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3 results on '"Lubbert M."'

1. 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

2. 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

Marco Sborgia, Marco Vignetti, Massimo Breccia, Fabio Efficace, Roberto Cairoli, Hartmut Link, Uwe Platzbecker, Norbert Schmitz, Ombretta Annibali, Agostino Cortelezzi, Francesca Paoloni, Eros Di Bona, Nicola Di Renzo, Alfonso Maria D'Arco, Lorella Melillo, Francesco Lo-Coco, Peter Brossart, Felicetto Ferrara, Chiara Frairia, Franco Mandelli, Christoph Röllig, Laura Cicconi, Claudio Fozza, Konstanze Döhner, Walter Fiedler, Bernd Hertenstein, Francesco Fabbiano, Richard F. Schlenk, Mariadomenica Divona, Francesco Albano, Mohammed Wattad, Maria Teresa Voso, Christian Thiede, Christian Brandts, Paola Fazi, Gerhard Ehninger, Mathias Hänel, Sergio Amadori, Alessandro Rambaldi, Giorgio La Nasa, Helmut R. Salih, Hartmut Döhner, Michael Lübbert, Giuseppe Avvisati, Arnold Ganser, Erika Borlenghi, 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
Adult, Male, Oncology, Acute promyelocytic leukemia, Cancer Research, medicine.medical_specialty, Adolescent, Retinoic acid, Tretinoin, Follow-Up Studie, law.invention, Young Adult, chemistry.chemical_compound, Leukemia, Promyelocytic, Acute, Randomized controlled trial, law, Germany, Internal medicine, medicine, acute leukemia, Arsenic trioxide, Aged, Antineoplastic Combined Chemotherapy Protocol, business.industry, All trans, Hematology, Long term results, Middle Aged, APL, arsenic trioxide, medicine.disease, Clinical trial, Prospective Studie, Leukemia, Treatment Outcome, Italy, chemistry, Female, business, Settore MED/15 - Malattie del Sangue, Human
Published
2019

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

Author

Michael Heuser, Manoj Garg, T Haferlach, L. Z. Liu, Shih Ly, Yuichi Shiraishi, Takayuki Ikezoe, Michael Lill, Hwei-Fang Tien, Henry Yang, Ling-Wen Ding, Hagop M. Kantarjian, H P Koeffler, T. Ma, Yasunobu Nagata, Wolf-K. Hofmann, Qiao-Yang Sun, Satoru Miyano, Richard A. Larson, Noreen Fulton, Seishi Ogawa, Pavithra Shyamsunder, Masashi Sanada, Kamran Alimoghaddam, W. J. Chng, Norimichi Hattori, Saravanan Ganesan, Wendy Stock, Tamara Alpermann, S. Rostami, Ezhilarasi Chendamarai, Vikram Mathews, Kenichi Yoshida, Anand Mayakonda, Steve Kornblau, M. C. Kuo, Gregory Malnassy, Vikas Madan, Lin Han, A. Ghavamzadeh, Hsin-An Hou, Andrea Biondi, Bayard L. Powell, W. Chien, Jairo Matthews, Janani Sundaresan, Michael Lübbert, Daniel Nowak, Deepika Kanojia, Arnold Ganser, Kar Tong Tan, Maya Koren-Michowitz, 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, and Koeffler, H

Subjects
0301 basic medicine, Neuroblastoma RAS viral oncogene homolog, Acute promyelocytic leukemia, Cancer Research, ARID1A, DNA-Binding Protein, DNA Mutational Analysis, Clinical Sciences, Oncology and Carcinogenesis, Immunology, Acute, Biology, DNA Mutational Analysi, Fusion gene, 03 medical and health sciences, 0302 clinical medicine, Leukemia, Promyelocytic, Acute, Recurrence, immune system diseases, medicine, Humans, Exome, neoplasms, Nuclear Protein, Promyelocytic, Genetics, Leukemia, Gene Expression Profiling, Nuclear Proteins, Myeloid leukemia, Cell Differentiation, Hematology, medicine.disease, DNA-Binding Proteins, 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, Original Article, Human, Transcription Factors
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

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