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Goyal A, O'Leary D, Dabaja B, Weng WK, Zain J, Cutler C, Guitart J, Kim YH, Geskin LJ, Hoppe RT, Wilson LD, Beaven AW, Horwitz S, Allen PB, Barta SK, Bohjanen K, Brammer JE, Carter JB, Comfere N, DeSimone JA, Dusenbery K, Duvic M, Huen A, Jagadeesh D, Kelsey CR, Khodadoust MS, Lechowicz MJ, Mehta-Shah N, Moskowitz AJ, Olsen EA, Poh C, Pro B, Querfeld C, Sauter C, Sokol L, Sokumbi O, Wilcox RA, Zic JA, Gru A, Hamadani M, Foss F. ASTCT and USCLC clinical practice recommendations for allogeneic stem cell transplant in mycosis fungoides and Sézary syndrome. J Am Acad Dermatol 2025:S0190-9622(25)00594-8. [PMID: 40199382 DOI: 10.1016/j.jaad.2025.04.005] [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: 09/19/2024] [Revised: 03/30/2025] [Accepted: 04/02/2025] [Indexed: 04/10/2025]
Abstract
INTRODUCTION Mycosis fungoides (MF) and Sézary syndrome (SS) are the most common subtypes of cutaneous T-cell lymphoma. While MF generally follows an indolent course, a subset of patients will experience progressive and/or treatment-refractory disease. SS is an aggressive cutaneous T-cell lymphoma associated with high morbidity and mortality secondary to immune compromise and opportunistic infection. Although allogeneic hematopoietic cell transplant (allo-HCT) is currently the only available potentially curative treatment modality for MF/SS and is included in the National Comprehensive Cancer Network and the American Society for Transplantation and Cellular Therapy treatment guidelines, there is no published guidance regarding referral criteria, timing and allo-HCT approach to help guide clinicians caring for these patients. METHODS Delphi survey of 32 specialists in dermatology (n = 9), transplant hematology/oncology (n = 10), nontransplant hematology/oncology (n = 8), and radiation oncology (n = 5) from across the United States. Consensus required agreement of ≥75% of participants. RESULTS Sixteen consensus statements were generated on 4 topics: 1) criteria for referral for consideration for allo-HCT, 2) allo-HCT preparative regimens and procedures, 3) disease status at the time of allo-HCT, and 4) multidisciplinary management in the pre- and post-transplant settings. CONCLUSION These clinical practice guidelines provide a framework for decision-making regarding allo-HCT for MF/SS and highlight areas for future prospective investigation.
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Affiliation(s)
- Amrita Goyal
- Department of Dermatology, University of Minnesota, Minneapolis, Minnesota.
| | - Daniel O'Leary
- Division of Hematology, Oncology, and Transplantation, University of Minnesota, Minneapolis, Minnesota
| | - Bouthaina Dabaja
- Department of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Wen-Kai Weng
- Blood and Marrow Transplantation, and Cellular Therapy, Department of Medicine, Stanford University, Stanford, California
| | - Jasmine Zain
- Division of Lymphoma, Department of Hematology & Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, California
| | - Corey Cutler
- Division of Transplantation and Cellular Therapy, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Joan Guitart
- Department of Dermatology, Northwestern Feinberg School of Medicine, Evanston, Illinois
| | - Youn H Kim
- Division of Oncology, Departments of Dermatology and Medicine, Stanford University, Stanford, California
| | - Larisa J Geskin
- Department of Dermatology, Columbia University, New York, New York
| | - Richard T Hoppe
- Department of Radiation Oncology, Stanford University, Stanford, California
| | - Lynn D Wilson
- Department of Therapeutic Radiology, Yale School of Medicine, New Haven, Connecticut
| | - Anne W Beaven
- Division of Hematology, University of North Carolina, Chapel Hill, North Carolina
| | - Steve Horwitz
- Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Pamela B Allen
- Department of Hematology & Medical Oncology, Emory University Winship Cancer Institute, Atlanta, Georgia
| | - Stefan K Barta
- Division of Hematology and Oncology, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Kimberly Bohjanen
- Department of Dermatology, University of Minnesota, Minneapolis, Minnesota
| | - Jonathan E Brammer
- Division of Hematology, Ohio State University James Comprehensive Cancer Center, Columbus, Ohio
| | - Joi B Carter
- Department of Dermatology, Dartmouth Hitchcock Medical Center, Lebanon, New Hampshire
| | - Nneka Comfere
- Departments of Dermatology and Laboratory Medicine & Pathology, Mayo Clinic, Rochester, Minnesota
| | - Jennifer A DeSimone
- Department of Dermatology, University of Virginia Schar Cancer Institute, Fairfax, Virginia
| | - Kathryn Dusenbery
- Department of Radiation Oncology, University of Minnesota, Minneapolis, Minnesota
| | - Madeleine Duvic
- Department of Dermatology, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Auris Huen
- Department of Dermatology, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Deepa Jagadeesh
- Department of Hematology and Medical Oncology, Cleveland Clinic Taussig Cancer Center, Cleveland, Ohio
| | - Chris R Kelsey
- Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina
| | - Michael S Khodadoust
- Division of Oncology, Department of Medicine, Stanford University, Stanford, California
| | - Mary Jo Lechowicz
- Department of Hematology and Medical Oncology, Emory University, Atlanta, Georgia
| | - Neha Mehta-Shah
- Division of Oncology, Department of Medicine, Washington University School of Medicine in St. Louis, St. Louis, Missouri
| | - Alison J Moskowitz
- Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Elise A Olsen
- Departments of Dermatology and Medicine, Duke University Medical Center, Durham, North Carolina
| | - Christina Poh
- Division of Hematology and Oncology, University of Washington, Seattle, Washington
| | - Barbara Pro
- Department of Hematology and Oncology, New York Presbyterian - Columbia University Irving Medical Center, New York, New York
| | - Christiane Querfeld
- Division of Dermatology, Department of Pathology, Beckman Research Institute, City of Hope National Medical Center, Duarte, California
| | - Craig Sauter
- Department of Hematology and Medical Oncology, Cleveland Clinic Taussig Cancer Center, Cleveland, Ohio
| | - Lubomir Sokol
- Malignant Hematology, Moffitt Cancer Center, Tampa, Florida
| | - Olayemi Sokumbi
- Departments of Dermatology and Laboratory Medicine & Pathology, Mayo Clinic, Jacksonville, Florida
| | - Ryan A Wilcox
- Division of Internal Medicine, Hematology/Oncology, University of Michigan, Ann Arbor, Michigan
| | - John A Zic
- Department of Dermatology, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Alejandro Gru
- Department of Dermatology, Columbia University, New York, New York
| | - Mehdi Hamadani
- Division of Hematology & Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Francine Foss
- Department of Hematology/Oncology, Yale University School of Medicine, New Haven, Connecticut
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Shatila M, Machado AP, Shah J, Rivera AU, Naz S, Glombicki S, Wali S, Lu E, Short N, Thomas A, Zhang HC, Wang Y. Checkpoint Inhibition Prior to Stem Cell Transplantation Increases the Risk of Inflammatory Adverse Events. Target Oncol 2025; 20:329-337. [PMID: 39904838 DOI: 10.1007/s11523-025-01127-7] [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: 01/15/2025] [Indexed: 02/06/2025]
Abstract
BACKGROUND Stem cell transplantation (SCT) and immune checkpoint inhibitors (ICIs) are both used in the treatment of hematological malignancies. There may be an overlap in patient exposure to both treatments. Theoretically, ICIs potentiate the graft-versus-tumor effect following SCT but may increase the risk of inflammatory adverse events (AEs). Conversely, immunosuppression following SCT may decrease the risk of immune-mediated AEs. OBJECTIVES We aimed to explore the effect of immunotherapy on the risk and severity of inflammatory AEs following SCT. PATIENTS AND METHODS We performed a single-center, retrospective chart review that included all patients with a hematological malignancy treated with immunotherapy and who received SCT. Patients who did not receive immunosuppressive regimens after their transplant (e.g., autologous transplants) were excluded. Patients were divided into two groups based on ICI timing: pre-SCT ICI (group 1) and post-SCT ICI (group 2). RESULTS A total of 63 patients were included. Around 82% of patients in group 1 experienced a post-transplant AE compared with 50% in group 2 (p = 0.014). These AEs occurred earlier in group 1 patients (median 57 days in group 1 versus 195 in group 2; p = 0.007). Roughly 80% of the inflammatory conditions involved the gastrointestinal system. Severity and complication rates did not differ between groups, but gastrointestinal inflammation in group 1 was more likely to require immunosuppressive medication (75.7% and 37.8% requiring corticosteroids and selective immunosuppressive therapy, respectively, in group 1 patients versus 33.3% and 0% in group 2 patients; p < 0.05). CONCLUSION To our knowledge, our study is one of few exploring the impact of ICI timing in relation to SCT on the risk of post-SCT inflammatory AEs. Administration of immunotherapy prior to SCT may predispose patients to inflammatory AEs after SCT, which may occur earlier and last longer than if ICIs are started after SCT. Future studies are needed to further explore this phenomenon.
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Affiliation(s)
- Malek Shatila
- Department of Gastroenterology, Hepatology, and Nutrition, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 1466, Houston, TX, 77030, USA
| | - Antonio Pizuorno Machado
- Department of Internal Medicine, The University of Texas Health Science Center, Houston, TX, USA
| | - Jay Shah
- Department of Internal Medicine, Baylor College of Medicine, Houston, TX, USA
| | - Andres Urias Rivera
- Department of Internal Medicine, Baylor College of Medicine, Houston, TX, USA
| | - Sidra Naz
- Department of Gastroenterology, Hepatology, and Nutrition, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 1466, Houston, TX, 77030, USA
| | - Stephen Glombicki
- Department of Internal Medicine, The University of Texas Health Science Center, Houston, TX, USA
| | - Sharada Wali
- Department of Gastroenterology, Hepatology, and Nutrition, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 1466, Houston, TX, 77030, USA
| | - Eric Lu
- Department of Gastroenterology, Hepatology, and Nutrition, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 1466, Houston, TX, 77030, USA
- Department of Biology, Texas A&M University, College Station, TX, USA
| | - Nicholas Short
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Anusha Thomas
- Department of Gastroenterology, Hepatology, and Nutrition, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 1466, Houston, TX, 77030, USA
| | - Hao Chi Zhang
- Department of Gastroenterology, Hepatology, and Nutrition, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 1466, Houston, TX, 77030, USA
| | - Yinghong Wang
- Department of Gastroenterology, Hepatology, and Nutrition, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 1466, Houston, TX, 77030, USA.
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3
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Brijs J, Peczynski C, Boreland W, Cuoghi A, Maertens J, Mohty M, Kröger N, Nakov P, Broers AEC, Eder M, Herrera Arroyo C, Kaufmann M, Ram R, Schaap NPM, Graham C, Mussetti A, Penack O, Moiseev I, Peric Z, Schoemans H. Immune checkpoint inhibitors therapy for solid organ malignancies after allogeneic hematopoietic stem cell transplantation: a retrospective study from the EBMT Transplant Complications Working Party. Bone Marrow Transplant 2025; 60:415-417. [PMID: 39668190 DOI: 10.1038/s41409-024-02497-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2024] [Revised: 11/23/2024] [Accepted: 12/05/2024] [Indexed: 12/14/2024]
Affiliation(s)
- J Brijs
- Department of Hematology, University Hospitals Leuven, Leuven, Belgium.
| | - C Peczynski
- EBMT Paris Study Office / CEREST-TC, INSERM UMR-S 938, Department of Hematology, Sorbonne University, Hôpital Saint Antoine, Paris, France
- EBMT Transplant Complications Working Party (TCWP), Paris, France
| | - W Boreland
- EBMT Paris Study Office / CEREST-TC, INSERM UMR-S 938, Department of Hematology, Sorbonne University, Hôpital Saint Antoine, Paris, France
- EBMT Transplant Complications Working Party (TCWP), Paris, France
| | - A Cuoghi
- Azienda Ospedaliero-Universitaria di Modena, Modena, Italy
| | - J Maertens
- Department of Hematology, University Hospitals Leuven, Leuven, Belgium
- Department of Microbiology, Immunology, and Transplantation, KU Leuven, Leuven, Belgium
| | - M Mohty
- Department of Hematology, Sorbonne University, Hôpital Saint Antoine, Paris, France
| | - N Kröger
- Department for Stem Cell Transplantation, University Medical Centre Hamburg, Hamburg, Germany
| | - P Nakov
- Division for Stem Cell Transplantation and Cellular Immunotherapy, Department of Medicine II, University Hospital Schleswig-Holstein Campus Kiel, Kiel, Germany
| | - A E C Broers
- Department of Hematology, Erasmus MC Cancer Institute, Rotterdam, Netherlands
| | - M Eder
- Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany
| | | | - M Kaufmann
- Robert Bosch Hospital, Stuttgart, Germany
| | - R Ram
- Bone Marrow Transplantation Unit, Hematology department, Tel Aviv Sourasky Medical Centre, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - N P M Schaap
- Radboud University Medical Centre, Nijmegen, Netherlands
| | - C Graham
- EBMT Transplant Complications Working Party (TCWP), Paris, France
- Comprehensive Cancer Centre, King's College London, London, UK
| | - A Mussetti
- EBMT Transplant Complications Working Party (TCWP), Paris, France
- Department of Hematology, Catalan Institute of Oncology, Hospital Duran i Reynals, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain
| | - O Penack
- EBMT Transplant Complications Working Party (TCWP), Paris, France
- Medical Clinic, Department of Hematology, Oncology and Tumor Immunology, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - I Moiseev
- EBMT Transplant Complications Working Party (TCWP), Paris, France
- RM Gorbacheva Research Institute, First Pavlov State Medical University of St Petersburg, St Petersburg, Russian Federation
| | - Z Peric
- EBMT Transplant Complications Working Party (TCWP), Paris, France
- Department of Hematology, University Hospital Centre Rijeka, and School of Medicine, University of Rijeka, Rijeka, Croatia
| | - H Schoemans
- Department of Hematology, University Hospitals Leuven, Leuven, Belgium
- EBMT Transplant Complications Working Party (TCWP), Paris, France
- Department of Public Health and Primary Care, ACCENT VV, KU Leuven - University of Leuven, Leuven, Belgium
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4
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Choi JK, Mbanefo EC, Yadav MK, Alhakeem SA, Nagarajan V, Nunes NS, Kanakry CG, Egwuagu CE. Interleukin 35-producing B cells prolong the survival of GVHD mice by secreting exosomes with membrane-bound IL-35 and upregulating PD-1/LAG-3 checkpoint proteins. Theranostics 2025; 15:3610-3626. [PMID: 40093899 PMCID: PMC11905137 DOI: 10.7150/thno.105069] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2024] [Accepted: 01/18/2025] [Indexed: 03/19/2025] Open
Abstract
Background: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an effective treatment for aggressive hematologic malignancies. However, the risk of developing graft-versus-host disease (GVHD) is a significant barrier to allo-HSCT. GVHD is a debilitating condition with high mortality rates and current therapeutic options for GVHD are limited, with corticosteroids being the standard treatment. However, the adverse effects of steroids make prolonged use difficult, necessitating the development of safer therapies. IL-35-producing B-cells (i35-Bregs) have emerged as critical regulators of immunity during autoimmune diseases. In this study, we investigated whether i35-Bregs immunotherapy can suppress and mitigate GVHD. Methods: We administered a single dose of i35-Bregs (1.5×106) to mice undergoing allo-HSCT and monitored disease severity and survival of GVHD mice over 90 days post-transplantation. We discovered that i35-Bregs secrete exosomes containing membrane-bound IL-35 (i35-Exosomes) and investigated whether ex-vivo generated i35-exosomes can be used as stand-alone immunotherapy for GVHD. i35-Breg-induced expression of cytokines or checkpoint proteins (PD-1, LAG-3, CTLA-4) was analyzed by Flow cytometry, ELISA, and RNA-seq analysis. Characterization of membrane-bound IL-35 was by Proximity ligation assay (PLA), immunohistochemistry/Confocal microscopy and Alpha Fold-Multimer modeling. Results: A single dose of 1.5×106 i35-Breg reduced severity of GVHD and prolonged GVHD survival, with more than 70% i35-Breg-treated mice surviving beyond day-90 post-transplantation while observing 100% mortality among untreated mice by day-45. Contrary to the view that IL-35 is secreted cytokine, we show here that i35-Bregs mitigate GVHD via membrane-bound IL-35 and by secreting i35-exosomes. Furthermore, i35-Bregs or ex-vivo generated i35-exosomes induce alloreactive T-cells to upregulate checkpoint proteins associated with T-cell exhaustion and anergy, inhibiting alloreactive responses and propagating infectious-tolerance mechanisms that suppress GVHD. Importantly, i35-Bregs or i35-exosomes suppresses GVHD by increasing bystander lymphocytes coated with immunosuppressive i35-exosomes. Conclusions: This study demonstrates that i35-Bregs and i35-exosomes play a critical role in mitigating GVHD. The combination of i35-Breg and i35-exosome immunotherapy may be an effective strategy for treating GVHD and other inflammatory diseases.
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Affiliation(s)
- Jin Kyeong Choi
- Molecular Immunology Section, Laboratory of Immunology, National Eye Institute (NEI), National Institutes of Health (NIH), Bethesda, MD 20892, United States of America (USA)
- Department of Immunology, Jeonbuk National University Medical School, Jeonju, Jeonbuk, 54907, Republic of Korea
| | - Evaristus C. Mbanefo
- Molecular Immunology Section, Laboratory of Immunology, National Eye Institute (NEI), National Institutes of Health (NIH), Bethesda, MD 20892, United States of America (USA)
| | - Manoj Kumar Yadav
- Molecular Immunology Section, Laboratory of Immunology, National Eye Institute (NEI), National Institutes of Health (NIH), Bethesda, MD 20892, United States of America (USA)
| | - Sahar A. Alhakeem
- Molecular Immunology Section, Laboratory of Immunology, National Eye Institute (NEI), National Institutes of Health (NIH), Bethesda, MD 20892, United States of America (USA)
- Department of Biomedical Sciences, College of Health Sciences, University of Wisconsin-Milwaukee, Milwaukee, WI, United States
| | - Vijayaraj Nagarajan
- Molecular Immunology Section, Laboratory of Immunology, National Eye Institute (NEI), National Institutes of Health (NIH), Bethesda, MD 20892, United States of America (USA)
| | - Natalia S. Nunes
- Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda MD 20892, United States of America
| | - Christopher G. Kanakry
- Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda MD 20892, United States of America
| | - Charles E. Egwuagu
- Molecular Immunology Section, Laboratory of Immunology, National Eye Institute (NEI), National Institutes of Health (NIH), Bethesda, MD 20892, United States of America (USA)
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5
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Perales MA, Ahmed S. When to use stem cell transplantation for classical Hodgkin lymphoma. HEMATOLOGY. AMERICAN SOCIETY OF HEMATOLOGY. EDUCATION PROGRAM 2024; 2024:517-523. [PMID: 39644064 DOI: 10.1182/hematology.2024000575] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/09/2024]
Abstract
Hodgkin lymphoma (HL) is a rare hematologic malignancy with a bimodal distribution of incidence, with most patients diagnosed between the ages of 15 and 30 years and another peak in patients older than 55 years. It is estimated that in 2023, almost 9000 people were diagnosed with HL in the United States. Most patients will be cured using conventional chemotherapy and radiotherapy. The treatment of HL has changed significantly over the past decade following the approval of highly effective novel therapies, including brentuximab vedotin and the checkpoint inhibitors (CPIs) nivolumab and pembrolizumab. The increasing use of these novel therapies has resulted in decreased utilization of both autologous and allogeneic hematopoietic cell transplantation (HCT) in patients with HL. In this review, we discuss the role of stem cell transplantation in patients with HL, with a particular focus on recent data supporting allogeneic HCT as a curative option in patients who progress on or are intolerant to CPI treatment.
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Affiliation(s)
- Miguel-Angel Perales
- Adult Bone Marrow Transplantation Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
- Department of Medicine, Weill Cornell Medical College, New York, NY
| | - Sairah Ahmed
- Department of Lymphoma/Myeloma and Department of Stem Cell Transplantation/Cellular Therapy, MD Anderson Cancer Center, Houston, TX
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6
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Guo SY, Wang J, Fang JP, Lei JY, Wu XQ, Qiu KY, Zhou DH. Treatment of pediatric refractory or relapsed Epstein-Barr virus-associated hemophagocytic syndrome with PD-1 inhibitors. Pediatr Blood Cancer 2024; 71:e31340. [PMID: 39334539 DOI: 10.1002/pbc.31340] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Revised: 08/28/2024] [Accepted: 09/08/2024] [Indexed: 09/30/2024]
Abstract
PURPOSE Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis (EBV-HLH) is a type of pediatric HLH that occurs frequently in Asia. Although immunochemotherapy based on etoposide and hormone has improved survival rates, there are still about 30% of HLH patients that do not respond. The objective of the article is to examine the efficacy and safety of programmed cell death protein 1 (PD-1) inhibitors for children with relapsed/refractory (r/r) EBV-HLH. METHODS A retrospective case note review of four pediatric patients with r/r EBV-HLH who were treated with PD-1 inhibitors at Sun Yat-sen Memorial Hospital, Sun Yat-sen University. RESULTS All four patients responded to PD-1 inhibitors and achieved partial response after their first infusion. Plasma EBV DNA copy number and HLH-related monitoring indicators decreased in all of these patients. All patients received allogeneic hematopoietic stem cell transplantation (allo-HSCT), and two were still alive at the last follow-up on December 30, 2022. Two patients died because of transplantation-related complications. Serious side effects included increased liver enzymes and edema in two patients. CONCLUSION PD-1 inhibitors are an effective salvage therapy and can provide a bridge to allo-HSCT for pediatric patients with r/r EBV-HLH. However, side effects should be monitered.
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Affiliation(s)
- Shu-Yi Guo
- Department of Hematology/Oncology, Children's Medical Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Jian Wang
- Department of Hematology/Oncology, Children's Medical Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Jian-Pei Fang
- Department of Hematology/Oncology, Children's Medical Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Jia-Ying Lei
- Department of Hematology/Oncology, Children's Medical Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Xiao-Qin Wu
- Department of Hematology/Oncology, Children's Medical Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Kun-Yin Qiu
- Department of Hematology/Oncology, Children's Medical Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Dun-Hua Zhou
- Department of Hematology/Oncology, Children's Medical Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
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7
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Goyal A, O'Leary D, Dabaja B, Weng WK, Zain J, Cutler C, Guitart J, Kim YH, Geskin LJ, Hoppe RT, Wilson LD, Beaven AW, Horwitz S, Allen PB, Barta SK, Bohjanen K, Brammer JE, Carter JB, Comfere N, DeSimone JA, Dusenbery K, Duvic M, Huen A, Jagadeesh D, Kelsey CR, Khodadoust MS, Lechowicz MJ, Mehta-Shah N, Moskowitz AJ, Olsen EA, Poh C, Pro B, Querfeld C, Sauter C, Sokol L, Sokumbi O, Wilcox RA, Zic JA, Hamadani M, Foss F. ASTCT and USCLC Clinical Practice Recommendations for Allogeneic Stem Cell Transplant in Mycosis Fungoides and Sézary Syndrome. Transplant Cell Ther 2024; 30:1047-1060. [PMID: 39222792 DOI: 10.1016/j.jtct.2024.08.020] [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: 08/25/2024] [Accepted: 08/26/2024] [Indexed: 09/04/2024]
Abstract
Mycosis fungoides (MF) and Sézary syndrome (SS) are the most common subtypes of cutaneous T-cell lymphoma (CTCL). While MF generally follows an indolent course, a subset of patients will experience progressive and/or treatment-refractory disease; Sézary syndrome is an aggressive lymphoma associated with high morbidity and mortality. Although allogeneic hematopoietic cell transplant (allo-HCT) is the only currently available potentially curative treatment modality for MF/SS there is no published guidance on referral criteria, transplant timing orallo-HCT approach. To develop consensus clinical practice recommendations, we performed a Delphi survey of 32 specialists in dermatology (n = 9), transplant hematology/oncology (n = 10), non-transplant hematology/oncology (n = 8), and radiation oncology (n = 5) from across the United States. Consensus required agreement of ≥75% of participants. Sixteen consensus statements were generated on four topics: (1) criteria for referral for consideration for allo-HCT, (2) allo-HCT preparative regimens and procedures (3) disease status at the time of allo-HCT, and (4) multidisciplinary management in the pre- and post-transplant settings. These clinical practice guidelines provide a framework for decision-making regarding allo-HCT for MF/SS and highlight areas for future prospective investigation.
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Affiliation(s)
- Amrita Goyal
- Department of Dermatology, University of Minnesota, Minneapolis, Minnesota.
| | - Daniel O'Leary
- Division of Hematology, Oncology, and Transplantation, University of Minnesota, Minneapolis, Minnesota
| | - Bouthaina Dabaja
- Department of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Wen-Kai Weng
- Blood and Marrow Transplantation, and Cellular Therapy, Department of Medicine, Stanford University, Stanford, California
| | - Jasmine Zain
- Division of Lymphoma, Department of Hematology & Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, California
| | - Corey Cutler
- Division of Transplantation and Cellular Therapy, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Joan Guitart
- Department of Dermatology, Northwestern Feinberg School of Medicine, Evanston, Illinois
| | - Youn H Kim
- Departments of Dermatology and Medicine/Division of Oncology, Stanford University, Stanford, California
| | - Larisa J Geskin
- Department of Dermatology, Columbia University, New York, New York
| | - Richard T Hoppe
- Department of Radiation Oncology, Stanford University, Stanford, California
| | - Lynn D Wilson
- Department of Therapeutic Radiology, Yale School of Medicine, New Haven, Connecticut
| | - Anne W Beaven
- Division of Hematology, University of North Carolina, Chapel Hill, North Carolina
| | - Steve Horwitz
- Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Pamela B Allen
- Department of Hematology & Medical Oncology, Emory University Winship Cancer Institute, Atlanta, Georgia
| | - Stefan K Barta
- Division of Hematology and Oncology, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Kimberly Bohjanen
- Department of Dermatology, University of Minnesota, Minneapolis, Minnesota
| | - Jonathan E Brammer
- Division of Hematology, Ohio State University James Comprehensive Cancer Center, Columbus, Ohio
| | - Joi B Carter
- Department of Dermatology, Dartmouth Hitchcock Medical Center, Lebanon, New Hampshire
| | - Nneka Comfere
- Departments of Dermatology and Laboratory Medicine & Pathology, Mayo Clinic, Rochester, Minnesota
| | - Jennifer A DeSimone
- Department of Dermatology, University of Virginia Schar Cancer Institute, Fairfax, Virginia
| | - Kathryn Dusenbery
- Department of Radiation Oncology, University of Minnesota, Minneapolis, Minnesota
| | - Madeleine Duvic
- Department of Dermatology, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Auris Huen
- Department of Dermatology, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Deepa Jagadeesh
- Department of Hematology and Medical Oncology, Cleveland Clinic Taussig Cancer Center, Cleveland, Ohio
| | - Chris R Kelsey
- Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina
| | - Michael S Khodadoust
- Division of Oncology, Department of Medicine, Stanford University, Stanford, California
| | - Mary Jo Lechowicz
- Department of Hematology and Medical Oncology, Emory University, Atlanta, Georgia
| | - Neha Mehta-Shah
- Department of Medicine, Division of Oncology, Washington University School of Medicine in St. Louis, St. Louis, Missouri
| | - Alison J Moskowitz
- Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Elise A Olsen
- Departments of Dermatology and Medicine, Duke University Medical Center, Durham, North Carolina
| | - Christina Poh
- Division of Hematology and Oncology, University of Washington, Seattle, Washington
| | - Barbara Pro
- Department of Hematology and Oncology, New York Presbyterian - Columbia University Irving Medical Center, New York, New York
| | - Christiane Querfeld
- Department of Pathology, Division of Dermatology & Beckman Research Institute, City of Hope National Medical Center, Duarte, California
| | - Craig Sauter
- Department of Hematology and Medical Oncology, Cleveland Clinic Taussig Cancer Center, Cleveland, Ohio
| | - Lubomir Sokol
- Malignant Hematology, Moffitt Cancer Center, Tampa, Florida
| | - Olayemi Sokumbi
- Departments of Dermatology and Laboratory Medicine & Pathology, Mayo Clinic, Jacksonville, Florida
| | - Ryan A Wilcox
- Division of Internal Medicine, Division of Hematology/Oncology, University of Michigan, Ann Arbor, Michigan
| | - John A Zic
- Department of Dermatology, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Mehdi Hamadani
- Division of Hematology & Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Francine Foss
- Department of Hematology/Oncology, Yale University School of Medicine, New Haven, Connecticut
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8
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Schafer ES, Rushing T, Crews KR, Annesley C, Colace SI, Kaiser N, Pommert L, Ramsey LB, Sabnis HS, Wong K, Chang BH, Cooper TM, Shah NN, Rheingold SR, Place AE, Chi YY, Bhojwani D, Wayne AS, Bernhardt MB. Optimizing early phase clinical trial washout periods: a report from the Therapeutic Advances in Childhood Leukemia and Lymphoma consortium. J Natl Cancer Inst 2024; 116:1721-1729. [PMID: 38964343 PMCID: PMC11542989 DOI: 10.1093/jnci/djae165] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2024] [Revised: 05/30/2024] [Accepted: 06/26/2024] [Indexed: 07/06/2024] Open
Abstract
BACKGROUND The National Cancer Institute (NCI) issued a 2021 memorandum adopting the American Society of Clinical Oncology (ASCO) and Friends of Cancer Research (Friends) task force recommendations to broaden clinical study eligibility criteria. They recommended that washout periods be eliminated for most prior cancer therapy and when required to utilize evidence- and/or rationale-based criteria. The Therapeutic Advances in Childhood Leukemia and Lymphoma (TACL) consortium responded to this guidance. METHODS A TACL task force reviewed the consortium's research portfolio, the relevant literature and guidance documents from ASCO-Friends, NCI, and US Food and Drug Administration to make expert consensus and evidence-based recommendations for modernizing, broadening, and codifying TACL-study washout periods while ensuring consistency with pediatric ethics, and federal regulations. TACL's screening log was reviewed to estimate the impact that updated washout periods would have on patient inclusivity and recruitment. RESULTS Over a 19-year period, 42 (14.6% of all screened ineligible patients [n = 287]) patients were identified as excluded from TACL early phase studies exclusively because of not meeting washout criteria. An additional 6 (2.1%) did not meet washout and at least 1 other exclusion criterion. A new TACL washout guidance document was developed and then adopted for use. Where washout criteria were not eliminated, rationale- and/or evidenced-based criteria were established with citation. CONCLUSION In an effort to reduce unnecessary exclusion from clinical trials, TACL created rationale- and/or evidenced-based washout period standards largely following guidance from the NCI and ASCO-Friends recommendations. These new, expanded eligibility criteria are expected to increase access to TACL clinical trials while maintaining safety and scientific excellence.
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Affiliation(s)
- Eric S Schafer
- Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA
- Texas Children’s Cancer and Hematology Center, Texas Children’s Hospital, Houston, TX, USA
| | - Teresa Rushing
- Cancer and Blood Disease Institute, Children’s Hospital Los Angeles, Los Angeles, CA, USA
| | - Kristine R Crews
- Department of Pharmacy and Pharmaceutical Sciences, St Jude Children’s Research Hospital, Memphis, TN, USA
| | - Colleen Annesley
- Seattle Children’s Hospital Cancer and Blood Disorders Service, University of Washington School of Medicine, Seattle, WA, USA
| | - Susan I Colace
- Division of Hematology, Oncology and Blood and Marrow Transplant, Nationwide Children’s Hospital, Columbus, OH, USA
- Department of Pediatrics, the Ohio State University College of Medicine, Columbus, OH, USA
| | - Nicole Kaiser
- Center for Cancer and Blood Disorders, Children’s Hospital Colorado, Aurora, CO, USA
| | - Lauren Pommert
- Division of Oncology, Cancer and Blood Diseases Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Laura B Ramsey
- Division of Clinical Pharmacology, Toxicology and Therapeutic Innovation, Children’s Mercy Kansas City, Department of Pediatrics, University of Missouri, Kansas City, MO, USA
| | - Himalee S Sabnis
- Aflac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta, Atlanta, GA, USA
- Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA
| | - Kenneth Wong
- Cancer and Blood Disease Institute, Children’s Hospital Los Angeles, Los Angeles, CA, USA
- University of Southern California Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Bill H Chang
- Division of Pediatric Hematology Oncology, Oregon Health and Science University, Portland, OR, USA
| | - Todd M Cooper
- Seattle Children’s Hospital Cancer and Blood Disorders Service, University of Washington School of Medicine, Seattle, WA, USA
| | - Nirali N Shah
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Susan R Rheingold
- Division of Oncology and Center for Childhood Cancer Research, Children’s Hospital of Philadelphia, Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Andrew E Place
- Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, Harvard Medical School, Boston, MA, USA
| | - Yueh-Yun Chi
- Cancer and Blood Disease Institute, Children’s Hospital Los Angeles, Los Angeles, CA, USA
- University of Southern California Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Deepa Bhojwani
- Cancer and Blood Disease Institute, Children’s Hospital Los Angeles, Los Angeles, CA, USA
- University of Southern California Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Alan S Wayne
- Cancer and Blood Disease Institute, Children’s Hospital Los Angeles, Los Angeles, CA, USA
- University of Southern California Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - M Brooke Bernhardt
- Department of Pharmacy and Pharmaceutical Sciences, St Jude Children’s Research Hospital, Memphis, TN, USA
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9
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Kaphan E, Bettega F, Vallet N, Fegueux N, Robin M, Bazarbachi A, Nguyen S, Beauvais D, Forcade E, De Oca MCM, Devillier R, Chevallier P, Loschi M, Huynh A, Bay JO, Rubio MT, Suarez F, Francois S, Poire X, Contentin N, Desmier D, Charbonnier A, Cornillon J, Chantepie S, Turlure P, Bulabois CE, Michonneau D, Villate A, Sfgm-Tc. PD-1 blockade and allogeneic hematopoietic stem cell transplantation in Hodgkin lymphoma, a matter of time: a national study on behalf of the Société Francophone de Greffe de Moelle et de Thérapie Cellulaire. Haematologica 2024; 109:3373-3378. [PMID: 38867585 PMCID: PMC11443360 DOI: 10.3324/haematol.2024.284968] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2024] [Accepted: 05/24/2024] [Indexed: 06/14/2024] Open
Affiliation(s)
- Eleonore Kaphan
- Hematology and transplantation Unit, Saint Louis Hospital, Assistance Publique des Hopitaux de Paris, Paris.
| | - Francois Bettega
- HP2 Laboratory, INSERM U1042, University Grenoble Alpes, Grenoble
| | - Nicolas Vallet
- Hematology and transplantation Unit, Tours Hospital, Tours
| | - Nathalie Fegueux
- Hematology and transplantation Unit, Montpellier Hospital, Montpellier
| | - Marie Robin
- Hematology and transplantation Unit, Saint Louis Hospital, Assistance Publique des Hopitaux de Paris, Paris
| | - Ali Bazarbachi
- Bone Marrow Transplantation Program, Department of Internal Medicine, American University of Beirut Medical Center, Beirut
| | - Stephanie Nguyen
- Hematology and transplantation Unit, Pitie-Salpetriere Hospital, Assistance Publique des Hopitaux de Paris, Paris
| | | | - Edouard Forcade
- Hematology and transplantation Unit, Bordeaux Hospital, Bordeaux
| | | | - Raynier Devillier
- Hematology and transplantation Unit, Paoli Calmettes Institut, Marseille
| | | | - Michael Loschi
- Hematology and transplantation Unit, Nice Hospital, Nice
| | - Anne Huynh
- Hematology and transplantation Unit, CRCT, Toulouse
| | - Jacques-Olivier Bay
- Hematology and transplantation Unit, Clermont-Ferrand Hospital, Clermont-Ferrand
| | - Marie-Therese Rubio
- Service d'Hematologie Adulte, Hopital Brabois, CHRU Nancy, 54500 Vandoeuvre les Nancy
| | - Felipe Suarez
- Service Hematologie Adultes Hopital universitaire Necker Enfants Malades, APHP, Paris
| | | | - Xavier Poire
- Hematology and transplantation Unit, Saint-Luc Clinical universitary, Belgium
| | | | - Deborah Desmier
- Service d'Hematologie et Therapie Cellulaire, Hopital La Miletrie, Poitiers
| | | | - Jerome Cornillon
- Departement d'Hematologie clinique et de therapie cellulaire, CHU St-Etienne, St Etienne
| | | | - Pascal Turlure
- Hematology and transplantation Unit, Limoges Hospital, Limoges
| | | | - David Michonneau
- Hematology and transplantation Unit, Saint Louis Hospital, Assistance Publique des Hopitaux de Paris, Paris, France; INSERM U976, Human Immunology, Pathophysiology and Immunotherapy, Universite Paris Cite, F-75010, Paris
| | - Alban Villate
- Hematology and transplantation Unit, Tours Hospital, Tours
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10
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Pang L, Wu WR, Xu LB, Liu C. Fatal graft-versus-host disease in recipient with pretransplant exposure to immune checkpoint inhibitors and donor-dominant one-way HLA matching after liver transplantation: A case report. Int J Surg Case Rep 2024; 123:110267. [PMID: 39265369 PMCID: PMC11415855 DOI: 10.1016/j.ijscr.2024.110267] [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: 08/03/2024] [Revised: 09/03/2024] [Accepted: 09/06/2024] [Indexed: 09/14/2024] Open
Abstract
INTRODUCTION AND IMPORTANCE Graft-versus-host disease (GvHD) is a rare but severe complication following liver transplantation (LT), occurring in 1-2 % of cases with a mortality rate exceeding 80 %. Immune checkpoint inhibitors (ICIs) used pretransplant are associated with increased allograft rejection risk, but their impact on GvHD in LT remains unclear. Dominant one-way donor-recipient human leukocyte antigen (HLA) matching is a known risk factor for GvHD. This report presents a rare case of fatal GvHD in a hepatocellular carcinoma (HCC) patient treated with PD-1 inhibitors before LT and transplanted with a liver graft from a deceased donor with donor-dominant one-way HLA matching. CASE PRESENTATION A 59-year-old male with a 30-year history of hepatitis B and unresectable HCC underwent LT after receiving the last dose of PD-1 inhibitors 7 days prior to the transplant. On post-operative day (POD) 12, the patient developed a skin rash, fever, and vomiting, and was diagnosed with GvHD. Despite aggressive treatment, including high-dose corticosteroids and extracorporeal membrane oxygenation (ECMO), the patient succumbed to gastrointestinal bleeding and multi-organ failure on POD 30. HLA genotyping revealed typical donor-dominant one-way HLA matching. CLINICAL DISCUSSION This case highlights a potential link between pretransplant exposure to ICIs and GvHD, particularly with donor-dominant one-way HLA matching. Residual anti-PD-1 antibodies may activate graft-resident immune cells, precipitating GvHD. Further research with larger cohorts and animal models is required to clarify this relationship and understand the underlying mechanisms. CONCLUSION Besides allograft rejection, caution should also be exercised regarding GvHD in patients with prior exposure to ICIs before LT.
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Affiliation(s)
- Li Pang
- Liver Transplantation Center, Department of Biliary-Pancreatic Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, 510120 Guangzhou, China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China
| | - Wen-Rui Wu
- Liver Transplantation Center, Department of Biliary-Pancreatic Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, 510120 Guangzhou, China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China
| | - Lei-Bo Xu
- Liver Transplantation Center, Department of Biliary-Pancreatic Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, 510120 Guangzhou, China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China
| | - Chao Liu
- Liver Transplantation Center, Department of Biliary-Pancreatic Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, 510120 Guangzhou, China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China.
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11
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Mariotti J, Zucchinetti C, Giordano L, De Philippis C, Mannina D, Sarina B, Taurino D, Carbon R, Santoro A, Bramanti S. Allogeneic transplantation after immunotherapy for relapsed/refractory non-Hodgkin lymphoma: a comparison with a historical cohort. Cytotherapy 2024; 26:1163-1169. [PMID: 38775776 DOI: 10.1016/j.jcyt.2024.05.002] [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: 03/22/2024] [Revised: 05/01/2024] [Accepted: 05/01/2024] [Indexed: 09/28/2024]
Abstract
BACKGROUND AIMS New immunotherapy drugs, such as bispecific T-cell engager antibodies, checkpoint inhibitors and antibody-drug conjugates, are commonly used as salvage therapy for patients with non-Hodgkin lymphoma relapsing after chimeric antigen receptor (CAR) T-cell therapy. Nevertheless, their potential long-term effects on the outcome of allogeneic stem cell transplantation (Allo-SCT) are not well known. METHODS We retrospectively analyzed the outcomes of 27 relapsed/refractory non-Hodgkin lymphoma patients receiving Allo-SCT after immunotherapy in the pre-CAR T-cell therapy era and compared them with a historical cohort of 28 subjects undergoing Allo-SCT after conventional therapy. RESULTS The two cohorts had similar outcomes in terms of graft-versus-host disease/relapse-free survival (4 years, 59% versus 46%), overall survival (4 years, 77% versus 44%), non-relapse mortality (4 years, 19% versus 22%) and acute (6 months, 15% versus 21%) and chronic (4 years, 18% versus 24%) graft-versus-host disease. Of note, the cumulative incidence of relapse was lower after immunotherapy (4 years, 4% versus 14%), although significance was not reached. The cumulative incidence of cytomegalovirus and fungal infection did not differ among the two cohorts. CONCLUSIONS Consolidation with Allo-SCT is a safe and curative option for patients achieving disease response after new immunotherapy drugs that could represent a desirable salvage strategy for patients relapsing after CAR T-cell therapy.
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Affiliation(s)
- Jacopo Mariotti
- Department of Oncology/Hematology, Humanitas Research Hospital, Istituto di Ricovero e cura a carattere scientifico, Rozzano, Milan, Italy.
| | - Cristina Zucchinetti
- Department of Oncology/Hematology, Humanitas Research Hospital, Istituto di Ricovero e cura a carattere scientifico, Rozzano, Milan, Italy; Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy
| | - Laura Giordano
- Biostatistic Unit, Humanitas Research Hospital, Istituto di Ricovero e Cura a Carattere Scientifico, Rozzano, Milan, Italy
| | - Chiara De Philippis
- Department of Oncology/Hematology, Humanitas Research Hospital, Istituto di Ricovero e cura a carattere scientifico, Rozzano, Milan, Italy
| | - Daniele Mannina
- Department of Oncology/Hematology, Humanitas Research Hospital, Istituto di Ricovero e cura a carattere scientifico, Rozzano, Milan, Italy
| | - Barbara Sarina
- Department of Oncology/Hematology, Humanitas Research Hospital, Istituto di Ricovero e cura a carattere scientifico, Rozzano, Milan, Italy
| | - Daniela Taurino
- Department of Oncology/Hematology, Humanitas Research Hospital, Istituto di Ricovero e cura a carattere scientifico, Rozzano, Milan, Italy
| | - Rachele Carbon
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy
| | - Armando Santoro
- Department of Oncology/Hematology, Humanitas Research Hospital, Istituto di Ricovero e cura a carattere scientifico, Rozzano, Milan, Italy; Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy
| | - Stefania Bramanti
- Department of Oncology/Hematology, Humanitas Research Hospital, Istituto di Ricovero e cura a carattere scientifico, Rozzano, Milan, Italy
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12
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Surmeli ZG, Ibrahim RHM, Alkhalfan N, Mahmood Z. Cisplatin-induced bone marrow failure in an adult patient with Fanconi anemia. J Oncol Pharm Pract 2024; 30:1274-1277. [PMID: 39095039 DOI: 10.1177/10781552241268468] [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: 08/04/2024]
Abstract
INTRODUCTION Fanconi anemia (FA) is a genetic disorder characterized by bone marrow failure typically developing in the first decade of life, congenital abnormalities, and an increased predisposition to malignancy. However, patients with FA can remain undiagnosed until adulthood and present with solid organ malignancies. Due to impaired DNA repair mechanisms, patients with FA are highly susceptible to severe bone marrow toxicity when treated with cisplatin. CASE REPORT A 38-year-old woman, diagnosed with locally advanced squamous cell carcinoma (SCC) of the uterine cervix, underwent treatment with weekly cisplatin concurrent with radiotherapy. After the second week of cisplatin treatment, she presented with severe pancytopenia. The prolonged and severe pancytopenia following cisplatin and radiation, along with cervical SCC in the absence of risk factors and the presence of parental consanguinity, raised the possibility of FA as the underlying cause. Whole exome sequencing revealed a homozygous FANCI c.668A > C (p.Lys223Thr) missense variant confirming the diagnosis of FA. MANAGEMENT AND OUTCOME The pancytopenia exhibited a protracted course, necessitating admission and supportive treatment with antibiotics, red blood cell and platelet transfusions, as well as filgrastim and eltrombopag. Eventually, the pancytopenia improved after approximately 40 days of hospitalization. DISCUSSION SCC of the head and neck or gynecologic organs in a young adult without known risk factors should prompt consideration of FA. Cisplatin should be avoided in patients with FA.
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Affiliation(s)
| | | | - Nawaf Alkhalfan
- Department of Medical Oncology, Bahrain Oncology Center, Muharraq, Bahrain
| | - Zeyad Mahmood
- Department of Medical Oncology, Bahrain Oncology Center, Muharraq, Bahrain
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13
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Verma K, Croft W, Margielewska-Davies S, Pearce H, Stephens C, Diaconescu D, Bevington S, Craddock C, Amel-Kashipaz R, Zuo J, Kinsella FAM, Moss P. CD70 identifies alloreactive T cells and represents a potential target for prevention and treatment of acute GVHD. Blood Adv 2024; 8:4900-4912. [PMID: 39028952 PMCID: PMC11421336 DOI: 10.1182/bloodadvances.2024012909] [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: 02/12/2024] [Revised: 06/08/2024] [Accepted: 07/11/2024] [Indexed: 07/21/2024] Open
Abstract
ABSTRACT Graft-versus-host disease (GVHD) remains a major challenge after allogeneic hematopoietic stem cell transplantation (allo-HSCT), and further understanding of its immunopathology is crucial for developing new treatments. CD70 interacts with CD27 and is upregulated transiently on T cells after recent T-cell receptor (TCR) engagement. Here, we investigated the functional and clinical significance of CD70 expression on T cells during the early posttransplantation period. CD70 was expressed on a subset of highly activated memory T cells within the first 2 weeks after transplant, which then gradually declined in most patients. CD70+ T cells exhibited an open chromatin landscape and a transcriptional profile indicative of intense Myelocytomatosis oncogene (MYC)-driven glycolysis and proliferation. CD4+ and CD8+CD70+ T-cell numbers increased by ninefold and fourfold, respectively, during acute GVHD (aGVHD) and displayed an oligoclonal TCR repertoire. These cells expressed CCR4 and CCR6 chemokine receptors and were markedly increased in aGVHD tissue samples. Furthermore, CD70+ T cells demonstrated alloreactive specificity in vitro, and proliferative and inflammatory cytokine responses were markedly attenuated by CD70 blockade. These findings identify CD70 as a marker of highly activated alloreactive T cells and reveal the potential therapeutic importance of inhibiting CD27-CD70 costimulation in both the prophylaxis and treatment of aGVHD.
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Affiliation(s)
- Kriti Verma
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
| | - Wayne Croft
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
| | | | - Hayden Pearce
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
| | - Christine Stephens
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
| | - Diana Diaconescu
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
| | - Sarah Bevington
- Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom
| | - Charles Craddock
- Centre for Clinical Haematology, Queen Elizabeth Hospital Birmingham, Birmingham, United Kingdom
- Warwick Clinical Trials Unit, Warwick University, Coventry, United Kingdom
| | | | - Jianmin Zuo
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
| | - Francesca A. M. Kinsella
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
- Centre for Clinical Haematology, Queen Elizabeth Hospital Birmingham, Birmingham, United Kingdom
| | - Paul Moss
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
- Centre for Clinical Haematology, Queen Elizabeth Hospital Birmingham, Birmingham, United Kingdom
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14
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Khaddour K, Murakami N, Ruiz ES, Silk AW. Cutaneous Squamous Cell Carcinoma in Patients with Solid-Organ-Transplant-Associated Immunosuppression. Cancers (Basel) 2024; 16:3083. [PMID: 39272941 PMCID: PMC11394667 DOI: 10.3390/cancers16173083] [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: 07/23/2024] [Revised: 08/26/2024] [Accepted: 09/03/2024] [Indexed: 09/15/2024] Open
Abstract
The management of advanced cutaneous squamous cell carcinoma (CSCC) has been revolutionized by the introduction of immunotherapy. Yet, successful treatment with immunotherapy relies on an adequate antitumor immune response. Patients who are solid-organ transplant recipients (SOTRs) have a higher incidence of CSCC compared to the general population. This review discusses the current knowledge of epidemiology, pathophysiology, and management of patients with CSCC who are immunocompromised because of their chronic exposure to immunosuppressive medications to prevent allograft rejection. First, we discuss the prognostic impact of immunosuppression in patients with CSCC. Next, we review the risk of CSCC development in immunosuppressed patients due to SOT. In addition, we provide an overview of the biological immune disruption present in transplanted immunosuppressed CSCC patients. We discuss the available evidence on the use of immunotherapy and provide a framework for the management approach with SOTRs with CSCC. Finally, we discuss potential novel approaches that are being investigated for the management of immunosuppressed patients with CSCC.
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Affiliation(s)
- Karam Khaddour
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
- Center for Cutaneous Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA
- Harvard Medical School, Boston, MA 02115, USA
| | - Naoka Murakami
- Harvard Medical School, Boston, MA 02115, USA
- Division of Renal Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA
| | - Emily S Ruiz
- Center for Cutaneous Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA
- Harvard Medical School, Boston, MA 02115, USA
- Department of Dermatology, Brigham and Women's Hospital, Boston, MA 02115, USA
| | - Ann W Silk
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
- Center for Cutaneous Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA
- Harvard Medical School, Boston, MA 02115, USA
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15
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Wang YX, Wang A, Su YF, Wang J, Li YH, Li F, Jing Y, Xu L, Wang YZ, Zheng X, Gao CJ, Hu LD, Gao XN, Liu DH. Anti-PD-1 combined with hypomethylating agent and CAG regimen bridging to allogeneic hematopoietic stem cell transplantation: a novel strategy for relapsed/refractory acute myeloid leukemia. Front Immunol 2024; 15:1409302. [PMID: 39221255 PMCID: PMC11361969 DOI: 10.3389/fimmu.2024.1409302] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2024] [Accepted: 07/29/2024] [Indexed: 09/04/2024] Open
Abstract
Introduction The prognosis of relapsed/refractory acute myeloid leukemia (r/rAML) is dismal, and allogeneic hematopoietic stem cell transplant (allo-HSCT) is a potential cure. Combining anti-PD-1, hypomethylating agent (HMA), and CAG (cytarabine, aclarubicin/idarubicin, granulocyte colony-stimulating factor) regimen has showed primary efficacy in r/rAML. However, pre-transplant exposure to anti-PD-1 may lead to severe graft-versus-host disease (GVHD). This preliminary study aimed to evaluate the safety and efficacy of allo-HSCT in r/rAML patients receiving the anti-PD-1+HMA+CAG regimen. Methods Fifteen r/rAML patients (12 related haploidentical donors [HIDs], 2 matched siblings, 1 unrelated donor) received this regimen and subsequent peripheral blood HSCT. Results Four patients with HIDs received a GVHD prophylaxis regimen consisted of Anti-thymocyte globulin and a reduced-dose of post-transplant cyclophosphamide. The median follow-up was 20.9 months (range, 1.2-34.2). The cumulative incidences of acute GVHD grade 2-4 and grade 3-4 were 40% and 13.3%, respectively. The 2-year incidence of moderate-to-severe chronic GVHD, non-relapse mortality, and relapse were 10%, 22.3%, and 22.5%, respectively. The 2-year overall survival and GVHD-free/relapse-free survival rates were 54% and 48.6%, respectively. No death or relapse was observed in the PTCy group. Conclusion The anti-PD-1+HMA+CAG regimen bridging to allo-HSCT for r/r AML was tolerable with promising efficacy. GVHD prophylaxis with PTCy for HID-HSCT showed preliminary survival advantage.
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Affiliation(s)
- Yu-Xin Wang
- Senior Department of Hematology, the Fifth Medical Center of PLA General Hospital, Beijing, China
- Graduate School, Chinese PLA General Hospital, Beijing, China
| | - An Wang
- Senior Department of Hematology, the Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Yong-Feng Su
- Senior Department of Hematology, the Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Jun Wang
- Senior Department of Hematology, the Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Yu-Hang Li
- Senior Department of Hematology, the Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Fei Li
- Senior Department of Hematology, the Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Yu Jing
- Senior Department of Hematology, the Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Lei Xu
- Senior Department of Hematology, the Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Yi-Zhi Wang
- Senior Department of Hematology, the Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Xuan Zheng
- Senior Department of Hematology, the Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Chun-Ji Gao
- Senior Department of Hematology, the Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Liang-Ding Hu
- Senior Department of Hematology, the Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Xiao-Ning Gao
- Senior Department of Hematology, the Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Dai-Hong Liu
- Senior Department of Hematology, the Fifth Medical Center of PLA General Hospital, Beijing, China
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Montoro J, Ngoya M, Kulagin A, Giebel S, Broers AEC, Bramanti S, Halahleh K, Pérez-Simón JA, Solano C, Ozcelik T, Blaise D, Sanz J, Henriques M, Peffault de Latour R, Martino R, Scheid C, Fox L, Gromek T, Jurado M, Sakellari I, Van Gorkom G, Matteucci P, Nagler A, Koc Y, Glass B. PTCy vs CNI-based GVHD prophylaxis in HLA-matched transplants for Hodgkin lymphoma: a study of the LWP of the EBMT. Blood Adv 2024; 8:3985-3992. [PMID: 38810260 PMCID: PMC11331730 DOI: 10.1182/bloodadvances.2024013328] [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: 04/03/2024] [Revised: 05/13/2024] [Accepted: 05/19/2024] [Indexed: 05/31/2024] Open
Abstract
ABSTRACT Studies comparing the efficacy of posttransplant cyclophosphamide (PTCy) to conventional calcineurin inhibitor (CNI)-based graft-versus-host disease (GVHD) prophylaxis regimens in patients with Hodgkin lymphoma (HL) are scarce. This study aimed to compare the outcomes of patients with HL undergoing hematopoietic stem cell transplantation (HSCT) from HLA-matched donors who received GVHD prophylaxis with either PTCy- or conventional CNI-based regimens, using data reported in the European Society for Blood and Marrow Transplantation database between January 2015 and December 2022. Among the cohort, 270 recipients received conventional CNI-based prophylaxis and 176 received PTCy prophylaxis. Notably, PTCy prophylaxis was associated with delayed hematopoietic recovery but also with a lower risk of chronic (25% vs 43%; P < .001) and extensive chronic GVHD (13% vs 28%; P = .003) compared with the CNI-based cohort. The 2-year cumulative incidence of nonrelapse mortality and relapse was 11% vs 17% (P = .12) and 17% vs 30% (P = .007) for PTCy- and CNI-based, respectively. Moreover, the 2-year overall survival (OS), progression-free survival (PFS), and GVHD-free, relapse-free survival (GRFS) were all significantly better in the PTCy group compared with the CNI-based group: 85% vs 72% (P = .005), 72% vs 53% (P < .001), and 59% vs 31% (P < .001), respectively. In multivariable analysis, PTCy was associated with a lower risk of chronic and extensive chronic GVHD, reduced relapse, and better OS, PFS, and GRFS than the CNI-based platform. Our findings suggest that PTCy as GVHD prophylaxis offers more favorable outcomes than conventional CNI-based prophylaxis in adult patients with HL undergoing HSCT from HLA-matched donors.
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Affiliation(s)
- Juan Montoro
- Department of Hematology, Hospital Universitario y Politécnico La Fe, Valencia, Spain
- Department of Hematology, Universidad Católica de Valencia, Valencia, Spain
| | - Maud Ngoya
- Department of Biostatistics, EBMT Lymphoma Working Party, Paris, France
| | - Alexander Kulagin
- RM Gorbacheva Research Institute, Pavlov University, Saint-Petersburg, Russia
| | - Sebastian Giebel
- Department of Bone Marrow Transplantation and Oncohematology, Fundacja Na Ratunek Dzieciom z Chorobą Nowotworową, Gliwice, Poland
| | - Annoek E. C. Broers
- Department of Hematology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
| | - Stefania Bramanti
- IRCCS Humanitas Research Hospital, Transplantation Unit Department of Oncology and Haematology, Milan, Italy
| | - Khalid Halahleh
- King Hussein Cancer Centre, Adult BMT Program, Amman, Jordan
| | - Jose A. Pérez-Simón
- Department of Hematology. Hospital Universitario Virgen del Rocío, Instituto de Biomedicina de Sevilla, CISC, Universidad de Sevilla, Seville, Spain
| | - Carlos Solano
- Hospital Clínico Universitario-INCLIVA, University of Valencia, Valencia, Spain
| | - Tulay Ozcelik
- Demiroglu Bilim University, Istanbul Florence Nightingale Hospital, Istanbul, Turkey
| | - Didier Blaise
- Programme de Transplantation & Therapie Cellulaire, Marseille, France
| | - Jaime Sanz
- Department of Hematology, Hospital Universitario y Politécnico La Fe, Valencia, Spain
- Departament de Medicina, Universitat de Valencia, Valencia, Spain
| | - Marta Henriques
- Department of Hematology, Unversity Hospital Sao Joao, Oporto, Portugal
| | | | - Rodrigo Martino
- Department of Hematology, Hospital Santa Creu i Sant Pau, Barcelona, Spain
| | - Christof Scheid
- Department of Internal Medicine, University of Cologne, Cologne, Germany
| | - Laura Fox
- Department of Hematology, Hospital Vall d`Hebron, Barcelona, Spain
| | - Tomasz Gromek
- Department of Hematology, Samodzielny Publiczny Szpital Kliniczny, Lublin, Poland
| | - Manuel Jurado
- Department of Hematology, Hospital Universitario Virgen de las Nieves, Granada, Spain
| | - Ioanna Sakellari
- Department of Hematology, George Papanicolaou General Hospital, Thessaloniki, Greece
| | - Gwendolyn Van Gorkom
- Division of Hematology, Department of Internal Medicine, GROW School for Oncology and Development Biology, Maastricht, The Netherlands
| | - Paola Matteucci
- Department of Hematology, University of Milano, Milan, Italy
| | - Arnon Nagler
- Chaim Sheba Medical Center, Tel-Hashomer, Israel
| | - Yener Koc
- Department of Hematology, Medicana International Hospital Istanbul, Istanbul, Turkey
| | - Bertram Glass
- Department of Hematology, Oncology, and Stem Cell Transplantation, Asklepios Klinik St. Georg, Hamburg, Germany
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van Harten AM, Shah R, de Boer DV, Buijze M, Kreft M, Song JY, Zürcher LM, Jacobs H, Brakenhoff RH. Gemcitabine as chemotherapy of head and neck cancer in Fanconi anemia patients. Oncogenesis 2024; 13:26. [PMID: 38992100 PMCID: PMC11239817 DOI: 10.1038/s41389-024-00525-2] [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: 08/10/2023] [Revised: 06/04/2024] [Accepted: 07/01/2024] [Indexed: 07/13/2024] Open
Abstract
Fanconi anemia (FA) is a rare hereditary disease resulting from an inactivating mutation in the FA/BRCA pathway, critical for the effective repair of DNA interstrand crosslinks (ICLs). The disease is characterized by congenital abnormalities, progressing bone marrow failure, and an increased risk of developing malignancies early in life, in particular head and neck squamous cell carcinoma (HNSCC). While ICL-inducing cisplatin combined with radiotherapy is a mainstay of HNSCC treatment, cisplatin is contra-indicated for FA-HNSCC patients. This dilemma necessitates the identification of novel treatment modalities tolerated by FA-HNSCC patients. To identify druggable targets, an siRNA-based genetic screen was previously performed in HNSCC-derived cell lines from FA and non-FA tumor origin. Here, we report that the Ribonucleotide Reductase (RNR) complex, consisting of the RRM1 and RRM2 subunits, was identified as a therapeutic target for both, FA and non-FA HNSCC. While non-FA HNSCC cells responded differentially to RNR depletion, FA-HNSCC cells were consistently found hypersensitive. This insight was confirmed pharmacologically using 2', 2'-difluoro 2'deoxycytidine (dFdC), also known as gemcitabine, a clinically used nucleotide analog that is a potent inhibitor of the RNR complex. Importantly, while cisplatin exposure displayed severe, long-lasting toxicity on the hematopoietic stem and progenitor compartments in Fancg-/- mice, gemcitabine was well tolerated and had only a mild, transient impact. Taken together, our data implicate that gemcitabine-based chemoradiotherapy could serve as an alternative HNSCC treatment in Fanconi patients, and deserves clinical testing.
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Affiliation(s)
- Anne M van Harten
- Amsterdam UMC location Vrije Universiteit Amsterdam, Otolaryngology-Head and Neck Surgery, Head and Neck Cancer Biology & Immunology Section, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands
- Cancer Center Amsterdam, Cancer Biology and Immunology, Amsterdam, The Netherlands
| | - Ronak Shah
- Division of Tumor Biology & Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - D Vicky de Boer
- Amsterdam UMC location Vrije Universiteit Amsterdam, Otolaryngology-Head and Neck Surgery, Head and Neck Cancer Biology & Immunology Section, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands
- Cancer Center Amsterdam, Cancer Biology and Immunology, Amsterdam, The Netherlands
| | - Marijke Buijze
- Amsterdam UMC location Vrije Universiteit Amsterdam, Otolaryngology-Head and Neck Surgery, Head and Neck Cancer Biology & Immunology Section, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands
- Cancer Center Amsterdam, Cancer Biology and Immunology, Amsterdam, The Netherlands
| | - Maaike Kreft
- Division of Tumor Biology & Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Ji-Ying Song
- Department of Experimental Animal Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Lisa M Zürcher
- Division of Tumor Biology & Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Heinz Jacobs
- Division of Tumor Biology & Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Ruud H Brakenhoff
- Amsterdam UMC location Vrije Universiteit Amsterdam, Otolaryngology-Head and Neck Surgery, Head and Neck Cancer Biology & Immunology Section, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands.
- Cancer Center Amsterdam, Cancer Biology and Immunology, Amsterdam, The Netherlands.
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18
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Mosna F. The Immunotherapy of Acute Myeloid Leukemia: A Clinical Point of View. Cancers (Basel) 2024; 16:2359. [PMID: 39001421 PMCID: PMC11240611 DOI: 10.3390/cancers16132359] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2024] [Revised: 06/16/2024] [Accepted: 06/26/2024] [Indexed: 07/16/2024] Open
Abstract
The potential of the immune system to eradicate leukemic cells has been consistently demonstrated by the Graft vs. Leukemia effect occurring after allo-HSCT and in the context of donor leukocyte infusions. Various immunotherapeutic approaches, ranging from the use of antibodies, antibody-drug conjugates, bispecific T-cell engagers, chimeric antigen receptor (CAR) T-cells, and therapeutic infusions of NK cells, are thus currently being tested with promising, yet conflicting, results. This review will concentrate on various types of immunotherapies in preclinical and clinical development, from the point of view of a clinical hematologist. The most promising therapies for clinical translation are the use of bispecific T-cell engagers and CAR-T cells aimed at lineage-restricted antigens, where overall responses (ORR) ranging from 20 to 40% can be achieved in a small series of heavily pretreated patients affected by refractory or relapsing leukemia. Toxicity consists mainly in the occurrence of cytokine-release syndrome, which is mostly manageable with step-up dosing, the early use of cytokine-blocking agents and corticosteroids, and myelosuppression. Various cytokine-enhanced natural killer products are also being tested, mainly as allogeneic off-the-shelf therapies, with a good tolerability profile and promising results (ORR: 20-37.5% in small trials). The in vivo activation of T lymphocytes and NK cells via the inhibition of their immune checkpoints also yielded interesting, yet limited, results (ORR: 33-59%) but with an increased risk of severe Graft vs. Host disease in transplanted patients. Therefore, there are still several hurdles to overcome before the widespread clinical use of these novel compounds.
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Affiliation(s)
- Federico Mosna
- Hematology and Bone Marrow Transplantation Unit (BMTU), Hospital of Bolzano (SABES-ASDAA), Teaching Hospital of Paracelsus Medical University (PMU), 39100 Bolzano, Italy
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19
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Pavlin T, Blatnik A, Šeruga B. Challenges in the management of operable triple-negative breast cancer in a survivor of the B-cell acute lymphoblastic leukemia: a case report. Front Oncol 2024; 14:1404706. [PMID: 38817905 PMCID: PMC11137578 DOI: 10.3389/fonc.2024.1404706] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2024] [Accepted: 04/30/2024] [Indexed: 06/01/2024] Open
Abstract
Background Operable triple-negative breast cancer (TNBC) is an unfavorable subtype of breast cancer, which usually requires an aggressive perioperative systemic treatment. When TNBC presents as a second primary cancer after cured acute leukemia, its management might be challenging. Case presentation We present a case report of a young postmenopausal woman with an operable TNBC who had a history of the B-cell acute lymphoblastic leukemia (B-ALL) and graft versus host disease (GVHD) after allogeneic stem cell transplantation (allo-SCT). A history of previous treatment with anthracyclines and radiotherapy and GVHD limited the use of doxorubicin for treatment of her TNBC. Due to the history of GVHD, perioperative treatment with pembrolizumab was omitted. Genetic testing was challenging due to the possible contamination of her tissues with the donor's cells after allo-SCT. In samples of our patient's buccal swab, peripheral blood, and tumor tissue, a pathogenic variant in the partner and localizer of BRCA2 (PALB2) gene was found. With neoadjuvant chemotherapy which included carboplatin, a pathologic complete response was achieved. Although our patient has a low risk for recurrence of TNBC, her risk for the development of new primary cancers remains substantial. Conclusion This case highlights challenges in the systemic treatment, genetic testing, and follow-up of patients with operable TNBC and other solid cancers who have a history of acute leukemia.
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Affiliation(s)
- Tina Pavlin
- Division of Medical Oncology, Institute of Oncology Ljubljana, Ljubljana, Slovenia
- Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Ana Blatnik
- Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
- Department of Clinical Cancer Genetics, Institute of Oncology Ljubljana, Ljubljana, Slovenia
| | - Boštjan Šeruga
- Division of Medical Oncology, Institute of Oncology Ljubljana, Ljubljana, Slovenia
- Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
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20
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Giannotti F, De Ramon Ortiz C, Simonetta F, Morin S, Bernardi C, Masouridi-Levrat S, Chalandon Y, Mamez AC. Remission of relapsed/refractory classical Hodgkin lymphoma induced by brentuximab vedotin and pembrolizumab combination after allogeneic hematopoietic stem cell transplantation: a case report. Front Immunol 2024; 15:1360275. [PMID: 38510239 PMCID: PMC10950903 DOI: 10.3389/fimmu.2024.1360275] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2023] [Accepted: 02/08/2024] [Indexed: 03/22/2024] Open
Abstract
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative treatment option for patients with highly chemorefractory Hodgkin lymphoma (HL). The CD30-targeting antibody-drug conjugate Brentuximab-Vedotin (BV) and programmed cell death protein-1 (PD-1) blocking agents have demonstrated clinical activity with durable responses in relapsed/refractory (r/r) HL. However, patients with a history of allo-HSCT were frequently excluded from clinical trials due to concerns about the risk of graft-versus-host disease (GVHD). We report the clinical history of a patient with refractory classical HL who underwent two allo-HSCTs (first from matched unrelated and second from haploidentical donor) after relapsing on BV and nivolumab and for whom durable remission was finally obtained using BV-pembrolizumab combination for relapse after haploidentical HSCT. Such treatment was associated with the onset of GVHD after only two cycles which led to treatment discontinuation. However, the side effects were rapidly controlled, and after 2 years of follow-up, the patient is still in remission. Our data support the feasibility and efficacy of combining PD-1 blockade with BV to enhance the graft-versus-lymphoma effect after allo-HSCT.
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Affiliation(s)
- Federica Giannotti
- Division of Hematology, Department of Oncology, Geneva University Hospitals and Faculty of Medicine, University of Geneva, Geneva, Switzerland
- Translational Research Center for Oncohematology, Department of Medicine, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Carmen De Ramon Ortiz
- Division of Hematology, Department of Oncology, Geneva University Hospitals and Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Federico Simonetta
- Division of Hematology, Department of Oncology, Geneva University Hospitals and Faculty of Medicine, University of Geneva, Geneva, Switzerland
- Translational Research Center for Oncohematology, Department of Medicine, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Sarah Morin
- Division of Hematology, Department of Oncology, Geneva University Hospitals and Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Chiara Bernardi
- Division of Hematology, Department of Oncology, Geneva University Hospitals and Faculty of Medicine, University of Geneva, Geneva, Switzerland
- Translational Research Center for Oncohematology, Department of Medicine, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Stavroula Masouridi-Levrat
- Division of Hematology, Department of Oncology, Geneva University Hospitals and Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Yves Chalandon
- Division of Hematology, Department of Oncology, Geneva University Hospitals and Faculty of Medicine, University of Geneva, Geneva, Switzerland
- Translational Research Center for Oncohematology, Department of Medicine, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Anne-Claire Mamez
- Division of Hematology, Department of Oncology, Geneva University Hospitals and Faculty of Medicine, University of Geneva, Geneva, Switzerland
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21
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You E, Park CJ, Cho YU, Jang S, Lee MY, Kim H, Koh KN, Im HJ, Choi EJ, Lee JH, Lee KH. Increased PD-1 expression of bone marrow T-cells in acute myeloid leukaemia patients after stem cell transplantation, and its association with overall survival. Ann Clin Biochem 2024; 61:79-89. [PMID: 37314798 DOI: 10.1177/00045632231184716] [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: 06/15/2023]
Abstract
BACKGROUND Immune checkpoints are involved in mechanisms by which tumours escape from the host immune system. Our aim was to evaluate acute myeloid leukaemia (AML) patients to determine expression levels of checkpoint molecules according to diagnosis and treatments, and to identify optimal candidates for checkpoint blockade. METHODS Bone marrow (BM) samples were obtained from 279 AML patients at different disease status and from 23 controls. Flow cytometric analyses of PD-1 and PD-L1/PD-L2 expression were performed. RESULTS Programmed death-1 (PD-1) expression levels on CD8+ T-cells at AML diagnosis were increased compared to controls. PD-L1 and PD-L2 expression levels on leukaemic cells at diagnosis were significantly higher in secondary AML than in de novo AML. PD-1 levels on CD8+ and CD4+ T-cells after allo-SCT were significantly higher than those at diagnosis and after CTx. PD-1 expression on CD8+ T-cells increased in the acute GVHD group than in the non-GVHD group. The overall survival of patients with high PD-1 expression on CD8+ T-cells was significantly shorter than that of patients with low PD-1 expression. CONCLUSIONS In conclusion, patients who underwent allo-SCT exhibited high PD-1 expression, suggesting that allo-SCT increases PD-1 expression on T-cells, and the patients with high PD-1 expression on CD8+ T-cells after allo-SCT showed the poor prognosis. For these patients, PD-1 blockade could be an immunotherapeutic strategy.
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Affiliation(s)
- Eunkyoung You
- Department of Laboratory Medicine, Inje University College of Medicine, Busan Paik Hospital, Busan, Korea
| | - Chan-Jeoung Park
- Department of Laboratory Medicine, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
| | - Young-Uk Cho
- Department of Laboratory Medicine, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
| | - Seongsoo Jang
- Department of Laboratory Medicine, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
| | - Min Young Lee
- Department of Laboratory Medicine, Kyung Hee University School of Medicine and Kyung Hee University Hospital at Gangdong, Seoul, Korea
| | - Hery Kim
- Department of Pediatrics, University of Ulsan College of Medicine, Asan Medical Center Children's Hospital, Seoul, Korea
| | - Kyung Nam Koh
- Department of Pediatrics, University of Ulsan College of Medicine, Asan Medical Center Children's Hospital, Seoul, Korea
| | - Ho Joon Im
- Department of Pediatrics, University of Ulsan College of Medicine, Asan Medical Center Children's Hospital, Seoul, Korea
| | - Eun-Ji Choi
- Department of Hematology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
| | - Je-Hwan Lee
- Department of Hematology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
| | - Kyoo-Hyung Lee
- Department of Hematology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
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22
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Pophali P, Varela JC, Rosenblatt J. Immune checkpoint blockade in hematological malignancies: current state and future potential. Front Oncol 2024; 14:1323914. [PMID: 38322418 PMCID: PMC10844552 DOI: 10.3389/fonc.2024.1323914] [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: 10/18/2023] [Accepted: 01/03/2024] [Indexed: 02/08/2024] Open
Abstract
Malignant cells are known to evade immune surveillance by engaging immune checkpoints which are negative regulators of the immune system. By restoring the T-lymphocyte mediated anti-tumor effect, immune checkpoint inhibitors (ICI) have revolutionized the treatment of solid tumors but have met rather modest success in hematological malignancies. Currently, the only FDA approved indications for ICI therapy are in classic hodgkin lymphoma and primary mediastinal B cell lymphoma. Multiple clinical trials have assessed ICI therapy alone and in combination with standard of care treatments in other lymphomas, plasma cell neoplasms and myeloid neoplasms but were noted to have limited efficacy. These trials mostly focused on PD-1/PDL-1 and CTLA-4 inhibitors. Recently, there has been an effort to target other T-lymphocyte checkpoints like LAG-3, TIM-3, TIGIT along with improving strategies of PD-1/PDL-1 and CTLA-4 inhibition. Drugs targeting the macrophage checkpoint, CD47, are also being tested. Long term safety and efficacy data from these ongoing studies are eagerly awaited. In this comprehensive review, we discuss the mechanism of immune checkpoint inhibitors, the key takeaways from the reported results of completed and ongoing studies of these therapies in the context of hematological malignancies.
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Affiliation(s)
- Prateek Pophali
- Division of Hematology and Hematological Malignancies, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States
| | - Juan Carlos Varela
- Division of Hematology and Oncology, Orlando Health Regional Medical Center, Orlando, FL, United States
| | - Jacalyn Rosenblatt
- Division of Hematology and Hematological Malignancies, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States
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23
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Guarnera L, Santinelli E, Galossi E, Cristiano A, Fabiani E, Falconi G, Voso MT. Microenvironment in acute myeloid leukemia: focus on senescence mechanisms, therapeutic interactions, and future directions. Exp Hematol 2024; 129:104118. [PMID: 37741607 DOI: 10.1016/j.exphem.2023.09.005] [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: 05/30/2023] [Revised: 09/10/2023] [Accepted: 09/12/2023] [Indexed: 09/25/2023]
Abstract
Acute myeloid leukemia (AML) is a disease with a dismal prognosis, mainly affecting the elderly. In recent years, new drugs have improved life expectancy and quality of life, and a better understanding of the genetic-molecular nature of the disease has shed light on previously unknown aspects of leukemogenesis. In parallel, increasing attention has been attracted to the complex interactions between cells and soluble factors in the bone marrow (BM) environment, collectively known as the microenvironment. In this review, we discuss the central role of the microenvironment in physiologic and pathologic hematopoiesis and the mechanisms of senescence, considered a fundamental protective mechanism against the proliferation of damaged and pretumoral cells. The microenvironment also represents a fertile ground for the development of myeloid malignancies, and the leukemic niche significantly interacts with drugs commonly used in AML treatment. Finally, we focus on the role of the microenvironment in the engraftment and complications of allogeneic hematopoietic stem cell transplantation, the only curative option in a conspicuous proportion of patients.
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Affiliation(s)
- Luca Guarnera
- Department of Biomedicine and Prevention, Tor Vergata University, Rome, Italy
| | - Enrico Santinelli
- Department of Biomedicine and Prevention, Tor Vergata University, Rome, Italy; Fondazione Policlinico Universitario Campus Bio-Medico, Rome, Italy
| | - Elisa Galossi
- Department of Biomedicine and Prevention, Tor Vergata University, Rome, Italy
| | - Antonio Cristiano
- Department of Biomedicine and Prevention, Tor Vergata University, Rome, Italy
| | - Emiliano Fabiani
- Department of Biomedicine and Prevention, Tor Vergata University, Rome, Italy; Saint Camillus International, University of Health Sciences, Rome, Italy
| | - Giulia Falconi
- Department of Biomedicine and Prevention, Tor Vergata University, Rome, Italy
| | - Maria Teresa Voso
- Department of Biomedicine and Prevention, Tor Vergata University, Rome, Italy; Neuro-Oncohematology Unit, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Fondazione Santa Lucia, Rome, Italy.
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24
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Brami I, Zuckerman T, Ram R, Avni B, Peretz G, Ostrovsky D, Lior Y, Faour C, McElvaney O, McElvaney NG, Lewis EC. Altered Serum Alpha1-Antitrypsin Protease Inhibition before and after Clinical Hematopoietic Stem Cell Transplantation: Association with Risk for Non-Relapse Mortality. Int J Mol Sci 2023; 25:422. [PMID: 38203593 PMCID: PMC10779144 DOI: 10.3390/ijms25010422] [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: 11/21/2023] [Revised: 12/23/2023] [Accepted: 12/25/2023] [Indexed: 01/12/2024] Open
Abstract
α1-Antitrypsin (AAT), an acute-phase reactant not unsimilar to C-reactive protein (CRP), is a serine protease inhibitor that harbors tissue-protective and immunomodulatory attributes. Its concentrations appropriately increase during conditions of extensive tissue injury, and it induces immune tolerance, in part, by inhibiting the enzymatic activity of the inflammatory serine protease, proteinase 3 (PR3). Typically administered to patients with genetic AAT deficiency, AAT treatment was recently shown to improve outcomes in patients with steroid-refractory graft-versus-host disease (GVHD). GVHD represents a grave outcome of allogeneic hematopoietic stem cell transplantation (HSCT), a potentially curative intervention for hematological diseases. The procedure requires radio/chemotherapy conditioning of the prospective marrow recipient, a cytotoxic process that causes vast tissue injury and, in some formats, interferes with liver production of AAT. To date, changes in the functional profile of AAT during allogeneic HSCT, and during the cytotoxic intervention that precedes HSCT, are unknown. The present study followed 53 patients scheduled for allogeneic HSCT (trial registration NCT03188601). Serum samples were tested before and after HSCT for AAT and CRP levels and for intrinsic anti-proteolytic activity. The ex vivo response to clinical-grade AAT was tested on circulating patient leukocytes and on a human epithelial cell line treated with patient sera in a gap closure assay. According to the ex vivo experiments, circulating leukocytes responded to AAT with a favorable immune-regulated profile, and epithelial gap closure was enhanced by AAT in sera from GVHD-free patients but not in sera from patients who developed GVHD. According to serum collected prior to HSCT, non-relapse mortality was reliably predicted by combining three components: AAT and CRP levels and serum anti-proteolytic activity. Taken together, HSCT outcomes are significantly affected by the anti-proteolytic function of circulating AAT, supporting early AAT augmentation therapy for allogeneic HSCT patients.
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Affiliation(s)
- Ido Brami
- Department of Clinical Biochemistry and Pharmacology, Ben-Gurion University of the Negev, Be’er-Sheva 8410501, Israel;
| | - Tsila Zuckerman
- Hematology Department and Bone Marrow Transplantation Unit, Rambam Health Care Campus, Haifa 3109601, Israel;
| | - Ron Ram
- Bone Marrow Transplantation Unit, The Division of Hematology, Tel-Aviv Sourasky Medical Center, Tel-Aviv 6423906, Israel;
| | - Batia Avni
- Department of Bone Marrow Transplantation and Cancer Immunotherapy, Hadassah-Hebrew University Medical Center, Ein Kerem, Jerusalem 9112001, Israel;
| | - Galit Peretz
- Department of Hematology, Soroka University Medical Center, Be’er-Sheva 8410101, Israel;
| | - Daniel Ostrovsky
- Clinical Research Center, Soroka University Medical Center and Faculty of Health Sciences, Ben-Gurion University of the Negev, Be’er-Sheva 8410101, Israel;
| | - Yotam Lior
- Division of Anesthesiology, Pain and Intensive Care, Tel-Aviv Sourasky Medical Center, Tel-Aviv 6423906, Israel;
| | - Caroline Faour
- Ruth and Bruce Rappaport Faculty of Medicine, Technion, Israeli Institute of Technology, Haifa 3109601, Israel;
| | - Oisin McElvaney
- The Irish Centre for Genetic Lung Disease, Royal College of Surgeons in Ireland, Beaumont Hospital, D02 YN77 Dublin, Ireland; (O.M.); (N.G.M.)
| | - Noel G. McElvaney
- The Irish Centre for Genetic Lung Disease, Royal College of Surgeons in Ireland, Beaumont Hospital, D02 YN77 Dublin, Ireland; (O.M.); (N.G.M.)
| | - Eli C. Lewis
- Department of Clinical Biochemistry and Pharmacology, Ben-Gurion University of the Negev, Be’er-Sheva 8410501, Israel;
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25
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Hong J, Fraebel J, Yang Y, Tkacyk E, Kitko C, Kim TK. Understanding and treatment of cutaneous graft-versus-host-disease. Bone Marrow Transplant 2023; 58:1298-1313. [PMID: 37730800 PMCID: PMC11759061 DOI: 10.1038/s41409-023-02109-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2023] [Revised: 08/28/2023] [Accepted: 09/08/2023] [Indexed: 09/22/2023]
Abstract
The skin is the outermost mechanical barrier where dynamic immune reactions take place and is the most commonly affected site in both acute and chronic graft-versus-host disease (GVHD). If not properly treated, pain and pruritis resulting from cutaneous GVHD can increase the risk of secondary infection due to erosions, ulcerations, and damage of underlying tissues. Furthermore, resulting disfiguration can cause distress and significantly impact patients' quality of life. Thus, a deeper understanding of skin-specific findings of GVHD is needed. This review will highlight some promising results of recent pre-clinical studies on the pathophysiology of skin GVHD and summarize the diagnostic and staging/grading procedures according to the clinical manifestations of skin GVHD. In addition, we will summarize outcomes of various GVHD treatments, including skin-specific response rates.
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Affiliation(s)
- Junshik Hong
- Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
- Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
- Division of Hematology/Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Johnathan Fraebel
- Division of Hematology/Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Yenny Yang
- Division of Hematology/Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Eric Tkacyk
- Veterans Affairs Tennessee Valley Health Care, Nashville, TN, USA
- Department of Dermatology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Carrie Kitko
- Monroe Carell Jr Children's Hospital, Vanderbilt Division of Pediatric Hematology-Oncology, Nashville, TN, USA
- Vanderbilt-Ingram Cancer Center, Nashville, TN, USA
| | - Tae Kon Kim
- Division of Hematology/Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
- Veterans Affairs Tennessee Valley Health Care, Nashville, TN, USA.
- Vanderbilt-Ingram Cancer Center, Nashville, TN, USA.
- Vanderbilt Center for Immunobiology, Vanderbilt University Medical Center, Nashville, TN, USA.
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26
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Bailey C, Wei Y, Yan J, Huang D, Zhang P, Qi C, Lazarski C, Su J, Tang F, Wong CS, Zheng P, Liu Y, Liu Y, Wang Y. Genetic and pharmaceutical targeting of HIF1α allows combo-immunotherapy to boost graft vs. leukemia without exacerbation graft vs. host disease. Cell Rep Med 2023; 4:101236. [PMID: 37827154 PMCID: PMC10694596 DOI: 10.1016/j.xcrm.2023.101236] [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: 04/17/2023] [Revised: 07/27/2023] [Accepted: 09/20/2023] [Indexed: 10/14/2023]
Abstract
Despite potential impact on the graft vs. leukemia (GVL) effect, immunotherapy targeting CTLA-4 and/or PD-1 has not been successfully combined with bone marrow transplant (BMT) because it exacerbates graft vs. host disease (GVHD). Here, using models of GVHD and leukemia, we demonstrate that targeting hypoxia-inducible factor 1α (HIF1α) via pharmacological or genetic approaches reduces GVHD by inducing PDL1 expression on host tissue while selectively inhibiting PDL1 in leukemia cells to enhance the GVL effect. More importantly, combination of HIF1α inhibition with anti-CTLA-4 antibodies allows simultaneous inhibition of both PDL1 and CTLA-4 checkpoints to achieve better outcomes in models of mouse and human BMT-leukemia settings. These findings provide an approach to enhance the curative effect of BMT for leukemia and broaden the impact of cancer immunotherapy.
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Affiliation(s)
- Christopher Bailey
- Division of Immunotherapy, Institute of Human Virology, Department of Surgery and Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA
| | - Yuanyi Wei
- Division of Immunotherapy, Institute of Human Virology, Department of Surgery and Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA
| | - Jinsong Yan
- Department of Hematology, The Second Hospital of Dalian Medical University, Dalian, China
| | - Dan Huang
- Department of Hematology, The Second Hospital of Dalian Medical University, Dalian, China
| | - Peng Zhang
- Department of Neurosurgery, Beijing Children's Hospital, Capital Medical University, National Cancer for Children's Health, Beijing, China
| | - Chong Qi
- Institute of Translational Medicine, The First Hospital, Jilin University, Changchun, Jilin 130061, China
| | - Christopher Lazarski
- Center for Cancer and Immunology Research, Children's Research Institute, Washington, DC 20010, USA
| | - JuanJuan Su
- Division of Immunotherapy, Institute of Human Virology, Department of Surgery and Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA
| | - Fei Tang
- Division of Immunotherapy, Institute of Human Virology, Department of Surgery and Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA
| | - Chun-Shu Wong
- Center for Cancer and Immunology Research, Children's Research Institute, Washington, DC 20010, USA
| | - Pan Zheng
- Division of Immunotherapy, Institute of Human Virology, Department of Surgery and Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA; OncoC4, Inc., Rockville, MD 20852, USA
| | - Yan Liu
- Division of Immunotherapy, Institute of Human Virology, Department of Surgery and Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
| | - Yang Liu
- Division of Immunotherapy, Institute of Human Virology, Department of Surgery and Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA; OncoC4, Inc., Rockville, MD 20852, USA.
| | - Yin Wang
- Division of Immunotherapy, Institute of Human Virology, Department of Surgery and Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
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27
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Butera S, Tavarozzi R, Brunello L, Rivela P, Sofia A, Viero L, Salvio M, Ladetto M, Zallio F. The black swan: a case of central nervous system graft-versus-host disease. J Basic Clin Physiol Pharmacol 2023; 34:805-809. [PMID: 37843253 DOI: 10.1515/jbcpp-2023-0194] [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: 08/16/2023] [Accepted: 08/25/2023] [Indexed: 10/17/2023]
Abstract
OBJECTIVES Graft-versus-host disease (GVHD) of central nervous system is an atypical and rare manifestation of chronic GVHD, presenting with a heterogeneous spectrum of signs and symptoms. Diagnosis of neurological manifestations of GVHD can be highly challenging and remain associated with dismal prognosis, significant morbidity, and reduced quality of life. CASE PRESENTATION In this report, we describe a 39-year-old woman developing neurological signs and symptoms 8 months after allogeneic HSCT magnetic resonance imaging showed multifocal hyperintense lesions involving the periventricular region and frontal subcortical white matter. There was no laboratory evidence of infective or malignant etiology, and the case was diagnosed as CNS-GVHD. The patient was treated with intravenous methylprednisolone pulse therapy and the clinical conditions gradually improved. After few months, patient symptoms progressed despite the addition of high-dose intravenous immunoglobulin, tacrolimus, and a new course of high dose steroids. To engage targeted therapy, the patient underwent brain biopsy that revealed a loss of myelin fibers, perivascular and diffuse infiltration of T cells, and macrophages associated with reactive gliosis, representing a demyelinating disease. We intensified treatment with cyclophosphamide and subsequently introduced ibrutinib as salvage strategy. Despite a magnetic resonance imaging showing great regression of the demyelinating lesions, patient's conditions deteriorated and she died 16 months after HSCT. CONCLUSIONS CNS-GVHD is a rare complication of HSCT that is difficult to diagnose. Based on our experience, brain biopsy may represent a useful diagnostic tool when the clinical features of neurological symptoms are ambiguous or in patients without evidence of preceding chronic GVHD.
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Affiliation(s)
- Sara Butera
- Struttura Complessa di Ematologia a Direzione Universitaria, Azienda Ospedaliera SS Antonio e Biagio e Cesare Arrigo, Alessandria, Italy
| | - Rita Tavarozzi
- Struttura Complessa di Ematologia a Direzione Universitaria, Azienda Ospedaliera SS Antonio e Biagio e Cesare Arrigo, Alessandria, Italy
- Department of Translational Medicine, University of Eastern Piedmont, Novara, Italy
| | - Lucia Brunello
- Struttura Complessa di Ematologia a Direzione Universitaria, Azienda Ospedaliera SS Antonio e Biagio e Cesare Arrigo, Alessandria, Italy
| | - Paolo Rivela
- Struttura Complessa di Ematologia a Direzione Universitaria, Azienda Ospedaliera SS Antonio e Biagio e Cesare Arrigo, Alessandria, Italy
- Department of Translational Medicine, University of Eastern Piedmont, Novara, Italy
| | - Antonella Sofia
- Struttura Complessa di Ematologia a Direzione Universitaria, Azienda Ospedaliera SS Antonio e Biagio e Cesare Arrigo, Alessandria, Italy
| | - Lorenzo Viero
- Struttura Complessa di Ematologia a Direzione Universitaria, Azienda Ospedaliera SS Antonio e Biagio e Cesare Arrigo, Alessandria, Italy
- Department of Translational Medicine, University of Eastern Piedmont, Novara, Italy
| | - Michela Salvio
- Struttura Complessa di Ematologia a Direzione Universitaria, Azienda Ospedaliera SS Antonio e Biagio e Cesare Arrigo, Alessandria, Italy
| | - Marco Ladetto
- Struttura Complessa di Ematologia a Direzione Universitaria, Azienda Ospedaliera SS Antonio e Biagio e Cesare Arrigo, Alessandria, Italy
- Department of Translational Medicine, University of Eastern Piedmont, Novara, Italy
| | - Francesco Zallio
- Struttura Complessa di Ematologia a Direzione Universitaria, Azienda Ospedaliera SS Antonio e Biagio e Cesare Arrigo, Alessandria, Italy
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28
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Wu S, Li H, Wang X, Ji T, Xu X, Yang Q. Effects of different allo-Treg/allo-NK ratios on graft-versus-host disease in transplanted mice. Transpl Immunol 2023; 80:101893. [PMID: 37406712 DOI: 10.1016/j.trim.2023.101893] [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: 09/06/2022] [Revised: 06/26/2023] [Accepted: 07/01/2023] [Indexed: 07/07/2023]
Abstract
To investigate the effects of allo-Treg cells, allo-NK cells, and their mixtures in different proportions on Graft-versus-host disease (GVHD) in bone marrow transplant mouse model. In this study, C57BL/6 mice were used as donors, and 6 Gy dose of 60Co γ was used as the receptor of BALB/c mice. The recipient mice were divided into NC (normal saline), CON (bone marrow cells), NK (bone marrow cells + NK cells), Treg (bone marrow cells + Treg cells), NK+ Treg (1:1) (bone marrow cells +1:1 ratio of Treg cells, NK cells), and NK+ Treg (6:1) (bone marrow cells +1:6 ratio of Treg cells, NK cells), according to the different injection mode through the tail vein. The differences of white blood cell (WBC), platelet (PLT), clinical manifestations, and GVHD score of target organs (liver, lung, small intestine) in each group after transplantation were observed, and the differences of chimerism rate and survival rate in each group at 28 days after transplantation were compared. The interaction between Treg cells and NK cells in different proportions (1:1, 1:2, 1:6, 1:12) was investigated in vitro in mouse erythroleukemia (MEL) cells of mouse erythroleukemia. The results showed that at the 28th day of transplantation, the clinical manifestations and GVHD scores of target organs of mice in NK+ Treg (1:1) group and NK+ Treg (6:1) group were significantly lower than other groups (P < 0.05); the WBC and PLT counts were significantly higher than other groups (P < 0.05), and the survival time was significantly longer than other groups (P < 0.05); the clinical manifestations and GVHD scores of each target organ in NK+ Treg (1:1) group were significantly lower than those in NK+ Treg (6:1) group (P < 0.05); the chimerism rate of each group was >90% on day 28 after transplantation. In vitro experiments showed that the inhibition of Treg cells on NK cell killing activity was dose-dependent, and the proportion of 1:6 and 1:12, killing activity of NK cell was significantly lower than that of groups 1:1 and 1:2 (P < 0.05), which showed that allo-NK and allo-Treg alone had a significant effect on the improvement of GVHD after transplantation, and Treg cells inhibited the killing activity of NK cells by direct contact and showed a dose-dependent effect.
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Affiliation(s)
- Shunjie Wu
- Hematology Darpartment, The Seventh Affiliated Hospital of Sun Yat-sen University, China
| | - Haizhen Li
- Hematology Darpartment, The Seventh Affiliated Hospital of Sun Yat-sen University, China
| | - Xianchao Wang
- Department of Pathology and Pathophysiology, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, China
| | - Tuanyun Ji
- Department of Pathology and Pathophysiology, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, China
| | - Xiaojun Xu
- Hematology Darpartment, The Seventh Affiliated Hospital of Sun Yat-sen University, China.
| | - Qiaohong Yang
- Department of Pathology and Pathophysiology, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, China.
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29
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Kumbhalwar K, Punatar S, Gokarn A, Nayak L, Chichra A, Mirgh S, Jindal N, Mathew L, Khattry N. Lenalidomide with or without dexamethasone for relapsed or refractory Hodgkin lymphoma post autologous stem cell transplant. BLOOD CELL THERAPY 2023; 6:95-103. [PMID: 38146353 PMCID: PMC10749212 DOI: 10.31547/bct-2023-009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Accepted: 06/06/2023] [Indexed: 12/27/2023]
Abstract
Background The prognosis of Hodgkin lymphoma (HL) relapsing post autologous transplant (AuSCT) is poor. Even with novel therapies, only approximately 20%-25% of patients attain complete remissions, with a median progression-free survival (PFS) of approximately 5-15 months. Lenalidomide has been shown to have activity in relapsed HL. We retrospectively analyzed the outcomes of patients with relapsed HL post AuSCT treated with lenalidomide alone or in combination with dexamethasone at our center. Patients and methods Records of 143 patients transplanted from November 2007 to October 2021 were reviewed. Of these patients, 41 (28%) relapsed, and 16 (39%) received lenalidomide alone or in combination with dexamethasone. Data collected included demographic, pathological, staging, and prior therapy details. Lenalidomide was administered at 10-25 mg/day on an intermittent or continuous schedule alone or in combination with dexamethasone (20-40 mg weekly). Response was assessed using PET-CT scan in accordance with Lugano criteria. Standard definitions were used for response, PFS, and overall survival (OS). Toxicities were graded using Common Terminology Criteria for Adverse Events version 5.0. Statistical analysis was done using SPSS Version 21. Results The median age of the patients was 25.5 years, and 10 were males. Eleven (69%) had advanced disease, and 7 (44%) were refractory to last systemic therapy. Nine patients received lenalidomide alone and 7 with dexamethasone. Four (25%) had complete response, and another four (25%) had partial response, with an overall response rate of 50%. The 3-year PFS and OS were 31% and 38%, respectively. Grade III/IV toxicities were only hematological, neutropenia and thrombocytopenia in four and three patients, respectively. No therapy-related deaths were recorded. Conclusions Lenalidomide alone or in combination with dexamethasone is a safe and effective therapy for relapsed HL post AuSCT and results in durable response and long-term survival in approximately one-third of the patients. However, these results needs verification in larger prospective studies.
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Affiliation(s)
- Komal Kumbhalwar
- Stem Cell Transplant Unit, Department of Medical Oncology, ACTREC, Tata Memorial Centre, Navi Mumbai, India
| | - Sachin Punatar
- Stem Cell Transplant Unit, Department of Medical Oncology, ACTREC, Tata Memorial Centre, Navi Mumbai, India
- Homi Bhabha National Institute (HBNI), Anushaktinagar, Mumbai, India
| | - Anant Gokarn
- Stem Cell Transplant Unit, Department of Medical Oncology, ACTREC, Tata Memorial Centre, Navi Mumbai, India
- Homi Bhabha National Institute (HBNI), Anushaktinagar, Mumbai, India
| | - Lingaraj Nayak
- Stem Cell Transplant Unit, Department of Medical Oncology, ACTREC, Tata Memorial Centre, Navi Mumbai, India
- Homi Bhabha National Institute (HBNI), Anushaktinagar, Mumbai, India
| | - Akanksha Chichra
- Stem Cell Transplant Unit, Department of Medical Oncology, ACTREC, Tata Memorial Centre, Navi Mumbai, India
- Homi Bhabha National Institute (HBNI), Anushaktinagar, Mumbai, India
| | - Sumeet Mirgh
- Stem Cell Transplant Unit, Department of Medical Oncology, ACTREC, Tata Memorial Centre, Navi Mumbai, India
- Homi Bhabha National Institute (HBNI), Anushaktinagar, Mumbai, India
| | - Nishant Jindal
- Stem Cell Transplant Unit, Department of Medical Oncology, ACTREC, Tata Memorial Centre, Navi Mumbai, India
- Homi Bhabha National Institute (HBNI), Anushaktinagar, Mumbai, India
| | - Libin Mathew
- Stem Cell Transplant Unit, Department of Medical Oncology, ACTREC, Tata Memorial Centre, Navi Mumbai, India
| | - Navin Khattry
- Stem Cell Transplant Unit, Department of Medical Oncology, ACTREC, Tata Memorial Centre, Navi Mumbai, India
- Homi Bhabha National Institute (HBNI), Anushaktinagar, Mumbai, India
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30
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El Fakih R, Albabtain AA, Alhayli S, Farhan K, Rasheed W, Alshaibani A, Chaudhri N, Aljurf M. Successful restoration of checkpoint inhibitors efficacy after allogeneic hematopoietic cell transplant for classic Hodgkin lymphoma patients. Semin Oncol 2023; 50:76-85. [PMID: 37598020 DOI: 10.1053/j.seminoncol.2023.05.001] [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: 03/29/2023] [Revised: 05/07/2023] [Accepted: 05/10/2023] [Indexed: 08/21/2023]
Abstract
BACKGROUND Classic Hodgkin lymphoma (cHL) is a highly-curable disease. However, relapses after bone marrow transplant are challenging especially relapses after allogeneic transplant. METHODS A retrospective chart review of the institution transplant database to summarize the safety and efficacy of checkpoint inhibitors (CPIs) use for cHL relapses postallo-HCT in patients who already failed to derive sustained benefit from CPIs received prior to allo-HCT. RESULTS Six cases were identified and reviewed. All patients received and failed to derive sustained benefit from CPIs and brentuximab vedotin preallo-HCT. The median age at the time of allo-HCT was 28.6 years (IQR 23.6-34.2), the median number of lines received prior to allo-HCT was 6.5 (range 5-9). The median duration of CPI therapy prior to allo-HCT was 8.1 months (IQR 6.7-12.9). The median time between the discontinuation of CPI and allo-HCT was 5.78 months (IQR 3.15-15.8). The median time to progression postallo-HCT was 5.75 months (IQR 2.6-11.7). The median time between allo-HCT and re-challenge with a CPI was 7.6 months (IQR 3.2-28.6). The median time of follow up after starting postallo-HCT CPIs was 16 months (IQR 7.25-25.75). Five out six patients responded and two patients developed GvHD. CONCLUSION Our report shows preserved efficacy without any new safety signals by using CPIs postallo-HCT despite using and having failed to derive sustained benefit from CPIs preallo-HCT.
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Affiliation(s)
- Riad El Fakih
- King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
| | | | - Saud Alhayli
- King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Khawlah Farhan
- King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Walid Rasheed
- King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Alfadel Alshaibani
- King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Naeem Chaudhri
- King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Mahmoud Aljurf
- King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
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31
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Jain N, Senapati J, Thakral B, Ferrajoli A, Thompson P, Burger J, Basu S, Kadia T, Daver N, Borthakur G, Konopleva M, Pemmaraju N, Parry E, Wu CJ, Khoury J, Bueso-Ramos C, Garg N, Wang X, Lopez W, Ayala A, O’Brien S, Kantarjian H, Keating M, Allison J, Sharma P, Wierda W. A phase 2 study of nivolumab combined with ibrutinib in patients with diffuse large B-cell Richter transformation of CLL. Blood Adv 2023; 7:1958-1966. [PMID: 36287248 PMCID: PMC10189379 DOI: 10.1182/bloodadvances.2022008790] [Citation(s) in RCA: 38] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Revised: 10/11/2022] [Accepted: 10/11/2022] [Indexed: 11/20/2022] Open
Abstract
Richter transformation (RT) is a rare complication of chronic lymphocytic leukemia (CLL) that has dismal outcomes. Upregulation of PD-1/PD-L1 drives immunological evasion in patients with RT. We hypothesized that combining nivolumab, a PD-1 blocking antibody, with the BTK inhibitor (BTKi) ibrutinib could potentiate tumor-cell killing. We conducted an investigator-initiated phase 2 clinical trial to assess the efficacy of combined nivolumab and ibrutinib in patients with diffuse large B-cell lymphoma (DLBCL) RT and CLL. Patients included were ≥18 years of age with adequate hepatic and renal function. Patients received nivolumab every 2 weeks of a 4-week cycle for a maximum of 24 cycles. A standard dose ibrutinib was initiated from cycle 2 onward and continued daily until progression. For patients who were already on ibrutinib at the time of study entry, the same was continued while nivolumab was initiated. A total of 24 patients with RT with a median age of 64.5 years (range, 47-88) were enrolled. Ten patients (42%) had received prior treatment for RT and 13 patients (54%) had received a prior BTKi. A total of 10 patients (42%) responded with a median duration of response of 15 months. The median overall survival was 13 months. Four of 24 (17%) patients had checkpoint inhibition-related immunological toxicities. In the CLL cohort, 10 patients were enrolled, of whom 3 patients converted from partial to complete remission; 1 patient had a grade 2 immunological toxicity. Combined nivolumab and ibrutinib is an active regimen for patients with DLBCL RT with an overall response rate of 42%. Given the limited treatment options for patients with RT, checkpoint inhibition provides a potential therapeutic option. This trial is registered at www.clinicaltrials.gov as #NCT02420912.
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Affiliation(s)
- Nitin Jain
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Jayastu Senapati
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Beenu Thakral
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Alessandra Ferrajoli
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Philip Thompson
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Jan Burger
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Sreyashi Basu
- Immunotherapy Platform, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Tapan Kadia
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Naval Daver
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Gautam Borthakur
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Marina Konopleva
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Naveen Pemmaraju
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Erin Parry
- Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA
| | - Catherine J. Wu
- Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA
| | - Joseph Khoury
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Carlos Bueso-Ramos
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Naveen Garg
- Department of Radiology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Xuemei Wang
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Wanda Lopez
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Ana Ayala
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Susan O’Brien
- Chao Family Comprehensive Cancer Center, University of California Irvine Medical Center, Orange, CA
| | - Hagop Kantarjian
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Michael Keating
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - James Allison
- Immunotherapy Platform, The University of Texas MD Anderson Cancer Center, Houston, TX
- Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Padmanee Sharma
- Immunotherapy Platform, The University of Texas MD Anderson Cancer Center, Houston, TX
- Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX
- Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - William Wierda
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
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Gao XN, Su YF, Li MY, Jing Y, Wang J, Xu L, Zhang LL, Wang A, Wang YZ, Zheng X, Li YF, Liu DH. Single-center phase 2 study of PD-1 inhibitor combined with DNA hypomethylation agent + CAG regimen in patients with relapsed/refractory acute myeloid leukemia. Cancer Immunol Immunother 2023:10.1007/s00262-023-03454-y. [PMID: 37166484 DOI: 10.1007/s00262-023-03454-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Accepted: 04/19/2023] [Indexed: 05/12/2023]
Abstract
Anti-PD-1 monotherapy had limited clinical efficacy in relapsed/refractory (r/r) AML patients with higher PD-1 and PD-L1 expression. Hence, we investigated the efficacy and safety of PD-1 inhibitor with DNA hypomethylating agent (HMA) + CAG regimen in patients who had failed prior AML therapy. In this phase 2, single-arm study, r/r AML patients received azacitidine or decitabine plus CAG regimen with tislelizumab. Primary endpoints were efficacy (objective response rate [ORR]) and safety. Secondary endpoints included overall survival (OS), event-free survival (EFS) and duration of response (DOR). Statistical analyses were performed using Stata 14.0 and SPSS 20.0 software where P < 0.05 denoted significance. Twenty-seven patients were enrolled patients and completed 1 cycle, and 14 (51.9%) and 4 (14.8%) patients completed 2 and 3 cycles, respectively. ORR was 63% (14: complete remission [CR]/CR with incomplete hematologic recovery [CRi], 3: partial remission (PR), 10: no response [NR]). Median OS (mOS) and EFS were 9.7 and 9.2 months, respectively. With a median follow-up of 8.2 months (1.1-26.9), the mOS was not reached in responders (CR/CRi/PR) while it was 2.4 months (0.0-5.4) in nonresponders (P = 0.002). Grade 2-3 immune-related adverse events (irAEs) were observed in 4 (14.8%) patients and 3 nonresponders died of lung infection after treatment. Tislelizumab + HMA + CAG regimen showed improved outcomes in r/r AML patients with lower pretherapy leukemia burden. irAEs were mild and low-grade and higher pretherapy bone marrow CD4+ CD127+ PD-1+ T cells might serve as a predictor of treatment response.ClinicalTrials.gov identifier NCT04541277.
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Affiliation(s)
- Xiao-Ning Gao
- Senior Department of Hematology, The Fifth Medical Center, Chinese PLA General Hospital, 8 East Main Street, Beijing, 100071, China.
| | - Yong-Feng Su
- Senior Department of Hematology, The Fifth Medical Center, Chinese PLA General Hospital, 8 East Main Street, Beijing, 100071, China
| | - Meng-Yue Li
- Senior Department of Hematology, The Fifth Medical Center, Chinese PLA General Hospital, 8 East Main Street, Beijing, 100071, China
- Graduate School, Chinese PLA General Hospital, Beijing, 100853, China
| | - Yu Jing
- Department of Hematology, The First Medical Center, Chinese PLA General Hospital, Beijing, 100853, China
| | - Jun Wang
- Senior Department of Hematology, The Fifth Medical Center, Chinese PLA General Hospital, 8 East Main Street, Beijing, 100071, China
| | - Lei Xu
- Senior Department of Hematology, The Fifth Medical Center, Chinese PLA General Hospital, 8 East Main Street, Beijing, 100071, China
| | - Lin-Lin Zhang
- Department of Hematology, The First Medical Center, Chinese PLA General Hospital, Beijing, 100853, China
| | - An Wang
- Senior Department of Hematology, The Fifth Medical Center, Chinese PLA General Hospital, 8 East Main Street, Beijing, 100071, China
| | - Yi-Zhi Wang
- Senior Department of Hematology, The Fifth Medical Center, Chinese PLA General Hospital, 8 East Main Street, Beijing, 100071, China
| | - Xuan Zheng
- Senior Department of Hematology, The Fifth Medical Center, Chinese PLA General Hospital, 8 East Main Street, Beijing, 100071, China
| | - Yan-Fen Li
- Department of Hematology, The First Medical Center, Chinese PLA General Hospital, Beijing, 100853, China
| | - Dai-Hong Liu
- Senior Department of Hematology, The Fifth Medical Center, Chinese PLA General Hospital, 8 East Main Street, Beijing, 100071, China.
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Guberina N, Wirsdörfer F, Stuschke M, Jendrossek V. Combined radiation- and immune checkpoint-inhibitor-induced pneumonitis – The challenge to predict and detect overlapping immune-related adverse effects from evolving laboratory biomarkers and clinical imaging. Neoplasia 2023; 39:100892. [PMID: 37011458 PMCID: PMC10124136 DOI: 10.1016/j.neo.2023.100892] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Revised: 02/17/2023] [Accepted: 02/23/2023] [Indexed: 04/04/2023]
Abstract
The risk of overlapping pulmonary toxicity induced by thoracic radio(chemo)therapy and immune checkpoint inhibitor therapy in the treatment of patients suffering from non-small cell lung cancer (NSCLC) is one important challenge in successful radioimmunotherapy. In the present opinion we highlight factors that we find important to be considered before treatment initiation, during the treatment sequence, and after treatment completion combined or sequential application of radio(chemo)therapy and immune checkpoint inhibitor therapy. A major aim is to optimize the therapeutic index and to avoid immune related adverse effects. The goals in the future will be focused not only on identifying patients already in the pretreatment phase who could benefit from this complex treatment, but also in identifying patients, who are most likely to have higher grade toxicity. In this respect, proper assessment of clinical performance status, monitoring for the presence of certain comorbidities, evaluation of laboratory parameters such as TGF-α and IL-6 levels, human leukocyte antigens (HLA), and consideration of other potential biomarkers which will evolve in near future are essential. Likewise, the critical parameters must be monitored during the treatment phase and follow-up care to detect potential side effects in time. With the help of high-end imaging which is already used on a daily basis in image guided radiotherapy (IGRT) for intensity modulated radiotherapy (IMRT), its advanced form volumetric modulated arc therapy (VMAT), and adaptive radiation therapy (ART), clinically relevant changes in lung tissue can be detected at an early stage of disease. Concurrent radiotherapy and immunotherapy requires a special focus on adverse events, particularly of the lung, but, when properly approached and applied, it may offer new perspectives for patients with locally advanced NSCLC to be seriously considered as a curative option.
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Maher J, Davies DM. CAR Based Immunotherapy of Solid Tumours-A Clinically Based Review of Target Antigens. BIOLOGY 2023; 12:287. [PMID: 36829563 PMCID: PMC9953298 DOI: 10.3390/biology12020287] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 01/27/2023] [Revised: 02/07/2023] [Accepted: 02/08/2023] [Indexed: 02/15/2023]
Abstract
Immunotherapy with CAR-engineered immune cells has transformed the management of selected haematological cancers. However, solid tumours have proven much more difficult to control using this emerging therapeutic modality. In this review, we survey the clinical impact of solid tumour CAR-based immunotherapy, focusing on specific targets across a range of disease indications Among the many candidates which have been the subject of non-clinical CAR T-cell research, clinical data are available for studies involving 30 of these targets. Here, we map out this clinical experience, highlighting challenges such as immunogenicity and on-target off-tumour toxicity, an issue that has been both unexpected and devastating in some cases. We also summarise how regional delivery and repeated dosing have been used in an effort to enhance impact and safety. Finally, we consider how emerging armouring systems and multi-targeted CAR approaches might be used to enhance tumour access and better enable discrimination between healthy and transformed cell types.
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Affiliation(s)
- John Maher
- CAR Mechanics Group, Guy’s Cancer Centre, School of Cancer and Pharmaceutical Sciences, King’s College London, Great Maze Pond, London SE1 9RT, UK
- Department of Immunology, Eastbourne Hospital, Kings Drive, Eastbourne BN21 2UD, UK
- Leucid Bio Ltd., Guy’s Hospital, Great Maze Pond, London SE1 9RT, UK
| | - David M. Davies
- Leucid Bio Ltd., Guy’s Hospital, Great Maze Pond, London SE1 9RT, UK
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35
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Palmieri R, Montgomery RB, Doney K. Allogeneic stem cell transplantation in patients with a prior history of prostate cancer. Ann Hematol 2023; 102:407-412. [PMID: 36394580 DOI: 10.1007/s00277-022-05041-0] [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: 02/09/2022] [Accepted: 11/08/2022] [Indexed: 11/18/2022]
Abstract
A retrospective analysis of 25 patients with a history of prostate cancer (PC) who subsequently underwent allogeneic hematopoietic cell transplantation (HCT) for treatment of a hematologic malignancy was performed. Median patient age was 66.7 years. Median duration from the diagnosis of PC to HCT was 4.2 years. Twenty-three patients had Gleason group 1 or 2 disease. Therapy included prostatectomy (n = 13) and external beam or brachytherapy (n = 9). Hematologic diagnoses included both myeloid (n = 15) and lymphoid neoplasms (n = 10). Twenty-four patients received either a nonmyeloablative or reduced intensity conditioning regimen. GVHD prophylaxis included a calcineurin inhibitor and mycophenolate mofetil ± sirolimus. Twenty patients had HLA-matched sibling or HLA-matched unrelated donors; five patients had HLA-mismatched donors. Eleven patients are alive, and 14 have died. Median survival was 2.5 years (range, .02-12.6 years). The major cause of death was hematologic relapse. Only one patient had evidence of recurrent PC, occurring 1.5 years posttransplant. In carefully selected patients with a prior history of PC, there was no evidence of rapid recurrence of the solid tumor (ST) after HCT. PC patients who are in remission from their ST or have control of their disease on therapy should be considered eligible for HCT.
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Affiliation(s)
- Raffaele Palmieri
- Clinical Research Division, Fred Hutchinson Cancer Center, 1100 Fairview Ave. N., D5-280, PO Box 19024, Seattle, WA, 98109-1024, USA.,Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy
| | - Robert B Montgomery
- Department of Medicine, Division of Oncology, University of Washington Medical Center, Seattle, WA, USA.,VA Puget Sound, Seattle, WA, USA
| | - Kristine Doney
- Clinical Research Division, Fred Hutchinson Cancer Center, 1100 Fairview Ave. N., D5-280, PO Box 19024, Seattle, WA, 98109-1024, USA. .,Department of Medicine, Division of Oncology, University of Washington Medical Center, Seattle, WA, USA.
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36
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Saad A, Loren A, Bolaños-Meade J, Chen G, Couriel D, Di Stasi A, El-Jawahri A, Elmariah H, Farag S, Gundabolu K, Gutman J, Ho V, Hoeg R, Horwitz M, Hsu J, Kassim A, Kharfan Dabaja M, Magenau J, Martin T, Mielcarek M, Moreira J, Nakamura R, Nieto Y, Ninos C, Oliai C, Patel S, Randolph B, Schroeder M, Tzachanis D, Varshavsky-Yanovsky AN, Vusirikala M, Algieri F, Pluchino LA. NCCN Guidelines® Insights: Hematopoietic Cell Transplantation, Version 3.2022. J Natl Compr Canc Netw 2023; 21:108-115. [PMID: 36791762 DOI: 10.6004/jnccn.2023.0007] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/17/2023]
Abstract
The NCCN Guidelines for Hematopoietic Cell Transplantation (HCT) provide an evidence- and consensus-based approach for the use of autologous and allogeneic HCT in the management of malignant diseases in adult patients. HCT is a potentially curative treatment option for patients with certain types of malignancies; however, recurrent malignancy and transplant-related complications often limit the long-term survival of HCT recipients. The purpose of these guidelines is to provide guidance regarding aspects of HCT, including pretransplant recipient evaluation, hematopoietic cell mobilization, and treatment of graft-versus-host disease-a major complication of allogeneic HCT-to enable the patient and clinician to assess management options in the context of an individual patient's condition. These NCCN Guidelines Insights provide a summary of the important recent updates to the NCCN Guidelines for HCT, including the incorporation of a newly developed section on the Principles of Conditioning for HCT.
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Affiliation(s)
- Ayman Saad
- The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute
| | - Alison Loren
- Abramson Cancer Center at the University of Pennsylvania
| | | | | | | | | | | | | | - Sherif Farag
- Indiana University Melvin and Bren Simon Comprehensive Cancer Center
| | | | | | - Vincent Ho
- Dana-Farber/Brigham and Women's Cancer Center
| | | | | | | | | | | | | | - Thomas Martin
- UCSF Helen Diller Family Comprehensive Cancer Center
| | | | - Jonathan Moreira
- Robert H. Lurie Comprehensive Cancer Center of Northwestern University
| | | | - Yago Nieto
- The University of Texas MD Anderson Cancer Center
| | | | | | - Seema Patel
- Case Comprehensive Cancer Center/University Hospitals Seidman Cancer Center and Cleveland Clinic Taussig Cancer Institute
| | - Brion Randolph
- St. Jude Children's Research Hospital/The University of Tennessee Health Science Center
| | - Mark Schroeder
- Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine
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37
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Maranzano M, Mead M. The role of transplantation in Hodgkin lymphoma. Front Oncol 2023; 12:1054314. [PMID: 36776370 PMCID: PMC9908991 DOI: 10.3389/fonc.2022.1054314] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Accepted: 12/06/2022] [Indexed: 01/27/2023] Open
Abstract
Despite the success of frontline anthracycline-based chemotherapy for classical Hodgkin Lymphoma (cHL), approximately 15% of patients do not achieve an adequate response and require further therapy. For transplant-eligible patients, additional treatment followed by high-dose chemotherapy and autologous hematopoietic stem cell transplantation (autoHCT) provides a durable response in 50% of patients. The most refractory patients, including those requiring multiple lines of therapy to achieve a response or those relapsing after an autoHCT, may achieve long-term survival with allogeneic hematopoietic stem cell transplant (alloHCT). Contemporary salvage regimens used as a bridge to transplant have expanded to include not only non-cross resistant chemotherapy, but also brentuximab vedotin (BV) and checkpoint inhibitors (CPI). As the management of relapsed/refractory (R/R) cHL evolves with the introduction of novel agents, so too does the role of transplantation. The paradigm of chemosensitivity as a predictor for autoHCT efficacy is being challenged by favorable post- autoHCT outcomes in heavily pre-treated CPI-exposed patients. Contemporary supportive care measures, validated comorbidity assessments, and an increased donor pool with haploidentical donors have broadened the application of transplantation to an increasingly older and diverse patient population. Despite the introduction of increasingly effective treatment options for R/R cHL, transplantation continues to play an important role in the management of these patients. In this review, we explore the impact of salvage therapy on autoHCT, conditioning regimens, maintenance therapy and the diminishing role of alloHCT for patients with cHL.
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Affiliation(s)
| | - Monica Mead
- Division of Hematology/Oncology, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, United States
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38
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Varadarajan I, Pierce E, Scheuing L, Morris A, El Chaer F, Keng M. Post-Hematopoietic Cell Transplantation Relapsed Acute Lymphoblastic Leukemia: Current Challenges and Future Directions. Onco Targets Ther 2023; 16:1-16. [PMID: 36685611 PMCID: PMC9849790 DOI: 10.2147/ott.s274551] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2022] [Accepted: 12/14/2022] [Indexed: 01/15/2023] Open
Abstract
Allogeneic hematopoietic cell transplantation (allo-HCT) represents an important and potentially curative treatment option for adult patients with acute lymphoblastic leukemia. Relapse continues to remain the most important factor influencing overall survival post allo-HCT. We discuss early identification, clinical manifestations, and management of relapsed disease. Routine evaluation of measurable residual disease (MRD) and change in donor chimerism play a crucial role in early detection. Pivotal clinical trials have led to FDA approval of multiple novel agents like blinatumomab and inotuzumab. Combining targeted therapy with cellular immunotherapy serves as the backbone for prolonging overall survival in these patients. Donor lymphocyte infusions have traditionally been used in relapsed disease with suboptimal outcomes. This review provides insight into use of cellular therapy in MRD positivity and decreasing donor chimerism. It also discusses various modalities of combining cellular therapy with novel agents and discussing the impact of chimeric antigen receptor T-cell therapy in the setting of post allo-HCT relapse both as consolidative therapy and as a bridge to second transplant.
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Affiliation(s)
- Indumathy Varadarajan
- Department of Medicine, Division of Hematology and Oncology, University of Virginia, Charlottesville, VA, USA
| | - Eric Pierce
- Department of Medicine, Division of Hematology and Oncology, University of Virginia, Charlottesville, VA, USA
| | - Lisa Scheuing
- Department of Medicine, Division of Hematology and Oncology, University of Virginia, Charlottesville, VA, USA
| | - Amy Morris
- Department of Pharmacy Services, University of Virginia, Charlottesville, VA, USA
| | - Firas El Chaer
- Department of Medicine, Division of Hematology and Oncology, University of Virginia, Charlottesville, VA, USA
| | - Michael Keng
- Department of Medicine, Division of Hematology and Oncology, University of Virginia, Charlottesville, VA, USA,Correspondence: Michael Keng, Division of Hematology & Oncology, University of Virginia Comprehensive Cancer Center, West Complex Room 6009, 1300 Jefferson Park Ave, PO Box 800716, Charlottesville, VA, 22908, USA, Tel +1 434 924 4257, Fax +1 434- 243 6068, Email
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39
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How I prevent GVHD in high-risk patients: posttransplant cyclophosphamide and beyond. Blood 2023; 141:49-59. [PMID: 35405017 DOI: 10.1182/blood.2021015129] [Citation(s) in RCA: 38] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Revised: 03/09/2022] [Accepted: 03/21/2022] [Indexed: 01/10/2023] Open
Abstract
Advances in conditioning, graft-versus-host disease (GVHD) prophylaxis and antimicrobial prophylaxis have improved the safety of allogeneic hematopoietic cell transplantation (HCT), leading to a substantial increase in the number of patients transplanted each year. This influx of patients along with progress in remission-inducing and posttransplant maintenance strategies for hematologic malignancies has led to new GVHD risk factors and high-risk groups: HLA-mismatched related (haplo) and unrelated (MMUD) donors; older recipient age; posttransplant maintenance; prior checkpoint inhibitor and autologous HCT exposure; and patients with benign hematologic disorders. Along with the changing transplant population, the field of HCT has dramatically shifted in the past decade because of the widespread adoption of posttransplantation cyclophosphamide (PTCy), which has increased the use of HLA-mismatched related donors to levels comparable to HLA-matched related donors. Its success has led investigators to explore PTCy's utility for HLA-matched HCT, where we predict it will be embraced as well. Additionally, combinations of promising new agents for GVHD prophylaxis such as abatacept and JAK inhibitors with PTCy inspire hope for an even safer transplant platform. Using 3 illustrative cases, we review our current approach to transplantation of patients at high risk of GVHD using our modern armamentarium.
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40
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Konova ZV, Parovichnikova EN, Galtseva IV, Khamaganova EG. Impact of natural killer cell’s functional reconstruction on the results of allogeneic hematopoietic stem cell transplantation. RUSSIAN JOURNAL OF HEMATOLOGY AND TRANSFUSIOLOGY 2022. [DOI: 10.35754/0234-5730-2022-67-4-551-569] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Introduction. Currently, more and more attention is being paid to possible strategies for preventing the development of graft-versus-host disease (GVHD) and reducing the risk of infections while maintaining the antitumor effect — graft-versus-leukemia effect (GVL). In this context, the study of natural killer cells (NK-cells) seems to be quite promising.Aim – to analyze the biological and functional properties of NK-cells after allo-HSCT, their reconstitution after transplantation and factors affecting this process, as well as the mechanisms of alloreactivity of NK cells in patients after allo-HSCT. Main findings. Various types of activating or inhibiting receptors, which are expressed on NK-cells, regulate the functions of NK-cells. Among them, the main role is played by the killer immunoglobin-like receptor (KIR-receptor), which mediates tolerance to one’s own cells and the immune response, both antitumor and directed against infectious agents. NK-cells can play a decisive role in preventing early relapses and infectious complications, as they are among the first to recover after allo-HSCT. They also have the ability to eliminate the recipient’s T-cells and antigen presenting cells (APCs), thereby preventing the development of graft failure and GVHD. There are several models of NK alloreactivity based on KIR; however, the results of studies in this area are contradictory. This review summarizes the available literature data.
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41
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Alabdaljabar MS, Durani U, Thompson CA, Constine LS, Hashmi SK. The forgotten survivor: A comprehensive review on Non-Hodgkin lymphoma survivorship. Am J Hematol 2022; 97:1627-1637. [PMID: 36069675 DOI: 10.1002/ajh.26719] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Revised: 08/15/2022] [Accepted: 08/23/2022] [Indexed: 01/31/2023]
Abstract
The number of non-Hodgkin lymphoma (NHL) survivors is increasing. With the advancement of NHL therapies, it is crucial to focus on the challenges these survivors may face. Three main categories are to be considered in NHL survivorship, including quality of life and uncertainty about the future, possible physical health complications (including cardiovascular disease, infertility, and subsequent neoplasms), and the impact of novel NHL treatments and their potential complications. The latter includes CAR T-cell therapy, monoclonal antibodies, checkpoint inhibitors, and hematopoietic stem cell transplantation. In this report, we aim to shed the light on these aspects and to discuss survivorship care plan for NHL.
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Affiliation(s)
| | - Urshila Durani
- Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA
| | - Carrie A Thompson
- Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA
| | - Louis S Constine
- Departments of Radiation Oncology and Pediatrics, University of Rochester Medical Center, New York City, New York, USA
| | - Shahrukh K Hashmi
- Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA.,Sheikh Shakhbout Medical City / Mayo Clinic, Abu Dhabi, United Arab Emirates
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42
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Zibara V, Sen F, Scordo M, Falchi L. Successful brentuximab vedotin and nivolumab therapy of multiply refractory diffuse large B-cell lymphoma with Hodgkin features. Leuk Lymphoma 2022; 63:3241-3244. [PMID: 36120859 DOI: 10.1080/10428194.2022.2113528] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Affiliation(s)
- Victor Zibara
- Department of Medicine, Mount Sinai Morningside West, New York, NY, USA.,Lymphoma, Hematopathology, and Bone Marrow Transplantation Services, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
| | - Filiz Sen
- Lymphoma, Hematopathology, and Bone Marrow Transplantation Services, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
| | - Michael Scordo
- Lymphoma, Hematopathology, and Bone Marrow Transplantation Services, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
| | - Lorenzo Falchi
- Lymphoma, Hematopathology, and Bone Marrow Transplantation Services, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
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43
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Minnie SA, Waltner OG, Ensbey KS, Nemychenkov NS, Schmidt CR, Bhise SS, Legg SRW, Campoy G, Samson LD, Kuns RD, Zhou T, Huck JD, Vuckovic S, Zamora D, Yeh A, Spencer A, Koyama M, Markey KA, Lane SW, Boeckh M, Ring AM, Furlan SN, Hill GR. Depletion of exhausted alloreactive T cells enables targeting of stem-like memory T cells to generate tumor-specific immunity. Sci Immunol 2022; 7:eabo3420. [PMID: 36240285 PMCID: PMC10184646 DOI: 10.1126/sciimmunol.abo3420] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022]
Abstract
Some hematological malignancies such as multiple myeloma are inherently resistant to immune-mediated antitumor responses, the cause of which remains unknown. Allogeneic bone marrow transplantation (alloBMT) is the only curative immunotherapy for hematological malignancies due to profound graft-versus-tumor (GVT) effects, but relapse remains the major cause of death. We developed murine models of alloBMT where the hematological malignancy is either sensitive [acute myeloid leukemia (AML)] or resistant (myeloma) to GVT effects. We found that CD8+ T cell exhaustion in bone marrow was primarily alloantigen-driven, with expression of inhibitory ligands present on myeloma but not AML. Because of this tumor-independent exhaustion signature, immune checkpoint inhibition (ICI) in myeloma exacerbated graft-versus-host disease (GVHD) without promoting GVT effects. Administration of post-transplant cyclophosphamide (PT-Cy) depleted donor T cells with an exhausted phenotype and spared T cells displaying a stem-like memory phenotype with chromatin accessibility present in cytokine signaling genes, including the interleukin-18 (IL-18) receptor. Whereas ICI with anti-PD-1 or anti-TIM-3 remained ineffective after PT-Cy, administration of a decoy-resistant IL-18 (DR-18) strongly enhanced GVT effects in both myeloma and leukemia models, without exacerbation of GVHD. We thus defined mechanisms of resistance to T cell-mediated antitumor effects after alloBMT and described an immunotherapy approach targeting stem-like memory T cells to enhance antitumor immunity.
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Affiliation(s)
- Simone A. Minnie
- Clinical Research Division, Fred Hutchinson Cancer Center; Seattle, WA, 98109, UNITED STATES
| | - Olivia G. Waltner
- Clinical Research Division, Fred Hutchinson Cancer Center; Seattle, WA, 98109, UNITED STATES
| | - Kathleen S. Ensbey
- Clinical Research Division, Fred Hutchinson Cancer Center; Seattle, WA, 98109, UNITED STATES
| | - Nicole S. Nemychenkov
- Clinical Research Division, Fred Hutchinson Cancer Center; Seattle, WA, 98109, UNITED STATES
| | - Christine R. Schmidt
- Clinical Research Division, Fred Hutchinson Cancer Center; Seattle, WA, 98109, UNITED STATES
| | - Shruti S. Bhise
- Clinical Research Division, Fred Hutchinson Cancer Center; Seattle, WA, 98109, UNITED STATES
| | - Samuel RW. Legg
- Clinical Research Division, Fred Hutchinson Cancer Center; Seattle, WA, 98109, UNITED STATES
| | - Gabriela Campoy
- Clinical Research Division, Fred Hutchinson Cancer Center; Seattle, WA, 98109, UNITED STATES
| | - Luke D. Samson
- Clinical Research Division, Fred Hutchinson Cancer Center; Seattle, WA, 98109, UNITED STATES
| | - Rachel D. Kuns
- QIMR Berghofer Medical Research Institute; Brisbane, QLD, 4006, AUSTRALIA
| | - Ting Zhou
- Department of Immunobiology, Yale School of Medicine; New Haven, CT, 06519, UNITED STATES
| | - John D. Huck
- Department of Immunobiology, Yale School of Medicine; New Haven, CT, 06519, UNITED STATES
| | - Slavica Vuckovic
- QIMR Berghofer Medical Research Institute; Brisbane, QLD, 4006, AUSTRALIA
| | - Danniel Zamora
- Department of Medicine, University of Washington; Seattle, WA, 98109, UNITED STATES
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center; Seattle, WA, 98109, UNITED STATES
| | - Albert Yeh
- Clinical Research Division, Fred Hutchinson Cancer Center; Seattle, WA, 98109, UNITED STATES
- Department of Medicine, University of Washington; Seattle, WA, 98109, UNITED STATES
| | - Andrew Spencer
- Australian Center for Blood Diseases, Monash University/The Alfred Hospital; Melbourne, VIC, 3004, AUSTRALIA
- Malignant Haematology and Stem Cell Transplantation, The Alfred Hospital; Melbourne, VIC, 3004, AUSTRALIA
- Department of Clinical Haematology, Monash University; Melbourne, VIC, 3800, AUSTRALIA
| | - Motoko Koyama
- Clinical Research Division, Fred Hutchinson Cancer Center; Seattle, WA, 98109, UNITED STATES
| | - Kate A. Markey
- Clinical Research Division, Fred Hutchinson Cancer Center; Seattle, WA, 98109, UNITED STATES
- Department of Medicine, University of Washington; Seattle, WA, 98109, UNITED STATES
| | - Steven W. Lane
- QIMR Berghofer Medical Research Institute; Brisbane, QLD, 4006, AUSTRALIA
| | - Michael Boeckh
- Clinical Research Division, Fred Hutchinson Cancer Center; Seattle, WA, 98109, UNITED STATES
- Department of Medicine, University of Washington; Seattle, WA, 98109, UNITED STATES
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center; Seattle, WA, 98109, UNITED STATES
| | - Aaron M. Ring
- Department of Immunobiology, Yale School of Medicine; New Haven, CT, 06519, UNITED STATES
| | - Scott N. Furlan
- Clinical Research Division, Fred Hutchinson Cancer Center; Seattle, WA, 98109, UNITED STATES
- Department of Pediatrics, University of Washington; WA, 98105, UNITED STATES
| | - Geoffrey R. Hill
- Clinical Research Division, Fred Hutchinson Cancer Center; Seattle, WA, 98109, UNITED STATES
- Department of Medicine, University of Washington; Seattle, WA, 98109, UNITED STATES
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Construction of a Humanized PBMC-PDX Model to Study the Efficacy of a Bacterial Marker in Lung Cancer Immunotherapy. DISEASE MARKERS 2022; 2022:1479246. [PMID: 36072895 PMCID: PMC9441396 DOI: 10.1155/2022/1479246] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Accepted: 06/22/2022] [Indexed: 11/23/2022]
Abstract
Commensal microbiome is a key factor of lung cancer immunotherapy efficacy. Elucidating the role of specific strains as bacterial markers in immunotherapy has drawn great attention from the academia. At present, most preclinical studies about the relationship between bacterial markers and immunotherapy rely on the syngeneic mouse models. However, mice differ greatly from humans in immune system and tumor characteristics. In this study, humanized mouse models based on peripheral blood mononuclear cells (PBMCs) immune reconstitution and lung cancer cell line-derived xenograft (CDX) or patient-derived xenograft (PDX) were constructed. The PBMC-PDX model was shown to be superior to the PBMC-CDX model in preserving tumor heterogeneity and construction time-saving. Through optimizing the experimental process, the time it took for humanized models to evaluate the effect of cancer treatment was reduced to 42 days. Next, by utilizing PBMC-PDX mice treated with antibiotics (ATB), the role of Bifidobacterium longum in lung cancer immunotherapy was studied. It was found that although both Bifidobacterium longum and immunotherapy drug pembrolizumab alone showed suppressing tumor growth, the efficacy of pembrolizumab was attenuated when administrated to mice colonized with Bifidobacterium longum. Further exploration revealed that Bifidobacterium longum caused significant changes in the proportion of human CD45+ cells in the PBMC-PDX model. The PBMC-PDX model has the potential to be applied as an efficient platform to support evaluation of bacterial markers in immunotherapy research and facilitate development of precision medicine targeting human commensal bacteria.
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Liang Y, Shen J, Lan Q, Zhang K, Xu Y, Duah M, Xu K, Pan B. Blockade of PD-1/PD-L1 increases effector T cells and aggravates murine chronic graft-versus-host disease. Int Immunopharmacol 2022; 110:109051. [PMID: 35850051 DOI: 10.1016/j.intimp.2022.109051] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Revised: 07/05/2022] [Accepted: 07/10/2022] [Indexed: 11/05/2022]
Abstract
T-cells mediated immunopathology is crucial for pathogenesis of chronic graft-versus-host disease (cGVHD), a common complication following allogeneic hematopoietic cell transplantation. Programmed death-1 (PD-1) regulates long-term survival and functional exhaustion of T-cell which might play a role in regulating cGVHD. We examined PD-1 expression on T cells of cGVHD mice and tested the impact of a PD-1 antibody on severity of cGVHD in murine allotransplant models. We also used a murine graft-versus-tumor (GVT) model to explore how tumor cell-derived PD-L1 affect the GVT effect and occurrence of cGVHD. PD-1 fluorescence intensity on CD4+ T-cells increased in mice developing cGVHD. PD-1High T cells expressed higher levels of IFNγ and IL-17, comparing with PD-1Low T cells. Giving the PD-1 antibody increased proportions of Th1, Th17 and Tc1 cells, but decreased proportion of Treg cells in allotransplant mice. The PD-1 antibody decreased survival of recipients and induced severe lung cGVHD. In the GVT model, knockdown of PD-L1 in A20 tumor cells enhanced GVT effect but increased cGVHD. In vitro study showed knockdown of PD-L1 in tumor cells increased cytotoxicity of T cells and reduced apoptosis of T cells. Knockdown of PD-L1 in tumor cells increased protein levels of phosphorylated AKT, Bcl-2 and Mcl-1, but decreased protein levels of Bak and Bax in co-cultured allogeneic T cells. In conclusion, expression of PD-1 on T cells increased in mice undergoing cGVHD. Intervention of the PD-1/PD-L1 pathway showed a significant impact on occurrence of cGVHD and GVT effect.
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Affiliation(s)
- Yiwen Liang
- Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou Medical University, Xuzhou, China; Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China
| | - Jingyi Shen
- Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou Medical University, Xuzhou, China; Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China
| | - Qiu Lan
- Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou Medical University, Xuzhou, China; Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China
| | - Kexin Zhang
- Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou Medical University, Xuzhou, China; Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China
| | - Yan Xu
- Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou Medical University, Xuzhou, China; Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China
| | - Maxwell Duah
- Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou Medical University, Xuzhou, China; Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China
| | - Kailin Xu
- Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou Medical University, Xuzhou, China; Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China.
| | - Bin Pan
- Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou Medical University, Xuzhou, China; Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China.
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Doney K, Leisenring W, Linden H. Allogeneic hematopoietic cell transplantation in patients with a hematologic malignancy and a prior history of breast cancer. Breast Cancer Res Treat 2022; 194:507-516. [PMID: 35779160 DOI: 10.1007/s10549-022-06658-5] [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: 03/29/2022] [Accepted: 06/08/2022] [Indexed: 11/02/2022]
Abstract
PURPOSE To compare the outcome of allogeneic stem cell transplantation for myeloid malignancies in breast cancer survivors to a contemporaneous control group. METHODS Medical records of all patients with a history of breast cancer who received allogeneic stem cell transplants at a single, tertiary referral Comprehensive Cancer Center between 2002 and 2019 were reviewed. Transplant outcomes were compared to 289 control patients without a history of breast cancer from the same time period. Main outcomes included survival, disease-free survival, non-relapse mortality, relapse or progression of hematologic malignancy, and incidence of recurrent breast cancer after hematopoietic cell transplantation. Comparisons between women with a history of breast cancer and controls utilized propensity score weighting to balance patient characteristics. RESULTS Forty women, ages 30-74 years, with a history of breast cancer received an allogeneic hematopoietic cell transplant for a hematologic malignancy between December 2002 and February 2019. Twelve of the 40 patients are alive with a median survival of 7.4 years (range, 1.9-16.8 years). None of the patients had evidence of recurrent breast cancer prior to death or date of last contact. In multivariable Cox models, all transplant outcomes were similar between the patients and the control group with hematopoietic cell transplant comorbidity score as the most important confounding factor for adjustment in these models. CONCLUSION A history of treated breast cancer should not exclude patients from consideration for allogeneic hematopoietic cell transplantation.
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Affiliation(s)
- Kristine Doney
- Clinical Research Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave. N, D5-280, PO Box 19024, Seattle, WA, 98109-1024, USA. .,University of Washington Medical Center, Seattle, WA, USA.
| | - Wendy Leisenring
- Clinical Research Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave. N, D5-280, PO Box 19024, Seattle, WA, 98109-1024, USA.,University of Washington Medical Center, Seattle, WA, USA
| | - Hannah Linden
- University of Washington Medical Center, Seattle, WA, USA.,Seattle Cancer Care Alliance, Seattle, WA, USA
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47
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Vulasala SSR, Onteddu NK, Kumar SP, Lall C, Bhosale P, Virarkar MK. Advances and effectiveness of the immunotherapy after liver transplantation. World J Gastrointest Surg 2022; 14:629-631. [PMID: 35979423 PMCID: PMC9258234 DOI: 10.4240/wjgs.v14.i6.629] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Revised: 01/15/2022] [Accepted: 06/13/2022] [Indexed: 02/06/2023] Open
Abstract
Transplant recipients usually have increased chances of graft rejection and graft vs host disease, requiring chronic immunosuppressive therapy. Nonetheless, long-term immunosuppression risks malignancies such as skin cancer, lymphoma, and Kaposi sarcoma. However, there are very few studies that included solid organ transplant recipients while studying the efficacy of immunotherapy. "Immunotherapy after liver transplantation: Where are we now?" is a study, where the authors described the mechanism of action and outcomes of immune checkpoint inhibitors specific to liver transplant recipients. The authors reported the graft rejection rates and the factors contributing to the rejection in the liver transplant recipients.
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Affiliation(s)
- Sai Swarupa R Vulasala
- Department of Radiology, University of Florida College of Medicine, Jacksonville, FL 32209, United States
| | - Nirmal K Onteddu
- Department of Internal Medicine, Flowers Hospital, Dothan, AL 36305, United States
| | - Sindhu P Kumar
- Department of Radiology, University of Florida College of Medicine, Jacksonville, FL 32209, United States
| | - Chandana Lall
- Department of Radiology, University of Florida College of Medicine, Jacksonville, FL 32209, United States
| | - Priya Bhosale
- Division of Diagnostic Imaging, Department of Diagnostic Radiology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, United States
| | - Mayur K Virarkar
- Department of Radiology, University of Florida College of Medicine, Jacksonville, FL 32209, United States
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Barbullushi K, Rampi N, Serpenti F, Sciumè M, Fabris S, De Roberto P, Fracchiolla NS. Vaccination Therapy for Acute Myeloid Leukemia: Where Do We Stand? Cancers (Basel) 2022; 14:2994. [PMID: 35740657 PMCID: PMC9221207 DOI: 10.3390/cancers14122994] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Revised: 06/08/2022] [Accepted: 06/11/2022] [Indexed: 11/17/2022] Open
Abstract
Immunotherapy is changing the therapeutic landscape of many hematologic diseases, with immune checkpoint inhibitors, bispecific antibodies, and CAR-T therapies being its greatest expression. Unfortunately, immunotherapy in acute myeloid leukemia (AML) has given less brilliant results up to now, and the only approved drug is the antiCD33 antibody-drug conjugate gemtuzumab ozogamicin. A promising field of research in AML therapy relies on anti-leukemic vaccination to induce remission or prevent disease relapse. In this review, we analyze recent evidence on AML vaccines and their biological mechanisms. The principal proteins that have been exploited for vaccination strategies and have reached clinical experimental phases are Wilm's tumor 1, proteinase 3, and RHAMM. the majority of data deals with WT1-base vaccines, given also the high expression and mutation rates of WT1 in AML cells. Stimulators of immune responses such as TLR7 agonist and interleukin-2 have also proven anti-leukemic activity both in vivo and in vitro. Lastly, cellular vaccines mainly based on autologous or allogeneic off-the-shelf dendritic cell-based vaccines showed positive results in terms of T-cell response and safety, also in elderly patients. Compared to other immunotherapeutic strategies, anti-AML vaccines have the advantage of being a less toxic and a more manageable approach, applicable also to elderly patients with poorer performance status, and may be used in combination with currently available therapies. As for the best scenario in which to use vaccination, whether in a therapeutic, prophylactic, or preemptive setting, further studies are needed, but available evidence points to poorer results in the presence of active or high-burden disease. Given the poor prognosis of relapsed/refractory or high-risk AML, further research is urgently needed to better understand the biological pathways that sustain its pathogenesis. In this setting, research on novel frontiers of immunotherapy-based agents, among which vaccines represent important actors, is warranted to develop new and efficacious strategies to obtain long-term disease control by immune patrolling.
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Affiliation(s)
- Kordelia Barbullushi
- Hematology & BMT Unit, Fondazione IRCCS Ca’ Granda Policlinico Ospedale Maggiore di Milano, 20122 Milan, Italy; (K.B.); (N.R.); (F.S.); (M.S.); (S.F.); (P.D.R.)
- Department of Oncology and Onco-Hematology, University of Milan, 20122 Milan, Italy
| | - Nicolò Rampi
- Hematology & BMT Unit, Fondazione IRCCS Ca’ Granda Policlinico Ospedale Maggiore di Milano, 20122 Milan, Italy; (K.B.); (N.R.); (F.S.); (M.S.); (S.F.); (P.D.R.)
- Department of Oncology and Onco-Hematology, University of Milan, 20122 Milan, Italy
| | - Fabio Serpenti
- Hematology & BMT Unit, Fondazione IRCCS Ca’ Granda Policlinico Ospedale Maggiore di Milano, 20122 Milan, Italy; (K.B.); (N.R.); (F.S.); (M.S.); (S.F.); (P.D.R.)
- Department of Oncology and Onco-Hematology, University of Milan, 20122 Milan, Italy
| | - Mariarita Sciumè
- Hematology & BMT Unit, Fondazione IRCCS Ca’ Granda Policlinico Ospedale Maggiore di Milano, 20122 Milan, Italy; (K.B.); (N.R.); (F.S.); (M.S.); (S.F.); (P.D.R.)
| | - Sonia Fabris
- Hematology & BMT Unit, Fondazione IRCCS Ca’ Granda Policlinico Ospedale Maggiore di Milano, 20122 Milan, Italy; (K.B.); (N.R.); (F.S.); (M.S.); (S.F.); (P.D.R.)
| | - Pasquale De Roberto
- Hematology & BMT Unit, Fondazione IRCCS Ca’ Granda Policlinico Ospedale Maggiore di Milano, 20122 Milan, Italy; (K.B.); (N.R.); (F.S.); (M.S.); (S.F.); (P.D.R.)
| | - Nicola Stefano Fracchiolla
- Hematology & BMT Unit, Fondazione IRCCS Ca’ Granda Policlinico Ospedale Maggiore di Milano, 20122 Milan, Italy; (K.B.); (N.R.); (F.S.); (M.S.); (S.F.); (P.D.R.)
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Szczepanik A, Choi D, Brady B, Chandran MM, Diamond A, Do V, Fredrick S, Kaiser T, Khalil K, Laub MR, Leino A, Park JM, Pierce D, Rendulic T, Wiegel JJ, Fose J, Jorgenson MR. The use of non-transplant biologics in solid organ transplant recipients: A practical review for the frontline clinician. Clin Transplant 2022; 36:e14743. [PMID: 35690919 DOI: 10.1111/ctr.14743] [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: 02/18/2022] [Revised: 05/09/2022] [Accepted: 06/01/2022] [Indexed: 11/27/2022]
Abstract
Biologics have become the forefront of medicine for management of autoimmune conditions, leading to improved quality of life. Many autoimmune conditions occur in solid organ transplant (SOT) recipients and persist following transplant. However, the use of biologics in this patient population is not well studied, and questions arise related to risk of infection and adjustments to induction and maintenance immunosuppression. Guidelines have been published highlighting management strategies of biologics around the time of elective surgical procedures, but this is not always feasible in urgent situations, especially with deceased donor transplantation. The aim of this review is to summarize the current literature regarding the use of these agents in solid organ transplant recipients, and specifically address induction and maintenance immunosuppression, as well as the need for alternative infective prevention strategies to create a practical reference for the frontline clinician, when faced with this complex clinical scenario.
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Affiliation(s)
- Amanda Szczepanik
- Department of Pharmacy, University of Maryland Medical Center, Baltimore, Maryland, USA
| | - David Choi
- University of Chicago Medicine Inflammatory Bowel Disease Center, Chicago, USA
| | | | | | | | - Vincent Do
- Department of Pharmacy, Yale New Haven Hospital, New Haven, Connecticut, USA
| | | | | | | | - Melissa R Laub
- Department of Pharmacy, Augusta University Medical Center, Augusta, Georgia, USA
| | - Abbie Leino
- Department of Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, Michigan, USA
| | - Jeong M Park
- Department of Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, Michigan, USA
| | - Dana Pierce
- Department of Pharmacy, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois, USA
| | | | | | - Jillian Fose
- Department of Pharmacy, UW Health, Madison, Wisconsin, USA
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50
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Towards a Better Understanding of the Atypical Features of Chronic Graft-Versus-Host Disease: A Report from the 2020 National Institutes of Health Consensus Project Task Force. Transplant Cell Ther 2022; 28:426-445. [PMID: 35662591 PMCID: PMC9557927 DOI: 10.1016/j.jtct.2022.05.038] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Revised: 05/16/2022] [Accepted: 05/24/2022] [Indexed: 12/31/2022]
Abstract
Alloreactive and autoimmune responses after allogeneic hematopoietic cell transplantation can occur in non-classical chronic graft-versus-host disease (chronic GVHD) tissues and organ systems or manifest in atypical ways in classical organs commonly affected by chronic GVHD. The National Institutes of Health (NIH) consensus projects were developed to improve understanding and classification of the clinical features and diagnostic criteria for chronic GVHD. While still speculative whether atypical manifestations are entirely due to chronic GVHD, these manifestations remain poorly captured by the current NIH consensus project criteria. Examples include chronic GVHD impacting the hematopoietic system as immune mediated cytopenias, endothelial dysfunction, or as atypical features in the musculoskeletal system, central and peripheral nervous system, kidneys, and serous membranes. These purported chronic GVHD features may contribute significantly to patient morbidity and mortality. Most of the atypical chronic GVHD features have received little study, particularly within multi-institutional and prospective studies, limiting our understanding of their frequency, pathogenesis, and relation to chronic GVHD. This NIH consensus project task force report provides an update on what is known and not known about the atypical manifestations of chronic GVHD, while outlining a research framework for future studies to be undertaken within the next three to seven years. We also provide provisional diagnostic criteria for each atypical manifestation, along with practical investigation strategies for clinicians managing patients with atypical chronic GVHD features.
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