70 results on '"Langerbeins, P."'
Search Results
2. P622: GENETIC MARKERS AND OUTCOME OF CLL PATIENTS IN COMBINED TIME-LIMITED TREATMENT WITH ANTI-CD20 ANTIBODY + IBRUTINIB, IDELALISIB OR VENETOCLAX IN THE GCLLSG CLL2-BAG, -BCG, -BIG AND -BIO PHASE-II TRIALS
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Deyan Yosifov, Julia von Tresckow, Adam Giza, Sandra Robrecht, Christof Schneider, Billy Jebaraj, Daniel Mertens, Matthias Ritgen, Anke Schilhabel, Karl-Anton Kreuzer, Anna Maria Fink, Othman Al-Sawaf, Petra Langerbeins, Kirsten Fischer, Barbara Eichhorst, Michael Hallek, Hartmut Döhner, Stephan Stilgenbauer, Paula Cramer, and Eugen Tausch
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2023
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3. Sequential treatment with bendamustine, obinutuzumab (GA101) and Ibrutinib in chronic lymphocytic leukemia (CLL): final results of the CLL2-BIG trial
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von Tresckow, Julia, Cramer, Paula, Robrecht, Sandra, Langerbeins, Petra, Fink, Anna-Maria, Al-Sawaf, Othman, Fürstenau, Moritz, Illmer, Thomas, Klaproth, Holger, Tausch, Eugen, Ritgen, Matthias, Fischer, Kirsten, Wendtner, Clemens-Martin, Kreuzer, Karl-Anton, Stilgenbauer, Stephan, Böttcher, Sebastian, Eichhorst, Barbara F., and Hallek, Michael
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- 2022
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4. SARS-CoV-2 specific cellular response following COVID-19 vaccination in patients with chronic lymphocytic leukemia
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Mellinghoff, Sibylle C., Robrecht, Sandra, Mayer, Leonie, Weskamm, Leonie M., Dahlke, Christine, Gruell, Henning, Vanshylla, Kanika, Schlösser, Hans A., Thelen, Martin, Fink, Anna-Maria, Fischer, Kirsten, Klein, Florian, Addo, Marylyn M., Eichhorst, Barbara, Hallek, Michael, and Langerbeins, Petra
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- 2022
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5. SARS-CoV-2-specific cellular response following third COVID-19 vaccination in patients with chronic lymphocytic leukemia
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Sibylle C. Mellinghoff, Leonie Mayer, Sandra Robrecht, Leonie M. Weskamm, Christine Dahlke, Henning Gruell, Maike Schlotz, Kanika Vanshylla, Hans A. Schloser, Martin Thelen, Anna-Maria Fink, Kirsten Fischer, Florian Klein, Marylyn M. Addo, Barbara Eichhorst, Michael Hallek, and Petra Langerbeins
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2022
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6. P641: RETREATMENT WITH VENETOCLAX AFTER VENETOCLAX, OBINUTUZUMAB +/- IBRUTINIB: POOLED ANALYSIS OF 13 PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) TREATED IN GCLLSG TRIALS
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P. Cramer, M. Fürstenau, A. Giza, S. Robrecht, E. Tausch, C. Schneider, C.-M. Wendtner, M. Hoechstetter, J. Schetelig, S. Böttcher, P. Dreger, A.-M. Fink, P. Langerbeins, O. Al-Sawaf, K. Fischer, S. Stilgenbauer, B. Eichhorst, and M. Hallek
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2022
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7. Early treatment with FCR versus watch and wait in patients with stage Binet A high-risk chronic lymphocytic leukemia (CLL): a randomized phase 3 trial
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Herling, Carmen D., Cymbalista, Florence, Groß-Ophoff-Müller, Carolin, Bahlo, Jasmin, Robrecht, Sandra, Langerbeins, Petra, Fink, Anna-Maria, Al-Sawaf, Othman, Busch, Raymonde, Porcher, Raphael, Cazin, Bruno, Dreyfus, Brigitte, Ibach, Stefan, Leprêtre, Stéphane, Fischer, Kirsten, Kaiser, Florian, Eichhorst, Barbara, Wentner, Clemens-Martin, Hoechstetter, Manuela A., Döhner, Hartmut, Leblond, Veronique, Kneba, Michael, Letestu, Remi, Böttcher, Sebastian, Stilgenbauer, Stephan, Hallek, Michael, and Levy, Vincent
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- 2020
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8. COVID-19 among fit patients with CLL treated with venetoclax-based combinations
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Fürstenau, Moritz, Langerbeins, Petra, De Silva, Nisha, Fink, Anna Maria, Robrecht, Sandra, von Tresckow, Julia, Simon, Florian, Hohloch, Karin, Droogendijk, Jolanda, van der Klift, Marjolein, van der Spek, Ellen, Illmer, Thomas, Schöttker, Björn, Fischer, Kirsten, Wendtner, Clemens M., Tausch, Eugen, Stilgenbauer, Stephan, Niemann, Carsten U., Gregor, Michael, Kater, Arnon P., Hallek, Michael, and Eichhorst, Barbara
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- 2020
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9. Influence of obesity and gender on treatment outcomes in patients with chronic lymphocytic leukemia (CLL) undergoing rituximab-based chemoimmunotherapy
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Fürstenau, Moritz, Hopfinger, Georg, Robrecht, Sandra, Fink, Anna-Maria, Al-Sawaf, Othman, Langerbeins, Petra, Cramer, Paula, Tresckow, Julia Von, Maurer, Christian, Kutsch, Nadine, Hoechstetter, Manuela, Dreyling, Martin, Lange, Elisabeth, Kneba, Michael, Stilgenbauer, Stephan, Döhner, Hartmut, Hensel, Manfred, Kiehl, Michael G., Jaeger, Ulrich, Wendtner, Clemens-Martin, Goede, Valentin, Fischer, Kirsten, von Bergwelt-Baildon, Michael, Eichhorst, Barbara, Hallek, Michael, and Theurich, Sebastian
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- 2020
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10. CLL2-BIG: sequential treatment with bendamustine, ibrutinib and obinutuzumab (GA101) in chronic lymphocytic leukemia
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von Tresckow, Julia, Cramer, Paula, Bahlo, Jasmin, Robrecht, Sandra, Langerbeins, Petra, Fink, Anna-Maria, Al-Sawaf, Othman, Illmer, Thomas, Klaproth, Holger, Estenfelder, Sven, Ritgen, Matthias, Fischer, Kirsten, Wendtner, Clemens-Martin, Kreuzer, Karl-Anton, Stilgenbauer, Stephan, Böttcher, Sebastian, Eichhorst, Barbara F., and Hallek, Michael
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- 2019
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11. Bendamustine, followed by ofatumumab and ibrutinib in chronic lymphocytic leukemia (CLL2-BIO): primary endpoint analysis of a multicenter, open-label phase-II trial
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Paula Cramer, Julia v. Tresckow, Sandra Robrecht, Jasmin Bahlo, Moritz Fürstenau, Petra Langerbeins, Natali Pflug, Othman Al-Sawaf, Werner J. Heinz, Ursula Vehling-Kaiser, Jan Dürig, Eugen Tausch, Manfred Hensel, Stephanie Sasse, Anna-Maria Fink, Kirsten Fischer, Karl-Anton Kreuzer, Sebastian Böttcher, Matthias Ritgen, Michael Kneba, Clemens-Martin Wendtner, Stephan Stilgenbauer, Barbara Eichhorst, and Michael Hallek
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
The introduction of targeted agents has revolutionized the treatment of chronic lymphocytic leukemia but only few patients achieve complete remissions and minimal residual disease negativity with ibrutinib monotherapy. This multicenter, investigator-initiated phase-II study evaluates a sequential treatment with two cycles of bendamustine debulking for patients with a higher tumor load, followed by ofatumumab and ibrutinib induction and maintenance treatment. An all-comer population, irrespective of prior treatment, physical fitness and genetic factors was included. The primary endpoint was the investigator assessed overall response rate at the end of induction treatment. Of 66 patients enrolled, one patient with early treatment discontinuation was excluded from the efficacy analysis as predefined by the protocol. Thirty-nine patients (60%) were treatment-naive and 26 patients (40%) had relapsed/refractory CLL, 21 patients (32%) had a del(17p) and/or TP53 mutation and 45 patients (69%) had an unmutated IGHV status. At the end of the induction, 60 of 65 patients (92%) responded and 9 (14%) achieved minimal residual disease negativity (
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- 2020
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12. Effect of first-line treatment on second primary malignancies and Richter’s transformation in patients with CLL
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Maurer, C, Langerbeins, P, Bahlo, J, Cramer, P, Fink, A M, Pflug, N, Engelke, A, von Tresckow, J, Kovacs, G, Stilgenbauer, S, Wendtner, C-M, Müller, L, Ritgen, M, Seiler, T, Fischer, K, Hallek, M, and Eichhorst, B
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- 2016
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13. Nonmyeloablative allogeneic stem cell transplantation for chronic lymphocytic leukaemia offers the possibility of disease control with minimal morbidity and mortality—a single institution experience
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Chakupurakal, G., Leitzke, S., Langerbeins, P., Schiller, J., Schneider, P. M., Holtick, U., Shimabukuro-Vornhagen, A., Theurich, S., Chemnitz, J., Hallek, M., von Bergwelt-Baildon, M., and Scheid, C.
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- 2015
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14. Outcome of advanced chronic lymphocytic leukemia following different first-line and relapse therapies: a meta-analysis of five prospective trials by the German CLL Study Group (GCLLSG)
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Paula Cramer, Susanne Isfort, Jasmin Bahlo, Stephan Stilgenbauer, Hartmut Döhner, Manuela Bergmann, Martina Stauch, Michael Kneba, Elisabeth Lange, Petra Langerbeins, Natali Pflug, Gabor Kovacs, Valentin Goede, Anna-Maria Fink, Thomas Elter, Kirsten Fischer, Clemens-Martin Wendtner, Michael Hallek, and Barbara Eichhorst
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
To evaluate the effect of first-line and subsequent therapies, the outcome of 1,558 patients with chronic lymphocytic leukemia from five prospective phase II/III trials conducted between 1999 and 2010 was analyzed. The 3-year overall survival rate was higher after first-line treatment with chemoimmunotherapies such as fludarabine/cyclophosphamide/rituximab (87.9%) or bendamustine/rituximab (90.7%) compared to chemotherapies without an antibody (fludarabine/cyclophosphamide: 84.6%; fludarabine: 77.5%; chlorambucil: 77.4%). Furthermore, the median overall survival was longer in patients receiving at least one antibody-containing regimen in any treatment line (94.4 months) compared to the survival in patients who never received an antibody (84.3 months, P24 months after first-line therapy repeated the first-line regimen. Among 315 patients requiring treatment ≤24 months after first-line therapy, cyclophosphamide/doxorubicin/vincristine/prednisone with or without rituximab as well as alemtuzumab were the most commonly used therapies. In these early relapsing patients, the median overall survival was shorter following therapies containing an anthracycline and/or three or more cytotoxic agents (e.g. cyclophosphamide/doxorubicin/vincristine/prednisone or fludarabine/cyclophosphamide/mitoxantrone, 30.0 months) compared to single agent chemotherapy (e.g. fludarabine; 39.6 months) and standard chemoimmunotherapy (e.g. fludarabine/cyclophosphamide/rituximab: 61.6 months). In conclusion, the analysis confirms the superior efficacy of chemoimmunotherapies in patients with chronic lymphocytic leukemia. Moreover, the use of aggressive chemo(immuno)therapy combinations in patients with an early relapse does not offer any benefit when compared to less intensive therapies. Trial identifier: NCT00281918, ISRCTN75653261, ISRCTN36294212, NCT00274989 and NCT00147901.
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- 2015
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15. IBRUTINIB VERSUS PLACEBO IN PATIENTS WITH ASYMPTOMATIC, TREATMENT‐NAïVE EARLY STAGE CHRONIC LYMPHOCYTIC LEUKEMIA (CLL): FINAL RESULTS OF THE CLL12 TRIAL.
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Langerbeins, P., Robrecht, S., Nieper, P., Cramer, P., Fürstenau, M., Al‐Sawaf, O., Fink, A., Kreuzer, K., Vehling‐Kaiser, U., Tausch, E., Schneider, C., Müller, L., Schlag, R., Freier, W., Gaska, T., Balser, C., Reiser, M., Stauch, M., Zahn, M., and Dörfel, S.
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CHRONIC lymphocytic leukemia ,ASYMPTOMATIC patients ,PLACEBOS ,RICHTER syndrome - Abstract
B Conclusions: b Early ibrutinib-treatment of patients with asymptomatic Binet stage A CLL at high risk of progression failed to demonstrate an overall survival benefit when compared to placebo. B Introduction: b We present the final analysis of the phase 3, double-blind, placebo-controlled CLL12 trial evaluating ibrutinib in patients with early stage CLL at increased risk of progression defined by a comprehensive score (NCT02863718). [Extracted from the article]
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- 2023
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16. Secondary immunodeficiency in lymphoproliferative malignancies
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Friman, V, Winqvist, O, Blimark, C, Langerbeins, P, Chapel, H, and Dhalla, F
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Male ,Hematologic Neoplasms ,hemic and lymphatic diseases ,Immunologic Deficiency Syndromes ,Humans ,Female ,Multiple Myeloma ,Leukemia, Lymphocytic, Chronic, B-Cell - Abstract
Secondary immunodeficiencies occur as a consequence of various diseases, including hematological malignancies, and the use of pharmacological therapies, such as immunosuppressive, anti-inflammatory, and biological drugs. Infections are the main cause of morbidity and mortality in multiple myeloma (MM) and chronic lymphocytic leukemia (CLL) patients. Recent advances in treatment have prolonged the duration of remission and the time between relapse phases in MM and CLL patients. However, managing multiple relapses and the use of salvage therapies can lead to cumulative immunosuppression and a higher risk of infections. The pathogenesis of immune deficiency secondary to lymphoproliferative malignancy is multifactorial including disease- and treatment-related factors. Supportive treatment, including early vaccination, anti-infective prophylaxis, and replacement immunoglobulin, plays a key role in preventing infections in MM and CLL. This article provides an overview of the basic immunology necessary to understand the pathogenesis of secondary immunodeficiency and the infectious complications in MM and CLL. We also discuss the evidence supporting the role of prophylactic replacement immunoglobulin treatment in patients with antibody failure secondary to MM and CLL and the indications for its use. Copyright © 2016 John WileySons, Ltd.
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- 2016
17. BENDAMUSTINE, FOLLOWED BY OBINUTUZUMAB, ACALABRUTINIB AND VENETOCLAX IN PATIENTS (PTS) WITH RELAPSED/REFRACTORY CHRONIC LYMPHOCYTIC LEUKEMIA (CLL): CLL2‐BAAG TRIAL OF THE GCLLSG.
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Cramer, P, Fürstenau, M, Robrecht, S, Giza, A, Fink, A. M, Fischer, K, Langerbeins, P, Al Sawaf, O, Tausch, E, Schneider, C, Schetelig, J, Dreger, P, Böttcher, S, Kreuzer, K. A, Schilhabel, A, Brüggemann, M, Kneba, M, Wendtner, C. M, Stilgenbauer, S, and Eichhorst, B
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- 2021
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18. P641: RETREATMENT WITH VENETOCLAX AFTER VENETOCLAX, OBINUTUZUMAB +/‐ IBRUTINIB: POOLED ANALYSIS OF 13 PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) TREATED IN GCLLSG TRIALS.
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Cramer, P., Fürstenau, M., Giza, A., Robrecht, S., Tausch, E., Schneider, C., Wendtner, C.‐M., Hoechstetter, M., Schetelig, J., Böttcher, S., Dreger, P., Fink, A.‐M., Langerbeins, P., Al‐Sawaf, O., Fischer, K., Stilgenbauer, S., Eichhorst, B., and Hallek, M.
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- 2022
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19. Minimal Residual Disease Assessment Improves Prediction of Outcome in Patients With Chronic Lymphocytic Leukemia (CLL) Who Achieve Partial Response: Comprehensive Analysis of Two Phase III Studies of the German CLL Study Group.
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Kovacs, Gabor, Robrecht, Sandra, Fink, Anna Maria, Bahlo, Jasmin, Cramer, Paula, von Tresckow, Julia, Maurer, Christian, Langerbeins, Petra, Fingerle-Rowson, Günter, Ritgen, Matthias, Kneb, Michael, Döhner, Hartmut, Stilgenbauer, Stephan, Klapper, Wolfram, Wendtner, Clemens-Martin, Fischer, Kirsten, Hallek, Michael, Eichhorst, Barbara, Böttcher, Sebastian, and Kneba, Michael
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- 2016
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20. IBRUTINIB VERSUS PLACEBO IN PATIENTS WITH ASYMPTOMATIC, TREATMENT‐NAÏVE EARLY STAGE CLL: PRIMARY ENDPOINT RESULTS OF THE PHASE 3 DOUBLE‐BLIND RANDOMIZED CLL12 TRIAL.
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Langerbeins, P., Bahlo, J., Rhein, C., Gerwin, H., Cramer, P., Fürstenau, M., Al‐Sawaf, O., Tresckow, J., Fink, A.M., Kreuzer, K., Vehling‐Kaiser, U., Tausch, E., Müller, L., Eckart, M., Schlag, R., Freier, W., Gaska, T., Balser, C., Reiser, M., and Stauch, M.
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PLACEBOS ,PROGRESSION-free survival - Published
- 2019
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21. Combination of Targeted Drugs to Control Chronic Lymphocytic Leukemia: Harnessing the Power of New Monoclonal Antibodies in Combination With Ibrutinib.
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Cramer, Paula, Langerbeins, Petra, and Hallek, Michael
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CHRONIC lymphocytic leukemia diagnosis ,ANTINEOPLASTIC agents ,DRUG therapy ,CHRONIC lymphocytic leukemia ,CLINICAL trials ,HETEROCYCLIC compounds ,MONOCLONAL antibodies ,TREATMENT effectiveness ,PROTEIN kinase inhibitors - Abstract
The landscape of treatment for chronic lymphocytic leukemia is rapidly changing at present. Considerable improvement has been achieved with the introduction of the anti-CD20 antibodies, and chemoimmunotherapy has now become an established standard for patients without the high-risk features del(17p)/TP53 mutation. Also, the outcome of patients with these adverse genetic aberrations was dramatically improved with the introduction of the kinase inhibitors ibrutinib and idelalisib. Different combinations of these and additional novel agents are currently evaluated in clinical trials. The combination of the Bruton tyrosine kinase inhibitor ibrutinib with an anti-CD20 antibody is an attractive option, because both drugs act synergistically: ibrutinib redistributes the CLL cells from their homing organs to the peripheral blood, and obinutuzumab eliminates the leukemic cells in the blood with particular efficiency. Adding the Bcl-2 antagonist venetoclax could further intensify the treatment of CLL. This combination might hold the potential to achieve a deep remission with an eradication of residual CLL cells and thus lead to long-term remissions of CLL. [ABSTRACT FROM AUTHOR]
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- 2016
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22. BENDAMUSTINE (B), FOLLOWED BY OBINUTUZUMAB (G) AND VENETOCLAX (A) IN PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA (CLL): CLL2-BAG TRIAL OF THE GERMAN CLL STUDY GROUP (GCLLSG).
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Cramer, P., Tresckow, J., Bahlo, J., Robrecht, S., Al ‐ Sawaf, O., Langerbeins, P., Engelke, A., Fink, A.M., Fischer, K., Seiler, T., Weikersthal, L.Fischer, Hebart, H., Kreuzer, K.A., Ritgen, M., Kneba, M., Wendtner, C.M., Stilgenbauer, S., Eichhorst, B., and Hallek, M.
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- 2017
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23. INTERNATIONAL PROGNOSTIC SCORE FOR EARLY STAGE CHRONIC LYMPHOCYTIC LEUKEMIA (IPS‐A).
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Condoluci, A., Terzi di Bergamo, L., Langerbeins, P., Hoechstetter, M., Herling, C., De Paoli, L., Delgado, J., Gentile, M., Doubek, M., Mauro, F.R., Chiodin, G., Mattsson, M., Bahlo, J., Cutrona, G., Kotaskova, J., Deambrogi, C., Moia, R., Gerber, B., Zucca, E., and Ghielmini, M.
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CHRONIC lymphocytic leukemia - Published
- 2019
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24. CHARACTERISTICS, TREATMENT, AND OUTCOMES OF ≥ 80 YEAR OLD PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) ENROLLED TO PROSPECTIVE TRIALS OF THE GERMAN CLL STUDY GROUP.
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Al ‐ Sawaf, O., Bahlo, J., Fischer, K., Herling, C., Bergmann, M., Fink, A.M., Tresckow, J., Langerbeins, P., Cramer, P., Stilgenbauer, S., Wendtner, C.M., Eichhorst, B., Hallek, M., and Goede, V.
- Published
- 2017
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25. Endpoint Surrogacy in First-Line Chronic Lymphocytic Leukemia.
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Simon F, Ligtvoet R, Robrecht S, Cramer P, Kutsch N, Fürstenau M, Goede V, von Tresckow J, Langerbeins P, Fink AM, Huber H, Tausch E, Schneider C, Wendtner CM, Ritgen M, Dreyling M, Müller L, Jacobasch L, Heinz WJ, Vehling-Kaiser U, Sivcheva L, Böttcher S, Dreger P, Illmer T, Gregor M, Staber PB, Stilgenbauer S, Niemann CU, Kater AP, Fischer K, Eichhorst B, Hallek M, and Al-Sawaf O
- Abstract
Purpose: Surrogate endpoints are commonly used to estimate treatment efficacy in clinical studies of chronic lymphocytic leukemia (CLL). This patient- and trial-level analysis describes the correlation between progression-free survival (PFS) and minimal residual disease (MRD) with overall survival (OS) in first-line trials for CLL., Patients and Methods: First, patient-level correlation was confirmed using source data from 12 front-line GCLLSG-trials. Additionally, a joint-frailty copula model was fitted to validate correlation in the setting of targeted therapies.Second, a meta-analysis of first-line phase III trials in CLL from 2008-2024 was performed. Treatment effect correlation was quantified from seven GCLLSG and nine published trials, using hazard ratios for time-to-event and odds ratios for binary endpoints., Results: The GCLLSG analysis set comprised 4237 patients. Patient-level correlation for PFS/OS was strong with Spearman's Rho >0.9. The joint-frailty copula indicated a weak correlation for C/CIT with a tau of 0.52, (95% CI: 0.49 - 0.55) while the correlation was strong for TT (tau = 0.91, 95% CI: 0.89 - 0.93).The meta-analysis set contained a total of 8065 patients including 5198 (64%) patients treated with C/CIT and 2867 (36%) treated with TT. Treatment effect correlation of the hazard ratios (HR) for PFS and OS was R = 0.75 (95% CI: 0.74 - 0.76, R
2 = 0.56), while correlation of end-of-treatment MRD with PFS and OS was R = 0.88 (95%CI: -0.87 - 0.89; R2 = 0.78) and 0.71 (95%CI: 0.69 - 0.73; R2 = 0.5), respectively., Conclusion: Patient-level correlation was confirmed in the setting of targeted therapies while treatment-effect correlation between PFS and OS remains uncertain. MRD response status showed a high treatment-effect correlation with PFS but not OS, with the caveat of a limited number of randomized trials with available MRD data.- Published
- 2024
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26. Infections in patients with chronic lymphocytic leukemia treated with time limited targeted drug combinations.
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Langerbeins P, Giza A, Robrecht S, Cramer P, von Tresckow J, Al-Sawaf O, Fink AM, Fürstenau M, Kater AP, van der Spek E, Niemann CU, da Cunha-Bang C, Tausch E, Schneider C, Stilgenbauer S, Fischer K, Hallek M, and Eichhorst B
- Subjects
- Humans, Male, Female, Aged, Infections etiology, Infections chemically induced, Middle Aged, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Leukemia, Lymphocytic, Chronic, B-Cell complications, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Antineoplastic Combined Chemotherapy Protocols adverse effects, Antineoplastic Combined Chemotherapy Protocols administration & dosage
- Published
- 2024
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27. Acalabrutinib, venetoclax, and obinutuzumab in relapsed/refractory CLL: final efficacy and ctDNA analysis of the CLL2-BAAG trial.
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Fürstenau M, Giza A, Weiss J, Kleinert F, Robrecht S, Franzen F, Stumpf J, Langerbeins P, Al-Sawaf O, Simon F, Fink AM, Schneider C, Tausch E, Schetelig J, Dreger P, Böttcher S, Fischer K, Kreuzer KA, Ritgen M, Schilhabel A, Brüggemann M, Stilgenbauer S, Eichhorst B, Hallek M, and Cramer P
- Subjects
- Humans, Aged, Middle Aged, Female, Male, Aged, 80 and over, Adult, Recurrence, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Leukemia, Lymphocytic, Chronic, B-Cell mortality, Sulfonamides administration & dosage, Sulfonamides therapeutic use, Bridged Bicyclo Compounds, Heterocyclic administration & dosage, Bridged Bicyclo Compounds, Heterocyclic therapeutic use, Circulating Tumor DNA genetics, Circulating Tumor DNA blood, Pyrazines administration & dosage, Pyrazines therapeutic use, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Antibodies, Monoclonal, Humanized administration & dosage, Antibodies, Monoclonal, Humanized therapeutic use, Neoplasm, Residual, Benzamides administration & dosage, Benzamides therapeutic use
- Abstract
Abstract: The phase 2 CLL2-BAAG trial tested the measurable residual disease (MRD)-guided triple combination of acalabrutinib, venetoclax, and obinutuzumab after optional bendamustine debulking in 45 patients with relapsed/refractory chronic lymphocytic leukemia (CLL). MRD was measured by flow cytometry (FCM; undetectable MRD <10-4) in peripheral blood (PB) and circulating tumor DNA (ctDNA) using digital droplet polymerase chain reaction of variable-diversity-joining (VDJ) rearrangements and CLL-related mutations in plasma. The median number of previous treatments was 1 (range, 1-4); 18 patients (40%) had received a Bruton tyrosine kinase inhibitor (BTKi) and/or venetoclax before inclusion, 14 of 44 (31.8%) had TP53 aberrations, and 34 (75.6%) had unmutated immunoglobulin heavy-chain variable region genes. With a median observation time of 36.3 months and all patients off-treatment for a median of 21.9 months, uMRD <10-4 in PB was achieved in 42 of the 45 patients (93.3%) at any time point, including 17 of 18 (94.4%) previously exposed to venetoclax/BTKi and 13 of 14 (92.9%) with TP53 aberrations. The estimated 3-year progression-free and overall survival rates were 85.0% and 93.8%, respectively. Overall, 585 paired FCM/ctDNA samples were analyzed and 18 MRD recurrences (5 with and 13 without clinical progression) occurred after the end of treatment. Twelve samples were first detected by ctDNA, 3 by FCM, and 3 synchronously. In conclusion, time-limited MRD-guided acalabrutinib, venetoclax, and obinutuzumab achieved deep remissions in almost all patients with relapsed/refractory CLL. The addition of ctDNA-based analyses to FCM MRD assessment seems to improve early detection of relapses. This trial was registered at www.clinicaltrials.gov as #NCT03787264., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)
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- 2024
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28. Reassessing the chronic lymphocytic leukemia International Prognostic Index in the era of targeted therapies.
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Langerbeins P, Giza A, Robrecht S, Cramer P, von Tresckow J, Al-Sawaf O, Fink AM, Fürstenau M, Kutsch N, Simon F, Goede V, Hoechstetter M, Niemann CU, da Cunha-Bang C, Kater A, Dubois J, Gregor M, Staber PB, Tausch E, Schneider C, Stilgenbauer S, Eichhorst B, Fischer K, and Hallek M
- Subjects
- Humans, Female, Male, Aged, Middle Aged, Prognosis, Aged, 80 and over, Adult, beta 2-Microglobulin, Survival Rate, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Leukemia, Lymphocytic, Chronic, B-Cell mortality, Leukemia, Lymphocytic, Chronic, B-Cell diagnosis, Molecular Targeted Therapy
- Abstract
Abstract: We evaluated the chronic lymphocytic leukemia International Prognostic Index (CLL-IPI) in patients with CLL treated first line with targeted drugs (n = 991) or chemoimmunotherapy (n = 1256). With a median observation time of 40.5 months, the 3-year progression-free survival (PFS) rates for targeted drug-treated patients varied by CLL-IPI risk group: 96.5% (low), 87.6% (intermediate), 82.4% (high), and 78.7% (very high). Differences between consecutive CLL-IPI risk groups were observed for intermediate vs low and high vs intermediate, but not very high vs high. CLL-IPI factors β2-microglobulin, immunoglobulin heavy variable (IGHV) status, and TP53 status each retained prognostic value for PFS. The 3-year overall survival (OS) rates by CLL-IPI risk groups were 100%, 96%, 93.9%, and 89.4%, respectively, with no differences between consecutive risk groups. Age, Binet stage, β2-microglobulin, and TP53 status each retained prognostic value for OS. In chemoimmunotherapy patients (median observation time, 66.9 months), 3-year PFS rates for CLL-IPI risk groups were 78.1%, 51.4%, 40.1%, and 16.5%, respectively; corresponding 3-year OS rates were 97.4%, 93.1%, 81.8%, and 57.3%. In a matched-pair analysis, PFS differences in targeted therapies (n = 812) vs chemoimmunotherapy (n = 812) across all risk groups and OS differences in all but patients at low risk were demonstrated. The CLL-IPI maintains its prognostic value in predicting PFS outcomes with targeted drugs, but its impact in predicting survival appears diminished. Targeted therapies showed enhanced outcomes over chemoimmunotherapy, highlighting their effectiveness across various risk groups. Our findings support ongoing assessment of prognostic tools in CLL treatment evolution. These trials were registered at www.ClinicalTrials.gov as #NCT02345863, #NCT02401503, #NCT02689141, #NCT02445131, #NCT02758665, #NCT02950051, #NCT02242942, #NCT00262782, #NCT00281918, and #NCT01010061., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)
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- 2024
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29. Bendamustine, followed by obinutuzumab and idelalisib in chronic lymphocytic leukemia (CLL2-BCG): Final analysis of a multicenter, open-label phase-II-trial.
- Author
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Cramer P, von Tresckow J, Fink AM, Robrecht S, Giza A, Tausch E, Müller L, Knauf W, Zingerle M, Al-Sawaf O, Langerbeins P, Fischer K, Kreuzer KA, Kneba M, Wendtner CM, Stilgenbauer S, Eichhorst B, and Hallek M
- Subjects
- Humans, Aged, Male, Female, Middle Aged, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Purines administration & dosage, Purines therapeutic use, Purines adverse effects, Quinazolinones administration & dosage, Quinazolinones therapeutic use, Quinazolinones adverse effects, Bendamustine Hydrochloride administration & dosage, Bendamustine Hydrochloride therapeutic use, Antibodies, Monoclonal, Humanized therapeutic use, Antibodies, Monoclonal, Humanized administration & dosage, Antibodies, Monoclonal, Humanized adverse effects, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Antineoplastic Combined Chemotherapy Protocols adverse effects, Antineoplastic Combined Chemotherapy Protocols administration & dosage
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- 2024
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30. Hybrid immunity to SARS-CoV-2 in patients with chronic lymphocytic leukemia.
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Mellinghoff SC, Robrecht S, Sprute R, Mayer L, Weskamm LM, Dahlke C, Gruell H, Teipel F, Schlößer HA, Siepmann K, Thelen M, Fink AM, Fischer K, Klein F, Addo MM, Kolovou A, Cornely OA, Eichhorst B, Hallek M, and Langerbeins P
- Subjects
- Humans, SARS-CoV-2, COVID-19 Vaccines, Leukocytes, Mononuclear, Immunoglobulin G, Postoperative Complications, Vaccination, Adaptive Immunity, Antibodies, Viral, Leukemia, Lymphocytic, Chronic, B-Cell complications, Leukemia, Lymphocytic, Chronic, B-Cell therapy, COVID-19
- Abstract
Objective: Preventing severe COVID-19 remains a priority globally, particularly in the immunocompromised population. As shown in healthy individuals, immunity against SARS-CoV-2 can be yielded by previous infection, vaccination, or both (hybrid immunity). The objective of this observation study was to investigate hybrid immunity in patients with chronic lymphocytic leukemia (CLL)., Methods/results: Blood samples of six patients with CLL were collected 55 days after fourth COVID-19 vaccination. All patients had a SARS-CoV-2 infection within 12 months before the second booster (fourth vaccination). SARS-CoV-2 spike receptor binding domain (RBD)-specific IgG antibodies were detectable in 6/6 (100.0%) CLL patients after four compared to 4/6 (66.7%) after three vaccinations. The median number of SARS-CoV-2 spike-specific T cells after repeated booster vaccination plus infection was 166 spot-forming cells (SFC) per million peripheral blood mononuclear cells. Overall, 5/5 (100%) studied patients showed a detectable increase in T cell activity., Conclusion: Our data reveal an increase of cellular and humoral immune response in CLL patients after fourth COVID-19 vaccination combined with SARS-CoV-2 infection, even in those undergoing B cell-depleting treatment. Patients with prior vaccination failure now show a specific IgG response. Future research should explore the duration and effectiveness of hybrid immunity considering various factors like past infection and vaccination rates, types and numbers of doses, and emerging variants., (© 2024 The Authors. European Journal of Haematology published by John Wiley & Sons Ltd.)
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- 2024
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31. Cardiotoxicity in patients treated with acalabrutinib.
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Langerbeins P
- Subjects
- Humans, Death, Sudden, Arrhythmias, Cardiac chemically induced, Cardiotoxicity etiology, Benzamides adverse effects
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- 2022
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32. SARS-CoV-2-specific cellular response following third COVID-19 vaccination in patients with chronic lymphocytic leukemia.
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Mellinghoff SC, Mayer L, Robrecht S, Weskamm LM, Dahlke C, Gruell H, Schlotz M, Vanshylla K, Schloser HA, Thelen M, Fink AM, Fischer K, Klein F, Addo MM, Eichhorst B, Hallek M, and Langerbeins P
- Subjects
- Antibodies, Viral, COVID-19 Vaccines, Humans, SARS-CoV-2, Vaccination, COVID-19 prevention & control, Leukemia, Lymphocytic, Chronic, B-Cell complications
- Published
- 2022
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33. Obinutuzumab, acalabrutinib, and venetoclax, after an optional debulking with bendamustine in relapsed or refractory chronic lymphocytic leukaemia (CLL2-BAAG): a multicentre, open-label, phase 2 trial.
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Cramer P, Fürstenau M, Robrecht S, Giza A, Zhang C, Fink AM, Fischer K, Langerbeins P, Al-Sawaf O, Tausch E, Schneider C, Schetelig J, Dreger P, Böttcher S, Kreuzer KA, Schilhabel A, Ritgen M, Brüggemann M, Kneba M, Stilgenbauer S, Eichhorst B, and Hallek M
- Subjects
- Antibodies, Monoclonal, Humanized, Antineoplastic Combined Chemotherapy Protocols adverse effects, Bendamustine Hydrochloride adverse effects, Benzamides, Bridged Bicyclo Compounds, Heterocyclic, Cytoreduction Surgical Procedures, Female, Humans, Male, Neoplasm, Residual, Proto-Oncogene Proteins c-bcl-2, Pyrazines, Sulfonamides, Antineoplastic Agents therapeutic use, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Leukemia, Lymphocytic, Chronic, B-Cell pathology
- Abstract
Background: Although BTK inhibitors provide long-term disease-control in patients with chronic lymphocytic leukaemia, they need to be combined with BCL2 inhibitors or antibodies to achieve deep responses with undetectable minimal residual disease (uMRD), which allows for time-limited treatment. This trial aims to evaluate the triple combination of obinutuzumab, acalabrutinib, and venetoclax after an optional debulking with bendamustine., Methods: This multicentre, open-label, investigator-initiated, phase 2 study evaluates a sequential treatment consisting of a debulking with two cycles of bendamustine for patients with a higher tumour load (70 mg/m
2 intravenously on days 1 and 2, repeated after 28 days), followed by an induction and a maintenance with obinutuzumab (1000 mg intravenously on days 1-2, 8, and 15 of the first induction cycle, every 4 weeks in induction cycles 2-6 and every 12 weeks in the maintenance phase), acalabrutinib (100 mg orally twice daily continuously from induction cycle 2 day 1 onwards) and venetoclax (starting in induction cycle 3 with 20 mg per day with a weekly dose ramp-up over 5 weeks to the target dose of 400 mg per day). Eligible patients were aged 18 years or older with an ECOG performance score 0-2 and had relapsed or refractory chronic lymphocytic leukaemia requiring treatment according to the 2018 International Workshop on Chronic Lymphocytic Leukemia criteria. The primary endpoint was uMRD (<10-4 ) in peripheral blood at the end of induction treatment assessed centrally at the final restaging, 12 weeks after the start of the last induction cycle. As per protocol, all patients with more than two induction cycles were included in the analyses. This study is registered with ClinicalTrials.gov, number NCT03787264, and is ongoing., Findings: Between Jan 14, 2019, and June 25, 2020, 45 evaluable patients with relapsed or refractory chronic lymphocytic leukaemia were enrolled; 13 (29%) were female, 32 (71%) were male, 21 (47%) had already received a targeted agent, and 14 (32%) had del(17)(p13.1) or TP53 mutation. Ethnicity-race data was not collected. At data cutoff (Feb 25, 2021), all patients had completed the induction treatment. 34 patients (76%; 95% CI 61-87, p=0·26) had uMRD in peripheral blood after 6 months of triple therapy. Until data cutoff, 32 (71%) patients started maintenance and nine (28%) were able to stop with uMRD. After a median observation time of 13·8 months (IQR 10·4-18·4), there were two (4%) Richter transformations, but no progressions and no deaths observed. The most common adverse events of grade 3 and 4 during the entire treatment were thrombocytopenia and neutropenia (12 [27%] of 45 patients each), tumour lysis syndrome and infections (five [11%] of 45 patients each, grade 3 adverse events only), infusion-associated reactions (four [9%] of 45 patients) and anaemia (four [9%] of 45 patients)., Interpretation: With 76% of patients achieving uMRD in peripheral blood, this trial did not reach the prespecified activity threshold. Triple therapy with obinutuzumab, acalabrutinib, and venetoclax after an optional debulking with bendamustine regimen requires further evaluation in larger trials to define its value compared with double treatment with a BTK or BCL2 inhibitor combined with obinutuzumab or a combination of the two oral targeted drugs. Until these trials show a clear benefit, the use of the triple combination in routine practice cannot be recommended., Funding: Acerta, AstraZeneca, F Hoffmann-La Roche, and AbbVie., Competing Interests: Declaration of interests PC reports research funding from Acerta, AstraZeneca, Beigene, F Hoffmann-LaRoche, Gilead, Janssen-Cilag and Novartis, honoraria for scientific talks from AbbVie, AstraZeneca, F Hoffmann-LaRoche and Janssen-Cilag, advisory boards at AbbVie, AstraZeneca, and BeiGene, travel grants from AbbVie, AstraZeneca, F Hoffmann LaRoche, and Janssen-Cilag. SR reports honoraria from AstraZeneca. A-MF reports research funding from AstraZeneca and Celgene (Bristol Myers Squibb) and travel grants from AbbVie. KF reports honoraria, consulting, and advisory board from AbbVie and F Hoffmann-LaRoche, and travel grants from F Hoffmann-LaRoche. PL reports research funding, travel grants, and honoraria from AbbVie, F Hoffmann-LaRoche, and Janssen-Cilag. OA-S reports consultant or advisory board member, honoraria, and personal fees from AbbVie, Adaptive, AstraZeneca, BeiGene, Janssen, Gilead, and Roche, and research support from AbbVie, BeiGene, Janssen, and Roche. ET reports consultant or advisory board member, honoraria, and research support from AbbVie, Janssen-Cilag, and Roche. JS reports lecture fees and advisory board member honoraria from AbbVie, AstraZeneca, BeiGene, Janssen, Roche, and Gilead. PD reports a consultancy for AbbVie, AstraZeneca, Gilead, Janssen, Novartis, Riemser, and Roche, speakers bureau for AbbVie, Gilead, Novartis, Riemser, and Roche, and research support from Neovii and Riemser. SB reports honoraria from AbbVie, AstraZeneca, F Hoffmann-LaRoche, Janssen-Cilag, and Sanofi, and research support by Janssen-Cilag Neuss (to Institution). K-AK reports consultant or advisory board member, honoraria, paid expert testimony, speakers bureau, and research support from AbbVie, Amgen, Celgene, F Hoffmann-LaRoche, Gilead, Janssen-Cilag and Mundipharma. MR reports consultancy payments from AbbVie, Chugai, F Hoffmann-LaRoche, MSD, research funding from AbbVie, F Hoffmann-LaRoche and, travel grants from AbbVie, Celgene, F Hoffmann-LaRoche, and MSD. MB was a consultant or advisory board member at, or reports research support, or travel support from Affimed, Amgen, Incyte, Janssen, Regeneron. SS was a consultant or advisory board member at, or reports research support, and travel support from AbbVie, Amgen, Boehringer-Ingelheim, Celgene, F Hoffmann-LaRoche, Genentech, Genzyme, Gilead, GlaxoSmithKline, Janssen-Cilag, Mundipharma, Novartis, Pharmacyclics, and Sunesis. BE was a consultant or advisory board member at, or reports research support, or travel support from AbbVie, AstraZeneca, and F Hoffmann-LaRoche. MH was a consultant or advisory board member at, or reports honoraria and research support from AbbVie, Amgen, Celgene, F Hoffmann-LaRoche, Gilead, Janssen-Cilag and Mundipharma. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)- Published
- 2022
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34. COVID-19 in patients with hematologic malignancy.
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Langerbeins P and Hallek M
- Subjects
- Antiviral Agents, COVID-19 Vaccines therapeutic use, Humans, SARS-CoV-2, COVID-19, Communicable Diseases, Hematologic Neoplasms complications, Hematologic Neoplasms therapy
- Abstract
The coronavirus infectious disease (COVID-19) shows a remarkable symptomatic heterogeneity. Several risk factors including advanced age, previous illnesses, and a compromised immune system contribute to an unfavorable outcome. In patients with hematologic malignancy, the immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is significantly reduced explaining why the mortality rate of hematologic patients hospitalized for a SARS-CoV-2 infection is about 34%. Active immunization is an essential pillar to prevent SARS-CoV-2 infections in patients with hematologic malignancy. However, the immune response to SARS-CoV-2 vaccines may be significantly impaired, as only half of patients with hematologic malignancy develop a measurable antiviral antibody response. The subtype of hematologic malignancy and B cell-depleting treatment predict a poor immune response to vaccination. Recently, antiviral drugs and monoclonal antibodies for pre-exposure or postexposure prophylaxis and for early treatment of COVID-19 have become available. These therapies should be offered to patients at high risk for severe COVID-19 and vaccine nonresponders. Importantly, as the virus evolves, some therapies may lose their clinical efficacy against new variants. Therefore, the ongoing pandemic will remain a major challenge for patients with hematologic malignancy and their caregivers who need to constantly monitor the scientific progress in this area., (© 2022 by The American Society of Hematology.)
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- 2022
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35. The CLL12 trial: ibrutinib vs placebo in treatment-naïve, early-stage chronic lymphocytic leukemia.
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Langerbeins P, Zhang C, Robrecht S, Cramer P, Fürstenau M, Al-Sawaf O, von Tresckow J, Fink AM, Kreuzer KA, Vehling-Kaiser U, Tausch E, Müller L, Eckart MJ, Schlag R, Freier W, Gaska T, Balser C, Reiser M, Stauch M, Wendtner CM, Fischer K, Stilgenbauer S, Eichhorst B, and Hallek M
- Subjects
- Adenine adverse effects, Adenine therapeutic use, Adult, Aged, Aged, 80 and over, Disease Progression, Double-Blind Method, Female, Humans, Kaplan-Meier Estimate, Leukemia, Lymphocytic, Chronic, B-Cell diagnosis, Leukemia, Lymphocytic, Chronic, B-Cell pathology, Male, Middle Aged, Piperidines adverse effects, Placebo Effect, Protein Kinase Inhibitors adverse effects, Adenine analogs & derivatives, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Piperidines therapeutic use, Protein Kinase Inhibitors therapeutic use
- Abstract
Observation is the current standard of care for patients with early-stage asymptomatic chronic lymphocytic leukemia (CLL), as chemotherapy-based interventions have failed to prolong survival. We hypothesized that early intervention with ibrutinib would be well tolerated and lead to superior disease control in a subgroup of early-stage patients with CLL. The phase 3, double-blind, placebo-controlled CLL12 trial randomly assigned asymptomatic, treatment-naïve Binet stage A CLL patients at increased risk of progression in a 1:1 ratio to receive ibrutinib (n = 182) or placebo (n = 181) at a dose of 420 mg daily. At a median follow-up of 31 months, the study met its primary endpoint by significantly improving event-free survival in the ibrutinib group (median, not reached vs 47.8 months; hazard ratio = 0.25; 95% confidence interval = 0.14-0.43, P < .0001). Compared with placebo, ibrutinib did not increase overall toxicity, yielding similar incidence and severity of adverse events (AEs). The most common serious AEs were atrial fibrillation, pneumonia, and rash in the ibrutinib group, and basal cell carcinoma, pneumonia, and myocardial infarction in the placebo group. Ibrutinib-associated risk for bleeding (33.5%) was decreased by prohibiting the use of oral anticoagulants through an amendment of the study protocol and by avoiding CYP3A4 drug-drug interactions. Ibrutinib confirms efficacy in CLL patients at an early stage with an increased risk of progression. However, the results do not justify changing the current standard of "watch and wait." This trial was registered at www.clinicaltrials.gov as #NCT02863718., (© 2022 by The American Society of Hematology.)
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- 2022
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36. Durable remissions following combined targeted therapy in patients with CLL harboring TP53 deletions and/or mutations.
- Author
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Cramer P, Tausch E, von Tresckow J, Giza A, Robrecht S, Schneider C, Fürstenau M, Langerbeins P, Al-Sawaf O, Pelzer BW, Fink AM, Fischer K, Wendtner CM, Eichhorst B, Kneba M, Stilgenbauer S, and Hallek M
- Subjects
- Adenine therapeutic use, Adult, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Female, Gene Deletion, Humans, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Male, Middle Aged, Mutation drug effects, Progression-Free Survival, Prospective Studies, Adenine analogs & derivatives, Antibodies, Monoclonal, Humanized therapeutic use, Bendamustine Hydrochloride therapeutic use, Bridged Bicyclo Compounds, Heterocyclic therapeutic use, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Piperidines therapeutic use, Sulfonamides therapeutic use, Tumor Suppressor Protein p53 genetics
- Abstract
Fifty-one of 189 evaluable patients from 3 prospective phase 2 trials evaluating a sequential targeted treatment had high-risk chronic lymphocytic leukemia (CLL) with a 17p deletion, TP53 mutation, or both. Twenty-seven patients started treatment with bendamustine debulking before induction and maintenance treatment, which was ibrutinib/ofatumumab (IO) in 21 patients, ibrutinib/obinutuzumab (IG) in 13, and venetoclax/obinutuzumab (AG) in 17. The primary end point was overall response rate after 8 months of induction treatment, which was 81%, 100%, and 94% for IO, IG, and AG, respectively. Minimal residual disease (MRD) was undetectable (uMRD) in peripheral blood (<10-4 by flow cytometry) in 0%, 23%, and 82% of patients, respectively. Median progression-free survival (PFS) was 45 months. Seventeen patients discontinued maintenance treatment due to uMRD: 9 progressed, 2 died without progression (median PFS, 28 months after discontinuation of treatment), and 6 remained in remission after a median observation time of 46 months (range, 6-47 months) after treatment discontinuation. Thus, MRD-guided fixed-duration therapies combining obinutuzumab with venetoclax or ibrutinib can induce deep and durable remissions in CLL patients with high-risk genetic lesions, which can persist after treatment discontinuation (due to a predefined fixed-duration or MRD-guided early termination). The median PFS was 45 months. These trials were registered at www.clinicaltrials.gov as #NCT02345863, #NCT02401503, and #NCT02689141., (© 2021 by The American Society of Hematology.)
- Published
- 2021
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37. Bendamustine, followed by ofatumumab and ibrutinib in chronic lymphocytic leukemia (CLL2-BIO): primary endpoint analysis of a multicenter, open-label phase-II trial.
- Author
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Cramer P, Tresckow JV, Robrecht S, Bahlo J, Fürstenau M, Langerbeins P, Pflug N, Al-Sawaf O, Heinz WJ, Vehling-Kaiser U, Dürig J, Tausch E, Hensel M, Sasse S, Fink AM, Fischer K, Kreuzer KA, Böttcher S, Ritgen M, Kneba M, Wendtner CM, Stilgenbauer S, Eichhorst B, and Hallek M
- Subjects
- Adenine analogs & derivatives, Antibodies, Monoclonal, Humanized, Antineoplastic Combined Chemotherapy Protocols adverse effects, Bendamustine Hydrochloride, Humans, Piperidines, Treatment Outcome, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Leukemia, Lymphocytic, Chronic, B-Cell genetics
- Abstract
The introduction of targeted agents has revolutionized the treatment of chronic lymphocytic leukemia but only few patients achieve complete remissions and minimal residual disease negativity with ibrutinib monotherapy. This multicenter, investigator-initiated phase-II study evaluates a sequential treatment with two cycles of bendamustine debulking for patients with a higher tumor load, followed by ofatumumab and ibrutinib induction and maintenance treatment. An all-comer population, irrespective of prior treatment, physical fitness and genetic factors was included. The primary endpoint was the investigator assessed overall response rate at the end of induction treatment. Of 66 patients enrolled, one patient with early treatment discontinuation was excluded from the efficacy analysis as predefined by the protocol. Thirty-nine patients (60%) were treatment-naive and 26 patients (40%) had relapsed/refractory CLL, 21 patients (32%) had a del(17p) and/or TP53 mutation and 45 patients (69%) had an unmutated IGHV status. At the end of the induction, 60 of 65 patients (92%) responded and 9 (14%) achieved minimal residual disease negativity (<10-4) in peripheral blood. No unexpected or cumulative toxicities occurred, most common CTC °III/IV adverse events were neutropenias, anaemia, infusion-related reactions, and diarrhoea. This sequential treatment of bendamustine debulking, followed by ofatumumab and ibrutinib was well tolerated without unexpected safety signals and showed a good efficacy with an overall response rate of 92%. Ongoing maintenance treatment aims at deeper responses with minimal residual disease negativity. However, ibrutinib should still be used as a single agent outside clinical trials. Clinicaltrials.gov number: NCT02689141.
- Published
- 2021
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38. Immune Dysfunction in Patients with Chronic Lymphocytic Leukemia and Challenges during COVID-19 Pandemic.
- Author
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Langerbeins P and Eichhorst B
- Subjects
- COVID-19 complications, COVID-19 pathology, COVID-19 therapy, COVID-19 virology, Humans, Immunization, Passive, Immunocompromised Host, Immunotherapy, Leukemia, Lymphocytic, Chronic, B-Cell complications, Leukemia, Lymphocytic, Chronic, B-Cell immunology, Leukemia, Lymphocytic, Chronic, B-Cell pathology, Palliative Care, Pandemics, Protein Kinase Inhibitors therapeutic use, SARS-CoV-2 isolation & purification, COVID-19 Serotherapy, COVID-19 epidemiology, Leukemia, Lymphocytic, Chronic, B-Cell therapy
- Abstract
The novel severe acute respiratory syndrome coronavirus (SARS-CoV-2) has been first described in December 2019 in Wuhan, China, and has led to a worldwide pandemic ever since. Initial clinical data imply that cancer patients are particularly at risk for a severe course of SARS-CoV-2. In patients with chronic lymphocytic leukemia (CLL), infections are a main contributor to morbidity and mortality driven by an impaired immune system. Treatment initiation is likely to induce immune modulation that further increases the risk for severe infections. This article aims to give an overview on pathogenesis and risk of infectious complications in patients with CLL. In this context, we discuss current data of SARS-CoV-2 infections in patients with CLL and how the pandemic impacts their management., (© 2021 S. Karger AG, Basel.)
- Published
- 2021
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39. COVID-19 complicated by parainfluenza co-infection in a patient with chronic lymphocytic leukemia.
- Author
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Langerbeins P, Fürstenau M, Gruell H, Klein F, Persigehl T, Rybniker J, Seeger-Nukpezah T, Kochanek M, Hallek M, Eichhorst B, Koehler P, and Böll B
- Subjects
- Antibodies, Viral blood, COVID-19 immunology, COVID-19 therapy, Humans, IgG Deficiency complications, IgG Deficiency immunology, IgG Deficiency therapy, Immunoglobulins, Intravenous therapeutic use, Leukemia, Lymphocytic, Chronic, B-Cell immunology, Leukemia, Lymphocytic, Chronic, B-Cell therapy, Male, Middle Aged, Pandemics, SARS-CoV-2 immunology, Spike Glycoprotein, Coronavirus immunology, COVID-19 complications, Coinfection complications, Leukemia, Lymphocytic, Chronic, B-Cell complications, Paramyxoviridae Infections complications
- Abstract
The number of people suffering from the new coronavirus SARS-CoV-2 continues to rise. In SARS-CoV-2, superinfection with bacteria or fungi seems to be associated with increased mortality. The role of co-infections with respiratory viral pathogens has not yet been clarified. Here, we report the course of COVID-19 in a CLL patient with secondary immunodeficiency and viral co-infection with parainfluenza., (© 2020 The Authors. European Journal of Haematology published by John Wiley & Sons Ltd.)
- Published
- 2020
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40. International prognostic score for asymptomatic early-stage chronic lymphocytic leukemia.
- Author
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Condoluci A, Terzi di Bergamo L, Langerbeins P, Hoechstetter MA, Herling CD, De Paoli L, Delgado J, Rabe KG, Gentile M, Doubek M, Mauro FR, Chiodin G, Mattsson M, Bahlo J, Cutrona G, Kotaskova J, Deambrogi C, Smedby KE, Spina V, Bruscaggin A, Wu W, Moia R, Bianchi E, Gerber B, Zucca E, Gillessen S, Ghielmini M, Cavalli F, Stussi G, Hess MA, Baumann TS, Neri A, Ferrarini M, Rosenquist R, Forconi F, Foà R, Pospisilova S, Morabito F, Stilgenbauer S, Döhner H, Parikh SA, Wierda WG, Montserrat E, Gaidano G, Hallek M, and Rossi D
- Subjects
- Aged, Combined Modality Therapy, Disease Progression, Female, Follow-Up Studies, Humans, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Leukemia, Lymphocytic, Chronic, B-Cell therapy, Male, Prognosis, Retrospective Studies, Survival Rate, Biomarkers, Tumor genetics, Clinical Trials as Topic statistics & numerical data, Leukemia, Lymphocytic, Chronic, B-Cell pathology, Mutation, Nomograms
- Abstract
Most patients with chronic lymphocytic leukemia (CLL) are diagnosed with early-stage disease and managed with active surveillance. The individual course of patients with early-stage CLL is heterogeneous, and their probability of needing treatment is hardly anticipated at diagnosis. We aimed at developing an international prognostic score to predict time to first treatment (TTFT) in patients with CLL with early, asymptomatic disease (International Prognostic Score for Early-stage CLL [IPS-E]). Individual patient data from 11 international cohorts of patients with early-stage CLL (n = 4933) were analyzed to build and validate the prognostic score. Three covariates were consistently and independently correlated with TTFT: unmutated immunoglobulin heavy variable gene (IGHV), absolute lymphocyte count higher than 15 × 109/L, and presence of palpable lymph nodes. The IPS-E was the sum of the covariates (1 point each), and separated low-risk (score 0), intermediate-risk (score 1), and high-risk (score 2-3) patients showing a distinct TTFT. The score accuracy was validated in 9 cohorts staged by the Binet system and 1 cohort staged by the Rai system. The C-index was 0.74 in the training series and 0.70 in the aggregate of validation series. By meta-analysis of the training and validation cohorts, the 5-year cumulative risk for treatment start was 8.4%, 28.4%, and 61.2% among low-risk, intermediate-risk, and high-risk patients, respectively. The IPS-E is a simple and robust prognostic model that predicts the likelihood of treatment requirement in patients with early-stage CLL. The IPS-E can be useful in clinical management and in the design of early intervention clinical trials., (© 2020 by The American Society of Hematology.)
- Published
- 2020
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41. Rapid response infrastructure for pandemic preparedness in a tertiary care hospital: lessons learned from the COVID-19 outbreak in Cologne, Germany, February to March 2020.
- Author
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Augustin M, Schommers P, Suárez I, Koehler P, Gruell H, Klein F, Maurer C, Langerbeins P, Priesner V, Schmidt-Hellerau K, Malin JJ, Stecher M, Jung N, Wiesmüller G, Meissner A, Zweigner J, Langebartels G, Kolibay F, Suárez V, Burst V, Valentin P, Schedler D, Cornely OA, Hallek M, Fätkenheuer G, Rybniker J, and Lehmann C
- Subjects
- Adult, Betacoronavirus, COVID-19, Germany epidemiology, Humans, Middle Aged, Pandemics, Risk Assessment, SARS-CoV-2, Tertiary Care Centers, Triage, Civil Defense organization & administration, Coronavirus, Coronavirus Infections epidemiology, Disease Outbreaks, Patient Care Management, Pneumonia, Viral epidemiology
- Abstract
The coronavirus disease (COVID-19) pandemic has caused tremendous pressure on hospital infrastructures such as emergency rooms (ER) and outpatient departments. To avoid malfunctioning of critical services because of large numbers of potentially infected patients seeking consultation, we established a COVID-19 rapid response infrastructure (CRRI), which instantly restored ER functionality. The CRRI was also used for testing of hospital personnel, provided epidemiological data and was a highly effective response to increasing numbers of suspected COVID-19 cases.
- Published
- 2020
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42. Mode of progression after first line treatment correlates with outcome of chronic lymphocytic leukemia (CLL).
- Author
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Al-Sawaf O, Bazeos A, Robrecht S, Bahlo J, Gower C, Fink AM, Tresckow J, Cramer P, Langerbeins P, Kutsch N, Humphrey K, Fingerle-Rowson G, Stilgenbauer S, Wendtner CM, Fischer K, Eichhorst B, Hallek M, and Goede V
- Subjects
- Aged, Disease Progression, Disease-Free Survival, Female, Humans, Leukemia, Lymphocytic, Chronic, B-Cell blood, Leukemia, Lymphocytic, Chronic, B-Cell pathology, Male, Middle Aged, Survival Rate, Immunotherapy, Leukemia, Lymphocytic, Chronic, B-Cell mortality, Leukemia, Lymphocytic, Chronic, B-Cell therapy
- Abstract
In CLL, progressive disease (PD) following remission after first line treatment can present with varying phenotypes. We hypothesized that the mode of PD correlates with clinical outcomes. Data from three phase III trials of the German CLL Study Group (GCLLSG) (CLL8, CLL10, CLL11) including a total of 2159 patients receiving first line (immuno)-chemotherapy (FCR, FC, CLB, CLB-R, CLB-Ob) were analyzed. Patients were categorized as "ALC" if PD was due to increasing absolute lymphocyte count, or as "Ly" if due to lymphadenopathy. A group of 241 patients progressed with ALC, and 727 progressed with Ly, including 329 who progressed on both modalities. In fit patients, median TTNT after PD in the Ly group was 12.3 months vs 17.0 months in the ALC group (HR 1.299 [1.036-1.628]; P = .024). Median OS after PD was 45.1 months in the Ly group and 42.4 months in the ALC group (HR=1.023 [0.753-1.389]; P = .885). For unfit patients, median TTNT in the Ly group was 11.7 months vs 21.4 months in the ALC group (HR 1.357 [1.051-1.753]; P = .019). Median OS was 42.8 months in the Ly group and not reached in the ALC group (HR 1.851 [1.280-2.677]; P = .001). Patients in the Ly group more frequently showed impairment of quality of life (QoL). This analysis demonstrates that patients with progressive lymphadenopathy have a significantly shorter TTNT, OS and less favorable QoL. Our findings might help physicians to better estimate the clinical course of a progressing CLL patient., (© 2019 Wiley Periodicals, Inc.)
- Published
- 2019
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43. Outcome of patients aged 80 years or older treated for chronic lymphocytic leukaemia.
- Author
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Al-Sawaf O, Bahlo J, Robrecht S, Fischer K, Herling CD, Hoechstetter M, Fink AM, von Tresckow J, Langerbeins P, Cramer P, Stilgenbauer S, Wendtner CM, Eichhorst B, Hallek M, and Goede V
- Subjects
- Aged, 80 and over, Cause of Death, Clinical Trials, Phase III as Topic, Combined Modality Therapy, Disease-Free Survival, Germany epidemiology, Hematologic Diseases chemically induced, Humans, Immunotherapy methods, Infections chemically induced, Leukemia, Lymphocytic, Chronic, B-Cell mortality, Neoplasms, Second Primary mortality, Treatment Outcome, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy
- Abstract
Clinical management of chronic lymphocytic leukaemia (CLL) in patients aged ≥80 years is based on limited evidence due to the lack of published information. Therefore, we analysed CLL patients aged ≥80 years using data from seven phase III clinical trials of the German CLL Study Group. Among 3552 participants, 152 were ≥80 years old at initiation of first-line study treatment. Median age was 82 years (range 80-90). Concomitant diseases were present in 99% of the patients, with a median cumulative illness rating scale score of 8 (0-18). Chemoimmunotherapy with chlorambucil-obinutuzumab (CLB-OB) or chlorambucil-rituximab (CLB-R) was administered to 61 (40%) and 56 (37%) patients. The remaining patients received CLB (n = 19) or fludarabine (F, n = 10), F/cyclophosphamide (FC, n = 1), FC/rituximab (FCR, n = 2) or bendamustine/rituximab (BR, n = 3). Rates of grade 3 or 4 neutropenia and infections were 35% and 13%. Overall response rate was 77% with 13% complete remissions. Median progression-free survival and treatment-free survival were 17·2 and 32·3 months, respectively. Median overall survival was 48·3 months; adverse events (22%) and progressive CLL (16·4%) were the most frequent causes of death. These findings suggest that anti-leukaemic treatment including chemoimmunotherapy is feasible and efficacious in ≥80-year-old CLL patients. However, this group of patients lives for a shorter time than age-matched controls of the general population., (© 2018 British Society for Haematology and John Wiley & Sons Ltd.)
- Published
- 2018
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44. Bendamustine followed by obinutuzumab and venetoclax in chronic lymphocytic leukaemia (CLL2-BAG): primary endpoint analysis of a multicentre, open-label, phase 2 trial.
- Author
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Cramer P, von Tresckow J, Bahlo J, Robrecht S, Langerbeins P, Al-Sawaf O, Engelke A, Fink AM, Fischer K, Tausch E, Seiler T, Fischer von Weikersthal L, Hebart H, Kreuzer KA, Böttcher S, Ritgen M, Kneba M, Wendtner CM, Stilgenbauer S, Eichhorst B, and Hallek M
- Subjects
- Aged, Antibodies, Monoclonal, Humanized adverse effects, Antineoplastic Combined Chemotherapy Protocols adverse effects, Bendamustine Hydrochloride adverse effects, Bridged Bicyclo Compounds, Heterocyclic adverse effects, Drug Administration Schedule, Female, Germany, Humans, Leukemia, Lymphocytic, Chronic, B-Cell mortality, Leukemia, Lymphocytic, Chronic, B-Cell pathology, Male, Middle Aged, Prospective Studies, Sulfonamides adverse effects, Time Factors, Treatment Outcome, Antibodies, Monoclonal, Humanized administration & dosage, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Bendamustine Hydrochloride administration & dosage, Bridged Bicyclo Compounds, Heterocyclic administration & dosage, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Sulfonamides administration & dosage
- Abstract
Background: Targeted agents such as the type II anti-CD20 antibody obinutuzumab and the B-cell lymphoma-2 antagonist venetoclax have shown impressive therapeutic activity in chronic lymphocytic leukaemia. The CLL2-BAG trial was initiated to investigate the combination of these two agents in patients with chronic lymphocytic leukaemia., Methods: In this ongoing multicentre, open-label, investigator-initiated phase 2 trial, patients (aged ≥18 years) with chronic lymphocytic leukaemia requiring treatment according to the 2008 International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria and an Eastern Cooperative Oncology Group performance status of 0-2 were enrolled at 16 sites in Germany. Patients with a relevant tumour load (absolute lymphocyte count ≥25 000 cells per μL or lymph nodes with a diameter of ≥5 cm) received sequential treatment of debulking with two cycles of bendamustine (70 mg/m
2 intravenously on days 1 and 2 of each of the two 28-day cycles), followed by induction and maintenance with obinutuzumab (1000 mg intravenously on days 1-2, 8, and 15 of the first induction cycle, every 4 weeks in induction cycles 2-6, and every 12 weeks in the maintenance phase) and oral venetoclax (starting in induction cycle 2 with 20 mg/day, with a weekly dose escalation over 5 weeks to the target dose of 400 mg/day). The primary endpoint was the proportion of patients achieving an overall response by investigator assessment at the end of induction treatment. All patients who received at least two induction cycles were included in the efficacy analyses and all patients who received at least one dose of study drug were included in the safety analyses. This study is registered with ClinicalTrials.gov, number NCT02401503., Findings: Between May 6, 2015, and Jan 4, 2016, 66 patients were enrolled (35 treatment naive and 31 with relapsed or refractory disease), three of whom were excluded from the efficacy analysis because they received fewer than two induction cycles. Of the remaining 63 patients in the efficacy-evaluable population, 34 patients (54%) were treatment naive and 29 (46%) had relapsed or refractory disease. At data cutoff (Feb 28, 2017), all patients had completed induction treatment. At the end of the induction, 60 (95%) of 63 patients (95% CI 87-99) had responded, including all 34 patients in the treatment-naive cohort and 26 [90%] of 29 relapsed or refractory patients. The most common grade 3-4 adverse events during debulking were neutropenia and anaemia (five [11%] of 47 patients each), and thrombocytopenia and infection (three [6%] each). The most common grade 3-4 adverse events during induction were neutropenia (29 [44%] of 66 patients), infection (nine [14%]), thrombocytopenia (eight [12%]), infusion-related reactions (five [8%]), and secondary primary malignancy (four [6%]). 89 serious adverse events, including 69 related to study treatment, were reported. These serious adverse events were also mainly infections (four cases in four patients during debulking and 18 cases in 11 patients during induction) and cytopenia (four cases in four patients during debulking and ten cases in seven patients in induction). Five relapsed or refractory patients died: three cases of sepsis were deemed related to study treatment, whereas two deaths from Richter's transformation were not., Interpretation: The sequential application of bendamustine and obinutuzumab combined with venetoclax caused no unexpected or cumulative toxicities. The high proportion of patients who achieved overall responses, both treatment-naive and relapsed or refractory patients irrespective of physical fitness and genetic risk factors, compare favourably to established chronic lymphocytic leukaemia therapies. Further follow-up will help to define whether the remissions with eradication of minimal residual disease achieved with this combination are durable after treatment discontinuation., Funding: F Hoffmann-La Roche and AbbVie., (Copyright © 2018 Elsevier Ltd. All rights reserved.)- Published
- 2018
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45. CLL2-BXX Phase II trials: sequential, targeted treatment for eradication of minimal residual disease in chronic lymphocytic leukemia.
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Cramer P, von Tresckow J, Bahlo J, Engelke A, Langerbeins P, Fink AM, Fischer K, Wendtner CM, Kreuzer KA, Stilgenbauer S, Böttcher S, Eichhorst B, and Hallek M
- Subjects
- Antibodies, Monoclonal administration & dosage, Antibodies, Monoclonal, Humanized administration & dosage, Antineoplastic Combined Chemotherapy Protocols adverse effects, Bendamustine Hydrochloride administration & dosage, Bone Marrow pathology, Bridged Bicyclo Compounds, Heterocyclic administration & dosage, Humans, Induction Chemotherapy, Maintenance Chemotherapy, Neoplasm, Residual pathology, Purines administration & dosage, Quinazolinones administration & dosage, Sulfonamides administration & dosage, Treatment Outcome, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Leukemia, Lymphocytic, Chronic, B-Cell pathology, Molecular Targeted Therapy, Neoplasm, Residual drug therapy
- Abstract
Aim: Four Phase II trials (clinical trials numbers: NCT02345863, NCT02401503, NCT02445131 and NCT02689141) evaluate a different combination of targeted agents in an all-comer population of approximately 60 patients with chronic lymphocytic leukemia irrespective of prior treatment, physical fitness and genetic risk factors. Patients with a higher tumor load start with a debulking treatment with bendamustine. The subsequent induction and maintenance treatment with an anti-CD20 antibody (obinutuzumab or ofatumumab) and a targeted oral agent (ibrutinib, idelalisib or venetoclax) are continued until achievement of a complete response and minimal residual disease negativity., Conclusion: This strategy represents a new era of chronic lymphocytic leukemia therapy where chemotherapy is increasingly replaced by targeted agents and treatment duration is tailored to the patient's individual tumor load and response.
- Published
- 2018
- Full Text
- View/download PDF
46. Bendamustine and rituximab in combination with lenalidomide in patients with chronic lymphocytic leukemia.
- Author
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Maurer C, Pflug N, Bahlo J, Kluth S, Rhein C, Cramer P, Gross-Ophoff C, Langerbeins P, Fink AM, Eichhorst B, Kreuzer KA, Fischer N, Tausch E, Stilgenbauer S, Böttcher S, Döhner H, Kneba M, Dreyling M, Binder M, Hallek M, Wendtner CM, Bergmann M, and Fischer K
- Subjects
- Aged, Antineoplastic Combined Chemotherapy Protocols adverse effects, Bendamustine Hydrochloride administration & dosage, Chromosome Aberrations, Drug Administration Schedule, Female, Humans, Lenalidomide, Leukemia, Lymphocytic, Chronic, B-Cell diagnosis, Leukemia, Lymphocytic, Chronic, B-Cell mortality, Male, Maximum Tolerated Dose, Middle Aged, Mutation, Neoplasm Staging, Prognosis, Rituximab administration & dosage, Thalidomide administration & dosage, Thalidomide analogs & derivatives, Treatment Outcome, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy
- Abstract
Purpose: A phase I/II trial to assess safety and efficacy of the combination bendamustine, rituximab, and lenalidomide (BRL) in patients with chronic lymphocytic leukemia (CLL)., Patients and Methods: Seventeen relapsed or refractory (R/R) and five previously untreated (FL) CLL patients were enrolled in the trial. In the R/R cohort, four different dose levels of lenalidomide (maximum 15 mg/d) were used. In the FL cohort, lenalidomide was dose escalated from 5 mg/d to 15 mg/d. Bendamustine was used at doses of 50 or 90 mg/m(2) for R/R or FL treatment, respectively. 375 mg/m(2) Rituximab were used for the first and 500 mg/m(2) for subsequent treatment courses. Treatment consisted of up to six courses of 28 d., Results: The maximal tolerable dose of lenalidomide was 5 mg/d. The response rate was 47.1% in R/R and 60% in FL patients. Median progression-free survival was 8.0 months. Median overall survival was 22.9 and 12.3 months, respectively, in R/R and FL patients. Grade 3/4 hematological toxicity was observed in 71.4%, and severe infections in 47.6% of patients. Due to high toxicity and low response rate of BRL, the trial was closed prematurely., Conclusion: BRL was associated with a high toxicity rate, a high number of treatment interruptions, and a low remission rate. Therefore, BRL cannot be considered an appropriate treatment option for patients with CLL., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
- Published
- 2016
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47. Dose-reduced fludarabine, cyclophosphamide and rituximab (FCR) in older patients with chronic lymphocytic leukemia: does one size fit all?
- Author
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Cramer P, Langerbeins P, Fischer K, Eichhorst B, Hallek M, and Goede V
- Subjects
- Antibodies, Monoclonal therapeutic use, Antibodies, Monoclonal, Murine-Derived therapeutic use, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Humans, Rituximab, Cyclophosphamide therapeutic use, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy
- Published
- 2016
- Full Text
- View/download PDF
48. Long-term remissions after FCR chemoimmunotherapy in previously untreated patients with CLL: updated results of the CLL8 trial.
- Author
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Fischer K, Bahlo J, Fink AM, Goede V, Herling CD, Cramer P, Langerbeins P, von Tresckow J, Engelke A, Maurer C, Kovacs G, Herling M, Tausch E, Kreuzer KA, Eichhorst B, Böttcher S, Seymour JF, Ghia P, Marlton P, Kneba M, Wendtner CM, Döhner H, Stilgenbauer S, and Hallek M
- Subjects
- Adult, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols adverse effects, Combined Modality Therapy, Cyclophosphamide adverse effects, Disease-Free Survival, Female, Follow-Up Studies, Humans, Leukemia, Lymphocytic, Chronic, B-Cell epidemiology, Male, Middle Aged, Remission Induction, Rituximab adverse effects, Treatment Outcome, Vidarabine administration & dosage, Vidarabine adverse effects, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Cyclophosphamide administration & dosage, Immunotherapy adverse effects, Immunotherapy methods, Leukemia, Lymphocytic, Chronic, B-Cell therapy, Rituximab administration & dosage, Vidarabine analogs & derivatives
- Abstract
Despite promising results with targeted drugs, chemoimmunotherapy with fludarabine, cyclophosphamide (FC), and rituximab (R) remains the standard therapy for fit patients with untreated chronic lymphocytic leukemia (CLL). Herein, we present the long-term follow-up of the randomized CLL8 trial reporting safety and efficacy of FC and FCR treatment of 817 treatment-naïve patients with CLL. The primary end point was progression-free survival (PFS). With a median follow-up of 5.9 years, median PFS were 56.8 and 32.9 months for the FCR and FC group (hazard ratio [HR], 0.59; 95% confidence interval [CI], 0.50-0.69, P < .001). Median overall survival (OS) was not reached for the FCR group and was 86.0 months for the FC group (HR, 0.68; 95% CI, 0.54-0.89, P = .001). In patients with mutated IGHV (IGHV MUT), FCR improved PFS and OS compared with FC (PFS: HR, 0.47; 95% CI, 0.33-0.68, P < .001; OS: HR, 0.62; 95% CI, 0.34-1.11, P = .1). This improvement remained applicable for all cytogenetic subgroups other than del(17p). Long-term safety analyses showed that FCR had a higher rate of prolonged neutropenia during the first year after treatment (16.6% vs 8.8%; P = .007). Secondary malignancies including Richter's transformation occurred in 13.1% in the FCR group and in 17.4% in the FC group (P = .1). First-line chemoimmunotherapy with FCR induces long-term remissions and highly relevant improvement in OS in specific genetic subgroups of fit patients with CLL, in particular those with IGHV MUT. This trial was registered at www.clinicaltrials.gov as #NCT00281918., (© 2016 by The American Society of Hematology.)
- Published
- 2016
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49. Advances in first-line treatment of chronic lymphocytic leukemia: current recommendations on management and first-line treatment by the German CLL Study Group (GCLLSG).
- Author
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Cramer P, Langerbeins P, Eichhorst B, and Hallek M
- Subjects
- Aged, Aged, 80 and over, Bendamustine Hydrochloride therapeutic use, Chromosome Deletion, Chromosomes, Human, Pair 17 genetics, Chromosomes, Human, Pair 17 metabolism, Cyclophosphamide therapeutic use, Female, Germany, Humans, Leukemia, Lymphocytic, Chronic, B-Cell diagnosis, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Leukemia, Lymphocytic, Chronic, B-Cell metabolism, Male, Practice Guidelines as Topic, Rituximab therapeutic use, Tumor Suppressor Protein p53 genetics, Tumor Suppressor Protein p53 metabolism, Vidarabine analogs & derivatives, Vidarabine therapeutic use, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy
- Abstract
The management of patients with CLL is undergoing significant changes; during the last decade, the outcome of first-line therapies has been markedly improved with the addition of anti-CD20 antibodies to chemotherapy. Today, chemoimmunotherapy for physically fit patients ≤ 65 years should consist of fludarabine, cyclophosphamide, and rituximab (FCR). The combination of bendamustine and rituximab (BR) should be considered in physically fit patients > 65 years and in patients with a higher risk of infections. Patients with reduced fitness and/or relevant comorbidity should receive chlorambucil with a CD20 antibody, preferably obinutuzumab. Regardless of their fitness, patients with CLL carrying genetic aberrations such as del(17p) and/or TP53 mutation poorly respond to chemoimmunotherapy and therefore require different therapeutic approaches. An increasing understanding of the disease biology has led to the development of targeted drugs for the treatment of CLL, such as the BTK inhibitor ibrutinib and PI3K inhibitor idelalisib. These agents have shown efficacy in high-risk and relapsed/refractory patients and are currently being evaluated in clinical trials for first-line therapy. It is anticipated that these compounds and further other novel agents will profoundly change the therapy of CLL., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
- Published
- 2016
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50. Risk-Adapted Therapy in Early-Stage Chronic Lymphocytic Leukemia.
- Author
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Langerbeins P, Groß-Ophoff-Müller C, and Herling CD
- Subjects
- Animals, Early Detection of Cancer methods, Evidence-Based Medicine, Genetic Markers genetics, Genetic Predisposition to Disease genetics, Humans, Leukemia, Lymphocytic, Chronic, B-Cell diagnosis, Neoplasm Staging, Outcome Assessment, Health Care methods, Polymorphism, Single Nucleotide genetics, Risk Assessment methods, Treatment Outcome, Biomarkers, Tumor genetics, Genetic Testing methods, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Leukemia, Lymphocytic, Chronic, B-Cell therapy, Molecular Diagnostic Techniques methods, Precision Medicine methods
- Abstract
Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults and usually affects the elderly patient. More than 50% of CLL cases are diagnosed at an early disease stage, often as an incidental lymphocytosis found in a routine blood screen. For about 40 years, the classifications according to Binet or Rai have been the hands-on staging systems to stratify patients in daily clinical practice. An increasing molecular understanding of the disease and the identification of strong prognostic markers, such as genetic lesions in TP53, have urged clinical scientists to create new scoring systems that improve prognostic risk assessment and treatment allocation. Until today, studies on early treatment interventions in asymptomatic patients using single chemo- or combined chemoimmunotherapy have failed to demonstrate a survival benefit. However, improved risk stratification tools integrating molecular disease features and the availability of new targeted drugs with attractive efficacy and limited toxicity might open new possibilities to re-investigate early treatment in well-defined clinical settings in the future., (© 2016 S. Karger GmbH, Freiburg.)
- Published
- 2016
- Full Text
- View/download PDF
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