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1
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Zhao Z, Lan J. Detection methods and prognosis implications of measurable residual disease in acute myeloid leukemia. Ann Hematol 2024; 103:4869-4881. [PMID: 39283479 DOI: 10.1007/s00277-024-06008-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2024] [Accepted: 09/11/2024] [Indexed: 01/16/2025]
Abstract
Measurable residual disease (MRD) in acute myeloid leukemia (AML) refers to the quantity of residual leukemic cells in a patient after treatment.According to the latest agreements, MRD in AML offering essential prognostic insights. However, there is ongoing debate regarding MRD-based monitoring and treatment strategies. There are multiple platforms for detecting MRD, each varying in sensitivity and suitability for different patients. MRD not only predicts treatment outcomes but also serves as an indicator of treatment effectiveness and a prognostic biomarker. In AML, most retrospective studies indicate that patients who are MRD-positive or show increasing MRD levels at specific time points during remission have significantly higher risks of relapse and mortality compared to MRD-negative patients. Although achieving MRD-negative status can improve patient prognosis, the possibility of relapse remains. Despite the correlation between MRD and clinical outcomes, MRD assessment methods are not yet standardized, leading to discrepancies in results across different techniques. To provide reliable MRD results, it is essential to optimize and standardize MRD detection methods. Methods for assessing MRD include multiparameter flow cytometry (MFC) and molecular assays, chosen based on disease characteristics. This review focuses on currently available MRD detection methods and discusses how the prognostic value of MRD test results informs personalized treatment strategies for AML patients.
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Affiliation(s)
- Zihan Zhao
- The Second Clinical Medical College, Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Jianping Lan
- Cancer Center, Department of Hematology, Affiliated People's Hospital, Zhejiang Provincial People's Hospital, Hangzhou Medical College, 58 Shangtang Road, Zhejiang, Hangzhou, 310014, China.
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2
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Susana A, Galletti G, De Simone G, Camisaschi C, Lugli E. Identification and analysis of alloreactive T lymphocytes from peripheral blood mononuclear cells. Methods Cell Biol 2024; 189:71-84. [PMID: 39393887 DOI: 10.1016/bs.mcb.2024.05.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/13/2024]
Abstract
Alloreactive T-cell responses against mismatched MHC or minor histocompatibility antigens may result in deleterious graft-versus-host disease (GVHD) and increased morbidity and mortality in allogeneic hematopoietic stem cell transplantation (allo-HSCT). Nevertheless, these T-cell responses may be directed against residual tumor cells (the graft-versus-tumor effect, GVT), thus preventing relapse of the disease. Recent findings have shown that CD45RA+ naïve T cells, but not CD45RA- memory T cells are the major contributors to GVHD, thus leading to clinical trials where CD45RA+-depleted, memory-enriched T-cell products are adoptively transferred following allo-HSCT to prevent GVHD and enhance immune reconstitution. However, residual alloreactivity may still be present in the memory T-cell compartment, thus contributing to prevent disease relapse by GVT. Here, we describe a simple cell-based protocol to identify alloreactive naïve and memory T cells by co-culturing T-cell subsets and third-party antigen-presenting cells. The responding cells are identified following dilution of carboxyfluorescein succinimidyl ester (CFSE) and upregulation of the activation marker CD25. These CFSE-diluting cells can be further phenotyped by high-dimensional flow cytometry, or purified with a cell sorter for downstream genomic and functional assays.
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Affiliation(s)
- Alberto Susana
- IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Giovanni Galletti
- Department of Molecular Biology, School of Biological Sciences, University of California, San Diego, San Diego, CA, United States
| | | | | | - Enrico Lugli
- IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy.
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3
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Fein JA, Shouval R, Krieger E, Spellman SR, Wang T, Baldauf H, Fleischhauer K, Kröger N, Horowitz M, Maiers M, Miller JS, Mohty M, Nagler A, Weisdorf D, Malmberg KJ, Toor AA, Schetelig J, Romee R, Koreth J. Systematic evaluation of donor-KIR/recipient-HLA interactions in HLA-matched hematopoietic cell transplantation for AML. Blood Adv 2024; 8:581-590. [PMID: 38052043 PMCID: PMC10837477 DOI: 10.1182/bloodadvances.2023011622] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2023] [Revised: 11/20/2023] [Accepted: 11/20/2023] [Indexed: 12/07/2023] Open
Abstract
ABSTRACT In acute myeloid leukemia (AML), donor natural killer cell killer immunoglobulin-like receptors (KIR) and recipient HLA interactions may contribute to the graft-versus-leukemia effect of allogeneic hematopoietic cell transplantation (HCT). Analyses of individual KIR/HLA interactions, however, have yielded conflicting findings, and their importance in the HLA-matched unrelated donor (MUD) setting remains controversial. We systematically studied outcomes of individual donor-KIR/recipient-HLA interactions for HCT outcomes and empirically evaluated prevalent KIR genotypes for clinical benefit. Adult patients with AML (n = 2025) who received HCT with MUD grafts in complete remission reported to the Center for International Blood and Marrow Transplantation were evaluated. Only the donor-2DL2+/recipient-HLA-C1+ pair was associated with reduced relapse (hazard ratio [HR], 0.79; 95% confidence interval [CI], 0.67-0.93; P = .006) compared with donor-2DL2-/recipient-HLA-C1+ pair. However, no association was found when comparing HLA-C groups among KIR-2DL2+-graft recipients. We identified 9 prevalent donor KIR genotypes in our cohort and screened them for association with relapse risk. Genotype 5 (G5) in all recipients and G3 in Bw4+ recipients were associated with decreased relapse risk (HR, 0.52; 95% CI, 0.35-0.78; P = .002; and HR, 0.32; 95% CI, 0.14-0.72; P = .006; respectively) and G2 (HR 1.63, 95% CI, 1.15-2.29; P = .005) with increased relapse risk in C1-homozygous recipients, compared with other patients with the same ligand. However, we could not validate these findings in an external data set of 796 AML transplants from the German transplantation registry. Neither a systematic evaluation of known HLA-KIR interactions nor an empiric assessment of prevalent KIR genotypes demonstrated clinically actionable associations; therefore, these data do not support these KIR-driven strategies for MUD selection in AML.
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Affiliation(s)
- Joshua A. Fein
- Depatment of Hematology and Medical Oncology, Weill Cornell Medicine, New York Presbyterian Hospital, New York, NY
| | - Roni Shouval
- Adult Bone Marrow Transplant Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Elizabeth Krieger
- Children’s Hospital of Richmond, Virginia Commonwealth University, Richmond, VA
| | - Stephen R. Spellman
- Center for International Blood and Marrow Transplant Research, National Marrow Donor Program/Be The Match, Minneapolis, MN
| | - Tao Wang
- Center for International Blood and Marrow Transplant Research, National Marrow Donor Program/Be The Match, Minneapolis, MN
- Center for International Blood and Marrow Transplant Research, Medical College of Wisconsin, Milwaukee, WI
| | - Henning Baldauf
- Clinical Trials Unit, DKMS Bone Marrow Registry, Tübingen, Germany
| | | | - Nicolaus Kröger
- Department of Stem Cell Transplantation, University Hospital Hamburg-Eppendorf, Hamburg, Germany
| | - Mary Horowitz
- Center for International Blood and Marrow Transplant Research, Medical College of Wisconsin, Milwaukee, WI
| | - Martin Maiers
- Center for International Blood and Marrow Transplant Research, National Marrow Donor Program/Be The Match, Minneapolis, MN
| | - Jeffrey S Miller
- Division of Hematology, Oncology, and Transplantation, University of Minnesota, Minneapolis, MN
| | - Mohamad Mohty
- Department of Hematology, Saint Antoine Hospital, Sorbonne University, Paris, France
| | - Arnon Nagler
- Division of Hematoloy, Chaim Sheba Medical Center, Tel HaShomer, Israel
| | - Daniel Weisdorf
- Division of Hematology, Oncology, and Transplantation, University of Minnesota, Minneapolis, MN
| | - Karl-Johan Malmberg
- Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
| | - Amir A. Toor
- Topper Cancer Institute, Lehigh Valley Health Network, Allentown, PA
| | - Johannes Schetelig
- Clinical Trials Unit, DKMS Bone Marrow Registry, Tübingen, Germany
- Medizinische Klinik I, University Hospital TU Dresden, Dresden, Germany
| | - Rizwan Romee
- Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA
| | - John Koreth
- Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA
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4
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Styczynski J, Tridello G, Koster L, Knelange N, Wendel L, van Biezen A, van der Werf S, Mikulska M, Gil L, Cordonnier C, Ljungman P, Averbuch D, Cesaro S, Baldomero H, Chabannon C, Corbacioglu S, Dolstra H, Glass B, Greco R, Kröger N, de Latour RP, Mohty M, Neven B, Peric Z, Snowden JA, Sureda A, Yakoub-Agha I, de la Camara R. Decrease of lethal infectious complications in the context of causes of death (COD) after hematopoietic cell transplantation: COD-2 and COD-1 study of the Infectious Diseases Working Party EBMT. Bone Marrow Transplant 2023; 58:881-892. [PMID: 37149673 DOI: 10.1038/s41409-023-01998-2] [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: 12/20/2022] [Revised: 04/15/2023] [Accepted: 04/19/2023] [Indexed: 05/08/2023]
Abstract
We previously analyzed trends in incidence and factors associated with lethal complications in ALL/AML/CML patients (causes of deaths; COD-1 study). The objective of this study was the analysis of incidence and specific causes of death after HCT, with focus on infectious deaths in two time periods, 1980-2001 (cohort-1) and 2002-2015 (cohort-2). All patients with HCT for lymphoma, plasma cell disorders, chronic leukemia (except CML), myelodysplastic/myeloproliferative disorders, registered in the EBMT-ProMISe-database were included (n = 232,618) (COD-2 study). Results were compared to those in the ALL/AML/CML COD-1 study. Mortality from bacterial, viral, fungal, and parasitic infections decreased in very early, early and intermediate phases. In the late phase, mortality from bacterial infections increased, while mortality from fungal, viral, or unknown infectious etiology did not change. This pattern was similar for allo- and auto-HCT in COD-1 and COD-2 studies, with a distinct and constant lower incidence of all types of infections at all phases, after auto-HCT. In conclusion, infections were the main cause of death before day +100, followed by relapse. Mortality from infectious deaths significantly decreased, except late phase. Post-transplant mortality has significantly decreased in all phases, from all causes after auto-HCT; it has decreased in all phases after allo-HCT except late phase.
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Affiliation(s)
- Jan Styczynski
- Department of Pediatric Hematology and Oncology, Collegium Medicum, Nicolaus Copernicus University, Torun, Bydgoszcz, Poland.
| | - Gloria Tridello
- Pediatric Hematology Oncology, Department of Mother and Child, Azienda Ospedaliera Universitaria Integrata, Verona, Italy
- EBMT Leiden Study Unit, Leiden, The Netherlands
| | | | | | | | | | | | - Malgorzata Mikulska
- Division of Infectious Diseases, University of Genoa (DISSAL) and Ospedale Policlinico San Martino, Genoa, Italy
| | - Lidia Gil
- Department of Hematology and Bone Marrow Transplantation, Poznan University of Medical Sciences, Poznan, Poland
| | - Catherine Cordonnier
- Hôpital Henri Mondor, Assistance Publique-Hopitaux de Paris (AP-HP) and Paris-Est-Créteil University, Creteil, France
| | - Per Ljungman
- Deptartment of Cellular Therapy and Allogeneic Stem Cell Transplantation, Karolinska Comprehensive Cancer Center, Karolinska University Hospital Huddinge, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden
| | - Diana Averbuch
- Faculty of Medicine, Hebrew University of Jerusalem, Pediatric Infectious Diseases, Hadassah Medical Center, Jerusalem, Israel
| | - Simone Cesaro
- Pediatric Hematology Oncology, Department of Mother and Child, Azienda Ospedaliera Universitaria Integrata, Verona, Italy
| | - Helen Baldomero
- EBMT Activity Survey Office, Hematology, Department of Medicine, University Hospital, Basel, Switzerland
| | - Christian Chabannon
- Institut Paoli Calmettes Comprehensive Cancer Center and Inserm CBT-1409, Centre d'Investigations Cliniques en Biothérapies, Marseille, France
| | - Selim Corbacioglu
- Department of Pediatric Hematology, Oncology and Stem Cell Transplantation, University of Regensburg, Regensburg, Germany
| | - Harry Dolstra
- Laboratory of Hematology, Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Bertram Glass
- Klinik für Hämatologie und Stammzelltransplantation, HELIOS Klinikum Berlin-Buch, Berlin, Germany
| | - Raffaella Greco
- Unit of Hematology and Bone Marrow Transplantation, IRCCS San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy
| | - Nicolaus Kröger
- Department of Stem Cell Transplantation, University Hospital Eppendorf, Hamburg, Germany
| | | | - Mohamad Mohty
- Department of Hematology, Hospital Saint Antoine, Sorbonne University, INSERM UMRs938, Paris, France
| | - Benedicte Neven
- Pediatric Immune-Hematology Unit, Necker Children Hospital, Assistance Publique Hôpitaux de Paris, Paris, France
| | - Zinaida Peric
- School of Medicine, University of Zagreb, University Hospital Center Zagreb, Zagreb, Croatia
| | - John A Snowden
- Department of Haematology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
| | - Anna Sureda
- Clinical Hematology Department, Institut Català d'Oncologia-Hospitalet, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), University of Barcelona, Barcelona, Spain
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5
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Dowlut-McElroy T, Shin S, Stepanek E, Jacobsohn D, Gomez-Lobo V. Pediatric Vulvovaginal Graft-Versus-Host Disease: A Retrospective Cohort Study and Literature Review. J Pediatr Adolesc Gynecol 2022; 35:552-557. [PMID: 35472468 PMCID: PMC9560972 DOI: 10.1016/j.jpag.2022.04.005] [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: 10/11/2021] [Revised: 04/04/2022] [Accepted: 04/14/2022] [Indexed: 11/21/2022]
Abstract
STUDY OBJECTIVE To assess genital symptomatology, characterize the findings of genital examination, and describe the incidence and treatment of vulvovaginal graft-versus-host disease (vvGvHD) in girls and adolescents after allogeneic hematopoietic stem cell transplantation (HSCT). DESIGN Retrospective cohort. SETTING Metropolitan-area children's hospital. PARTICIPANTS Female allogeneic HSCT recipients ages 0 to 22 years. MAIN OUTCOME MEASURES Genital symptoms, genital examination, diagnosis, and treatment of vvGvHD. RESULTS A total of 57 participants were included in the analysis. The median age at the time of HSCT was 10 years (range 4 months-23 years). Most (n = 40, 71%) underwent transplant for a nonmalignant condition, most commonly sickle cell anemia (n = 19, 33%). The median time of onset of GvHD post HSCT was 62 days (IQR = 42 to 151 days). The most common initial site of GvHD was skin (n = 21, 64%), followed by GI tract (n = 10, 30%). Three patients (5%) were diagnosed with vvGvHD. The time of onset of vvGvHD post HSCT ranged from 62 to 1565 days. One patient (33%) was asymptomatic at the time of diagnosis. There was no difference in diagnosis of vvGvHD when race (P = 0.15), age at allogeneic HSCT (P = 0.64), nonmalignant vs malignant indication (P = 0.21), source of stem cells (P = 0.25), partial vs full human leukocyte antigens (HLA) donor match (P = 0.34), and GvHD prophylaxis regimen (P = 0.18) were compared. None had isolated vvGvHD. Vulvovaginal GvHD was preceded by skin GvHD in 1 patient, was preceded by lung GvHD in 1 patient, and occurred concurrently with skin GvHD in the third patient. CONCLUSIONS Pediatric vvGvHD can occur within the first 100 days after transplant and can be asymptomatic. Routine gynecologic evaluation post allogeneic HSCT in children and adolescents should include a thorough review of vulvovaginal symptoms and a gynecologic exam for the detection and treatment of vvGvHD.
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Affiliation(s)
- Tazim Dowlut-McElroy
- Pediatric and Adolescent Gynecology, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD, United States; Department of Surgery, Children's National Hospital, Washington, DC, United States.
| | - Stephanie Shin
- Georgetown University School of Medicine, Washington, DC, United States
| | - Elizabeth Stepanek
- Division of Hematology, Children's National Hospital, Washington DC, United States
| | - David Jacobsohn
- Division of Blood and Marrow Transplantation, Children's National Hospital, Washington DC, United States
| | - Veronica Gomez-Lobo
- Pediatric and Adolescent Gynecology, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD, United States; Department of Surgery, Children's National Hospital, Washington, DC, United States
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6
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Snowden JA, McGrath E, Orchard K, Kröger N, Sureda A, Gratwohl A. Visions for a JACIE Quality Management System 4.0. Bone Marrow Transplant 2021; 56:2876-2881. [PMID: 34588628 PMCID: PMC8479268 DOI: 10.1038/s41409-021-01467-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2021] [Revised: 08/30/2021] [Accepted: 09/09/2021] [Indexed: 11/13/2022]
Abstract
Quality management has been part of hematopoietic stem cell transplantation (HSCT) from the very beginning. It evolved step-wise from open data exchange up to the introduction of the FACT/JACIE-based quality management system (QMS) 2 decades ago. This formal step has eased cooperation, and improved outcome for patients. Today’s expansion of cellular and targeted therapies and new drugs, and the regulatory requirements for advanced therapeutic medicinal products have touched the limits of the current system. Based on the Medicine 4.0 concept, the next step should integrate novel views of QMS. The old definition “Best Quality Transplant” will be replaced by “Optimal Treatment,” and encompass the entire health care journey. “Best outcome” will refer to overall survival, quality of life and costs, with or without HSCT, and will be compatible with all requirements by competent authorities. Decisions will be based on high-level evidence, supported by real-time digitized data collection, data analysis, incorporated into artificial-intelligence systems. To reach this goal, EBMT/JACIE will be challenged to start the process by further fostering harmonization within and between organizations at institutional, national, and European levels. Acceleration in information technology and modifications to working practices during the pandemic should facilitate this development to the next stage.
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Affiliation(s)
- John A Snowden
- Department of Haematology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
| | | | - Kim Orchard
- Department of Haematology, University Hospital Southampton, NHS Foundation Trust, Southampton, UK
| | - Nicolaus Kröger
- Department of Stem Cell Transplantation, University Hospital Eppendorf, Hamburg, Germany
| | - Anna Sureda
- Catalan Institute of Oncology, Barcelona, Spain
| | - Alois Gratwohl
- Hematology, Medical Faculty, University of Basel, Basel, Switzerland.
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7
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Spector LG, Spellman SR, Thyagarajan B, Beckman KB, Hoffmann C, Garbe J, Hahn T, Sucheston-Campbell L, Richardson M, De For TE, Tolar J, Verneris MR. Neither Donor nor Recipient Mitochondrial Haplotypes Are Associated with Unrelated Donor Transplant Outcomes: A Validation Study from the CIBMTR. Transplant Cell Ther 2021; 27:836.e1-836.e7. [PMID: 34174468 DOI: 10.1016/j.jtct.2021.06.019] [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: 04/14/2021] [Revised: 06/04/2021] [Accepted: 06/16/2021] [Indexed: 11/18/2022]
Abstract
Graft-versus-host-disease (GVHD) is a multistep process that involves T-cell recognition and priming toward alloantigen, expansion, acquisition of effector function, and repeated tissue injury, resulting in clinical manifestations of the disease. All of these processes have considerable metabolic demands and understanding the key role of mitochondria in cellular metabolism as it relates to GVHD has increased significantly. Mitochondrial DNA (mtDNA) haplotypes have been linked to functional differences in vitro, suggesting they have functional differences at an organismal level. We previously used mtDNA typing to assess the impact of mtDNA haplotypes on outcomes of ~400 allo-HCT patients. This pilot study identified uncommon mtDNA haplotypes potentially associated with inferior outcomes. We sought to validate pilot findings of associations between donor and recipient mitochondrial haplotypes and transplant outcome. We examined a cohort of 4143 donor-recipient pairs obtained from the Center for International Blood and Marrow Transplant Research. MtDNA was extracted from whole blood or peripheral blood mononuclear cells from donors and recipients and sequenced to discern haplotype. We used multiple regression analysis to examine the independent association of mtDNA haplotype with overall survival and grade III-IV acute GVHD (aGVHD) adjusting for known risk factors for poor transplant outcome. Neither recipient nor donor mtDNA haplotype reached groupwise significance for overall survival (P =.26 and .39, respectively) or grade III-IV aGVHD (P = .68 and.57, respectively). Adjustment for genomically determined ancestry in the subset of donor-recipient pairs for which this was available did not materially change results. We conclude that our original finding was due to chance in a small sample size and that there is essentially no evidence that mtDNA haplotype or haplotype mismatch contributes to risk of serious outcomes after allogeneic transplantation.
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Affiliation(s)
- Logan G Spector
- Division of Epidemiology and Clinical Research, Department of Pediatrics, University of Minnesota Medical School, Minneapolis, Minnesota.
| | - Stephen R Spellman
- Center for International Blood and Marrow Transplant Research, Milwaukee, Wisconsin
| | - Bharat Thyagarajan
- Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, Minnesota
| | - Kenneth B Beckman
- University of Minnesota Genomics Center, University of Minnesota, Minneapolis, Minnesota
| | - Cody Hoffmann
- University of Minnesota Genomics Center, University of Minnesota, Minneapolis, Minnesota
| | - John Garbe
- University of Minnesota Genomics Center, University of Minnesota, Minneapolis, Minnesota
| | - Theresa Hahn
- Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, New York
| | | | - Michaela Richardson
- Division of Epidemiology and Clinical Research, Department of Pediatrics, University of Minnesota Medical School, Minneapolis, Minnesota
| | - Todd E De For
- Division of Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota Medical School, Minneapolis, Minnesota
| | - Jakub Tolar
- Division of Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota Medical School, Minneapolis, Minnesota
| | - Michael R Verneris
- University of Colorado Denver, Children's Cancer and Blood Disorders, Denver, Colorado
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8
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Minculescu L, Sengelov H, Marquart HV, Ryder LP, Fischer-Nielsen A, Haastrup E. Granulocyte Colony-Stimulating Factor Effectively Mobilizes TCR γδ and NK Cells Providing an Allograft Potentially Enhanced for the Graft-Versus-Leukemia Effect for Allogeneic Stem Cell Transplantation. Front Immunol 2021; 12:625165. [PMID: 33777007 PMCID: PMC7988077 DOI: 10.3389/fimmu.2021.625165] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Accepted: 01/18/2021] [Indexed: 12/28/2022] Open
Abstract
Allogeneic hematopoietic stem cell transplantation (HSCT) is a potential cure for patients with hematological malignancies but substantial risks of recurrence of the malignant disease remain. TCR γδ and NK cells are perceived as potent innate effector cells in HSCT and have been associated with post-transplant protection from relapse in clinical studies. Immunocompetent cells from the donor are crucial for patient outcomes and peripheral blood stem cells (PBSC) are being increasingly applied as graft source. G-CSF is the preferential mobilizing agent in healthy donors for PBSC grafts, yet effects of G-CSF on TCR γδ and NK cells are scarcely uncovered and could influence the graft composition and potency of these cells. Therefore, we analyzed T and NK cell subsets and activation markers in peripheral blood samples of 49 donors before and after G-CSF mobilization and—for a subset of donors—also in the corresponding graft samples using multicolor flowcytometry with staining for CD3, CD4, CD8, TCRαβ, TCRγδ, Vδ1, Vδ2, HLA-DR, CD45RA, CD197, CD45RO, HLA-DR, CD16, CD56, and CD314. We found that TCR γδ cells were mobilized and harvested with an efficiency corresponding that of TCR αβ cells. For TCR γδ as well as for TCR αβ cells, G-CSF preferentially mobilized naïve and terminally differentiated effector (TEMRA) cells over memory cells. In the TCR γδ cell compartment, G-CSF preferentially mobilized cells of the nonVδ2 types and increased the fraction of HLA-DR positive TCR γδ cells. For NK cells, mobilization by G-CSF was increased compared to that of T cells, yet NK cells appeared to be less efficiently harvested than T cells. In the NK cell compartment, G-CSF-stimulation preserved the proportion of CD56dim NK effector cells which have been associated with relapse protection. The expression of the activating receptor NKG2D implied in anti-leukemic responses, was significantly increased in both CD56dim and CD56bright NK cells after G-CSF stimulation. These results indicate differentiated mobilization and altering properties of G-CSF which could improve the effects of donor TCR γδ and NK cells in the processes of graft-versus-leukemia for relapse prevention after HSCT.
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Affiliation(s)
- Lia Minculescu
- Department of Clinical Immunology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Henrik Sengelov
- Department of Hematology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Hanne Vibeke Marquart
- Department of Clinical Immunology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Lars Peter Ryder
- Department of Clinical Immunology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Anne Fischer-Nielsen
- Department of Clinical Immunology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Eva Haastrup
- Department of Clinical Immunology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
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9
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Ngai LL, Kelder A, Janssen JJWM, Ossenkoppele GJ, Cloos J. MRD Tailored Therapy in AML: What We Have Learned So Far. Front Oncol 2021; 10:603636. [PMID: 33575214 PMCID: PMC7871983 DOI: 10.3389/fonc.2020.603636] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Accepted: 11/16/2020] [Indexed: 12/22/2022] Open
Abstract
Acute myeloid leukemia (AML) is a heterogeneous clonal disease associated with a dismal survival, partly due to the frequent occurrence of relapse. Many patient- and leukemia-specific characteristics, such as age, cytogenetics, mutations, and measurable residual disease (MRD) after intensive chemotherapy, have shown to be valuable prognostic factors. MRD has become a rich field of research where many advances have been made regarding technical, biological, and clinical aspects, which will be the topic of this review. Since many laboratories involved in AML diagnostics have experience in immunophenotyping, multiparameter flow cytometry (MFC) based MRD is currently the most commonly used method. Although molecular, quantitative PCR based techniques may be more sensitive, their disadvantage is that they can only be applied in a subset of patients harboring the genetic aberration. Next-generation sequencing can assess and quantify mutations in many genes but currently does not offer highly sensitive MRD measurements on a routine basis. In order to provide reliable MRD results, MRD assay optimization and standardization is essential. Different techniques for MRD assessment are being evaluated, and combinations of the methods have shown promising results for improving its prognostic value. In this regard, the load of leukemic stem cells (LSC) has also been shown to add to the prognostic value of MFC-MRD. At this moment, MRD after intensive chemotherapy is most often used as a prognostic factor to help stratify patients, but also to select the most appropriate consolidation therapy. For example, to guide post-remission treatment for intermediate-risk patients where MRD positive patients receive allogeneic stem cell transplantation and MRD negative receive autologous stem cell transplantation. Other upcoming uses of MRD that are being investigated include: selecting the type of allogeneic stem cell transplantation therapy (donor, conditioning), monitoring after stem cell transplantation (to allow intervention), and determining drug efficacy for the use of a surrogate endpoint in clinical trials.
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Affiliation(s)
| | | | | | | | - Jacqueline Cloos
- Department of Hematology, Amsterdam UMC, Cancer Center Amsterdam, Vrije Universiteit, Amsterdam, Netherlands
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10
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Holtan SG, Versluis J, Weisdorf DJ, Cornelissen JJ. Optimizing Donor Choice and GVHD Prophylaxis in Allogeneic Hematopoietic Cell Transplantation. J Clin Oncol 2021; 39:373-385. [PMID: 33434075 DOI: 10.1200/jco.20.01771] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Affiliation(s)
- Shernan G Holtan
- Division of Hematology, Oncology, and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN
| | - Jurjen Versluis
- Department of Hematology, Erasmus University Medical Center Cancer Institute, Rotterdam, the Netherlands
| | - Daniel J Weisdorf
- Division of Hematology, Oncology, and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN
| | - Jan J Cornelissen
- Department of Hematology, Erasmus University Medical Center Cancer Institute, Rotterdam, the Netherlands
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11
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Fleischhauer K. Selection of matched unrelated donors moving forward: from HLA allele counting to functional matching. HEMATOLOGY. AMERICAN SOCIETY OF HEMATOLOGY. EDUCATION PROGRAM 2019; 2019:532-538. [PMID: 31808865 PMCID: PMC6913495 DOI: 10.1182/hematology.2019000057] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/10/2023]
Abstract
Matched unrelated donors (URD) are the most frequent source of stem cells for allogeneic hematopoietic cell transplantation (HCT) to date, with HCT performed mainly under conventional immunosuppression by methotrexate and cyclosporine. In this setting, every single allelic donor-recipient mismatch for HLA-A, -B, -C, -DRB1 (8/8), but not for HLA-DQB1, -DPB1, has a significant negative effect on overall survival (OS). When several 8/8 HLA-matched URD are available, donor age is the most important factor impacting OS. Moving forward from the traditional way of counting the number of donor-recipient HLA allele mismatches to biology-driven algorithms for functional matching has led to the unraveling of an association between permissive, low-risk HLA-DPB1 mismatches and improved outcome after URD HCT for malignant disease but not for nonmalignant disease. Functional HLA matching might prove to have increasing importance for URD selection in the era of new immunosuppressive regimens that have the potential to substantially reshuffle the role of HLA mismatches in URD HCT.
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12
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Shouval R, Fein JA, Labopin M, Kröger N, Duarte RF, Bader P, Chabannon C, Kuball J, Basak GW, Dufour C, Galimard JE, Polge E, Lankester A, Montoto S, Snowden JA, Styczynski J, Yakoub-Agha I, Mohty M, Nagler A. Outcomes of allogeneic haematopoietic stem cell transplantation from HLA-matched and alternative donors: a European Society for Blood and Marrow Transplantation registry retrospective analysis. LANCET HAEMATOLOGY 2019; 6:e573-e584. [DOI: 10.1016/s2352-3026(19)30158-9] [Citation(s) in RCA: 98] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/20/2019] [Revised: 06/19/2019] [Accepted: 06/20/2019] [Indexed: 01/24/2023]
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13
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Gratwohl A, Duarte R, Snowden JA, van Biezen A, Baldomero H, Apperley J, Cornelissen J, Greinix HT, Grath EM, Mohty M, Kroeger N, Nagler A, Niederwieser D, Putter H, Brand R, the Joint Accreditation Committee JACIE. Pre-transplantation Risks and Transplant-Techniques in Haematopoietic Stem Cell Transplantation for Acute Leukaemia. EClinicalMedicine 2019; 15:33-41. [PMID: 31709412 PMCID: PMC6833359 DOI: 10.1016/j.eclinm.2019.07.019] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2019] [Revised: 07/06/2019] [Accepted: 07/30/2019] [Indexed: 01/08/2023] Open
Abstract
BACKGROUND The role of conditioning intensity and stem cell source on modifying pre-transplantation risk in allogeneic haematopoietic stem cell transplantation (HSCT) is a matter of debate, but crucial when benchmarking centres. METHODS This Retrospective, multicenter exploratory-validation analysis of 9103 patients, (55.5% male, median age 50 years; 1-75 years range) with an allogeneic HSCT between 2010 and 2016 from a matched sibling (N = 8641; 95%) or matched unrelated donor (N = 462; 5%) for acute myeloid (N = 6432; 71%) or acute lymphoblastic (N = 2671; 29%) leukaemia in first complete remission, and reported by 240 centres in 30 countries to the benchmark database of the European Society for Blood and Marrow Transplantation (EBMT) searched for factors associated with use of transplant techniques (standard N = 6375;70% or reduced intensity conditioning N = 2728;30%, respectively bone marrow N = 1945;21% or peripheral blood N = 7158;79% as stem cell source), and their impact on outcome. FINDINGS Treatment groups differed significantly from baseline population (p < 0.001), and within groups regarding patient-, disease-, donor-, and centre-related pre-transplantation risk factors (p < 0.001); choice of technique did depend on pre-transplantation risk factors and centre (p < 0.001). Probability of overall survival at 5 years decreased systematically and significantly with increasing pre-transplantation risk score (score 2 vs 0/1 HR: 1·2, 95% c.i. [1·1-1·.3], p = 0.002; score 3 vs 0/1 HR: 1·5, 95% c.i. [1·3-1·7], p < 0.001; score 4/5/6 vs 0/1 HR: 1·9, 95% c.i. [1·6-2·2], p < 0.001) with no significant differences between treatment groups (likelihood ratio test on interaction: p = 0.40). Overall survival was significantly associated with selection steps and completeness of information (p < 0.001). INTERPRETATION Patients' pre-transplantation risk factors determine survival, independent of transplant techniques. Transplant techniques should be regarded as centre policy, not stratification factor in benchmarking. Selection criteria and completeness of data bias outcome. Outcomes may be improved more effectively through better identifying pre-transplantation factors as opposed to refinement of transplant techniques. FUNDING The study was funded by EBMT.
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Affiliation(s)
- Alois Gratwohl
- Hematology, Medical Faculty, University of Basel, Basel, Switzerland
- Corresponding author at: Hematology, Medical Faculty, University of Basel, Dittingerstrasse 4, CH-4053 Basel, Switzerland.
| | - Rafael Duarte
- Department of Hematology, University Hospital Puerta de Hierro Majadahonda, Madrid, Spain
| | - John A. Snowden
- Department of Haematology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, United Kingdom
| | - Anja van Biezen
- Department of Biomedical Data Sciences, Section Medical Statistics, Leiden University Medical Centre, Leiden, the Netherlands
| | - Helen Baldomero
- EBMT activity survey office, University Hospital, Basel, Switzerland
| | - Jane Apperley
- Centre for Haematology, Hammersmith Hospital, Imperial College London, United Kingdom
| | - Jan Cornelissen
- Hematology, Erasmus University Medical Center, Rotterdam, the Netherlands
| | | | | | - Mohamad Mohty
- Hematology, Hôpital St. Antoine, Paris, France
- Sorbonne University, Paris, France
| | - Nicolaus Kroeger
- Department of Stem Cell Transplantation, University Hospital Eppendorf, Hamburg, Germany
| | - Arnon Nagler
- Chaim Sheba Medical Center, Tel-Hashomer, Israel
| | | | - Hein Putter
- Department of Biomedical Data Sciences, Section Medical Statistics, Leiden University Medical Centre, Leiden, the Netherlands
| | - Ronald Brand
- Department of Biomedical Data Sciences, Section Medical Statistics, Leiden University Medical Centre, Leiden, the Netherlands
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14
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Styczyński J, Tridello G, Koster L, Iacobelli S, van Biezen A, van der Werf S, Mikulska M, Gil L, Cordonnier C, Ljungman P, Averbuch D, Cesaro S, de la Camara R, Baldomero H, Bader P, Basak G, Bonini C, Duarte R, Dufour C, Kuball J, Lankester A, Montoto S, Nagler A, Snowden JA, Kröger N, Mohty M, Gratwohl A. Death after hematopoietic stem cell transplantation: changes over calendar year time, infections and associated factors. Bone Marrow Transplant 2019; 55:126-136. [PMID: 31455899 PMCID: PMC6957465 DOI: 10.1038/s41409-019-0624-z] [Citation(s) in RCA: 222] [Impact Index Per Article: 37.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2018] [Revised: 04/02/2019] [Accepted: 05/28/2019] [Indexed: 01/02/2023]
Abstract
Information on incidence, and factors associated with mortality is a prerequisite to improve outcome after hematopoietic stem cell transplantation (HSCT). Therefore, 55'668 deaths in 114'491 patients with HSCT (83.7% allogeneic) for leukemia were investigated in a landmark analysis for causes of death at day 30 (very early), day 100 (early), at 1 year (intermediate) and at 5 years (late). Mortality from all causes decreased from cohort 1 (1980-2001) to cohort 2 (2002-2015) in all post-transplant phases after autologous HSCT. After allogeneic HSCT, mortality from infections, GVHD, and toxicity decreased up to 1 year, increased at 5 years; deaths from relapse increased in all post-transplant phases. Infections of unknown origin were the main cause of infectious deaths. Lethal bacterial and fungal infections decreased from cohort 1 to cohort 2, not unknown or mixed infections. Infectious deaths were associated with patient-, disease-, donor type, stem cell source, center, and country- related factors. Their impact varied over the post-transplant phases. Transplant centres have successfully managed to reduce death after HSCT in the early and intermediate post-transplant phases, and have identified risk factors. Late post-transplant care could be improved by focus on groups at risk and better identification of infections of "unknown origin".
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Affiliation(s)
- Jan Styczyński
- Pediatric Hematology and Oncology, Collegium Medicum, Nicolaus Copernicus University Torun, Bydgoszcz, Poland.
| | | | | | | | | | | | - Małgorzata Mikulska
- Division of Infectious Diseases, University of Genoa (DISSAL) and Ospedale Policlinico San Martino, Genoa, Italy
| | | | - Catherine Cordonnier
- Hôpital Henri Mondor, Assistance Publique-Hopitaux de Paris (AP-HP) and Paris-Est-Créteil University, Creteil, France
| | - Per Ljungman
- Karolinska University Hospital, and Karolinska Institutet Stockholm, Stockholm, Sweden
| | | | | | | | - Helen Baldomero
- EBMT Activity Survey Office, Hematology, Department of Medicine, University Hospital, Basel, Switzerland
| | - Peter Bader
- Universitätsklinikum Frankfurt, Goethe-Universität, Frankfurt am Main, Germany
| | - Grzegorz Basak
- Department of Hematology, Oncology and Internal Medicine, Medical University of Warsaw, Warsaw, Poland
| | | | - Rafael Duarte
- Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain
| | - Carlo Dufour
- Hematology Unit, G. Gaslini Children's Institute, Genova, Italy
| | - Jurgen Kuball
- Department of Haematology, University Medical Centre, Utrecht, The Netherlands
| | | | - Silvia Montoto
- Department of Haemato-oncology, St Bartholomew's Hospital, Barts Health NHS Trust, London, UK
| | - Arnon Nagler
- Chaim Sheba Medical Center, Tel-Hashomer, Israel
| | - John A Snowden
- Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
| | - Nicolaus Kröger
- Department of Stem Cell Transplantation, University Hospital Eppendorf, Hamburg, Germany
| | - Mohamad Mohty
- Department of Hematology, Hospital Saint Antoine, Paris, France
| | - Alois Gratwohl
- Hematology, Medical Faculty, University of Basel, Basel, Switzerland
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15
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Shouval R, Labopin M, Gorin NC, Bomze D, Houhou M, Blaise D, Zuckerman T, Baerlocher GM, Capria S, Forcade E, Huynh A, Saccardi R, Martino M, Schaap M, Wu D, Mohty M, Nagler A. Individualized prediction of leukemia‐free survival after autologous stem cell transplantation in acute myeloid leukemia. Cancer 2019; 125:3566-3573. [DOI: 10.1002/cncr.32344] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2019] [Revised: 05/22/2019] [Accepted: 05/23/2019] [Indexed: 12/16/2022]
Affiliation(s)
- Roni Shouval
- Hematology and Bone Marrow Transplantation Division Chaim Sheba Medical Center at Tel HaShomer Ramat‐Gan Israel
- Sackler School of Medicine Tel Aviv University Tel Aviv Israel
- Dr. Pinchas Bornstein Talpiot Medical Leadership Program Chaim Sheba Medical Center at Tel HaShomer Ramat‐Gan Israel
| | - Myriam Labopin
- Department of Hematology and Cell Therapy Saint‐Antoine Hospital Paris France
- Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation Saint‐Antoine Hospital Paris France
| | - Norbert C. Gorin
- Department of Hematology and Cell Therapy Saint‐Antoine Hospital Paris France
- Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation Saint‐Antoine Hospital Paris France
| | - David Bomze
- Hematology and Bone Marrow Transplantation Division Chaim Sheba Medical Center at Tel HaShomer Ramat‐Gan Israel
- Sackler School of Medicine Tel Aviv University Tel Aviv Israel
| | - Mohamed Houhou
- Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation Saint‐Antoine Hospital Paris France
| | - Didier Blaise
- Transplantation and Cell Therapy Program Marseille Cancer Research Center, Paoli Calmettes Institute Marseille France
| | | | - Gabriela M. Baerlocher
- Department of Hematology, Inselspital Bern University Hospital, University of Bern Switzerland
| | | | - Edouard Forcade
- Service Hématologie Clinique et Thérapie CellulaireCentre Hospitalier Universitaire de Bordeaux Hôpital Haut‐Leveque Pessac France
| | - Anne Huynh
- Department of HematologyInstitut Universitaire du Cancer Toulouse Oncopole Toulouse France
| | - Riccardo Saccardi
- Department of Cellular Therapies and Transfusion MedicineCareggi University Hospital Firenze Italy
| | - Massimo Martino
- Stem Cell Transplant Unit, Hemato‐Oncology Department Grande Ospedale Metropolitano Bianchi Melacrino Morelli Reggio Calabria Italy
| | - Michel Schaap
- Department of HematologyRadboud University Medical Centre Nijmegen the Netherlands
| | - Depei Wu
- First Affiliated Hospital of Soochow University Suzhou China
| | - Mohamad Mohty
- Department of Hematology and Cell Therapy Saint‐Antoine Hospital Paris France
- Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation Saint‐Antoine Hospital Paris France
| | - Arnon Nagler
- Hematology and Bone Marrow Transplantation Division Chaim Sheba Medical Center at Tel HaShomer Ramat‐Gan Israel
- Sackler School of Medicine Tel Aviv University Tel Aviv Israel
- Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation Saint‐Antoine Hospital Paris France
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16
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Fleischhauer K, Hsu KC, Shaw BE. Prevention of relapse after allogeneic hematopoietic cell transplantation by donor and cell source selection. Bone Marrow Transplant 2018; 53:1498-1507. [PMID: 29795435 PMCID: PMC7286200 DOI: 10.1038/s41409-018-0218-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2017] [Revised: 03/16/2018] [Accepted: 03/24/2018] [Indexed: 01/27/2023]
Abstract
Allogeneic hematopoietic cell transplantation (HCT) is the most established form of cancer immunotherapy and has been successfully applied for the treatment and cure of otherwise lethal neoplastic blood disorders. Cancer immune surveillance is mediated to a large extent by alloreactive T and natural killer (NK) cells recognizing genetic differences between patient and donor. Profound insights into the biology of these effector cells has been obtained over recent years and used for the development of innovative strategies for intelligent donor selection, aiming for improved graft-versus-leukemia effect without unmanageable graft-versus-host disease. The cellular composition of the stem cell source plays a major role in modulating these effects. This review summarizes the current state-of the-art of donor selection according to HLA, NK alloreactivity and stem cell source.
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Affiliation(s)
- Katharina Fleischhauer
- Institute for Experimental Cellular Therapy, University Hospital Essen, Essen, Germany.
- German Cancer Consortium, Heidelberg, Germany.
| | - Katharine C Hsu
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
- Immunology Program, Sloan Kettering Institute, New York, NY, USA.
- Department of Medicine, Weill Cornell Medical College, New York, NY, USA.
| | - Bronwen E Shaw
- Center for International Blood and Marrow Transplant Research (CIBMTR), Froedtert & the Medical College of Wisconsin, Milwaukee, WI, USA.
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17
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Yanada M, Masuko M, Mori J, Aoki J, Mizuno S, Fukuda T, Kakihana K, Ozawa Y, Ota S, Kanamori H, Mori T, Nakamae H, Eto T, Shiratori S, Maeda T, Iwato K, Ichinohe T, Kanda Y, Tanaka J, Atsuta Y, Yano S. Patients with acute myeloid leukemia undergoing allogeneic hematopoietic cell transplantation: trends in survival during the past two decades. Bone Marrow Transplant 2018; 54:578-586. [PMID: 30108330 DOI: 10.1038/s41409-018-0301-7] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2018] [Revised: 07/24/2018] [Accepted: 07/27/2018] [Indexed: 11/09/2022]
Abstract
It remains unclear how specific innovations in allogeneic hematopoietic cell transplantation (HCT) attained over the past decades have contributed to improvement in transplantation outcomes. To address this question, we conducted a registry-based study of adults with acute myeloid leukemia in first or second complete remission who underwent allogeneic HCT between 1994 and 2013 from a sibling (N = 1600) or unrelated (N = 2113) donor matched at the antigen level for HLA-A, -B, and -DR. Preliminary analysis led us to focus on comparisons between the 1994-2006 and 2007-2013 periods. Significant improvement in survival was observed in the later cohort compared to the earlier cohort for unrelated HCT (P = 0.004), but not for related HCT (P = 0.767). The improvement in unrelated HCT was solely due to diminished non-relapse mortality (P = 0.001), while incidence of relapse did not change over time (P = 0.934). The percentage of patients receiving transplants from 8/8-matched unrelated donors was significantly higher in the later cohort (P < 0.001), and their survival was significantly better than that of those undergoing mismatched unrelated HCT (P = 0.022). These findings suggest that advances in HLA-typing technology have been vital for improvement in transplantation outcomes.
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Affiliation(s)
- Masamitsu Yanada
- Aichi Cancer Center, Nagoya, Japan. .,Fujita Health University School of Medicine, Toyoake, Japan.
| | | | - Jinichi Mori
- Jyoban Hospital Tokiwa Foundation, Fukushima, Japan
| | - Jun Aoki
- Yokohama City University Medical Center, Yokohama, Japan
| | | | | | | | | | | | | | | | - Hirohisa Nakamae
- Graduate School of Medicine, Osaka City University, Osaka, Japan
| | | | | | - Tetsuo Maeda
- Osaka University Graduate School of Medicine, Osaka, Japan
| | - Koji Iwato
- Hiroshima Red Cross Hospital and Atomic-Bomb Survivors Hospital, Hiroshima, Japan
| | | | | | | | - Yoshiko Atsuta
- Japanese Data Center for Hematopoietic Cell Transplantation, Nagoya, Japan.,Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Shingo Yano
- Jikei University School of Medicine, Tokyo, Japan
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18
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Ayuk F, Beelen DW, Bornhäuser M, Stelljes M, Zabelina T, Finke J, Kobbe G, Wolff D, Wagner EM, Christopeit M, Schmid C, Ottinger H, Groth C, Faul C, Bertz H, Rachlis E, Wolschke C, Schetelig J, Horn PA, Mytilineos J, Guellstorf M, Kelsch R, Fleischhauer K, Kröger N, Bethge W. Relative Impact of HLA Matching and Non-HLA Donor Characteristics on Outcomes of Allogeneic Stem Cell Transplantation for Acute Myeloid Leukemia and Myelodysplastic Syndrome. Biol Blood Marrow Transplant 2018; 24:2558-2567. [PMID: 29966760 DOI: 10.1016/j.bbmt.2018.06.026] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2018] [Accepted: 06/21/2018] [Indexed: 12/13/2022]
Abstract
Increasing donor-recipient HLA disparity is associated with negative outcomes of allogeneic hematopoietic stem cell transplantation (HSCT), but its comparative relevance amid non-HLA donor characteristics is not well established. We addressed this question in 3215 HSCTs performed between 2005 and 2013 in Germany for acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). Donors were HLA-matched related (MRD; n = 872) or unrelated (10/10 MUD, n = 1553) or HLA-mismatched unrelated (<10/10 MMUD, n = 790). Overall survival (OS) was similar after MRD compared with 10/10 MUD HSCT, reflecting opposing hazards of relapse (hazard ratio [HR], 1.32; P < .002) and nonrelapse mortality (HR, .63; P < .001). After UD HSCT, increasing HLA disparity was associated with inferior OS (HR, 1.21 [P < .02] and HR, 1.57 [P < .001] for 9/10 and ≤8/10 MMUD, respectively, compared with 10/10 MUD). Among non-HLA donor characteristics, age, sex mismatching (male recipient-female donor), and cytomegalovirus (CMV) mismatching (positive recipient-negative donor) impacted OS. Multivariate subgroup analysis showed that OS was similar after HSCT from the youngest 9/10 MMUD (<30 years) compared with the oldest 10/10 MUD (>40 years) (HR, 1.18; P = .25) and also in male patients transplanted from female 10/10 MUD compared with male 9/10 MMUD (HR, .89; P = .46). In contrast, OS of CMV-positive patients tended to be better with CMV-negative 10/10 MUDs compared with CMV-positive 9/10 MMUDs (HR, 1.31; P = .04). Because of low patient numbers in subgroups, definite conclusions and establishment of a hierarchy among HLA matching and non-HLA donor characteristics could not be made. Our data suggest that the impact of donor age and sex mismatch but not CMV mismatch on outcome of allogeneic HSCT may be comparable with that of single HLA disparity.
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Affiliation(s)
- Francis Ayuk
- Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Germany.
| | - Dietrich W Beelen
- Department of Bone Marrow Transplantation, West German Cancer Center, University Hospital Essen, Essen, Germany; DRST - German Registry for Stem Cell Transplantation, Essen, Germany
| | - Martin Bornhäuser
- Medical Clinic and Policlinic I, University Hospital of TU, Dresden, Germany
| | | | - Tatjana Zabelina
- Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Germany
| | - Jürgen Finke
- Hematology/Oncology, University Medical Center Freiburg, Freiburg, Germany
| | - Guido Kobbe
- Department of Hematology, Oncology and Clinical Immunology, Heinrich-Heine University, Düsseldorf, Germany
| | - Daniel Wolff
- Department of Hematology and Medical Oncology, University Hospital Regensburg, Regensburg, Germany
| | - Eva-Maria Wagner
- Third Department of Medicine-Hematology, Oncology and Pneumology, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany
| | - Maximilian Christopeit
- Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Germany
| | - Christoph Schmid
- Department of Haematology and Oncology, Klinikum Augsburg, Augsburg, Germany
| | - Hellmut Ottinger
- DRST - German Registry for Stem Cell Transplantation, Essen, Germany
| | - Christoph Groth
- Medizinische Klinik A, Universitätsklinikum Münster, Germany
| | - Christoph Faul
- Department of Hematology and Oncology, Eberhard Karls University Tubingen, Tubingen, Germany
| | - Hartmut Bertz
- Hematology/Oncology, University Medical Center Freiburg, Freiburg, Germany
| | - Elena Rachlis
- Department of Hematology, Oncology and Clinical Immunology, Heinrich-Heine University, Düsseldorf, Germany
| | - Christine Wolschke
- Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Germany
| | - Johannes Schetelig
- Medical Clinic and Policlinic I, University Hospital of TU, Dresden, Germany
| | - Peter A Horn
- Department of Transfusion medicine, University Hospital Essen, Essen, Germany
| | | | - Martina Guellstorf
- Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Germany
| | - Reinhard Kelsch
- Department of Transfusion medicine, University of Münster, Münster, Germany
| | | | - Nicolaus Kröger
- Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Germany
| | - Wolfgang Bethge
- Department of Hematology and Oncology, Eberhard Karls University Tubingen, Tubingen, Germany
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