[en] In the post-rituximab era, patients with relapsed/refractory non-Hodgkin B-cell lymphoma (R/R B-NHL) responding to a platinum salt-based salvage regimen can potentially be cured after intensification followed by autologous stem cell transplantation, with the quality of the response to salvage predicting survival. The Bruton tyrosine kinase inhibitor ibrutinib, given as monotherapy or combined with other molecules, has proven effective in numerous B-cell lymphomas. To evaluate the safety of the combination of ibrutinib, rituximab, dexamethasone, and cytarabine with either cisplatin (R-DHAP) or oxaliplatin (R-DHAOx), we conducted a multicenter Phase 1b-II study in transplant-eligible R/R B-NHL patients, with ibrutinib given using a 3-by-3 dose-escalation design. The combination of R-DHAP and ibrutinib (given from Day 1 to Day 21 of each cycle) was associated with dose-limiting hematological, infectious, and renal toxicities, while we were unable to reach a dose to recommend for Phase II. R-DHAOx could only be combined with a daily dosage of 280 mg ibrutinib when administered continuously. R-DHAP combined with intermittent ibrutinib administration (from Day 5 to Day 18) was found to be highly toxic. On the other hand, when this administration schedule was combined with R-DHAOx, ibrutinib dosing could be increased up to 560 mg but with relevant toxicities. Despite a strong rationale for combining ibrutinib and R-DHAP/R-DHAOx, as both target lymphoma B-cells by different mechanisms, this approach was limited by significant toxicities.
Disciplines :
Hematology
Author, co-author :
BONNET, Christophe ; Centre Hospitalier Universitaire de Liège - CHU > > Service d'hématologie clinique
Dupuis, Jehan; Lymphoid Malignancies Unit, Hôpital Henri Mondor, 51 Avenue du Maréchal de Lattre de Tassigny, CEDEX, 94000 Créteil, France
Tilly, Hervé; Hematology Department Henri Becquerel, Rue d'Amiens, CEDEX, 76000 Rouen, France
Lamy, Thierry; Centre Hospitalier Universitaire de Rennes, Service d'Hématologie Clinique, 35033 Rennes, France ; Institut National de la Recherche Médicale, Unité Mixte de Recherche U1236, Université de Rennes 1, Etablissement Français du Sang Bretagne, 35000 Rennes, France
Fruchart, Christophe; Hematology Unit, Centre Hospitalier de Dunkerque, 130, Avenue Louis Herbeaux, CS 76 367, CEDEX 1, 59385 Dunkerque, France
le Gouill, Steven ; Institut Curie, 26 Rue d'Ulm, 75005 Paris, France
Thieblemont, Catherine; Hemato-Oncology Department, Hôpital Saint Louis, 1 Av. Claude Vellefaux, 75010 Paris, France
Morschhauser, Franck; Hematology Unit, Centre Hospitalier de Lille, 2, Avenue Oscar Lambret, 59037 Lille, France
Casasnovas, Olivier ; Department of Hematology, Centre Hospitalier Universitaire de Dijon Bourgogne and INSERM 1231, 14 Rue Paul Gaffarel, 21000 Dijon, France
Bouabdallah, Krimo; Hematology Department, Centre Hospitalier de Bordeaux, 12, Rue Dubernat, 33000 Bordeaux, France
Ghesquieres, Hervé; Hematology Unit, Hopital Lyon Sud, Pierre-Benite, 165 Chemin du Grand Revoyet, 69310 Pierre-Bénite, France
Van Den Neste, Eric; Hematology Unit, Cliniques Universitaires Saint-Luc, 10 Avenue Hippocrate, 1200 Bruxelles, Belgium
André, Marc; Department of Hematology, Centre Hospitalier Universaitaire, Université Catholique de Louvain Namur, Université Catholique de Louvain, 1 Rue Dr Gaston Therasse, 5530 Yvoir, Belgium
Cartron, Guillaume; Department of Hematology, Centre Hospitalier Universtaire de Montpellier, UMR-CNRS 5535, 34090 Montpellier, France
Salles, Gilles ; Department of Medicine, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, 530 East 74th Street, New York, NY 10065, USA
The Lymphoma Academic Research Organization (LYSARC) was the study sponsor. LYSARC collected data, which were then analyzed by the authors. The authors of this report were the LYSA investigators. Ibrutinib was provided by Pharmacyclics Inc., and the LYSA group received funding from Janssen Pharmaceutics. Janssen played no role in the study design or data collection, analysis, and interpretation, nor in report drafting. The corresponding author had full access to all study data, as well as the final responsibility for the decision to submit the report for publication.Funding: The Lymphoma Academic Research Organization (LYSARC) was the study sponsor. LYSARC collected data, which were then analyzed by the authors. The authors of this report were the LYSA investigators. Ibrutinib was provided by Pharmacyclics Inc., and the LYSA group received funding from Janssen Pharmaceutics. Janssen played no role in the study design or data collection, analysis, and interpretation, nor in report drafting. The corresponding author had full access to all study data, as well as the final responsibility for the decision to submit the report for publication.
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