Universität zu Köln

Chanan-Khan, Asher, Cramer, Paula, Demirkan, Fatih ORCID: 0000-0002-1172-8668, Fraser, Graeme, Silva, Rodrigo Santucci, Grosicki, Sebastian ORCID: 0000-0003-2644-1050, Pristupa, Aleksander, Janssens, Ann, Mayer, Jiri, Bartlett, Nancy L., Dilhuydy, Marie-Sarah, Pylypenko, Halyna, Loscertales, Javier, Avigdor, Abraham, Rule, Simon, Villa, Diego, Samoilova, Olga, Panagiotidis, Panagiots, Goy, Andre ORCID: 0000-0001-5125-6522, Mato, Anthony, Pavlovsky, Miguel A., Karlsson, Claes, Mahler, Michelle, Salman, Mariya, Sun, Steven, Phelps, Charles, Balasubramanian, Sriram, Howes, Angela, Hallek, Michael, Assouline, S., Bence-Bruckler, I., Buckstein, R., Fraser, G., Larratt, L., Minuk, L., Villa, D., Angevine, A., Bartlett, N., Bixby, D., Caimi, P., Chanan-Khan, A., Craig, M., Forero-Torres, A., Ganguly, S., Goy, A., Heffner, L., Hermann, R., Lansigan, F., Leis, J., Letzer, J., Link, B., Liu, D., McCaul, K., McGuire, E., Skinner, W., Starodub, A., Stuart, R., Thirman, M., Tirumali, N., Yang, J., Janssens, A., Offner, F., Van den Neste, E., Van Hoof, A., Mayer, J., Novak, J., Trneny, M., Cartron, G., Dartigeas, C., Dilhuydy, M., Ghez, D., Haioun, C., Leblond, V., Salles, G., Balser, C., Cramer, P., Dreger, P., Durig, J., Eckart, M., Heinrich, B., Illmer, T., Jentsch-Ullrich, K., Pfreundschuh, M., Schetelig, J., Schlag, R., Soling, U., Stilgenbaue, S., Anagnostopoulos, A., Dimopoulos, A., Panagiotidis, P., Vrakidou, E., Bairey, O., Ben Yehuda, D., Braester, A., Fineman, R., Herishanu, Y., Nagler, A., Ruchlemer, R., Tadmor, T., Grosicki, S., Homenda, W., Jurczak, W., Pluta, A., Woszczyk, D., Espirito Santo, A., Luis, R., Raposo, J., Viveiros, C., Alexeeva, J., Dunaev, Y., Golubeva, M., Khuageva, N., Loginov, A., Lysenko, I., Osmanov, E., Pavlov, V., Pristupa, A., Proydakov, A., Rossiev, V., Samarina, I., Samoilova, O., Serduk, O., Shneider, T., Udovitsa, D., Voloshin, S., Gayoso, J., Gonzalez, M., Gonzalez Barca, E., Hernandez Rivas, J., Jargue, I., Loscertales, J., Karlsson, C., Sender, M., Aktan, M., Arslan, O., Demirkan, F., Ferhanoglu, B., Kaynar, L., Sayinalp, N., Vaural, F., Yagci, M., Dyagil, I., Kaplan, P., Masliak, Z., Oliynyk, H., Popovska, T., Pylypenko, H., Rekhtman, G., Dearden, C., Morley, N., Moss, P., Rule, S., Pavlovsky, M., Riveros, D., Santucci-Silva, R., Romeo, M., Scheliga, A., Salazar, L., Gomez, D., Ramirez, E. and Jung, C. (2016). Ibrutinib combined with bendamustine and rituximab compared with placebo, bendamustine, and rituximab for previously treated chronic lymphocytic leukaemia or small lymphocytic lymphoma (HELIOS): a randomised, double-blind, phase 3 study. Lancet Oncol., 17 (2). S. 200 - 212. NEW YORK: ELSEVIER SCIENCE INC. ISSN 1474-5488

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Abstract

Background Most patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma relapse after initial therapy. Bendamustine plus rituximab is often used in the relapsed or refractory setting. We assessed the efficacy and safety of adding ibrutinib, an oral covalent inhibitor of Bruton's tyrosine kinase (BTK), to bendamustine plus rituximab in patients with previously treated chronic lymphocytic leukaemia or small lymphocytic lymphoma. Methods The HELIOS trial was an international, double-blind, placebo-controlled, phase 3 study in adult patients (>= 18 years of age) who had active chronic lymphocytic leukaemia or small lymphocytic lymphoma with measurable lymph node disease (>1.5 cm) by CT scan, and had relapsed or refractory disease following one or more previous lines of systemic therapy consisting of at least two cycles of a chemotherapy-containing regimen, an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, and adequate bone marrow, liver, and kidney function. Patients with del(17p) were excluded because of known poor response to bendamustine plus rituximab. Patients who had received previous treatment with ibrutinib or other BTK inhibitors, refractory disease or relapse within 24 months with a previous bendamustine-containing regimen, or haemopoietic stem-cell transplant were also excluded. Patients were randomly assigned (1:1) by a web-based system to receive bendamustine plus rituximab given in cycles of 4 weeks' duration (bendamustine: 70 mg/m.intravenously on days 2-3 in cycle 1, and days 1-2 in cycles 2-6; rituximab: 375 mg/m.on day 1 of cycle 1, and 500 mg/m.on day 1 of cycles 2-6 for a maximum of six cycles) with either ibrutinib (420 mg daily orally) or placebo until disease progression or unacceptable toxicity. Patients were stratified according to whether they were refractory to purine analogues and by number of previous lines of therapy. The primary endpoint was independent review committee (IRC)-assessed progression-free survival. Crossover to ibrutinib was permitted for patients in the placebo group with IRC-confirmed disease progression. Analysis was by intention-to-treat and is continuing for further long-term follow-up. The trial is registered with ClinicalTrials.gov, number NCT01611090. Findings Between Sept 19, 2012, and Jan 21, 2014, 578 eligible patients were randomly assigned to ibrutinib or placebo in combination with bendamustine plus rituximab (289 in each group). The primary endpoint was met at the preplanned interim analysis (March 10, 2015). At a median follow-up of 17 months (IQR 13.7-20.7), progression-free survival was significantly improved in the ibrutinib group compared with the placebo group (not reached in the ibrutinib group (95% CI not evaluable) vs 13.3 months (11.3-13.9) in the placebo group (hazard ratio [HR] 0.203, 95% CI 0.150-0.276; p<0.0001). IRC-assessed progression-free survival at 18 months was 79% (95% CI 73-83) in the ibrutinib group and 24% (18-31) in the placebo group (HR 0.203, 95% CI 0.150-0.276; p<0.0001). The most frequent all-grade adverse events were neutropenia and nausea. 222 (77%) of 287 patients in the ibrutinib group and 212 (74%) of 287 patients in the placebo group reported grade 3-4 events; the most common grade 3-4 adverse events in both groups were neutropenia (154 [54%] in the ibrutinib group vs 145 [51%] in the placebo group) and thrombocytopenia (43 [15%] in each group). A safety profile similar to that previously reported with ibrutinib and bendamustine plus rituximab individually was noted. Interpretation In patients eligible for bendamustine plus rituximab, the addition of ibrutinib to this regimen results in significant improvements in outcome with no new safety signals identified from the combination and a manageable safety profile.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Chanan-Khan, Asher UNSPECIFIED UNSPECIFIED UNSPECIFIED Cramer, Paula UNSPECIFIED UNSPECIFIED UNSPECIFIED Demirkan, Fatih UNSPECIFIED orcid.org/0000-0002-1172-8668 UNSPECIFIED Fraser, Graeme UNSPECIFIED UNSPECIFIED UNSPECIFIED Silva, Rodrigo Santucci UNSPECIFIED UNSPECIFIED UNSPECIFIED Grosicki, Sebastian UNSPECIFIED orcid.org/0000-0003-2644-1050 UNSPECIFIED Pristupa, Aleksander UNSPECIFIED UNSPECIFIED UNSPECIFIED Janssens, Ann UNSPECIFIED UNSPECIFIED UNSPECIFIED Mayer, Jiri UNSPECIFIED UNSPECIFIED UNSPECIFIED Bartlett, Nancy L. UNSPECIFIED UNSPECIFIED UNSPECIFIED Dilhuydy, Marie-Sarah UNSPECIFIED UNSPECIFIED UNSPECIFIED Pylypenko, Halyna UNSPECIFIED UNSPECIFIED UNSPECIFIED Loscertales, Javier UNSPECIFIED UNSPECIFIED UNSPECIFIED Avigdor, Abraham UNSPECIFIED UNSPECIFIED UNSPECIFIED Rule, Simon UNSPECIFIED UNSPECIFIED UNSPECIFIED Villa, Diego UNSPECIFIED UNSPECIFIED UNSPECIFIED Samoilova, Olga UNSPECIFIED UNSPECIFIED UNSPECIFIED Panagiotidis, Panagiots UNSPECIFIED UNSPECIFIED UNSPECIFIED Goy, Andre UNSPECIFIED orcid.org/0000-0001-5125-6522 UNSPECIFIED Mato, Anthony UNSPECIFIED UNSPECIFIED UNSPECIFIED Pavlovsky, Miguel A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Karlsson, Claes UNSPECIFIED UNSPECIFIED UNSPECIFIED Mahler, Michelle UNSPECIFIED UNSPECIFIED UNSPECIFIED Salman, Mariya UNSPECIFIED UNSPECIFIED UNSPECIFIED Sun, Steven UNSPECIFIED UNSPECIFIED UNSPECIFIED Phelps, Charles UNSPECIFIED UNSPECIFIED UNSPECIFIED Balasubramanian, Sriram UNSPECIFIED UNSPECIFIED UNSPECIFIED Howes, Angela UNSPECIFIED UNSPECIFIED UNSPECIFIED Hallek, Michael UNSPECIFIED UNSPECIFIED UNSPECIFIED Assouline, S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Bence-Bruckler, I. UNSPECIFIED UNSPECIFIED UNSPECIFIED Buckstein, R. UNSPECIFIED UNSPECIFIED UNSPECIFIED Fraser, G. UNSPECIFIED UNSPECIFIED UNSPECIFIED Larratt, L. UNSPECIFIED UNSPECIFIED UNSPECIFIED Minuk, L. UNSPECIFIED UNSPECIFIED UNSPECIFIED Villa, D. UNSPECIFIED UNSPECIFIED UNSPECIFIED Angevine, A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Bartlett, N. UNSPECIFIED UNSPECIFIED UNSPECIFIED Bixby, D. UNSPECIFIED UNSPECIFIED UNSPECIFIED Caimi, P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Chanan-Khan, A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Craig, M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Forero-Torres, A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Ganguly, S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Goy, A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Heffner, L. UNSPECIFIED UNSPECIFIED UNSPECIFIED Hermann, R. UNSPECIFIED UNSPECIFIED UNSPECIFIED Lansigan, F. UNSPECIFIED UNSPECIFIED UNSPECIFIED Leis, J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Letzer, J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Link, B. UNSPECIFIED UNSPECIFIED UNSPECIFIED Liu, D. UNSPECIFIED UNSPECIFIED UNSPECIFIED McCaul, K. UNSPECIFIED UNSPECIFIED UNSPECIFIED McGuire, E. UNSPECIFIED UNSPECIFIED UNSPECIFIED Skinner, W. UNSPECIFIED UNSPECIFIED UNSPECIFIED Starodub, A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Stuart, R. UNSPECIFIED UNSPECIFIED UNSPECIFIED Thirman, M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Tirumali, N. UNSPECIFIED UNSPECIFIED UNSPECIFIED Yang, J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Janssens, A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Offner, F. UNSPECIFIED UNSPECIFIED UNSPECIFIED Van den Neste, E. UNSPECIFIED UNSPECIFIED UNSPECIFIED Van Hoof, A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Mayer, J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Novak, J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Trneny, M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Cartron, G. UNSPECIFIED UNSPECIFIED UNSPECIFIED Dartigeas, C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Dilhuydy, M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Ghez, D. UNSPECIFIED UNSPECIFIED UNSPECIFIED Haioun, C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Leblond, V. UNSPECIFIED UNSPECIFIED UNSPECIFIED Salles, G. UNSPECIFIED UNSPECIFIED UNSPECIFIED Balser, C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Cramer, P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Dreger, P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Durig, J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Eckart, M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Heinrich, B. UNSPECIFIED UNSPECIFIED UNSPECIFIED Illmer, T. UNSPECIFIED UNSPECIFIED UNSPECIFIED Jentsch-Ullrich, K. UNSPECIFIED UNSPECIFIED UNSPECIFIED Pfreundschuh, M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Schetelig, J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Schlag, R. UNSPECIFIED UNSPECIFIED UNSPECIFIED Soling, U. UNSPECIFIED UNSPECIFIED UNSPECIFIED Stilgenbaue, S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Anagnostopoulos, A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Dimopoulos, A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Panagiotidis, P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Vrakidou, E. UNSPECIFIED UNSPECIFIED UNSPECIFIED Bairey, O. UNSPECIFIED UNSPECIFIED UNSPECIFIED Ben Yehuda, D. UNSPECIFIED UNSPECIFIED UNSPECIFIED Braester, A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Fineman, R. UNSPECIFIED UNSPECIFIED UNSPECIFIED Herishanu, Y. UNSPECIFIED UNSPECIFIED UNSPECIFIED Nagler, A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Ruchlemer, R. UNSPECIFIED UNSPECIFIED UNSPECIFIED Tadmor, T. UNSPECIFIED UNSPECIFIED UNSPECIFIED Grosicki, S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Homenda, W. UNSPECIFIED UNSPECIFIED UNSPECIFIED Jurczak, W. UNSPECIFIED UNSPECIFIED UNSPECIFIED Pluta, A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Woszczyk, D. UNSPECIFIED UNSPECIFIED UNSPECIFIED Espirito Santo, A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Luis, R. UNSPECIFIED UNSPECIFIED UNSPECIFIED Raposo, J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Viveiros, C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Alexeeva, J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Dunaev, Y. UNSPECIFIED UNSPECIFIED UNSPECIFIED Golubeva, M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Khuageva, N. UNSPECIFIED UNSPECIFIED UNSPECIFIED Loginov, A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Lysenko, I. UNSPECIFIED UNSPECIFIED UNSPECIFIED Osmanov, E. UNSPECIFIED UNSPECIFIED UNSPECIFIED Pavlov, V. UNSPECIFIED UNSPECIFIED UNSPECIFIED Pristupa, A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Proydakov, A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Rossiev, V. UNSPECIFIED UNSPECIFIED UNSPECIFIED Samarina, I. UNSPECIFIED UNSPECIFIED UNSPECIFIED Samoilova, O. UNSPECIFIED UNSPECIFIED UNSPECIFIED Serduk, O. UNSPECIFIED UNSPECIFIED UNSPECIFIED Shneider, T. UNSPECIFIED UNSPECIFIED UNSPECIFIED Udovitsa, D. UNSPECIFIED UNSPECIFIED UNSPECIFIED Voloshin, S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Gayoso, J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Gonzalez, M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Gonzalez Barca, E. UNSPECIFIED UNSPECIFIED UNSPECIFIED Hernandez Rivas, J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Jargue, I. UNSPECIFIED UNSPECIFIED UNSPECIFIED Loscertales, J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Karlsson, C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Sender, M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Aktan, M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Arslan, O. UNSPECIFIED UNSPECIFIED UNSPECIFIED Demirkan, F. UNSPECIFIED UNSPECIFIED UNSPECIFIED Ferhanoglu, B. UNSPECIFIED UNSPECIFIED UNSPECIFIED Kaynar, L. UNSPECIFIED UNSPECIFIED UNSPECIFIED Sayinalp, N. UNSPECIFIED UNSPECIFIED UNSPECIFIED Vaural, F. UNSPECIFIED UNSPECIFIED UNSPECIFIED Yagci, M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Dyagil, I. UNSPECIFIED UNSPECIFIED UNSPECIFIED Kaplan, P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Masliak, Z. UNSPECIFIED UNSPECIFIED UNSPECIFIED Oliynyk, H. UNSPECIFIED UNSPECIFIED UNSPECIFIED Popovska, T. UNSPECIFIED UNSPECIFIED UNSPECIFIED Pylypenko, H. UNSPECIFIED UNSPECIFIED UNSPECIFIED Rekhtman, G. UNSPECIFIED UNSPECIFIED UNSPECIFIED Dearden, C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Morley, N. UNSPECIFIED UNSPECIFIED UNSPECIFIED Moss, P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Rule, S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Pavlovsky, M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Riveros, D. UNSPECIFIED UNSPECIFIED UNSPECIFIED Santucci-Silva, R. UNSPECIFIED UNSPECIFIED UNSPECIFIED Romeo, M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Scheliga, A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Salazar, L. UNSPECIFIED UNSPECIFIED UNSPECIFIED Gomez, D. UNSPECIFIED UNSPECIFIED UNSPECIFIED Ramirez, E. UNSPECIFIED UNSPECIFIED UNSPECIFIED Jung, C. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-286544
DOI:	10.1016/S1470-2045(15)00465-9
Journal or Publication Title:	Lancet Oncol.
Volume:	17
Number:	2
Page Range:	S. 200 - 212
Date:	2016
Publisher:	ELSEVIER SCIENCE INC
Place of Publication:	NEW YORK
ISSN:	1474-5488
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language BRUTON TYROSINE KINASE; MANTLE CELL LYMPHOMA; INHIBITOR IBRUTINIB; BTK; CYCLOPHOSPHAMIDE; FLUDARABINE; DISEASE; CLL Multiple languages Oncology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/28654