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1. Prognostic model for newly diagnosed CLL patients in Binet stage A: results of the multicenter, prospective CLL1 trial of the German CLL study group

Author

Hoechstetter, Manuela A., Busch, Raymonde, Eichhorst, Barbara, Bühler, Andreas, Winkler, Dirk, Bahlo, Jasmin, Robrecht, Sandra, Eckart, Michael J., Vehling-Kaiser, Ursula, Jacobs, Georg, Jäger, Ulrich, Hurtz, Hans Jürgen, Hopfinger, Georg, Hartmann, Frank, Fuss, Harald, Abenhardt, Wolfgang, Blau, Ilona, Freier, Werner, Müller, Lothar, Goebeler, Maria, Wendtner, Clemens, Fischer, Kirsten, Herling, Carmen D., Starck, Michael, Bentz, Martin, Emmerich, Bertold, Döhner, Hartmut, Stilgenbauer, Stephan, and Hallek, Michael

Published
2020
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2. Impact of comorbidities on overall survival in patients with chronic myeloid leukemia: results of the randomized CML Study IV

Author

Saußele, Susanne, Krauß, Marie-Paloma, Hehlmann, Rüdiger, Lauseker, Michael, Proetel, Ulrike, Kalmanti, Lida, Hanfstein, Benjamin, Fabarius, Alice, Kraemer, Doris, Berdel, Wolfgang E., Bentz, Martin, Staib, Peter, de Wit, Maike, Wernli, Martin, Zettl, Florian, Hebart, Holger F., Hahn, Markus, Heymanns, Jochen, Schmidt-Wolf, Ingo, Schmitz, Norbert, Eckart, Michael J., Gassmann, Winfried, Bartholomäus, Andrea, Pezzutto, Antonio, Leibundgut, Elisabeth Oppliger, Heim, Dominik, Krause, Stefan W., Burchert, Andreas, Hofmann, Wolf-Karsten, Hasford, Joerg, Hochhaus, Andreas, Pfirrmann, Markus, and Müller, Martin C.

Published
2015
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4. Development of a comprehensive prognostic index for patients with chronic lymphocytic leukemia

Author

Pflug, Natali, Bahlo, Jasmin, Shanafelt, Tait D., Eichhorst, Barbara F., Bergmann, Manuela A., Elter, Thomas, Bauer, Kathrin, Malchau, Gebhart, Rabe, Kari G., Stilgenbauer, Stephan, Döhner, Hartmut, Jäger, Ulrich, Eckart, Michael J., Hopfinger, Georg, Busch, Raymonde, Fink, Anna-Maria, Wendtner, Clemens-Martin, Fischer, Kirsten, Kay, Neil E., and Hallek, Michael

Published
2014
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6. Treatment with trastuzumab for 1 year after adjuvant chemotherapy in patients with HER2-positive early breast cancer: a 4-year follow-up of a randomised controlled trial

Author

Gianni, Luca, Dafni, Urania, Gelber, Richard D, Azambuja, Evandro, Muehlbauer, Susanne, Goldhirsch, Aron, Untch, Michael, Smith, Ian, Baselga, José, Jackisch, Christian, Cameron, David, Mano, Max, Pedrini, José Luiz, Veronesi, Andrea, Mendiola, Cesar, Pluzanska, Anna, Semiglazov, Vladimir, Vrdoljak, Eduard, Eckart, Michael J, Shen, Zhenzhou, Skiadopoulos, George, Procter, Marion, Pritchard, Kathleen I, Piccart-Gebhart, Martine J, and Bell, Richard

Published
2011
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7. Genetic markers and ibrutinib vs placebo treatment in early stage chronic lymphocytic leukemia -results from the GCLLSG CLL12 trial

Author

Riecke, Armin, Tausch, Eugen, Yosifov, Deyan Y., Schneider, Christof, Robrecht, Sandra, Giza, Adam, Müller, Lothar, Vehling-Kaiser, Ursula, Eckart, Michael J., Freier, Werner, Schöttker, Björn, Gaska, Tobias, Reiser, Marcel, Fink, Anna-Maria, Eichhorst, Barbara F., Fischer, Kirsten, Hallek, Michael, Langerbeins, Petra, and Stilgenbauer, Stephan

Published
2023
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8. IGLV3-21 R110 Is a Prognostic Marker for Early Stage CLL Patients Under Ibrutinib Treatment or Watch & Wait: Results from the Double-Blind, Randomized, Placebo-Controlled GCLLSG CLL12 Trial

Author

Yosifov, Deyan Y., Robrecht, Sandra, Giza, Adam, Riecke, Armin, Schneider, Christof, Jebaraj, Billy, Jumaa, Hassan, Young, Marc, Müller, Lothar, Vehling-Kaiser, Ursula, Eckart, Michael J., Freier, Werner, Schöttker, Björn, Gaska, Tobias, Reiser, Marcel, Fink, Anna-Maria, Fischer, Kirsten, Eichhorst, Barbara F., Hallek, Michael, Langerbeins, Petra, Stilgenbauer, Stephan, and Tausch, Eugen

Published
2023
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9. The Randomized AMBORA Trial: Impact of Pharmacological/Pharmaceutical Care on Medication Safety and Patient-Reported Outcomes During Treatment With New Oral Anticancer Agents

Author

Dürr, Pauline, primary, Schlichtig, Katja, additional, Kelz, Carolin, additional, Deutsch, Birgit, additional, Maas, Renke, additional, Eckart, Michael J., additional, Wilke, Jochen, additional, Wagner, Harald, additional, Wolff, Kerstin, additional, Preuß, Caroline, additional, Brückl, Valeska, additional, Meidenbauer, Norbert, additional, Staerk, Christian, additional, Mayr, Andreas, additional, Fietkau, Rainer, additional, Goebell, Peter J., additional, Kunath, Frank, additional, Beckmann, Matthias W., additional, Mackensen, Andreas, additional, Neurath, Markus F., additional, Pavel, Marianne, additional, Dörje, Frank, additional, and Fromm, Martin F., additional

Published
2021
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10. Ibrutinib versus placebo in patients with asymptomatic, treatment-naive early stage chronic lymphocytic leukemia (CLL): primary endpoint results of the phase 3 double-blind randomized CLL12 trial

Author

Langerbeins, Petra, Bahlo, Jasmin, Rhein, Christina, Gerwin, Henrik, Cramer, Paula, Fuerstenau, Moritz, Al-Sawaf, Othman, von Tresckow, Julia, Fink, Anna-Maria, Kreuzer, Karl-Anton, Vehling-Kaiser, Ursula, Tausch, Eugen, Mueller, Lothar, Eckart, Michael J., Schlag, Rudolf, Freier, Werner, Gaska, Tobias, Balser, Christina, Reiser, Marcel, Stauch, Martina, Wendtner, Clemens Martin, Fischer, Kirsten, Stilgenbauer, Stephan, Eichhorst, Barbara, Hallek, Michael, Langerbeins, Petra, Bahlo, Jasmin, Rhein, Christina, Gerwin, Henrik, Cramer, Paula, Fuerstenau, Moritz, Al-Sawaf, Othman, von Tresckow, Julia, Fink, Anna-Maria, Kreuzer, Karl-Anton, Vehling-Kaiser, Ursula, Tausch, Eugen, Mueller, Lothar, Eckart, Michael J., Schlag, Rudolf, Freier, Werner, Gaska, Tobias, Balser, Christina, Reiser, Marcel, Stauch, Martina, Wendtner, Clemens Martin, Fischer, Kirsten, Stilgenbauer, Stephan, Eichhorst, Barbara, and Hallek, Michael

Published
2020

11. Imatinib dose reduction in major molecular response of chronic myeloid leukemia: results from the German Chronic Myeloid Leukemia-Study IV

Author

Michel, Christian, Burchert, Andreas, Hochhaus, Andreas, Saussele, Susanne, Neubauer, Andreas, Lauseker, Michael, Krause, Stefan W, Kolb, Hans-Jochem, Hossfeld, Dieter Kurt, Nerl, Christoph, Baerlocher, Gabriela M., Heim, Dominik, Brümmendorf, Tim H, Fabarius, Alice, Haferlach, Claudia, Schlegelberger, Brigitte, Balleisen, Leopold, Goebeler, Maria-Elisabeth, Hänel, Mathias, Ho, Anthony, Dengler, Jolanta, Falge, Christiane, Möhle, Robert, Kremers, Stephan, Kneba, Michael, Stegelmann, Frank, Köhne, Claus-Henning, Lindemann, Hans-Walter, Waller, Cornelius F, Spiekermann, Karsten, Berdel, Wolfgang E, Müller, Lothar, Edinger, Matthias, Mayer, Jiri, Beelen, Dietrich W, Bentz, Martin, Link, Hartmut, Hertenstein, Bernd, Fuchs, Roland, Wernli, Martin, Schlegel, Frank, Schlag, Rudolf, De Wit, Maike, Trümper, Lorenz, Hebart, Holger, Hahn, Markus, Thomalla, Jörg, Scheid, Christof, Schafhausen, Philippe, Verbeek, Walter, Eckart, Michael J, Gassmann, Winfried, Schenk, Michael, Brossart, Peter, Wündisch, Thomas, Geer, Thomas, Bildat, Stephan, Schäfer, Erhardt, Hasford, Joerg, Hehlmann, Rüdiger, and Pfirrmann, Markus

Subjects
hemic and lymphatic diseases, 610 Medicine & health, neoplasms
Abstract

Standard first-line therapy of chronic myeloid leukemia is treatment with imatinib. In the randomized German Chronic Myeloid Leukemia-Study IV, more potent BCR-ABL inhibition with 800mg (high-dose) imatinib accelerated achievement of a deep molecular remission. However, whether and when a de-escalation of the dose intensity under high-dose imatinib can be safely performed without increasing the risk of losing deep molecular response is unknown. To gain insights into this clinically relevant question, we analyzed the outcome of imatinib dose reductions from 800mg to 400mg daily in the Chronic Myeloid Leukemia-Study IV. Of the 422 patients that were randomized to the 800mg arm, 68 reduced imatinib to 400mg after they had achieved at least a stable major molecular response. 61 of these 68 patients (90%) maintained major molecular remission on imatinib at 400mg. Five of the seven patients, who lost major molecular remission on the imatinib standard dose, regained major molecular remission while still on 400mg imatinib. Only two of 68 patients had to switch to more potent kinase inhibition to regain major molecular remission. Importantly, the lengths of the imatinib high-dose treatment intervals before and after achieving major molecular remission were associated with the probabilities of maintaining major molecular remission with the standard dose of imatinib. Together, data support that a deep molecular remission achieved with high-dose imatinib, can be safely maintained with standard dose in most patients. The study protocol was registered at ClinicalTrials.gov (NCT00055874).

Published
2019
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12. A Prospective, Open-Label, Multicenter, Phase 2 Trial to Evaluate the Safety and Efficacy of the Combination of Tirabrutinib (ONO/GS-4059) and Idelalisib with and without Obinutuzumab in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL)

Author

Kutsch, Nadine, primary, Pallasch, Christian, additional, Decker, Thomas, additional, Hebart, Holger, additional, Chow, Kai Uwe, additional, Graeven, Ullrich, additional, Kisro, Jens, additional, Kroeber, Alexander, additional, Tausch, Eugen, additional, Wendtner, Clemens-Martin, additional, Eckart, Michael J., additional, Stilgenbauer, Stephan, additional, Huang, Xi, additional, Jürgensmeier, Juliane M., additional, Bhargava, Pankaj, additional, Hallek, Michael, additional, and Eichhorst, Barbara F., additional

Published
2019
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13. Imatinib dose reduction in major molecular response of chronic myeloid leukemia: results from the German Chronic Myeloid Leukemia-Study IV

Author

Michel, Christian, primary, Burchert, Andreas, additional, Hochhaus, Andreas, additional, Saussele, Susanne, additional, Neubauer, Andreas, additional, Lauseker, Michael, additional, Krause, Stefan W., additional, Kolb, Hans-Jochem, additional, Hossfeld, Dieter Kurt, additional, Nerl, Christoph, additional, Baerlocher, Gabriela M., additional, Heim, Dominik, additional, Brümmendorf, Tim H, additional, Fabarius, Alice, additional, Haferlach, Claudia, additional, Schlegelberger, Brigitte, additional, Balleisen, Leopold, additional, Goebeler, Maria-Elisabeth, additional, Hänel, Mathias, additional, Ho, Anthony, additional, Dengler, Jolanta, additional, Falge, Christiane, additional, Möhle, Robert, additional, Kremers, Stephan, additional, Kneba, Michael, additional, Stegelmann, Frank, additional, Köhne, Claus-Henning, additional, Lindemann, Hans-Walter, additional, Waller, Cornelius F., additional, Spiekermann, Karsten, additional, Berdel, Wolfgang E., additional, Müller, Lothar, additional, Edinger, Matthias, additional, Mayer, Jiri, additional, Beelen, Dietrich W., additional, Bentz, Martin, additional, Link, Hartmut, additional, Hertenstein, Bernd, additional, Fuchs, Roland, additional, Wernli, Martin, additional, Schlegel, Frank, additional, Schlag, Rudolf, additional, de Wit, Maike, additional, Trümper, Lorenz, additional, Hebart, Holger, additional, Hahn, Markus, additional, Thomalla, Jörg, additional, Scheid, Christof, additional, Schafhausen, Philippe, additional, Verbeek, Walter, additional, Eckart, Michael J., additional, Gassmann, Winfried, additional, Schenk, Michael, additional, Brossart, Peter, additional, Wündisch, Thomas, additional, Geer, Thomas, additional, Bildat, Stephan, additional, Schäfer, Erhardt, additional, Hasford, Joerg, additional, Hehlmann, Rüdiger, additional, and Pfirrmann, Markus, additional

Published
2018
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14. Serious adverse events (SAE) and suspected unexpected serious adverse reactions (SUSAR) in early stage patients with CLL treated with ibrutinib or placebo: safety results of the ongoing randomized CLL12 phase III-trial

Author

Langerbeins, Petra, Bahlo, Jasmin, Rhein, Christina, Cramer, Paula, Fink, Anna-Maria, Pflug, Natali, von Tresckow, Julia, Stilgenbauer, Stephan, Kreuzer, Karl-Anton, Eckart, Michael J., Vehling-Kaiser, Ursula, Schlag, Rudolf, Balser, Christina, Mueller, Lothar, Reiser, Marcel, Wendtner, Clemens, Fischer, Kirsten, Eichhorst, Barbara, Hallek, Michael, Langerbeins, Petra, Bahlo, Jasmin, Rhein, Christina, Cramer, Paula, Fink, Anna-Maria, Pflug, Natali, von Tresckow, Julia, Stilgenbauer, Stephan, Kreuzer, Karl-Anton, Eckart, Michael J., Vehling-Kaiser, Ursula, Schlag, Rudolf, Balser, Christina, Mueller, Lothar, Reiser, Marcel, Wendtner, Clemens, Fischer, Kirsten, Eichhorst, Barbara, and Hallek, Michael

Published
2017

15. 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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16. Ibrutinib in Early Stage CLL: Preliminary Safety Results of a Placebo-Controlled Phase III Study

Author

Langerbeins, Petra, Bahlo, Jasmin, Rhein, Christina, Cramer, Paula, Fink, Anna-Maria, Pflug, Natali, von Tresckow, Julia, Stilgenbauer, Stephan, Kreuzer, Karl-Anton, Eckart, Michael J., Vehling-Kaiser, Ursula, Schlag, Rudolf, Balser, Christina, Mueller, Lothar, Wendtner, Clemens-Martin, Fischer, Kirsten, Eichhorst, Barbara, Hallek, Michael, Langerbeins, Petra, Bahlo, Jasmin, Rhein, Christina, Cramer, Paula, Fink, Anna-Maria, Pflug, Natali, von Tresckow, Julia, Stilgenbauer, Stephan, Kreuzer, Karl-Anton, Eckart, Michael J., Vehling-Kaiser, Ursula, Schlag, Rudolf, Balser, Christina, Mueller, Lothar, Wendtner, Clemens-Martin, Fischer, Kirsten, Eichhorst, Barbara, and Hallek, Michael

Published
2015

17. IGLV3-21 R110Is a Prognostic Marker for Early Stage CLL Patients Under Ibrutinib Treatment or Watch & Wait: Results from the Double-Blind, Randomized, Placebo-Controlled GCLLSG CLL12 Trial

Author

Yosifov, Deyan Y., Robrecht, Sandra, Giza, Adam, Riecke, Armin, Schneider, Christof, Jebaraj, Billy, Jumaa, Hassan, Young, Marc, Müller, Lothar, Vehling-Kaiser, Ursula, Eckart, Michael J., Freier, Werner, Schöttker, Björn, Gaska, Tobias, Reiser, Marcel, Fink, Anna-Maria, Fischer, Kirsten, Eichhorst, Barbara F., Hallek, Michael, Langerbeins, Petra, Stilgenbauer, Stephan, and Tausch, Eugen

Abstract

INTRODUCTION:IGLV3-21 R110is a point mutation that can confer the ability for autonomous signaling to B cell receptors (BCR) using light chains encoded by the allele IGLV3-21 ∗ 01or IGLV3-21 ∗ 04. Chronic lymphocytic leukemia (CLL) patients with IGLV3-21 R110have a shorter time to first treatment and shorter overall survival, independent of their IGHV mutational status. However, outcomes of CLL patients using IGLV3-21 R110have not been evaluated in clinical trials of BTK inhibitors.

Published
2023
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18. Ibrutinib in Early Stage CLL: Preliminary Safety Results of a Placebo-Controlled Phase III Study

Author

Langerbeins, Petra, primary, Bahlo, Jasmin, additional, Rhein, Christina, additional, Cramer, Paula, additional, Fink, Anna-Maria, additional, Pflug, Natali, additional, von Tresckow, Julia, additional, Stilgenbauer, Stephan, additional, Kreuzer, Karl-Anton, additional, Eckart, Michael J., additional, Vehling-Kaiser, Ursula, additional, Schlag, Rudolf, additional, Balser, Christina, additional, Müller, Lothar, additional, Wendtner, Clemens-Martin, additional, Fischer, Kirsten, additional, Eichhorst, Barbara, additional, and Hallek, Michael, additional

Published
2015
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19. Bendamustine Combined With Rituximab in Patients With Relapsed and/or Refractory Chronic Lymphocytic Leukemia: A Multicenter Phase II Trial of the German Chronic Lymphocytic Leukemia Study Group

Author

Fischer, Kirsten, Cramer, Paula, Busch, Raymonde, Stilgenbauer, Stephan, Bahlo, Jasmin, Schweighofer, Carmen D., Boettcher, Sebastian, Staib, Peter, Kiehl, Michael, Eckart, Michael J., Kranz, Gabriele, Goede, Valentin, Elter, Thomas, Buehler, Andreas, Winkler, Dirk, Kneba, Michael, Doehner, Hartmut, Eichhorst, Barbara F., Hallek, Michael, Wendtner, Clemens-Martin, Fischer, Kirsten, Cramer, Paula, Busch, Raymonde, Stilgenbauer, Stephan, Bahlo, Jasmin, Schweighofer, Carmen D., Boettcher, Sebastian, Staib, Peter, Kiehl, Michael, Eckart, Michael J., Kranz, Gabriele, Goede, Valentin, Elter, Thomas, Buehler, Andreas, Winkler, Dirk, Kneba, Michael, Doehner, Hartmut, Eichhorst, Barbara F., Hallek, Michael, and Wendtner, Clemens-Martin

Abstract

Purpose The objective of this trial was to evaluate safety and efficacy of bendamustine combined with rituximab (BR) in patients with relapsed and/or refractory chronic lymphocytic leukemia (CLL). Patients and Methods Seventy-eight patients, including 22 patients with fludarabine-refractory disease (28.2%) and 14 patients (17.9%) with deletion of 17p, received BR chemoimmunotherapy. Bendamustine was administered at a dose of 70 mg/m(2) on days 1 and 2 combined with rituximab 375 mg/m(2) on day 0 of the first course and 500 mg/m(2) on day 1 during subsequent courses for up to six courses. Results On the basis of intent-to-treat analysis, the overall response rate was 59.0% (95% CI, 47.3% to 70.0%). Complete response, partial response, and nodular partial response were achieved in 9.0%, 47.4%, and 2.6% of patients, respectively. Overall response rate was 45.5% in fludarabine-refractory patients and 60.5% in fludarabine-sensitive patients. Among genetic subgroups, 92.3% of patients with del(11q), 100% with trisomy 12, 7.1% with del(17p), and 58.7% with unmutated IGHV status responded to treatment. After a median follow-up time of 24 months, the median event-free survival was 14.7 months. Severe infections occurred in 12.8% of patients. Grade 3 or 4 neutropenia, thrombocytopenia, and anemia were documented in 23.1%, 28.2%, and 16.6% of patients, respectively. Conclusion Chemoimmunotherapy with BR is effective and safe in patients with relapsed CLL and has notable activity in fludarabine-refractory disease. Major but tolerable toxicities were myelosuppression and infections. These promising results encouraged us to initiate a further phase II trial evaluating the BR regimen in patients with previously untreated CLL.

Published
2011

20. Overall Survival In Early Stage Chronic Lymphocytic Leukemia Patients With Treatment Indication Due To Disease Progression: Follow-Up Data Of The CLL1 Trial Of The German CLL Study Group (GCLLSG)

Author

Bergmann, Manuela A., primary, Busch, Raymonde, additional, Eichhorst, Barbara, additional, Buehler, Andreas, additional, Fischer, Norbert, additional, Eckart, Michael J, additional, Vehling-Kaiser, Ursula, additional, Jäger, Ulrich, additional, Hopfinger, Georg, additional, Wendtner, Clemens, additional, Fischer, Kirsten, additional, Emmerich, Bertold, additional, Döhner, Hartmut, additional, Hallek, Michael, additional, and Stilgenbauer, Stephan, additional

Published
2013
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22. Bendamustine Combined With Rituximab in Patients With Relapsed and/or Refractory Chronic Lymphocytic Leukemia: A Multicenter Phase II Trial of the German Chronic Lymphocytic Leukemia Study Group

Author

Fischer, Kirsten, primary, Cramer, Paula, additional, Busch, Raymonde, additional, Stilgenbauer, Stephan, additional, Bahlo, Jasmin, additional, Schweighofer, Carmen D., additional, Böttcher, Sebastian, additional, Staib, Peter, additional, Kiehl, Michael, additional, Eckart, Michael J., additional, Kranz, Gabriele, additional, Goede, Valentin, additional, Elter, Thomas, additional, Bühler, Andreas, additional, Winkler, Dirk, additional, Kneba, Michael, additional, Döhner, Hartmut, additional, Eichhorst, Barbara F., additional, Hallek, Michael, additional, and Wendtner, Clemens-Martin, additional

Published
2011
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23. CLL-cells induce IDOhiCD14+HLA-DRlomyeloid-derived suppressor cells that inhibit T-cell responses and promote TRegs

Author

Jitschin, Regina, Braun, Martina, Büttner, Maike, Dettmer-Wilde, Katja, Bricks, Juliane, Berger, Jana, Eckart, Michael J., Krause, Stefan W., Oefner, Peter J., Le Blanc, Katarina, Mackensen, Andreas, and Mougiakakos, Dimitrios

Abstract

Myeloid-derived suppressor cells (MDSCs) represent a heterogeneous population that shares certain characteristics including an aberrant myeloid phenotype and the ability to suppress T cells. MDSCs have been predominantly studied in malignant diseases and findings suggest involvement in tumor-associated immune suppression. Chronic lymphocytic leukemia (CLL) is the leukemia with the highest incidence among adults. Immune defects occur already at early disease stages and impact the clinical course. We assessed presence, frequency, association to other immune parameters, and functional properties of circulating CD14+cells lacking HLA-DR expression (HLA-DRlo) in patients with untreated CLL. These monocytic cells represent one of the best-defined human MDSC subsets. Frequency of CD14+HLA-DRlocells was significantly increased in CLL patients. Furthermore, MDSCs suppressed in vitro T-cell activation and induced suppressive regulatory T cells (TRegs). The MDSC-mediated modulation of T cells could be attributed to their increased indoleamine 2,3-dioxygenase (IDO) activity. CLL cells induced IDOhiMDSCs from healthy donor monocytes suggesting bidirectional crosstalk between CLL-cells, MDSCs, and TRegs. Overall, we identified a MDSC population that expands in CLL. The exact mechanisms responsible for such accumulation remain to be elucidated and it will be of interest to test whether antagonizing suppressive functions of CLL MDSCs could represent a mean for enhancing immune responses.

Published
2014
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24. Bendamustine in Combination with Rituximab (BR) for Patients with Relapsed Chronic Lymphocytic Leukemia (CLL): A Multicentre Phase II Trial of the German CLL Study Group (GCLLSG)

Author

Fischer, Kirsten, Stilgenbauer, Stephan, Schweighofer, Carmen D, Busch, Raymonde, Renschler, Jasmin, Kiehl, Michael, Balleisen, Leopold, Eckart, Michael J, Fink, Anna- Maria, Kilp, Julia, Ritgen, Matthias, Böttcher, Sebastian, Kneba, Michael, Döhner, Hartmut, Eichhorst, Barbara F, Hallek, Michael, and Wendtner, Clemens- Martin

Published
2008
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26. CLL-cells induce IDOhi CD14+HLA-DRlo myeloid-derived suppressor cells that inhibit T-cell responses and promote TRegs.

Author

Jitschin, Regina, Braun, Martina, Büttner, Maike, Dettmer-Wilde, Katja, Bricks, Juliane, Berger, Jana, Eckart, Michael J., Krause, Stefan W., Oefner, Peter J., Blanc, Katarina Le, Mackensen, Andreas, and Mougiakakos, Dimitrios

Subjects
*SUPPRESSOR cells, *T cells, *MYELOID leukemia, *MONOCYTIC leukemia, *IMMUNE response
Abstract

Myeloid-derived suppressor cells (MDSCs) represent a heterogeneous population that shares certain characteristics including an aberrant myeloid phenotype and the ability to suppress T cells. MDSCs have been predominantly studied in malignant diseases and findings suggest involvement in tumor-associated immune suppression. Chronic lymphocytic leukemia (CLL) is the leukemia with the highest incidence among adults. Immune defects occur already at early disease stages and impact the clinical course. We assessed presence, frequency, association to other immune parameters, and functional properties of circulating CD14+ cells lacking HLA-DR expression (HLA-DRlo) in patients with untreated CLL. These monocytic cells represent one of the best-defined human MDSC subsets. Frequency of CD14+HLA-DRlo cells was significantly increased in CLL patients. Furthermore, MDSCs suppressed in vitro T-cell activation and induced suppressive regulatory T cells (TRegs). The MDSC-mediated modulation of T cells could be attributed to their increased indoleamine 2,3-dioxygenase (IDO) activity. CLL cells induced IDOhi MDSCs from healthy donor monocytes suggesting bidirectional crosstalk between CLL-cells, MDSCs, and TRegs. Overall, we identified a MDSC population that expands in CLL. The exact mechanisms responsible for such accumulation remain to be elucidated and it will be of interest to test whether antagonizing suppressive functions of CLL MDSCs could represent a mean for enhancing immune responses. [ABSTRACT FROM AUTHOR]

Published
2014
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27. Imatinib dose reduction in major molecular response of chronic myeloid leukemia: results from the German Chronic Myeloid Leukemia-Study IV.

Author

Michel C, Burchert A, Hochhaus A, Saussele S, Neubauer A, Lauseker M, Krause SW, Kolb HJ, Hossfeld DK, Nerl C, Baerlocher GM, Heim D, Brümmendorf TH, Fabarius A, Haferlach C, Schlegelberger B, Balleisen L, Goebeler ME, Hänel M, Ho A, Dengler J, Falge C, Möhle R, Kremers S, Kneba M, Stegelmann F, Köhne CH, Lindemann HW, Waller CF, Spiekermann K, Berdel WE, Müller L, Edinger M, Mayer J, Beelen DW, Bentz M, Link H, Hertenstein B, Fuchs R, Wernli M, Schlegel F, Schlag R, de Wit M, Trümper L, Hebart H, Hahn M, Thomalla J, Scheid C, Schafhausen P, Verbeek W, Eckart MJ, Gassmann W, Schenk M, Brossart P, Wündisch T, Geer T, Bildat S, Schäfer E, Hasford J, Hehlmann R, and Pfirrmann M

Subjects
Aged, Dose-Response Relationship, Drug, Female, Follow-Up Studies, Humans, Leukemia, Myelogenous, Chronic, BCR-ABL Positive pathology, Male, Middle Aged, Neoplasm Recurrence, Local pathology, Remission Induction, Retrospective Studies, Survival Rate, Time Factors, Treatment Outcome, Antineoplastic Agents therapeutic use, Imatinib Mesylate therapeutic use, Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy, Neoplasm Recurrence, Local drug therapy, Withholding Treatment statistics & numerical data
Abstract

Standard first-line therapy of chronic myeloid leukemia is treatment with imatinib. In the randomized German Chronic Myeloid Leukemia-Study IV, more potent BCR-ABL inhibition with 800 mg ('high-dose') imatinib accelerated achievement of a deep molecular remission. However, whether and when a de-escalation of the dose intensity under high-dose imatinib can be safely performed without increasing the risk of losing deep molecular response is unknown. To gain insights into this clinically relevant question, we analyzed the outcome of imatinib dose reductions from 800 mg to 400 mg daily in the Chronic Myeloid Leukemia-Study IV. Of the 422 patients that were randomized to the 800 mg arm, 68 reduced imatinib to 400 mg after they had achieved at least a stable major molecular response. Of these 68 patients, 61 (90%) maintained major molecular remission on imatinib at 400 mg. Five of the seven patients who lost major molecular remission on the imatinib standard dose regained major molecular remission while still on 400 mg imatinib. Only two of 68 patients had to switch to more potent kinase inhibition to regain major molecular remission. Importantly, the lengths of the intervals between imatinib high-dose treatment before and after achieving major molecular remission were associated with the probabilities of maintaining major molecular remission with the standard dose of imatinib. Taken together, the data support the view that a deep molecular remission achieved with high-dose imatinib can be safely maintained with standard dose in most patients. Study protocol registered at clinicaltrials.gov 00055874 ., (Copyright© 2019 Ferrata Storti Foundation.)

Published
2019
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28. Impact of comorbidities on overall survival in patients with chronic myeloid leukemia: results of the randomized CML study IV.

Author

Saussele S, Krauss MP, Hehlmann R, Lauseker M, Proetel U, Kalmanti L, Hanfstein B, Fabarius A, Kraemer D, Berdel WE, Bentz M, Staib P, de Wit M, Wernli M, Zettl F, Hebart HF, Hahn M, Heymanns J, Schmidt-Wolf I, Schmitz N, Eckart MJ, Gassmann W, Bartholomäus A, Pezzutto A, Leibundgut EO, Heim D, Krause SW, Burchert A, Hofmann WK, Hasford J, Hochhaus A, Pfirrmann M, and Müller MC

Subjects
Adolescent, Adult, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Benzamides administration & dosage, Benzamides adverse effects, Combined Modality Therapy, Comorbidity, Cytarabine administration & dosage, Cytarabine adverse effects, Female, Hematopoietic Stem Cell Transplantation adverse effects, Humans, Imatinib Mesylate, Interferon-alpha administration & dosage, Interferon-alpha adverse effects, Leukemia, Myelogenous, Chronic, BCR-ABL Positive mortality, Male, Middle Aged, Piperazines administration & dosage, Piperazines adverse effects, Pyrimidines administration & dosage, Pyrimidines adverse effects, Survival Analysis, Treatment Outcome, Young Adult, Leukemia, Myelogenous, Chronic, BCR-ABL Positive epidemiology, Leukemia, Myelogenous, Chronic, BCR-ABL Positive therapy
Abstract

We studied the influence of comorbidities on remission rate and overall survival (OS) in patients with chronic myeloid leukemia (CML). Participants of the CML Study IV, a randomized 5-arm trial designed to optimize imatinib therapy, were analyzed for comorbidities at diagnosis using the Charlson Comorbidity Index (CCI); 511 indexed comorbidities were reported in 1519 CML patients. Age was an additional risk factor in 863 patients. Resulting CCI scores were as follows: CCI 2, n = 589; CCI 3 or 4, n = 599; CCI 5 or 6, n = 229; and CCI ≥ 7, n = 102. No differences in cumulative incidences of accelerated phase, blast crisis, or remission rates were observed between patients in the different CCI groups. Higher CCI was significantly associated with lower OS probabilities. The 8-year OS probabilities were 93.6%, 89.4%, 77.6%, and 46.4% for patients with CCI 2, 3 to 4, 5 to 6, and ≥7, respectively. In multivariate analysis, CCI was the most powerful predictor of OS, which was still valid after removal of its age-related components. Comorbidities have no impact on treatment success but do have a negative effect on OS, indicating that survival of patients with CML is determined more by comorbidities than by CML itself. OS may therefore be inappropriate as an outcome measure for specific CML treatments. The trial was registered at www.clinicaltrials.gov as #NCT00055874., (© 2015 by The American Society of Hematology.)

Published
2015
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