32 results on '"Beelen, Dietrich"'
Search Results
2. Pre-transplant testosterone and outcome of men after allogeneic stem cell transplantation
- Author
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Radujkovic, Aleksandar, primary, Kordelas, Lambros, additional, Krzykalla, Julia, additional, Benner, Axel, additional, Schult, David, additional, Majer-Lauterbach, Joshua, additional, Beelen, Dietrich W., additional, Müller-Tidow, Carsten, additional, Kasperk, Christian, additional, Dreger, Peter, additional, and Luft, Thomas, additional
- Published
- 2019
- Full Text
- View/download PDF
3. Long-term outcome after allogeneic hematopoietic cell transplantation for myelofibrosis
- Author
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Robin, Marie, primary, de Wreede, Liesbeth C., additional, Wolschke, Christine, additional, Schetelig, Johannes, additional, Eikema, Diderik-Jan, additional, Van Lint, Maria Teresa, additional, Knelange, Nina Simone, additional, Beelen, Dietrich, additional, Brecht, Arne, additional, Niederwieser, Dietger, additional, Vitek, Antonin, additional, Bethge, Wolfgang, additional, Arnold, Renate, additional, Finke, Jürgen, additional, Volin, Liisa, additional, Yakoub-Agha, Ibrahim, additional, Nagler, Arnon, additional, Poiré, Xavier, additional, Einsele, Hermann, additional, Chevallier, Patrice, additional, Holler, Ernst, additional, Ljungman, Per, additional, Robinson, Stephen, additional, Radujkovic, Alekxandar, additional, McLornan, Donal, additional, Chalandon, Yves, additional, and Kröger, Nicolaus, additional
- Published
- 2019
- Full Text
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4. Optimized EBMT transplant-specific risk score in myelodysplastic syndromes after allogeneic stem-cell transplantation
- Author
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Gagelmann, Nico, primary, Eikema, Diderik-Jan, additional, Stelljes, Matthias, additional, Beelen, Dietrich, additional, de Wreede, Liesbeth, additional, Mufti, Ghulam, additional, Knelange, Nina Simone, additional, Niederwieser, Dietger, additional, Friis, Lone S., additional, Ehninger, Gerhard, additional, Nagler, Arnon, additional, Yakoub-Agha, Ibrahim, additional, Meijer, Ellen, additional, Ljungman, Per, additional, Maertens, Johan, additional, Kanz, Lothar, additional, Lopez-Corral, Lucia, additional, Brecht, Arne, additional, Craddock, Charles, additional, Finke, Jürgen, additional, Cornelissen, Jan J., additional, Bernasconi, Paolo, additional, Chevallier, Patrice, additional, Sierra, Jorge, additional, Robin, Marie, additional, and Kröger, Nicolaus, additional
- Published
- 2019
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5. Imatinib dose reduction in major molecular response of chronic myeloid leukemia: results from the German Chronic Myeloid Leukemia-Study IV
- Author
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Michel, Christian, primary, Burchert, Andreas, additional, Hochhaus, Andreas, additional, Saussele, Susanne, additional, Neubauer, Andreas, additional, Lauseker, Michael, additional, Krause, Stefan W., additional, Kolb, Hans-Jochem, additional, Hossfeld, Dieter Kurt, additional, Nerl, Christoph, additional, Baerlocher, Gabriela M., additional, Heim, Dominik, additional, Brümmendorf, Tim H, additional, Fabarius, Alice, additional, Haferlach, Claudia, additional, Schlegelberger, Brigitte, additional, Balleisen, Leopold, additional, Goebeler, Maria-Elisabeth, additional, Hänel, Mathias, additional, Ho, Anthony, additional, Dengler, Jolanta, additional, Falge, Christiane, additional, Möhle, Robert, additional, Kremers, Stephan, additional, Kneba, Michael, additional, Stegelmann, Frank, additional, Köhne, Claus-Henning, additional, Lindemann, Hans-Walter, additional, Waller, Cornelius F., additional, Spiekermann, Karsten, additional, Berdel, Wolfgang E., additional, Müller, Lothar, additional, Edinger, Matthias, additional, Mayer, Jiri, additional, Beelen, Dietrich W., additional, Bentz, Martin, additional, Link, Hartmut, additional, Hertenstein, Bernd, additional, Fuchs, Roland, additional, Wernli, Martin, additional, Schlegel, Frank, additional, Schlag, Rudolf, additional, de Wit, Maike, additional, Trümper, Lorenz, additional, Hebart, Holger, additional, Hahn, Markus, additional, Thomalla, Jörg, additional, Scheid, Christof, additional, Schafhausen, Philippe, additional, Verbeek, Walter, additional, Eckart, Michael J., additional, Gassmann, Winfried, additional, Schenk, Michael, additional, Brossart, Peter, additional, Wündisch, Thomas, additional, Geer, Thomas, additional, Bildat, Stephan, additional, Schäfer, Erhardt, additional, Hasford, Joerg, additional, Hehlmann, Rüdiger, additional, and Pfirrmann, Markus, additional
- Published
- 2018
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6. Asymmetric dimethylarginine serum levels are associated with early mortality after allogeneic stem cell transplantation
- Author
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Radujkovic, Aleksandar, primary, Dai, Hao, additional, Kordelas, Lambros, additional, Beelen, Dietrich, additional, Rachakonda, Sivaramakrishna P., additional, Müller-Tidow, Carsten, additional, Kumar, Rajiv, additional, Dreger, Peter, additional, and Luft, Thomas, additional
- Published
- 2018
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7. Competing-risk outcomes after hematopoietic stem cell transplantation from the perspective of time-dependent effects
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Fuerst, Daniel, primary, Frank, Sandra, additional, Mueller, Carlheinz, additional, Beelen, Dietrich W, additional, Schetelig, Johannes, additional, Niederwieser, Dietger, additional, Finke, Jürgen, additional, Bunjes, Donald, additional, Kröger, Nicolaus, additional, Neuchel, Christine, additional, Tsamadou, Chrysanthi, additional, Schrezenmeier, Hubert, additional, Beyersmann, Jan, additional, and Mytilineos, Joannis, additional
- Published
- 2018
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8. Outcome after relapse of myelodysplastic syndrome and secondary acute myeloid leukemia following allogeneic stem cell transplantation: a retrospective registry analysis on 698 patients by the Chronic Malignancies Working Party of the European Society of Blood and Marrow Transplantation
- Author
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Schmid, Christoph, primary, de Wreede, Liesbeth C., additional, van Biezen, Anja, additional, Finke, Jürgen, additional, Ehninger, Gerhard, additional, Ganser, Arnold, additional, Volin, Liisa, additional, Niederwieser, Dietger, additional, Beelen, Dietrich, additional, Alessandrino, Paolo, additional, Kanz, Lothar, additional, Schleuning, Michael, additional, Passweg, Jakob, additional, Veelken, Hendrik, additional, Maertens, Johan, additional, Cornelissen, Jan J., additional, Blaise, Didier, additional, Gramatzki, Martin, additional, Milpied, Noel, additional, Yakoub-Agha, Ibrahim, additional, Mufti, Ghulam, additional, Rovira, Montserrat, additional, Arnold, Renate, additional, de Witte, Theo, additional, Robin, Marie, additional, and Kröger, Nikolaus, additional
- Published
- 2017
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9. Improving results of allogeneic hematopoietic cell transplantation for adults with acute lymphoblastic leukemia in first complete remission: an analysis from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation
- Author
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Giebel, Sebastian, primary, Labopin, Myriam, additional, Socié, Gerard, additional, Beelen, Dietrich, additional, Browne, Paul, additional, Volin, Liisa, additional, Kyrcz-Krzemien, Slawomira, additional, Yakoub-Agha, Ibrahim, additional, Aljurf, Mahmoud, additional, Wu, Depei, additional, Michallet, Mauricette, additional, Arnold, Renate, additional, Mohty, Mohamad, additional, and Nagler, Arnon, additional
- Published
- 2016
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10. Allogeneic stem cell transplantation in second complete remission for core binding factor acute myeloid leukemia: a study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation.
- Author
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Halaburda K, Labopin M, Mailhol A, Socié G, Craddock C, Aljurf M, Beelen D, Cornelissen JJ, Bourhis JH, Labussière-Wallet H, Blaise D, Gedde-Dahl T, Gilleece M, Yakoub-Agha I, Mufti G, Esteve J, Mohty M, and Nagler A
- Subjects
- Bone Marrow, Core Binding Factors genetics, Humans, Remission Induction, Retrospective Studies, Transplantation Conditioning, Graft vs Host Disease etiology, Hematopoietic Stem Cell Transplantation, Leukemia, Myeloid, Acute diagnosis, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute therapy
- Abstract
Core binding factor acute myeloid leukemia (AML) comprises two subtypes with distinct cytogenetic abnormalities of either t(8;21)(q22;q22) or inv(16)(p13q22)/t(16;16)(p13;q22). Since long-term response to chemotherapy in these leukemias is relatively good, allogeneic hematopoietic stem cell transplantation is considered in patients who relapse and achieve second complete remission. To evaluate the outcomes of allogeneic transplantation in this indication, we studied 631 patients reported to the European Society for Blood and Marrow Transplantation Registry between the years 2000 and 2014. Leukemia-free survival probabilities at two and five years were 59.1% and 54.1%, while overall survival probabilities were 65% and 58.2%, respectively. The incidence of relapse and risk of non-relapse mortality at the same time points were 19.8% and 22.5% for relapse and 20.9% and 23.3% for non-relapse mortality, respectively. The most important adverse factors influencing leukemia-free and overall survival were: leukemia with t(8;21), presence of three or more additional chromosomal abnormalities, and Karnofsky performance score <80. Relapse risk was increased in t(8;21) leukemia and associated with additional cytogenetic abnormalities as well as reduced intensity conditioning. Measurable residual disease in molecular evaluation before transplantation was associated with increased risk of relapse and inferior leukemia-free survival., (Copyright© 2020 Ferrata Storti Foundation.)
- Published
- 2020
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11. Pre-transplant testosterone and outcome of men after allogeneic stem cell transplantation.
- Author
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Radujkovic A, Kordelas L, Krzykalla J, Benner A, Schult D, Majer-Lauterbach J, Beelen DW, Müller-Tidow C, Kasperk C, Dreger P, and Luft T
- Subjects
- Humans, Male, Prospective Studies, Retrospective Studies, Stem Cell Transplantation, Testosterone, Transplantation Conditioning, Transplantation, Homologous, Hematopoietic Stem Cell Transplantation adverse effects, Leukemia, Myeloid, Acute therapy
- Abstract
Testosterone is an important determinant of endothelial function and vascular health in men. As both factors play a role in mortality after allogeneic stem cell transplantation (alloSCT), we retrospectively evaluated the impact of pre-transplant testosterone levels on outcome in male patients undergoing alloSCT. In the discovery cohort (n=346), an impact on outcome was observed only in the subgroup of patients allografted for acute myeloid leukemia (AML) (n=176, hereafter termed 'training cohort'). In the training cohort, lower pre-transplant testosterone levels were significantly associated with shorter overall survival (OS) [hazard ratio (HR) for a decrease of 100 ng/dL: 1.11, P =0.045]. This was based on a higher hazard of non-relapse mortality (NRM) (cause-specific HR: 1.25, P =0.013), but not relapse (cause-specific HR: 1.06, P =0.277) in the multivariable models. These findings were replicated in a confirmation cohort of 168 male patients allografted for AML in a different center (OS, HR: 1.15, P =0.012 and NRM, cause-specific HR: 1.23; P =0.008). Next, an optimized cut-off point for pre-transplant testosterone was derived from the training set and evaluated in the confirmation cohort. In multivariable models, low pre-transplant testosterone status (<250 ng/dL) was associated with worse OS (hazard ratio 1.95, P =0.021) and increased NRM (cause-specific HR 2.68, P =0.011) but not with relapse (cause-specific HR: 1.28, P =0.551). Our findings may provide a rationale for prospective studies on testosterone/androgen assessment and supplementation in male patients undergoing alloSCT for AML., (Copyright© 2020 Ferrata Storti Foundation.)
- Published
- 2020
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12. Imatinib dose reduction in major molecular response of chronic myeloid leukemia: results from the German Chronic Myeloid Leukemia-Study IV.
- Author
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Michel C, Burchert A, Hochhaus A, Saussele S, Neubauer A, Lauseker M, Krause SW, Kolb HJ, Hossfeld DK, Nerl C, Baerlocher GM, Heim D, Brümmendorf TH, Fabarius A, Haferlach C, Schlegelberger B, Balleisen L, Goebeler ME, Hänel M, Ho A, Dengler J, Falge C, Möhle R, Kremers S, Kneba M, Stegelmann F, Köhne CH, Lindemann HW, Waller CF, Spiekermann K, Berdel WE, Müller L, Edinger M, Mayer J, Beelen DW, Bentz M, Link H, Hertenstein B, Fuchs R, Wernli M, Schlegel F, Schlag R, de Wit M, Trümper L, Hebart H, Hahn M, Thomalla J, Scheid C, Schafhausen P, Verbeek W, Eckart MJ, Gassmann W, Schenk M, Brossart P, Wündisch T, Geer T, Bildat S, Schäfer E, Hasford J, Hehlmann R, and Pfirrmann M
- Subjects
- Aged, Dose-Response Relationship, Drug, Female, Follow-Up Studies, Humans, Leukemia, Myelogenous, Chronic, BCR-ABL Positive pathology, Male, Middle Aged, Neoplasm Recurrence, Local pathology, Remission Induction, Retrospective Studies, Survival Rate, Time Factors, Treatment Outcome, Antineoplastic Agents therapeutic use, Imatinib Mesylate therapeutic use, Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy, Neoplasm Recurrence, Local drug therapy, Withholding Treatment statistics & numerical data
- Abstract
Standard first-line therapy of chronic myeloid leukemia is treatment with imatinib. In the randomized German Chronic Myeloid Leukemia-Study IV, more potent BCR-ABL inhibition with 800 mg ('high-dose') imatinib accelerated achievement of a deep molecular remission. However, whether and when a de-escalation of the dose intensity under high-dose imatinib can be safely performed without increasing the risk of losing deep molecular response is unknown. To gain insights into this clinically relevant question, we analyzed the outcome of imatinib dose reductions from 800 mg to 400 mg daily in the Chronic Myeloid Leukemia-Study IV. Of the 422 patients that were randomized to the 800 mg arm, 68 reduced imatinib to 400 mg after they had achieved at least a stable major molecular response. Of these 68 patients, 61 (90%) maintained major molecular remission on imatinib at 400 mg. Five of the seven patients who lost major molecular remission on the imatinib standard dose regained major molecular remission while still on 400 mg imatinib. Only two of 68 patients had to switch to more potent kinase inhibition to regain major molecular remission. Importantly, the lengths of the intervals between imatinib high-dose treatment before and after achieving major molecular remission were associated with the probabilities of maintaining major molecular remission with the standard dose of imatinib. Taken together, the data support the view that a deep molecular remission achieved with high-dose imatinib can be safely maintained with standard dose in most patients. Study protocol registered at clinicaltrials.gov 00055874 ., (Copyright© 2019 Ferrata Storti Foundation.)
- Published
- 2019
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13. Asymmetric dimethylarginine serum levels are associated with early mortality after allogeneic stem cell transplantation.
- Author
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Radujkovic A, Dai H, Kordelas L, Beelen D, Rachakonda SP, Müller-Tidow C, Kumar R, Dreger P, and Luft T
- Subjects
- Allografts, Arginine blood, Disease-Free Survival, Female, Humans, Male, Middle Aged, Risk Factors, Survival Rate, Arginine analogs & derivatives, Graft vs Host Disease blood, Graft vs Host Disease mortality, Hematopoietic Stem Cell Transplantation
- Abstract
Increasing evidence suggests that endothelial cell distress is associated with mortality after allogeneic stem cell transplantation and acute graft- versus -host disease. Asymmetric dimethylarginine is an endogenous nitric oxide synthase inhibitor that induces endothelial cell dysfunction. We analyzed the impact of pre-transplant serum levels of asymmetric dimethylarginine on outcome after allogeneic stem cell transplantation. Since acute graft- versus -host disease and its treatment are major contributors to post-transplant mortality, the effect of asymmetric dimethylarginine on outcome measures was also assessed after onset of acute graft- versus -host disease. A total of 938 patients allografted at two centers between 2002 and 2013 were included in the retrospective study. In multivariable models, higher pre-transplant asymmetric dimethylarginine levels were significantly associated with an increased risk of non-relapse mortality (hazard ratio 1.43 per 1-log
2 increase, P =0.005) but not with relapse (hazard ratio 1.21, P =0.109) within the first year after transplantation. This translated into worse overall survival (hazard ratio 1.45, P <0.0001) and shorter progression-free survival (hazard ratio 1.30, P =0.002) in the first year after transplantation. Higher pre-transplant asymmetric dimethylarginine levels were also associated with shorter overall survival (hazard ratio 1.46, P =0.001) and progression-free survival (hazard ratio 1.32, P =0.010) and higher non-relapse mortality (hazard ratio 1.36, P =0.042) within 1 year after the onset of acute graft- versus -host disease. Taken together, our data indicate an association between pre-transplant asymmetric dimethylarginine status and early non-relapse mortality in allografted patients, both overall and after the onset of acute graft- versus -host disease. These findings underline the relevance of endothelial dysfunction for transplant complications., (Copyright© 2019 Ferrata Storti Foundation.)- Published
- 2019
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14. Outcome after relapse of myelodysplastic syndrome and secondary acute myeloid leukemia following allogeneic stem cell transplantation: a retrospective registry analysis on 698 patients by the Chronic Malignancies Working Party of the European Society of Blood and Marrow Transplantation.
- Author
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Schmid C, de Wreede LC, van Biezen A, Finke J, Ehninger G, Ganser A, Volin L, Niederwieser D, Beelen D, Alessandrino P, Kanz L, Schleuning M, Passweg J, Veelken H, Maertens J, Cornelissen JJ, Blaise D, Gramatzki M, Milpied N, Yakoub-Agha I, Mufti G, Rovira M, Arnold R, de Witte T, Robin M, and Kröger N
- Subjects
- Adolescent, Adult, Aged, Allografts, Europe, Female, Humans, Lymphocyte Transfusion, Male, Middle Aged, Myelodysplastic Syndromes therapy, Recurrence, Registries, Reoperation, Retrospective Studies, Risk Factors, Treatment Outcome, Young Adult, Hematopoietic Stem Cell Transplantation methods, Leukemia, Myeloid, Acute etiology, Myelodysplastic Syndromes pathology
- Abstract
No standard exists for the treatment of myelodysplastic syndrome relapsing after allogeneic stem cell transplantation. We performed a retrospective registry analysis of outcomes and risk factors in 698 patients, treated with different strategies. The median overall survival from relapse was 4.7 months (95% confidence interval: 4.1-5.3) and the 2-year survival rate was 17.7% (95% confidence interval: 14.8-21.2%). Shorter remission after transplantation ( P <0.001), advanced disease ( P =0.001), older age ( P =0.007), unrelated donor ( P =0.008) and acute graft- versus -host disease before relapse ( P <0.001) adversely influenced survival. At 6 months from relapse, patients had received no cellular treatment, (i.e. palliative chemotherapy or best supportive care, n=375), donor lymphocyte infusion (n=213), or a second transplant (n=110). Treatment groups were analyzed separately because of imbalanced characteristics and difficulties in retrospectively evaluating the reason for individual treatments. Of the patients who did not receive any cellular therapy, 109 were alive at 6 months after relapse, achieving a median overall survival from this landmark of 8.9 months (95% confidence interval: 5.1-12.6). Their 2-year survival rate was 29.7%. Recipients of donor lymphocytes achieved a median survival from first infusion of 6.0 months (95% confidence interval: 3.7-8.3) with a 2-year survival rate of 27.6%. Longer remission after first transplantation ( P <0.001) and younger age ( P =0.009) predicted better outcome. Among recipients of a second transplant, the median survival from second transplantation was 4.2 months (95% confidence interval: 2.5-5.9), and their 2-year survival rate was 17.0%. Longer remission after first transplantation ( P <0.001), complete remission at second transplant ( P =0.008), no prior chronic graft- versus -host disease ( P <0.001) and change to a new donor ( P =0.04) predicted better outcome. The data enabled identification of patients benefiting from donor lymphocyte infusion and second transplantation, and may serve as a baseline for prospective trials., (Copyright© 2018 Ferrata Storti Foundation.)
- Published
- 2018
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15. Improving results of allogeneic hematopoietic cell transplantation for adults with acute lymphoblastic leukemia in first complete remission: an analysis from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation.
- Author
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Giebel S, Labopin M, Socié G, Beelen D, Browne P, Volin L, Kyrcz-Krzemien S, Yakoub-Agha I, Aljurf M, Wu D, Michallet M, Arnold R, Mohty M, and Nagler A
- Subjects
- Adolescent, Adult, Female, Humans, Male, Middle Aged, Myeloablative Agonists therapeutic use, Precursor Cell Lymphoblastic Leukemia-Lymphoma diagnosis, Precursor Cell Lymphoblastic Leukemia-Lymphoma mortality, Prognosis, Recurrence, Retrospective Studies, Risk Factors, Siblings, Transplantation Conditioning, Transplantation, Homologous, Treatment Outcome, Unrelated Donors, Young Adult, Hematopoietic Stem Cell Transplantation adverse effects, Hematopoietic Stem Cell Transplantation methods, Precursor Cell Lymphoblastic Leukemia-Lymphoma therapy, Remission Induction
- Abstract
Allogeneic hematopoietic cell transplantation is widely used to treat adults with high-risk acute lymphoblastic leukemia. The aim of this study was to analyze whether the results changed over time and to identify prognostic factors. Adult patients treated between 1993 and 2012 with myeloablative allogeneic hematopoietic cell transplantation from HLA matched sibling (n=2681) or unrelated (n=2178) donors in first complete remission were included. For transplantations from sibling donors performed between 2008 and 2012, 2-year probabilities of overall survival were: 76% (18-25 years old), 69% (26-35 and 36-45 years old) and 60% (46-55 years old). Among recipients of transplantations from unrelated donors, the respective survival rates were 66%, 70%, 61%, and 62%. In comparison with the 1993-2007 period, significant improvements were observed for all age groups except for the 26-35-year old patients. In a multivariate model, transplantations performed between 2008 and 2012, when compared to 1993-2007, were associated with significantly reduced risks of non-relapse mortality (Hazard Ratio 0.77, P=0.00006), relapse (Hazard Ratio 0.85, P=0.007), treatment failure (Hazard Ratio 0.81, P<0.00001), and overall mortality (Hazard Ratio 0.79, P<0.00001). In the analysis restricted to transplantations performed between 2008 and 2012, the use of total body irradiation-based conditioning was associated with reduced risk of relapse (Hazard Ratio 0.48, P=0.004) and treatment failure (Hazard Ratio 0.63, P=0.02). We conclude that results of allogeneic hematopoietic cell transplantation for adults with acute lymphoblastic leukemia improved significantly over time. Total body irradiation should be considered as the preferable type of myeloablative conditioning., (Copyright© Ferrata Storti Foundation.)
- Published
- 2017
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16. Time-dependent effects of clinical predictors in unrelated hematopoietic stem cell transplantation.
- Author
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Fuerst D, Mueller C, Beelen DW, Neuchel C, Tsamadou C, Schrezenmeier H, and Mytilineos J
- Subjects
- Adolescent, Adult, Aged, Antineoplastic Agents therapeutic use, Female, Germany, Graft vs Host Disease diagnosis, Graft vs Host Disease mortality, Graft vs Host Disease pathology, Graft vs Host Disease prevention & control, Humans, Leukemia, Myeloid, Acute mortality, Leukemia, Myeloid, Acute pathology, Leukemia, Myeloid, Acute therapy, Lymphoma, Non-Hodgkin mortality, Lymphoma, Non-Hodgkin pathology, Lymphoma, Non-Hodgkin therapy, Male, Middle Aged, Myelodysplastic Syndromes mortality, Myelodysplastic Syndromes pathology, Myelodysplastic Syndromes therapy, Precursor Cell Lymphoblastic Leukemia-Lymphoma mortality, Precursor Cell Lymphoblastic Leukemia-Lymphoma pathology, Precursor Cell Lymphoblastic Leukemia-Lymphoma therapy, Prognosis, Proportional Hazards Models, Retrospective Studies, Risk, Time Factors, Transplantation, Homologous, Unrelated Donors, Hematopoietic Stem Cell Transplantation methods, Leukemia, Myeloid, Acute diagnosis, Lymphoma, Non-Hodgkin diagnosis, Myelodysplastic Syndromes diagnosis, Precursor Cell Lymphoblastic Leukemia-Lymphoma diagnosis, Registries, Transplantation Conditioning methods
- Abstract
Hematopoietic stem cell transplantation is a multifactorial process. Some of the predictors exhibit time-dependent effects. We present a systematic analysis and description of selected clinical predictors influencing outcome in a time-dependent manner based on an analysis of registry data from the German Registry for Stem Cell Transplantation. A total of 14,951 patients with acute myeloid leukemia, acute lymphocytic leukemia, myelodysplastic syndrome and non-Hodgkin lymphoma transplanted with peripheral blood stem cells or bone marrow grafts were included. Multivariate Cox regression models were tested for time-dependent effects within each diagnosis group. Predictors not satisfying the proportional hazards assumption were modeled in a time-dependent manner, extending the Cox regression models. Similar patterns occurred in all diagnosis groups. Patients with a poor Karnofsky performance score (<80) had a high risk for early mortality until day 139 following transplantation (HR 2.42, CI: 2.19-2.68; P<0.001) compared to patients with a good Karnofsky performance score (80-100). Afterwards the risk reduced to HR 1.43, CI: 1.25-1.63; P<0.001. A lower mortality risk was found for patients after conditioning treatment with reduced intensity until day 120 post transplant (HR: 0.81 CI: 0.75-0.88; P<0.001). After this, a slightly higher risk could be shown for these patients. Similarly, patients who had received a PBSC graft exhibited a significantly lower mortality risk until day 388 post transplantation (HR 0.79, CI: 0.73-0.85; P<0.001), reversing to a significantly higher risk afterwards (HR 1.23, CI: 1.08-1.40; P=0.002). Integrating time dependency in regression models allows a more accurate description and quantification of clinical predictors to be made, which may help in risk assessment and patient counseling., (Copyright© Ferrata Storti Foundation.)
- Published
- 2016
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17. Current outcome of HLA identical sibling versus unrelated donor transplants in severe aplastic anemia: an EBMT analysis.
- Author
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Bacigalupo A, Socié G, Hamladji RM, Aljurf M, Maschan A, Kyrcz-Krzemien S, Cybicka A, Sengelov H, Unal A, Beelen D, Locasciulli A, Dufour C, Passweg JR, Oneto R, Signori A, and Marsh JC
- Subjects
- Anemia, Aplastic epidemiology, Europe epidemiology, Female, Graft Survival, Graft vs Host Disease epidemiology, Graft vs Host Disease etiology, HLA Antigens genetics, HLA Antigens immunology, Humans, Incidence, Male, Risk Factors, Survival Analysis, Transplantation Conditioning methods, Transplantation, Homologous, Treatment Outcome, Anemia, Aplastic mortality, Anemia, Aplastic therapy, Hematopoietic Stem Cell Transplantation adverse effects, Siblings, Unrelated Donors
- Abstract
We have analyzed 1448 patients with acquired aplastic anemia grafted between 2005 and 2009, and compared outcome of identical sibling (n=940) versus unrelated donor (n=508) transplants. When compared to the latter, sibling transplants were less likely to be performed beyond 180 days from diagnosis (39% vs. 85%), to have a cytomegalovirus negative donor/recipient status (15% vs. 23%), to receive antithymocyte globulin in the conditioning (52% vs. 61%), and more frequently received marrow as a stem cell source (60% vs. 52%). Unrelated donor grafts had significantly more acute grade II-IV (25% vs. 13%) and significantly more chronic graft-versus-host disease (26% vs. 14%). In multivariate analysis, the risk of death of unrelated donor grafts was higher, but not significantly higher, compared to a sibling donor (P=0.16). The strongest negative predictor of survival was the use of peripheral blood as a stem cell source (P<0.00001), followed by an interval of diagnosis to transplant of 180 days or more (P=0.0005), patient age 20 years or over (P=0.0005), no antithymocyte globulin in the conditioning (P=0.003), and donor/recipient cytomegalovirus sero-status, other than negative/negative (P=0.04). In conclusion, in multivariate analysis, the outcome of unrelated donor transplants for acquired aplastic anemia, is currently not statistically inferior when compared to sibling transplants, although patients are at greater risk of acute and chronic graft-versus-host disease. The use of peripheral blood grafts remains the strongest negative predictor of survival., (Copyright© Ferrata Storti Foundation.)
- Published
- 2015
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18. T-cell-replete haploidentical transplantation versus autologous stem cell transplantation in adult acute leukemia: a matched pair analysis.
- Author
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Gorin NC, Labopin M, Piemontese S, Arcese W, Santarone S, Huang H, Meloni G, Ferrara F, Beelen D, Sanz M, Bacigalupo A, Ciceri F, Mailhol A, Nagler A, and Mohty M
- Subjects
- Acute Disease, Adolescent, Adult, Aged, Female, Follow-Up Studies, Graft vs Host Disease etiology, Graft vs Host Disease prevention & control, Haplotypes, Humans, Leukemia diagnosis, Leukemia mortality, Lymphocyte Depletion, Male, Matched-Pair Analysis, Middle Aged, Survival Analysis, Transplantation Conditioning, Transplantation, Autologous, Transplantation, Homologous, Treatment Outcome, Young Adult, Hematopoietic Stem Cell Transplantation adverse effects, Hematopoietic Stem Cell Transplantation methods, Leukemia therapy
- Abstract
Adult patients with acute leukemia in need of a transplant but without a genoidentical donor are usually considered upfront for transplantation with stem cells from any other allogeneic source, rather than autologous stem cell transplantation. We used data from the European Society for Blood and Marrow Transplantation and performed a matched pair analysis on 188 T-cell-replete haploidentical and 356 autologous transplants done from January 2007 to December 2012, using age, diagnosis, disease status, cytogenetics, and interval from diagnosis to transplant as matching factors. "Haploidentical expert" centers were defined as having reported more than five haploidentical transplants for acute leukemia (median value for the study period). The median follow-up was 28 months. Multivariate analyses, including type of transplant categorized into three classes ("haploidentical regular", "haploidentical expert" and autologous), conditioning intensity (reduced intensity versus myeloablative conditioning) and the random effect taking into account associations related to matching, showed that non-relapse mortality was higher following haploidentical transplants in expert (HR: 4.7; P=0.00004) and regular (HR: 8.98; P<10(-5)) centers. Relapse incidence for haploidentical transplants was lower in expert centers (HR:0.39; P=0.0003) but in regular centers was similar to that for autologous transplants. Leukemia-free survival and overall survival rates were higher following autologous transplantation than haploidentical transplants in regular centers (HR: 1.63; P=0.008 and HR: 2.31; P=0.0002 respectively) but similar to those following haploidentical transplants in expert centers. We conclude that autologous stem cell transplantation should presently be considered as a possible alternative to haploidentical transplantation in regular centers that have not developed a specific expert program., (Copyright© Ferrata Storti Foundation.)
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- 2015
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19. Impact of the revised International Prognostic Scoring System, cytogenetics and monosomal karyotype on outcome after allogeneic stem cell transplantation for myelodysplastic syndromes and secondary acute myeloid leukemia evolving from myelodysplastic syndromes: a retrospective multicenter study of the European Society of Blood and Marrow Transplantation.
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Koenecke C, Göhring G, de Wreede LC, van Biezen A, Scheid C, Volin L, Maertens J, Finke J, Schaap N, Robin M, Passweg J, Cornelissen J, Beelen D, Heuser M, de Witte T, and Kröger N
- Subjects
- Adolescent, Adult, Aged, Antineoplastic Agents therapeutic use, Bone Marrow drug effects, Bone Marrow pathology, Cytogenetic Analysis, Europe, Female, Humans, Karyotype, Leukemia, Myeloid, Acute etiology, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute mortality, Male, Middle Aged, Myelodysplastic Syndromes complications, Myelodysplastic Syndromes genetics, Myelodysplastic Syndromes mortality, Prognosis, Proportional Hazards Models, Recurrence, Retrospective Studies, Risk, Societies, Medical, Survival Analysis, Transplantation, Homologous, Hematopoietic Stem Cell Transplantation, Leukemia, Myeloid, Acute therapy, Monosomy, Myelodysplastic Syndromes therapy, Research Design
- Abstract
The aim of this study was to determine the impact of the revised 5-group International Prognostic Scoring System cytogenetic classification on outcome after allogeneic stem cell transplantation in patients with myelodysplastic syndromes or secondary acute myeloid leukemia who were reported to the European Society for Blood and Marrow Transplantation database. A total of 903 patients had sufficient cytogenetic information available at stem cell transplantation to be classified according to the 5-group classification. Poor and very poor risk according to this classification was an independent predictor of shorter relapse-free survival (hazard ratio 1.40 and 2.14), overall survival (hazard ratio 1.38 and 2.14), and significantly higher cumulative incidence of relapse (hazard ratio 1.64 and 2.76), compared to patients with very good, good or intermediate risk. When comparing the predictive performance of a series of Cox models both for relapse-free survival and for overall survival, a model with simplified 5-group cytogenetics (merging very good, good and intermediate cytogenetics) performed best. Furthermore, monosomal karyotype is an additional negative predictor for outcome within patients of the poor, but not the very poor risk group of the 5-group classification. The revised International Prognostic Scoring System cytogenetic classification allows patients with myelodysplastic syndromes to be separated into three groups with clearly different outcomes after stem cell transplantation. Poor and very poor risk cytogenetics were strong predictors of poor patient outcome. The new cytogenetic classification added value to prediction of patient outcome compared to prediction models using only traditional risk factors or the 3-group International Prognostic Scoring System cytogenetic classification., (Copyright© Ferrata Storti Foundation.)
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- 2015
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20. Impact of the International Prognostic Scoring System cytogenetic risk groups on the outcome of patients with primary myelodysplastic syndromes undergoing allogeneic stem cell transplantation from human leukocyte antigen-identical siblings: a retrospective analysis of the European Society for Blood and Marrow Transplantation-Chronic Malignancies Working Party.
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Onida F, Brand R, van Biezen A, Schaap M, von dem Borne PA, Maertens J, Beelen DW, Carreras E, Alessandrino EP, Volin L, Kuball JH, Figuera A, Sierra J, Finke J, Kröger N, and de Witte T
- Subjects
- Adolescent, Adult, Aged, Child, Child, Preschool, Female, Humans, Infant, Infant, Newborn, Male, Middle Aged, Myelodysplastic Syndromes mortality, Prognosis, Retrospective Studies, Transplantation Conditioning, Transplantation, Homologous, Treatment Outcome, Young Adult, HLA Antigens immunology, Hematopoietic Stem Cell Transplantation, Myelodysplastic Syndromes immunology, Myelodysplastic Syndromes therapy, Siblings
- Abstract
Acquired chromosomal abnormalities are important prognostic factors in patients with myelodysplastic syndromes treated with supportive care and with disease-modifying therapeutic interventions, including allogeneic hematopoietic stem cell transplantation. To assess the prognostic impact of cytogenetic characteristics after hematopoietic stem cell transplantation accurately, we investigated a homogeneous group of 523 patients with primary myelodysplastic syndromes who have received stem cells from human leukocyte antigen-identical siblings. Overall survival at five years from transplantation in good, intermediate, and poor cytogenetic risk groups according to the International Prognostic Scoring System was 48%, 45% and 30%, respectively (P<0.01). Both the disease status (complete remission vs. not in complete remission) and the morphological classification at transplant in the untreated patients were significantly associated with probability of overall survival and relapse-free survival (P<0.01). The cytogenetic risk groups have no prognostic impact in untreated patients with refractory anemia ± ringed sideroblasts (P=0.90). However, combining the good and intermediate cytogenetic risk groups and comparing them to the poor-risk group showed within the other three disease-status-at-transplant groups a hazard ratio of 1.86 (95%CI: 1.41-2.45). In conclusion, this study shows that, in a large series of patients with primary myelodysplastic syndromes, poor-risk cytogenetics as defined by the standard International Prognostic Scoring System is associated with a relatively poor survival after allogeneic stem cell transplantation from human leukocyte antigen-identical siblings except in patients who are transplanted in refractory anemia/refractory anemia with ringed sideroblasts stage before progression to higher myelodysplastic syndrome stages., (Copyright© Ferrata Storti Foundation.)
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- 2014
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21. Syngeneic transplantation in aplastic anemia: pre-transplant conditioning and peripheral blood are associated with improved engraftment: an observational study on behalf of the Severe Aplastic Anemia and Pediatric Diseases Working Parties of the European Group for Blood and Marrow Transplantation.
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Gerull S, Stern M, Apperley J, Beelen D, Brinch L, Bunjes D, Butler A, Ganser A, Ghavamzadeh A, Koh MB, Komarnicki M, Kröger N, Maertens J, Maschan A, Peters C, Rovira M, Sengeløv H, Socié G, Tischer J, Oneto R, Passweg J, and Marsh J
- Subjects
- Adolescent, Adult, Aged, Anemia, Aplastic diagnosis, Anemia, Aplastic epidemiology, Child, Child, Preschool, Databases, Factual trends, Europe epidemiology, Female, Follow-Up Studies, Humans, Male, Middle Aged, Pediatrics methods, Transplantation, Isogeneic, Young Adult, Anemia, Aplastic surgery, Bone Marrow Transplantation methods, Graft Survival physiology, Peripheral Blood Stem Cell Transplantation methods, Severity of Illness Index, Transplantation Conditioning methods
- Abstract
Aplastic anemia is usually treated with immunosuppression or allogeneic transplant, depending on patient and disease characteristics. Syngeneic transplant offers a rare treatment opportunity with minimal transplant-related mortality, and offers an insight into disease mechanisms. We present here a retrospective analysis of all syngeneic transplants for aplastic anemia reported to the European Group for Blood and Marrow Transplantation. Between 1976 and 2009, 88 patients received 113 transplants. Most transplants (n=85) were preceded by a conditioning regimen, 22 of these including anti-thymocyte globulin. About half of transplants with data available (39 of 86) were followed by posttransplant immunosuppression. Graft source was bone marrow in the majority of cases (n=77). Transplant practice changed over time with more transplants with conditioning and anti-thymocyte globulin as well as peripheral blood stem cells performed in later years. Ten year overall survival was 93% with 5 transplant-related deaths. Graft failure occurred in 32% of transplants. Risk of graft failure was significantly increased in transplants without conditioning, and with bone marrow as graft source. Lack of posttransplant immunosuppression also showed a trend towards increased risk of graft failure, while anti-thymocyte globulin did not have an influence. In summary, syngeneic transplant is associated with a significant risk of graft failure when no conditioning is given, but has an excellent long-term outcome. Furthermore, our comparatively large series enables us to recommend the use of pre-transplant conditioning rather than not and possibly to prefer peripheral blood as a stem cell source.
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- 2013
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22. Dynamic International Prognostic Scoring System scores, pre-transplant therapy and chronic graft-versus-host disease determine outcome after allogeneic hematopoietic stem cell transplantation for myelofibrosis.
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Ditschkowski M, Elmaagacli AH, Trenschel R, Gromke T, Steckel NK, Koldehoff M, and Beelen DW
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- Adolescent, Adult, Aged, Child, Female, Graft vs Host Disease etiology, Humans, Male, Middle Aged, Primary Myelofibrosis mortality, Prognosis, Recurrence, Risk Factors, Transplantation, Homologous, Treatment Outcome, Young Adult, Hematopoietic Stem Cell Transplantation adverse effects, Primary Myelofibrosis diagnosis, Primary Myelofibrosis therapy
- Abstract
Background: Myelofibrosis is a myeloproliferative stem cell disorder curable exclusively by allogeneic hematopoietic stem cell transplantation and is associated with substantial mortality and morbidity. The aim of this study was to assess disease-specific and transplant-related risk factors that influence post-transplant outcome in patients with myelofibrosis., Design and Methods: We retrospectively assessed 76 consecutive patients with primary (n=47) or secondary (n=29) myelofibrosis who underwent bone marrow (n=6) or peripheral blood stem cell (n=70) transplantation from sibling (n=30) or unrelated (n=46) donors between January 1994 and December 2010. The median follow-up of surviving patients was 55 ± 7.5 months., Results: Primary graft failure occurred in 5% and the non-relapse mortality rate at 1 year was 28%. The relapse-free survival rate was 50% with a relapse rate of 19% at 5 years. The use of pharmacological pre-treatment and the post-transplant occurrence of chronic graft-versus-host disease were significant independent unfavourable risk factors for post-transplant survival in multivariate analysis. Using the Dynamic International Prognostic Scoring System for risk stratification, low-risk patients had significantly better overall survival (P=0.014, hazard ratio 1.4) and relapse-free survival (P=0.02, hazard ratio 1.3) compared to the other risk groups of patients. The additional inclusion of thrombocytopenia, abnormal karyotype and transfusion need (Dynamic International Prognostic Scoring System Plus) resulted in a predicted 5-year overall survival of 100%, 51%, 54% and 30% for low, intermediate-1, intermediate-2 and high-risk groups, respectively. The relapse incidence was significantly higher in the absence of chronic graft-versus-host disease (P=0.006), and pharmacological pre-treatment (n=43) was associated with reduced relapse-free survival (P=0.001)., Conclusions: The data corroborate a strong correlation between alloreactivity and long-term post-transplant disease control and confirm an inverse relationship between disease stage, pharmacotherapy and outcome after allogeneic hematopoietic stem cell transplantation for myelofibrosis. The Dynamic International Prognostic Scoring System was demonstrated to be useful for risk stratification of patients with myelofibrosis who are to undergo hematopoietic stem cell transplantation.
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- 2012
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23. Haploidentical allogeneic hematopoietic cell transplantation in adults using CD3/CD19 depletion and reduced intensity conditioning: a phase II study.
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Federmann B, Bornhauser M, Meisner C, Kordelas L, Beelen DW, Stuhler G, Stelljes M, Schwerdtfeger R, Christopeit M, Behre G, Faul C, Vogel W, Schumm M, Handgretinger R, Kanz L, and Bethge WA
- Subjects
- Adult, Aged, Antigens, CD34, Chimerism, Female, Graft Survival, Graft vs Host Disease, Haplotypes, Hematologic Diseases mortality, Hematopoietic Stem Cells metabolism, Humans, Leukemia therapy, Lymphoma, Non-Hodgkin therapy, Major Histocompatibility Complex genetics, Male, Middle Aged, Multiple Myeloma therapy, Myelodysplastic Syndromes therapy, Receptors, KIR immunology, Risk Factors, Tissue Donors, Transplantation, Homologous, Treatment Outcome, Young Adult, Antigens, CD19, CD3 Complex, Hematologic Diseases therapy, Hematopoietic Stem Cell Transplantation adverse effects, Lymphocyte Depletion, Transplantation Conditioning
- Abstract
Background: We report a prospective multicenter phase II study of haploidentical hematopoietic stem cell transplantation using CD3/CD19-depleted grafts after reduced intensity conditioning with fludarabine, thiotepa, melphalan and OKT-3., Design and Methods: Sixty-one adults with a median age of 46 years (range 19-65 years) have been enrolled. Diagnoses were acute myeloid leukemia (n=38), acute lymphoblastic leukemia (n=8), non-Hodgkin's lymphoma (n=6), myeloma (n=4), chronic myeloid leukemia (n=3), chronic lymphatic leukemia (n=1) and myelodysplastic syndrome (n=1). Patients were considered high risk because of refractory disease (n=18), cytogenetics (n=6), complete remission (≥ 2) (n=9), chemosensitive relapse in partial remission (n=4) or relapse after prior hematopoietic stem cell transplantation (n=15 allogeneic, n=8 autologous, n=1 both). At haploidentical hematopoietic stem cell transplantation, 30 patients were in complete remission and 31 in partial remission. Grafts contained a median of 7.0 × 10(6) (range 3.2-22) CD34(+) cells/kg, 4.2 × 10(4) (range 0.6-44) CD3(+) T cells/kg and 2.7 × 10(7) (range 0.00-37.3) CD56(+) cells/kg., Results: Engraftment was rapid with a median of 12 days to granulocytes more than 0.5 × 10(9)/L (range 9-50 days) and 11 days to platelets more than 20 × 10(9) (range 7-38 days). Incidence of grade IIIV acute graft-versus-host-disease and chronic graft-versus-host-disease was 46% and 18%, respectively. Non-relapse mortality on Day 100 was 23% and 42% at two years. Cumulative incidence of relapse/progression at two years was 31%. Kaplan-Meier estimated 1-year and 2-year overall survival with median follow up of 869 days (range 181-1932) is 41% and 28%, respectively., Conclusions: This regimen allows successful haploidentical hematopoietic stem cell transplantation with reduced intensity conditioning in high-risk patients lacking a suitable donor. (clinicaltrials.gov identifier:NCT00202917).
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- 2012
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24. Lenalidomide maintenance after allogeneic HSCT seems to trigger acute graft-versus-host disease in patients with high-risk myelodysplastic syndromes or acute myeloid leukemia and del(5q): results of the LENAMAINT trial.
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Sockel K, Bornhaeuser M, Mischak-Weissinger E, Trenschel R, Wermke M, Unzicker C, Kobbe G, Finke J, Germing U, Mohr B, Greiner J, Beelen D, Thiede C, Ehninger G, and Platzbecker U
- Subjects
- Female, Humans, Male, Antineoplastic Agents administration & dosage, Chromosome Aberrations, Chromosomes, Human, Pair 5 genetics, Leukemia, Myeloid, Acute drug therapy, Myelodysplastic Syndromes drug therapy, Thalidomide analogs & derivatives
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- 2012
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25. Reduced-toxicity conditioning with treosulfan and fludarabine in allogeneic hematopoietic stem cell transplantation for myelodysplastic syndromes: final results of an international prospective phase II trial.
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Ruutu T, Volin L, Beelen DW, Trenschel R, Finke J, Schnitzler M, Holowiecki J, Giebel S, Markiewicz M, Uharek L, Blau IW, Kienast J, Stelljes M, Larsson K, Zander AR, Gramatzki M, Repp R, Einsele H, Stuhler G, Baumgart J, Mylius HA, Pichlmeier U, Freund M, and Casper J
- Subjects
- Adult, Antineoplastic Agents adverse effects, Busulfan adverse effects, Busulfan therapeutic use, Chimerism, Female, Graft vs Host Disease etiology, Humans, Male, Middle Aged, Myelodysplastic Syndromes mortality, Recurrence, Transplantation, Homologous, Treatment Outcome, Vidarabine adverse effects, Vidarabine therapeutic use, Young Adult, Antineoplastic Agents therapeutic use, Busulfan analogs & derivatives, Hematopoietic Stem Cell Transplantation adverse effects, Myelodysplastic Syndromes therapy, Transplantation Conditioning, Vidarabine analogs & derivatives
- Abstract
Background: An alternative reduced-toxicity conditioning regimen for allogeneic transplantation, based on treosulfan and fludarabine, has recently been identified. The rationale for this study was to investigate the efficacy and safety of this regimen prospectively in patients with a primary myelodysplastic syndrome., Design and Methods: A total of 45 patients with primary myelodysplastic syndromes were conditioned with 3×14 g/m(2) treosulfan and 5×30 mg/m(2) fludarabine followed by allogeneic hematopoietic stem cell transplantation. Subtypes of myelodysplastic syndromes were refractory anemia with excess blasts-2 (44%), refractory cytopenia with multilineage dysplasia (27%), refractory anemia (9%), refractory anemia with ringed sideroblasts (4%), refractory cytopenia with multilineage dysplasia and ringed sideroblasts (4%), refractory anemia with excess blasts-1 (2%), and myelodysplastic syndrome with isolated del (5q) (2%). The myelodysplastic syndrome was unclassified in 7% of the patients. Forty-seven percent of the patients had a favorable karyotype, 29% an unfavorable one, and 18% an intermediate karyotype. Patients were evaluated for engraftment, adverse events, graft-versus-host disease, non-relapse mortality, relapse incidence, overall survival and disease-free survival., Results: All but one patient showed primary engraftment of neutrophils after a median of 17 days. Non-hematologic adverse events of grade III-IV in severity included mainly infections and gastrointestinal symptoms (80% and 22% of the patients, respectively). Acute graft-versus-host disease grade II-IV developed in 24%, and extensive chronic graft-versus-host disease in 28% of the patients. After a median follow-up of 780 days, the 2-year overall and disease-free survival estimates were 71% and 67%, respectively. The 2-year cumulative incidences of non-relapse mortality and relapse were 17% and 16%, respectively., Conclusions: Our safety and efficacy data suggest that treosulfan-based conditioning therapy is a promising treatment option for patients with myelodysplastic syndromes. clinicaltrials.gov identifier: NCT01062490.
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- 2011
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26. Allogeneic transplantation as post-remission therapy for cytogenetically high-risk acute myeloid leukemia: landmark analysis from a single prospective multicenter trial.
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Stelljes M, Beelen DW, Braess J, Sauerland MC, Heinecke A, Berning B, Kolb HJ, Holler E, Schwerdtfeger R, Arnold R, Spiekermann K, Müller-Tidow C, Serve HL, Silling G, Hiddemann W, Berdel WE, Büchner T, and Kienast J
- Subjects
- Adult, Cytogenetics, Female, Humans, Leukemia, Myeloid, Acute mortality, Male, Middle Aged, Monosomy genetics, Neoadjuvant Therapy, Recurrence, Remission Induction, Survival Analysis, Transplantation, Homologous, Treatment Outcome, Young Adult, Hematopoietic Stem Cell Transplantation, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute therapy
- Abstract
Unlabelled: Background Allogeneic hematopoietic cell transplantation is considered the preferred post-remission therapy in patients with acute myeloid leukemia cytogenetically defined as being at high risk. To substantiate evidence for allogeneic hematopoietic cell transplantation in first complete remission in these high-risk patients we performed a landmark analysis within a single prospective multicenter treatment trial., Design and Methods: By the time of analysis, 2,347 patients had been accrued into the AMLCG 99 trial between 1999 - 2007. Out of this population, 243 patients under 60 years old fulfilled the criteria for high-risk cytogenetics. Landmark analyses were performed with a control cohort, who remained in first complete remission at least the median time from complete remission to transplantation in the intervention group., Results: After standardized induction therapy, 111 patients under 60 years old achieved complete remission. A matched allogeneic donor was identified for 59 patients (30 sibling donors, 29 unrelated donors). Fifty-five patients received an allogeneic hematopoietic cell transplant after a median time of 88 days in first complete remission. Of the remaining 56 patients, 21 relapsed within 90 days after achieving first complete remission and for 7 patients with relevant comorbidities no donors search was initiated, leaving 28 patients given conventional post-remission therapy as the control cohort. The median follow-up of surviving patients was 60.4 months. Patients with an allogeneic donor had substantially better 5-year overall and relapse-free survival rates than the control group (48% versus 18%, P=0.004 and 39% versus 10%, P<0.001, respectively). A survival benefit from transplantation was evident regardless of donor type, age and monosomal karyotype. Conclusions Beyond evidence available for subgroups of high-risk patients, the findings of this study establish in a broader manner that allogeneic hematopoietic cell transplantation is a preferable consolidation treatment for patients with acute myeloid leukemia and high-risk cytogenetics. The study was registered at Clinicaltrials.gov as NCT00266136.
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- 2011
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27. Small interfering RNA against BCR-ABL transcripts sensitize mutated T315I cells to nilotinib.
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Koldehoff M, Kordelas L, Beelen DW, and Elmaagacli AH
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- Animals, Apoptosis drug effects, Benzamides, Cell Line, Tumor, Cell Proliferation drug effects, Combined Modality Therapy, Gene Expression Regulation, Leukemic, Humans, Imatinib Mesylate, Mice, Piperazines administration & dosage, Pyrimidines administration & dosage, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Drug Resistance, Neoplasm, Fusion Proteins, bcr-abl genetics, Leukemia genetics, Leukemia therapy, Mutation genetics, RNA, Small Interfering pharmacology
- Abstract
Background: Selective inhibition of the BCR-ABL tyrosine kinase by RNA interference has been demonstrated in leukemic cells. We, therefore, evaluated specific BCR-ABL small interfering RNA silencing in BCR-ABL-positive cell lines, including those resistant to imatinib and particularly those with the T315I mutation., Design and Methods: The factor-independent 32Dp210 BCR-ABL oligoclonal cell lines and human imatinib-resistant BCR-ABL-positive cells from patients with leukemic disorders were investigated. The effects of BCR-ABL small interfering RNA or the combination of BCR-ABL small interfering RNA with imatinib and nilotinib were compared with those of the ABL inhibitors imatinib and nilotinib., Results: Co-administration of BCR-ABL small interfering RNA with imatinib or nilotinib dramatically reduced BCR-ABL expression in wild-type and mutated BCR-ABL cells and increased the lethal capacity. BCR-ABL small interfering RNA significantly induced apoptosis and inhibited proliferation in wild-type (P<0.0001) and mutated cells (H396P, T315I, P<0.0001) versus controls. Co-treatment with BCR-ABL small interfering RNA and imatinib or nilotinib resulted in increased inhibition of proliferation and induction of apoptosis in T315I cells as compared to imatinib or nilotinib alone (P<0.0001). Furthermore, the combination of BCR-ABL small interfering RNA with imatinib or nilotinib significantly (P<0.01) reversed multidrug resistance-1 gene-dependent resistance of mutated cells. In T315I cells BCR-ABL small interfering RNA with nilotinib had powerful effects on cell cycle distribution., Conclusions: Our data suggest that silencing by BCR-ABL small interfering RNA combined with imatinib or nilotinib may be associated with an additive antileukemic activity against tyrosine kinase inhibitor-sensitive and resistant BCR-ABL cells, and might be an alternative approach to overcome BCR-ABL mutations.
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- 2010
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28. Risk factors for therapy-related myelodysplastic syndrome and acute myeloid leukemia treated with allogeneic stem cell transplantation.
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Kröger N, Brand R, van Biezen A, Zander A, Dierlamm J, Niederwieser D, Devergie A, Ruutu T, Cornish J, Ljungman P, Gratwohl A, Cordonnier C, Beelen D, Deconinck E, Symeonidis A, and de Witte T
- Subjects
- Adolescent, Adult, Aged, Child, Child, Preschool, Humans, Leukemia, Myeloid, Acute mortality, Leukemia, Myeloid, Acute therapy, Middle Aged, Myelodysplastic Syndromes mortality, Myelodysplastic Syndromes therapy, Neoplasms, Second Primary epidemiology, Neoplasms, Second Primary mortality, Prognosis, Retrospective Studies, Risk Factors, Transplantation, Homologous, Treatment Outcome, Young Adult, Hematopoietic Stem Cell Transplantation mortality, Leukemia, Myeloid, Acute chemically induced, Myelodysplastic Syndromes chemically induced, Neoplasms, Second Primary therapy
- Abstract
Background: After successful treatment of malignant diseases, therapy-related myelodysplastic syndrome and acute myeloid leukemia have emerged as significant problems., Design and Methods: The aim of this study was to investigate outcome and risk factors in patients with therapy-related myelodysplastic syndrome or acute myeloid leukemia who underwent allogeneic stem cell transplantation. Between 1981 and 2006, 461 patients with therapy-related myelodysplastic syndrome or acute myeloid, a median age of 40 years and a history of solid tumor (n=163), malignant lymphoma (n=133), or other hematologic diseases (n=57) underwent stem cell transplantation and their data were reported to the European Group for Blood and Marrow Transplantation., Results: The cumulative incidence of non-relapse mortality and relapse at 3 years was 37% and 31%, respectively. In a multivariate analysis significant factors for relapse were not being in complete remission at the time of transplantation (p=0.002), abnormal cytogenetics (p=0.005), higher patients' age (p=0.03) and therapy-related myelodysplastic syndrome (p=0.04), while higher non-relapse mortality was influenced by higher patients' age. Furthermore, there was a marked reduction in non-relapse mortality per calendar year during the study period (p<0.001). The 3-year relapse-free and overall survival rates were 33% and 35%, respectively. In a multivariate analysis significant higher overall survival rates were seen per calendar year (p<0.001), for younger age (<40 years) and normal cytogenetics (p=0.05). Using age (<40 years), abnormal cytogenetics and not being in complete remission at the time of transplantation as risk factors, three different risk groups with overall survival rates of 62%, 33% and 24% could be easily distinguished., Conclusions: Allogeneic stem cell transplantation can cure patients with therapy-related myelodysplastic syndrome and acute myeloid leukemia and has markedly improved over time. Non-complete remission, abnormal cytogenetics and higher patients' age are the most significant factors predicting survival.
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- 2009
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29. Characterization of 35 new cases with four different MPLW515 mutations and essential thrombocytosis or primary myelofibrosis.
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Schnittger S, Bacher U, Haferlach C, Beelen D, Bojko P, Bürkle D, Dengler R, Distelrath A, Eckart M, Eckert R, Fries S, Knoblich J, Köchling G, Laubenstein HP, Petrides P, Planker M, Pihusch R, Weide R, Kern W, and Haferlach T
- Subjects
- Adult, Aged, Aged, 80 and over, Female, Humans, Male, Middle Aged, Mutation genetics, Primary Myelofibrosis classification, Primary Myelofibrosis metabolism, Receptors, Thrombopoietin genetics, Thrombocythemia, Essential classification, Thrombocythemia, Essential metabolism, Tryptophan genetics, Tryptophan metabolism, Primary Myelofibrosis genetics, Receptors, Thrombopoietin metabolism, Thrombocythemia, Essential genetics
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- 2009
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30. Results of syngeneic hematopoietic stem cell transplantation for acute leukemia: risk factors for outcomes of adults transplanted in first complete remission.
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Fouillard L, Labopin M, Gratwohl A, Gluckman E, Frassoni F, Beelen DW, Willemze R, Montserrat E, Blaise D, Atienza AI, Sierra J, Santos M, Gorin NC, and Rocha V
- Subjects
- Adolescent, Adult, Aged, Antineoplastic Agents therapeutic use, Diseases in Twins, Female, Graft vs Host Disease, Humans, Male, Middle Aged, Recurrence, Remission Induction, Risk Factors, Treatment Outcome, Hematopoietic Stem Cell Transplantation methods, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute therapy, Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy, Precursor Cell Lymphoblastic Leukemia-Lymphoma therapy
- Abstract
Background: The possibility of performing syngeneic hematopoietic stem cell transplantation is rare and there are concerns about the absence of a graft-versus-leukemia effect following such a strategy. We report the outcomes of a large series of adult patients who underwent syngeneic hematopoietic stem cell transplantation for acute myeloblastic leukemia or acute lymphoblastic leukemia., Design and Methods: The outcomes of all syngeneic transplants for acute myeloblastic or lymphoblastic leukemia reported to the European Group for Blood and Marrow Transplantation registry were analyzed; a study of prognostic factors was performed for those transplanted in first complete remission., Results: One hundred and sixty-two patients, 109 with acute myeloblastic leukemia and 53 with acute lymphoblastic leukemia, were identified; 116 were in first complete remission. Most of the patients did not receive prophylaxis against graft-versus-host disease. Nineteen patients developed acute graft-versus-host disease and only three patients developed chronic graft-versus-host disease. The median follow-up was 60 months. At 5 years the non-relapse mortality was 8 +/- 5%, the relapse incidence 49 +/- 8% and the leukemia-free survival 43 +/- 3%. The corresponding figures for patients in first complete remission were 7 +/- 2%, 40 +/- 4% and 53 +/- 5% at 5 years. Analysis of patients in first complete remission showed that the number of courses of chemotherapy required to induce first complete remission was the main risk factor: the leukemia-free survival at 5 years was 66 +/- 6% when first complete remission was reached after one induction course of chemotherapy and was only 20 +/- 9% when first complete remission was reached after at least two induction courses of chemotherapy (p = 0.0001); the relapse incidence was 30 +/- 6% and 54 +/- 10%, respectively (p = 0.007)., Conclusions: Outcomes were better for patients transplanted in first complete remission than in second complete remission or a more advanced phase of the disease. When a syngeneic donor is available for patients with high risk acute leukemia, allotransplantation should be performed as soon as the first complete remission has been achieved, ideally with one course of chemotherapy.
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- 2008
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31. T-cell depletion prevents from bronchiolitis obliterans and bronchiolitis obliterans with organizing pneumonia after allogeneic hematopoietic stem cell transplantation with related donors.
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Ditschkowski M, Elmaagacli AH, Trenschel R, Peceny R, Koldehoff M, Schulte C, and Beelen DW
- Subjects
- Adult, Aged, Bronchiolitis Obliterans etiology, Bronchiolitis Obliterans genetics, Bronchiolitis Obliterans immunology, Cryptogenic Organizing Pneumonia etiology, Cryptogenic Organizing Pneumonia genetics, Cryptogenic Organizing Pneumonia immunology, Female, Graft vs Host Disease etiology, Graft vs Host Disease prevention & control, Humans, Kaplan-Meier Estimate, Lymphocyte Transfusion, Male, Middle Aged, Nod2 Signaling Adaptor Protein genetics, Postoperative Complications etiology, Postoperative Complications mortality, Proportional Hazards Models, Respiratory Insufficiency mortality, Retrospective Studies, Sex Factors, Tissue Donors, Toll-Like Receptor 4 genetics, Transplantation, Homologous, Bone Marrow Transplantation adverse effects, Bronchiolitis Obliterans prevention & control, Cryptogenic Organizing Pneumonia prevention & control, Lymphocyte Depletion statistics & numerical data, Peripheral Blood Stem Cell Transplantation adverse effects, Postoperative Complications prevention & control, T-Lymphocytes immunology, T-Lymphocytes transplantation, Transplantation Conditioning adverse effects
- Abstract
Bronchiolitis obliterans (BO) and bronchiolitis obliterans organizing pneumonia (BOOP) are late-onset non-infectious pulmonary complications (LONIPCs) following allogeneic hematopoietic stem cell transplantation (HSCT). In the present study 10 of 197 conventionally prepared stem cell recipients developed BOOP after 365 days and 6 patients developed BO 333 days post-transplant. No BOOP or BO was diagnosed following T-cell depletion (p<0.05). Chronic GVHD was ascertained in all BOOP patients and appeared significantly (p<0,001) more frequent in the conventional transplant group. The data confirm a strong association between T-cell activity, chronic GVHD, BO and BOOP and point out the impact of T lymphocytes in the pathomechanism of BOOP.
- Published
- 2007
- Full Text
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32. WT1 and BCR-ABL specific small interfering RNA have additive effects in the induction of apoptosis in leukemic cells.
- Author
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Elmaagacli AH, Koldehoff M, Peceny R, Klein-Hitpass L, Ottinger H, Beelen DW, and Opalka B
- Subjects
- Drug Synergism, Fusion Proteins, bcr-abl drug effects, Gene Expression Regulation, Neoplastic drug effects, Humans, Leukemia pathology, RNA, Small Interfering therapeutic use, Tumor Cells, Cultured, WT1 Proteins genetics, Apoptosis drug effects, Fusion Proteins, bcr-abl genetics, Leukemia drug therapy, RNA, Small Interfering pharmacology, WT1 Proteins drug effects
- Abstract
Background and Objectives: The Wilms' tumor gene (WT1) is aberrantly over-expressed in leukemic cells. Therefore, we wanted to study the effect of small interfering (siRNA) targeting WT1 in leukemic cells and normal CD34-positive cells with regard to proliferation, induction of apoptosis, and cell differentiation. Furthermore, we wanted to evaluate whether the additional use of BCR-ABL siRNA could increase the anti-leukemic effects of WT1 siRNA in chronic myeloid leukemia (CML) cells., Design and Methods: We measured WT1 expression by reverse transcription polymerase chain reaction (RT-PCR) in various cell lines and in leukemic cells from patients, then transfected the cells with WT1-specific and BCR-ABL-specific siRNA before carrying out microarray analysis. We used the tunnel assay to measure apoptotic cells., Results: We observed a reduction of WT1 gene expression, measured by real-time RT-PCR, in all studied cell lines: K-562, Kasumi-1, MV 4-11 and NB-4, as well as in cells of AML and CML patients. The results also demonstrated that WT1 siRNA significantly induced apoptosis and inhibited proliferation in MV4-11 cells, NB-4 cells, Kasumi-1 cells (p<0.01) and in K-562 cells (p<0.02) versus controls. In normal CD34-positive cells, the proliferation was only slightly inhibited (by about 20%) and no induction of apoptosis was found. Combined transfection with WT1 and BCR-ABL siRNA together in K-562 cells increased the inhibition of the rate of proliferation and the rate of induced apoptosis compared to transfection with BCR-ABL siRNA or WT1 siRNA alone (p<0.01). We found that most genes involved in cell signaling and protein metabolism were regulated by the WT1 gene in K-562 cells in a microarray analysis., Interpretation and Conclusions: In conclusion, WT1 might be a suitable target for new therapeutic strategies using siRNAs in leukemic cells.
- Published
- 2005
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