebli Atarsh
- Atrium Health Levine Cancer Institute, Wake Forest University School of Medicine, Charlotte, NC, USA
| | - Joseph McGuirk
- University of Kansas Medical Center, Kansas City, KS, USA
| | - Douglas Sborov
- Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA
| | - Peter Voorhees
- Atrium Health Levine Cancer Institute, Wake Forest University School of Medicine, Charlotte, NC, USA
| | - Faiz Anwer
- Cleveland Clinic Lerner College of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH, USA
| | | | | | - Alfred L Garfall
- Abramson Cancer Center and Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Beatrice M Razzo
- Abramson Cancer Center and Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | | | | | - Larry D Anderson
- Myeloma, Waldenstrom's, and Amyloidosis Program, Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX, USA
| | | | | | | | - Hans C Lee
- MD Anderson Cancer Center, Houston, TX, USA.
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30
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Liu JH, Liu KY, Zhao X, Zhou X, Jiang Y. Cardiovascular toxicities associated with chimeric antigen receptor T-cell therapy. Front Pharmacol 2025; 16:1578157. [PMID: 40406483 PMCID: PMC12094984 DOI: 10.3389/fphar.2025.1578157] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2025] [Accepted: 04/08/2025] [Indexed: 05/26/2025] Open
Abstract
Chimeric antigen receptor (CAR) T-cell therapy has emerged as a groundbreaking immunotherapeutic approach, particularly for oncohematological patients who are refractory to conventional treatments. As clinical trials expand the applications of CAR T-cell therapy beyond hematologic malignancies, a critical understanding of its associated toxicities, particularly cardiovascular complications, becomes imperative. This review synthesizes current literature on the interplay between cytokine release syndrome (CRS) and cardiotoxicity related to CAR T-cell therapy, emphasizing the potential severity of these adverse events. While significant progress has been made in managing CRS, the cardiac manifestations-ranging from mild events to life-threatening complications-remain underreported in pivotal studies. We explore the incidence and nature of cardiotoxicity in real-world and clinical trial settings, identify risk factors contributing to cardiovascular events, and propose guidelines for pre-therapy evaluations, post-infusion monitoring, and management strategies. By highlighting the urgent need for heightened awareness and proactive care, this review aims to enhance patient safety and optimize outcomes in the evolving landscape of CAR T-cell therapy.
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Affiliation(s)
- Jia-Hui Liu
- Cancer Center, The First Hospital of Jilin University, Changchun, China
- Cancer Research Institute of Jilin University, The First Hospital of Jilin University, Changchun, China
- International Center of Future Science, Jilin University, Changchun, China
| | - Kun-Yao Liu
- Cancer Research Institute of Jilin University, The First Hospital of Jilin University, Changchun, China
| | - Xiang Zhao
- Cancer Research Institute of Jilin University, The First Hospital of Jilin University, Changchun, China
| | - Xin Zhou
- Cancer Center, The First Hospital of Jilin University, Changchun, China
- Cancer Research Institute of Jilin University, The First Hospital of Jilin University, Changchun, China
- International Center of Future Science, Jilin University, Changchun, China
| | - Yichuan Jiang
- Department of Pharmacy, China-Japan Union Hospital of Jilin University, Changchun, China
- Department of Clinical Pharmacy, The First Hospital of Jilin University, Changchun, China
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31
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Svoboda J, Landsburg DJ, Gerson J, Nasta SD, Barta SK, Chong EA, Cook M, Frey NV, Shea J, Cervini A, Marshall A, Four M, Davis MM, Jadlowsky JK, Chew A, Pequignot E, Gonzalez V, Noll JH, Paruzzo L, Rojas-Levine J, Plesa G, Scholler J, Siegel DL, Levine BL, Porter DL, Ghassemi S, Ruella M, Rech A, Leskowitz RM, Fraietta JA, Hwang WT, Hexner E, Schuster SJ, June CH. Enhanced CAR T-Cell Therapy for Lymphoma after Previous Failure. N Engl J Med 2025; 392:1824-1835. [PMID: 40334157 DOI: 10.1056/nejmoa2408771] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/09/2025]
Abstract
BACKGROUND Chimeric antigen receptor (CAR) T cells targeting CD19 have transformed the treatment of B-cell cancers, but many patients do not have long-term remission. We designed an anti-CD19 enhanced (armored) CAR T-cell product (huCART19-IL18) that secretes interleukin-18 to enhance antitumor activity. METHODS In this study, we assessed the safety, feasibility, and preliminary efficacy of huCART19-IL18 in patients with relapsed or refractory lymphoma after previous anti-CD19 CAR T-cell therapy. Using a 3-day manufacturing process, we administered huCART19-IL18-positive cells in doses ranging from 3×106 to 3×108. RESULTS A total of 21 patients received huCART19-IL18. Cytokine release syndrome occurred in 62% of the patients (47% with grade 1 or 2), and immune effector-cell-associated neurotoxicity syndrome occurred in 14% (all grade 1 or 2). No unexpected adverse events were observed. Robust CAR T-cell expansion was detected across all dose levels. At 3 months after infusion, a complete or partial response was seen in 81% of the patients (90% confidence interval [CI], 62 to 93) and a complete response in 52% (90% CI, 33 to 71). With a median follow-up of 17.5 months (range, 3 to 34), the median duration of response was 9.6 months (90% CI, 5.5 to not reached). CONCLUSIONS In this small study, huCART19-IL18 had a safety profile consistent with other CAR T-cell treatments and showed promising efficacy at low cell doses in patients with lymphoma after the failure of previous anti-CD19 CAR T-cell therapy. (ClinicalTrials.gov number, NCT04684563.).
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Affiliation(s)
- Jakub Svoboda
- Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia
| | - Daniel J Landsburg
- Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia
| | - James Gerson
- University of Vermont Medical Center, Burlington
| | - Sunita D Nasta
- Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia
| | - Stefan K Barta
- Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia
| | - Elise A Chong
- Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia
| | - Michael Cook
- Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia
| | - Noelle V Frey
- Cell Therapy and Transplant Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia
| | - Joanne Shea
- Cell Therapy and Transplant Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia
| | - Amanda Cervini
- Cell Therapy and Transplant Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia
| | - Amy Marshall
- Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia
| | - Megan Four
- Cell Therapy and Transplant Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia
| | - Megan M Davis
- Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia
| | - Julie K Jadlowsky
- Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia
| | - Anne Chew
- Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia
| | - Edward Pequignot
- Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia
| | - Vanessa Gonzalez
- Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia
| | - Julia Han Noll
- Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia
| | - Luca Paruzzo
- Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia
- Cell Therapy and Transplant Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia
| | - Juliana Rojas-Levine
- Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia
| | - Gabriela Plesa
- Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia
| | - John Scholler
- Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia
| | - Donald L Siegel
- Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia
| | - Bruce L Levine
- Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia
| | - David L Porter
- Cell Therapy and Transplant Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia
| | - Saba Ghassemi
- Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia
| | - Marco Ruella
- Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia
- Cell Therapy and Transplant Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia
| | - Andrew Rech
- Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia
| | - Rachel M Leskowitz
- Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia
| | - Joseph A Fraietta
- Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia
- Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia
- Parker Institute for Cancer Immunotherapy, University of Pennsylvania, Philadelphia
| | - Wei-Ting Hwang
- Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania, Philadelphia
| | - Elizabeth Hexner
- Cell Therapy and Transplant Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia
| | - Stephen J Schuster
- Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia
| | - Carl H June
- Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia
- Parker Institute for Cancer Immunotherapy, University of Pennsylvania, Philadelphia
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Geraghty AC, Acosta-Alvarez L, Rotiroti MC, Dutton S, O'Dea MR, Kim W, Trivedi V, Mancusi R, Shamardani K, Malacon K, Woo PJ, Martinez-Velez N, Pham T, Reche-Ley NN, Otubu G, Castenada EH, Nwangwu K, Xu H, Mulinyawe SB, Zamler DB, Ni L, Cross K, Rustenhoven J, Kipnis J, Liddelow SA, Mackall CL, Majzner RG, Monje M. Immunotherapy-related cognitive impairment after CAR T cell therapy in mice. Cell 2025:S0092-8674(25)00391-5. [PMID: 40359942 DOI: 10.1016/j.cell.2025.03.041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2023] [Revised: 01/06/2025] [Accepted: 03/25/2025] [Indexed: 05/15/2025]
Abstract
Immunotherapies have revolutionized cancer care for many tumor types, but their potential long-term cognitive impacts are incompletely understood. Here, we demonstrated in mouse models that chimeric antigen receptor (CAR) T cell therapy for both central nervous system (CNS) and non-CNS cancers impaired cognitive function and induced a persistent CNS immune response characterized by white matter microglial reactivity, microglial chemokine expression, and elevated cerebrospinal fluid (CSF) cytokines and chemokines. Consequently, oligodendroglial homeostasis and hippocampal neurogenesis were disrupted. Single-nucleus sequencing studies of human frontal lobe from patients with or without previous CAR T cell therapy for brainstem tumors confirmed reactive states of microglia and oligodendrocytes following treatment. In mice, transient microglial depletion or CCR3 chemokine receptor blockade rescued oligodendroglial deficits and cognitive performance in a behavioral test of attention and short-term memory function following CAR T cell therapy. Taken together, these findings illustrate targetable neural-immune mechanisms underlying immunotherapy-related cognitive impairment.
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Affiliation(s)
- Anna C Geraghty
- Department of Neurology and Neurosciences, Stanford School of Medicine, Stanford, CA 94305, USA; Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305, USA
| | - Lehi Acosta-Alvarez
- Department of Neurology and Neurosciences, Stanford School of Medicine, Stanford, CA 94305, USA
| | - Maria C Rotiroti
- Department of Pediatrics, Stanford School of Medicine, Stanford, CA 94305, USA
| | - Selena Dutton
- Department of Neurology and Neurosciences, Stanford School of Medicine, Stanford, CA 94305, USA
| | - Michael R O'Dea
- Neuroscience Institute, NYU Grossman School of Medicine, New York, NY 10016, USA
| | - Wonju Kim
- Department of Pediatrics, Stanford School of Medicine, Stanford, CA 94305, USA
| | - Vrunda Trivedi
- Department of Neurology and Neurosciences, Stanford School of Medicine, Stanford, CA 94305, USA
| | - Rebecca Mancusi
- Department of Neurology and Neurosciences, Stanford School of Medicine, Stanford, CA 94305, USA
| | - Kiarash Shamardani
- Department of Neurology and Neurosciences, Stanford School of Medicine, Stanford, CA 94305, USA
| | - Karen Malacon
- Department of Neurology and Neurosciences, Stanford School of Medicine, Stanford, CA 94305, USA
| | - Pamelyn J Woo
- Department of Neurology and Neurosciences, Stanford School of Medicine, Stanford, CA 94305, USA
| | | | - Theresa Pham
- Department of Neurology and Neurosciences, Stanford School of Medicine, Stanford, CA 94305, USA
| | - Noemi N Reche-Ley
- Department of Neurology and Neurosciences, Stanford School of Medicine, Stanford, CA 94305, USA
| | - Gabriel Otubu
- Department of Neurology and Neurosciences, Stanford School of Medicine, Stanford, CA 94305, USA
| | - Enrique H Castenada
- Department of Neurology and Neurosciences, Stanford School of Medicine, Stanford, CA 94305, USA
| | - Kamsi Nwangwu
- Department of Neurology and Neurosciences, Stanford School of Medicine, Stanford, CA 94305, USA
| | - Haojun Xu
- Department of Neurology and Neurosciences, Stanford School of Medicine, Stanford, CA 94305, USA
| | - Sara B Mulinyawe
- Department of Neurology and Neurosciences, Stanford School of Medicine, Stanford, CA 94305, USA
| | - Daniel B Zamler
- Department of Neurology and Neurosciences, Stanford School of Medicine, Stanford, CA 94305, USA
| | - Lijun Ni
- Department of Neurology and Neurosciences, Stanford School of Medicine, Stanford, CA 94305, USA
| | - Kevin Cross
- Brain immunology and Glia (BIG) Center and Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63130, USA
| | - Justin Rustenhoven
- Brain immunology and Glia (BIG) Center and Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63130, USA
| | - Jonathan Kipnis
- Brain immunology and Glia (BIG) Center and Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63130, USA
| | - Shane A Liddelow
- Neuroscience Institute, NYU Grossman School of Medicine, New York, NY 10016, USA; Department of Neuroscience and Physiology, NYU Grossman School of Medicine, New York, NY 10016, USA; Department of Ophthalmology, NYU Grossman School of Medicine, New York, NY 10016, USA; Parekh Center for Interdisciplinary Neurology, NYU Grossman School of Medicine, New York, NY 10016, USA
| | - Crystal L Mackall
- Department of Pediatrics, Stanford School of Medicine, Stanford, CA 94305, USA; Center for Cancer Cellular Therapy, Stanford School of Medicine, Stanford, CA 94305, USA; Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Robbie G Majzner
- Department of Pediatrics, Stanford School of Medicine, Stanford, CA 94305, USA; Center for Cancer Cellular Therapy, Stanford School of Medicine, Stanford, CA 94305, USA
| | - Michelle Monje
- Department of Neurology and Neurosciences, Stanford School of Medicine, Stanford, CA 94305, USA; Department of Pediatrics, Stanford School of Medicine, Stanford, CA 94305, USA; Center for Cancer Cellular Therapy, Stanford School of Medicine, Stanford, CA 94305, USA; Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305, USA.
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Yin J, Cui QY, Dai HP, Qu CJ, Li Z, Kang LQ, Cui W, Tian XP, Zhu XM, Yu L, Wu DP, Tang XW. CD19 CAR-T in relapsed t(8;21) AML: a single-center prospective phase II clinical trial. J Hematol Oncol 2025; 18:53. [PMID: 40329358 PMCID: PMC12057151 DOI: 10.1186/s13045-025-01708-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2025] [Accepted: 04/28/2025] [Indexed: 05/08/2025] Open
Abstract
Approximately 78.3% of patients with t(8;21) acute myeloid leukemia (AML) express CD19, making it a potential target for chimeric antigen receptor (CAR)-T cell therapy focused on CD19. This prospective phase II trial (NCT03896854) evaluated the safety and efficacy of CD19 CAR-T cell treatment in 10 relapsed CD19-positive t(8;21) AML patients. This study enrolled eight patients with hematologic and two with molecular relapsed AML. The median bone marrow blast percentage was 12.4% (0.1-50.2%), and the blasts exhibited a median CD19 positivity of 55.7% (22.6-97.1%). Genetic profiling revealed TP53 alterations (n = 1), KIT (n = 3) and FLT3-ITD (n = 1) mutations. After lymphodepletion with fludarabine and cyclophosphamide (FC), 5-20 × 106 cells per kilogram of CAR-T cells were administered. All patients experienced grade 3 or higher hematologic toxicities following tumor-reduction chemotherapy and the FC regimen, which were managed for a median of two weeks after CAR-T treatment. Non-hematological toxicities were mild and reversible. Eight patients presented with mild (grade 1-2) cytokine release syndrome (CRS), and one experienced grade 3 CRS. The immune effector cell-associated neurotoxicity syndrome was not observed. All patients achieved complete remission (CR) after CAR-T, with 60% achieving a molecularly MRD-negative CR. RUNX1::RUNX1T1 fusion transcript levels demonstrated a median 2.5-log reduction (range: 0.7-4.5 log; P = 0.002). At a median follow-up of 64.6 months (range: 11.2-88.8 months), the median overall survival and leukemia-free survival were 11.6 and 3.8 months, respectively. The 12-month cumulative incidence of relapse was 53.3%. These findings indicated that CD19 CAR-T was a safe and effective option for relapsed CD19-positive t(8;21) AML.
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MESH Headings
- Humans
- Leukemia, Myeloid, Acute/therapy
- Leukemia, Myeloid, Acute/genetics
- Leukemia, Myeloid, Acute/immunology
- Male
- Female
- Middle Aged
- Adult
- Antigens, CD19/immunology
- Immunotherapy, Adoptive/methods
- Immunotherapy, Adoptive/adverse effects
- Prospective Studies
- Aged
- Translocation, Genetic
- Receptors, Chimeric Antigen/therapeutic use
- Chromosomes, Human, Pair 8/genetics
- Chromosomes, Human, Pair 21/genetics
- Young Adult
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Affiliation(s)
- Jia Yin
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China
- Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
| | - Qing-Ya Cui
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China
- Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
| | - Hai-Ping Dai
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China
- Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
| | - Chang-Ju Qu
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China
- Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
| | - Zheng Li
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China
- Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
| | - Li-Qing Kang
- Shanghai Unicar-Therapy Bio-Medicine Technology Co., Ltd., Shanghai, 201203, China
| | - Wei Cui
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China
- Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
| | - Xiao-Peng Tian
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China
- Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
| | - Xia-Ming Zhu
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China
- Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
| | - Lei Yu
- Shanghai Unicar-Therapy Bio-Medicine Technology Co., Ltd., Shanghai, 201203, China
| | - De-Pei Wu
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China.
- Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China.
- Department of Hematology, the First Affiliated Hospital of Soochow University, and Jiangsu Institute of Hematology, Suzhou, China.
| | - Xiao-Wen Tang
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China.
- Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China.
- Department of Hematology, the First Affiliated Hospital of Soochow University, and Jiangsu Institute of Hematology, Suzhou, China.
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34
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Joly F, Castel H, Compter A, Nicola C, Duivon M, Lange M. Neuropsychological and central neurologic effects of cancer immunotherapy: the start of a new challenge. J Clin Exp Neuropsychol 2025:1-20. [PMID: 40323211 DOI: 10.1080/13803395.2025.2498713] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2024] [Accepted: 04/22/2025] [Indexed: 05/15/2025]
Abstract
INTRODUCTION Cognitive difficulties are frequently reported after cancer treatments, such as chemotherapy or hormone therapy, and have a negative impact on patients' quality of life. Recently, some studies have shown that new cancer treatments, such as immunotherapy agents, can induce cognitive changes. METHOD This review presents the central neurological immune adverse events of immunotherapy treatments including Immune Checkpoint Inhibitors (ICI) and Chimeric Antigen Receptor (CAR) T-cell therapy. The physiopathological mechanisms and risk factors are developed and clinical studies on immunotherapy agents and cognition (among adult patients, using validated questionnaires and/or cognitive tests), psychological factors and quality of life were presented. RESULTS Neurological toxicities are frequently observed with CAR-T cell therapies at acute stage, such as the immune effector cell-associated neurotoxicity syndrome (ICANS), inducing cognitive disorders such as disorientation and aphasia. However, few studies have accurately assessed the impact of immunotherapy on cognition. The methodology of these studies is heterogeneous and they mainly included nonspecific self-report questionnaires of cognitive complaints. Variable results have been obtained concerning the cognitive impact of ICI and CAR-T cell several months following immunotherapy: overall, while some studies reported cognitive difficulties (mainly processing speed and executive functions), the majority has not. Although anxiety and depression are frequently reported in patients treated with ICI or CAR-T cells, these symptoms tend to decrease after the start of immunotherapy. The current neurobiological investigations are too fragmentary to explain neurological symptoms and potential cognitive alteration, but neuroinflammation, vascular inflammation, brain blood barrier disruption, and immune cell brain infiltration would constitute common mechanisms relayed by CAR-T and to a lesser degree, ICI. CONCLUSIONS Acute neurological toxicities following CAR-T cell therapies are a major issue. Further studies are needed to better assess cognitive difficulties after the initiation of immunotherapy, in particular ICI, to better understand the physiopathology, including imaging studies, and risk factors.
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Affiliation(s)
- Florence Joly
- ANTICIPE U1086 INSERM-UCN, Equipe Labellisée Ligue Contre le Cancer, Centre François Baclesse, Normandie Université UNICAEN, Caen, France
- Services Unit PLATON, Cancer and Cognition Platform, University of Caen Normandy, Caen, France
- Clinical Research Department, Centre François Baclesse, Caen, France
- Medical oncology department, CHU de Caen, Caen, France
| | - Hélène Castel
- Services Unit PLATON, Cancer and Cognition Platform, University of Caen Normandy, Caen, France
- UNIROUEN, INSERM, U1245, Cancer and Brain Genomics, Normandie University, Rouen, France
- Institute for Research and Innovation in Biomedicine (IRIB), Rouen, France
| | - Annette Compter
- Department of Neuro-Oncology, The Netherlands Cancer Institute, Amsterdam, Netherlands
| | - Celeste Nicola
- UNIROUEN, INSERM, U1245, Cancer and Brain Genomics, Normandie University, Rouen, France
- Institute for Research and Innovation in Biomedicine (IRIB), Rouen, France
| | - Mylène Duivon
- ANTICIPE U1086 INSERM-UCN, Equipe Labellisée Ligue Contre le Cancer, Centre François Baclesse, Normandie Université UNICAEN, Caen, France
- Services Unit PLATON, Cancer and Cognition Platform, University of Caen Normandy, Caen, France
| | - Marie Lange
- ANTICIPE U1086 INSERM-UCN, Equipe Labellisée Ligue Contre le Cancer, Centre François Baclesse, Normandie Université UNICAEN, Caen, France
- Services Unit PLATON, Cancer and Cognition Platform, University of Caen Normandy, Caen, France
- Clinical Research Department, Centre François Baclesse, Caen, France
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35
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Yan S, Zhou M, Zhu X, Xiao Y. Neurological complications associated with chimeric antigen receptor T cell therapy. J Cereb Blood Flow Metab 2025:271678X251332492. [PMID: 40314208 PMCID: PMC12048402 DOI: 10.1177/0271678x251332492] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2024] [Revised: 02/20/2025] [Accepted: 03/14/2025] [Indexed: 05/03/2025]
Abstract
Chimeric antigen receptor T (CAR-T) cells have made brilliant achievements in the treatment of many kinds of malignant tumors, and six kinds of CAR-T products have been approved by the Food and Drug Administration (FDA), bringing new hope for the treatment of diseases. However, the complications associated with CAR-T cell therapy should not be ignored. Neurological complications often jeopardize patients' lives, including immune effector cell-associated neurotoxicity syndrome, cerebrovascular accidents, movement and neurocognitive treatment-emergent adverse events. The current knowledge of the mechanism and treatment of these complications is still insufficient, which is a direction that needs to be solved in the future.
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Affiliation(s)
| | | | - Xiaojian Zhu
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yi Xiao
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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36
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Xia J, Sun Q, Zhou D, Li H, Wang Y, Qi Y, Cao J, Yan Z, Li D, Cheng H, Sang W, Zhu F, Sun H, Chen W, Qi K, Yan D, Qiu T, Hu T, Gu W, Qian J, Xia F, Qi N, Jin C, Liu Y, Wang X, Zhang Y, Peng S, Li Z, Chang AH, Xu K. Anti-GPRC5D CAR T-cell therapy as a salvage treatment in patients with progressive multiple myeloma after anti-BCMA CAR T-cell therapy: a single-centre, single-arm, phase 2 trial. Lancet Haematol 2025; 12:e365-e375. [PMID: 40228504 DOI: 10.1016/s2352-3026(25)00048-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2024] [Revised: 02/13/2025] [Accepted: 02/14/2025] [Indexed: 04/16/2025]
Abstract
BACKGROUND For patients with multiple myeloma progression after anti-BCMA chimeric antigen receptor (CAR) T-cell therapy, the optimal salvage treatment strategies remain unclear. GPRC5D-directed CAR T cell might be a potential option. The aim of this trial was to investigate the activity and safety of anti-GPRC5D CAR T cells in patients with progressive multiple myeloma after anti-BCMA CAR T-cell therapy. METHODS In this phase 2, open-label, single-arm, phase 2 trial, at the Affiliated Hospital of Xuzhou Medical University in China, we enrolled patients (aged 18-70 years old) with relapsed or refractory multiple myeloma who had progressed disease after anti-BCMA CAR T-cell therapy and a life expectancy of more than 12 weeks without active infections, serious liver, heart, or other diseases. Patients were assigned to receive a single dose of intravenous anti-GPRC5D CAR T cell at 2 × 106 cells per kg. The primary endpoint was the overall response rate, including stringent complete response, complete response, very good partial response, and partial response, according to the standard International Myeloma Working Group response assessment criteria. Activity and safety analyses were done in the patients who received a dose of anti-GPRC5D CAR T cell as defined in the protocol. This trial is registered with the Chinese Clinical Trial Registration Center, ChiCTR2100048888, and is ongoing. FINDINGS Between Dec 1, 2021, and May 1, 2024, 42 patients were screened, 37 were enrolled and received anti-GPRC5D CAR T-cell therapy. Median age was 59 years (IQR 51-65), 17 (46%) of 37 patients were male and 20 (54%) female. All patients were Asian. At a median follow-up of 12·6 months (IQR 8·2-20·8), the overall response rate was 84% (95% CI 68-94, 31 of 37 patients), including 13 (35%) complete responses or better. The most common grade 3-4 adverse events were haematological toxicities, including leukopenia (34 [92%] of 37 patients), lymphopenia (36 [97%]), neutropenia (29 [78%]), anaemia (23 [62%]), and thrombocytopenia (23 [62%]). 26 (70%) of 37 patients had cytokine release syndrome, which was of grade 3 in two (5%) patients. One case of grade 1 immune effector cell-associated neurotoxicity syndrome was observed. There were no treatment-related deaths in the trial. INTERPRETATION Anti-GPRC5D CAR T-cell salvage therapy induced a high response rate, and could be a potential treatment option in relapsed or refractory multiple myeloma patients who have progressed after anti-BCMA CAR T-cell treatment. Further investigations are warranted to establish the long-term efficacy and safety of this therapeutic approach. FUNDING National Natural Science Foundation of China and the General Project of Jiangsu Commission of Health.
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Affiliation(s)
- Jieyun Xia
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China; Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China; Jiangsu Key Laboratory of Bone Marrow Stem Cells, Xuzhou, China
| | - Qian Sun
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China; Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China; Jiangsu Key Laboratory of Bone Marrow Stem Cells, Xuzhou, China
| | - Dian Zhou
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China; Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China; Jiangsu Key Laboratory of Bone Marrow Stem Cells, Xuzhou, China
| | - Hujun Li
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China; Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China; Jiangsu Key Laboratory of Bone Marrow Stem Cells, Xuzhou, China
| | - Ying Wang
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China; Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China; Jiangsu Key Laboratory of Bone Marrow Stem Cells, Xuzhou, China
| | - Yuekun Qi
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China; Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China; Jiangsu Key Laboratory of Bone Marrow Stem Cells, Xuzhou, China
| | - Jiang Cao
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China; Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China; Jiangsu Key Laboratory of Bone Marrow Stem Cells, Xuzhou, China
| | - Zhiling Yan
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China; Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China; Jiangsu Key Laboratory of Bone Marrow Stem Cells, Xuzhou, China
| | - Depeng Li
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China; Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China; Jiangsu Key Laboratory of Bone Marrow Stem Cells, Xuzhou, China
| | - Hai Cheng
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China; Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China; Jiangsu Key Laboratory of Bone Marrow Stem Cells, Xuzhou, China
| | - Wei Sang
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China; Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China; Jiangsu Key Laboratory of Bone Marrow Stem Cells, Xuzhou, China
| | - Feng Zhu
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China; Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China; Jiangsu Key Laboratory of Bone Marrow Stem Cells, Xuzhou, China
| | - Haiying Sun
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China; Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China; Jiangsu Key Laboratory of Bone Marrow Stem Cells, Xuzhou, China
| | - Wei Chen
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China; Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China; Jiangsu Key Laboratory of Bone Marrow Stem Cells, Xuzhou, China
| | - Kunming Qi
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China; Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China; Jiangsu Key Laboratory of Bone Marrow Stem Cells, Xuzhou, China
| | - Dongmei Yan
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China; Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China; Jiangsu Key Laboratory of Bone Marrow Stem Cells, Xuzhou, China
| | - Tingting Qiu
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China; Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China; Jiangsu Key Laboratory of Bone Marrow Stem Cells, Xuzhou, China
| | - Tingyu Hu
- Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China; Jiangsu Key Laboratory of Bone Marrow Stem Cells, Xuzhou, China
| | - Weiying Gu
- Department of Hematology, The First People's Hospital of Changzhou, Third Affiliated to Suzhou University, Changzhou, China
| | - Jun Qian
- Department of Hematology, The Affiliated People's Hospital of Jiangsu University, Zhenjiang, China
| | - Fan Xia
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China; Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China; Jiangsu Key Laboratory of Bone Marrow Stem Cells, Xuzhou, China
| | - Na Qi
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China; Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China; Jiangsu Key Laboratory of Bone Marrow Stem Cells, Xuzhou, China
| | - Congqian Jin
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China
| | - Yang Liu
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China; Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China; Jiangsu Key Laboratory of Bone Marrow Stem Cells, Xuzhou, China
| | - Xue Wang
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China; Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China; Jiangsu Key Laboratory of Bone Marrow Stem Cells, Xuzhou, China
| | | | | | - Zhenyu Li
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China; Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China; Jiangsu Key Laboratory of Bone Marrow Stem Cells, Xuzhou, China
| | - Alex H Chang
- Shanghai YaKe Biotechnology, Shanghai, China; Engineering Research Center of Gene Technology, Ministry of Education, Institute of Genetics, School of Life Sciences, Fudan University, Shanghai, China
| | - Kailin Xu
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China; Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China; Jiangsu Key Laboratory of Bone Marrow Stem Cells, Xuzhou, China.
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Yoon B, Bennett TD. Parsimonious Electronic Health Record-Based Models to Assign Subphenotypes in Children With Acute Respiratory Distress Syndrome. Pediatr Crit Care Med 2025; 26:e735-e737. [PMID: 40126068 DOI: 10.1097/pcc.0000000000003733] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/25/2025]
Affiliation(s)
- Benjamin Yoon
- Department of Pediatrics (Critical Care Medicine), University of Colorado School of Medicine, Aurora, CO
| | - Tellen D Bennett
- Department of Pediatrics (Critical Care Medicine), University of Colorado School of Medicine, Aurora, CO
- Department of Biomedical Informatics, University of Colorado School of Medicine, Aurora, CO
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38
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Grunblatt E, Meng Z, Baldridge AS, Patel NP, Stanisic A, Feinstein MJ, Rao A, Gordon LI, Winter JN, Ma S, Mehta J, Singhal S, Karmali R, Akhter N. Variance in development of early and late cardiotoxicities in patients with lymphoma and myeloma receiving CAR T-cell therapies. Leuk Lymphoma 2025; 66:858-868. [PMID: 39772871 DOI: 10.1080/10428194.2024.2448713] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2024] [Revised: 12/17/2024] [Accepted: 12/27/2024] [Indexed: 01/11/2025]
Abstract
Cardiovascular adverse events (CVAEs) are recognized complications of chimeric antigen receptor (CAR) T-cell therapies. However, data are lacking regarding subtypes of adverse events that develop in patients with different malignancies, and little is known about the timeframe in which different cardiotoxicities are most likely to occur post-CAR T-cell therapies. In this study, 211 patients, including 138 lymphoma patients and 66 myeloma patients who received CAR T-cell therapies were retrospectively identified. Of these, 42 patients (19.9%) developed CVAEs post-treatment. Myeloma patients predominantly experienced heart failure while lymphoma patients predominantly experienced arrhythmia. Severe CVAEs were observed even at >12 months post-treatment. Lower baseline global longitudinal strain was significantly associated with development of post-CAR T-cell therapy CVAEs in both lymphoma and myeloma patients. These findings highlight the spectra of post-CAR T-cell cardiotoxicities in lymphoma and myeloma patients and the importance of echocardiography for pretreatment risk stratification and long-term surveillance.
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Affiliation(s)
- Eli Grunblatt
- Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Zhiying Meng
- Division of Cardiovascular Medicine, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Abigail S Baldridge
- Division of Cardiovascular Medicine, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Nikita P Patel
- Division of Hematology and Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Robert H. Lurie Comprehensive Cancer Center, Chicago, IL, USA
| | - Alexander Stanisic
- Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Matthew J Feinstein
- Division of Cardiovascular Medicine, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Anjali Rao
- Division of Cardiovascular Medicine, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Leo I Gordon
- Division of Hematology and Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Robert H. Lurie Comprehensive Cancer Center, Chicago, IL, USA
| | - Jane N Winter
- Division of Hematology and Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Robert H. Lurie Comprehensive Cancer Center, Chicago, IL, USA
| | - Shuo Ma
- Division of Hematology and Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Robert H. Lurie Comprehensive Cancer Center, Chicago, IL, USA
| | - Jayesh Mehta
- Division of Hematology and Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Robert H. Lurie Comprehensive Cancer Center, Chicago, IL, USA
| | - Seema Singhal
- Division of Hematology and Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Robert H. Lurie Comprehensive Cancer Center, Chicago, IL, USA
| | - Reem Karmali
- Division of Hematology and Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Robert H. Lurie Comprehensive Cancer Center, Chicago, IL, USA
| | - Nausheen Akhter
- Division of Cardiovascular Medicine, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
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39
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Saied G, Halford Z. Engaging a New Treatment Paradigm: Elranatamab in Relapsed/Refractory Multiple Myeloma. Ann Pharmacother 2025; 59:473-484. [PMID: 39415515 DOI: 10.1177/10600280241281742] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2024] Open
Abstract
OBJECTIVE To review the therapeutic profile of elranatamab, a novel bispecific T-cell-redirecting therapy, in treating relapsed or refractory (R/R) multiple myeloma (MM). DATA SOURCES A PubMed search was conducted for English-language articles published from January 2000 through June 2024, using the search terms: PF-06863135, elranatamab, Elrexfio, and "Multiple Myeloma." Additional data were obtained from ClinicalTrials.gov and other pertinent publications and meeting abstracts. STUDY SELECTION AND DATA EXTRACTION Clinical trials, guidelines, and prescribing information pertaining to elranatamab were included. DATA SYNTHESIS The phase II MagentisMM-3 trial demonstrated an overall response rate of 61.0% (95% confidence interval, 51.8-69.6) in patients naïve to B-cell maturation antigen targeting therapy (cohort A, n = 123), establishing elranatamab monotherapy as a viable treatment option for patients with R/R MM who have received at least 4 prior lines of therapy. The duration of response and progression-free survival at 12 months were 75.3% and 56.6%, respectively.Relevance to patient care and clinical practice in comparison with existing drugs:Despite the promising activity of elranatamab in R/R MM, the significant treatment-related adverse effects (AEs) associated with this therapy necessitate careful monitoring and expert management. Common AEs include cytokine release syndrome, neurotoxicity, hematologic toxicity, and infectious complications. The cost-effectiveness of elranatamab has yet to be evaluated. CONCLUSIONS Elranatamab is approved by the Food and Drug Administration as a treatment option for patients with heavily pretreated R/R MM. Further studies are warranted to identify the optimal treatment strategy for elranatamab and other bispecific antibodies in the management of R/R MM.
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Affiliation(s)
- George Saied
- Union University College of Pharmacy, Jackson, TN, USA
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40
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Testa U, Castelli G, Pelosi E, Galli E, Chiusolo P. Toxicities Associated with CAR-T Cell Therapies. Mediterr J Hematol Infect Dis 2025; 17:e2025039. [PMID: 40375917 PMCID: PMC12081046 DOI: 10.4084/mjhid.2025.039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2025] [Accepted: 04/14/2025] [Indexed: 05/18/2025] Open
Abstract
Chimeric antigen receptor (CAR) T-cell therapy has improved the outcomes of patients with relapsed/refractory B-cell lymphomas, B-cell acute lymphoblastic leukemia, and multiple myeloma. However, CAR-T cell therapy is also associated with distinct toxicities that contribute to morbidity and mortality. A large number of studies now define the different toxicities associated with CAR-T cell therapy and have, in part, clarified their mechanisms. In particular, cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) are the two main acute toxicity events that occur after CAR-T cell infusion. Other CAR-T-related toxicities occur later after CAR-T cell infusion and include B-cell aplasia, hypogammaglobulinemia, infections, and cytopenias. Infections represent the main cause of non-relapse death observed in patients undergoing CAR-T cell therapy. Second primary malignancies are rare and are mainly represented by myeloid malignancies.
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Affiliation(s)
- Ugo Testa
- Department of Oncology, Istituto Superiore di Sanità, ROME, Italy
| | - Germana Castelli
- Department of Oncology, Istituto Superiore di Sanità, ROME, Italy
| | - Elvira Pelosi
- Department of Oncology, Istituto Superiore di Sanità, ROME, Italy
| | - Eugenio Galli
- Hematology Department, Fondazione Policlinico Universitario Agostino Gemelli, Rome, Italy
| | - Patrizia Chiusolo
- Hematology Department, Fondazione Policlinico Universitario Agostino Gemelli, Rome, Italy
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41
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Peery MR, Hill H, Sharps A, Zaver A, Moore DC. B-Cell Maturation Antigen-Directed Immunotherapies for the Treatment of Relapsed/Refractory Multiple Myeloma: A Review of the Literature and Implications for Clinical Practice. Ann Pharmacother 2025; 59:463-472. [PMID: 39373355 DOI: 10.1177/10600280241282115] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/08/2024] Open
Abstract
OBJECTIVE To review the pharmacology, efficacy, safety, dosing and administration, and relevance to patient care and clinical practice of B-cell maturation antigen (BCMA) directed immunotherapies, including chimeric antigen receptor T-cell (CAR-T) therapy and bispecific antibodies (BsAb), for the management of relapsed/refractory multiple myeloma (RRMM). DATA SOURCES A literature review of PubMed (1966 to July 2024) was conducted using the keywords idecabtagene vicleucel, ciltacabtagene autoleucel, teclistamab, elranatamab, and multiple myeloma. Data was also obtained from unpublished meeting abstracts and prescribing information. STUDY SELECTION AND DATA EXTRACTION All relevant published articles, unpublished abstracts, and prescribing information on anti-BCMA immunotherapies for the treatment of RRMM were reviewed. DATA SYNTHESIS Idecabtagene vicleucel and ciltacabtagene autoleucel are BCMA-directed CAR-T cell therapies that have been compared to standard of care (SOC) regimens for MM in early relapse in the phase III trials KarMMa-3 and CARTITUDE-4, respectively. Both studies demonstrated a significantly improved in response rates, depth of response, and progression-free survival compared to SOC. BsAbs teclistamab and elranatamab have been evaluated in the phase II trials MajesTEC-1 and MagnetisMM-3, respectively. Overall response rates of 63 and 61% were observed with teclistamab and elranatamab, respectively, in a population of patients with heavily pretreated RRMM.Relevance to Patient Care and Clinical Practice in Comparison with Existing Drugs:BCMA-directed immunotherapies have demonstrated efficacy in the treatment of RRMM. Safety issues with BCMA-directed immunotherapies include cytokine release syndrome, neurotoxicity, infections, and cytopenias. Operational challenges and issues with access to care exist with these therapies as they may be limited to institutions with the infrastructure to safely administer and monitor patients for toxicities. CONCLUSION BCMA-directed immunotherapies represent an important advancement in the management of RRMM and have significantly added to the available treatment options for this disease.
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Affiliation(s)
- Matthew R Peery
- Department of Pharmacy, Virginia Commonwealth University Medical Center, VCU Health, Richmond, VA, USA
| | - Hailey Hill
- Division of Pharmacy, Atrium Health Levine Cancer Institute, Atrium Health, Charlotte, NC, USA
| | - Amanda Sharps
- Department of Pharmacy, Virginia Commonwealth University Medical Center, VCU Health, Richmond, VA, USA
| | - Aarti Zaver
- Department of Pharmacy, Virginia Commonwealth University Medical Center, VCU Health, Richmond, VA, USA
| | - Donald C Moore
- Division of Pharmacy, Atrium Health Levine Cancer Institute, Atrium Health, Charlotte, NC, USA
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Varma G, Fogel L, Gordon B, Saldarriaga MM, Ahn J, Aleman A, Caro J, Rosenberg MC, Monge J, Parmar H, Kaminetzky D, Moskovits T, Siegel DS, Morgan GJ, Niesvizky R, Davies FE, Biran N. Real-world safety and efficacy of teclistamab in relapsed/refractory multiple myeloma: results from a multicenter, retrospective study and descriptive meta-analysis. Leuk Lymphoma 2025; 66:942-951. [PMID: 39756041 DOI: 10.1080/10428194.2024.2446617] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2024] [Revised: 12/19/2024] [Accepted: 12/20/2024] [Indexed: 01/07/2025]
Abstract
Patients participating in clinical trials are highly selected and may not represent the general population. The pivotal study of teclistamab (MajesTEC-1), a B-cell maturation antigen (BCMA)xCD3 bispecific antibody, demonstrated impressive response rates and progression free survival in relapsed/refractory multiple myeloma (RRMM) with acceptable toxicity. We performed a retrospective study of 58 patients treated as standard of care at four US academic centers to determine how these results translated to the real-world. Most patients (87.9%) would not have been eligible for the MajesTEC-1 study due to either disease related factors, patient related comorbidities or socio-economic/geographical factors. Despite these 'less-favorable' characteristics we observed similar efficacy and toxicity to MajesTEC-1. A meta-analysis with six other published real-world series (n = 546) confirmed these results. These data support the significant clinical activity of teclistamab in RRMM and highlights the importance of real-world data to accompany the pivotal trial data to further inform daily clinical practice.
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Affiliation(s)
- Gaurav Varma
- Center for Blood Cancers, Perlmutter Cancer Center, NYU Langone Health, New York, NY, USA
| | - Lindsay Fogel
- Multiple Myeloma Division, The John Theurer Cancer Center, Hackensack Meridian Health, Hackensack, NJ, USA
| | - Beth Gordon
- Center for Blood Cancers, Perlmutter Cancer Center, NYU Langone Health, New York, NY, USA
| | - Mateo Mejia Saldarriaga
- Myeloma Program, Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA
| | - Jaeil Ahn
- Department of Biostatistics, Bioinformatics, and Biomathematics, Georgetown University, Washington, DC, USA
| | - Adolfo Aleman
- Multiple Myeloma Division, The John Theurer Cancer Center, Hackensack Meridian Health, Hackensack, NJ, USA
| | - Jessica Caro
- Zuckerberg Cancer Center, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Lake Success, NY, USA
| | - Maya C Rosenberg
- Center for Blood Cancers, Perlmutter Cancer Center, NYU Langone Health, New York, NY, USA
| | - Jorge Monge
- Myeloma Program, Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA
| | - Harsh Parmar
- Multiple Myeloma Division, The John Theurer Cancer Center, Hackensack Meridian Health, Hackensack, NJ, USA
| | - David Kaminetzky
- Center for Blood Cancers, Perlmutter Cancer Center, NYU Langone Health, New York, NY, USA
| | - Tibor Moskovits
- Center for Blood Cancers, Perlmutter Cancer Center, NYU Langone Health, New York, NY, USA
| | - David S Siegel
- Multiple Myeloma Division, The John Theurer Cancer Center, Hackensack Meridian Health, Hackensack, NJ, USA
| | - Gareth J Morgan
- Center for Blood Cancers, Perlmutter Cancer Center, NYU Langone Health, New York, NY, USA
| | - Ruben Niesvizky
- Myeloma Program, Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA
| | - Faith E Davies
- Center for Blood Cancers, Perlmutter Cancer Center, NYU Langone Health, New York, NY, USA
| | - Noa Biran
- Multiple Myeloma Division, The John Theurer Cancer Center, Hackensack Meridian Health, Hackensack, NJ, USA
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Haddad A, Zedet M, Roulin L, Degoutte C, Gounot R, Leclerc M, Menouche D, Razazi K, Saeed W, Lemonnier F, Bachoud-Levi AC, Gendre T. Short-term neurological tolerance of chimeric antigen receptor-T cell therapy for refractory B-cell malignancy in patients with pre-existing cognitive impairment: A retrospective cohort study. J Geriatr Oncol 2025; 16:102236. [PMID: 40179711 DOI: 10.1016/j.jgo.2025.102236] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2024] [Revised: 02/11/2025] [Accepted: 03/26/2025] [Indexed: 04/05/2025]
Affiliation(s)
- Andrei Haddad
- Department of Neurology, East Paris University, Henri Mondor University Hospital - AP-HP, Créteil, France
| | - Mickaël Zedet
- Department of Neurology, East Paris University, Henri Mondor University Hospital - AP-HP, Créteil, France
| | - Louise Roulin
- Lymphoid Malignancies Unit, Henri Mondor University Hospital - AP-HP, Créteil, France
| | - Charlotte Degoutte
- Lymphoid Malignancies Unit, Henri Mondor University Hospital - AP-HP, Créteil, France
| | - Romain Gounot
- Lymphoid Malignancies Unit, Henri Mondor University Hospital - AP-HP, Créteil, France
| | - Mathieu Leclerc
- Myeloid Malignancies Unit, Henri Mondor University Hospital - AP-HP, Créteil, France
| | - Dehbia Menouche
- Myeloid Malignancies Unit, Henri Mondor University Hospital - AP-HP, Créteil, France
| | - Keyvan Razazi
- Medical Intensive Care Unit, Henri Mondor University Hospital - AP-HP, Créteil, France
| | - Wesam Saeed
- Department of Pharmacy, Henri Mondor University Hospital - AP-HP, Créteil, France
| | - François Lemonnier
- Lymphoid Malignancies Unit, Henri Mondor University Hospital - AP-HP, Créteil, France
| | - Anne-Catherine Bachoud-Levi
- Department of Neurology, East Paris University, Henri Mondor University Hospital - AP-HP, Créteil, France; Department of Cognitive Study, École Normale Supérieure, PSL University, Paris, France; Inserm U955, Mondor Institute of Biomedical Research, Team E01 NeuroPsychologie Interventionnelle, Créteil, France
| | - Thierry Gendre
- Department of Neurology, East Paris University, Henri Mondor University Hospital - AP-HP, Créteil, France.
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Chen Z, Chen Y, Liu J, Sun Y, Zhang X, Shao L, Wang D, Wang X, Chen W, Sang W, Qi K, Li Z, Sun C, Shi M, Qiao J, Wu Q, Zeng L, Zheng J, Xu K, Li L, Cheng H, Cao J. Nephrotoxicity of CAR-T therapy in patients with relapsed and refractory multiple myeloma. Int Urol Nephrol 2025:10.1007/s11255-025-04503-4. [PMID: 40310507 DOI: 10.1007/s11255-025-04503-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2024] [Accepted: 03/30/2025] [Indexed: 05/02/2025]
Abstract
OBJECTIVE Chimeric antigen receptor T (CAR-T) cell therapy has achieved impressive efficacy in treating relapsed and refractory multiple myeloma (R/R MM). Nephrotoxicity after CAR-T cell therapy has rarely been reported. METHODS We investigated the occurrence and clinical outcomes of acute kidney injury (AKI) in 111 patients with R/R MM after CAR-T cell therapy. RESULTS Thirteen patients (12.1%) developed AKI within 1 month of CAR-T cell therapy, of which 11 had grade 1 AKI, 1 had grade 2, and 1 had grade 3. Eleven (84.6%) cases resolved within 1 month after CAR-T cell therapy. The baseline tumor burden was an independent risk factor for the development of AKI. The finding of a high baseline tumor burden or hyponatremia after CAR-T cell therapy and close monitoring of lactate dehydrogenase, uric acid, interleukin (IL)-5 and IL-10 levels were helpful in predicting the development of AKI. The incidence of cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome were similar between the AKI and non-AKI groups. There was also no significant difference in clinical efficacy between the two groups. CONCLUSION AKI is a mild severity and reversible complication. It has no impact on clinical outcomes in R/R MM patients receiving CAR-T cell therapy.
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Affiliation(s)
- Zihan Chen
- Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, No.99 West Huaihai Road, Xuzhou, 221002, Jiangsu, China
| | - Yegan Chen
- Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, No.99 West Huaihai Road, Xuzhou, 221002, Jiangsu, China
| | - Jiaying Liu
- Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, No.99 West Huaihai Road, Xuzhou, 221002, Jiangsu, China
| | - Yingjun Sun
- Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, No.99 West Huaihai Road, Xuzhou, 221002, Jiangsu, China
| | - Xiaoxue Zhang
- Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, No.99 West Huaihai Road, Xuzhou, 221002, Jiangsu, China
| | - Lingyan Shao
- Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, No.99 West Huaihai Road, Xuzhou, 221002, Jiangsu, China
| | - Dandan Wang
- Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, No.99 West Huaihai Road, Xuzhou, 221002, Jiangsu, China
| | - Xue Wang
- Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, No.99 West Huaihai Road, Xuzhou, 221002, Jiangsu, China
| | - Wei Chen
- Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, No.99 West Huaihai Road, Xuzhou, 221002, Jiangsu, China
| | - Wei Sang
- Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, No.99 West Huaihai Road, Xuzhou, 221002, Jiangsu, China
| | - Kunming Qi
- Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, No.99 West Huaihai Road, Xuzhou, 221002, Jiangsu, China
| | - Zhenyu Li
- Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, No.99 West Huaihai Road, Xuzhou, 221002, Jiangsu, China
| | - Cai Sun
- Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, No.99 West Huaihai Road, Xuzhou, 221002, Jiangsu, China
| | - Ming Shi
- Cancer Institute, Xuzhou Medical University, Xuzhou, 221002, China
| | - Jianlin Qiao
- Jiangsu Bone Marrow Stem Cell Institute, Xuzhou, 221002, China
| | - Qingyun Wu
- Jiangsu Bone Marrow Stem Cell Institute, Xuzhou, 221002, China
| | - Lingyu Zeng
- Jiangsu Bone Marrow Stem Cell Institute, Xuzhou, 221002, China
| | - Junnian Zheng
- Cancer Institute, Xuzhou Medical University, Xuzhou, 221002, China
| | - Kailin Xu
- Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, No.99 West Huaihai Road, Xuzhou, 221002, Jiangsu, China
| | - Li Li
- Department of Gastroenterology, The Affiliated Hospital of Xuzhou Medical University, No.99 West Huaihai Road, Xuzhou, 221002, Jiangsu, China.
| | - Hai Cheng
- Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, No.99 West Huaihai Road, Xuzhou, 221002, Jiangsu, China.
| | - Jiang Cao
- Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, No.99 West Huaihai Road, Xuzhou, 221002, Jiangsu, China.
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Ossami Saidy A, Peczynski C, Thieblemont C, Daskalakis M, Wehrli M, Beauvais D, Finke J, Schorb E, Vandenberghe P, Berning P, Stelljes M, Ayuk F, Ram R, Von Bonin M, Dreger P, Bethge W, Kuhnl A, Jost L, Stölzel F, von Tresckow B, Renner C, Fuhrmann S, Galimard J, Michel E, Bazarbachi A, Balari AS, Schmitz N, Glass B. Efficacy and safety of CAR T-cell therapy in patients with primary or secondary CNS lymphoma: A study on behalf of the EBMT and the GoCART coalition. Hemasphere 2025; 9:e70146. [PMID: 40400509 PMCID: PMC12093105 DOI: 10.1002/hem3.70146] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2025] [Revised: 03/13/2025] [Accepted: 04/04/2025] [Indexed: 05/23/2025] Open
Abstract
Patients with relapsed or refractory (r/r) primary central nervous system (CNS) lymphoma (PCNSL) or secondary central nervous system (CNS) lymphoma (SCNSL) face a dismal prognosis. They have been excluded from most clinical CAR T-cell trials as investigators feared an increased risk for severe immune effector cell-associated neurotoxicity (ICANS). To investigate the potential of anti-CD19 CAR T-cell therapy (CART) in such patients, we analyzed data of 100 patients with CNS manifestation treated with CART between January 2018 and July 2023 and reported to European Society for Blood and Marrow Transplantation. Median age was 62 years. Of patients, 58% had failed ≥3 treatment lines, and 40% had received autologous stem-cell transplantation before CART. Fifty-nine patients received axicabtagene ciloleucel, 38 patients were treated with tisagenlecleucel, three patients received other products. At the time of CART, 67 patients had active CNS disease. Overall and progression-free survival (PFS) at 24 months were 37% and 28%. Relapse incidence (RI) at 24 months was 59%, whereas non-relapse mortality at 1 year was 7%. Cytokine release syndrome (CRS) and ICANS of any grade occurred in 83% and 42% of patients, respectively. CRS grade 3 occurred in 11 and ICANS grades 3-4 in 17 patients. Two patients died of neurotoxicity. Elevated lactate dehydrogenase was an independent risk factor for RI and PFS (hazard ratio [HR] 2.4, p = 0.003; HR: 1.9, p = 0.016). Patients with ECOG 2-3 had a significantly increased risk for the development of ICANS (HR 2.68, p = 0.002). These data support the implementation of CART as treatment for patients with r/r PCNSL and SCNSL.
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Affiliation(s)
- Anna Ossami Saidy
- Department of Hematology and Cell TherapyHelios Klinikum Berlin‐BuchBerlinGermany
| | - Christophe Peczynski
- EBMT Paris Study OfficeEuropean Society for Blood and Marrow TransplantationParisFrance
| | - Catherine Thieblemont
- University Paris Cité, Assistance Publique‐Hôpitaux de Paris Hemato‐oncology, INSERM U1153, Hôpital Saint‐LouisParisFrance
| | - Michael Daskalakis
- Department of Hematology and Central Hematology LaboratoryInselspital, Bern University HospitalBernSwitzerland
| | - Marc Wehrli
- Department of Medical OncologyInselspital, Bern University HospitalBernSwitzerland
| | - David Beauvais
- Department of HematologyCentre Hospitalier Universitaire de LilleLilleFrance
| | - Jürgen Finke
- Department of Medicine I, Faculty of Medicine, Medical Center‐University of FreiburgUniversity of FreiburgFreiburgGermany
| | - Elisabeth Schorb
- Department of Medicine I, Faculty of Medicine, Medical Center‐University of FreiburgUniversity of FreiburgFreiburgGermany
| | | | - Philipp Berning
- Department of HematologyUniversity Hospitals LeuvenLeuvenBelgium
| | | | - Francis Ayuk
- Department of Stem Cell TransplantationUniversity Medical Center Hamburg‐EppendorfHamburgGermany
| | - Ron Ram
- Bone Marrow Transplantation Unit, Faculty of Medicine, Tel Aviv Sourasky Medical CenterTel Aviv UniversityTel AvivIsrael
| | - Malte Von Bonin
- Medical Clinic IUniversity Hospital Carl Gustav Carus, Technische Universität DresdenDresdenGermany
| | - Peter Dreger
- Department of Medicine VUniversity of HeidelbergHeidelbergGermany
| | - Wolfgang Bethge
- Department of Internal Medicine II, Hematology, Oncology, Clinical Immunology, and RheumatologyUniversity Hospital TübingenTübingenGermany
| | - Andrea Kuhnl
- Department of HaematologyKing's College HospitalLondonUnited Kingdom
| | - Lasse Jost
- Department of Medicine II, Division for Stem Cell Transplantation and Cellular ImmunotherapyUniversity Cancer Center Schleswig‐Holstein, University Hospital Schleswig‐Holstein KielKielGermany
| | - Friedrich Stölzel
- Department of Medicine II, Division for Stem Cell Transplantation and Cellular ImmunotherapyUniversity Cancer Center Schleswig‐Holstein, University Hospital Schleswig‐Holstein KielKielGermany
| | - Bastian von Tresckow
- Department of Hematology and Stem Cell Transplantation, West German Cancer Center and German Cancer Consortium (DKTK partner site Essen)University Hospital Essen, University of Duisburg‐EssenEssenGermany
| | - Christoph Renner
- Division of Hematology/OncologyClinic HirslandenZurichSwitzerland
| | | | | | - Eva Michel
- EBMT Paris Study OfficeEuropean Society for Blood and Marrow TransplantationParisFrance
| | - Ali Bazarbachi
- Department of Internal Medicine, Bone Marrow Transplantation ProgramUniversity of BeirutBeirutLebanon
| | - Anna Sureda Balari
- Clinical Hematology Department, Institut Català d'Oncologia‐Hospitalet, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL)University of BarcelonaBarcelonaSpain
| | - Norbert Schmitz
- Department of Medicine AUniversity Hospital MuensterMuensterGermany
| | - Bertram Glass
- Department of Hematology and Cell TherapyHelios Klinikum Berlin‐BuchBerlinGermany
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Iacoboni G, Rejeski K, Navarro V, van Meerten T, Rampotas A, Martín-López AÁ, Bastos M, Benzaquén A, Reguera-Ortega JL, Carpio C, Roddie C, López-Corral L, Delgado-Serrano J, Landwehr M, Stock S, Silva de Tena P, Abrisqueta P, de Boer J, Martin Garcia-Sancho A, Hernani R, Kwon M, Subklewe M, O'Reilly M, Barba P. Site-specific analysis of extranodal involvement in large B-cell lymphoma reveals distinct efficacy with chimeric antigen receptor T-cell therapy. Leukemia 2025; 39:1196-1205. [PMID: 40169762 DOI: 10.1038/s41375-025-02582-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2025] [Revised: 03/06/2025] [Accepted: 03/20/2025] [Indexed: 04/03/2025]
Abstract
Over 60% of relapsed/refractory large B-cell lymphoma (R/R LBCL) patients treated with chimeric antigen receptor (CAR) T-cells experience progressive disease. The impact of site-specific extranodal involvement on CAR-T outcomes has not been fully elucidated. This multicenter study included 516 R/R LBCL patients infused with CD19-targeted CAR T-cells; 177 (34%) had only-nodal (N), 66 (13%) only-extranodal (E) and 273 (53%) nodal and extranodal (NE) disease at time of CAR T-cells. The NE cohort included more patients with a poor performance status and high tumor burden. In the multivariable analysis, the NE group had a shorter progression-free survival (PFS) (HR 1.27 [95%CI 0.98-1.64], p = 0.07) and overall survival (HR 1.41 [95%CI 1.05-1.88], p = 0.02) compared to N. Conversely, we did not identify efficacy differences between N and E patients. A higher number of extranodal sites and specific organ involvement (liver, adrenal glands, pancreas), were associated with shorter PFS. Finally, extranodal involvement increased at time of relapse, displaying heterogeneous individual site clearance rates. In conclusion, patients with concomitant nodal and extranodal involvement at time of CAR-T had worse outcomes, but this cohort harbored high-risk baseline characteristics. An increasing number of extranodal sites and certain disease locations were associated with lower CAR-T efficacy.
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MESH Headings
- Humans
- Male
- Female
- Middle Aged
- Lymphoma, Large B-Cell, Diffuse/therapy
- Lymphoma, Large B-Cell, Diffuse/pathology
- Lymphoma, Large B-Cell, Diffuse/mortality
- Lymphoma, Large B-Cell, Diffuse/immunology
- Aged
- Receptors, Chimeric Antigen/immunology
- Immunotherapy, Adoptive/methods
- Adult
- Aged, 80 and over
- Survival Rate
- Prognosis
- Young Adult
- Follow-Up Studies
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Affiliation(s)
- Gloria Iacoboni
- Department of Hematology, University Hospital Vall d'Hebron, Barcelona, Spain.
- Experimental Hematology, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain.
- Department of Medicine, Universitat Autònoma de Barcelona, Bellaterra, Spain.
| | - Kai Rejeski
- Department of Medicine III, LMU University Hospital, LMU Munich, Munich, Germany
| | - Víctor Navarro
- Statistics Unit, Vall d´Hebron Institute of Oncology (VHIO), Barcelona, Spain
| | - Tom van Meerten
- Department of Hematology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
| | - Alex Rampotas
- Hematology Department, University College London Cancer Institute, London, UK
| | - Ana África Martín-López
- Hematology Department, Hospital Universitario de Salamanca, IBSAL, CIBERONC, Salamanca, Spain
- Centro de Investigación del Cáncer-IBMCC, Universidad de Salamanca, Salamanca, Spain
| | - Mariana Bastos
- Department of Hematology, Hospital General Universitario Gregorio Marañón, Madrid, Spain
- Gregorio Marañón Health Research Institute (IiSGM), Madrid, Spain
| | - Ana Benzaquén
- Haematology Department, Hospital Clínico Universitario, Valencia, Spain
- INCLIVA Research Institute, Valencia, Spain
| | - Juan Luis Reguera-Ortega
- Hematology Department, Hospital Virgen del Rocío, Instituto de Biomedicina de Sevilla (IBIS) / CSIC, Universidad de Sevilla, Sevilla, Spain
| | - Cecilia Carpio
- Department of Hematology, University Hospital Vall d'Hebron, Barcelona, Spain
- Experimental Hematology, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
- Department of Medicine, Universitat Autònoma de Barcelona, Bellaterra, Spain
| | - Claire Roddie
- Hematology Department, University College London Cancer Institute, London, UK
| | - Lucia López-Corral
- Hematology Department, Hospital Universitario de Salamanca, IBSAL, CIBERONC, Salamanca, Spain
- Centro de Investigación del Cáncer-IBMCC, Universidad de Salamanca, Salamanca, Spain
| | - Javier Delgado-Serrano
- Hematology Department, Hospital Virgen del Rocío, Instituto de Biomedicina de Sevilla (IBIS) / CSIC, Universidad de Sevilla, Sevilla, Spain
| | - Maria Landwehr
- Department of Hematology, University Hospital Vall d'Hebron, Barcelona, Spain
| | - Sophia Stock
- Department of Medicine III, LMU University Hospital, LMU Munich, Munich, Germany
- Division of Clinical Pharmacology, LMU University Hospital, LMU Munich, Munich, Germany
- German Cancer Consortium (DKTK), Partner Site Munich, a partnership between the DKFZ Heidelberg and LMU University Hospital, Munich, Germany
| | - Pablo Silva de Tena
- Department of Hematology, Hospital General Universitario Gregorio Marañón, Madrid, Spain
| | - Pau Abrisqueta
- Department of Hematology, University Hospital Vall d'Hebron, Barcelona, Spain
- Experimental Hematology, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
- Department of Medicine, Universitat Autònoma de Barcelona, Bellaterra, Spain
| | - Janneke de Boer
- Department of Hematology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
| | - Alejandro Martin Garcia-Sancho
- Hematology Department, Hospital Universitario de Salamanca, IBSAL, CIBERONC, Salamanca, Spain
- Centro de Investigación del Cáncer-IBMCC, Universidad de Salamanca, Salamanca, Spain
| | - Rafael Hernani
- Haematology Department, Hospital Clínico Universitario, Valencia, Spain
- INCLIVA Research Institute, Valencia, Spain
| | - Mi Kwon
- Department of Hematology, Hospital General Universitario Gregorio Marañón, Madrid, Spain
- Gregorio Marañón Health Research Institute (IiSGM), Madrid, Spain
| | - Marion Subklewe
- Department of Medicine III, LMU University Hospital, LMU Munich, Munich, Germany
| | - Maeve O'Reilly
- Hematology Department, University College London Cancer Institute, London, UK
| | - Pere Barba
- Department of Hematology, University Hospital Vall d'Hebron, Barcelona, Spain.
- Experimental Hematology, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain.
- Department of Medicine, Universitat Autònoma de Barcelona, Bellaterra, Spain.
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47
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Mulvey A, Trueb L, Coukos G, Arber C. Novel strategies to manage CAR-T cell toxicity. Nat Rev Drug Discov 2025; 24:379-397. [PMID: 39901030 DOI: 10.1038/s41573-024-01100-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/08/2024] [Indexed: 02/05/2025]
Abstract
The immune-related adverse events associated with chimeric antigen receptor (CAR)-T cell therapy result in substantial morbidity as well as considerable cost to the health-care system, and can limit the use of these treatments. Current therapeutic strategies to manage immune-related adverse events include interleukin-6 receptor (IL-6R) blockade and corticosteroids. However, because these interventions do not always address the side effects, nor prevent progression to higher grades of adverse events, new approaches are needed. A deeper understanding of the cell types involved, and their associated signalling pathways, cellular metabolism and differentiation states, should provide the basis for alternative strategies. To preserve treatment efficacy, cytokine-mediated toxicity needs to be uncoupled from CAR-T cell function, expansion, long-term persistence and memory formation. This may be achieved by targeting CAR or independent cytokine signalling axes transiently, and through novel T cell engineering strategies, such as low-affinity CAR-T cells, reversible on-off switches and versatile adaptor systems. We summarize the current management of cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, and review T cell- and myeloid cell-intrinsic druggable targets and cellular engineering strategies to develop safer CAR-T cells.
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Affiliation(s)
- Arthur Mulvey
- Department of Oncology UNIL-CHUV, Service of Immuno-Oncology, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), Lausanne, Switzerland
- Ludwig Institute for Cancer Research Lausanne, Lausanne, Switzerland
| | - Lionel Trueb
- Department of Oncology UNIL-CHUV, Service of Immuno-Oncology, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), Lausanne, Switzerland
| | - George Coukos
- Department of Oncology UNIL-CHUV, Service of Immuno-Oncology, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), Lausanne, Switzerland
- Ludwig Institute for Cancer Research Lausanne, Lausanne, Switzerland
| | - Caroline Arber
- Department of Oncology UNIL-CHUV, Service of Immuno-Oncology, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), Lausanne, Switzerland.
- Ludwig Institute for Cancer Research Lausanne, Lausanne, Switzerland.
- Departments of Oncology UNIL-CHUV and Laboratory Medicine and Pathology, Service and Central Laboratory of Hematology, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), Lausanne, Switzerland.
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48
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Suresh A, Wishart HA, Arslan MN, Lizcano RA, Shah PS, PonnamReddy S, Hayes CA, Jacobson BS, Moncrief G, Martinez-Camblor P, Chan AM, Meehan KR, Hill JM. Novel Neurocognitive Testing Tool for Early Neurotoxicity Detection Following Anti-CD19 and Anti-BCMA Chimeric Antigen Receptor (CAR) T-cell Therapy: A Pilot Study. CLINICAL LYMPHOMA, MYELOMA & LEUKEMIA 2025; 25:365-378. [PMID: 39814673 DOI: 10.1016/j.clml.2024.12.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/21/2024] [Revised: 12/11/2024] [Accepted: 12/19/2024] [Indexed: 01/18/2025]
Abstract
BACKGROUND Immune effector cell-associated neurotoxicity syndrome (ICANS) can be a severe, life-threatening toxicity following CAR T-cell therapy. While currently evaluated by the immune effector cell-associated encephalopathy (ICE) score, not all patients have changes in their ICE score and not all signs and symptoms of neurotoxicity are captured. METHODS We conducted a prospective, single center cohort pilot study to evaluate a novel, rapid neurocognitive assessment tool (CART-NS) in detecting early, subtle neurotoxicity prior to the onset of ICANS and any deterioration in the ICE score. CART-NS includes 8 abbreviated forms of neurocognitive tests and 2 symptom questionnaires. Following baseline measurements, CART-NS was administered at 8-hour intervals during the first 30 days after CAR T-cell infusion. RESULTS Performance on all measures was significantly lower when patients developed Grade 1 or 2 ICANS (P < .05). Performance on Oral Symbol Digit, Stroop, and the Paced Visual Serial Addition Test was lower between Day 0 and +3 in patients who developed ICANS and persisted even after clinical resolution. Early changes in the Stroop test (AUC = 0.857, 95% CI 0.628-1.000) were most predictive of ICANS onset when measured during the first 36 hour following CAR T-cell infusion. Significant elevations in CRP, G-CSF, GM-CSF, IFNγ, IL-10, IL-15, IL-27, and MIG/CXCL-9 were associated with ICANS development. CONCLUSION Brief neurocognitive testing can be feasibly applied for the early detection of ICANS after CAR T-cell therapy, predict which patients may go on to develop ICANS in the first 30 days, and overcome limitations of the ICE assessment tool.
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Affiliation(s)
- Arvind Suresh
- Department of Medicine, University of California, San Francisco, CA.
| | - Heather A Wishart
- Department of Psychiatry, Dartmouth-Hitchcock Medical Center, Lebanon, NH
| | | | - Raphael A Lizcano
- Transplant and Cellular Therapy Program, Dartmouth Cancer Center, Dartmouth-Hitchcock Medical Center, Lebanon, NH
| | - Parth S Shah
- Transplant and Cellular Therapy Program, Dartmouth Cancer Center, Dartmouth-Hitchcock Medical Center, Lebanon, NH
| | - Swaroopa PonnamReddy
- Transplant and Cellular Therapy Program, Dartmouth Cancer Center, Dartmouth-Hitchcock Medical Center, Lebanon, NH
| | - Christi Ann Hayes
- Transplant and Cellular Therapy Program, Dartmouth Cancer Center, Dartmouth-Hitchcock Medical Center, Lebanon, NH
| | - Bryce S Jacobson
- Department of Psychiatry, Dartmouth-Hitchcock Medical Center, Lebanon, NH
| | - Grant Moncrief
- Department of Psychiatry, Dartmouth-Hitchcock Medical Center, Lebanon, NH
| | - Pablo Martinez-Camblor
- Department of Biomedical Data Science, Geisel School of Medicine at Dartmouth, Lebanon, NH
| | - Amy M Chan
- Transplant and Cellular Therapy Program, Dartmouth Cancer Center, Dartmouth-Hitchcock Medical Center, Lebanon, NH
| | - Kenneth R Meehan
- Transplant and Cellular Therapy Program, Dartmouth Cancer Center, Dartmouth-Hitchcock Medical Center, Lebanon, NH
| | - John M Hill
- Transplant and Cellular Therapy Program, Dartmouth Cancer Center, Dartmouth-Hitchcock Medical Center, Lebanon, NH
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49
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Won SE, Lee ES, Suh CH, Kim S, Park HJ, Kim KW, Guenette JP. Frequently Asked Questions on Imaging in Chimeric Antigen Receptor T-Cell Therapy Clinical Trials. Korean J Radiol 2025; 26:471-484. [PMID: 40307201 PMCID: PMC12055261 DOI: 10.3348/kjr.2024.1126] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2024] [Revised: 01/16/2025] [Accepted: 02/21/2025] [Indexed: 05/02/2025] Open
Abstract
Clinical trials for chimeric antigen receptor (CAR) T-cell therapy are in the early stages but are expected to progress alongside new treatment approaches. This suggests that imaging will play an important role in monitoring disease progression, treatment response, and treatment-related side effects. There are, however, challenges that remain unresolved, regarding imaging in CAR T-cell therapy. We herein discuss the role of imaging, focusing on how tumor response evaluation varies according to cancer type and target antigens in CAR T-cell therapy. CAR T-cell therapy often produces rapid and significant responses, and imaging is vital for identifying side effects such as cytokine release syndrome and neurotoxicity. Radiologists should be aware of drug mechanisms, response assessments, and associated toxicities to effectively support these therapies. Additionally, this article highlights the importance of the Lugano criteria, which is essential for standardized assessment of treatment response, particularly in lymphoma therapies, and also explores other factors influencing imaging-based evaluation, including emerging methodologies and their potential to improve the accuracy and consistency of response assessments.
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Affiliation(s)
- Sang Eun Won
- Asan Image Metrics, Clinical Trial Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Eun Sung Lee
- Asan Image Metrics, Clinical Trial Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Chong Hyun Suh
- Asan Image Metrics, Clinical Trial Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
- Department of Radiology and Research Institute of Radiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
| | - Sinae Kim
- Asan Image Metrics, Clinical Trial Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Hyo Jung Park
- Asan Image Metrics, Clinical Trial Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
- Department of Radiology and Research Institute of Radiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Kyung Won Kim
- Asan Image Metrics, Clinical Trial Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
- Department of Radiology and Research Institute of Radiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Jeffrey P Guenette
- Division of Neuroradiology, Brigham and Women's Hospital, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
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50
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Sandahl TB, Soefje SA, Fonseca R, Ailawadhi S, Parrondo R, Lin D, Wu B, Calay ES, Silvert E, Kim N, Carpenter C, Wagner TE, Fowler J, Hester L, Rangarajan N, Murugadoss K, Marshall A, Stoy P, Gifkins D, Lin Y, Kumar S. Real-World Safety and Health Care Resource Utilization of Teclistamab Under an Outpatient Model for Step-Up Dosing Administration. JCO Oncol Pract 2025; 21:702-709. [PMID: 39705632 DOI: 10.1200/op-24-00489] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Revised: 10/08/2024] [Accepted: 11/14/2024] [Indexed: 12/22/2024] Open
Abstract
PURPOSE Teclistamab is initiated with a step-up dosing (SUD) schedule to mitigate the risk of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Early teclistamab users commonly received SUD in a hospital setting. This study aimed to evaluate safety and health care resource utilization (HRU) in real-world patients with multiple myeloma who initiated teclistamab SUD in an outpatient setting. METHODS This was a retrospective study using Mayo Clinic's electronic medical records from October 26, 2022, to October 31, 2023. Patient characteristics were summarized for all patients treated with teclistamab and separately for patients who started SUD outpatient. SUD pattern, safety, HRU, and post-SUD dosing schedule were described in patients with complete SUD. RESULTS At data cutoff, 65 patients received ≥1 teclistamab dose, including 58 patients who initiated SUD outpatient (median age, 69.2 years; male, 63.8%; White, 89.7%). Among 57 patients who completed SUD in an outpatient setting, all received premedications on the days of teclistamab administrations per label recommendation; 18 (31.6%) developed CRS (13 grade 1, four grade 2, and one grade 4) and two developed ICANS (one each with grade 2 and 4). All CRS and ICANS resolved with supportive care and all patients continued treatment. Eighteen patients were admitted to the hospital for CRS treatment, with a median CRS-related hospital stay of 2 days per admission. Most (60%) doses during SUD required <1 hour clinic time between administration and checkout. Post-SUD, clinic time for treatment doses decreased to <30 minutes for most doses (82%). CONCLUSION Outcomes of this study support outpatient administration as a safe and feasible option for teclistamab SUD to potentially reduce HRU and improve patient experiences.
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Affiliation(s)
| | | | | | | | | | - Dee Lin
- Janssen Scientific Affairs, LLC, Horsham, PA
| | - Bingcao Wu
- Janssen Scientific Affairs, LLC, Horsham, PA
| | | | | | - Nina Kim
- Janssen Scientific Affairs, LLC, Horsham, PA
| | | | | | | | | | | | | | | | | | | | - Yi Lin
- Mayo Clinic, Rochester, MN
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