67 results on '"Nicolaus Kröger"'
Search Results
2. Worldwide Network for Blood and Marrow Transplantation Special Article on Key Elements in Quality and Accreditation in Hematopoietic Stem Cell Transplantation and Cellular Therapy
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Amal Alseraihy, Eoin McGrath, Dietger Niederwieser, Christian Chabannon, Jeff Szer, Mohamad Mohty, Mohamed A. Kharfan-Dabaja, Kim Orchard, Joseph Schwartz, Walid Rasheed, Mickey Koh, Nicolaus Kröger, Yoshihisa Kodera, Riad El Fakih, Nina Worel, Lynn Manson, Tuula Rintala, Abdelghani Tabakhi, Bipin Savani, Usama Gergis, Anna Sureda, Paul W. Eldridge, Ibrahim Yakoub‐Agha, Mehdi Hamadani, Daniel Weisdorf, Hildegard Greinix, and Mahmoud Aljurf
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Transplantation ,Bone Marrow ,Cell- and Tissue-Based Therapy ,Hematopoietic Stem Cell Transplantation ,Molecular Medicine ,Immunology and Allergy ,Health Facilities ,Cell Biology ,Hematology ,Accreditation - Abstract
Hematopoietic stem cell transplantation (HSCT) represents an example of a highly complex and costly medical procedure with major applications in hematology and oncology. It is associated with life-threatening complications and, consequently, increased demands on healthcare resources. Although improving quality is an integral component of healthcare strategic planning, drivers of quality may be variable, and there is logical debate as to what drives quality in HSCT. Moreover, HSCT programs differ in structure and availability of resources, which drive the type of transplantations provided and determine what is affordable and/or economically feasible. The complexity of HSCT procedures with involvement of different stakeholders necessitates not only regulatory frameworks, but also robust quality systems to ensure consistent standards, demonstrate transparency for regulators, and define what quality means within the HSCT program. In an era of escalating healthcare complexity and heightened fiscal responsibility, transparency and accountability, accreditation contributes to ensuring that care meets the highest standards and can serve as a risk mitigation strategy. Quality management has become an indispensable tool for the management of a complex medical intervention such as HSCT. It allows the transplantation team to monitor its activities and identify areas for continuous improvement. The Worldwide Network for Blood and Marrow Transplantation invited a group of international experts in HSCT and quality management to work on providing a summary document about the key elements in quality and accreditation in HSCT and highlight the foremost challenges of implementing them, with a special focus on low- and middle-income economies.
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- 2022
3. KIR2DS4 and Its Variant KIR1D in KIR-AA Genotype Donors Showed Differential Survival Impact in Patients with Lymphoid Disease after HLA-Matched Unrelated Hematopoietic Stem Cell Transplantation
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Sowmya Gowdavally, Chrysanthi Tsamadou, Uwe Platzbecker, Elisa Sala, Thomas Valerius, Stefan Klein, Nicolaus Kröger, Gerald Wulf, Hermann Einsele, Lorenz Thurner, Kerstin Schaefer-Eckart, Sebastian Freitag, Jochen Casper, Mareike Dürholt, Martin Kaufmann, Bernd Hertenstein, Mark Ringhoffer, Sandra Schmeller, Christine Neuchel, Immanuel Rode, Elisa Maria Amann, Anita Richter, Hubert Schrezenmeier, Joannis Mytilineos, and Daniel Fuerst
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Transplantation ,Molecular Medicine ,Immunology and Allergy ,Cell Biology ,Hematology - Published
- 2023
4. Enhanced Immune Reconstitution of γδ T Cells after Allogeneic Stem Cell Transplantation Overcomes the Negative Impact of Pretransplantation Minimal Residual Disease-Positive Status in Patients with Acute Myelogenous Leukemia
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Anita Badbaran, Ulrike Fritsche-Friedland, Nicolaus Kröger, Ulrike Bacher, Francis Ayuk, Evgeny Klyuchnikov, Dietlinde Janson, Christine Wolschke, and Radwan Massoud
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Neoplasm, Residual ,Lymphocyte ,T cell ,Population ,Immune Reconstitution ,Immune system ,Antigen ,hemic and lymphatic diseases ,medicine ,Humans ,Transplantation, Homologous ,Immunology and Allergy ,education ,Transplantation ,education.field_of_study ,business.industry ,Hematopoietic Stem Cell Transplantation ,Cell Biology ,Hematology ,Middle Aged ,Minimal residual disease ,Leukemia, Myeloid, Acute ,medicine.anatomical_structure ,Immunology ,Molecular Medicine ,business ,CD8 - Abstract
Minimal/measurable residual disease (MRD) before allogeneic stem cell transplantation (allo-SCT) in patients with acute myelogenous leukemia (AML) is a poor risk factor for outcome. γδ T cells represent a unique minority lymphocyte population that is preferentially located in peripheral tissues, can recognize antigens in a non-MHC-restricted manner, and plays a "bridging" role between the innate and adaptive immune systems. In this study, we investigated a potential graft-versus-leukemia effect of γδ T cell reconstitution post-transplantation in AML patients with pretransplantation positive MRD status (MRD+). MRD assessment was performed in 202 patients using multicolored flow cytometry ("different from normal" strategy); 100 patients were deemed MRD+. Analysis for absolute concentrations of CD3+, CD4+, CD8+, natural killer, and γδ T cells were performed by flow cytometry according to an internal protocol at day +30 and +100 post-transplantation. Differences between categorical and continuous variables were determined using the chi-square and Student t test, respectively. The Mann-Whitney U test was used to compare medians of continuous variables. Spearman's correlation was used for nonparametric assessment of correlation between different cell subsets during immune reconstitution. Kaplan-Meier survival analysis and Cox regression analysis were used to investigate the associations between immune reconstitution and survival outcomes. Gray's analysis was used to compute incidences of relapse, nonrelapse mortality, and graft-versus-host disease (GVHD). The median follow-up of survivors was 28 months (range 3 to 59 months). Younger age (≤58 years) of recipient and donor (
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- 2021
5. Harmonizing Definitions for Diagnostic Criteria and Prognostic Assessment of Transplant Associated Thrombotic Microangiopathy: A Report on Behalf of the European Society for Blood and Marrow Transplantation (EBMT), American Society for Transplantation and Cellular Therapy (ASTCT), Asia-Pacific Blood and Marrow Transplantation Group (APBMT) and the Center for International Blood and Marrow Transplant Research (CIBMTR)
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Michelle Long Schoettler, Mr. Enric Carreras, Bin Cho, Dr. Christopher E. Dandoy, Dr. Vincent T. Ho, Sonata Jodele, Ivan Moiseev, Isabel Sanchez-Ortega, Alok Srivastava, Yoshiko Atsuta, Paul A. Carpenter, John Koreth, Nicolaus Kröger, Per T. Ljungman, Shinichiro Okamoto, Uday R. Popat, Bronwen E. Shaw, Robert J. Soiffer, Anna Sureda, Andre Williams, and Sumithira Vasu
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Transplantation ,Molecular Medicine ,Immunology and Allergy ,Cell Biology ,Hematology - Published
- 2023
6. Incidence and Outcome of Late Relapse after Allogeneic Stem Cell Transplantation for Myelofibrosis
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Christine Wolschke, Gaby Zeck, Maximilian Christopeit, Francis Ayuk, Nicolaus Kröger, and Isik Kaygusuz Atagunduz
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medicine.medical_specialty ,Donor cell ,Gastroenterology ,Donor lymphocyte infusion ,03 medical and health sciences ,0302 clinical medicine ,Recurrence ,Internal medicine ,medicine ,Humans ,Myelofibrosis ,Retrospective Studies ,Transplantation ,business.industry ,Incidence ,Incidence (epidemiology) ,Hematopoietic Stem Cell Transplantation ,Hematology ,medicine.disease ,Confidence interval ,Cross-Sectional Studies ,Treatment Outcome ,Primary Myelofibrosis ,Lymphocyte Transfusion ,030220 oncology & carcinogenesis ,Stem cell ,Late Relapse ,business ,030215 immunology - Abstract
In this cross-sectional study, we retrospectively evaluated the files of 227 patients with myelofibrosis who underwent transplantation between 1994 and 2015 for relapse later than 5 years after allogeneic stem cell transplantation (SCT). A total of 94 patients who were alive and in remission at 5 years were identified with follow-up of at least 5 years (median, 9.15 years) after SCT. Thirteen patients (14%) experienced late molecular (n = 6) or hematologic (n = 7) relapse at a median of 7.1 years while 81 patients did not experience relapse. Relapse patients received either donor lymphocyte infusion (DLI) (n = 7) and/or second transplantation (n = 4). Of those, 72.7% achieved again full donor cell chimerism and molecular remission, and after a median follow-up of 45 months, the 3-year overall survival rates for patients with or without relapse were 90.9% (95% confidence interval [CI], 77% to 100%) and 98.8% (95% CI, 96% to 100%), respectively (P = .13). We conclude that late relapse occurs in about 14% of the patients and the majority can be successfully salvaged with DLI and/or second allograft. All patients with molecular relapse are alive and support the long-time molecular monitoring in myelofibrosis patients after allogeneic SCT.
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- 2020
7. Clonal Evolution after Allogeneic Hematopoietic Stem Cell Transplantation: The Case of Myelofibrosis
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Nicolaus Kröger, Johanna Flach, Boris Fehse, Anita Badbaran, Maximilian Christopeit, and Malik Alawi
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Transplantation ,business.industry ,medicine.medical_treatment ,Hematopoietic Stem Cell Transplantation ,Hematology ,Hematopoietic stem cell transplantation ,medicine.disease ,Somatic evolution in cancer ,Clonal Evolution ,03 medical and health sciences ,0302 clinical medicine ,Paired samples ,Primary Myelofibrosis ,Recurrence ,030220 oncology & carcinogenesis ,Mutation ,Cancer research ,Humans ,Medicine ,business ,Myelofibrosis ,Gene ,030215 immunology - Abstract
The significance of clonal evolution in myelofibrosis (MF) relapse remains poorly understood. Here we performed panel sequencing in paired samples of 30 patients with MF who relapsed after undergoing allogeneic hematopoietic stem cell transplantation (alloSCT). We identified a median of 2 mutations (range, 0 to 12) in a median of 2 genes (range, 0 to 8) before allo-SCT, along with a median of 2 mutations (range, 0 to 12) in 2 genes (range, 0 to 6) at relapse. Additional whole-genome sequencing (n = 6) did not elucidate additional molecular changes. Taken together, our data provide further evidence, here on MF, that clonal evolution after alloSCT is limited and that instead, alloSCT selects specific (sub)clones.
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- 2020
8. Outcome of Allogeneic Hematopoietic Stem Cell Transplantation in Patients Age >69 Years with Acute Myelogenous Leukemia: On Behalf of the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation
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Myriam Labopin, Jonathan Canaani, Behnam Sadeghi, Lothar Kantz, Ariane Boumendil, Bipin N. Savani, Olle Ringdén, Jürgen Finke, Mohamad Mohty, Armin Gerbitz, Gerhard Ehninger, Arne Brecht, Nicolaus Kröger, Dietrich W. Beelen, Matthias Stelljes, Arnon Nagler, Arnold Ganser, and Dietger Niederwieser
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Male ,Oncology ,medicine.medical_specialty ,Transplantation Conditioning ,medicine.medical_treatment ,Medizin ,Hematopoietic stem cell transplantation ,03 medical and health sciences ,Myelogenous ,0302 clinical medicine ,hemic and lymphatic diseases ,Internal medicine ,Humans ,Transplantation, Homologous ,Medicine ,In patient ,Aged ,Retrospective Studies ,Transplantation ,Acute leukemia ,business.industry ,Marrow transplantation ,Hematopoietic Stem Cell Transplantation ,Hematology ,Middle Aged ,medicine.disease ,Europe ,Survival Rate ,Leukemia ,Regimen ,Treatment Outcome ,surgical procedures, operative ,Graft-versus-host disease ,030220 oncology & carcinogenesis ,Female ,business ,030215 immunology - Abstract
Reduced-intensity conditioning (RIC) allows for the use of allogeneic hematopoietic stem cell transplantation (HSCT) in older patients with acute myelogenous leukemia (AML). We compared outcomes between 713 patients age ≥70 years and 16,161 patients age 50 to 69 years who underwent HSCT between 2004 and 2014. A higher proportion of the older patients were male and had secondary AML, active disease, a peripheral blood stem cell graft, a matched unrelated donor, an RIC regimen, and a lower Karnofsky Performance Status (KPS) score (P.001). In multivariate analysis, the incidences of acute and chronic graft-versus-host disease and relapse were similar in the 2 age groups. Nonrelapse mortality at 2 years was 34% (95% confidence interval [CI], 31% to 38%) in patients age ≥70 years and 24% (95% CI, 25% to 32%) in those age 50 to 69 years (P.001). Survival at 2 years in the 2 groups was 38% (95% CI, 34% to 42%) and 50% (95% CI, 49% to 50%), respectively (P.001). In patients with active disease, the corresponding percentages were 35% (95% CI, 29% to 41%) in those age ≥70 years and 33% (95% CI, 31% to 34%) in those age70 years (P = .36). In patients age ≥70 years, a KPS score of ≥80% was associated with improved survival (hazard ratio, 1.53; 95% CI, 1.14 to 2.06; P = .003). In summary, patients age ≥70 years had worse outcomes, except for those with active AML.
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- 2019
9. P-277: Carfilzomib, lenalidomide and dexamethasone followed by a second autologous hematopoietic cell transplantation is an effective strategy in first-relapsed multiple myeloma
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Remi Tilmont, Ibrahim Yakoub-Agha, Diderik-Jan Eikema, Nienke Zinger, Mathias Haenel, Nicolaas Schaap, Concepcion Herrera Arroyo, Christine Schuermans, Wolfgang Bethge, Monika Engelhardt, Jürgen Kuball, Mariagrazia Michieli, Natalie Schub, Keith M.O. Wilson, Jean Henri Bourhis, María-Victoria Mateos, Neil Rabin, Edgar Jost, Nicolaus Kröger, José Mª Moraleda, Simona Sica, Patrick J. Hayden, Meral Beksac, Stefan Schönland, and Salomon Manier
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Cancer Research ,Oncology ,Hematology - Published
- 2022
10. Immune Signatures Associated With Clonal Isotype Switch After Autologous Stem Cell Transplantation for Multiple Myeloma
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Ehsan Malek, Sirisha Kundrapu, Stanton L. Gerson, Rebecca Ye, Naveed Ali, Nicolaus Kröger, George Luo, Marcos de Lima, Paolo Caimi, James J. Driscoll, Willem vanHeeckeren, Rose Beck, and Ola Landgren
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Adult ,Male ,Immunofixation ,Cancer Research ,Transplantation Conditioning ,Transplantation, Autologous ,Article ,03 medical and health sciences ,Immune Reconstitution ,0302 clinical medicine ,Autologous stem-cell transplantation ,Tumor Microenvironment ,medicine ,Humans ,Postoperative Period ,Multiple myeloma ,Aged ,Retrospective Studies ,B-Lymphocytes ,Dose-Response Relationship, Drug ,biology ,medicine.diagnostic_test ,business.industry ,Hematopoietic Stem Cell Transplantation ,Standard of Care ,Hematology ,Middle Aged ,Myeloablative Agonists ,Prognosis ,medicine.disease ,Immunoglobulin Class Switching ,Isotype ,Progression-Free Survival ,Immunoglobulin Isotypes ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,Serum protein electrophoresis ,Immunology ,biology.protein ,Female ,Bone marrow ,Antibody ,Multiple Myeloma ,business ,CD8 ,030215 immunology - Abstract
Background High-dose chemotherapy and autologous stem cell transplantation (ASCT) are integral components of the overall treatment for patients with multiple myeloma (MM) aged ≤ 65 years. The emergence of oligoclonal immunoglobulin bands (ie, immunoglobulins differing from those originally identified at diagnosis [termed clonal isotype switch (CIS)]) has been reported in patients with MM after high-dose chemotherapy followed by autologous stem cell transplantation. However, the clinical relevance and the correlation with immune reconstitution remains unclear. Patients and Methods Patients with MM who had undergone ASCT from 2007 to 2016 were included in the present study. The percentage of natural killer cells, B-cells, and T-cells was measured using flow cytometry in pre- and post-ASCT bone marrow samples. CIS was defined as the appearance of a new serum monoclonal spike on serum protein electrophoresis and immunofixation that differed from original heavy or light chain detected at diagnosis. Results A retrospective analysis of 177 patients with MM who had undergone ASCT detected CIS in 39 (22%). CIS after ASCT correlated with improved progression-free survival (52.2 vs. 36.6 months; P = .21) and overall survival (75.1 vs. 65.4 months; P = .021). Patients with a relapse had an isotype that differed from a CIS, confirming the benign nature of this phenomenon. CIS was also associated with lower CD8 T-cell percentages and a greater CD4/CD8 ratio (2.8 vs. 0.2; P = .001) compared with patients who did not demonstrate a CIS, suggestive of more profound T-cell immune reconstitution in this group. Conclusion Taken together, our data have demonstrated that a CIS is a benign phenomenon and correlates with a reduced disease burden and enriched immune repertoire beyond the B-cell compartment.
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- 2019
11. Biology-Driven Approaches to Prevent and Treat Relapse of Myeloid Neoplasia after Allogeneic Hematopoietic Stem Cell Transplantation
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Martin Bornhäuser, Jürgen Finke, Lutz P. Müller, Christoph Schmid, Nicolaus Kröger, Wolfgang Bethge, Uwe Platzbecker, Maximilian Christopeit, Robert Zeiser, Dietrich W. Beelen, Guido Kobbe, Carsten Müller-Tidow, Mathias Stelljes, Justus Duyster, Wolf Rösler, Michael Lübbert, Martin Sauer, Thomas Schroeder, Armin Gerbitz, Jan-Henning Klusmann, Gesine Bug, and Andreas Burchert
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Male ,Oncology ,medicine.medical_specialty ,medicine.medical_treatment ,Medizin ,Context (language use) ,Disease ,Hematopoietic stem cell transplantation ,Donor lymphocyte infusion ,Myelogenous ,Recurrence ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Humans ,Transplantation, Homologous ,ddc:610 ,Transplantation ,Chemotherapy ,business.industry ,Hematopoietic Stem Cell Transplantation ,Hematology ,medicine.disease ,Leukemia ,surgical procedures, operative ,Myelodysplastic Syndromes ,Female ,business - Abstract
The curative potential of allogeneic hematopoietic cell transplantation (allo-HCT) in the treatment of acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) relies mainly on the graft-versus-leukemia effect. Relapse after allo-HCT occurs in a considerable proportion of patients and has a dismal prognosis, with still very limited curative potential. This review provides an overview of the established and evolving approaches to preventing or treating relapse of AML and MDS after allo-HCT, in the context of novel insight into the biology of relapse. Established prophylactic measures to prevent relapse include optimized conditioning and graft-versus-host disease (GVHD) prophylaxis, as well as donor lymphocyte infusion (DLI) for high-risk patients; novel immunomodulatory interventions and maintenance approaches are still experimental. Improved diagnostics can detect persistent or recurring disease at a molecular level, enabling early preemptive interventions. Established options include hypomethylating agents and DLI. Standard treatments for hematologic relapse include chemotherapy, cessation of immunosuppressive treatment, and DLI. Experimental approaches include molecular targeted therapies, novel immunomodulatory treatments, and second allo-HCT. For all interventions, the potential risks, including occurrence of GVHD, must be weighed against the benefits individually in each patient. Concurrently, prevention and treatment of relapse after allo-HCT remain challenging and unmet medical needs.
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- 2019
12. GVHD prophylaxis plus ATLG after myeloablative allogeneic haemopoietic peripheral blood stem-cell transplantation from HLA-identical siblings in patients with acute leukaemia in remission: final results of quality of life and long-term outcome analysis of a phase 3 randomised study
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Giuseppe Messina, Edoardo Benedetti, Tapani Ruutu, Andreas Völp, Christelle Ferra, Fabio Benedetti, Elisabetta Terruzzi, Antonio M. Risitano, Francesco Zallio, Franco Narni, Manuel Jurado, Carmine Selleri, Jorge Sierra, Domenico Russo, Roberto Sorasio, Michele Cimminiello, Christine Wolschke, Carlos Solano, Pilar Herrera, Francesca Patriarca, Domenico Pastore, Francis Ayuk, Giuseppe Milone, Anna Sureda, Stefano Guidi, Mariarosaria Sessa, Wolfgang Bethge, Angelo Michele Carella, Marion Heinzelmann, Nicolaus Kröger, Arnon Nagler, Francesca Bonifazi, and Jürgen Finke
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medicine.medical_specialty ,business.industry ,medicine.medical_treatment ,Context (language use) ,Hematology ,Hematopoietic stem cell transplantation ,Total body irradiation ,3. Good health ,Anti-thymocyte globulin ,Transplantation ,03 medical and health sciences ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Internal medicine ,medicine ,Clinical endpoint ,Cumulative incidence ,business ,Busulfan ,030215 immunology ,medicine.drug - Abstract
Summary Background We previously showed that human anti-T-lymphocyte globulin (ATLG) plus ciclosporin and methotrexate given to patients with acute leukaemia in remission, having allogeneic haemopoietic stem-cell transplantation with peripheral blood stem cells from an HLA-identical sibling donor after myeloablative conditioning, significantly reduced 2-year chronic graft-versus-host disease (cGVHD) incidence and severity, without increasing disease relapse and infections, and improves cGVHD-free and relapse-free survival (cGRFS). The aim of an extended follow-up study was the assessment of long-term outcomes, which are, in this context, scarcely reported in the literature. We report unpublished data on quality of life (QoL) from the original study and the results of a follow-up extension. Methods In the original open-label study, patients with acute myeloid and lymphoblastic leukaemia in first or subsequent remission, having sibling HLA-identical allogeneic peripheral blood stem-cell transplantation, were randomly assigned (1:1) to receive ATLG plus standard GVHD prophylaxis with ciclosporin and short-term methotrexate (ATLG group) or standard GVHD prophylaxis without ATLG (non-ATLG group). Conditioning regimens were cyclophosphamide 120 mg/kg with either total body irradiation (12 Gy) or busulfan (12·8 mg/kg intravenously or 16 mg/kg orally), with or without etoposide (30–60 mg/kg). Randomisation was stratified according to centre and disease risk. The primary endpoint was cumulative incidence of cGVHD at 2 years. The primary and secondary endpoints, excluding QoL, have been published. QoL, assessed using European Organisation for Research and Treatment of Cancer QLQ-C30 and QLQ-HDC29 questionnaires, was an unpublished secondary endpoint, which we now report here. A follow-up extension was then done, with the primary endpoint cumulative incidence of cGVHD. Enrolment has been completed for both studies. The original trial (number, NCT00678275 ) and follow-up extension (number, NCT03042676 ) are registered at ClinicalTrials.gov . Findings In the original study, from Dec 14, 2006, to Feb 2, 2012, 161 patients were enrolled and 155 were randomly assigned to either the ATLG group (n=83) or to the non-ATLG group (n=72). In the follow-up study, which started on Feb 7, 2017, and was completed on June 30, 2017, 61 patients were included in the ATLG group and 53 were included in the non-ATLG group. Global health status showed a more favourable time course in the ATLG group compared with the non-ATLG group (p=0·02; treatment by visit interaction). ATLG was descriptively superior to non-ATLG at 24 months for physical function (points estimate −14·8 [95% CI −26·4 to −3·1]; p=0·014) and social function (–19·1 [–38·0 to −0·2]; p=0·047), gastrointestinal side-effects (8·8 [2·5–15·1]; p=0·008) and effect on family (13·5 [1·2–25·8]; p=0·032). Extended follow-up (median 5·9 years [IQR 1·7–7·9]) confirmed a lower 5-year cGVHD incidence (30·0% [95% CI 21·4–41·9] vs 69·1% [59·1–80·1]; analysis for entire follow-up, p Interpretation The addition of ATLG to standard GVHD prophylaxis improves the probability of surviving without disease relapse and cGVHD after myeloablative peripheral blood stem-cell transplantation from an HLA-identical sibling donor for patients with acute leukaemia in remission. Further additional benefits are better QoL and shorter immunosuppressive treatment compared with standard GVHD prophylaxis without ATLG. Therefore, in this setting, ATLG plus standard GVHD prophylaxis should be preferred over the standard GVHD prophylaxis alone. Funding Neovii Biotech.
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- 2019
13. High Mortality of COVID-19 Early after Allogeneic Stem Cell Transplantation: A Retrospective Multicenter Analysis on Behalf of the German Cooperative Transplant Study Group
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Judith Schaffrath, Christina Brummer, Daniel Wolff, Udo Holtick, Nicolaus Kröger, Martin Bornhäuser, Sabrina Kraus, Inken Hilgendorf, Igor-Wolfgang Blau, Olaf Penack, Christoph Wittke, Normann Steiner, David Nachbaur, Lorenz Thurner, Heidrun Hindahl, Robert Zeiser, Claus-Philipp Maier, Wolfgang Bethge, and Lutz P. Müller
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Adult ,Aged, 80 and over ,Transplantation ,SARS-CoV-2 ,Hematopoietic Stem Cell Transplantation ,COVID-19 ,Cell Biology ,Hematology ,Middle Aged ,Young Adult ,Humans ,Molecular Medicine ,Immunology and Allergy ,Pandemics ,Aged ,Retrospective Studies - Abstract
Recipients of allogeneic stem cell transplantation (alloSCT) are at high risk for contracting infectious diseases with high morbidity and mortality. Coronavirus disease 2019 (COVID-19) is a viral respiratory disease that can lead to severe pneumonia and acute respiratory distress syndrome, with a potentially fatal outcome. In this retrospective study conducted on behalf of the German Cooperative Transplant Study Group, we aimed to analyze risk factors, disease course, and outcomes of COVID-19 in patients who underwent alloSCT. AlloSCT recipients who became infected with SARS-CoV-2 at German and Austrian transplant centers between February 2020 and July 2021 were included. Classification of COVID-19 severity into mild, moderate-severe, or critical disease and division of the course of the pandemic into 4 phases were done according to the German Robert Koch Institute. The main endpoint was overall mortality at the end of follow-up. We further analyzed the need for treatment in an intensive care unit (ICU) and the severity of disease. Risk factors were evaluated using univariate and multivariate analyses, and survival analysis was performed using Kaplan-Meier method. The study cohort comprised 130 patients from 14 transplant centers, with a median age at diagnosis of COVID-19 of 59 years (range, 20 to 81 years) and a median interval between alloSCT and COVID-19 of 787 days (range, 19 to 8138 days). The most common underlying diseases were acute myeloid leukemia (45.4%) and lymphoma (10.8%). The majority of patients (84.9%) were infected in the later phases of the pandemic; 20.8% had moderate-severe disease, 12.3% had critical disease, and 19.2% were treated in an ICU. After a median follow-up of 127 days, overall mortality was 16.2%, 52.0% among patients treated in an ICU. Risk factors for mortality in multivariate analysis were active disease (odds ratio [OR], 4.46), infection with SARS-CoV-2 ≤365 days after alloSCT (OR, 5.60), age60 years (OR, 5.39), and ongoing immunosuppression with cyclosporine (OR, 8.55). Risk factors for developing moderate-severe or critical disease were concurrent immunosuppression (OR, 4.06) and age40 years (OR, 4.08). Patients after alloSCT exhibit a substantially increased mortality risk after COVID-19 infection compared with the normal population, without considerable improvement over the course of the pandemic. Risk factors include age, early infection post-alloSCT, and active immunosuppression. Further studies are needed to improve prevention and treatment in this high-risk patient group.
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- 2022
14. Relative Impact of HLA Matching and Non-HLA Donor Characteristics on Outcomes of Allogeneic Stem Cell Transplantation for Acute Myeloid Leukemia and Myelodysplastic Syndrome
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Tatjana Zabelina, Christoph Groth, Hellmut Ottinger, Martina Guellstorf, Wolfgang Bethge, Martin Bornhäuser, Reinhard Kelsch, Christoph Schmid, Christoph Faul, Peter A. Horn, Jürgen Finke, Nicolaus Kröger, Johannes Schetelig, Christine Wolschke, Dietrich W. Beelen, Francis Ayuk, Guido Kobbe, Elena Rachlis, Joannis Mytilineos, Katharina Fleischhauer, Hartmut Bertz, Daniel Wolff, Maximilian Christopeit, Eva-Maria Wagner, and Matthias Stelljes
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Adult ,Male ,Oncology ,medicine.medical_specialty ,medicine.medical_treatment ,Medizin ,Hematopoietic stem cell transplantation ,Human leukocyte antigen ,Donor age ,03 medical and health sciences ,0302 clinical medicine ,Recurrence ,Internal medicine ,medicine ,Humans ,Transplantation, Homologous ,Transplantation ,business.industry ,Hematopoietic Stem Cell Transplantation ,Myeloid leukemia ,Hematology ,Middle Aged ,Tissue Donors ,Leukemia, Myeloid, Acute ,Treatment Outcome ,Male patient ,Myelodysplastic Syndromes ,030220 oncology & carcinogenesis ,Allogeneic hsct ,Female ,Stem cell ,business ,030215 immunology - 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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- 2018
15. Antibody Response to COVID-19 Vaccination in Adults with Haematological Malignancies: A Systematic Review and Meta-Analysis
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Nico Gagelmann, Christian Niederwieser, Christine Wolschke, Raissa Adjallé, Barbara Mora, Evgeny Klyuchnikov, Francesco Passamonti, Radwan Massoud, Francis Ayuk, and Nicolaus Kröger
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History ,Ruxolitinib ,medicine.medical_specialty ,Polymers and Plastics ,Venetoclax ,business.industry ,medicine.disease ,Industrial and Manufacturing Engineering ,Confidence interval ,Lymphoma ,Vaccination ,chemistry.chemical_compound ,chemistry ,Meta-analysis ,Internal medicine ,medicine ,Clinical endpoint ,Business and International Management ,business ,Multiple myeloma ,medicine.drug - Abstract
Background: Vaccines against SARS-CoV-2 have shown remarkable efficacy and thus constitute an important preventive option against COVID-19, especially in fragile patients. We aimed to systematically analyse the outcomes of patients with haematological malignancies who received COVID-19 vaccination and to identify specific groups with differences in outcomes. Methods: We developed a living systematic review and meta-analysis of published studies that reported data on the outcomes of adult patients with haematological malignancies that received COVID-19 vaccination, reported between July 1, 2020, and September 15, 2021. Studies with ten patients or fewer were excluded and summary data were extracted from the reports. The primary end point was the number of patients with antibody response after full vaccination. This study is registered with PROSPERO (CRD42021279051). Findings: We identified 43 studies comprising 10416 patients. Overall risk of bias was low. The pooled response for haematological malignancies was 65% (95% confidence interval [CI], 60-70; I²=93%) compared with 95% (95% CI, 92-97; I²=27%) for solid cancer and 98% (95% CI, 96-99; I² =60%) for healthy controls (P
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- 2021
16. Iron Chelation With Deferasirox Increases Busulfan AUC During Conditioning Chemotherapy Prior to Allogeneic Stem Cell Transplantation
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Nicolaus Kröger, Adrin Dadkhah, Claudia Langebrake, Christine Wolschke, Sonja Essmann, Francis Ayuk, and Dietlinde Janson
- Subjects
Adult ,medicine.medical_specialty ,Iron Overload ,Dose ,Population ,Urology ,Iron Chelating Agents ,medicine ,Humans ,Immunology and Allergy ,Prospective Studies ,education ,Busulfan ,Transplantation ,education.field_of_study ,medicine.diagnostic_test ,Cumulative dose ,business.industry ,Deferasirox ,Hematopoietic Stem Cell Transplantation ,Area under the curve ,Bayes Theorem ,Cell Biology ,Hematology ,Therapeutic drug monitoring ,Area Under Curve ,Molecular Medicine ,business ,medicine.drug - Abstract
Background : The negative effects of iron overload due to repetitive blood transfusions and iron release during cytotoxic chemotherapy might be ameliorated by early treatment with an iron chelator. However, in the setting of allogeneic hematopoietic stem cell transplantation (HSCT) chelation therapy is often postponed until the late posttransplant period because of potential drug interactions. Objective : To systematically investigate the influence of iron chelation with deferasirox on the pharmacokinetics of intravenous busulfan in adult patients in the context of routine therapeutic drug monitoring (TDM) prior to HSCT. Study design : We conducted a single-center, prospective, observational study in 25 adult patients with planned allogeneic HSCT after myeloablative, busulfan-based, TDM-guided conditioning chemotherapy. Busulfan was administered i.v. over 3 h with an initial dose of 3.2 mg/kg once daily (based on AIBW in overweight patients). Four consecutive dosages were planned to achieve a cumulative area under the curve (AUC) of 80 mg*h/l. Patients received deferasirox for transfusional iron overload as per approval from the start of conditioning until d3 after transplantation. Model-based calculation of the busulfan area under the curve (AUC) was carried out by means of Bayesian prediction based on a population pharmacokinetic model after the first or second dose of busulfan and dose adjustments were performed accordingly. Results : Calculated median cumulative AUC before dose adjustment was 93.7 mg*h/l (65.1 - 151.4 mg*h/l), which was considerably above the target AUC of 80 mg*h/l ± 10 %. Median dose adjustment was -17.1 % (-50.0 – 18.2 %) and patients ultimately received busulfan with a median cumulative dose of 10.60 mg/kg (6.38 – 15.62 mg/kg). A busulfan dose reduction was necessary in 19 patients (76 %) whereas a dose increase was only necessary in one patient. After dose adjustment the median AUC was 79.7 mg/L*h (62.5 – 84.2 mg/l*h). Median busulfan clearance was 0.134 l/h/kg (0.084 – 0.203 l/h/kg), which is significantly lower than the average clearance of 0.2 l/h/kg reported in the literature, while volume of distribution was not altered. Conclusions : We were able to demonstrate, that TDM is the key point to facilitate a safe co-administration of both medications, since the intake of deferasirox leads to a considerable increase in the busulfan AUC of about 35 - 40 %. The reason for the increase in busulfan AUC is a reduction in busulfan clearance by about one third, therefore a lower initial dose of busulfan followed by TDM could be considered in this case.
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- 2022
17. Incidence of Second Primary Malignancies after Autologous Transplantation for Multiple Myeloma in the Era of Novel Agents
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Didier Blaise, Soledad González Muñiz, Jane F. Apperley, Nicolaus Kröger, Péter Reményi, Nicolaas Schaap, Firoozeh Sahebi, Stig Lenhoff, Ibrahim Yakoub-Agha, Marta Krejčí, Nigel H. Russell, Giulia Sbianchi, Marek Trneny, Guido Kobbe, Wieslaw Wiktor-Jedrzejczak, Cecilia Isaksson, Christof Scheid, Stefan Schönland, Laurent Garderet, Curly Morris, Per Ljungman, Paul Browne, Linda Koster, Simona Iacobelli, James F. Sanchez, Keith Wilson, University of Rome TorVergata, European Society for Blood and Marrow Transplantation (EBMT), Service d’Hématologie [Institut Paoli Calmettes, Marseille], Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Clinical Haematology, Nottingham University Hospitals—City Campus, Dept. of Hematology, University hospitals, Department of Haematology, Charles University Hospital, University Hospital Brno, Department of Hematology, Oncology and Internal Diseases, Medical University of Warsaw - Poland, Department of Hematology, University Hospital Lund, Trinity College Dublin, Department I of Internal Medicine, University of Cologne, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Lille Inflammation Research International Center - U 995 (LIRIC), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Queen's University [Belfast] (QUB), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), University Hospital Hamburg-Eppendorf, Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] (UKE), and National Institute for Health Research
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Male ,Oncology ,Benzylamines ,[SDV]Life Sciences [q-bio] ,Cancer development and immune defence Radboud Institute for Molecular Life Sciences [Radboudumc 2] ,medicine.medical_treatment ,Hematopoietic stem cell transplantation ,Cyclams ,0302 clinical medicine ,Heterocyclic Compounds ,Cumulative incidence ,Prospective Studies ,Prospective cohort study ,Multiple myeloma ,Incidence ,Incidence (epidemiology) ,Age Factors ,Hematopoietic Stem Cell Transplantation ,Neoplasms, Second Primary ,Hematology ,Middle Aged ,second primary malignancies ,Hematopoietic Stem Cell Mobilization ,3. Good health ,030220 oncology & carcinogenesis ,Female ,Multiple Myeloma ,medicine.drug ,Adult ,medicine.medical_specialty ,Immunology ,proteasome inhibitors ,Transplantation, Autologous ,Settore MED/01 - Statistica Medica ,Young Adult ,03 medical and health sciences ,All institutes and research themes of the Radboud University Medical Center ,immunomodulatory drugs ,Internal medicine ,medicine ,Humans ,Autologous transplantation ,Aged ,Transplantation ,business.industry ,Plerixafor ,fungi ,plerixafor ,1103 Clinical Sciences ,medicine.disease ,business ,030215 immunology - Abstract
The advent of novel agents for multiple myeloma (MM) is cause for a re-examination of the incidence of second primary malignancies (SPM5). We examined the SPM rate in MM patients who were enrolled in the prospective observational CALM (Collaboration to Collect Autologous Transplant outcome in Lymphoma and Myeloma) study. Between 2008 and 2012, 3204 patients with MM underwent a first autologous hematopoietic stem cell transplantation. Plerixafor was used as a mobilizing agent for patients with poor (or potentially poor) stem cell mobilization as defined by the respective centers. A total of 135 patients developed SPM5, with a cumulative incidence of 5.3% (95% confidence interval, 4.4 to 6.3) at 72 months. Ninety-four patients developed solid tumors, 30 developed hematologic malignancies, and 11 developed an SPM of an unknown type. The cumulative incidence of known hematologic and solid malignancies were 1.4% and 3.6%, respectively, at 72 months. In a univariate analysis, use of radiotherapy, type of induction regimen, hematopoietic stem cell dose, poor mobilizer status, plerixafor use, and sex did not influence the cumulative incidence of SPMs. Only age over 65 years was statistically associated with an increased incidence. Overall, the incidence of SPMs was comparable to earlier estimations of SPMs in MM. (C) 2018 American Society for Blood and Marrow Transplantation.
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- 2018
18. Chemotherapy-Based Stem Cell Mobilization Does Not Result in Significant Paraprotein Reduction in Myeloma Patients in the Era of Novel Induction Regimens
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Gerald Wulf, Lorenz Trümper, Nicolaus Kröger, Andreas Burchert, Ulrike Bacher, Patrick Wuchter, Philippe Kostrewa, A A Oyekunle, and Evgenii Shumilov
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Adult ,Male ,Oncology ,medicine.medical_specialty ,medicine.medical_treatment ,Transplantation, Autologous ,Sepsis ,03 medical and health sciences ,0302 clinical medicine ,Autologous stem-cell transplantation ,Internal medicine ,medicine ,Humans ,Multiple myeloma ,Etoposide ,Aged ,Retrospective Studies ,Lenalidomide ,Transplantation ,Chemotherapy ,business.industry ,Bortezomib ,Remission Induction ,Hematopoietic Stem Cell Transplantation ,Hematology ,Middle Aged ,medicine.disease ,Survival Analysis ,Hematopoietic Stem Cell Mobilization ,3. Good health ,Surgery ,Treatment Outcome ,030220 oncology & carcinogenesis ,Female ,Stem cell ,Multiple Myeloma ,business ,Paraproteins ,030215 immunology ,medicine.drug - Abstract
Novel induction agents markedly improved remission rates in multiple myeloma (MM), and the continued use of chemotherapy for CD34+ stem cell mobilization (SCM) has been questioned. We examined the additional effect of chemotherapy in SCM regarding remission status/morbidity. We reviewed 236 consecutive MM patients (aged 36 to 75 years) with first autologous stem cell transplantation from January 2009 to March 2016 after chemotherapy-based SCM. Responses were measured by changes in intact Ig and free light chain levels before and after chemomobilization (International Myeloma Working Group [IMWG] criteria). Most patients (225/236, 95.3%) received novel induction regimens, which were bortezomib-based (n = 223) and/or lenalidomide-based (n = 19). Most patients (170/190, 89.5%) achieved at least partial remission postinduction and pre-SCM. Stem cells were mobilized with granulocyte colony-stimulating factor and cyclophosphamide-based (212/227, 93.4%) or etoposide-based (15/227, 6.6%) regimens. There were insignificant changes in serum Ig and free light chain levels before and after chemomobilization either in the whole cohort or subgroups. Significant improvements of the IMWG remission status were documented in only 7 of 236 patients (3.0%). Sixty-seven patients (28.4%) developed chemotherapy-related complications (neutropenic fever, sepsis, and others), resulting in 9 hospitalizations (3.8%). Our study suggests that although causing significant morbidity, chemotherapy-based mobilization fails to improve remission status. The value of incorporating additional chemotherapy for SCM is thus not evident.
- Published
- 2018
19. Induction, Bridging, or Straight Ahead: The Ongoing Dilemma of Allografting in Advanced Myelodysplastic Syndrome
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Nicolaus Kröger
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Transplantation ,medicine.medical_specialty ,Bridging (networking) ,business.industry ,Cytoreduction Surgical Procedures ,Hematology ,Treatment related mortality ,Dilemma ,Straight ahead ,Leukemia, Myeloid, Acute ,Myelodysplastic Syndromes ,medicine ,Humans ,Transplantation, Homologous ,Longitudinal Studies ,Intensive care medicine ,business - Published
- 2019
20. Current status of pretransplant intensive chemotherapy or hypomethylating agents for myelodysplastic syndrome
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Nicolaus Kröger and Christian Niederwieser
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Oncology ,medicine.medical_specialty ,Hematopoietic cell ,business.industry ,Incidence (epidemiology) ,Clinical Biochemistry ,Hematopoietic Stem Cell Transplantation ,Tumor burden ,Retrospective cohort study ,Disease ,Intensive chemotherapy ,law.invention ,Transplantation ,Randomized controlled trial ,law ,Myelodysplastic Syndromes ,Internal medicine ,medicine ,Humans ,Neoplasm Recurrence, Local ,business ,Retrospective Studies - Abstract
Myelodysplastic syndrome is a heterogeneous disease with survival probabilities ranging from a few months to several years. Allogeneic hematopoietic cell transplantation (HCT) remains the only curative treatment. Although access (up to 75 years) and outcome of HCT have improved steadily in recent years, high relapse rates and, to a lower extent, treatment related mortalities are a persisting problem. Reduction of tumor burden before HCT has been shown to decrease relapse incidence and often overall survival (OS) in hematological malignancies but the role of pretransplant therapy in MDS remains controversial. We reviewed the role of pretransplant therapy on outcome in MDS patients. No prospective randomized trial addressed this issue so far. Retrospective studies have shown that pretransplant therapy reduces the risk of relapse, but does not improve survival. In addition, registry studies from diagnosis with standard protocols are proposed in order to exclude patient selection. With the availability of new, more effective and low-toxicity therapies, it may be possible to achieve a significant improvement of OS in the future.
- Published
- 2021
21. Maximizing the benefit of allogeneic stem cell transplantation in myelodysplastic syndromes
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Nicolaus Kröger
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Oncology ,medicine.medical_specialty ,Transplantation Conditioning ,medicine.medical_treatment ,Disease ,Hematopoietic stem cell transplantation ,Biology ,Cytogenetics ,03 medical and health sciences ,0302 clinical medicine ,Risk Factors ,Internal medicine ,medicine ,Humans ,Transplantation, Homologous ,Retrospective Studies ,Framingham Risk Score ,Myelodysplastic syndromes ,Hematopoietic Stem Cell Transplantation ,Retrospective cohort study ,Hematology ,Prognosis ,medicine.disease ,Transplantation ,International Prognostic Scoring System ,Myelodysplastic Syndromes ,030220 oncology & carcinogenesis ,Immunology ,030215 immunology - Abstract
Allogeneic stem cell transplantation (AHSCT) is an evolving field in the treatment of patients with myelodysplastic syndrome (MDS) and has become the third most frequent indication for AHSCT worldwide. Less toxic conditioning regimens, as well as extension of the donor pool to include haplo-identical donors, have led to a broader utility of AHSCT, especially in older patients with MDS. While disease-specific scoring systems such as the International Prognostic Scoring System (IPSS), IPSS-Revised (IPSS-R), or World Health Organization (WHO) Prognostic Scoring System (WPSS) have been used to select patients for AHSCT, new transplant-specific scoring systems have been developed to determine outcome after AHSCT, which include also transplant- and patient-related factors that determine more precisely outcome and allows to balance more properly the risk of relapse and non-relapse mortality. More recent studies suggested beside cytogenetics also a major impact of molecular genetics on outcome after AHSCT, mainly for p53 and RAS pathway mutations, which are currently not included in any available risk score. The risk of clonal evolution and the known poor outcome of worse cytogenetics and molecular mutations argue to perform AHSCT at an earlier stage of the disease, which is supported by an IPSS-R-based multistate model that recommends AHSCT at IPSS-R intermediate-risk stage.
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- 2017
22. CD25 Blockade Delays Regulatory T Cell Reconstitution and Does Not Prevent Graft-versus-Host Disease After Allogeneic Hematopoietic Cell Transplantation
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Niels Jacobsen, Francisca Beato, Frederick L. Locke, Michael A. Pulsipher, Thomas R. Chauncey, Susan Light, Nicolaus Kröger, Gérard Socié, Claudio Anasetti, Armand Keating, Bronwen E. Shaw, Paul J. Martin, Ginna G. Laport, Barry E. Storer, Joseph Pidala, Irwin Walker, and Auayporn Nademanee
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Adult ,Male ,0301 basic medicine ,Daclizumab ,Adolescent ,Regulatory T cell ,medicine.medical_treatment ,T cell ,Graft vs Host Disease ,chemical and pharmacologic phenomena ,Hematopoietic stem cell transplantation ,Antibodies, Monoclonal, Humanized ,T-Lymphocytes, Regulatory ,Article ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Double-Blind Method ,medicine ,Humans ,Transplantation, Homologous ,IL-2 receptor ,Child ,Transplantation ,business.industry ,Hematopoietic Stem Cell Transplantation ,Interleukin-2 Receptor alpha Subunit ,Infant ,FOXP3 ,Hematology ,Middle Aged ,medicine.disease ,CD4 Lymphocyte Count ,030104 developmental biology ,medicine.anatomical_structure ,Graft-versus-host disease ,Child, Preschool ,Immunoglobulin G ,Immunology ,Female ,business ,030215 immunology ,medicine.drug - Abstract
Daclizumab, a humanized monoclonal antibody, binds CD25 and blocks formation of the IL-2 receptor on T cells. A study of daclizumab as acute graft-versus-host disease (GVHD) prophylaxis after unrelated bone marrow transplantation was conducted before the importance of CD25+FOXP3+ regulatory T cells (Tregs) was recognized. Tregs can abrogate the onset of GVHD. The relation between Tregs and a graft-versus-malignancy effect is not fully understood. An international, multicenter, double-blind clinical trial randomized 210 adult or pediatric patients to receive 5 weekly doses of daclizumab at 0.3 mg/kg (n = 69) or 1.2 mg/kg (n = 76) or placebo (n = 65) after unrelated marrow transplantation for treatment of hematologic malignancies or severe aplastic anemia. The risk of acute GVHD did not differ among the groups (P = .68). Long-term follow-up of clinical outcomes and correlative analysis of peripheral blood T cell phenotype suggested that the patients treated with daclizumab had an increased risk of chronic GVHD (hazard ratio [HR], 1.49; 95% confidence interval [CI], 1.0 to 2.3; P = .08) and a decreased risk of relapse (HR, 0.57; 95% CI, 0.3 to 1.0; P = .05), but similar survival (HR, 0.89; 95% CI, 0.6 to 1.3; P = .53). T cells from a subset of patients (n = 107) were analyzed by flow cytometry. Compared with placebo, treatment with daclizumab decreased the proportion of Tregs among CD4 T cells at days 11-35 and increased the proportion of central memory cells among CD4 T cells at 1 year. Prophylactic administration of daclizumab does not prevent acute GVHD, but may increase the risk of chronic GVHD and decrease the risk of relapse. By delaying Treg reconstitution and promoting immunologic memory, anti-CD25 therapy may augment alloreactivity and antitumor immunity.
- Published
- 2017
23. Obituary Rolf Neth 1926–2020
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Carol Stocking, Axel R. Zander, Nicolaus Kröger, and Boris Fehse
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Cancer Research ,Philosophy ,Genetics ,Art history ,Cell Biology ,Hematology ,Obituary ,Molecular Biology - Published
- 2020
24. Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Acute Lymphoblastic Leukemia and Poor Karnofsky Performance Status. a Study from the Acute Leukemia Working Party (ALWP) of the European Society for Blood and Marrow Transplantation (EBMT)
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Riitta Niittyvuopio, Nicolaus Kröger, Eolia Brissot, Stephen P. Robinson, Myriam Labopin, Péter Reményi, Edouard Forcade, Gérard Socié, Arnon Nagler, Mohamad Mohty, Thierry Lamy, Bipin N. Savani, Paul Browne, Francesco Saraceni, Ibrahim Yakoub-Agha, and Jan J. Cornelissen
- Subjects
Transplantation ,medicine.medical_specialty ,education.field_of_study ,Acute leukemia ,Multivariate analysis ,business.industry ,Lymphoblastic Leukemia ,Incidence (epidemiology) ,medicine.medical_treatment ,Population ,Retrospective cohort study ,Hematology ,Hematopoietic stem cell transplantation ,surgical procedures, operative ,hemic and lymphatic diseases ,Internal medicine ,medicine ,In patient ,business ,education - Abstract
Recently, an increasing number of patients with acute lymphoblastic leukemia with a poor Karnofsky Performance Status (KPS) score are considered for allogeneic hematopoietic stem cell transplantation (allo-HCT). Nevertheless, there is paucity of available data about outcome of this fragile population. We report here the results of a retrospective study designed to evaluate outcome of ALL patients undergoing allo-HCT with KPS score ≤80%. The analysis included ALL patients aged ≥18 years, undergoing allo-HCT in first remission between 2000 and 2018, with a KPS score of 50% to 80% at the time of transplant. A total of 1,010 patients were identified. Median age at transplant was 43 years (18-76 years). Median year of transplant was 2011. The KPS score was =80% in 83% of the patients and On multivariate analysis, transplant from 10/10 UD was associated with higher incidence of aGVHD (HR 1.8, p In conclusion, allo-HCT is feasible in patients with acute lymphoblastic leukemia in first remission and KPS score ≤80%, with acceptable NRM and survival rates. Transplant from a MSD was associated with reduced risk of NRM and aGVHD as compared to 10/10 UD. Interestingly, despite the poor KPS score of the patients included in the analysis, a MAC protocol was associated with similar NRM, lower relapse and better LFS and GRFS as compared to RIC in the selected population. Finally, administration of ATG was associated with reduced acute and chronic GVHD rates.
- Published
- 2020
25. Allogeneic Stem Cell Transplantation for AML Patients with RUNX1 Mutation in First Complete Remission: A Study on Behalf of the ALWP of the EBMT
- Author
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Dietrich W. Beelen, Montserrat Rovira, Arnon Nagler, Tobias Gedde-Dahl, Johanna Waidhauser, Nicolaus Kröger, Gwendolyn Van Gorkom, Jürgen Finke, Christoph Schmid, Myriam Labopin, Eefke Petersen, Jordi Esteve, Nicolaas Schaap, Mohamad Mohty, Donald Bunjes, and Jan J. Cornelissen
- Subjects
Oncology ,Transplantation ,medicine.medical_specialty ,Acute leukemia ,NPM1 ,business.industry ,Myeloid leukemia ,Retrospective cohort study ,Hematology ,medicine.disease ,Log-rank test ,Leukemia ,hemic and lymphatic diseases ,Internal medicine ,embryonic structures ,CEBPA ,medicine ,ddc:610 ,business - Abstract
Introduction Acute myeloid leukemia bearing a RUNX1 gene mutation (RUNX1+ AML) has been proposed as a provisional entity in the 2016 WHO classification. Clinically, it has been associated with inferior response rates and outcome after conventional chemotherapy. Accordingly, RUNX1+ AML is allocated in the unfavorable prognostic category of the 2017 European Leukemia Net classification. Following allogeneic stem cell transplantation (alloSCT), RUNX1 was an unfavorable factor in one study in MDS/secondary AML, while data in de novo AML are scarce. Objectives Here, we present a retrospective study by the EBMT Acute Leukemia Working Party, aiming to elucidate the prognostic value of RUNX1 mutation in patients undergoing alloSCT for AML in first complete remission (CR1). Methods Adults undergoing alloSCT for AML in CR1 from matched related or unrelated donors between 2013 and 2018 with complete information on conventional cytogenetics and RUNX1 mutational status were selected from the EBMT registry. Variables of interest were overall and leukemia-free survival (OS/LFS), GvHD/relapse free survival (GRFS), cumulative relapse incidence (RI), non-relapse mortality (NRM) and GvHD. Log rank test, Gray test and Cox regression models were used. Results 128 RUNX+ and 388 RUNX- patients were identified, >80% of both subgroups presenting as de novo AML. As expected, RUNX1+ patients rarely had co-mutations in NPM1 (6% vs. 26%, p=10−3), and showed a positive correlation with ASXL1 mutations (50% vs. 16%, p=10−4). Cytogenetic categories and other mutations (FLT3-ITD, CEBPA) were equally distributed between the two groups, as were age, donor and graft type, CMV, conditioning and T cell depletion (TCD). Median follow-up was 16.4 (RUNX+) and 19.8 (RUNX-) months. 2y OS/LFS of the entire cohort were 64% [59-69]/57% [52-62], with no difference between RUNX1+ and RUNX1- patients either in univariate or multivariate analysis (2y OS: 67.9% [57.3-78.5] vs. 63.1%v[57.4-68.7]p=0.15; 2y LFS: 57.6% [46.4-68.7] vs. 57% [51.4-62.6], p=0.38], figure 1). RUNX1 mutation neither had any impact among patients with normal karyotype (figure 2). Similarly, no other outcome parameter was influenced by RUNX1 mutational status. Instead, multivariate analysis revealed age and donor type as risk factors for OS, LFS and NRM. Poor cytogenetic was associated with higher RI and inferior LFS/GRFS, in vivo TCD with a lower rate of aGvHD II-IV, cGvHD, and better GRFS. Among patients with available information, FLT3-ITD was an independent risk factor for relapse, LFS and GRFS. RUNX1 did not modify the role of FLT3-ITD. Conclusion Within the limits of a retrospective registry analysis, we could not find a negative influence of RUNX1 mutation on outcome after allogeneic SCT in CR1. Hence, transplantation in CR1 might overcome the unfavorable prognostic value of RUNX1 mutation and can be recommended as consolidation treatment in this entity.
- Published
- 2020
26. Long-Term Survival Benefit after Allogeneic Hematopoietic Cell Transplantation for Chronic Myelomonocytic Leukemia
- Author
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Nico Gagelmann, Friedrich Stölzel, Christina Rautenberg, Michael Koldehoff, Ulrich Germing, Thomas Luft, Victoria Panagiota, Markus Ditschkowski, Thomas Schroeder, Uwe Platzbecker, Rashit Bogdanov, Jürgen Finke, Michael Heuser, Maximilian Christopeit, Heiko Becker, Guido Kobbe, Nicolaus Kröger, Aleksandar Radujkovic, and Dietrich W. Beelen
- Subjects
Oncology ,medicine.medical_specialty ,Scoring system ,Medizin ,Chronic myelomonocytic leukemia ,Lower risk ,hemic and lymphatic diseases ,Internal medicine ,Long term survival ,medicine ,Humans ,Transplantation, Homologous ,Immunology and Allergy ,Prospective Studies ,Aged ,Retrospective Studies ,Transplantation ,Hematopoietic cell ,business.industry ,Hematopoietic Stem Cell Transplantation ,Leukemia, Myelomonocytic, Chronic ,Retrospective cohort study ,Cell Biology ,Hematology ,medicine.disease ,surgical procedures, operative ,Molecular Medicine ,Risk assessment ,business - Abstract
The critical question in the management of chronic myelomonocytic leukemia (CMML) is which patients may benefit from allogeneic hematopoietic cell transplantation (allo-HCT). Using ad hoc statistical analysis, we designed a multicenter retrospective study to determine outcomes in 261 patients age ≤70 years at diagnosis who underwent allo-HCT (n = 119) compared with those who did not (n = 142) according to the current CMML-specific prognostic scoring system (CPSS). Categorizing patients as lower risk (CPSS low/intermediate-1) or higher risk (intermediate-2/high) showed significantly improved outcomes after transplantation in higher-risk patients, with a 37% reduced hazard for death. However, although higher CPSS was associated with worse outcomes in the nontransplantation group, the score was of limited utility for post-transplantation risk stratification. This study may provide further support for the potentially beneficial role of allo-HCT in terms of long-term survival in higher-risk patients but also underscores the need for transplantation-specific risk assessment. Recognizing limitations of retrospective comparisons, larger and prospective comparisons are needed to further refine the indication for allo-HCT and thus counseling of patients with CMML. © 2020 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.
- Published
- 2021
27. Cytokine Expression Pattern in Bone Marrow Microenvironment after Allogeneic Stem Cell Transplantation in Primary Myelofibrosis
- Author
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Kais Hussein, Hans Kreipe, Nicolaus Kröger, Angelika Stucki-Koch, Ioanna Triviai, and Haefaa Alchalby
- Subjects
Adult ,Male ,0301 basic medicine ,medicine.medical_treatment ,Hematopoietic stem cell transplantation ,03 medical and health sciences ,0302 clinical medicine ,Bone Marrow ,medicine ,Humans ,Transplantation, Homologous ,Myelofibrosis ,Multiple myeloma ,Aged ,Retrospective Studies ,Platelet-Derived Growth Factor ,Extracellular Matrix Proteins ,Transplantation ,business.industry ,Growth factor ,Hematopoietic Stem Cell Transplantation ,Tissue Inhibitor of Metalloproteinases ,Hematology ,Middle Aged ,medicine.disease ,Hematopoiesis ,Haematopoiesis ,030104 developmental biology ,medicine.anatomical_structure ,Cellular Microenvironment ,Gene Expression Regulation ,Primary Myelofibrosis ,Case-Control Studies ,030220 oncology & carcinogenesis ,Immunology ,Cancer research ,Cytokines ,Female ,Bone marrow ,Stem cell ,Multiple Myeloma ,business - Abstract
The only curative therapy for primary myelofibrosis (PMF) is allogeneic stem cell transplantation (ASCT). However, although we know that patients can benefit from ASCT, we do not know the extent of the changes of the expression profile of cytokines and matrix modulation factors. In this first systematic analysis, we evaluated the expression profile of 103 factors before and after transplantation to identify potential biomarkers. The expression of fibrosis-, inflammation-, and angiogenesis-associated genes was analyzed in a total of 52 bone marrow biopsies: PMF patients (n = 14) before and after ASCT and, for control purposes, post-ASCT multiple myeloma patients (n = 14) and non-neoplastic hematopoiesis (n = 10). In post-ASCT PMF cases, decreased expression of tissue inhibitor of metalloproteinases (TIMP) and platelet-derived growth factor alpha (PDGFA) correlated with bone marrow remodeling and hematological remission. Expression of several other matrix factors remained at high levels and may contribute to post-ASCT remodeling. This is the first systematic analysis of cytokine expression in post-ASCT PMF bone marrow that shows that normalization of bone marrow microenvironment is paralleled by decreased expression of TIMP and PDGFA.
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- 2016
28. Economics and Outcome After Hematopoietic Stem Cell Transplantation: A Retrospective Cohort Study
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Michael Gratwohl, Dietger Niederwieser, Anna Sureda, Theo Stijnen, Alois Gratwohl, Eoin McGrath, Mohamad Mohty, Alessandro Rambaldi, Arnon Nagler, Jakob Passweg, Nicolaus Kröger, Peter Dreger, Carmen Ruiz de Elvira, John A. Snowden, Per Ljungman, Helen Baldomero, Marrow Transplantation, Jane F. Apperley, and Ronald Brand
- Subjects
HDI ,medicine.medical_specialty ,Pathology ,Outcome assessment (Medical care) ,Multivariate analysis ,Right to health care ,Survival ,Program duration ,medicine.medical_treatment ,Macroeconomics ,lcsh:Medicine ,Hematopoietic stem cell transplantation ,Stem cells ,Disease ,HCE/cap ,General Biochemistry, Genetics and Molecular Biology ,Patient volume ,Internal medicine ,Dret a la salut ,Microeconomics ,medicine ,Young adult ,Outcome ,Risk assessment ,Public health ,lcsh:R5-920 ,business.industry ,lcsh:R ,Retrospective cohort study ,General Medicine ,Center effect ,Salut pública ,surgical procedures, operative ,Cohort ,Avaluació de resultats (Assistència mèdica) ,Cèl·lules mare ,lcsh:Medicine (General) ,Complication ,business ,GNI/cap - Abstract
© 2015 The Authors.Hematopoietic stem cell transplantation (HSCT) is a lifesaving expensive medical procedure. Hence, more transplants are performed in more affluent countries. The impact of economic factors on patient outcome is less defined. We analyzed retrospectively a defined cohort of 102,549 patients treated with an allogeneic (N = 37,542; 37%) or autologous (N = 65,007; 63%) HSCT. They were transplanted by one of 404 HSCT centers in 25 European countries between 1999 and 2006. We searched for associations between center-specific microeconomic or country-specific macroeconomic factors and outcome. Center patient-volume and center program-duration were significantly and systematically associated with improved survival after allogeneic HSCT (HR 0·87; 0·84-0·91 per 10 patients; p < 0·0001; HR 0·90;0·85-0·90 per 10 years; p < 0·001) and autologous HSCT (HR 0·91;0·87-0·96 per 10 patients; p < 0·001; HR 0·93;0·87-0·99 per 10 years; p = 0·02). The product of Health Care Expenditures by Gross National Income/capita was significantly associated in multivariate analysis with all endpoints (R2 = 18%; for relapse free survival) after allogeneic HSCT. Data indicate that country- and center-specific economic factors are associated with distinct, significant, systematic, and clinically relevant effects on survival after HSCT. They impact on center expertise in long-term disease and complication management. It is likely that these findings apply to other forms of complex treatments.
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- 2015
29. Reduced-Intensity Allografting as First Transplantation Approach in Relapsed/Refractory Grades One and Two Follicular Lymphoma Provides Improved Outcomes in Long-Term Survivors
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David G. Maloney, Jonathon B. Cohen, Siddhartha Ganguly, Andreas K. Klein, Veronika Bachanova, Alan M. Miller, Hillard M. Lazarus, Jeanette Carreras, Ulrike Bacher, Kwang Woo Ahn, Shimon Slavin, Cesar O. Freytes, Mark Hertzberg, Nicolaus Kröger, Leona Holmberg, Grace H. Ku, Saad Z. Usmani, Alberto Mussetti, Ravi Vij, Robert Peter Gale, Mohamed A. Kharfan-Dabaja, Ginna G. Laport, William A. Wood, Evgeny Klyuchnikov, Anita D'Souza, Parameswaran Hari, Asad Bashey, Sonali M. Smith, Anna Sureda, Mehdi Hamadani, and Richard F. Olsson
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Male ,Oncology ,Transplantation Conditioning ,medicine.medical_treatment ,Follicular lymphoma ,Hematopoietic stem cell transplantation ,Recurrence ,immune system diseases ,hemic and lymphatic diseases ,Long-time survival ,Longitudinal Studies ,Survivors ,Lymphoma, Follicular ,Hematology ,Hematopoietic Stem Cell Transplantation ,Middle Aged ,3. Good health ,Treatment Outcome ,surgical procedures, operative ,Disease Progression ,Female ,Rituximab ,medicine.drug ,Adult ,Grade 1 and 2 follicular lymphoma ,medicine.medical_specialty ,Reduced-intensity allogeneic hematopoietic cell transplantation ,Antineoplastic Agents ,Transplantation, Autologous ,Article ,Refractory ,Autologous hematopoietic cell transplantation ,Internal medicine ,medicine ,Humans ,Transplantation, Homologous ,Survival analysis ,Aged ,Transplantation ,business.industry ,Myeloablative Agonists ,medicine.disease ,Survival Analysis ,Surgery ,Drug Resistance, Neoplasm ,Neoplasm Grading ,business - Abstract
This study was conducted to compare long-term outcomes in patients with refractory/relapsed grades 1 and 2 follicular lymphoma (FL) after allogeneic (allo) versus autologous (auto) hematopoietic cell transplantation (HCT) in the rituximab era. Adult patients with relapsed/refractory grades 1 and 2 FL undergoing first reduced-intensity allo-HCT or first autograft during 2000 to 2012 were evaluated. A total of 518 rituximab-treated patients were included. Allo-HCT patients were younger and more heavily pretreated, and more patients had advanced stage and chemoresistant disease. The 5-year adjusted probabilities, comparing auto-HCT versus allo-HCT groups for nonrelapse mortality (NRM) were 5% versus 26% (P < .0001); relapse/progression: 54% versus 20% (P < .0001); progression-free survival (PFS): 41% versus 58% (P < .001), and overall survival (OS): 74% versus 66% (P = .05). Auto-HCT was associated with a higher risk of relapse/progression beyond 5 months after HCT (relative risk [RR], 4.4; P < .0001) and worse PFS (RR, 2.9; P < .0001) beyond 11 months after HCT. In the first 24 months after HCT, auto-HCT was associated with improved OS (RR, .41; P < .0001), but beyond 24 months, it was associated with inferior OS (RR, 2.2; P = .006). A landmark analysis of patients alive and progression-free at 2 years after HCT confirmed these observations, showing no difference in further NRM between both groups, but there was significantly higher risk of relapse/progression (RR, 7.3; P < .0001) and inferior PFS (RR, 3.2; P < .0001) and OS (RR, 2.1; P = .04) after auto-HCT. The 10-year cumulative incidences of second hematological malignancies after allo-HCT and auto-HCT were 0% and 7%, respectively. Auto-HCT and reduced-intensity–conditioned allo-HCT as first transplantation approach can provide durable disease control in grades 1 and 2 FL patients. Continued disease relapse risk after auto-HCT translates into improved PFS and OS after allo-HCT in long-term survivors.
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- 2015
30. Treosulfan Conditioning for Allogeneic Transplantation in Multiple Myeloma – Improved Overall Survival in first line Hematopoietic Stem Cell Transplantation
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Gösta Gahrton, Hareth Nahi, Didier Blaise, Dietrich W. Beelen, Laure Vincent, Junfeng Wang, Ellen Meier, Eefke Petersen, Per Ljungman, Christine Wolschke, Riitta Niittyvoupio, Noel Milpied, Nicolaus Kröger, Hendrik Veelken, Ibrahim Yakoub-Agha, Linda Koster, Friedrich Stölzel, Dietger Niederwieser, Liesbeth C. de Wreede, Jürgen Finke, Jean Bourhis, Charlotte Gran, Hermann Einsele, Jakob Passweg, Armin Gerbitz, Stefan Schoenland, Laurent Garderet, and Matthias Stelljes
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Oncology ,Cancer Research ,medicine.medical_specialty ,Allogeneic transplantation ,business.industry ,First line ,medicine.medical_treatment ,Medizin ,Hematology ,Hematopoietic stem cell transplantation ,Treosulfan ,medicine.disease ,Internal medicine ,medicine ,Overall survival ,business ,Multiple myeloma ,medicine.drug - Published
- 2019
31. Outcome of a Salvage Third Autologous Stem Cell Transplantation in Multiple Myeloma
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Mariella Grasso, Jan-Erik Johansson, Nicolaus Kröger, Kerstin Schäfer-Eckart, Didier Blaise, Xavier Leleu, Jakub Radocha, Denis Caillot, Michael Potter, Christian Koenecke, Jean Bourhis, David Pohlreich, Herman Einsele, Christian Peschel, Marta Krejčí, Laurent Garderet, Stefan Schönland, Bernd Metzner, Linda Koster, Simona Iacobelli, Pascal Lenain, Marco Ladetto, Hartmut Goldschmidt, Service d'hépatologie [CHU Saint-Antoine], CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), University of Rome TorVergata, European Society for Blood and Marrow Transplantation (EBMT), Heidelberg University, Department of Hematology (Sahlgrenska University Hospital, Goeteborg), Sahlgrenska University Hospital, Département d'hématologie [Gustave Roussy], Institut Gustave Roussy (IGR), University Hospital Brno, Facteurs de persistance des cellules leucémique - Equipe 3 (INSERM U 837), Département d'Hématologie [CHU Poitiers], Centre hospitalier universitaire de Poitiers (CHU Poitiers), Department of Hematology (Royal Marsden Hospital), The Royal Marsden Hospital, Service d’Hématologie [Institut Paoli Calmettes, Marseille], Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Hannover Medical School [Hannover] (MHH), Department of Hematology (Klinkum Rechts der Isar), Klinkum Rechts der Isar, Department of Hematology (Charles University Hospital, Hradec Králové), Charles University Hospital, Department of Hematology (Klinikum Oldenburg, Oldenburg), Klinikum Oldenburg, Service d'Hématologie (CRLCC Henri Becquerel), Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), Department of Hematology (Klinikum Nürnberg, Nürnberg), Klinikum Nürnberg Nord, Department of Hematology (Charles University Hospital, Prague), Department of Hematology (Azienda Ospedaliera S Croce e Carle, Cuneo), Azienda Ospedaliera S. Croce e Carle, Service d'Hématologie Clinique (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Department of Internal Medicine II (Universitätsklinikum Würzburg), Universitätsklinikum Würzburg, Hematology Division, Azienda Ospedaliera Santi Antonio e Biagio e Cesare Arrigo, Department of Hematology (Azienda Ospedaliera SS Antonio e Biagio, Alessandria), Azienda Ospedaliera SS Antonio e Biagio, Heidelberg University Hospital [Heidelberg], and Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] (UKE)
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Adult ,Male ,medicine.medical_specialty ,Transplantation Conditioning ,medicine.medical_treatment ,Salvage therapy ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Hematopoietic stem cell transplantation ,Malignancy ,Transplantation, Autologous ,Settore MED/01 - Statistica Medica ,03 medical and health sciences ,0302 clinical medicine ,Autologous stem-cell transplantation ,Autologous hematopoietic cell transplantation ,Humans ,Medicine ,In patient ,Relapse ,Multiple myeloma ,Aged ,Salvage Therapy ,Transplantation ,business.industry ,Incidence (epidemiology) ,Hematopoietic Stem Cell Transplantation ,Hematology ,Middle Aged ,medicine.disease ,3. Good health ,Surgery ,ddc ,Treatment Outcome ,030220 oncology & carcinogenesis ,Female ,Multiple Myeloma ,business ,Autologous ,030215 immunology - Abstract
IF 4.484 (2017); International audience; To evaluate the outcomes of salvage third autologous stem cell transplantation (ASCT) in patients with relapsed multiple myeloma. We analyzed 570 patients who had undergone a third ASCT between 1997 and 2010 (European Society for Blood and Marrow Transplantation data), of whom 482 patients underwent tandem ASCT and a third ASCT at first relapse (AARA group) and 88 patients underwent an upfront ASCT with second and third transplantations after subsequent relapses (ARARA group). With a median follow-up after salvage third ASCT of 61 months in the AARA group and 48 months in the ARARA group, the day +100 nonrelapse mortality in the 2 groups was 4% and 7%, the incidence of second primary malignancy was 6% and 7%, the median progression-free survival was 13 and 8 months, and median overall survival (OS) was 33 and 15 months. In the AARA group, according to the relapse-free interval (RFI) from the second ASCT, the median OS after the third ASCT was 17 months if the RFI was
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- 2018
32. Anti-T Lymphocyte Globulin (ATLG) Improves Quality of Life (QoL) and Chronic Graft vs Host Disease and Relapse Free Survival (GRFS) after Allogeneic Hematopoietic Stem Cell Transplantation from Hla-Identical Sibling in Acute Myeloid Leukemia: Final Results of QoL and Long-Term Outcome Analysis of a Phase 3 Randomized Study
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Francesca Bonifazi, Carlos Solano, Christine Wolschke, Mariarosaria Sessa, Francesca Patriarca, Francesco Zallio, Arnon Nagler, Carmine Selleri, Antonio Maria Risitano, Giuseppe Messina, Wolfgang Bethge, Pilar Herrera, Anna Sureda, Angelo Michelle Carella, Michele Cimminiello, Stefano Guidi, Jürgen Finke, Roberto Sorasio, Christelle Ferra, Jorge Sierra, Domenico Russo, Edoardo Benedetti, Giuseppe Milone, Fabio Benedetti, Marion Heinzelmann, Domenico Pastore, Manuel Jurado, Elisabetta Terruzzi, Franco Narni, Andreas Völp, Francis Ayuk, Tapani Ruutu, and Nicolaus Kröger
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- 2018
33. Janus Kinase Inhibitors and Allogeneic Stem Cell Transplantation for Myelofibrosis
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Jerald P. Radich, Vikas Gupta, Damiano Rondelli, H. Joachim Deeg, Nicolaus Kröger, Srdan Verstovsek, and Jason Gotlib
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Homologous ,Oncology ,medicine.medical_specialty ,Transplantation Conditioning ,medicine.medical_treatment ,Context (language use) ,INCB018424 ,Hematopoietic stem cell transplantation ,Article ,Internal medicine ,Medicine ,Humans ,Transplantation, Homologous ,Myelofibrosis ,Janus Kinases ,Transplantation ,Janus kinase 1 ,business.industry ,Hematopoietic Stem Cell Transplantation ,Janus Kinase 1 ,Hematology ,medicine.disease ,Primary Myelofibrosis ,Immunology ,Stem cell ,business ,Janus kinase - Abstract
Myelofibrosis (MF) is a manifestation of several disorders of hematopoiesis, collectively referred to as myeloproliferative neoplasms. Allogeneic hematopoietic stem cell transplantation (ASCT) is the only therapy with proven curative potential. However, most patients with MF are in their 6th or 7th decade of life, and only some of these patients have been considered suitable transplantation candidates. The development of reduced-intensity conditioning regimens with limited toxicity has allowed clinicians to offer ASCT to a growing number of older patients. The availability of Janus Kinase (JAK) 1/2 inhibitors allows clinicians to provide symptom relief and improved quality of life for MF patients. These drugs may also affect the decision regarding, in particular, the timing of ASCT. Future studies need to address the role of JAK1/2 inhibitors in patients who are transplantation candidates and determine their role before and, possibly, after transplantation. The identification of indications for the use of JAK1/2 inhibitors in the context of transplantation may lead to new therapeutic strategies for patients with MF.
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- 2014
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34. Allogeneic Stem Cell Transplant vs. Janus Kinase Inhibition in the Treatment of Primary Myelofibrosis or Myelofibrosis After Essential Thrombocythemia or Polycythemia Vera
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Nicolaus Kröger and Haefaa Alchalby
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Oncology ,Cancer Research ,Ruxolitinib ,medicine.medical_specialty ,medicine.medical_treatment ,Hematopoietic stem cell transplantation ,Polycythemia vera ,Internal medicine ,medicine ,Humans ,Transplantation, Homologous ,Myelofibrosis ,Polycythemia Vera ,Protein Kinase Inhibitors ,Janus Kinases ,Janus kinase 2 ,biology ,Essential thrombocythemia ,business.industry ,Hematopoietic Stem Cell Transplantation ,Hematology ,medicine.disease ,Extramedullary hematopoiesis ,Primary Myelofibrosis ,Immunology ,biology.protein ,Janus kinase ,business ,Thrombocythemia, Essential ,medicine.drug - Abstract
Primary myelofibrosis is one of the Philadelphia chromosome-negative myeloproliferative neoplasms and is the member of that group with the worst survival and the most significant limitations in quality of life. Hepatosplenomegaly due to extramedullary hematopoiesis, constitutional symptoms, and cytopenias are the main manifestations. The natural history is highly variable, and up to 30% of patients can experience acceleration to acute myelogenous leukemia. Conventional therapy is only palliative and not always effective. However, huge advances have been achieved in the past 2 decades toward a better understanding of the pathogenesis of this disease, as well as improved management. Powerful risk stratification systems are now available and can reliably separate the patients into different prognostic categories to aid clinical management. Allogeneic stem cell transplant can offer cure but is still not universally applicable owing to the treatment-related mortality and toxicity. Nevertheless, outcomes of transplant are improving, owing to the introduction of reduced-intensity conditioning regimens and the optimization of remission monitoring techniques and relapse prevention strategies. The discovery of the V617F mutation of JAK2 (Janus kinase 2) and some other molecular aberrations has shed more light on the molecular pathogenesis of the disease and has led to the introduction of novel therapies such as JAK2 inhibitors. In fact, JAK inhibitors have shown promising symptomatic efficacy, and the JAK inhibitor ruxolitinib has also shown a potential survival benefit. Future effort should be made to combine allogeneic stem cell transplant with JAK inhibition.
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- 2014
35. Dynamic of Bone Marrow Fibrosis Regression Predicts Survival after Allogeneic Stem Cell Transplantation for Myelofibrosis
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Haefaa Alchalby, Tatjana Zabelina, Natascha von Hünerbein, Hans-Michael Kvasnicka, Christine Wolschke, Guntram Büsche, Francis Ayuk, Thomas Stübig, Nicolaus Kröger, Jürgen Thiele, and Hans-Heinrich Kreipe
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Adult ,Male ,medicine.medical_specialty ,Transplantation Conditioning ,Adolescent ,Myelofibrosis ,Gastroenterology ,Young Adult ,Polycythemia vera ,Bone marrow fibrosis ,Bone Marrow ,Internal medicine ,medicine ,Humans ,Transplantation, Homologous ,Platelet ,JAK2 mutation ,Child ,Aged ,Transplantation ,Framingham Risk Score ,business.industry ,Hematopoietic Stem Cell Transplantation ,Hematology ,Middle Aged ,medicine.disease ,Regression ,Surgery ,Allogeneic stem cell transplantation ,Fibrosis regression ,International Prognostic Scoring System ,Primary Myelofibrosis ,Female ,Stem cell ,business - Abstract
We correlate regression of bone marrow fibrosis (BMF) on day 30 and 100 after dose- reduced allogeneic stem cell transplantation (allo-SCT) in 57 patients with primary or post–essential thrombocythemia/polycythemia vera myelofibrosis with graft function and survival. The distribution of International Prognostic Scoring System (IPSS) risk score categories was 1 patient with low risk, 5 patients with intermediate-1 risk, 18 patients with intermediate-2 risk, and 33 patients with high risk. Before allo-SCT, 41 patients (72%) were classified as XXX [myclofibrosis (MF)]-3 and 16 (28%) were classified as MF-2 according to the World Health Organization criteria. At postengraftment day +30 (±10 days), 21% of the patients had near-complete or complete regression of BMF (MF-0/-1), and on day +100 (±20 days), 54% were MF-0/-1. The 5-year overall survival rate at day +100 was 96% in patients with MF-0/-1 and 57% for those with MF-2/-3 (P = .04). There was no difference in BMF regression at day +100 between IPSS high-risk and low/intermediate-risk patients. Complete donor cell chimerism at day +100 was seen in 81% of patients with MF-0/-1 and in 31% of those with MF-2/-3. Patients with MF-2/-3 at day +100 were more likely to be transfusion-dependent for either RBCs (P = .014) or platelets (P = .018). Rapid BMF regression after reduced-intensity conditioning allo-SCT resulted in a favorable survival independent of IPSS risk score at transplantation.
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- 2014
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36. CD34+-Selected Stem Cell Boost without Further Conditioning for Poor Graft Function after Allogeneic Stem Cell Transplantation in Patients with Hematological Malignancies
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Didier Blaise, Michael Lioznov, Roberto Crocchiolo, Catherine Faucher, Boris Calmels, Thomas Stübig, Francis Ayuk, Nicolaus Kröger, Marie Luise Reckhaus, Jean El-Cheikh, Christine Wolschke, Ulrike Bacher, Claude Lemarie, Evgeny Klyuchnikov, Haefaa Alchalby, Sabine Furst, Andreas Sputtek, and Christian Chabannon
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Adult ,Male ,Allogeneic hematopoietic stem cell transplantation (HSCT) ,medicine.medical_specialty ,CD3 Complex ,Neutrophils ,CD34 ,Graft vs Host Disease ,Antigens, CD34 ,Severity of Illness Index ,Graft function ,Gastroenterology ,Immunophenotyping ,Internal medicine ,medicine ,Poor graft function ,Humans ,Transplantation, Homologous ,Cumulative incidence ,In patient ,Platelet ,Retrospective Studies ,Transplantation ,business.industry ,Hematopoietic Stem Cell Transplantation ,Stem cell boost ,Hematology ,Middle Aged ,Survival Analysis ,Surgery ,CD34+-selected cells ,Hematologic Neoplasms ,Acute Disease ,Chronic Disease ,Conditioning ,Female ,Stem cell ,business - Abstract
We retrospectively analyzed outcomes of a CD34(+)-selected stem cell boost (SCB) without prior conditioning in 32 patients (male/22; median age of 54 years; range, 20 to 69) with poor graft function, defined as neutrophils ≤1.5 x 10(9)/L, and/or platelets ≤30 x 10(9)/L, and/or hemoglobin ≤8.5 g/dL). The median interval between stem cell transplantation and SCB was 5 months (range, 2 to 228). The median number of CD34(+) and CD3(+) cells were 3.4 x 10(6)/kg (.96 to 8.30) and 9 x 10(3)/kg body weight (range, 2 to 70), respectively. Hematological improvement was observed in 81% of patients and noted after a median of 30 days (range, 14 to 120) after SCB. The recipients of related grafts responded faster than recipients of unrelated grafts (20 versus 30 days, P = .04). The cumulative incidence of acute (grade II to IV) and chronic graft-versus-host disease (GVHD) after SCB was 17% and 26%, respectively. Patients with acute GVHD received a higher median CD3(+) cell dose. The 2-year probability of overall survival was 45%. We suggest that SCB represents an effective approach to improve poor graft function post transplantation, but optimal timing of SCB administration, anti-infective, and GVHD prophylaxis needs further evaluation.
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- 2014
37. Immune-Modulating Drugs and Hypomethylating Agents to Prevent or Treat Relapse after Allogeneic Stem Cell Transplantation
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Djordje Atanackovic, Thomas Stübig, and Nicolaus Kröger
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Transplantation Conditioning ,medicine.medical_treatment ,T cell ,Hypomethylating agents ,Transplantation, Autologous ,Graft-versus-host disease ,Natural killer cell ,Immune system ,Recurrence ,Humans ,Medicine ,Transplantation ,biology ,business.industry ,Hematopoietic Stem Cell Transplantation ,Hematology ,medicine.disease ,Allogeneic stem cell transplantation ,Graft-versus-leukemia-effect ,Treatment Outcome ,Cytokine ,medicine.anatomical_structure ,Immune-modulatory drugs ,Immunology ,biology.protein ,Immunotherapy ,Antibody ,Stem cell ,business - Abstract
Allogeneic stem cell transplantation is a curative treatment option for many hematological diseases, and the numbers of transplantations are steadily increasing worldwide. Major progress has been made in lowering treatment-related mortality by reducing intensity of the conditioning regimen and by improving supportive care (eg, for infectious complications). Accordingly, relapse after allogeneic stem cell transplantation has become the major cause for treatment failure. Major efforts to prevent or treat relapse are focused on cellular- (T cell, natural killer cell), cytokine-, or antibody-based strategies to enhance the graft-versus-tumor effect or circumvent immunoescape. In the more recent years, new classes of agents have shown activity in several hematological malignancies, and besides their immediate antitumor activity, most of them also possess immune-modulatory qualities that may be useful alone or in combination with adoptive immunotherapy after allogeneic stem cell transplantation to enhance graft-versus-tumor effects. Here, we summarize the current knowledge and potential use of 2 of these compounds in preventing or treating relapse after allogeneic stem cell transplantation, namely immune-modulating drugs and hypomethylating agents.
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- 2014
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38. Proceedings from the National Cancer Institute’s Second International Workshop on the Biology, Prevention, and Treatment of Relapse after Hematopoietic Stem Cell Transplantation: Part III. Prevention and Treatment of Relapse after Allogeneic Transplantation
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Alan S. Wayne, Christoph Schmid, David L. Porter, Minoo Battiwalla, Nancy M. Hardy, Michael R. Bishop, Nicolaus Kröger, Marcos de Lima, and Sergio Giralt
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Oncology ,medicine.medical_specialty ,Allogeneic transplantation ,medicine.medical_treatment ,T cell ,Hematopoietic stem cell transplantation ,Donor lymphocyte infusion ,Article ,Cell therapy ,Internal medicine ,medicine ,ddc:610 ,Relapse ,Allogeneic ,Transplantation ,business.industry ,Prevention ,Stem cell transplantation ,Hematology ,Clinical trial ,Treatment ,medicine.anatomical_structure ,Immunology ,Transplantation Conditioning ,business - Abstract
In the Second Annual National Cancer Institute's Workshop on the Biology, Prevention, and Treatment of Relapse after Hematopoietic Stem Cell Transplantation, the Scientific/Educational Session on the Prevention and Treatment of Relapse after Allogeneic Transplantation highlighted progress in developing new therapeutic approaches since the first relapse workshop. Recent insights that might provide a basis for the development of novel, practical clinical trials were emphasized, including utilization of newer agents, optimization of donor lymphocyte infusion (DLI), and investigation of novel cellular therapies. Dr. de Lima discussed pre-emptive and maintenance strategies to prevent relapse after transplantation, for example, recent promising results suggestive of enhanced graft-versus-tumor activity with hypomethylating agents. Dr. Schmid provided an overview of adjunctive strategies to improve cell therapy for relapse, including cytoreduction before DLI, combination of targeted agents with DLI, and considerations in use of second transplantations. Dr. Porter addressed strategies to enhance T cell function, including ex vivo activated T cells and T cell engineering, and immunomodulatory approaches to enhance T cell function in vivo, including exogenous cytokines and modulation of costimulatory pathways.
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- 2014
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39. The Role of Measurable Residual Disease (MRD) at Time of Allogeneic Hematopoietic Cell Transplantation in Adults with Acute Lymphoblastic Leukemia Transplanted after Myeloablative Conditioning. A Study on Behalf of the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation
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Sebastian Giebel, Ibrahim Yakoub-Agha, Depei Wu, Péter Reményi, Hélène Labussière-Wallet, Mahmoud Aljurf, Jakob Passweg, Jiri Pavlu, Mohamad Mohty, Nicolaus Kröger, Dietrich W. Beelen, Arnon Nagler, Myriam Labopin, Riitta Niittyvuopio, and Gérard Socié
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Oncology ,Transplantation ,medicine.medical_specialty ,Acute leukemia ,Chemotherapy ,business.industry ,Incidence (epidemiology) ,medicine.medical_treatment ,Hazard ratio ,Hematology ,Disease ,Confidence interval ,body regions ,hemic and lymphatic diseases ,Internal medicine ,Cohort ,medicine ,business - Abstract
Assessment of measurable residual disease (MRD) is rapidly transforming the therapeutic and prognostic landscape of a wide range of hematological malignancies. Its prognostic value in acute lymphoblastic leukemia (ALL) has been established and MRD measured at the end of induction is increasingly used to guide further therapy. Although MRD detectable immediately before allogeneic hematopoietic cell transplantation (HCT) is known to be associated with poor outcomes, it is unclear if or to what extent this differs with different types of conditioning. Therefore, in this retrospective multicenter study we explored if MRD detectable before allogeneic HCT for ALL is associated with different outcomes in recipients of myeloablative TBI-based versus chemotherapy-based conditioning. We analyzed outcomes of 2780 patients (median age 38 years, range 18-72) who underwent first HCT in complete remission between 2000 and 2017 using sibling or unrelated 9/10 or 10/10 matched donors. In 1816 of these patients no disease was detectable before transplantation and in 964 patients MRD was detectable (MRD positivity). Conditioning was TBI-based in 2122 (76%) transplants. In the whole cohort MRD positivity was a significant independent factor for lower overall survival (OS) and leukemia-free survival (LFS), and for higher relapse incidence (RI), with respective hazard ratios (HR, 95% confidence intervals) of 1.19 (1.02-1.39), 1.26 (1.1-1.44), 1.51 (1.26-1.8). TBI was associated with a better OS, LFS and RI with HR of 0.75 (0.62-0.90), 0.70 (0.60-0.82) and 0.60 (0.49-0.74), respectively. No significant interaction was found between MRD status and conditioning. When investigating the impact of MRD separately in the TBI and chemotherapy-based conditioning cohorts by multivariate analysis, we found MRD positivity to be associated with lower OS (HR 1.26, 1.05-1.51) and LFS (HR 1.3,1.1-1.53), and higher RI (HR 1.53, 1.23-1.9) in the TBI group, and with higher RI (HR 1.58, 1.13-2.21) in the chemotherapy group. There was no significant association between MRD and other outcomes in this last cohort. TBI based conditioning was associated with improved OS, LFS, and RI in both MRD negative and MRD positive patients (figure). In this large study we confirmed that patients who are MRD negative prior to HCT achieve superior outcomes. This is particularly apparent if TBI conditioning is used. All patients with ALL irrespective of MRD status benefit from TBI based conditioning in myeloablative setting.
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- 2019
40. Impact of High-Risk Cytogenetics and Achievement of Molecular Remission on Long-Term Freedom from Disease after Autologous–Allogeneic Tandem Transplantation in Patients with Multiple Myeloma
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Boris Fehse, Silke Zeschke, Francis Ayuk, Axel R. Zander, Djordje Atanackovic, Thomas Stübig, Tatjana Zabelina, Christine Wolschke, Anita Badbaran, Nicolaus Kröger, Ulrike Bacher, Haefaa Alchalby, Evgeny Klyuchnikov, Timon Hansen, Georgia Schilling, Marion Heinzelmann, and Sabine Schwarz
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Adult ,Male ,Melphalan ,Unrelated donor ,medicine.medical_specialty ,Transplantation Conditioning ,Graft-versus-host disease ,Transplantation, Autologous ,Gastroenterology ,Disease-Free Survival ,Translocation, Genetic ,ASO primer ,Internal medicine ,medicine ,Humans ,Transplantation, Homologous ,Prospective Studies ,Prospective cohort study ,Multiple myeloma ,Transplantation ,business.industry ,Incidence (epidemiology) ,Remission Induction ,Hematopoietic Stem Cell Transplantation ,Plasma cell chimerism ,Induction chemotherapy ,Hematology ,Middle Aged ,Myeloablative Agonists ,Prognosis ,medicine.disease ,Surgery ,Fludarabine ,Treatment Outcome ,Cytogenetic Analysis ,Female ,Multiple Myeloma ,business ,Vidarabine ,medicine.drug - Abstract
Within a prospective protocol, the incidence and impact of achievement of molecular remission (mCR) and high-risk cytogenetics was investigated in 73 patients with multiple myeloma (MM) after autologous (auto)–allogeneic (allo) tandem stem cell transplantation (SCT). After induction chemotherapy, patients received melphalan 200 mg/m2 before undergoing auto-SCT, followed 3 months later by melphalan 140 mg/m2 and fludarabine 180 mg/m2 before allo-SCT. Sixteen patients had high-risk cytogenetic features, defined by positive FISH for del(17p13) and/or t(4;14). Overall, 66% of the patients achieved CR or near-CR, and 41% achieved mCR, which was sustained negative (at least 4 consecutive samples negative) in 15 patients (21%), with no significant difference in incidence between the patients with high-risk cytogenetics and others (P = .70). After a median follow-up of 6 years, overall 5-year progression-free survival was 29%, with no significant difference between del 17p13/t(4;14)-harboring patients and others (24% versus 30%; P = .70). The 5-year progression-free survival differed substantially according to the achieved remission: 17% for partial remission, 41% for CR, 57% for mCR, and 85% for sustained mCR. These results suggest that auto–allo tandem SCT may overcome the negative prognostic effect of del(17p13) and/or t(4;14) and that achievement of molecular remission resulted in long-term freedom from disease.
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- 2013
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41. Minimal Residual Disease following Allogeneic Hematopoietic Stem Cell Transplantation
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Koichi Miyamura, Nicolaus Kröger, and Michael R. Bishop
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Oncology ,medicine.medical_specialty ,Neoplasm, Residual ,medicine.medical_treatment ,Lymphoproliferative disorders ,Context (language use) ,Antineoplastic Agents ,Hematopoietic stem cell transplantation ,Immunotherapy, Adoptive ,Article ,Recurrence ,Internal medicine ,hemic and lymphatic diseases ,medicine ,Humans ,Transplantation, Homologous ,Relapse ,Allogeneic ,Transplantation ,business.industry ,Minimal residual disease ,Hematopoietic Stem Cell Transplantation ,Cancer ,Myeloid leukemia ,Hematology ,medicine.disease ,Lymphoproliferative Disorders ,body regions ,Clinical research ,Graft-versus-tumor ,Hematologic Neoplasms ,Immunology ,business ,DLI - Abstract
Minimal residual disease (MRD), both before and after transplantation, is a clinically important yet relatively poorly defined aspect of allogeneic hematopoietic stem cell transplantation (alloHSCT). The clinical relevance of MRD in the context of alloHSCT has been demonstrated by its association with the development of clinical relapse. However, with the possible exception of chronic myeloid leukemia (CML), the specific techniques, timing, frequency, and clinical utility, relative to improvement in patient outcomes, for monitoring MRD in the setting of alloHSCT has yet to be clearly defined. A concise overview of monitoring techniques for detecting MRD, as well as treatment strategies and biological and clinical research initiatives for MRD suggested by the National Cancer Institute First International Workshop on the Biology, Prevention, and Treatment of Relapse after Allogeneic Hematopoietic Stem Cell Transplantation, is covered in this article.
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- 2011
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42. NCI First International Workshop on the Biology, Prevention, and Treatment of Relapse after Allogeneic Hematopoietic Stem Cell Transplantation: Report from the Committee on Disease-Specific Methods and Strategies for Monitoring Relapse Following Allogeneic Stem Cell Transplantation. Part II: Chronic Leukemias, Myeloproliferative Neoplasms, and Lymphoid Malignancies
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Nicolaus Kröger, Sergio Giralt, Julie M. Vose, Issa F. Khouri, Alan S. Wayne, Ulrike Bacher, Michael J. Borowitz, Peter Dreger, Sebastian Böttcher, Daniel J. Weisdorf, Peter Bader, Andre Willasch, Wendy Stock, Eduardo Olavarria, Jerald P. Radich, and Michael R. Bishop
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Transplantation ,medicine.medical_specialty ,medicine.diagnostic_test ,business.industry ,Minimal residual disease ,medicine.medical_treatment ,Hematology ,Disease ,Hematopoietic stem cell transplantation ,Chimerism ,Allogeneic stem cell transplantation ,Myeloproliferative neoplasms, and lymphoid malignancies ,Molecular genetics ,Immunology ,Chronic leukemias ,Medicine ,Clinical significance ,Stem cell ,business ,Fluorescence in situ hybridization - Abstract
Relapse has become the major cause of treatment failure after allogeneic hematopoietic stem cell transplantation. Outcome of patients with clinical relapse after transplantation generally remains poor, but intervention prior to florid relapse improves outcome for certain hematologic malignancies. To detect early relapse or minimal residual disease, sensitive methods such as molecular genetics, tumor-specific molecular primers, fluorescence in situ hybridization (FISH), and multiparameter flow cytometry (MFC) are commonly used after allogeneic stem cell transplantation to monitor patients, but not all of them are included in the commonly employed disease-specific response criteria. The highest sensitivity and specificity can be achieved by molecular monitoring of tumor- or patient-specific markers measured by polymerase chain reaction-based techniques, but not all diseases have such targets for monitoring. Similar high sensitivity can be achieved by determination of recipient-donor chimerism, but its specificity regarding detection of relapse is low and differs substantially among diseases. Here, we summarize the current knowledge about the utilization of such sensitive monitoring techniques in chronic leukemias, myeloproliferative neoplasms, and lymphoid malignancies based on tumor-specific markers and cell chimerism and how these methods might augment the standard definitions of posttransplant remission, persistence, progression, relapse, and the prediction of relapse. Critically important is the need for standardization of the different residual disease techniques and to assess the clinical relevance of minimal residual disease and chimerism surveillance in individual diseases, which in turn must be followed by studies to assess the potential impact of specific interventional strategies.
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- 2010
43. Expression and prognostic relevance of MAGE-C1/CT7 and MAGE-C2/CT10 in osteolytic lesions of patients with multiple myeloma
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Djordje Atanackovic, Andreas H. Marx, Guido Sauter, Tim Luetkens, Caroline Pabst, Frank Jacobsen, Carsten Bokemeyer, Jozef Zustin, Nicolaus Kröger, and Georgia Schilling
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Male ,endocrine system ,Pathology ,medicine.medical_specialty ,Osteolysis ,Clinical Biochemistry ,Pathology and Forensic Medicine ,Antigen ,Antigens, Neoplasm ,medicine ,Humans ,neoplasms ,Molecular Biology ,Multiple myeloma ,Aged ,Aged, 80 and over ,Tissue microarray ,business.industry ,Cancer ,Anatomical pathology ,Prognosis ,medicine.disease ,Neoplasm Proteins ,medicine.anatomical_structure ,Cancer/testis antigens ,Bone marrow ,Multiple Myeloma ,business - Abstract
Cancer-testis (CT) antigens are promising targets for antigen-specific therapy of multiple myeloma (MM). Osteolytic lesions represent the most common clinical manifestation of myeloma and it is possible that osseous myeloma lesions differ from bone-infiltrating tumor cells with regard to the extent of CT antigen expression based on the epigenetic regulation of these genes. We, therefore, performed the first analysis of CT antigen expression in osteolytic lesions of myeloma patients to further define the diagnostic, prognostic, and therapeutic value of these proteins. Lytic bone samples were obtained from MM patients during surgical interventions and a tissue microarray was constructed. 105 bone samples and 24 bone marrow biopsies were stained immunohistochemically with antibodies against CT antigens MAGE-C1/CT7 and MAGE-C2/CT10 and Ki-67. MAGE-C1/CT7 and MAGE-C2/CT10 were frequently expressed in osteolytic lesions (46% and 54%) and bone marrow (75% and 54%). Expression of MAGE-C1/CT7 was significantly more frequent in patients with advanced stage of disease (p=0.023) and with a chromosomal deletion 17p13 (p53) (p=0.047). Samples with more than 75% MAGE-C1/CT7 expressing myeloma cells showed a higher proliferative rate (indicated by the expression of Ki67) than those with less than 25% MAGE-C1/CT7 expressing cells (p=0.011). Moreover, a content of ≥50% MAGE-C1/CT7 expressing myeloma cells in a sample was associated with reduced overall survival (p=0.013). Our results, therefore, suggest that expression of MAGE-C1/CT7 and MAGE-C2/CT10 in osteolytic lesions of myeloma patients can be used for diagnostic, prognostic, as well as immunotherapeutic purposes.
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- 2010
44. An optimized assay for the enumeration of antigen-specific memory B cells in different compartments of the human body
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Djordje Atanackovic, Carsten Bokemeyer, Tim Luetkens, Nicolaus Kröger, Maja Gordic, Sabrina Meyer, Anna Sophie Ihloff, Sebastian Kobold, Katrin Bartels, Yanran Cao, York Hildebrandt, and Nesrine Lajmi
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Antigens, CD19 ,CD40 Ligand ,Palatine Tonsil ,Plasma Cells ,Immunology ,B-Lymphocyte Subsets ,Bone Marrow Cells ,Cell Count ,Enzyme-Linked Immunosorbent Assay ,Cell Separation ,Lymphocyte Activation ,Peripheral blood mononuclear cell ,Microbiology ,Viral Proteins ,Antigen ,Tetanus Toxoid ,medicine ,Humans ,Immunology and Allergy ,Lymphocyte Count ,Antigens ,Memory B cell ,B cell ,Cell Proliferation ,Immunoassay ,CD40 ,biology ,Interleukins ,Viral Core Proteins ,RNA-Binding Proteins ,Cell Differentiation ,Nucleocapsid Proteins ,Phosphoproteins ,Molecular biology ,medicine.anatomical_structure ,Oligodeoxyribonucleotides ,Immunoglobulin G ,Humoral immunity ,Leukocytes, Mononuclear ,biology.protein ,Bone marrow ,Antibody ,Immunologic Memory - Abstract
Object In the framework of our current study we set out to develop an optimized assay for the quantification of antigen-specific B cells in different compartments of the human body. Methods Mononuclear cells (MNC) derived from the peripheral blood, bone marrow (BM), or human tonsils were incubated with different combinations of stimuli. The stimulated cells and culture supernatants were then applied to IgG-ELISPOT and ELISA read-out assays and tetanus toxoid (TT)-specific B cell responses were quantified. Results We found that a combination of CD40L, CpG, and IL21 was optimal for the induction of TT-specific IgG-producing cells from memory B cell (mBc) precursors. This cocktail of stimuli led to a proliferation-dependent induction of CD19intermediateCD38highCD138highIgDnegative terminally differentiated plasma cells. Applying our optimized methodology we were also able to quantify mBc specific for cytomegalovirus and influenza virus A. Most importantly, the same method proved useful for the comparison of mBc frequencies between different compartments of the body and, accordingly, we were able to demonstrate that TT-specific mBc preferably reside within tonsillar tissue. Conclusion Here, we optimized an assay for the quantification of antigen-specific B cells in different human tissues demonstrating, for example, that TT-specific mBc preferably reside in human tonsils but not in the BM or the peripheral blood. We suggest that our approach can be used for the enumeration of mBc specific for a wide variety of Ag (microbial, tumor-related, auto-antigens), which will lead to significant improvements regarding our knowledge about the biology of humoral immunity.
- Published
- 2010
45. Proceedings from the National Cancer Institute's Second International Workshop on the Biology, Prevention, and Treatment of Relapse after Hematopoietic Stem Cell Transplantation: Introduction
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Sergio Giralt, Michael R. Bishop, Alan S. Wayne, and Nicolaus Kröger
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medicine.medical_specialty ,Transplantation Conditioning ,medicine.medical_treatment ,Hematopoietic stem cell transplantation ,Article ,medicine ,Humans ,Intensive care medicine ,Allogeneic ,Cause of death ,Transplantation ,business.industry ,Hematopoietic Stem Cell Transplantation ,Cancer ,Hematology ,medicine.disease ,Minimal residual disease ,Post-transplant relapse ,National Cancer Institute (U.S.) ,United States ,Clinical research ,Hematologic Neoplasms ,Immunology ,Hematologic malignancies ,Neoplasm Recurrence, Local ,business ,Autologous - Abstract
Despite advances in hematopoietic stem cell transplantation (HSCT) for the treatment of hematologic malignancies, relapse remains the leading cause of death after transplant. Biologic and clinical investigations are needed to combat this primary cause of death after transplantation. The National Cancer Institute held international workshops in 2009 and 2012 to help address this problem. Three major initiatives for coordinated research were proposed: 1) To establish multicenter networks for basic, translational, epidemiologic and clinical research; 2) To establish a network of biorepositories for the collection of samples before and after HSCT to aid in laboratory and clinical studies; and 3) To refine, implement and study proposed definitions for disease-specific response and relapse and for monitoring of minimal residual disease. The workshop in 2012 also featured nine presentations, summaries of which follow in three manuscripts.
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- 2013
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46. HLA-Mismatched Unrelated Donors as an Alternative Graft Source for Allogeneic Stem Cell Transplantation after Antithymocyte Globulin-Containing Conditioning Regimen
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Tatjana Zabelina, Nicolaus Kröger, Thomas Eiermann, Ulrike Bacher, Heinrich Lellek, R. Erttmann, Thomas M.C. Binder, Axel R. Zander, Johanna Schrum, Francis Ayuk, and Gitta Amtsfeld
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Male ,Transplantation Conditioning ,Graft vs Host Disease ,Graft-versus-host disease ,Gastroenterology ,HLA Antigens ,Recurrence ,Risk Factors ,Living Donors ,Unrelated SCT ,Cumulative incidence ,Child ,biology ,Histocompatibility Testing ,Incidence ,Incidence (epidemiology) ,Hazard ratio ,Age Factors ,Hematology ,Middle Aged ,Survival Rate ,Child, Preschool ,Hematologic Neoplasms ,Acute Disease ,Female ,Immunosuppressive Agents ,Adult ,medicine.medical_specialty ,Adolescent ,Globulin ,Human leukocyte antigen ,Internal medicine ,medicine ,Humans ,Aged ,Antilymphocyte Serum ,Retrospective Studies ,Transplantation ,business.industry ,Infant ,medicine.disease ,HLA Mismatch ,ATG ,Surgery ,HLA-mismatch ,biology.protein ,business ,Stem Cell Transplantation - Abstract
Between August 1996 and December 2004, 369 patients with a median age of 41 years (range: 1-68 years) received stem cell transplantation (SCT) from unrelated donors after an antithymocyte-globulin (ATG)-containing conditioning regimen. In 268 patients, complete molecular typing (4-digit) of HLA-A, -B, -C, -DRB1, and -DQB1 was available: 110 patients were completely matched for 10 alleles, 91 patients had 1 allele-mismatch (9/10), and 67 patients were mismatched for 2-4 alleles (6-8/10). The incidence of grade II-IV acute graft-versus-host disease (aGVHD) was 33% in the 10/10, 41% in the 9/10, and 40% in the 6-8/10 group, respectively (P = .1). The cumulative incidence of treatment-related mortality (TRM) and relapse among the groups were similar (27%, 31%, and 32%, P = .2; and 28%, 27%, and 26%, P = .9. After a median follow-up of 35 months (range: 3-120 months), the estimated 5-year disease-free survival (DFS) was 42% and did not differ among the 10/10, the 9/10, and the 6-8/10-mismatched groups (45% versus 42% versus 39%) (P = .5). In multivariate analysis, only age (hazard ratio [HR] 1.013) (P = .004) and bad-risk disease (HR 1.975) (P < .001) were independent risk factors for DFS. In conclusion, pretransplant ATG allows allogeneic SCT from unrelated donors with HLA disparities.
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- 2009
47. Safety of percutaneous dilational tracheostomy in hematopoietic stem cell transplantation recipients requiring long-term mechanical ventilation
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Axel Nierhaus, Georg Kreymann, Stefan Kluge, Andreas Meyer, Nicolaus Kröger, and Hans Jörg Baumann
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Male ,medicine.medical_specialty ,Time Factors ,medicine.medical_treatment ,Hematopoietic stem cell transplantation ,Critical Care and Intensive Care Medicine ,law.invention ,Stoma ,Postoperative Complications ,Tracheostomy ,law ,medicine ,Humans ,Hospital Mortality ,Survival rate ,Retrospective Studies ,Mechanical ventilation ,business.industry ,Hematopoietic Stem Cell Transplantation ,Middle Aged ,medicine.disease ,Respiration, Artificial ,Intensive care unit ,Percutaneous dilational tracheostomy ,Surgery ,Intensive Care Units ,Pneumothorax ,Anesthesia ,Acute respiratory insufficiency ,Female ,Respiratory Insufficiency ,business - Abstract
Purpose Recent reports have shown that the outcome of mechanically ventilated patients after hematopoietic stem cell transplantation (HSCT) has improved. This study was conducted to clarify if percutaneous dilational tracheostomy is safe in this group of patients and to report the outcome of HSCT recipients requiring long-term mechanical ventilation. Methods A retrospective review of our 8-year experience with patients with acute respiratory insufficiency after HSCT, requiring long-term mechanical ventilation and percutaneous dilational tracheostomy and an analysis of patient outcomes were made. Results Percutaneous dilational tracheostomy was safely performed in all 51 patients. Although 1 patient (2%) developed a pneumothorax that required drainage, stoma infections or severe bleeding complications were not observed. Of the 51 patients in the study, 14 (27%) survived the intensive care unit stay, and 10 of them were ventilated for more than 20 days. The intensive care unit survival rate for the period from 1998 to 2001 was 11% compared with 38% for the period from 2002 to 2005 ( P = .053). Conclusions Percutaneous dilational tracheostomy can be safely performed on patients with acute respiratory failure after HSCT. This procedure did not result in postoperative wound infections or significant bleeding complications. Furthermore, the results of our study indicate that today even patients with prolonged mechanical ventilation (>20 days) have a chance of long-term survival.
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- 2008
48. Comparison of Two Doses of Antithymocyte Globulin in Patients Undergoing Matched Unrelated Donor Allogeneic Stem Cell Transplantation
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Galina Diyachenko, Ulrike Bacher, Boris Fehse, Christine Wolschke, Rudolf Erttmann, Francis Ayuk, Nicolaus Kröger, Axel R. Zander, and Tatjana Zabelina
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Adult ,Male ,endocrine system ,medicine.medical_specialty ,Transplantation Conditioning ,Adolescent ,Globulin ,Platelet Engraftment ,Graft vs Host Disease ,Infections ,Gastroenterology ,Recurrence ,Internal medicine ,medicine ,Humans ,Transplantation, Homologous ,Child ,Survival analysis ,Antilymphocyte Serum ,Transplantation ,Dose-Response Relationship, Drug ,biology ,business.industry ,Incidence (epidemiology) ,Graft Survival ,Hematopoietic Stem Cell Transplantation ,Stem cell transplantation ,Infant ,Hematology ,Middle Aged ,Survival Analysis ,ATG ,Histocompatibility ,Surgery ,Dose–response relationship ,Dose ,Child, Preschool ,Hematologic Neoplasms ,biology.protein ,Female ,Methotrexate ,business ,medicine.drug - Abstract
Antithymocyte globulin (ATG) as part of conditioning regimens is known to reduce the incidence and severity of acute and chronic graft-versus-host disease (aGVHD, cGVHD). The influence of ATG on transplant-related mortality (TRM) and disease-free survival (DFS) is controversial, and may depend on the dose and timing of ATG. We retrospectively compared 2 doses of ATG-Fresenius (ATG-F) in patients undergoing matched unrelated donor allogeneic hematopoetic stem cell transplantation (HSCT) for hematologic malignancies. A dose of 60 mg/kg body weight has previously been recommended for ATG-F. All patients received cyclosporine A and short course methotrexate. ATG-F was administered at a dose of 30 mg/kg on day –1 (ATG-30 group, n = 34) or 20 mg/kg/day on days –3 to –1 (ATG-60 group, n = 49). There was no difference in time to leukocyte and platelet engraftment in the 2 groups. The incidence of aGVHD grade II-IV (50% versus 53%, P = .83) and grade III-IV (27 versus 20%, P = .60) was similar in the ATG-30 versus ATG-60 groups, respectively. There was a trend to a higher incidence of cGVHD in the ATG-30 group (59% versus 40%, P = .14). The estimated 3-year incidence of relapse was similar in the ATG-30 and ATG-60 groups (15% versus 16%, P = .84) whereas the 2-year TRM was lower for the ATG-30 group (12% versus 33%, P = 0.02), mainly because of a higher incidence of fatal infections in the ATG-60 group. This resulted in a better DFS (73% versus 51%, P = .07) for the ATG-30 group. ATG-F (30 mg/kg) administered as a single dose on day –1 may lead to better outcome in patients undergoing unrelated donor allogeneic HSCT compared to 60 mg/kg given in 3 equivalent doses. A prospective randomized study comparing these 2 doses of ATG-F is warranted.
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- 2008
49. Rapid regression of bone marrow fibrosis after dose-reduced allogeneic stem cell transplantation in patients with primary myelofibrosis
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Hans Michael Kvasnicka, Martin Bornhäuser, Nicolaus Kröger, Rainer Schwerdtfeger, Jürgen Thiele, Axel R. Zander, Jörg Schubert, Guido Kobbe, Wolfgang Bethge, and Theo de Witte
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Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Pathology ,Transplantation Conditioning ,Graft vs Host Disease ,Severity of Illness Index ,Gastroenterology ,Polycythemia vera ,Immune Regulation [NCMLS 2] ,Translational research [ONCOL 3] ,Fibrosis ,Internal medicine ,Genetics ,Iron metabolism [IGMD 7] ,Humans ,Transplantation, Homologous ,Medicine ,Myelofibrosis ,Busulfan ,Molecular Biology ,Molecular diagnosis, prognosis and monitoring [UMCN 1.2] ,business.industry ,Essential thrombocythemia ,Remission Induction ,Hematopoietic Stem Cell Transplantation ,Immunotherapy, gene therapy and transplantation [UMCN 1.4] ,Bone Marrow Examination ,Cell Biology ,Hematology ,Middle Aged ,medicine.disease ,Fludarabine ,Transplantation ,Kinetics ,Treatment Outcome ,Primary Myelofibrosis ,Female ,Stem cell ,business ,Vidarabine ,medicine.drug - Abstract
Contains fulltext : 52760.pdf (Publisher’s version ) (Closed access) OBJECTIVE: To investigate the effect of a busulfan/fludarabine-based reduced intensity conditioning followed by allogeneic stem cell transplantation on regression of bone marrow fibrosis in patients with myelofibrosis. METHODS: Twenty-four patients (male, n = 16; female, n = 8) with a median age of 52 years (range, 32-63 years) were included. Six patients were transplanted from human leukocyte antigen-identical siblings and 18 patients from matched unrelated donors. Diagnosis was primary myelofibrosis in 18 patients and secondary myelofibrosis in 6 patients; in 4 of them, primary myelofibrosis evolved from polycythemia vera, and in 2 of them from essential thrombocythemia. Using the European Consensus on grading bone marrow fibrosis, all patients had advanced marrow fibrosis MF-2 (n = 13) or MF-3 (n = 11) before allografting According to the Lille Risk Factor Scoring System, patients were classified as low risk (n = 5), intermediate risk (n = 16), or high risk (n = 3). RESULTS: After stem cell transplantation, a complete (MF-0) or nearly complete (MF-1) regression of bone marrow fibrosis was seen in 59% at day +100, in 90% at day +180, and in 100% at day +360. No correlation between occurrence of acute graft-vs-host disease and fibrosis regression on day +180 was observed. CONCLUSION: This study shows that allogeneic stem cell transplantation after reduced-intensity conditioning resulted in rapid regression of bone-marrow fibrosis.
- Published
- 2007
50. Kinetics of plasma-cell chimerism after allogeneic stem cell transplantation by highly sensitive real-time PCR based on sequence polymorphism and its value to quantify minimal residual disease in patients with multiple myeloma
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Anita Badbaran, Nicolaus Kröger, Boris Fehse, Michael Lioznov, Sabine Schwartz, Francis Ayuk, Maria Zagrivnaja, Tatjana Zabelina, and Axel R. Zander
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Genetic Markers ,Cancer Research ,Neoplasm, Residual ,Allogeneic transplantation ,Plasma cell ,Biology ,Polymerase Chain Reaction ,Sensitivity and Specificity ,Chimera (genetics) ,Genetics ,medicine ,Humans ,Transplantation, Homologous ,Molecular Biology ,Multiple myeloma ,Polymorphism, Genetic ,Chimera ,Cell Biology ,Hematology ,medicine.disease ,Minimal residual disease ,Transplantation ,medicine.anatomical_structure ,Immunology ,Bone marrow ,Stem cell ,Multiple Myeloma ,Stem Cell Transplantation - Abstract
Objective To investigate lineage-specific chimerism of plasma cells after allogeneic transplantation by real-time PCR based on bi-allelic sequence polymorphism or, in case of female-to-male transplantation, on the detection of the DFFRY gene and to determine its value to quantify minimal residual disease in myeloma patients. Methods Forty-eight samples from bone marrow samples and peripheral blood from 34 nonmyeloma patients were analyzed at different times after transplantation. Sixty-two samples from 22 myeloma patients were analyzed at different times after allogeneic stem cell transplantation, and results were compared with immunofixation and, in some cases, with PCR data using patient-specific primers. Results The median chimerism for T cells at day +100 was greater than 99.9% and remained stable on day +180 and 1 year after transplantation. In contrast, the median donor plasma cell chimerism at day +100 was 95.5%, at day +180 98.6%, at day +360 99.8%, and 2 or more years after transplantation greater than 99.9%. Sensitivity of real-time PCR using human short insertion/deletion polymorphisms (SIDP) was 10 -4 and in case of Y-PCR 10 -5 . Sequential monitoring of donor plasma cell chimerism showed that increasing and stable chimerism were associated with ongoing remission in 15 out of 16 samples (93%), and decreases in chimerism predicted relapse in 5 out of 6 patients. Conclusion We conclude that plasma cell chimerism after allogeneic stem cell transplantation is delayed in comparison to T-cell chimerism. Sequential quantitative measurement of plasma cells after allogeneic stem cell transplantation with highly sensitive real-time PCR allows monitoring of residual host-tumor cells in patients with multiple myeloma and allows guiding adoptive immunotherapy strategies to enhance remission status and to prevent clinical relapse.
- Published
- 2006
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