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1. Long-term results of all-trans retinoic acid and arsenic trioxide in non-high-risk acute promyelocytic leukemia: update of the APL0406 Italian-German randomized trial

Author

Cicconi, L, Platzbecker, U, Avvisati, G, Paoloni, F, Thiede, C, Vignetti, M, Fazi, P, Ferrara, F, Divona, M, Albano, F, Efficace, F, Sborgia, M, Di Bona, E, Breccia, M, Borlenghi, E, Cairoli, R, Rambaldi, A, Melillo, L, La Nasa, G, Fiedler, W, Brossart, P, Hertenstein, B, Salih, H, Annibali, O, Wattad, M, Lubbert, M, Brandts, C, Hanel, M, Rollig, C, Schmitz, N, Lin, H, Frairia, C, Fozza, C, Maria D’Arco, A, Di Renzo, N, Cortelezzi, A, Fabbiano, F, Dohner, K, Ganser, A, Dohner, H, Amadori, S, Mandelli, F, Teresa Voso, M, Ehninger, G, Schlenk, R, Lo-Coco, F, Cicconi L, Platzbecker U, Avvisati G, Paoloni F, Thiede C, Vignetti M, Fazi P, Ferrara F, Divona M, Albano F, Efficace F, Sborgia M, Di Bona E, Breccia M, Borlenghi E, Cairoli R, Rambaldi A, Melillo L, La Nasa G, Fiedler W, Brossart P, Hertenstein B, Salih HR, Annibali O, Wattad M, Lubbert M, Brandts C, Hanel M, Rollig C, Schmitz N, Lin H, Frairia C, Fozza C, Maria D’Arco A, Di Renzo N, Cortelezzi A, Fabbiano F, Dohner K, Ganser A, Dohner H, Amadori S, Mandelli F, Teresa Voso M, Ehninger G, Schlenk RF, Lo-Coco F., Cicconi, L, Platzbecker, U, Avvisati, G, Paoloni, F, Thiede, C, Vignetti, M, Fazi, P, Ferrara, F, Divona, M, Albano, F, Efficace, F, Sborgia, M, Di Bona, E, Breccia, M, Borlenghi, E, Cairoli, R, Rambaldi, A, Melillo, L, La Nasa, G, Fiedler, W, Brossart, P, Hertenstein, B, Salih, H, Annibali, O, Wattad, M, Lubbert, M, Brandts, C, Hanel, M, Rollig, C, Schmitz, N, Lin, H, Frairia, C, Fozza, C, Maria D’Arco, A, Di Renzo, N, Cortelezzi, A, Fabbiano, F, Dohner, K, Ganser, A, Dohner, H, Amadori, S, Mandelli, F, Teresa Voso, M, Ehninger, G, Schlenk, R, Lo-Coco, F, Cicconi L, Platzbecker U, Avvisati G, Paoloni F, Thiede C, Vignetti M, Fazi P, Ferrara F, Divona M, Albano F, Efficace F, Sborgia M, Di Bona E, Breccia M, Borlenghi E, Cairoli R, Rambaldi A, Melillo L, La Nasa G, Fiedler W, Brossart P, Hertenstein B, Salih HR, Annibali O, Wattad M, Lubbert M, Brandts C, Hanel M, Rollig C, Schmitz N, Lin H, Frairia C, Fozza C, Maria D’Arco A, Di Renzo N, Cortelezzi A, Fabbiano F, Dohner K, Ganser A, Dohner H, Amadori S, Mandelli F, Teresa Voso M, Ehninger G, Schlenk RF, and Lo-Coco F.

Published
2020

2. VERY LONG-TERM RESULTS OF ALL-TRANS RETINOIC ACID AND ARSENIC TRIOXIDE IN NON-HIGH RISK ACUTE PROMYELOCYTIC LEUKEMIA: LATEST UPDATE OF THE ITALIAN-GERMAN APL0406 RANDOMIZED TRIAL

Author

Cicconi, L, Platzbecker, U, Avvisati, G, Paoloni, F, Thiede, C, Vignetti, M, Fazi, P, Ferrara, F, Divona, M, Albano, F, Efficace, F, Sborgia, M, Di Bona, E, Breccia, M, Borlenghi, E, Cairoli, R, Rambaldi, A, Melillo, L, La Nasa, G, Fiedler, W, Brossart, P, Hertenstein, B, Salih, H, Annibali, O, Wattad, M, Lubbert, M, Brandts, C, Hanel, M, Rollig, C, Schmitz, N, Lin, H, Frairia, C, Fozza, C, Maria D’Arco, A, Di Renzo, N, Cortelezzi, A, Fabbiano, F, Dohner, K, Ganser, A, Dohner, H, Amadori, S, Mandelli, F, Teresa Voso, M, Ehninger, G, Schlenk, R, Lo-Coco, F, Cicconi L, Platzbecker U, Avvisati G, Paoloni F, Thiede C, Vignetti M, Fazi P, Ferrara F, Divona M, Albano F, Efficace F, Sborgia M, Di Bona E, Breccia M, Borlenghi E, Cairoli R, Rambaldi A, Melillo L, La Nasa G, Fiedler W, Brossart P, Hertenstein B, Salih HR, Annibali O, Wattad M, Lubbert M, Brandts C, Hanel M, Rollig C, Schmitz N, Lin H, Frairia C, Fozza C, Maria D’Arco A, Di Renzo N, Cortelezzi A, Fabbiano F, Dohner K, Ganser A, Dohner H, Amadori S, Mandelli F, Teresa Voso M, Ehninger G, Schlenk RF, Lo-Coco F., Cicconi, L, Platzbecker, U, Avvisati, G, Paoloni, F, Thiede, C, Vignetti, M, Fazi, P, Ferrara, F, Divona, M, Albano, F, Efficace, F, Sborgia, M, Di Bona, E, Breccia, M, Borlenghi, E, Cairoli, R, Rambaldi, A, Melillo, L, La Nasa, G, Fiedler, W, Brossart, P, Hertenstein, B, Salih, H, Annibali, O, Wattad, M, Lubbert, M, Brandts, C, Hanel, M, Rollig, C, Schmitz, N, Lin, H, Frairia, C, Fozza, C, Maria D’Arco, A, Di Renzo, N, Cortelezzi, A, Fabbiano, F, Dohner, K, Ganser, A, Dohner, H, Amadori, S, Mandelli, F, Teresa Voso, M, Ehninger, G, Schlenk, R, Lo-Coco, F, Cicconi L, Platzbecker U, Avvisati G, Paoloni F, Thiede C, Vignetti M, Fazi P, Ferrara F, Divona M, Albano F, Efficace F, Sborgia M, Di Bona E, Breccia M, Borlenghi E, Cairoli R, Rambaldi A, Melillo L, La Nasa G, Fiedler W, Brossart P, Hertenstein B, Salih HR, Annibali O, Wattad M, Lubbert M, Brandts C, Hanel M, Rollig C, Schmitz N, Lin H, Frairia C, Fozza C, Maria D’Arco A, Di Renzo N, Cortelezzi A, Fabbiano F, Dohner K, Ganser A, Dohner H, Amadori S, Mandelli F, Teresa Voso M, Ehninger G, Schlenk RF, and Lo-Coco F.

Published
2019

3. Deferasirox in iron-overloaded patients with transfusion-dependent myelodysplastic syndromes: Results from the large 1-year EPIC study.

Author

Gattermann N., Finelli C., Della Porta M., Fenaux P., Ganser A., Guerci-Bresler A., Schmid M., Taylor K., Vassilieff D., Habr D., Domokos G., Roubert B., Rose C., Agaoglu L., Alimena G., Alonso D., Ame S., Angelucci E., Arrizabalaga B., Athanasiou-Metaxa M., Augustson B., Aydinok Y., Baba A., Baccarani M., Beck J., Beris P., Beyne-Rauzy O., Birgens H., Bordessoule D., Borgna-Pignatti C., Bosly A., Bouabdallah K., Bowden D., Bowen D., Bron D., Cappellini M.D., Capra M., Cartron G., Cazzola M., Chalkias C., Chan L.L., Chancharunee S., Chapman C., Charoenkwan P., Chasapopoulou E., Cheze S., Chuansumrit A., Cianciulli P., Dauriac C., Delforge M., Dolken G., Dombret H., Duyster J., Economopoulos T., Ehninger G., Elalfy M., El-Beshlawy A., Enggaard L., Fillet G., Filosa A., Forni G., Galanello R., Gastl G., Giraudier S., Goldfarb A., Grigg A., Gumruk F., Ha S.Y., Haase D., Heinrich B., Hertzberg M., Ho J., Hsu H.-C., Huang S., Hunault-Berger M., Inusa B., Jaulmes D., Jensen J., Kattamis A., Kilinc Y., Kim K.-H., Kinsey S., Kjeldsen L., Koren A., Lai M.E., Lai Y., Lee J.-W., Lee K.-H., Lee S.-H., Legros L., Li C., Li C.-K., Li Q., Lin K.-H., Linkesch W., Lubbert M., Lutz D., Mohamed Thalha A.J., Mufti G., Muus P., Nobile F., Papadopoulos N., Perrotta S., Petrini M., Pfeilstocker M., Piga A., Poole J., Porter J.B., Pungolino E., Quarta G., Ravoet C., Jolimont Lobbes H.H., Remacha A.F., Roy L., Saglio G., Sanz G., Schmugge M., Schots H., Secchi G., Seymour J.F., Shah F., Shah H., Shen Z., Slama B., Sutcharitchan P., Taher A., Tamary H., Tesch H.-J., Thein S.L., Troncy J., Villegas A., Viprakasit V., Wainwright L., Wassmann B., Wettervald M., Will A., Wormann B., Wright J., Yeh S.-P., Yoon S.-S., Zoumbos N.C., Zweegman S., Gattermann N., Finelli C., Della Porta M., Fenaux P., Ganser A., Guerci-Bresler A., Schmid M., Taylor K., Vassilieff D., Habr D., Domokos G., Roubert B., Rose C., Agaoglu L., Alimena G., Alonso D., Ame S., Angelucci E., Arrizabalaga B., Athanasiou-Metaxa M., Augustson B., Aydinok Y., Baba A., Baccarani M., Beck J., Beris P., Beyne-Rauzy O., Birgens H., Bordessoule D., Borgna-Pignatti C., Bosly A., Bouabdallah K., Bowden D., Bowen D., Bron D., Cappellini M.D., Capra M., Cartron G., Cazzola M., Chalkias C., Chan L.L., Chancharunee S., Chapman C., Charoenkwan P., Chasapopoulou E., Cheze S., Chuansumrit A., Cianciulli P., Dauriac C., Delforge M., Dolken G., Dombret H., Duyster J., Economopoulos T., Ehninger G., Elalfy M., El-Beshlawy A., Enggaard L., Fillet G., Filosa A., Forni G., Galanello R., Gastl G., Giraudier S., Goldfarb A., Grigg A., Gumruk F., Ha S.Y., Haase D., Heinrich B., Hertzberg M., Ho J., Hsu H.-C., Huang S., Hunault-Berger M., Inusa B., Jaulmes D., Jensen J., Kattamis A., Kilinc Y., Kim K.-H., Kinsey S., Kjeldsen L., Koren A., Lai M.E., Lai Y., Lee J.-W., Lee K.-H., Lee S.-H., Legros L., Li C., Li C.-K., Li Q., Lin K.-H., Linkesch W., Lubbert M., Lutz D., Mohamed Thalha A.J., Mufti G., Muus P., Nobile F., Papadopoulos N., Perrotta S., Petrini M., Pfeilstocker M., Piga A., Poole J., Porter J.B., Pungolino E., Quarta G., Ravoet C., Jolimont Lobbes H.H., Remacha A.F., Roy L., Saglio G., Sanz G., Schmugge M., Schots H., Secchi G., Seymour J.F., Shah F., Shah H., Shen Z., Slama B., Sutcharitchan P., Taher A., Tamary H., Tesch H.-J., Thein S.L., Troncy J., Villegas A., Viprakasit V., Wainwright L., Wassmann B., Wettervald M., Will A., Wormann B., Wright J., Yeh S.-P., Yoon S.-S., Zoumbos N.C., and Zweegman S.

Abstract

The prospective 1-year EPIC study enrolled 341 patients with myelodysplastic syndromes (MDS); although baseline iron burden was >2500. ng/mL, ~50% were chelation-naive. Overall median serum ferritin decreased significantly at 1 year (p=0.002). Decreases occurred irrespective of whether patients were chelation-naive or previously chelated; changes were dependent on dose adjustments and ongoing iron intake. Sustained reductions in labile plasma iron were observed. Discontinuation rate (48.7%) and adverse event profile were consistent with previously reported deferasirox data in MDS. Alanine aminotransferase levels decreased significantly; change correlated significantly with reduction in serum ferritin (p<0.0001). This large dataset prospectively confirms the efficacy and well characterizes the safety profile of deferasirox in MDS. © 2010 Elsevier Ltd.

Published
2021

4. VERY LONG-TERM RESULTS OF ALL-TRANS RETINOIC ACID AND ARSENIC TRIOXIDE IN NON-HIGH RISK ACUTE PROMYELOCYTIC LEUKEMIA: LATEST UPDATE OF THE ITALIAN-GERMAN APL0406 RANDOMIZED TRIAL

Author

Cicconi L, Platzbecker U, Avvisati G, Paoloni F, Thiede C, Vignetti M, Fazi P, Ferrara F, Divona M, Albano F, Efficace F, Sborgia M, Di Bona E, Breccia M, Borlenghi E, Cairoli R, Rambaldi A, Melillo L, La Nasa G, Fiedler W, Brossart P, Hertenstein B, Salih HR, Annibali O, Wattad M, Lubbert M, Brandts C, Hanel M, Rollig C, Schmitz N, Lin H, Frairia C, Fozza C, Maria D’Arco A, Di Renzo N, Cortelezzi A, Fabbiano F, Dohner K, Ganser A, Dohner H, Amadori S, Mandelli F, Teresa Voso M, Ehninger G, Schlenk RF, Lo-Coco F., Cicconi, L, Platzbecker, U, Avvisati, G, Paoloni, F, Thiede, C, Vignetti, M, Fazi, P, Ferrara, F, Divona, M, Albano, F, Efficace, F, Sborgia, M, Di Bona, E, Breccia, M, Borlenghi, E, Cairoli, R, Rambaldi, A, Melillo, L, La Nasa, G, Fiedler, W, Brossart, P, Hertenstein, B, Salih, H, Annibali, O, Wattad, M, Lubbert, M, Brandts, C, Hanel, M, Rollig, C, Schmitz, N, Lin, H, Frairia, C, Fozza, C, Maria D’Arco, A, Di Renzo, N, Cortelezzi, A, Fabbiano, F, Dohner, K, Ganser, A, Dohner, H, Amadori, S, Mandelli, F, Teresa Voso, M, Ehninger, G, Schlenk, R, and Lo-Coco, F

Subjects
Hematology
Published
2019

6. Proposed diagnostic criteria for classical chronic myelomonocytic leukemia (CMML), CMML variants and pre-CMML conditions

Author

Valent, P., Orazi, A., Savona, M.R., Patnaik, M.M., Onida, F., Loosdrecht, A.A. van de, Haase, D., Haferlach, T, Elena, C., Pleyer, L., Kern, W., Pemovska, T., Vladimer, G.I., Schanz, J., Keller, A., Lubbert, M., Lion, T., Sotlar, K., Reiter, A., Witte, T.J. de, Pfeilstocker, M., Geissler, K., Padron, E., Deininger, M., Orfao, A., Horny, H.P., Greenberg, P.L., Arber, D.A., Malcovati, L., Bennett, J.M., Valent, P., Orazi, A., Savona, M.R., Patnaik, M.M., Onida, F., Loosdrecht, A.A. van de, Haase, D., Haferlach, T, Elena, C., Pleyer, L., Kern, W., Pemovska, T., Vladimer, G.I., Schanz, J., Keller, A., Lubbert, M., Lion, T., Sotlar, K., Reiter, A., Witte, T.J. de, Pfeilstocker, M., Geissler, K., Padron, E., Deininger, M., Orfao, A., Horny, H.P., Greenberg, P.L., Arber, D.A., Malcovati, L., and Bennett, J.M.

Abstract

Contains fulltext : 215300.pdf (publisher's version ) (Open Access), Chronic myelomonocytic leukemia (CMML) is a myeloid neoplasm characterized by dysplasia, abnormal production and accumulation of monocytic cells and an elevated risk of transforming into acute leukemia. Over the past two decades, our knowledge about the pathogenesis and molecular mechanisms in CMML has increased substantially. In parallel, better diagnostic criteria and therapeutic strategies have been developed. However, many questions remain regarding prognostication and optimal therapy. In addition, there is a need to define potential pre-phases of CMML and special CMML variants, and to separate these entities from each other and from conditions mimicking CMML. To address these unmet needs, an international consensus group met in a Working Conference in August 2018 and discussed open questions and issues around CMML, its variants, and pre-CMML conditions. The outcomes of this meeting are summarized herein and include diag nostic criteria and a proposed classification of pre-CMML conditions as well as refined minimal diagnostic criteria for classical CMML and special CMML variants, including oligomonocytic CMML and CMML associated with systemic mastocytosis. Moreover, we propose diagnostic standards and tools to distinguish between 'normal', pre-CMML and CMML entities. These criteria and standards should facilitate diagnostic and prognostic evaluations in daily practice and clinical studies in applied hematology.

Published
2019

9. Decitabine improves progression-free survival in older high-risk MDS patients with multiple autosomal monosomies: results of a subgroup analysis of the randomized phase III study 06011 of the EORTC Leukemia Cooperative Group and German MDS Study Group

Author

Lubbert, M., Suciu, S., Hagemeijer, A., Ruter, B., Platzbecker, U., Giagounidis, A., Selleslag, D., Labar, B., Germing, U., Salih, H.R., Muus, P., Pfluger, K.H., Schaefer, H.E., Bogatyreva, L., Aul, C., Witte, T.J.M. de, Ganser, A., Becker, H., Huls, G.A., Helm, L. van der, Vellenga, E., Baron, F., Marie, J.P., Wijermans, P.W., Group, E.L., German, M.D.S.S.G. the, Stem Cell Aging Leukemia and Lymphoma (SALL), and Guided Treatment in Optimal Selected Cancer Patients (GUTS)

Subjects
Male, 0301 basic medicine, Oncology, Cancer development and immune defence Radboud Institute for Molecular Life Sciences [Radboudumc 2], Vascular damage Radboud Institute for Health Sciences [Radboudumc 16], NEWLY-DIAGNOSED AML, Monosomy, 0302 clinical medicine, Risk Factors, Germany, CONVENTIONAL CARE REGIMENS, ELDERLY-PATIENTS, Aged, 80 and over, Leukemia, Azacytidine, Hazard ratio, Hematology, General Medicine, Middle Aged, 030220 oncology & carcinogenesis, Azacitidine, Disease Progression, Female, medicine.drug, Antimetabolites, Antineoplastic, medicine.medical_specialty, MYELODYSPLASTIC SYNDROME MDS, Decitabine, Hypomethylating agents, Subgroup analysis, ACUTE MYELOID-LEUKEMIA, Disease-Free Survival, Adverse cytogenetics, 03 medical and health sciences, POOR-PROGNOSIS, Internal medicine, SUPPORTIVE CARE, medicine, Humans, Progression-free survival, Aged, RESPONSE CRITERIA, Epigenetic therapy, INTERNATIONAL WORKING GROUP, business.industry, Myelodysplastic syndromes, Monosomal karyotype, LOW-DOSE DECITABINE, medicine.disease, Elderly patients, 030104 developmental biology, Hypomethylating agent, Myelodysplastic Syndromes, Immunology, business
Abstract

Item does not contain fulltext In a study of elderly AML patients treated with the hypomethylating agent decitabine (DAC), we noted a surprisingly favorable outcome in the (usually very unfavorable) subgroup with two or more autosomal monosomies (MK2+) within a complex karyotype (Lubbert et al., Haematologica 97:393-401, 2012). We now analyzed 206 myelodysplastic syndrome (MDS) patients (88 % of 233 patients randomized in the EORTC/GMDSSG phase III trial 06011, 61 of them with RAEBt, i.e. AML by WHO) with cytogenetics informative for MK status.. Endpoints are the following: complete/partial (CR/PR) and overall response rate (ORR) and progression-free (PFS) and overall survival (OS). Cytogenetic subgroups are the following: 63 cytogenetically normal (CN) patients, 143 with cytogenetic abnormalities, 73 of them MK-negative (MK-), and 70 MK-positive (MK+). These MK+ patients could be divided into 17 with a single autosomal monosomy (MK1) and 53 with at least two monosomies (MK2+). ORR with DAC in CN patients: 36.1 %, in MK- patients: 16.7 %, in MK+ patients: 43.6 % (MK1: 44.4 %, MK2+ 43.3 %). PFS was prolonged by DAC compared to best supportive care (BSC) in the CN (hazard ratio (HR) 0.55, 99 % confidence interval (CI), 0.26; 1.15, p = 0.03) and MK2+ (HR 0.50; 99 % CI, 0.23; 1.06, p = 0.016) but not in the MK-, MK+, and MK1 subgroups. OS was not improved by DAC in any subgroup. In conclusion, we demonstrate for the first time in a randomized phase III trial that high-risk MDS patients with complex karyotypes harboring two or more autosomal monosomies attain encouraging responses and have improved PFS with DAC treatment compared to BSC.

Published
2015

10. Comprehensive mutational analysis of primary and relapse acute promyelocytic leukemia

Author

Madan, V, Shyamsunder, P, Han, L, Mayakonda, A, Nagata, Y, Sundaresan, J, Kanojia, D, Yoshida, K, Ganesan, S, Hattori, N, Fulton, N, Tan, K, Alpermann, T, Kuo, M, Rostami, S, Matthews, J, Sanada, M, Liu, L, Shiraishi, Y, Miyano, S, Chendamarai, E, Hou, H, Malnassy, G, Ma, T, Garg, M, Ding, L, Sun, Q, Chien, W, Ikezoe, T, Lill, M, Biondi, A, Larson, R, Powell, B, Lubbert, M, Chng, W, Tien, H, Heuser, M, Ganser, A, Koren-Michowitz, M, Kornblau, S, Kantarjian, H, Nowak, D, Hofmann, W, Yang, H, Stock, W, Ghavamzadeh, A, Alimoghaddam, K, Haferlach, T, Ogawa, S, Shih, L, Mathews, V, Koeffler, H, Madan V., Shyamsunder P., Han L., Mayakonda A., Nagata Y., Sundaresan J., Kanojia D., Yoshida K., Ganesan S., Hattori N., Fulton N., Tan K. -T., Alpermann T., Kuo M. -C., Rostami S., Matthews J., Sanada M., Liu L. -Z., Shiraishi Y., Miyano S., Chendamarai E., Hou H. -A., Malnassy G., Ma T., Garg M., Ding L. -W., Sun Q. -Y., Chien W., Ikezoe T., Lill M., Biondi A., Larson R. A., Powell B. L., Lubbert M., Chng W. J., Tien H. -F., Heuser M., Ganser A., Koren-Michowitz M., Kornblau S. M., Kantarjian H. M., Nowak D., Hofmann W. -K., Yang H., Stock W., Ghavamzadeh A., Alimoghaddam K., Haferlach T., Ogawa S., Shih L. -Y., Mathews V., Koeffler H. P., Madan, V, Shyamsunder, P, Han, L, Mayakonda, A, Nagata, Y, Sundaresan, J, Kanojia, D, Yoshida, K, Ganesan, S, Hattori, N, Fulton, N, Tan, K, Alpermann, T, Kuo, M, Rostami, S, Matthews, J, Sanada, M, Liu, L, Shiraishi, Y, Miyano, S, Chendamarai, E, Hou, H, Malnassy, G, Ma, T, Garg, M, Ding, L, Sun, Q, Chien, W, Ikezoe, T, Lill, M, Biondi, A, Larson, R, Powell, B, Lubbert, M, Chng, W, Tien, H, Heuser, M, Ganser, A, Koren-Michowitz, M, Kornblau, S, Kantarjian, H, Nowak, D, Hofmann, W, Yang, H, Stock, W, Ghavamzadeh, A, Alimoghaddam, K, Haferlach, T, Ogawa, S, Shih, L, Mathews, V, Koeffler, H, Madan V., Shyamsunder P., Han L., Mayakonda A., Nagata Y., Sundaresan J., Kanojia D., Yoshida K., Ganesan S., Hattori N., Fulton N., Tan K. -T., Alpermann T., Kuo M. -C., Rostami S., Matthews J., Sanada M., Liu L. -Z., Shiraishi Y., Miyano S., Chendamarai E., Hou H. -A., Malnassy G., Ma T., Garg M., Ding L. -W., Sun Q. -Y., Chien W., Ikezoe T., Lill M., Biondi A., Larson R. A., Powell B. L., Lubbert M., Chng W. J., Tien H. -F., Heuser M., Ganser A., Koren-Michowitz M., Kornblau S. M., Kantarjian H. M., Nowak D., Hofmann W. -K., Yang H., Stock W., Ghavamzadeh A., Alimoghaddam K., Haferlach T., Ogawa S., Shih L. -Y., Mathews V., and Koeffler H. P.

Abstract

Acute promyelocytic leukemia (APL) is a subtype of myeloid leukemia characterized by differentiation block at the promyelocyte stage. Besides the presence of chromosomal rearrangement t(15;17), leading to the formation of PML-RARA (promyelocytic leukemia-retinoic acid receptor alpha) fusion, other genetic alterations have also been implicated in APL. Here, we performed comprehensive mutational analysis of primary and relapse APL to identify somatic alterations, which cooperate with PML-RARA in the pathogenesis of APL. We explored the mutational landscape using whole-exome (n=12) and subsequent targeted sequencing of 398 genes in 153 primary and 69 relapse APL. Both primary and relapse APL harbored an average of eight non-silent somatic mutations per exome. We observed recurrent alterations of FLT3, WT1, NRAS and KRAS in the newly diagnosed APL, whereas mutations in other genes commonly mutated in myeloid leukemia were rarely detected. The molecular signature of APL relapse was characterized by emergence of frequent mutations in PML and RARA genes. Our sequencing data also demonstrates incidence of loss-of-function mutations in previously unidentified genes, ARID1B and ARID1A, both of which encode for key components of the SWI/SNF complex. We show that knockdown of ARID1B in APL cell line, NB4, results in large-scale activation of gene expression and reduced in vitro differentiation potential.

Published
2016

11. Sorafenib promotes graft-versus-leukemia activity in mice and humans through IL-15 production in FLT3-ITD-mutant leukemia cells

Author

Mathew, N.R., Baumgartner, F., Braun, L., O'Sullivan, D., Thomas, S., Waterhouse, M., Muller, T.A., Hanke, K., Taromi, S., Apostolova, P., Illert, A.L., Melchinger, W., Duquesne, S., Schmitt-Graeff, A., Osswald, L., Yan, K.L., Weber, A, Tugues, S., Spath, S., Pfeifer, D., Follo, M., Claus, R., Lubbert, M., Rummelt, C., Bertz, H., Wasch, R., Haag, J., Schmidts, A., Schultheiss, M., Bettinger, D., Thimme, R., Ullrich, E., Tanriver, Y., Vuong, G.L., Arnold, R., Hemmati, P., Wolf, D., Ditschkowski, M., Jilg, C., Wilhelm, K., Leiber, C., Gerull, S., Halter, J., Lengerke, C., Pabst, T., Schroeder, T., Kobbe, G., Rosler, W., Doostkam, S., Meckel, S., Stabla, K., Metzelder, S.K., Halbach, S., Brummer, T., Hu, Z, Dengjel, J., Hackanson, B., Schmid, C., Holtick, U., Scheid, C., Spyridonidis, A., Stolzel, F., Ordemann, R., Muller, L.P., Sicre-de-Fontbrune, F., Ihorst, G., Kuball, J., Ehlert, J.E., Feger, D., Wagner, E.M., Cahn, J.Y., Schnell, J., Kuchenbauer, F., Bunjes, D., Chakraverty, R., Richardson, S., Gill, S., Kroger, N., Ayuk, F., Vago, L., Ciceri, F., Muller, A.M., Kondo, T., Teshima, T., Klaeger, S., Kuster, B., Kim, D.D.H., Weisdorf, D., Velden, W.J. van der, Dorfel, D., Bethge, W., Hilgendorf, I., Hochhaus, A., Andrieux, G., Borries, M., Busch, H., Magenau, J., Reddy, P., Labopin, M., Antin, J.H., et al., Mathew, N.R., Baumgartner, F., Braun, L., O'Sullivan, D., Thomas, S., Waterhouse, M., Muller, T.A., Hanke, K., Taromi, S., Apostolova, P., Illert, A.L., Melchinger, W., Duquesne, S., Schmitt-Graeff, A., Osswald, L., Yan, K.L., Weber, A, Tugues, S., Spath, S., Pfeifer, D., Follo, M., Claus, R., Lubbert, M., Rummelt, C., Bertz, H., Wasch, R., Haag, J., Schmidts, A., Schultheiss, M., Bettinger, D., Thimme, R., Ullrich, E., Tanriver, Y., Vuong, G.L., Arnold, R., Hemmati, P., Wolf, D., Ditschkowski, M., Jilg, C., Wilhelm, K., Leiber, C., Gerull, S., Halter, J., Lengerke, C., Pabst, T., Schroeder, T., Kobbe, G., Rosler, W., Doostkam, S., Meckel, S., Stabla, K., Metzelder, S.K., Halbach, S., Brummer, T., Hu, Z, Dengjel, J., Hackanson, B., Schmid, C., Holtick, U., Scheid, C., Spyridonidis, A., Stolzel, F., Ordemann, R., Muller, L.P., Sicre-de-Fontbrune, F., Ihorst, G., Kuball, J., Ehlert, J.E., Feger, D., Wagner, E.M., Cahn, J.Y., Schnell, J., Kuchenbauer, F., Bunjes, D., Chakraverty, R., Richardson, S., Gill, S., Kroger, N., Ayuk, F., Vago, L., Ciceri, F., Muller, A.M., Kondo, T., Teshima, T., Klaeger, S., Kuster, B., Kim, D.D.H., Weisdorf, D., Velden, W.J. van der, Dorfel, D., Bethge, W., Hilgendorf, I., Hochhaus, A., Andrieux, G., Borries, M., Busch, H., Magenau, J., Reddy, P., Labopin, M., and Antin, J.H., et al.

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

12. Decitabine in combination with donor lymphocyte infusions can induce remissions in relapsed myeloid malignancies with higher leukemic burden after allogeneic hematopoietic cell transplantation

Author

Sommer, Sebastian, Cruijsen, M.J., Claus, R., Bertz, H., Waesch, Ralph, Marks, R., Blijlevens, N.M.A., Velden, W.J.F.M. van der, Finke, J., Lubbert, M., Sommer, Sebastian, Cruijsen, M.J., Claus, R., Bertz, H., Waesch, Ralph, Marks, R., Blijlevens, N.M.A., Velden, W.J.F.M. van der, Finke, J., and Lubbert, M.

Abstract

Item does not contain fulltext

Published
2018

13. RAS-pathway mutation patterns define epigenetic subclasses in juvenile myelomonocytic leukemia

Author

Lipka, D. B., Witte, T., Toth, R., Yang, J., Wiesenfarth, M., Nollke, P., Fischer, A., Brocks, D., Gu, Z., Park, J., Strahm, B., Wlodarski, M., Yoshimi, A., Claus, R., Lubbert, M., Busch, H., Boerries, M., Hartmann, M., Schonung, M., Kilik, U., Langstein, J., Wierzbinska, J. A., Pabst, C., Garg, S., Catala, A., De Moerloose, B., Dworzak, M., Hasle, H., Locatelli, Franco, Masetti, R., Schmugge, M., Smith, O., Stary, J., Ussowicz, M., Van Den Heuvel-Eibrink, M. M., Assenov, Y., Schlesner, M., Niemeyer, C., Flotho, C., Plass, C., Locatelli F. (ORCID:0000-0002-7976-3654), Lipka, D. B., Witte, T., Toth, R., Yang, J., Wiesenfarth, M., Nollke, P., Fischer, A., Brocks, D., Gu, Z., Park, J., Strahm, B., Wlodarski, M., Yoshimi, A., Claus, R., Lubbert, M., Busch, H., Boerries, M., Hartmann, M., Schonung, M., Kilik, U., Langstein, J., Wierzbinska, J. A., Pabst, C., Garg, S., Catala, A., De Moerloose, B., Dworzak, M., Hasle, H., Locatelli, Franco, Masetti, R., Schmugge, M., Smith, O., Stary, J., Ussowicz, M., Van Den Heuvel-Eibrink, M. M., Assenov, Y., Schlesner, M., Niemeyer, C., Flotho, C., Plass, C., and Locatelli F. (ORCID:0000-0002-7976-3654)

Abstract

Juvenile myelomonocytic leukemia (JMML) is an aggressive myeloproliferative disorder of early childhood characterized by mutations activating RAS signaling. Established clinical and genetic markers fail to fully recapitulate the clinical and biological heterogeneity of this disease. Here we report DNA methylome analysis and mutation profiling of 167 JMML samples. We identify three JMML subgroups with unique molecular and clinical characteristics. The high methylation group (HM) is characterized by somatic PTPN11 mutations and poor clinical outcome. The low methylation group is enriched for somatic NRAS and CBL mutations, as well as for Noonan patients, and has a good prognosis. The intermediate methylation group (IM) shows enrichment for monosomy 7 and somatic KRAS mutations. Hypermethylation is associated with repressed chromatin, genes regulated by RAS signaling, frequent co-occurrence of RAS pathway mutations and upregulation of DNMT1 and DNMT3B, suggesting a link between activation of the DNA methylation machinery and mutational patterns in JMML.

Published
2017

14. Decitabine improves progression-free survival in older high-risk MDS patients with multiple autosomal monosomies: results of a subgroup analysis of the randomized phase III study 06011 of the EORTC Leukemia Cooperative Group and German MDS Study Group

Author

Lubbert, M., Suciu, S., Hagemeijer, A., Ruter, B., Platzbecker, U., Giagounidis, A., Selleslag, D., Labar, B., Germing, U., Salih, H.R., Muus, P., Pfluger, K.H., Schaefer, H.E., Bogatyreva, L., Aul, C., Witte, T.J.M. de, Ganser, A., Becker, H., Huls, G.A., Helm, L. van der, Vellenga, E., Baron, F., Marie, J.P., Wijermans, P.W., Group, E.L., German, M.D.S.S.G. the, Lubbert, M., Suciu, S., Hagemeijer, A., Ruter, B., Platzbecker, U., Giagounidis, A., Selleslag, D., Labar, B., Germing, U., Salih, H.R., Muus, P., Pfluger, K.H., Schaefer, H.E., Bogatyreva, L., Aul, C., Witte, T.J.M. de, Ganser, A., Becker, H., Huls, G.A., Helm, L. van der, Vellenga, E., Baron, F., Marie, J.P., Wijermans, P.W., Group, E.L., and German, M.D.S.S.G. the

Abstract

Item does not contain fulltext, In a study of elderly AML patients treated with the hypomethylating agent decitabine (DAC), we noted a surprisingly favorable outcome in the (usually very unfavorable) subgroup with two or more autosomal monosomies (MK2+) within a complex karyotype (Lubbert et al., Haematologica 97:393-401, 2012). We now analyzed 206 myelodysplastic syndrome (MDS) patients (88 % of 233 patients randomized in the EORTC/GMDSSG phase III trial 06011, 61 of them with RAEBt, i.e. AML by WHO) with cytogenetics informative for MK status.. Endpoints are the following: complete/partial (CR/PR) and overall response rate (ORR) and progression-free (PFS) and overall survival (OS). Cytogenetic subgroups are the following: 63 cytogenetically normal (CN) patients, 143 with cytogenetic abnormalities, 73 of them MK-negative (MK-), and 70 MK-positive (MK+). These MK+ patients could be divided into 17 with a single autosomal monosomy (MK1) and 53 with at least two monosomies (MK2+). ORR with DAC in CN patients: 36.1 %, in MK- patients: 16.7 %, in MK+ patients: 43.6 % (MK1: 44.4 %, MK2+ 43.3 %). PFS was prolonged by DAC compared to best supportive care (BSC) in the CN (hazard ratio (HR) 0.55, 99 % confidence interval (CI), 0.26; 1.15, p = 0.03) and MK2+ (HR 0.50; 99 % CI, 0.23; 1.06, p = 0.016) but not in the MK-, MK+, and MK1 subgroups. OS was not improved by DAC in any subgroup. In conclusion, we demonstrate for the first time in a randomized phase III trial that high-risk MDS patients with complex karyotypes harboring two or more autosomal monosomies attain encouraging responses and have improved PFS with DAC treatment compared to BSC.

Published
2016

15. Outcomes in RBC transfusion-dependent patients with Low-/Intermediate-1-risk myelodysplastic syndromes with isolated deletion 5q treated with lenalidomide: a subset analysis from the MDS-004 study

Author

Giagounidis, A., Mufti, G.J., Mittelman, M., Sanz, G., Platzbecker, U., Muus, P., Selleslag, D., Beyne-Rauzy, O., Boekhorst, P. Te, Canizo, C. Del, Guerci-Bresler, A., Nilsson, L., Lubbert, M., Quesnel, B., Ganser, A., Bowen, D., Schlegelberger, B., Gohring, G., Fu, T., Benettaib, B., Hellstrom-Lindberg, E., and Fenaux, P.

Subjects
Adult, Male, Risk, Vascular damage Radboud Institute for Health Sciences [Radboudumc 16], lenalidomide, Antineoplastic Agents, Drug Administration Schedule, Humans, del(5q), acute myeloid leukaemia, Aged, Retrospective Studies, Aged, 80 and over, transfusion independence, Original Articles, Middle Aged, Survival Analysis, myelodysplastic syndromes, Thalidomide, Leukemia, Myeloid, Acute, Treatment Outcome, Cytogenetic Analysis, Disease Progression, Chromosomes, Human, Pair 5, Female, Chromosome Deletion, Erythrocyte Transfusion
Abstract

Item does not contain fulltext OBJECTIVE: A subset analysis of the randomised, phase 3, MDS-004 study to evaluate outcomes in patients with International Prognostic Scoring System (IPSS)-defined Low-/Intermediate (Int)-1-risk myelodysplastic syndromes (MDS) with isolated del(5q). METHODS: Patients received lenalidomide 10 mg/d (days 1-21; n = 47) or 5 mg/d (days 1-28; n = 43) on 28-d cycles or placebo (n = 45). From the placebo and lenalidomide 5 mg groups, 84% and 58% of patients, respectively, crossed over to lenalidomide 5 or 10 mg at 16 wk, respectively. RESULTS: Rates of red blood cell-transfusion independence (RBC-TI) >/=182 d were higher in the lenalidomide 10 mg (57.4%; P < 0.0001) and 5 mg (37.2%; P = 0.0001) groups vs. placebo (2.2%). Cytogenetic response rates (major + minor responses) were 56.8% (P < 0.0001), 23.1% (P = 0.0299) and 0%, respectively. Two-year cumulative risk of acute myeloid leukaemia progression was 12.6%, 17.4% and 16.7% in the lenalidomide 10 mg, 5 mg, and placebo groups, respectively. In a 6-month landmark analysis, overall survival was longer in lenalidomide-treated patients with RBC-TI >/=182 d vs. non-responders (P = 0.0072). The most common grade 3-4 adverse event was myelosuppression. CONCLUSIONS: These data support the clinical benefits and acceptable safety profile of lenalidomide in transfusion-dependent patients with IPSS-defined Low-/Int-1-risk MDS with isolated del(5q).

Published
2014

16. Decitabine versus best supportive care in older patients with refractory anemia with excess blasts in transformation (RAEBt) - results of a subgroup analysis of the randomized phase III study 06011 of the EORTC Leukemia Cooperative Group and German MDS Study Group (GMDSSG)

Author

Becker, H., Suciu, S., Ruter, B.H., Platzbecker, U., Giagounidis, A., Selleslag, D., Labar, B., Germing, U., Salih, H.R., Muus, P., Pfluger, K.H., Hagemeijer, A., Schaefer, H.E., Fiaccadori, V., Baron, F., Ganser, A., Aul, C., Witte, T.J. de, Wijermans, P.W., Lubbert, M., Becker, H., Suciu, S., Ruter, B.H., Platzbecker, U., Giagounidis, A., Selleslag, D., Labar, B., Germing, U., Salih, H.R., Muus, P., Pfluger, K.H., Hagemeijer, A., Schaefer, H.E., Fiaccadori, V., Baron, F., Ganser, A., Aul, C., Witte, T.J. de, Wijermans, P.W., and Lubbert, M.

Abstract

Item does not contain fulltext, In the European Organisation for Research and Treatment of Cancer (EORTC)/GMDSSG phase III trial 06011, we compared decitabine (15 mg/m(2) every 8 h for 3 days) with best supportive care (BSC) in patients >/=60 years with myelodysplastic syndromes (MDS) by French-American-British (FAB) criteria. Here, we reinvestigate trial 06011 for the activity and efficacy specifically in patients with refractory anemia with excess blasts in transformation (RAEBt). Response rates in the decitabine arm (N = 40) were as follows: complete or partial remission, 15 %; hematologic improvement, 15 %; resistant disease, 30 %. RAEBt patients in the decitabine arm had longer progression-free survival (PFS; hazard ratio (HR) 0.30, 95 % confidence interval (CI) 0.18-0.51; median, 6.2 vs 2.8 months) and overall survival (OS; HR 0.68, 95 % CI 0.42-1.11; median, 8.0 vs 6.0 months) than in the BSC arm (N = 35). Censoring at allogeneic hematopoietic stem cell transplantation, the OS difference between the treatment groups increased, particularly among patients aged 60-74 years (HR 0.48, 95 % CI 0.26-0.89). After regrouping the study cohort according to World Health Organization (WHO) criteria, patients with acute myeloid leukemia (AML) (i.e., >/=20 % blasts) in the decitabine arm (N = 27) also had longer PFS than in the BSC arm (N = 23) (HR 0.46, 95 % CI 0.26-0.83; median, 6.2 vs 2.8 months). In conclusion, 3-day decitabine displays clinical activity and efficacy in MDS and/or AML with 5-30 % blood or 20-30 % marrow blasts.

Published
2015

17. Ruxolitinib in corticosteroid-refractory graft-versus-host disease after allogeneic stem cell transplantation: a multicenter survey

Author

Zeiser, R., Burchert, A., Lengerke, C., Verbeek, M.M., Maas-Bauer, K., Metzelder, S.K., Spoerl, S., Ditschkowski, M., Ecsedi, M., Sockel, K., Ayuk, F., Ajib, S., Fontbrune, F.S. de, Na, I.K., Penter, L., Holtick, U., Wolf, D., Schuler, E., Meyer, E., Apostolova, P., Bertz, H., Marks, R., Lubbert, M., Wasch, R., Scheid, C., Stolzel, F., Ordemann, R., Bug, G., Kobbe, G., Negrin, R., Brune, M., Spyridonidis, A., Schmitt-Graff, A., Velden, W.J. van der, Huls, G.A., Mielke, S., Grigoleit, G.U., Kuball, J., Flynn, R., Ihorst, G., Du, J., Blazar, B.R., Arnold, R., Kroger, N., Passweg, J., Halter, J., Socie, G., Beelen, D., Peschel, C., Neubauer, A., Finke, J., Duyster, J., Bubnoff, N. von, Zeiser, R., Burchert, A., Lengerke, C., Verbeek, M.M., Maas-Bauer, K., Metzelder, S.K., Spoerl, S., Ditschkowski, M., Ecsedi, M., Sockel, K., Ayuk, F., Ajib, S., Fontbrune, F.S. de, Na, I.K., Penter, L., Holtick, U., Wolf, D., Schuler, E., Meyer, E., Apostolova, P., Bertz, H., Marks, R., Lubbert, M., Wasch, R., Scheid, C., Stolzel, F., Ordemann, R., Bug, G., Kobbe, G., Negrin, R., Brune, M., Spyridonidis, A., Schmitt-Graff, A., Velden, W.J. van der, Huls, G.A., Mielke, S., Grigoleit, G.U., Kuball, J., Flynn, R., Ihorst, G., Du, J., Blazar, B.R., Arnold, R., Kroger, N., Passweg, J., Halter, J., Socie, G., Beelen, D., Peschel, C., Neubauer, A., Finke, J., Duyster, J., and Bubnoff, N. von

Abstract

Item does not contain fulltext, Despite major improvements in allogeneic hematopoietic cell transplantation over the past decades, corticosteroid-refractory (SR) acute (a) and chronic (c) graft-versus-host disease (GVHD) cause high mortality. Preclinical evidence indicates the potent anti-inflammatory properties of the JAK1/2 inhibitor ruxolitinib. In this retrospective survey, 19 stem cell transplant centers in Europe and the United States reported outcome data from 95 patients who had received ruxolitinib as salvage therapy for SR-GVHD. Patients were classified as having SR-aGVHD (n=54, all grades III or IV) or SR-cGVHD (n=41, all moderate or severe). The median number of previous GVHD-therapies was 3 for both SR-aGVHD (1-7) and SR-cGVHD (1-10). The overall response rate was 81.5% (44/54) in SR-aGVHD including 25 complete responses (46.3%), while for SR-cGVHD the ORR was 85.4% (35/41). Of those patients responding to ruxolitinib, the rate of GVHD-relapse was 6.8% (3/44) and 5.7% (2/35) for SR-aGVHD and SR-cGVHD, respectively. The 6-month-survival was 79% (67.3-90.7%, 95% confidence interval (CI)) and 97.4% (92.3-100%, 95% CI) for SR-aGVHD and SR-cGVHD, respectively. Cytopenia and cytomegalovirus-reactivation were observed during ruxolitinib treatment in both SR-aGVHD (30/54, 55.6% and 18/54, 33.3%) and SR-cGVHD (7/41, 17.1% and 6/41, 14.6%) patients. Ruxolitinib may constitute a promising new treatment option for SR-aGVHD and SR-cGVHD that should be validated in a prospective trial.

Published
2015

18. Prevalence, severity and correlates of fatigue in newly diagnosed patients with myelodysplastic syndromes.

Author

Efficace, F, Gaidano, G, Breccia, M, Criscuolo, Marianna, Cottone, F, Caocci, G, Bowen, D, Lubbert, M, Angelucci, E, Stauder, R, Selleslag, D, Platzbecker, U, Sanpaolo, G, Jonasova, A, Buccisano, F, Specchia, G, Palumbo, G. A, Niscola, P, Wan, C, Zhang, H, Fenu, S, Klimek, V, Beyne Rauzy, O, Nguyen, K, Mandelli, F., Efficace, F, Gaidano, G, Breccia, M, Criscuolo, Marianna, Cottone, F, Caocci, G, Bowen, D, Lubbert, M, Angelucci, E, Stauder, R, Selleslag, D, Platzbecker, U, Sanpaolo, G, Jonasova, A, Buccisano, F, Specchia, G, Palumbo, G. A, Niscola, P, Wan, C, Zhang, H, Fenu, S, Klimek, V, Beyne Rauzy, O, Nguyen, K, and Mandelli, F.

Abstract

The primary objective of this study was to investigate factors associated with fatigue severity in newly diagnosed patients with higher-risk myelodysplastic syndromes (MDS). The secondary objectives were to assess symptom prevalence and to examine the relationships between fatigue, quality of life (QoL) and overall symptom burden in these patients. The analyses were conducted in 280 higher-risk MDS patients. Pre-treatment patient-reported fatigue was evaluated with the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scale and QoL was assessed with the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30). Female gender (P = 0·018), poor performance status (i.e., ECOG of 2-4) (P < 0·001) and lower levels of haemoglobin (Hb) (P = 0·026) were independently associated with higher fatigue severity. The three most prevalent symptoms were as follows: fatigue (92%), dyspnoea (63%) and pain (55%). Patients with higher levels of fatigue also had greater overall symptom burdens. The mean global QoL scores of patients with the highest versus those with the lowest levels of fatigue were 29·2 [standard deviation (SD), 18·3] and 69·0 (SD, 18·8), respectively and this difference was four times the magnitude of a clinically meaningful difference. Patient-reported fatigue severity revealed the effects of disease burden on overall QoL more accurately than did degree of anaemia. Special attention should be given to the female patients in the management of fatigue.

Published
2015

19. Long term follow up of elderly patients with Philadelphia-Positive Acute Lymphoblastic Leukaemia (Ph plus ALL) : Updated results of the GMALL elderly trials

Author

Pfeifer, H., Wystub, S., Voelp, C., Wassmann, B., Brueck, P., Giagounidis, A., Stelljes, M., Dührsen, Ulrich, Schmalzing, M., Schaich, M., de Wit, M., Ganser, A., Fritsch, G., Gassmann, W., Pfreundschuh, M., Muller, M., Wendelin, K., Schmid, M., Beck, H. J., Dengler, J., Horst, H. A., Lubbert, M., Serve, H., Hoelzer, D., and Ottmann, O.

Subjects
Medizin
Published
2010

20. Validation of cytogenetic risk groups according to International Prognostic Scoring Systems by peripheral blood CD34+FISH: results from a German diagnostic study in comparison with an international control group

Author

Braulke, F., primary, Platzbecker, U., additional, Muller-Thomas, C., additional, Gotze, K., additional, Germing, U., additional, Brummendorf, T. H., additional, Nolte, F., additional, Hofmann, W.-K., additional, Giagounidis, A. A. N., additional, Lubbert, M., additional, Greenberg, P. L., additional, Bennett, J. M., additional, Sole, F., additional, Mallo, M., additional, Slovak, M. L., additional, Ohyashiki, K., additional, Le Beau, M. M., additional, Tuchler, H., additional, Pfeilstocker, M., additional, Nosslinger, T., additional, Hildebrandt, B., additional, Shirneshan, K., additional, Aul, C., additional, Stauder, R., additional, Sperr, W. R., additional, Valent, P., additional, Fonatsch, C., additional, Trumper, L., additional, Haase, D., additional, and Schanz, J., additional

Published
2014
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22. Sequential Combination of Gemtuzumab Ozogamicin and Standard Chemotherapy in Older Patients With Newly Diagnosed Acute Myeloid Leukemia: Results of a Randomized Phase III Trial by the EORTC and GIMEMA Consortium (AML-17).

Author

Amadori, S., Suciu, S., Stasi, R., Salih, H.R., Selleslag, D., Muus, P., Fabritiis, P. De, Venditti, A., Ho, A.D., Lubbert, M., Thomas, X., Latagliata, R., Halkes, C.J., Falzetti, F., Magro, D., Guimaraes, J.E., Berneman, Z., Specchia, G., Karrasch, M., Fazi, P., Vignetti, M., Willemze, R., Witte, T.J. de, Marie, J.P., Amadori, S., Suciu, S., Stasi, R., Salih, H.R., Selleslag, D., Muus, P., Fabritiis, P. De, Venditti, A., Ho, A.D., Lubbert, M., Thomas, X., Latagliata, R., Halkes, C.J., Falzetti, F., Magro, D., Guimaraes, J.E., Berneman, Z., Specchia, G., Karrasch, M., Fazi, P., Vignetti, M., Willemze, R., Witte, T.J. de, and Marie, J.P.

Abstract

Item does not contain fulltext, PURPOSE: This randomized trial evaluated the efficacy and toxicity of sequential gemtuzumab ozogamicin (GO) and standard chemotherapy in older patients with newly diagnosed acute myeloid leukemia (AML). PATIENTS AND METHODS: Patients (n = 472) age 61 to 75 years were randomly assigned to induction chemotherapy with mitoxantrone, cytarabine, and etoposide preceded, or not, by a course of GO (6 mg/m(2) on days 1 and 15). In remission, patients received two consolidation courses with or without GO (3 mg/m(2) on day 0). The primary end point was overall survival (OS). RESULTS: The overall response rate was comparable between the two arms (GO, 45%; no GO, 49%), but induction and 60-day mortality rates were higher in the GO arm (17% v 12% and 22% v 18%, respectively). With median follow-up of 5.2 years, median OS was 7.1 months in the GO arm and 10 months in the no-GO arm (hazard ratio, 1.20; 95% CI, 0.99 to 1.45; P = .07). Other survival end points were similar in both arms. Grade 3 to 4 hematologic and liver toxicities were greater in the GO arm. Treatment with GO provided no benefit in any prognostic subgroup, with the possible exception of patients age < 70 years with secondary AML, but outcomes were significantly worse in the oldest age subgroup because of a higher risk of early mortality. CONCLUSION: As used in this trial, the sequential combination of GO and standard chemotherapy provides no benefit for older patients with AML and is too toxic for those age >/= 70 years.

Published
2013

23. Parameters detected by geriatric and quality of life assessment in 195 older patients with myelodysplastic syndromes and acute myeloid leukemia are highly predictive for outcome

Author

Deschler, B., Ihorst, G., Platzbecker, U., Germing, U., Marz, E., de Figuerido, M., Fritzsche, K., Haas, P. de, Salih, H.R., Giagounidis, A., Selleslag, D., Labar, B., Witte, T.J. de, Wijermans, P., Lubbert, M., Deschler, B., Ihorst, G., Platzbecker, U., Germing, U., Marz, E., de Figuerido, M., Fritzsche, K., Haas, P. de, Salih, H.R., Giagounidis, A., Selleslag, D., Labar, B., Witte, T.J. de, Wijermans, P., and Lubbert, M.

Abstract

Contains fulltext : 118926.pdf (publisher's version ) (Open Access), Myelodysplastic syndromes and acute myeloid leukemia exemplify the complexity of treatment allocation in older patients as options range from best supportive care, non-intensive treatment (e.g. hypomethylating agents) to intensive chemotherapy/hematopoietic cell transplantation. Novel metrics for non-disease variables are urgently needed to help define the best treatment for each older patient. We investigated the feasibility and prognostic value of geriatric/quality of life assessments aside from established disease-specific variables in 195 patients aged 60 years or over with myelodysplastic syndromes/acute myeloid leukemia. These patients were grouped according to treatment intensity and assessed. Assessment consisted of eight instruments evaluating activities of daily living, depression, mental functioning, mobility, comorbidities, Karnofsky Index and quality of life. Patients with a median age of 71 years (range 60-87 years) with myelodysplastic syndromes (n=63) or acute myeloid leukemia (n=132) were treated either with best supportive care (n=47), hypomethylating agents (n=73) or intensive chemotherapy/hematopoietic cell transplantation (n=75). After selection of variables, pathological activities of daily living and quality of life/fatigue remained highly predictive for overall survival in the entire patient group beyond disease-related risk factors adverse cytogenetics and blast count of 20% or over. In 107 patients treated non-intensively activities of daily living of less than 100 (hazard ratio, HR 2.94), Karnofsky Index below 80 (HR 2.34) and quality of life/'fatigue' of 50 or over (HR 1.77) were significant prognosticators. Summation of adverse features revealed a high risk of death (HR 9.36). In-depth evaluation of older patients prior to individual treatment allocation is feasible and provides additional information to standard assessment. Patients aged 60 years or over with newly diagnosed myelodysplastic syndromes/acute myeloid leukemia and impairmen

Published
2013

24. EORTC Leukemia Group Achievements

Author

Willemze, R., Suciu, S., Marie, J.P., Karrasch, M., Jansen, J.H., Amadori, S., Muus, P., Labar, B., Baron, F., Selleslag, D., Wijermans, P., Bron, D., Hagemeijer, A., Meloni, G., Lubbert, M., Witte, T.J. de, Willemze, R., Suciu, S., Marie, J.P., Karrasch, M., Jansen, J.H., Amadori, S., Muus, P., Labar, B., Baron, F., Selleslag, D., Wijermans, P., Bron, D., Hagemeijer, A., Meloni, G., Lubbert, M., and Witte, T.J. de

Abstract

Item does not contain fulltext

Published
2012

25. A randomized phase 3 study of lenalidomide versus placebo in RBC transfusion-dependent patients with Low-/Intermediate-1-risk myelodysplastic syndromes with del5q

Author

Fenaux, P., Giagounidis, A., Selleslag, D., Beyne-Rauzy, O., Mufti, G., Mittelman, M., Muus, P., Boekhorst, P. Te, Sanz, G., Del Canizo, C., Guerci-Bresler, A., Nilsson, L., Platzbecker, U., Lubbert, M., Quesnel, B., Cazzola, M., Ganser, A., Bowen, D., Schlegelberger, B., Aul, C., Knight, R., Francis, J., Fu, T., Hellstrom-Lindberg, E., Fenaux, P., Giagounidis, A., Selleslag, D., Beyne-Rauzy, O., Mufti, G., Mittelman, M., Muus, P., Boekhorst, P. Te, Sanz, G., Del Canizo, C., Guerci-Bresler, A., Nilsson, L., Platzbecker, U., Lubbert, M., Quesnel, B., Cazzola, M., Ganser, A., Bowen, D., Schlegelberger, B., Aul, C., Knight, R., Francis, J., Fu, T., and Hellstrom-Lindberg, E.

Abstract

Item does not contain fulltext, This phase 3, randomized, double-blind study assessed the efficacy and safety of lenalidomide in 205 red blood cell (RBC) transfusion-dependent patients with International Prognostic Scoring System Low-/Intermediate-1-risk del5q31 myelodysplastic syndromes. Patients received lenalidomide 10 mg/day on days 1-21 (n = 69) or 5 mg/day on days 1-28 (n = 69) of 28-day cycles; or placebo (n = 67). Crossover to lenalidomide or higher dose was allowed after 16 weeks. More patients in the lenalidomide 10- and 5-mg groups achieved RBC-transfusion independence (TI) for >/= 26 weeks (primary endpoint) versus placebo (56.1% and 42.6% vs 5.9%; both P < .001). Median duration of RBC-TI was not reached (median follow-up, 1.55 years), with 60% to 67% of responses ongoing in patients without progression to acute myeloid leukemia (AML). Cytogenetic response rates were 50.0% (10 mg) versus 25.0% (5 mg; P = .066). For the lenalidomide groups combined, 3-year overall survival and AML risk were 56.5% and 25.1%, respectively. RBC-TI for >/= 8 weeks was associated with 47% and 42% reductions in the relative risks of death and AML progression or death, respectively (P = .021 and .048). The safety profile was consistent with previous reports. Lenalidomide is beneficial and has an acceptable safety profile in transfusion-dependent patients with Low-/Intermediate-1-risk del5q myelodysplastic syndrome. This trial was registered at www.clinicaltrials.gov as #NCT00179621.

Published
2011

26. Low-dose decitabine versus best supportive care in elderly patients with intermediate- or high-risk myelodysplastic syndrome (MDS) ineligible for intensive chemotherapy: final results of the randomized phase III study of the European Organisation for Research and Treatment of Cancer Leukemia Group and the German MDS Study Group

Author

Lubbert, M., Suciu, S., Baila, L., Ruter, B.H., Platzbecker, U., Giagounidis, A., Selleslag, D., Labar, B., Germing, U., Salih, H.R., Beeldens, F., Muus, P., Pfluger, K.H., Coens, C., Hagemeijer, A., Eckart Schaefer, H., Ganser, A., Aul, C., Witte, T.J.M. de, Wijermans, P.W., Lubbert, M., Suciu, S., Baila, L., Ruter, B.H., Platzbecker, U., Giagounidis, A., Selleslag, D., Labar, B., Germing, U., Salih, H.R., Beeldens, F., Muus, P., Pfluger, K.H., Coens, C., Hagemeijer, A., Eckart Schaefer, H., Ganser, A., Aul, C., Witte, T.J.M. de, and Wijermans, P.W.

Abstract

Contains fulltext : 98066.pdf (publisher's version ) (Closed access), PURPOSE: To compare low-dose decitabine to best supportive care (BSC) in higher-risk patients with myelodysplastic syndrome (MDS) age 60 years or older and ineligible for intensive chemotherapy. PATIENTS AND METHODS: Two-hundred thirty-three patients (median age, 70 years; range, 60 to 90 years) were enrolled; 53% had poor-risk cytogenetics, and the median MDS duration at random assignment was 3 months. Primary end point was overall survival (OS). Decitabine (15 mg/m(2)) was given intravenously over 4 hours three times a day for 3 days in 6-week cycles. RESULTS: OS prolongation with decitabine versus BSC was not statistically significant (median OS, 10.1 v 8.5 months, respectively; hazard ratio [HR], 0.88; 95% CI, 0.66 to 1.17; two-sided, log-rank P = .38). Progression-free survival (PFS), but not acute myeloid leukemia (AML) -free survival (AMLFS), was significantly prolonged with decitabine versus BSC (median PFS, 6.6 v 3.0 months, respectively; HR, 0.68; 95% CI, 0.52 to 0.88; P = .004; median AMLFS, 8.8 v 6.1 months, respectively; HR, 0.85; 95% CI, 0.64 to 1.12; P = .24). AML transformation was significantly (P = .036) reduced at 1 year (from 33% with BSC to 22% with decitabine). Multivariate analyses indicated that patients with short MDS duration had worse outcomes. Best responses with decitabine versus BSC, respectively, were as follows: complete response (13% v 0%), partial response (6% v 0%), hematologic improvement (15% v 2%), stable disease (14% v 22%), progressive disease (29% v 68%), hypoplasia (14% v 0%), and inevaluable (8% v 8%). Grade 3 to 4 febrile neutropenia occurred in 25% of patients on decitabine versus 7% of patients on BSC; grade 3 to 4 infections occurred in 57% and 52% of patients on decitabine and BSC, respectively. Decitabine treatment was associated with improvements in patient-reported quality-of-life (QOL) parameters. CONCLUSION: Decitabine administered in 6-week cycles is active in older patients with higher-risk MDS, resulting in imp

Published
2011

28. An epigenetic approach to the treatment of advanced MDS; the experience with the DNA demethylating agent 5-aza-2 '-deoxycytidine (decitabine) in 177 patients

Author

UCL, Wijermans, PW, Lubbert, M, Verhoef, G., Klimek, V, Bosly, André, UCL, Wijermans, PW, Lubbert, M, Verhoef, G., Klimek, V, and Bosly, André

Abstract

During the last 10 years, three European phase 11 studies were performed to investigate the treatment of elderly patients with myelodysplastic syndrome (MDS) with low-dose 5-aza-2'-deoxycytidine (decitabine, DAC). All these European trial data were reviewed on the basis of the International Prognostic Scoring System (IPSS) risk criteria and the response criteria as recently published by an international working group. To investigate the results in a larger cohort of patients and to determine risk factors, all data were pooled with some observations from the PCH 95-06 US phase 11 study. The response rate in the 177 patients evaluated (median age 70 years) was 49%. The median response duration was 36 weeks, and the median survival was 15 months. Analysis of the data according to sex, age, French-American-British classification, percentage of blasts in the bone marrow, IPSS risk group, lactate dehydrogenase and cytogenetics did not reveal any factor predictive of response. Overall, 69% of patients benefited, including those with stable disease during therapy. Response duration was significantly shorter with increasing risk (according to the IPSS classification). Haemoglobin level and neutrophil count showed an inverse correlation to the IPSS classification. Univariate analysis showed a significantly inferior survival for elderly patients (>75 years of age) and for those with high levels of serum lactate dehydrogenase (LDH) (more than two times the normal values). Patients with high-risk cytogenetic abnormalities according to the IPSS risk criteria showed better overall survival than those with intermediate-risk abnormalities. When analysed according to the IPSS risk classification, high-risk patients had worse survival prospects following decitabine therapy than those with intermediate risk; however, compared to the originally reported IPPS outcomes for high-risk patients, they probably showed better survival. During the treatment period, 18% of the patients progressed

Published
2005

29. Parameters detected by geriatric and quality of life assessment in 195 older patients with myelodysplastic syndromes and acute myeloid leukemia are highly predictive for outcome

Author

Deschler, B., primary, Ihorst, G., additional, Platzbecker, U., additional, Germing, U., additional, Marz, E., additional, de Figuerido, M., additional, Fritzsche, K., additional, Haas, P., additional, Salih, H. R., additional, Giagounidis, A., additional, Selleslag, D., additional, Labar, B., additional, de Witte, T., additional, Wijermans, P., additional, and Lubbert, M., additional

Published
2012
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30. A multicenter phase II trial of decitabine as first-line treatment for older patients with acute myeloid leukemia judged unfit for induction chemotherapy

Author

Lubbert, M., primary, Ruter, B. H., additional, Claus, R., additional, Schmoor, C., additional, Schmid, M., additional, Germing, U., additional, Kuendgen, A., additional, Rethwisch, V., additional, Ganser, A., additional, Platzbecker, U., additional, Galm, O., additional, Brugger, W., additional, Heil, G., additional, Hackanson, B., additional, Deschler, B., additional, Dohner, K., additional, Hagemeijer, A., additional, Wijermans, P. W., additional, and Dohner, H., additional

Published
2011
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31. 166 Safety of panobinostat plus 5-azacitidine in myelodysplastic syndrome, chronic myelomonocytic leukemia, or acute myeloid leukemia patients: a phase Ib study

Author

Fenaux, P., primary, DeAngelo, D., additional, Garcia-Manero, G., additional, Lubbert, M., additional, Jillella, A., additional, Sekeres, M., additional, Zahlten, A., additional, Squier, M., additional, Acharyya, S., additional, Winiger-Candolfi, I., additional, and Ottmann, O., additional

Published
2011
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33. Cytogenetic responses in high-risk myelodysplastic syndrome following low-dose treatment with the DNA methylation inhibitor 5-aza-2 '-deoxycytidine

Author

UCL - Cliniques universitaires Saint-Luc, UCL - MD/MINT - Département de médecine interne, UCL - (SLuc) Service d'hématologie, UCL - (MGD) Service d'hématologie, Lubbert, M, Ferrant, Augustin, Wijermans, P, Kunzmann, R, Verhoef, G., Bosly, André, Ravoet, C, André, Marc, UCL - Cliniques universitaires Saint-Luc, UCL - MD/MINT - Département de médecine interne, UCL - (SLuc) Service d'hématologie, UCL - (MGD) Service d'hématologie, Lubbert, M, Ferrant, Augustin, Wijermans, P, Kunzmann, R, Verhoef, G., Bosly, André, Ravoet, C, and André, Marc

Abstract

Decitabine (5-aza-2'-deoxycytidine) acts as a powerful demethylating agent in vitro. Clinically, low-dose decitabine ameliorates cytopenias including induction of trilineage responses in approximate to 50% of patients with high-risk myelodysplastic syndrome (MDS). We examined the incidence and kinetics of cytogenetic responses to decitabine in these patients. Of 115 successfully karyotyped patients, 61 (53%) had clonal chromosomal abnormalities prior to treatment. Major cytogenetic responses were observed in 19 patients (31% of those with abnormal cytogenetics, 17% of all patients by intention-to-treat) after a median of three courses (range, 2-6) until best cytogenetic response. Progressive decrease of the abnormal clone over time was also determined using fluorescence in situ hybridization (FISH) analysis in two patients. Median duration of cytogenetic responses was 7.5 months (range, 3-15). Analysis of response by the International Prognostic Scoring System (IPSS) cytogenetic risk groups revealed three out of five cytogenetic responses (60%) in the IPSS 'low-risk' group, 6 out of 30 with 'intermediate risk' (20%) and 10 out of 26 in the 'high-risk' group (38%). Median survival in these cytogenetic subgroups was 30, 8 and 13 months respectively. The relative risk of death in patients achieving a major cytogenetic response was 0.38 (95% confidence interval 0.17-0.88) compared with patients in whom the cytogenetically abnormal clone persisted (P = 0.0213). In conclusion, repeated courses of low-dose decitabine induce cytogenetic remissions in a substantial number of elderly MDS patients with pre-existing chromosomal abnormalites; these are associated with improved survival compared with patients in whom the cytogenetically abnormal clone persists. Patients with 'high-risk' chromosomal abnormalities may particularly benefit from this treatment.

Published
2001

35. Low-dose 5-aza-2 '-deoxycytidine, a DNA hypomethylating agent, for the treatment of high-risk myelodysplastic syndrome: A multicenter phase II study in elderly patients

Author

UCL - Cliniques universitaires Saint-Luc, UCL, Wijermans, P, Ferrant, Augustin, Lubbert, M, Verhoef, G., Bosly, André, Ravoet, C, André, Marc, UCL - Cliniques universitaires Saint-Luc, UCL, Wijermans, P, Ferrant, Augustin, Lubbert, M, Verhoef, G., Bosly, André, Ravoet, C, and André, Marc

Abstract

Purpose: 5-Aza-2'-deoxycytidine (decitabine; DAC) is a DNA hypomethylating agent that has shown a 50% response rate in a small phase It study in elderly patients with high-risk myelodysplastic syndrome. We performed a second, multicenter phase II study in a larger group of patients ta confirm our findings and to study the toxicity of DAC. Patients and Methods: Between June 1996 and September 1997, 66 patients (median age, 68 years) from seven centers received PAC 45 mg/m(2)/d for 3 days every 6 weeks. For patients in whom a complete response (CR) was reached after two courses, two further cycles were administered as consolidation therapy, In case of a stable disease situation, improvement, or a partial response (PR), ct maximum of six cycles was administered, The primary end points were response rate and toxicity. The secondary end points were response duration, survival from the start of therapy, and overall survival, Results: The observed overall response rate was 49%, with a 64% response rate in the patients with an International Prognostic Scoring System (IPSS) high-risk score. The actuarial median response duration was 31 weeks, with a response duration of 39 weeks and 36 weeks for patients who reached a PR or CR, respectively. The actuarial median survival time from the time of diagnosis was 22 months and from the start of therapy was 15 months. For the IPSS high risk group, the median survival rime was 14 months. the median progression-free survival time was 25 weeks. Myelosuppression was rather common, and the treatment-related mortality rate was 7% and was primarily associated with pancytopenia and infection. Significant responses were observed with regard to megakaryopoiesis, with increases in platelet counts having already occurred after one cycle of DAC therapy in the majority of the responding patients. Conclusion: We were able to confirm our previous observation that DAC therapy was effective in half of the studied patients with high-risk myelodysplast

Published
2000

36. Cytogenetic remissions in high-risk myelodysplastic syndrome: Results in 124 patients treated with low-dose 5-aza-2 '-deoxycytidine (Decitabine), a DNA methylation inhibitor.

Author

UCL - Cliniques universitaires Saint-Luc, UCL, Lubbert, M, Ferrant, Augustin, Wijermans, P, Kunzmann, R, Verhoef, G., Bosly, André, Ravoet, C, André, Marc, UCL - Cliniques universitaires Saint-Luc, UCL, Lubbert, M, Ferrant, Augustin, Wijermans, P, Kunzmann, R, Verhoef, G., Bosly, André, Ravoet, C, and André, Marc

Published
2000

45. A phase II study with low dose decitabine, a DNA hypomethylating pyrimidine analogue, in high risk MDS patients.

Author

UCL - Cliniques universitaires Saint-Luc, UCL - MD/MINT - Département de médecine interne, Wijermans, P, Ferrant, Augustin, Lubbert, M, Verhoef, G., Bosly, André, Ravoet, C, André, Marc, UCL - Cliniques universitaires Saint-Luc, UCL - MD/MINT - Département de médecine interne, Wijermans, P, Ferrant, Augustin, Lubbert, M, Verhoef, G., Bosly, André, Ravoet, C, and André, Marc

Published
1998

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