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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

A Chanan-Khan, P Cramer, F Demirkan, G Fraser, RS Silva, S Grosicki, A Pristupa, A Janssens, J Mayer, NL Bartlett, et al. (2016) LANCET ONCOLOGY. 17(2). p.200-211
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.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
BTK, PCI-32765, MANTLE CELL LYMPHOMA, INHIBITOR IBRUTINIB, BRUTON TYROSINE KINASE, CYCLOPHOSPHAMIDE, FLUDARABINE, MALIGNANCY, DISEASE, TRIAL
journal title
LANCET ONCOLOGY
Lancet Oncol.
volume
17
issue
2
pages
200 - 211
Web of Science type
Article
Web of Science id
000369613900049
JCR category
ONCOLOGY
JCR impact factor
33.9 (2016)
JCR rank
3/217 (2016)
JCR quartile
1 (2016)
ISSN
1470-2045
DOI
10.1016/S1470-2045(15)00465-9
language
English
UGent publication?
yes
classification
A1
copyright statement
I have transferred the copyright for this publication to the publisher
id
8118616
handle
http://hdl.handle.net/1854/LU-8118616
date created
2016-10-18 15:51:52
date last changed
2016-12-19 15:40:47
@article{8118616,
  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 ({\textrangle}= 18 years of age) who had active chronic lymphocytic leukaemia or small lymphocytic lymphoma with measurable lymph node disease ({\textrangle}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{\textlangle}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{\textlangle}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.},
  author       = {Chanan-Khan, A and Cramer, P and Demirkan, F and Fraser, G and Silva, RS and Grosicki, S and Pristupa, A and Janssens, A and Mayer, J and Bartlett, NL and Dilhuydy, MS and Pylypenko, H and Loscertales, J and Avigdor, A and Rule, S and Villa, D and Samoilova, O and Panagiotidis, P and Goy, A and Mato, A and Pavlovsky, MA and Karlsson, C and Mahler, M and Salman, M and Sun, S and Phelps, C and Balasubramanian, S and Howes, A and Hallek, M and Assouline, S and Bence-Bruckler, I and Buckstein, R and Fraser, G and Larratt, L and Minuk, L and Villa, D and Angevine, A and Bartlett, N and Bixby, D and Caimi, P and Chanan-Khan, A and Craig, M and Forero-Torres, A and Ganguly, S and Goy, A and Heffner, L and Hermann, R and Lansigan, F and Leis, J and Letzer, J and Link, B and Liu, D and McCaul, K and McGuire, E and Skinner, W and Starodub, A and Stuart, R and Thirman, M and Tirumali, N and Yang, J and Janssens, A and Offner, Fritz and Van den Neste, E and Van Hoof, A and Mayer, J and Novak, J and Trneny, M and Cartron, G and Dartigeas, C and Dilhuydy, M and Ghez, D and Haioun, C and Leblond, V and Salles, G and Balser, C and Cramer, P and Dreger, P and Durig, J and Eckart, M and Heinrich, B and Illmer, T and Jentsch-Ullrich, K and Pfreundschuh, M and Schetelig, J and Schlag, R and Soling, U and Stilgenbaue, S and Anagnostopoulos, A and Dimopoulos, A and Panagiotidis, P and Vrakidou, E and Bairey, O and Ben Yehuda, D and Braester, A and Fineman, R and Herishanu, Y and Nagler, A and Ruchlemer, R and Tadmor, T and Grosicki, S and Homenda, W and Jurczak, W and Pluta, A and Woszczyk, D and Espirito Santo, A and Luis, R and Raposo, J and Viveiros, C and Alexeeva, J and Dunaev, Y and Golubeva, M and Khuageva, N and Loginov, A and Lysenko, I and Osmanov, E and Pavlov, V and Pristupa, A and Proydakov, A and Rossiev, V and Samarina, I and Samoilova, O and Serduk, O and Shneider, T and Udovitsa, D and Voloshin, S and Gayoso, J and Gonzalez, M and Gonzalez Barca, E and Hernandez Rivas, J and Jargue, I and Loscertales, J and Karlsson, C and Sender, M and Aktan, M and Arslan, O and Demirkan, F and Ferhanoglu, B and Kaynar, L and Sayinalp, N and Vaural, F and Yagci, M and Dyagil, I and Kaplan, P and Masliak, Z and Oliynyk, H and Popovska, T and Pylypenko, H and Rekhtman, G and Dearden, C and Morley, N and Moss, P and Rule, S and Pavlovsky, M and Riveros, D and Santucci-Silva, R and Romeo, M and Scheliga, A and Salazar, L and Gomez, D and Ramirez, E and Jung, C},
  issn         = {1470-2045},
  journal      = {LANCET ONCOLOGY},
  keyword      = {BTK,PCI-32765,MANTLE CELL LYMPHOMA,INHIBITOR IBRUTINIB,BRUTON TYROSINE KINASE,CYCLOPHOSPHAMIDE,FLUDARABINE,MALIGNANCY,DISEASE,TRIAL},
  language     = {eng},
  number       = {2},
  pages        = {200--211},
  title        = {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},
  url          = {http://dx.doi.org/10.1016/S1470-2045(15)00465-9},
  volume       = {17},
  year         = {2016},
}

Chicago
Chanan-Khan, A, P Cramer, F Demirkan, G Fraser, RS Silva, S Grosicki, A Pristupa, et al. 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 Oncology 17 (2): 200–211.
APA
Chanan-Khan, A., Cramer, P., Demirkan, F., Fraser, G., Silva, R., Grosicki, S., Pristupa, A., et al. (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 ONCOLOGY, 17(2), 200–211.
Vancouver
1.
Chanan-Khan A, Cramer P, Demirkan F, Fraser G, Silva R, Grosicki S, et al. 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 ONCOLOGY. 2016;17(2):200–11.
MLA
Chanan-Khan, A, P Cramer, F Demirkan, et al. “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 ONCOLOGY 17.2 (2016): 200–211. Print.