11 results on '"Finke, Jürgen"'
Search Results
2. Treosulfan compared with <scp>reduced‐intensity</scp> busulfan improves allogeneic hematopoietic cell transplantation outcomes of older acute myeloid leukemia and myelodysplastic syndrome patients: Final analysis of a prospective randomized trial
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Beelen, Dietrich, Stelljes, Matthias, Reményi, Péter, Wagner‐Drouet, Eva‐Maria, Dreger, Peter, Bethge, Wolfgang, Ciceri, Fabio, Stölzel, Friedrich, Junghanß, Christian, Labussiere‐Wallet, Hélène, Schaefer‐Eckart, Kerstin, Grigoleit, Goetz U., Scheid, Christof, Patriarca, Francesca, Rambaldi, Alessandro, Niederwieser, Dietger, Hilgendorf, Inken, Russo, Domenico, Socié, Gérard, Holler, Ernst, Glass, Bertram, Casper, Jochen, Wulf, Gerald, Basara, Nadezda, Bieniaszewska, Maria, Stuhler, Gernot, Verbeek, Mareike, La Rocca, Ursula, Finke, Jürgen, Benedetti, Fabio, Pichlmeier, Uwe, Klein, Anja, Baumgart, Joachim, Markiewicz, Miroslaw, and Rocca, Ursula La
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Leukemia, Myeloid, Acute ,Transplantation Conditioning ,Myelodysplastic Syndromes ,Medizin ,Hematopoietic Stem Cell Transplantation ,Graft vs Host Disease ,Humans ,Prospective Studies ,Hematology ,Middle Aged ,Busulfan ,Vidarabine ,Aged - Abstract
The phase III study was designed to compare event-free survival (EFS) after treosulfan-based conditioning with a widely applied reduced-intensity conditioning (RIC) busulfan regimen in older or comorbid patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) undergoing allogeneic hematopoietic cell transplantation (HCT). A previously reported confirmatory interim analysis of the randomized clinical study including 476 patients demonstrated statistically significant noninferiority for treosulfan with clinically meaningful improvement in EFS. Here, the final study results and pre-specified subgroup analyses of all 570 randomized patients with completed longer-term follow-up are presented. Patients presenting HCT-specific comorbidity index >2 or aged >= 50 years were randomly assigned (1:1) to intravenous (IV) fludarabine with either treosulfan (30 g/m(2) IV) or busulfan (6.4 mg/kg IV) after stratification by disease risk group, donor type, and participating institution. The primary endpoint was EFS with disease recurrence, graft failure, or death from any cause as events. EFS of patients (median age 60 years) was superior after treosulfan compared to RIC busulfan: 36-months-EFS rate 59.5% (95% CI, 52.2-66.1) vs. 49.7% (95% CI, 43.3-55.7) with a hazard ratio (HR) of 0.64 (95% CI, 0.49-0.84), p = 0.0006. Likewise, overall survival (OS) with treosulfan was superior compared to busulfan: 36-month-OS rate 66.8% vs. 56.3%; HR 0.64 (95% CI, 0.48-0.87), p = 0.0037. Post hoc analyses revealed that these differences were consistent with the confirmatory interim analysis, and thereby the treosulfan regimen appears particularly suitable for older AML and MDS patients.
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- 2022
3. Role of Age and Hematopoietic Cell Transplantation-Specific Comorbidity Index in Myelodysplastic Patients Undergoing an Allotransplant: A Retrospective Study from the Chronic Malignancies Working Party of the European Group for Blood and Marrow Transplantation
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Carré, Martin, Porcher, Raphaël, Finke, Jürgen, Ehninger, Gerhard, Koster, Linda, Beelen, Dietrich, Ganser, Arnold, Volin, Liisa, Lozano, Sara, Friis, Lone, Michallet, Mauricette, Tischer, Johanna, Olavarria, Eduardo, Cascon, Maria Jesús Pascual, Iacobelli, Simona, Koc, Yener, Jindra, Pavel, Arat, Mutlu, de Witte, Theo, Yakoub Agha, Ibrahim, Kröger, Nicolaus, Robin, Marie, and Agha, Ibrahim Yakoub
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Adult ,medicine.medical_specialty ,Transplantation Conditioning ,Multivariate analysis ,Cancer development and immune defence Radboud Institute for Molecular Life Sciences [Radboudumc 2] ,medicine.medical_treatment ,Myelodysplastic syndromes ,Medizin ,Comorbidity ,Hematopoietic stem cell transplantation ,Comorbidities ,03 medical and health sciences ,All institutes and research themes of the Radboud University Medical Center ,Age ,0302 clinical medicine ,Bone Marrow ,Neoplasms ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Humans ,Retrospective Studies ,Transplantation ,Nonrelapse mortality ,business.industry ,Hazard ratio ,Hematopoietic Stem Cell Transplantation ,Retrospective cohort study ,Hematology ,Settore MED/15 ,medicine.disease ,Settore MED/01 ,030220 oncology & carcinogenesis ,Stem cell ,business ,030215 immunology - Abstract
Allogeneic hematopoietic stem cell transplantation (HSCT) remains the only potentially curative option for myelodysplastic syndromes (MDSs) but is severely limited by nonrelapse mortality (NRM), especially in this mostly older population. Comorbidity assessment is crucial to predict NRM and often assessed with the Hematopoietic Cell Transplantation-Specific Comorbidity Index (HCT-CI). Moreover, the impact of age on NRM still remains a matter of debate. In recent years, the age at which transplants are made has been progressively increasing, and patients with comorbidities have become more common. Extricating the respective roles of age and comorbidities in toxic mortality is all the more important. This study by the European Group for Blood and Marrow Transplantation registry included 1245 adult patients who underwent a first allogeneic stem cell transplantation for MDSs between 2003 and 2014. Overall, 4-year NRM and overall survival were 32% and 47%, respectively. When considered as continuous predictors, HCT-CI score and age were associated with an increased hazard ratio (HR) for NRM. In multivariate analysis, age band (HR, 1.13; 95% CI, 1.02 to 1.25; P= .016), HCT-CI ≥3 (HR, 1.34; 95% CI, 1.04 to 1.73; P = .022), and Karnofsky Performance Status ≤80 (HR, 2.03; 95% CI, 1.52 to 2.73; P.0001) were significantly predictive of a worse NRM. In our large cohort, both comorbidities, evaluated by the original HCT-CI score, and chronological age significantly affected NRM. Thus, age should be part of the transplant decision-making process and should be integrated in future scoring systems predicting outcomes of HSCT in MDSs.
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- 2020
4. Comparison of Dynamic International Prognostic Scoring System and MYelofibrosis SECondary to PV and ET Prognostic Model for Prediction of Outcome in Polycythemia Vera and Essential Thrombocythemia Myelofibrosis after Allogeneic Stem Cell Transplantation
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Gagelmann, Nico, Eikema, Diderik-Jan, de Wreede, Liesbeth C, Koster, Linda, Wolschke, Christine, Arnold, Renate, Kanz, Lothar, McQuaker, Grant, Marchand, Tony, Socié, Gerard, Bourhis, Jean Henri, Mohty, Mohamad, Cornelissen, Jan J, Chevallier, Patrice, Bernasconi, Paolo, Stelljes, Matthias, Rohrlich, Pierre-Simon, Fanin, Renato, Finke, Jürgen, Maertens, Johan, Blaise, Didier, Itälä-Remes, Maija, Labussière-Wallet, Hélène, Robin, Marie, McLornan, Donal, Chalandon, Yves, Yakoub-Agha, Ibrahim, Kröger, Nicolaus, CMWP of the European Society for Blood and Marrow Transplantation, Hematology, and Medical Oncology
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Adult ,medicine.medical_specialty ,Essential thrombocythemia ,Gastroenterology ,03 medical and health sciences ,0302 clinical medicine ,Polycythemia vera ,Internal medicine ,Humans ,Transplantation, Homologous ,Medicine ,Allogeneic stem cell transplantation ,Secondary myelofibrosis ,Hematology ,Transplantation ,Myelofibrosis ,Polycythemia Vera ,Survival analysis ,Aged ,ddc:616 ,Framingham Risk Score ,business.industry ,Hematopoietic Stem Cell Transplantation ,Middle Aged ,Prognosis ,medicine.disease ,Survival Analysis ,Treatment Outcome ,Primary Myelofibrosis ,International Prognostic Scoring System ,030220 oncology & carcinogenesis ,Cohort ,business ,Thrombocythemia, Essential ,030215 immunology - Abstract
We aimed to validate the MYelofibrosis SECondary to PV and ET prognostic model (MYSEC-PM) in 159 patients with myelofibrosis secondary to polycythemia vera (PV) and essential thrombocythemia (ET) from the European Society for Blood and Marrow Transplantation registry undergoing transplantation from matched siblings or unrelated donors. Furthermore, we aimed to test its prognostic performance in comparison with the Dynamic International Prognostic Scoring System (DIPSS). Score performance was analyzed using the concordance index (C): the probability that a patient who experienced an event had a higher risk score than a patient who did not (C > .5 suggesting predictive ability). Median follow-up of the total cohort was 41 months (range, 34 to 54), 45 months in post-PV and 38 months in post-ET myelofibrosis. Survival at 1, 2, and 4 years was 70% (95% CI, 63% to 77%), 61% (95% CI, 53% to 69%), and 52% (95% CI, 43% to 61%) for the total cohort; 70% (95% CI, 59% to 80%), 61% (95% CI, 49% to 73%), and 51% (95% CI, 38% to 64%) for post-PV; and 71% (95% CI, 61% to 81%), 61% (95% CI, 50% to 72%), and 54% (95% CI, 42% to 66%) for post-ET myelofibrosis (P = .78). Overall, the DIPSS was not significantly predictive of outcome (P = .28). With respect to the MYSEC-PM, overall survival at 4 years was 69% for the low-risk, 55% for the intermediate 1-risk, 47% for the intermediate 2-risk, and 22% (0% to 45%) for the high-risk groups. The prognostic model was predictive of survival overall (P = .05), whereas groups with intermediate 2 and high risk showed no significant difference (P = .44). Assessment of prognostic utility yielded a C-index of .575 (95% CI, .502 to .648) for the DIPSS, whereas assessment of the MYSEC-PM resulted in a C-statistics of .636 (95% CI, .563 to .708), indicating improvement in prediction of post-transplant survival using the new MYSEC-PM. In addition, transplantations from an unrelated donor in comparison with an HLA-identical sibling showed worse outcome (P = .04), and transplant recipients seropositive for cytomegalovirus in comparison with seronegative recipients (P = .01) showed worse survival. In conclusion, incorporating transplant-specific and clinical and mutational information together with the MYSEC-PM may enhance risk stratification. ispartof: Biol Blood Marrow Transplant vol:25 issue:6 pages:e204-e208 ispartof: location:United States status: published
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- 2019
5. Centre characteristics and procedure-related factors have an impact on outcomes of allogeneic transplantation for patients with CLL: a retrospective analysis from the European Society for Blood and Marrow Transplantation (EBMT)
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Schetelig, Johannes, de Wreede, Liesbeth C., Andersen, Niels S., Moreno, Carol, van Gelder, Michel, Vitek, Antonin, Karas, Michal, Michallet, Mauricette, Machaczka, Maciej, Gramatzki, Martin, Beelen, Dietrich, Finke, Jürgen, Delgado, Julio, Volin, Liisa, Passweg, Jakob, Dreger, Peter, Schaap, Nicolaas, Wagner, Eva, Henseler, Anja, van Biezen, Anja, Bornhäuser, Martin, Iacobelli, Simona, Putter, Hein, Schönland, Stefan O., Kröger, Nicolaus, Esteve, Jordi, Ljungman, Per, de Witte, Theo, Stelljes, Matthias, Sierra, Jorge, Socié, Gerard, Ganser, Arnold, Wulf, Gerhard G., Deconinck, Eric, Faber, Edgar, Feguex, Nathalie, Gedde-Dahl, Tobias, Kolbe, Karin, Chalandon, Yves, Krüger, William, Huynh, Anne, Bourhis, Jean Henri, Schouten, Harry, Ribera Santasusana, Josep M., Interne Geneeskunde, MUMC+: MA Hematologie (9), RS: GROW - R3 - Innovative Cancer Diagnostics & Therapy, and Chalandon, Yves
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Oncology ,Male ,Transplantation Conditioning ,Cancer development and immune defence Radboud Institute for Molecular Life Sciences [Radboudumc 2] ,Chronic lymphocytic leukemia ,Medizin ,QUALITY MANAGEMENT-SYSTEM ,Kaplan-Meier Estimate ,risk factor analysis ,GUIDELINES ,Biochemistry ,allogeneic stem cell transplantation ,centre effects ,chronic lymphocytic leukaemia ,frailties ,Transplantation Conditioning / methods ,0302 clinical medicine ,Recurrence ,Risk Factors ,Leukemia, Lymphocytic, Chronic, B-Cell / mortality ,Registries ,Delivery of Health Care / statistics & numerical data ,IBRUTINIB ,ddc:616 ,0303 health sciences ,ALEMTUZUMAB ,Hazard ratio ,Hematopoietic Stem Cell Transplantation ,Professional Practice ,Hematology ,Middle Aged ,3. Good health ,Europe ,030220 oncology & carcinogenesis ,ABT-199 ,Cohort ,SURVIVAL ,Alemtuzumab ,Female ,Europe / epidemiology ,medicine.drug ,Adult ,medicine.medical_specialty ,Allogeneic transplantation ,Immunology ,Lower risk ,DIAGNOSIS ,Settore MED/01 - Statistica Medica ,03 medical and health sciences ,Leukemia, Lymphocytic, Chronic, B-Cell / therapy ,Hematopoietic Stem Cell Transplantation / methods ,Internal medicine ,medicine ,Humans ,Karnofsky Performance Status ,030304 developmental biology ,Aged ,Retrospective Studies ,business.industry ,Proportional hazards model ,CHRONIC LYMPHOCYTIC-LEUKEMIA ,Retrospective cohort study ,STEM-CELL TRANSPLANTATION ,Cell Biology ,medicine.disease ,Leukemia, Lymphocytic, Chronic, B-Cell ,Confidence interval ,Surgery ,Professional Practice / statistics & numerical data ,Transplantation ,business ,Delivery of Health Care ,030215 immunology ,RESPONSES - Abstract
Introduction:Even in the era of novel targeted therapies for the treatment of Chronic Lymphocytic Leukemia (CLL) patients, such as BTK, PI3K and BCL2 inhibitors, allogeneic hematopoietic stem cell transplantations (alloHCT) will remain an important treatment option for a subset of patients with very high risk CLL. The current study focused on the impact of center and procedure-related factors on outcomes after alloHCT, taking into account the impact of patient- and disease-related risk factors. Patients and Methods:Data of 684 CLL patients who received a first alloHCT between 2000 and 2011 were analyzed. Their data were collected as part of the EBMT CLL Data Quality Initiative. Outcomes of interest were Event-Free Survival (EFS) up to 5 years after transplantation and mortality in the first 100 days after alloHCT. Outcomes were analyzed by means of the Kaplan-Meier method and Cox proportional hazards models with a frailty (random effects) component to take into account unexplained center heterogeneity. The following factors describing center characteristics or the transplant procedure were analyzed: experience in alloHCT in general and, for CLL specifically, accreditation by the Joint Accreditation Committee-ISCT & EBMT (JACIE), Gross National Income (GNI)/capita based on purchasing power parity (PPP) (GNI/cap), donor type, donor-patient sex-match, type of conditioning, stem cell source and T-cell depletion (TCD). Results:Five-year EFS of the whole cohort was 37% (95% Confidence Interval, 33%-42%), Day-100 survival was 90% (88%-92%). Experience of the transplant center was measured by the number of all alloHCTs, and alloHCTs for patients with CLL respectively. The median total number of alloHCTs per center per year was 45 (range 0-169) and the median number of CLL alloHCTs was only 2 per center per year (range 0-19). Greater experience with transplantation of patients with CLL (Hazard Ratio (HR) 0.96 per additional transplant, p=0.002), JACIE accreditation (HR 0.7, p=0.045) and a higher GNI/cap (HR 0.4, 95% CI 0.2-0.96, p=0.04) showed a protective impact on 5-year EFS in the Cox model. In vivo TCD with alemtuzumab (HR 1.5 compared to no TCD, p=0.03) and a female donor for a male patient (HR 1.4 compared to a male donor for a male patient, p=0.02) were the only procedure-related factors significantly associated with EFS. Event-Free Survival after in vivo TCD with Anti-Thymocyte-Globulin or after ex vivo TCD was comparable to EFS without TCD (HR 0.9, 0.7-1.3, p=0.6; HR 0.9, 0.5-1.6, p=0.8). Non-myeloablative conditioning did not have a negative impact on 5-year EFS, and exposed patients to a lower risk of non-relapse mortality. Measured and unmeasured center characteristics did not have a significant impact on 100-day mortality. Even when correcting for patient-, procedure- and center-related characteristics, there was still significant variation in center outcome, expressed by center-specific HRs derived from the frailty models, ranging from 0.6 to 1.2. Their impact is illustrated in a model-based plot for EFS (see Figure) which shows outcomes for three reference patients with the same characteristics who would be transplanted in three centers with the same measured characteristics but with the highest, average and lowest HRs in the dataset. These unexplained center effects likely represent a mixture of differences which could apply to the location of the transplant center, unmeasured characteristics of the patient population transplanted at this center, selection criteria which were not reported and factors determining the success of the transplant procedure which might differ between centers. Conclusion: We have confirmed that both center- and procedure-related factors have a significant impact on the EFS of patients with CLL undergoing alloHCT. Our results may help to interpret outcomes of single or multicenter studies better. Since non-myeloablative conditioning did not have a negative impact on EFS and exposed patients to a lower risk of non-relapse mortality, this approach should be favored for future alloHCT for CLL. Probability of Event-Free Survival up to Five Years Post-HCT for three Reference Patients Contribution: J.S. designed the research and wrote the paper. L.C.d.W conducted the statistical analysis and produced the figure. Figure Figure. Disclosures Schetelig: Sanofi: Honoraria. Gramatzki:Janssen: Other: Travel/Accommodation/Expenses, Research Funding. Dreger:Gilead: Consultancy; Gilead: Speakers Bureau; Janssen: Consultancy; Novartis: Speakers Bureau; Novartis: Consultancy; Roche: Consultancy.
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- 2017
6. Additional file 1 Table 1S: of Comparison of matched sibling donors versus unrelated donors in allogeneic stem cell transplantation for primary refractory acute myeloid leukemia: a study on behalf of the Acute Leukemia Working Party of the EBMT
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Eolia Brissot, Labopin, Myriam, Stelljes, Matthias, Ehninger, Gerhard, Schwerdtfeger, Rainer, Finke, Jürgen, Hans-Jochem Kolb, Ganser, Arnold, Schäfer-Eckart, Kerstin, Zander, Axel, Bunjes, Donald, Mielke, Stephan, Bethge, Wolfgang, Milpied, Noël, Kalhs, Peter, Igor-Woflgang Blau, Kröger, Nicolaus, Vitek, Antonin, Gramatzki, Martin, Holler, Ernst, Schmid, Christoph, Esteve, Jordi, Mohty, Mohamad, and Nagler, Arnon
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Conditioning regimens: univariate analysis for RI, NRM, LFS, OS, cGVHD. (DOCX 20 kb)
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- 2017
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7. Additional file 1: Table S1. of The impact of HLA-matching on reduced intensity conditioning regimen unrelated donor allogeneic stem cell transplantation for acute myeloid leukemia in patients above 50 years—a report from the EBMT acute leukemia working party
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Rubio, Marie, Bipin Savani, Labopin, Myriam, Polge, Emmanuelle, Niederwieser, Dietger, Ganser, Arnold, Schwerdtfeger, Rainer, Ehninger, Gerhard, Finke, Jürgen, Renate, Arnold, Craddock, Charles, Kröger, Nicolaus, Hallek, Michael, Jindra, Pavel, Mohty, Mohamad, and Nagler, Arnon
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List of institutions reporting patients’ data for the study. (DOCX 29 kb)
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- 2016
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8. Association of Serum Ferritin Levels Before Start of Conditioning With Mortality After alloSCT – A Prospective, Non-interventional Study of the EBMT Transplant Complications Working Party
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Penack, Olaf, Peczynski, Christophe, Werf, Steffie, Van Der, Finke, Jürgen, Ganser, Arnold, Schoemans, Helene, Pavlu, Jiri, Niittyvuopio, Riitta, Schroyens, Wilfried, Kaynar, Leylagül, Blau, Igor W., Velden, Walter J. F. M., Van Der, Sierra, Jorge, Cortelezzi, Agostino, Wulf, Gerald, Turlure, Pascal, Rovira, Montserrat, Ozkurt, Zubeydenur, Pascual-Cascon, Maria J., Moreira, Maria C., Clausen, Johannes, Greinix, Hildegard, Duarte, Rafael F., and Basak, Grzegorz W.
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stem cell ,immunology ,ferritin ,biomarker ,iron metabolism ,600 Technik, Medizin, angewandte Wissenschaften::610 Medizin und Gesundheit::610 Medizin und Gesundheit ,3. Good health ,transplantation - Abstract
Elevated serum ferritin levels occur due to iron overload or during inflammation and macrophage activation. A correlation of high serum ferritin levels with increased mortality after alloSCT has been suggested by several retrospective analyses as well as by two smaller prospective studies. This prospective multicentric study aimed to study the association of ferritin serum levels before start of conditioning with alloSCT outcome. Patients with acute leukemia, lymphoma or MDS receiving a matched sibling alloSCT for the first time were considered for inclusion, regardless of conditioning. A comparison of outcomes between patients with high and low ferritin level was performed using univariate analysis and multivariate analysis using cause-specific Cox model. Twenty centers reported data on 298 alloSCT recipients. The ferritin cut off point was determined at 1500 mu g/l (median of measured ferritin levels). In alloSCT recipients with ferritin levels above cut off measured before the start of conditioning, overall survival (HR = 2.5, CI = 1.5-4.1, p = 0.0005) and progression-free survival (HR = 2.4, CI = 1.6-3.8, p < 0.0001) were inferior. Excess mortality in the high ferritin group was due to both higher relapse incidence (HR = 2.2, CI = 1.2-3.8, p = 0.007) and increased non-relapse mortality (NRM) (HR = 3.1, CI = 1.5-6.4, p = 0.002). NRM was driven by significantly higher infection-related mortality in the high ferritin group (HR = 3.9, CI = 1.6-9.7, p = 0.003). Acute and chronic GVHD incidence or severity were not associated to serum ferritin levels. We conclude that ferritin levels can serve as routine laboratory biomarker for mortality risk assessment before alloSCT.
9. Expanding transplant options to patients over 50 years. Improved outcome after reduced intensity conditioning mismatched-unrelated donor transplantation for patients with acute myeloid leukemia: a report from the Acute Leukemia Working Party of the EBMT
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Jordi Esteve, Gérard Socié, Fabio Ciceri, Jürgen Finke, Donald Bunjes, Myriam Labopin, Gerhard Ehninger, Norbert Claude Gorin, Bertram Glass, Nicolaus Kröger, Per Ljungman, Rainer Schwerdtfeger, Mohamad Mohty, Charles Craddock, Frédéric Baron, Sebastian Giebel, Bipin N. Savani, Arnon Nagler, Dietger Niederwieser, Christoph Schmid, Savani, Bipin N., Labopin, Myriam, Kröger, Nicolau, Finke, Jürgen, Ehninger, Gerhard, Niederwieser, Dietger, Schwerdtfeger, Rainer, Bunjes, Donald, Glass, Bertram, Socié, Gerard, Ljungman, Per, Craddock, Charle, Baron, Frédéric, Ciceri, Fabio, Gorin, Norbert Claude, Esteve, Jordi, Schmid, Christoph, Giebel, Sebastian, Mohty, Mohamad, and Nagler, Arnon
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Adult ,Male ,medicine.medical_specialty ,Transplantation Conditioning ,medicine.medical_treatment ,Graft vs Host Disease ,Hematopoietic stem cell transplantation ,Article ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Recurrence ,Internal medicine ,medicine ,Humans ,Transplantation, Homologous ,Survival analysis ,Aged ,Retrospective Studies ,Aged, 80 and over ,Acute leukemia ,business.industry ,Graft Survival ,Age Factors ,Hematopoietic Stem Cell Transplantation ,Myeloid leukemia ,Retrospective cohort study ,Hematology ,Middle Aged ,Survival Analysis ,Surgery ,Transplantation ,Leukemia, Myeloid, Acute ,Treatment Outcome ,030220 oncology & carcinogenesis ,Cohort ,Female ,Unrelated Donors ,business ,030215 immunology - Abstract
The outcome of patients undergoing HLA-matched unrelated donor allogeneic hematopoietic cell transplantation following reduced-intensity conditioning or myeloablative regimens is reported to be equivalent; however, it is not known if the intensity of the conditioning impacts outcomes after mismatched unrelated donor transplantation for acute myeloid leukemia. Eight hundred and eighty three patients receiving reduced-intensity conditioning were compared with 1041 myeloablative conditioning regimen recipients in the setting of mismatched unrelated donor transplantation. The donor graft was HLA-matched at 9/10 in 872 (83.8%) and at 8/10 in 169 (16.2%) myeloablative conditioning recipients, while in the reduced-intensity conditioning cohort, 754 (85.4%) and 129 (14.6%) were matched at 9/10 and 8/10 loci, respectively. Myeloablative conditioning regimen recipients were younger, 70% being
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- 2016
10. Oncogenic JAK2 V617F causes PD-L1 expression, mediating immune escape in myeloproliferative neoplasms
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Khalid Shoumariyeh, Robert Zeiser, Sivahari P. Gorantla, Sebastian Halbach, Frederike A. Hartl, Alica J. Emhardt, Julius Wehrle, Jonas S. Jutzi, Sebastian Fuchs, Ioanna Triviai, Sandra Duquesne, Michael Hettich, Annette Schmitt-Graeff, Eliana Ruggiero, Susana Minguet, Wolfgang Melchinger, Jürgen Finke, Chiara Bonini, Nicolaus Kröger, Pia Veratti, Anna Lena Illert, Bruce R. Blazar, Melanie Boerries, Mark Bartholomä, Teresa Poggio, Geoffrey R. Hill, Steven W. Lane, Gabriele Niedermann, Petya Apostolova, Slavica Vuckovic, Nikolas von Bubnoff, Konrad Aumann, Hauke Busch, Stephan Ehl, Florian H. Heidel, Sandra Pennisi, Dietmar Pfeifer, Justus Duyster, Cornelius Miething, David O’Sullivan, Marie Follo, Lukas Braun, Christine Dierks, Heiko Becker, Heike L. Pahl, Jan Rohr, Tilman Brummer, Alessandro Prestipino, Erika L. Pearce, Prestipino, Alessandro, Emhardt, Alica J, Aumann, Konrad, O'Sullivan, David, Gorantla, Sivahari P, Duquesne, Sandra, Melchinger, Wolfgang, Braun, Luka, Vuckovic, Slavica, Boerries, Melanie, Busch, Hauke, Halbach, Sebastian, Pennisi, Sandra, Poggio, Teresa, Apostolova, Petya, Veratti, Pia, Hettich, Michael, Niedermann, Gabriele, Bartholomä, Mark, Shoumariyeh, Khalid, Jutzi, Jonas S, Wehrle, Juliu, Dierks, Christine, Becker, Heiko, Schmitt-Graeff, Annette, Follo, Marie, Pfeifer, Dietmar, Rohr, Jan, Fuchs, Sebastian, Ehl, Stephan, Hartl, Frederike A, Minguet, Susana, Miething, Corneliu, Heidel, Florian H, Kröger, Nicolau, Triviai, Ioanna, Brummer, Tilman, Finke, Jürgen, Illert, Anna L, Ruggiero, Eliana, Bonini, Chiara, Duyster, Justu, Pahl, Heike L, Lane, Steven W, Hill, Geoffrey R, Blazar, Bruce R, von Bubnoff, Nikola, Pearce, Erika L, and Zeiser, Robert
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0301 basic medicine ,Janus kinase 2 ,Myeloid ,biology ,T cell ,food and beverages ,General Medicine ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,medicine.anatomical_structure ,hemic and lymphatic diseases ,030220 oncology & carcinogenesis ,biology.protein ,medicine ,STAT protein ,Cancer research ,Receptor ,STAT3 ,STAT5 ,K562 cells - Abstract
Recent evidence has revealed that oncogenic mutations may confer immune escape. A better understanding of how an oncogenic mutation affects immunosuppressive programmed death ligand 1 (PD-L1) expression may help in developing new therapeutic strategies. We show that oncogenic JAK2 (Janus kinase 2) activity caused STAT3 (signal transducer and activator of transcription 3) and STAT5 phosphorylation, which enhanced PD-L1 promoter activity and PD-L1 protein expression in JAK2V617F-mutant cells, whereas blockade of JAK2 reduced PD-L1 expression in myeloid JAK2V617F-mutant cells. PD-L1 expression was higher on primary cells isolated from patients with JAK2V617F–myeloproliferative neoplasms (MPNs) compared to healthy individuals and declined upon JAK2 inhibition. JAK2V617F mutational burden, pSTAT3, and PD-L1 expression were highest in primary MPN patient–derived monocytes, megakaryocytes, and platelets. PD-1 (programmed death receptor 1) inhibition prolonged survival in human MPN xenograft and primary murine MPN models. This effect was dependent on T cells. Mechanistically, PD-L1 surface expression in JAK2V617F-mutant cells affected metabolism and cell cycle progression of T cells. In summary, we report that in MPN, constitutive JAK2/STAT3/STAT5 activation, mainly in monocytes, megakaryocytes, and platelets, caused PD-L1–mediated immune escape by reducing T cell activation, metabolic activity, and cell cycle progression. The susceptibility of JAK2V617F-mutant MPN to PD-1 targeting paves the way for immunomodulatory approaches relying on PD-1 inhibition.
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- 2018
11. Sorafenib promotes graft-versus-leukemia activity in mice and humans through IL-15 production in FLT3-ITD-mutant leukemia cells
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Donald Bunjes, Sebastian Halbach, Dietmar Pfeifer, Philipp Hemmati, Robert S. Negrin, Fabio Ciceri, Jean-Yves Cahn, Markus Ditschkowski, Pavan Reddy, Kathrin Hanke, Daniela Dörfel, Susan Klaeger, Jürgen Finke, Zehan Hu, Gabriele Ihorst, Gérard Socié, Sanaz Taromi, Andreas Hochhaus, Glen A Kennedy, Omid Shah, Andreas Neubauer, Robert Thimme, Michael Schultheiss, Sabine Spath, Dietrich W. Beelen, Sandra Duquesne, Arnim Weber, Geoffrey R. Hill, Ronjon Chakraverty, Jürgen Kuball, Guido Kobbe, Nikolas von Bubnoff, Andrea S. Henden, Betul Oran, Burkhard Becher, Bernhard Kuster, Christoph Rummelt, Lena Osswald, Hartmut Bertz, Wolfgang Bethge, Eva-Maria Wagner, Arnon Nagler, Eliana Ruggiero, Saar Gill, Miguel Waterhouse, Andreas Mackensen, Dominik Bettinger, Francis Baumgartner, Florian Kuchenbauer, Anita Sarma, Takanori Teshima, Erika L. Pearce, Antonia M.S. Müller, Kathleen Stabla, John M. Magenau, Evelyn Ullrich, Nicolaus Kröger, Georg Häcker, Simone Thomas, Myriam Labopin, Ghulam J. Mufti, Jan E. Ehlert, Lutz P. Müller, Marie Follo, Dominik Wolf, Tony Andreas Müller, Michael Lübbert, Jacqueline Schnell, Christof Scheid, Takeshi Kondo, Donal P. McLornan, Thomas Pabst, Konrad Wilhelm, Chiara Bonini, Wolf Rösler, Simon Richardson, Cordula A. Jilg, Andrea Schmidts, Luca Vago, Joseph H. Antin, Annette Schmitt-Graeff, Yakup Tanriver, Michael A. Caligiuri, Wolfgang Herr, Kai-Li Yan, Lukas Braun, Daniel J. Weisdorf, Katayoun Rezvani, Giang Lam Vuong, Tilman Brummer, Stephan Meckel, Ralph Wäsch, Geoffroy Andrieux, Soroush Doostkam, Hauke Busch, Dennis Dong Hwan Kim, Sabine Gerull, Bruce R. Blazar, Robert Zeiser, Merav Bar, Flore Sicre-de-Fontbrune, Daniel Feger, Melanie Börries, Wolfgang Melchinger, Petya Apostolova, C. Leiber, Udo Holtick, Walter J.F.M. van der Velden, Renate Arnold, Rainer Claus, Justus Duyster, Nimitha R. Mathew, David O’Sullivan, Alexandros Spyridonidis, S K Metzelder, Thomas Schroeder, Jörg Halter, Johanna Haag, Friedrich Stölzel, Christoph Schmid, Anna Lena Illert, Claudia Lengerke, Björn Hackanson, Joern Dengjel, Francis Ayuk, Rainer Ordemann, Sonia Tugues, Marco Prinz, Inken Hilgendorf, Andreas Burchert, Mathew, Nimitha R, Baumgartner, Franci, Braun, Luka, O'Sullivan, David, Thomas, Simone, Waterhouse, Miguel, Müller, Tony A, Hanke, Kathrin, Taromi, Sanaz, Apostolova, Petya, Illert, Anna L, Melchinger, Wolfgang, Duquesne, Sandra, Schmitt-Graeff, Annette, Osswald, Lena, Yan, Kai-Li, Weber, Arnim, Tugues, Sonia, Spath, Sabine, Pfeifer, Dietmar, Follo, Marie, Claus, Rainer, Lübbert, Michael, Rummelt, Christoph, Bertz, Hartmut, Wäsch, Ralph, Haag, Johanna, Schmidts, Andrea, Schultheiss, Michael, Bettinger, Dominik, Thimme, Robert, Ullrich, Evelyn, Tanriver, Yakup, Vuong, Giang Lam, Arnold, Renate, Hemmati, Philipp, Wolf, Dominik, Ditschkowski, Marku, Jilg, Cordula, Wilhelm, Konrad, Leiber, Christian, Gerull, Sabine, Halter, Jörg, Lengerke, Claudia, Pabst, Thoma, Schroeder, Thoma, Kobbe, Guido, Rösler, Wolf, Doostkam, Soroush, Meckel, Stephan, Stabla, Kathleen, Metzelder, Stephan K, Halbach, Sebastian, Brummer, Tilman, Hu, Zehan, Dengjel, Joern, Hackanson, Björn, Schmid, Christoph, Holtick, Udo, Scheid, Christof, Spyridonidis, Alexandro, Stölzel, Friedrich, Ordemann, Rainer, Müller, Lutz P, Sicre-de-Fontbrune, Flore, Ihorst, Gabriele, Kuball, Jürgen, Ehlert, Jan E, Feger, Daniel, Wagner, Eva-Maria, Cahn, Jean-Yve, Schnell, Jacqueline, Kuchenbauer, Florian, Bunjes, Donald, Chakraverty, Ronjon, Richardson, Simon, Gill, Saar, Kröger, Nicolau, Ayuk, Franci, Vago, Luca, Ciceri, Fabio, Müller, Antonia M, Kondo, Takeshi, Teshima, Takanori, Klaeger, Susan, Kuster, Bernhard, Kim, Dennis Dong Hwan, Weisdorf, Daniel, van der Velden, Walter, Dörfel, Daniela, Bethge, Wolfgang, Hilgendorf, Inken, Hochhaus, Andrea, Andrieux, Geoffroy, Börries, Melanie, Busch, Hauke, Magenau, John, Reddy, Pavan, Labopin, Myriam, Antin, Joseph H, Henden, Andrea S, Hill, Geoffrey R, Kennedy, Glen A, Bar, Merav, Sarma, Anita, Mclornan, Donal, Mufti, Ghulam, Oran, Betul, Rezvani, Katayoun, Sha, Omid, Negrin, Robert S, Nagler, Arnon, Prinz, Marco, Burchert, Andrea, Neubauer, Andrea, Beelen, Dietrich, Mackensen, Andrea, von Bubnoff, Nikola, Herr, Wolfgang, Becher, Burkhard, Socié, Gerard, Caligiuri, Michael A, Ruggiero, Eliana, Bonini, Chiara, Häcker, Georg, Duyster, Justu, Finke, Jürgen, Pearce, Erika, Blazar, Bruce R, and Zeiser, Robert
- Subjects
0301 basic medicine ,Sorafenib ,medicine.drug_class ,Interferon Regulatory Factor-7 ,Medizin ,Graft vs Host Disease ,CD8-Positive T-Lymphocytes ,Article ,General Biochemistry, Genetics and Molecular Biology ,Tyrosine-kinase inhibitor ,Mice ,03 medical and health sciences ,0302 clinical medicine ,hemic and lymphatic diseases ,Animals ,Humans ,Transplantation, Homologous ,Medicine ,ddc:610 ,neoplasms ,Interleukin-15 ,business.industry ,Hematopoietic Stem Cell Transplantation ,Myeloid leukemia ,General Medicine ,Cellular Reprogramming ,medicine.disease ,Activating Transcription Factor 4 ,3. Good health ,Gene Expression Regulation, Neoplastic ,Transplantation ,Leukemia, Myeloid, Acute ,Leukemia ,030104 developmental biology ,fms-Like Tyrosine Kinase 3 ,Tandem Repeat Sequences ,Interleukin 15 ,030220 oncology & carcinogenesis ,Inflammatory diseases Radboud Institute for Health Sciences [Radboudumc 5] ,Cancer research ,IRF7 ,business ,CD8 ,medicine.drug - Abstract
Contains fulltext : 190745.pdf (Publisher’s version ) (Closed access) Individuals with acute myeloid leukemia (AML) harboring an internal tandem duplication (ITD) in the gene encoding Fms-related tyrosine kinase 3 (FLT3) who relapse after allogeneic hematopoietic cell transplantation (allo-HCT) have a 1-year survival rate below 20%. We observed that sorafenib, a multitargeted tyrosine kinase inhibitor, increased IL-15 production by FLT3-ITD(+) leukemia cells. This synergized with the allogeneic CD8(+) T cell response, leading to long-term survival in six mouse models of FLT3-ITD(+) AML. Sorafenib-related IL-15 production caused an increase in CD8(+)CD107a(+)IFN-gamma(+) T cells with features of longevity (high levels of Bcl-2 and reduced PD-1 levels), which eradicated leukemia in secondary recipients. Mechanistically, sorafenib reduced expression of the transcription factor ATF4, thereby blocking negative regulation of interferon regulatory factor 7 (IRF7) activation, which enhanced IL-15 transcription. Both IRF7 knockdown and ATF4 overexpression in leukemia cells antagonized sorafenib-induced IL-15 production in vitro. Human FLT3-ITD(+) AML cells obtained from sorafenib responders following sorafenib therapy showed increased levels of IL-15, phosphorylated IRF7, and a transcriptionally active IRF7 chromatin state. The mitochondrial spare respiratory capacity and glycolytic capacity of CD8(+) T cells increased upon sorafenib treatment in sorafenib responders but not in nonresponders. Our findings indicate that the synergism of T cells and sorafenib is mediated via reduced ATF4 expression, causing activation of the IRF7-IL-15 axis in leukemia cells and thereby leading to metabolic reprogramming of leukemia-reactive T cells in humans. Therefore, sorafenib treatment has the potential to contribute to an immune-mediated cure of FLT3-ITD-mutant AML relapse, an otherwise fatal complication after allo-HCT.
- Published
- 2018
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