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1. Standardization of molecular monitoring of CML: results and recommendations from the European treatment and outcome study

Author

White, Helen E., Salmon, Matthew, Albano, Francesco, Andersen, Christina Søs Auður, Balabanov, Stefan, Balatzenko, Gueorgui, Barbany, Gisela, Cayuela, Jean-Michel, Cerveira, Nuno, Cochaux, Pascale, Colomer, Dolors, Coriu, Daniel, Diamond, Joana, Dietz, Christian, Dulucq, Stéphanie, Engvall, Marie, Franke, Georg N., Gineikiene-Valentine, Egle, Gniot, Michal, Gómez-Casares, María Teresa, Gottardi, Enrico, Hayden, Chloe, Hayette, Sandrine, Hedblom, Andreas, Ilea, Anca, Izzo, Barbara, Jiménez-Velasco, Antonio, Jurcek, Tomas, Kairisto, Veli, Langabeer, Stephen E., Lion, Thomas, Meggyesi, Nora, Mešanović, Semir, Mihok, Luboslav, Mitterbauer-Hohendanner, Gerlinde, Moeckel, Sylvia, Naumann, Nicole, Nibourel, Olivier, Oppliger Leibundgut, Elisabeth, Panayiotidis, Panayiotis, Podgornik, Helena, Pott, Christiane, Rapado, Inmaculada, Rose, Susan J., Schäfer, Vivien, Touloumenidou, Tasoula, Veigaard, Christopher, Venniker-Punt, Bianca, Venturi, Claudia, Vigneri, Paolo, Vorkinn, Ingvild, Wilkinson, Elizabeth, Zadro, Renata, Zawada, Magdalena, Zizkova, Hana, Müller, Martin C., Saussele, Susanne, Ernst, Thomas, Machova Polakova, Katerina, Hochhaus, Andreas, and Cross, Nicholas C. P.

Published
2022
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2. BCL6-mediated repression of p53 is critical for leukemia stem cell survival in chronic myeloid leukemia

Author

Hurtz, Christian, Hatzi, Katerina, Cerchietti, Leandro, Braig, Melanie, Park, Eugene, Kim, Yong-mi, Herzog, Sebastian, Ramezani-Rad, Parham, Jumaa, Hassan, Müller, Martin C, Hofmann, Wolf-Karsten, Hochhaus, Andreas, Ye, B Hilda, Agarwal, Anupriya, Druker, Brian J, Shah, Neil P, Melnick, Ari M, and Müschen, Markus

Subjects
Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Hematology, Stem Cell Research - Nonembryonic - Non-Human, Stem Cell Research - Nonembryonic - Human, Cancer, Rare Diseases, Stem Cell Research, Development of treatments and therapeutic interventions, 2.1 Biological and endogenous factors, 5.1 Pharmaceuticals, Aetiology, Animals, Antigens, CD34, Benzamides, Cell Survival, DNA-Binding Proteins, Disease Models, Animal, Forkhead Transcription Factors, Hematopoietic Stem Cells, Humans, Imatinib Mesylate, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Mice, Mice, Inbred NOD, Mice, Knockout, Mice, SCID, Neoplasm Transplantation, Neoplastic Stem Cells, Piperazines, Protein Kinase Inhibitors, Protein-Tyrosine Kinases, Proto-Oncogene Proteins c-bcl-6, Pyrimidines, Tumor Cells, Cultured, Tumor Suppressor Protein p53, Medical and Health Sciences, Immunology, Biomedical and clinical sciences, Health sciences
Abstract

Chronic myeloid leukemia (CML) is induced by the oncogenic BCR-ABL1 tyrosine kinase and can be effectively treated for many years with tyrosine kinase inhibitors (TKIs). However, unless CML patients receive life-long TKI treatment, leukemia will eventually recur; this is attributed to the failure of TKI treatment to eradicate leukemia-initiating cells (LICs). Recent work demonstrated that FoxO factors are critical for maintenance of CML-initiating cells; however, the mechanism of FoxO-dependent leukemia initiation remained elusive. Here, we identified the BCL6 protooncogene as a critical effector downstream of FoxO in self-renewal signaling of CML-initiating cells. BCL6 represses Arf and p53 in CML cells and is required for colony formation and initiation of leukemia. Importantly, peptide inhibition of BCL6 in human CML cells compromises colony formation and leukemia initiation in transplant recipients and selectively eradicates CD34(+) CD38(-) LICs in patient-derived CML samples. These findings suggest that pharmacological inhibition of BCL6 may represent a novel strategy to eradicate LICs in CML. Clinical validation of this concept could limit the duration of TKI treatment in CML patients, which is currently life-long, and substantially decrease the risk of blast crisis transformation.

Published
2011

3. Defining therapy goals for major molecular remission in chronic myeloid leukemia: results of the randomized CML Study IV

Author

Saussele, Susanne, Hehlmann, Rüdiger, Fabarius, Alice, Jeromin, Sabine, Proetel, Ulrike, Rinaldetti, Sebastien, Kohlbrenner, Katharina, Einsele, Hermann, Falge, Christiane, Kanz, Lothar, Neubauer, Andreas, Kneba, Michael, Stegelmann, Frank, Pfreundschuh, Michael, Waller, Cornelius F., Oppliger Leibundgut, Elisabeth, Heim, Dominik, Krause, Stefan W., Hofmann, Wolf-Karsten, Hasford, Joerg, Pfirrmann, Markus, Müller, Martin C., Hochhaus, Andreas, and Lauseker, Michael

Published
2018
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4. POSTER: CML-310 Early Cytogenetic or Molecular Landmark Response to Ponatinib Treatment Predicts Outcomes in Heavily Pretreated Patients With Chronic-Phase Chronic Myeloid Leukemia (CP-CML) in PACE: 5-Year Data

Author

Müller, Martin C., primary, Cortes, Jorge, additional, Chuah, Charles, additional, DeAngelo, Daniel J., additional, Deininger, Michael, additional, Guilhot, François, additional, Hughes, Timothy, additional, Nicolini, Franck E., additional, Pinilla-Ibarz, Javier, additional, Rea, Delphine, additional, Rosti, Gianantonio, additional, Shah, Neil P., additional, Talpaz, Moshe, additional, Lu, Vickie, additional, Padukkavidana, Thihan, additional, and Kantarjian, Hagop M., additional

Published
2023
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5. CML-310 Early Cytogenetic or Molecular Landmark Response to Ponatinib Treatment Predicts Outcomes in Heavily Pretreated Patients With Chronic-Phase Chronic Myeloid Leukemia (CP-CML) in PACE: 5-Year Data

Author

Müller, Martin C., primary, Cortes, Jorge, additional, Chuah, Charles, additional, DeAngelo, Daniel J., additional, Deininger, Michael, additional, Guilhot, François, additional, Hughes, Timothy, additional, Nicolini, Franck E., additional, Pinilla-Ibarz, Javier, additional, Rea, Delphine, additional, Rosti, Gianantonio, additional, Shah, Neil P., additional, Talpaz, Moshe, additional, Lu, Vickie, additional, Padukkavidana, Thihan, additional, and Kantarjian, Hagop M., additional

Published
2023
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6. P670: EARLY CYTOGENETIC OR MOLECULAR LANDMARK RESPONSE TO PONATINIB TREATMENT PREDICTS OUTCOMES IN HEAVILY PRETREATED PATIENTS WITH CHRONIC-PHASE CHRONIC MYELOID LEUKEMIA IN PACE: 5-YEAR DATA

Author

Müller, Martin C., primary, Cortes, Jorge, additional, Chuah, Charles, additional, Deangelo, Daniel, additional, Deininger, Michael, additional, Guilhot, François, additional, Hughes, Timothy, additional, Emmanuel Nicolini, Franck, additional, Pinilla-Ibarz, Javier, additional, Rea, Delphine, additional, Rosti, Gianantonio, additional, Shah, Neil P., additional, Talpaz, Moshe, additional, Lu, Vickie, additional, Padukkavidana, Thihan, additional, and Kantarjian, Hagop, additional

Published
2023
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7. Supplementary Figure 4 from High BCR–ABL/GUSIS Levels at Diagnosis of Chronic Phase CML Are Associated with Unfavorable Responses to Standard-Dose Imatinib

Author

Vigneri, Paolo, primary, Stagno, Fabio, primary, Stella, Stefania, primary, Cupri, Alessandra, primary, Forte, Stefano, primary, Massimino, Michele, primary, Antolino, Agostino, primary, Siragusa, Sergio, primary, Mannina, Donato, primary, Impera, Stefana Stella, primary, Musolino, Caterina, primary, Malato, Alessandra, primary, Mineo, Giuseppe, primary, Tomaselli, Carmela, primary, Murgano, Pamela, primary, Musso, Maurizio, primary, Morabito, Fortunato, primary, Molica, Stefano, primary, Martino, Bruno, primary, Manzella, Livia, primary, Müller, Martin C., primary, Hochhaus, Andreas, primary, and Raimondo, Francesco Di, primary

Published
2023
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8. Supplementary Table 2 from High BCR–ABL/GUSIS Levels at Diagnosis of Chronic Phase CML Are Associated with Unfavorable Responses to Standard-Dose Imatinib

Author

Vigneri, Paolo, primary, Stagno, Fabio, primary, Stella, Stefania, primary, Cupri, Alessandra, primary, Forte, Stefano, primary, Massimino, Michele, primary, Antolino, Agostino, primary, Siragusa, Sergio, primary, Mannina, Donato, primary, Impera, Stefana Stella, primary, Musolino, Caterina, primary, Malato, Alessandra, primary, Mineo, Giuseppe, primary, Tomaselli, Carmela, primary, Murgano, Pamela, primary, Musso, Maurizio, primary, Morabito, Fortunato, primary, Molica, Stefano, primary, Martino, Bruno, primary, Manzella, Livia, primary, Müller, Martin C., primary, Hochhaus, Andreas, primary, and Raimondo, Francesco Di, primary

Published
2023
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9. Supplementary Figure 2 from High BCR–ABL/GUSIS Levels at Diagnosis of Chronic Phase CML Are Associated with Unfavorable Responses to Standard-Dose Imatinib

Author

Vigneri, Paolo, primary, Stagno, Fabio, primary, Stella, Stefania, primary, Cupri, Alessandra, primary, Forte, Stefano, primary, Massimino, Michele, primary, Antolino, Agostino, primary, Siragusa, Sergio, primary, Mannina, Donato, primary, Impera, Stefana Stella, primary, Musolino, Caterina, primary, Malato, Alessandra, primary, Mineo, Giuseppe, primary, Tomaselli, Carmela, primary, Murgano, Pamela, primary, Musso, Maurizio, primary, Morabito, Fortunato, primary, Molica, Stefano, primary, Martino, Bruno, primary, Manzella, Livia, primary, Müller, Martin C., primary, Hochhaus, Andreas, primary, and Raimondo, Francesco Di, primary

Published
2023
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10. Supplementary Figure 5 from High BCR–ABL/GUSIS Levels at Diagnosis of Chronic Phase CML Are Associated with Unfavorable Responses to Standard-Dose Imatinib

Author

Vigneri, Paolo, primary, Stagno, Fabio, primary, Stella, Stefania, primary, Cupri, Alessandra, primary, Forte, Stefano, primary, Massimino, Michele, primary, Antolino, Agostino, primary, Siragusa, Sergio, primary, Mannina, Donato, primary, Impera, Stefana Stella, primary, Musolino, Caterina, primary, Malato, Alessandra, primary, Mineo, Giuseppe, primary, Tomaselli, Carmela, primary, Murgano, Pamela, primary, Musso, Maurizio, primary, Morabito, Fortunato, primary, Molica, Stefano, primary, Martino, Bruno, primary, Manzella, Livia, primary, Müller, Martin C., primary, Hochhaus, Andreas, primary, and Raimondo, Francesco Di, primary

Published
2023
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11. Supplementary Figure 1 from High BCR–ABL/GUSIS Levels at Diagnosis of Chronic Phase CML Are Associated with Unfavorable Responses to Standard-Dose Imatinib

Author

Vigneri, Paolo, primary, Stagno, Fabio, primary, Stella, Stefania, primary, Cupri, Alessandra, primary, Forte, Stefano, primary, Massimino, Michele, primary, Antolino, Agostino, primary, Siragusa, Sergio, primary, Mannina, Donato, primary, Impera, Stefana Stella, primary, Musolino, Caterina, primary, Malato, Alessandra, primary, Mineo, Giuseppe, primary, Tomaselli, Carmela, primary, Murgano, Pamela, primary, Musso, Maurizio, primary, Morabito, Fortunato, primary, Molica, Stefano, primary, Martino, Bruno, primary, Manzella, Livia, primary, Müller, Martin C., primary, Hochhaus, Andreas, primary, and Raimondo, Francesco Di, primary

Published
2023
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12. Supplementary Figure 3 from High BCR–ABL/GUSIS Levels at Diagnosis of Chronic Phase CML Are Associated with Unfavorable Responses to Standard-Dose Imatinib

Author

Vigneri, Paolo, primary, Stagno, Fabio, primary, Stella, Stefania, primary, Cupri, Alessandra, primary, Forte, Stefano, primary, Massimino, Michele, primary, Antolino, Agostino, primary, Siragusa, Sergio, primary, Mannina, Donato, primary, Impera, Stefana Stella, primary, Musolino, Caterina, primary, Malato, Alessandra, primary, Mineo, Giuseppe, primary, Tomaselli, Carmela, primary, Murgano, Pamela, primary, Musso, Maurizio, primary, Morabito, Fortunato, primary, Molica, Stefano, primary, Martino, Bruno, primary, Manzella, Livia, primary, Müller, Martin C., primary, Hochhaus, Andreas, primary, and Raimondo, Francesco Di, primary

Published
2023
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13. Impact of unbalanced minor route versus major route karyotypes at diagnosis on prognosis of CML

Author

Fabarius, Alice, Kalmanti, Lida, Dietz, Christian T., Lauseker, Michael, Rinaldetti, Sébastien, Haferlach, Claudia, Göhring, Gudrun, Schlegelberger, Brigitte, Jotterand, Martine, Hanfstein, Benjamin, Seifarth, Wolfgang, Hänel, Mathias, Köhne, Claus-Henning, Lindemann, Hans W., Berdel, Wolfgang E., Staib, Peter, Müller, Martin C., Proetel, Ulrike, Balleisen, Leopold, Goebeler, Maria-Elisabeth, Dengler, Jolanta, Falge, Christiane, Kanz, Lothar, Burchert, Andreas, Kneba, Michael, Stegelmann, Frank, Pfreundschuh, Michael, Waller, Cornelius F., Spiekermann, Karsten, Brümmendorf, Tim H., Edinger, Matthias, Hofmann, Wolf-Karsten, Pfirrmann, Markus, Hasford, Joerg, Krause, Stefan, Hochhaus, Andreas, Saußele, Susanne, Hehlmann, Rüdiger, and for the SAKK and the German CML Study Group

Published
2015
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20. Older patients with chronic myeloid leukemia (≥65 years) profit more from higher imatinib doses than younger patients: a subanalysis of the randomized CML-Study IV

Author

Proetel, Ulrike, Pletsch, Nadine, Lauseker, Michael, Müller, Martin C., Hanfstein, Benjamin, Krause, Stefan W., Kalmanti, Lida, Schreiber, Annette, Heim, Dominik, Baerlocher, Gabriela M., Hofmann, Wolf-Karsten, Lange, Elisabeth, Einsele, Hermann, Wernli, Martin, Kremers, Stephan, Schlag, Rudolf, Müller, Lothar, Hänel, Mathias, Link, Hartmut, Hertenstein, Bernd, Pfirrmann, Markus, Hochhaus, Andreas, Hasford, Joerg, Hehlmann, Rüdiger, Saußele, Susanne, and for the German Chronic Myeloid Leukemia Study Group, and the Schweizerische Arbeitsgemeinschaft für Klinische Krebsforschung (SAKK).

Published
2014
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22. Younger patients with chronic myeloid leukemia do well in spite of poor prognostic indicators: results from the randomized CML study IV

Author

Kalmanti, Lida, Saussele, Susanne, Lauseker, Michael, Proetel, Ulrike, Müller, Martin C., Hanfstein, Benjamin, Schreiber, Annette, Fabarius, Alice, Pfirrmann, Markus, Schnittger, Susanne, Dengler, Jolanta, Falge, Christiane, Kanz, Lothar, Neubauer, Andreas, Stegelmann, Frank, Pfreundschuh, Michael, Waller, Cornelius F., Spiekermann, Karsten, Krause, Stefan W., Heim, Dominik, Nerl, Christoph, Hossfeld, Dieter K., Kolb, Hans-Jochem, Hochhaus, Andreas, Hasford, Joerg, Hehlmann, Rüdiger, German Chronic Myeloid Leukemia Study Group, and Schweizerische Arbeitsgemeinschaft für Klinische Krebsforschung (SAKK)

Published
2014
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25. Dasatinib induces significant hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in accelerated phase

Author

Guilhot, Francois, Apperley, Jane, Kim, Dong-Wook, Bullorsky, Eduardo O., Baccarani, Michele, Roboz, Gail J., Amadori, Sergio, de Souza, Carmino A., Lipton, Jeffrey H., Hochhaus, Andreas, Heim, Dominik, Larson, Richard A., Branford, Susan, Muller, Martin C., Agarwal, Prasheen, Gollerkeri, Ashwin, and Talpaz, Moshe

Published
2007
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26. Dasatinib induces notable hematologic and cytogenetic responses in chronic-phase chronic myeloid leukemia after failure of imatinib therapy

Author

Hochhaus, Andreas, Kantarjian, Hagop M., Baccarani, Michele, Lipton, Jeffrey H., Apperley, Jane F., Druker, Brian J., Facon, Thierry, Goldberg, Stuart L., Cervantes, Francisco, Niederwieser, Dietger, Silver, Richard T., Stone, Richard M., Hughes, Timothy P., Muller, Martin C., Ezzeddine, Rana, Countouriotis, Athena M., and Shah, Neil P.

Published
2007
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30. SOCS-2 gene expression at diagnosis does not predict for outcome of chronic myeloid leukemia patients on imatinib treatment.

Author

Egeli, Damla Buket, Hanfstein, Benjamin, Lauseker, Michael, Pfirrmann, Markus, Saussele, Susanne, Baerlocher, Gabriela M., and Müller, Martin C.

Subjects
CHRONIC myeloid leukemia, GENE expression, IMATINIB, PROGRESSION-free survival
Abstract

SOCS-2 gene expression at diagnosis has been suggested as a predictor of clinical outcome in chronic myeloid leukemia (CML). In this study SOCS-2 and GUS expression levels were determined by real-time PCR in pretherapeutic samples at diagnosis. First, three patient groups were compared after assessment at 48 months: optimal molecular responders (n = 35), patients with resistance to imatinib (n = 28), and blast crisis patients (n = 27). A significant difference in SOCS-2 gene expression at diagnosis was observed comparing blast crisis vs. resistant patients (p = 0.042) and optimal responders (p = 0.010). Second, a validation sample of consecutively randomized patients (n = 123) was investigated. No discriminative SOCS-2 gene expression cutoff could be derived to predict molecular or cytogenetic response, progression-free or overall survival. Although SOCS-2 gene was differentially expressed at the time of diagnosis in blast crisis patients when compared to other groups, a prognostic impact in consecutively randomized patients was not observed. [ABSTRACT FROM AUTHOR]

Published
2022
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37. The vascular bone marrow niche influences outcome in chronic myeloid leukemia via the E-selectin - SCL/TAL1 - CD44 axis

Author

Godavarthy, Parimala Sonika, primary, Kumar, Rahul, additional, Herkt, Stefanie C., additional, Pereira, Raquel S., additional, Hayduk, Nina, additional, Weissenberger, Eva S., additional, Aggoune, Djamel, additional, Manavski, Yosif, additional, Lucas, Tina, additional, Pan, Kuan-Ting, additional, Voutsinas, Jenna M., additional, Wu, Qian, additional, Müller, Martin C., additional, Saussele, Susanne, additional, Oellerich, Thomas, additional, Oehler, Vivian G., additional, Lausen, Joern, additional, and Krause, Daniela S., additional

Published
2019
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38. Ponatinib efficacy and safety in Philadelphia chromosome–positive leukemia: final 5-year results of the phase 2 PACE trial

Author

Cortes, Jorge E., primary, Kim, Dong-Wook, additional, Pinilla-Ibarz, Javier, additional, le Coutre, Philipp D., additional, Paquette, Ronald, additional, Chuah, Charles, additional, Nicolini, Franck E., additional, Apperley, Jane F., additional, Khoury, H. Jean, additional, Talpaz, Moshe, additional, DeAngelo, Daniel J., additional, Abruzzese, Elisabetta, additional, Rea, Delphine, additional, Baccarani, Michele, additional, Müller, Martin C., additional, Gambacorti-Passerini, Carlo, additional, Lustgarten, Stephanie, additional, Rivera, Victor M., additional, Haluska, Frank G., additional, Guilhot, François, additional, Deininger, Michael W., additional, Hochhaus, Andreas, additional, Hughes, Timothy P., additional, Shah, Neil P., additional, and Kantarjian, Hagop M., additional

Published
2018
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39. Discontinuation of tyrosine kinase inhibitor therapy in chronic myeloid leukaemia (EURO-SKI): a prespecified interim analysis of a prospective, multicentre, non-randomised, trial

Author

Saussele, Susanne, primary, Richter, Johan, additional, Guilhot, Joelle, additional, Gruber, Franz X, additional, Hjorth-Hansen, Henrik, additional, Almeida, Antonio, additional, Janssen, Jeroen J W M, additional, Mayer, Jiri, additional, Koskenvesa, Perttu, additional, Panayiotidis, Panayiotis, additional, Olsson-Strömberg, Ulla, additional, Martinez-Lopez, Joaquin, additional, Rousselot, Philippe, additional, Vestergaard, Hanne, additional, Ehrencrona, Hans, additional, Kairisto, Veli, additional, Machová Poláková, Katerina, additional, Müller, Martin C, additional, Mustjoki, Satu, additional, Berger, Marc G, additional, Fabarius, Alice, additional, Hofmann, Wolf-Karsten, additional, Hochhaus, Andreas, additional, Pfirrmann, Markus, additional, Mahon, Francois-Xavier, additional, Ossenkoppele, Gert, additional, Pagoni, Maria N., additional, Söderlund, Stina, additional, Escoffre-Barbe, Martine, additional, Etienne, Gabriel, additional, Dengler, Jolanta, additional, Huguet, Francoise, additional, von Bubnoff, Nikolas, additional, Klamova, Hana, additional, Faber, Edgar, additional, Guilhot, Francois, additional, Lotfi, Kourosh, additional, Rea, Delphine, additional, Brümmendorf, Tim H., additional, de Greef, Gorgine E., additional, Stenke, Leif, additional, Nicolini, Franck E., additional, Legros, Laurence, additional, Burchert, Andreas, additional, Voglova, Jaroslava, additional, Charbonnier, Aude, additional, Gyan, Emmanuel, additional, Kunzmann, Volker, additional, and Westerweel, Peter E., additional

Published
2018
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40. Ponatinib efficacy and safety in Philadelphia chromosome–positive leukemia: final 5-year results of the phase 2 PACE trial

Author

Cortes, J, Kim, D, Pinilla-Ibarz, J, le Coutre, P, Paquette, R, Chuah, C, Nicolini, F, Apperley, J, Khoury, H, Talpaz, M, Deangelo, D, Abruzzese, E, Rea, D, Baccarani, M, Müller, M, Gambacorti-Passerini, C, Lustgarten, S, Rivera, V, Haluska, F, Guilhot, F, Deininger, M, Hochhaus, A, Hughes, T, Shah, N, Kantarjian, H, Cortes, Jorge E., Kim, Dong-Wook, Pinilla-Ibarz, Javier, le Coutre, Philipp D., Paquette, Ronald, Chuah, Charles, Nicolini, Franck E., Apperley, Jane F., Khoury, H. Jean, Talpaz, Moshe, DeAngelo, Daniel J., Abruzzese, Elisabetta, Rea, Delphine, Baccarani, Michele, Müller, Martin C., Gambacorti-Passerini, Carlo, Lustgarten, Stephanie, Rivera, Victor M., Haluska, Frank G., Guilhot, François, Deininger, Michael W., Hochhaus, Andreas, Hughes, Timothy P., Shah, Neil P., Kantarjian, Hagop M., Cortes, J, Kim, D, Pinilla-Ibarz, J, le Coutre, P, Paquette, R, Chuah, C, Nicolini, F, Apperley, J, Khoury, H, Talpaz, M, Deangelo, D, Abruzzese, E, Rea, D, Baccarani, M, Müller, M, Gambacorti-Passerini, C, Lustgarten, S, Rivera, V, Haluska, F, Guilhot, F, Deininger, M, Hochhaus, A, Hughes, T, Shah, N, Kantarjian, H, Cortes, Jorge E., Kim, Dong-Wook, Pinilla-Ibarz, Javier, le Coutre, Philipp D., Paquette, Ronald, Chuah, Charles, Nicolini, Franck E., Apperley, Jane F., Khoury, H. Jean, Talpaz, Moshe, DeAngelo, Daniel J., Abruzzese, Elisabetta, Rea, Delphine, Baccarani, Michele, Müller, Martin C., Gambacorti-Passerini, Carlo, Lustgarten, Stephanie, Rivera, Victor M., Haluska, Frank G., Guilhot, François, Deininger, Michael W., Hochhaus, Andreas, Hughes, Timothy P., Shah, Neil P., and Kantarjian, Hagop M.

Abstract

Ponatinib has potent activity against native and mutant BCR-ABL1, including BCR-ABL1T315I. The pivotal phase 2 Ponatinib Ph1 ALL and CML Evaluation (PACE) trial evaluated efficacy and safety of ponatinib at a starting dose of 45 mg once daily in 449 patients with chronic myeloid leukemia (CML) or Philadelphia chromosome–positive acute lymphoblastic leukemia (ALL) resistant/intolerant to dasatinib or nilotinib, or with BCR-ABL1T315I. This analysis focuses on chronic-phase CML (CP-CML) patients (n 5 270) with 56.8-month median follow-up. Among 267 evaluable patients, 60%, 40%, and 24% achieved major cytogenetic response (MCyR), major molecular response (MMR), and 4.5-log molecular response, respectively. The probability of maintaining MCyR for 5 years was 82% among responders. Dose reductions were implemented in October 2013 to decrease the risk of arterial occlusive events (AOEs); ‡90% of CP-CML patients who had achieved MCyR or MMR maintained response 40 months after elective dose reductions. Estimated 5-year overall survival was 73%. In CP-CML patients, the most common treatment-emergent adverse events were rash (47%), abdominal pain (46%), thrombocytopenia (46%), headache (43%), dry skin (42%), and constipation (41%). The cumulative incidence of AOEs in CP-CML patients increased over time to 31%, while the exposure-adjusted incidence of new AOEs (15.8 and 4.9 per 100 patient-years in years 1 and 5, respectively) did not increase over time. These final PACE results demonstrate ponatinib provides durable and clinically meaningful responses, irrespective of dose reductions, in this population of heavily pretreated CP-CML patients. This trial was registered at www.clinicaltrials.gov as #NCT01207440

Published
2018

41. c-MYB is a transcriptional regulator of ESPL1/Separase in BCR-ABL-positive chronic myeloid leukemia

Author

Prinzhorn, Wiltrud, Stehle, Michael, Kleiner, Helga, Ruppenthal, Sabrina, Müller, Martin C., Hofmann, Wolf-Karsten, Fabarius, Alice, and Seifarth, Wolfgang

Subjects
610 Medical sciences Medicine, hemic and lymphatic diseases
Abstract

Background: Genomic instability and clonal evolution are hallmarks of progressing chronic myeloid leukemia (CML). Recently, we have shown that clonal evolution and blast crisis correlate with altered expression and activity of Separase, a cysteine endopeptidase that is a mitotic key player in chromosomal segregation and centriole duplication. Hyperactivation of Separase in human hematopoietic cells has been linked to a feedback mechanism that posttranslationally stimulates Separase proteolytic activity after imatinib therapy-induced reduction of Separase protein levels. Methods and Results: In search for potential therapy-responsive transcriptional mechanisms we have investigated the role of the transcription factor c-MYB for Separase expression in CML cell lines (LAMA-84, K562, BV-173) and in clinical samples. Quantitative RT-PCR and Western blot immunostaining experiments revealed that c-MYB expression levels are decreased in an imatinib-dependent manner and positively correlate with Separase expression levels in cell lines and in clinical CML samples. RNA silencing of c-MYB expression in CML cell lines resulted in reduced Separase protein levels. Gelshift and ChIP assays confirmed that c-MYB binds to a putative c-MYB binding sequence located within the ESPL1 promoter. Conclusions: Our data suggest that ESPL1/Separase is a regulatory target of c-MYB. Therefore, c-MYB, known to be required for BCR-ABL-dependent transformation of hematopoietic progenitors and leukemogenesis, may also control the Separase-dependent fidelity of mitotic chromosomal segregation and centriole duplication essential for maintenance of genomic stability.

Published
2016

42. Final Evaluation of Randomized CML-Study IV: 10-Year Survival and Evolution of Terminal Phase

Author

Hehlmann, Rüdiger, primary, Lauseker, Michael, additional, Saussele, Susanne, additional, Pfirrmann, Markus, additional, Krause, Stefan W., additional, Kolb, Hans-Jochem, additional, Neubauer, Andreas, additional, Hossfeld, Dieter K., additional, Nerl, Christoph, additional, Gratwohl, Alois, additional, Baerlocher, Gabriela M., additional, Heim, Dominik, additional, Bruemmendorf, Tim Henrik, additional, Fabarius, Alice, additional, Haferlach, Claudia, additional, Schlegelberger, Brigitte, additional, Müller, Martin C., additional, Jeromin, Sabine, additional, Proetel, Ulrike, additional, Kohlbrenner, Katharina, additional, Voskanyan, Astghik, additional, Rinaldetti, Sébastien, additional, Seifarth, Wolfgang, additional, Spiess, Birgit, additional, Balleisen, Leopold, additional, Goebeler, Maria E, additional, Hänel, Mathias, additional, Ho, Anthony D., additional, Dengler, J, additional, Falge, C, additional, Kanz, Lothar, additional, Köhne, Claus-Henning, additional, Burchert, Andreas, additional, Kneba, Michael, additional, Stegelmann, Frank, additional, Köhne, C, additional, Lindemann, Hans-Walter, additional, Waller, C, additional, Pfreundschuh, Michael, additional, Spiekermann, Karsten, additional, Berdel, Wolfgang E, additional, Müller, L, additional, Edinger, Matthias, additional, Mayer, Jiri, additional, Beelen, Dietrich W, additional, Bentz, Martin, additional, Link, Hartmut, additional, Hertenstein, Bernd, additional, Fuchs, R, additional, Wernli, Martin, additional, Schlegel, F, additional, Schlag, Rudolph, additional, de Wit, M, additional, Trümper, Lorenz, additional, Hebarth, H, additional, Hahn, M, additional, Thomalla, Jörg, additional, Scheid, Christof, additional, Schafhausen, Philippe, additional, Verbeek, Walter, additional, Eckart, Michael J., additional, Gassmann, Winfried, additional, Pezzutto, Antonio, additional, Schenk, Michael, additional, Brossart, Peter, additional, Geer, Thomas, additional, Bildat, Stephan, additional, Schäfer, E, additional, Hochhaus, Andreas, additional, and Hasford, Joerg, additional

Published
2017
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44. High BCR–ABL/GUSIS Levels at Diagnosis of Chronic Phase CML Are Associated with Unfavorable Responses to Standard-Dose Imatinib

Author

Vigneri, Paolo, primary, Stagno, Fabio, additional, Stella, Stefania, additional, Cupri, Alessandra, additional, Forte, Stefano, additional, Massimino, Michele, additional, Antolino, Agostino, additional, Siragusa, Sergio, additional, Mannina, Donato, additional, Impera, Stefana Stella, additional, Musolino, Caterina, additional, Malato, Alessandra, additional, Mineo, Giuseppe, additional, Tomaselli, Carmela, additional, Murgano, Pamela, additional, Musso, Maurizio, additional, Morabito, Fortunato, additional, Molica, Stefano, additional, Martino, Bruno, additional, Manzella, Livia, additional, Müller, Martin C., additional, Hochhaus, Andreas, additional, and Raimondo, Francesco Di, additional

Published
2017
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45. Clonal Evolution and Blast Crisis Correlate with Enhanced Proteolytic Activity of Separase in BCR-ABL b3a2 Fusion Type CML under Imatinib Therapy

Author

Haaß, Wiltrud, Kleiner, Helga, Weiß, Christel, Haferlach, Claudia, Schlegelberger, Brigitte, Müller, Martin C, Hehlmann, Rüdiger, Hofmann, Wolf-Karsten, Fabarius, Alice, Seifarth, Wolfgang, Baerlocher, Gabriela M., Lämmle, Bernhard, and Tobler, Andreas

Subjects
hemic and lymphatic diseases, 610 Medicine & health
Abstract

Unbalanced (major route) additional cytogenetic aberrations (ACA) at diagnosis of chronic myeloid leukemia (CML) indicate an increased risk of progression and shorter survival. Moreover, newly arising ACA under imatinib treatment and clonal evolution are considered features of acceleration and define failure of therapy according to the European LeukemiaNet (ELN) recommendations. On the basis of 1151 Philadelphia chromosome positive chronic phase patients of the randomized CML-study IV, we examined the incidence of newly arising ACA under imatinib treatment with regard to the p210BCR-ABL breakpoint variants b2a2 and b3a2. We found a preferential acquisition of unbalanced ACA in patients with b3a2 vs. b2a2 fusion type (ratio: 6.3 vs. 1.6, p = 0.0246) concurring with a faster progress to blast crisis for b3a2 patients (p = 0.0124). ESPL1/Separase, a cysteine endopeptidase, is a key player in chromosomal segregation during mitosis. Separase overexpression and/or hyperactivity has been reported from a wide range of cancers and cause defective mitotic spindles, chromosome missegregation and aneuploidy. We investigated the influence of p210BCR-ABL breakpoint variants and imatinib treatment on expression and proteolytic activity of Separase as measured with a specific fluorogenic assay on CML cell lines (b2a2: KCL-22, BV-173; b3a2: K562, LAMA-84). Despite a drop in Separase protein levels an up to 5.4-fold increase of Separase activity under imatinib treatment was observed exclusively in b3a2 but not in b2a2 cell lines. Mimicking the influence of imatinib on BV-173 and LAMA-84 cells by ESPL1 silencing stimulated Separase proteolytic activity in both b3a2 and b2a2 cell lines. Our data suggest the existence of a fusion type-related feedback mechanism that posttranslationally stimulates Separase proteolytic activity after therapy-induced decreases in Separase protein levels. This could render b3a2 CML cells more prone to aneuploidy and clonal evolution than b2a2 progenitors and may therefore explain the cytogenetic results of CML patients.

Published
2015
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46. Cost-effectiveness of Tyrosine Kinase Inhibitor Treatment Strategies for Chronic Myeloid Leukemia in Chronic Phase After Generic Entry of Imatinib in the United States

Author

Padula, William V., Larson, Richard A., Dusetzina, Stacie B., Apperley, Jane F., Hehlmann, Rudiger, Baccarani, Michele, Eigendorff, Ekkehard, Guilhot, Joelle, Guilhot, Francois, Mahon, Francois-Xavier, Martinelli, Giovanni, Mayer, Jiri, Müller, Martin C., Niederwieser, Dietger, Saussele, Susanne, Schiffer, Charles A., Silver, Richard T., Simonsson, Bengt, Conti, Rena M., Padula, William V., Larson, Richard A., Dusetzina, Stacie B., Apperley, Jane F., Hehlmann, Rudiger, Baccarani, Michele, Eigendorff, Ekkehard, Guilhot, Joelle, Guilhot, Francois, Mahon, Francois-Xavier, Martinelli, Giovanni, Mayer, Jiri, Müller, Martin C., Niederwieser, Dietger, Saussele, Susanne, Schiffer, Charles A., Silver, Richard T., Simonsson, Bengt, and Conti, Rena M.

Abstract

Background: We analyzed the cost-effectiveness of treating incident chronic myeloid leukemia in chronic phase (CML-CP) with generic imatinib when it becomes available in United States in 2016. In the year following generic entry, imatinib's price is expected to drop 70% to 90%. We hypothesized that initiating treatment with generic imatinib in these patients and then switching to the other tyrosine-kinase inhibitors (TKIs), dasatinib or nilotinib, because of intolerance or lack of effectiveness ("imatinib-first") would be cost-effective compared with the current standard of care: "physicians' choice" of initiating treatment with any one of the three TKIs. Methods: We constructed Markov models to compare the five-year cost-effectiveness of imatinib-first vs physician's choice from a US commercial payer perspective, assuming 3% annual discounting ($US 2013). The models' clinical endpoint was five-year overall survival taken from a systematic review of clinical trial results. Per-person spending on incident CML-CP treatment overall care components was estimated using Truven's MarketScan claims data. The main outcome of the models was cost per quality-adjusted life-year (QALY). We interpreted outcomes based on a willingness-to-pay threshold of $100 000/QALY. A panel of European LeukemiaNet experts oversaw the study's conduct. Results: Both strategies met the threshold. Imatinib-first ($277 401, 3.87 QALYs) offered patients a 0.10 decrement in QALYs at a savings of $88 343 over five years to payers compared with physician's choice ($365 744, 3.97 QALYs). The imatinibfirst incremental cost-effectiveness ratio was approximately $883 730/QALY. The results were robust to multiple sensitivity analyses. Conclusion: When imatinib loses patent protection and its price declines, its use will be the cost-effective initial treatment strategy for CML-CP.

Published
2016
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47. No Differences in Molecular Relapse-Free Survival after Stopping Imatinib Treatment of Chronic Myeloid Leukemia Between Patients with Prior 4.5 Log Reduction (MR4.5) but Detectable and Patients with Undetectable Disease in the EURO-SKI Trial

Author

Pfirrmann, Markus, primary, Mahon, Francois-Xavier, additional, Guilhot, Joelle, additional, Richter, Johan, additional, Almeida, Antonio, additional, Janssen, Jeroen J.W.M., additional, Mayer, Jiri, additional, Porkka, Kimmo, additional, Panayiotidis, Panayiotis, additional, Olsson-Stromberg, Ulla, additional, Berger, Marc G., additional, Diamond, Joana, additional, Ehrencrona, Hans, additional, Kairisto, Veli, additional, Machova Polakova, Katerina, additional, Müller, Martin C., additional, Mustjoki, Satu, additional, Hochhaus, Andreas, additional, Sauβele, Susanne, additional, and Hjorth-Hansen, Henrik, additional

Published
2016
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48. Treatment-Free Remission (TFR) in Patients with Chronic Phase Chronic Myeloid Leukemia (CML-CP) and in Stable Deep Molecular Response (DMR) to Dasatinib - the Dasfree Study

Author

Shah, Neil P., primary, Paquette, Ronald, additional, Müller, Martin C., additional, Saussele, Susanne, additional, Garcìa-Gutiérrez, Valentin, additional, Jiménez-Velasco, Antonio, additional, Nicolini, Franck-Emmanuel, additional, Mauro, Michael J., additional, Mahon, Francois-Xavier, additional, Rea, Delphine, additional, Martin-Regueira, Patricia, additional, Subar, Milayna, additional, Li, Li, additional, and Lipton, Jeffrey H., additional

Published
2016
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50. Quantification of BCR-ABL by digital PCR in samples with high copy numbers and rates of molecular responses (as defined by EUTOS) compared to those detected with standard quantitative real-time PCR.

Author

Franke, Georg-Nikolaus, primary, Maier, Jacqueline, additional, Cross, Michael, additional, Wildenberger, Kathrin, additional, Giles, Francis J., additional, Frank, Oliver, additional, Hochhaus, Andreas, additional, Dietz, Christian, additional, Müller, Martin C., additional, Niederwieser, Dietger, additional, and Lange, Thoralf, additional

Published
2016
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