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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

7. 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

8. 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

9. 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

10. 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

11. 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

12. 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

13. 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

14. 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

15. 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

16. 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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17. 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

18. 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

19. Netboost: Boosting-Supported Network Analysis Improves High-Dimensional Omics Prediction in Acute Myeloid Leukemia and Huntington's Disease.

Author

Schlosser P, Knaus J, Schmutz M, Dohner K, Plass C, Bullinger L, Claus R, Binder H, Lubbert M, and Schumacher M

Subjects
Algorithms, Animals, Cluster Analysis, DNA Methylation genetics, Female, Humans, Machine Learning, Male, Mice, Proportional Hazards Models, Computational Biology methods, Huntington Disease diagnosis, Huntington Disease genetics, Huntington Disease mortality, Leukemia, Myeloid, Acute diagnosis, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute mortality
Abstract

State-of-the art selection methods fail to identify weak but cumulative effects of features found in many high-dimensional omics datasets. Nevertheless, these features play an important role in certain diseases. We present Netboost, a three-step dimension reduction technique. First, a boosting-based filter is combined with the topological overlap measure to identify the essential edges of the network. Second, sparse hierarchical clustering is applied on the selected edges to identify modules and finally module information is aggregated by the first principal components. We demonstrate the application of the newly developed Netboost in combination with CoxBoost for survival prediction of DNA methylation and gene expression data from 180 acute myeloid leukemia (AML) patients and show, based on cross-validated prediction error curve estimates, its prediction superiority over variable selection on the full dataset as well as over an alternative clustering approach. The identified signature related to chromatin modifying enzymes was replicated in an independent dataset, the phase II AMLSG 12-09 study. In a second application we combine Netboost with Random Forest classification and improve the disease classification error in RNA-sequencing data of Huntington's disease mice. Netboost is a freely available Bioconductor R package for dimension reduction and hypothesis generation in high-dimensional omics applications.

Published
2021
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20. 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 HR, Annibali O, Wattad M, Lubbert M, Brandts CH, Hanel M, Rollig C, Schmitz N, Link 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, Voso MT, Ehninger G, Schlenk RF, and Lo-Coco F

Subjects
Adolescent, Adult, Aged, Female, Follow-Up Studies, Germany, Humans, Italy, Male, Middle Aged, Prospective Studies, Treatment Outcome, Young Adult, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Arsenic Trioxide administration & dosage, Leukemia, Promyelocytic, Acute drug therapy, Tretinoin administration & dosage
Published
2020
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