Journal ArticleDOI
Brentuximab vedotin combined with ABVD or AVD for patients with newly diagnosed Hodgkin's lymphoma: a phase 1, open-label, dose-escalation study
Anas Younes,Joseph M. Connors,Steven I. Park,Michelle A. Fanale,Megan M. O'Meara,Naomi N. H. Hunder,Dirk Huebner,Stephen M. Ansell +7 more
TLDR
A phase 1, open-label, dose-escalation safety study comparing brentuximab vedotin in combination with standard (ABVD) or a modified-standard (AVD) treatment was conducted in patients with advanced stage Hodgkin's lymphoma as mentioned in this paper.Abstract:
Summary Background Roughly 70–80% of patients with advanced stage Hodgkin's lymphoma are cured with various first-line and second-line treatments, including ABVD, BEACOPP, and stem-cell transplantation. Brentuximab vedotin has shown significant clinical activity, with a manageable safety profile, in patients with relapsed or refractory Hodgkin's lymphoma. We aimed to assess the safety and early clinical efficacy of this drug as first-line treatment in combination with standard or modified-standard treatment in patients with previously untreated Hodgkin's lymphoma. Methods We did a phase 1, open-label, dose-escalation safety study comparing brentuximab vedotin in combination with standard (ABVD) or a modified-standard (AVD) treatment. Patients were enrolled into the groups sequentially. Main entry criteria were newly diagnosed, treatment-naive, CD30-positive patients with Hodgkin's lymphoma who had histologically confirmed stage IIA bulky disease or stage IIB–IV disease and an Eastern Cooperative Oncology Group performance status of two or less. Patients received doses of 0·6, 0·9, or 1·2 mg/kg brentuximab vedotin by intravenous infusion every 2 weeks with either ABVD (25 mg/m 2 doxorubicin, 10 units/m 2 bleomycin, 6 mg/m 2 vinblastine, and 375 mg/m 2 dacarbazine) or AVD (ABVD modified regimen without the inclusion of bleomycin) for up to six cycles. Our primary objectives were to assess the safety profile and establish the maximum tolerated dose (MTD) of brentuximab vedotin in combination with ABVD and AVD. The safety profile and MTD was assessed for the safety population. The study has completed and the final analysis is presented. This study was registered with ClinicalTrials.gov, number NCT01060904. Findings Between Jan 29, 2010, and Sept 17, 2012, 51 patients were enrolled and received at least one dose of brentuximab vedotin. The maximum tolerated dose of brentuximab vedotin when combined with ABVD or AVD was not exceeded at 1·2 mg/kg. 21 (95%) of 22 patients given brentuximab vedotin and ABVD achieved complete remission, as did 24 (96%) of 25 patients given brentuximab vedotin and AVD. Adverse events were generally grade 1 or 2; however, an unacceptable number of patients in the brentuximab vedotin and ABVD groups had pulmonary toxic effects (11 [44%] of 25), which exceeded the historical incidence for ABVD alone. No patients experienced pulmonary toxic effects when treated with brentuximab vedotin plus AVD. The most common grade 3 or worse events were neutropenia (20 [80%] of 25 patients in the brentuximab vedotin and ABVD group vs 20 [77%] of 26 patients in the brentuximab vedotin and AVD group), anaemia (five [20%] vs three [12%]), febrile neutropenia (five [20%] vs two [8%]), pulmonary toxic effects (six [24%] vs 0), syncope (three [12%] vs two [8%]), dyspnoea (three [12%] vs one [4%]), pulmonary embolism (three [12%] vs 0), fatigue (one [4%] each), and leucopenia (one [4%] each). Serious events occured in 41% of all patients (14 [56%] in the brentuximab vedotin and ABVD group and seven [27%] in the brentuximab vedotin and AVD group). Serious events occurring in 10% of patients or more overall were febrile neutropenia (four [16%] in the brentuximab vedotin and ABVD group vs two [8%] in the brentuximab vedotin and AVD group), and, in the brentuximab vedotin and ABVD group only, pulmonary toxic effects (six [24%]). Interpretation Brentuximab vedotin should not be given with bleomycin in general or specifically as first-line therapy for patients with treatment naive, advanced stage Hodgkin's lymphoma. 1·2 mg/kg brentuximab vedotin combined with AVD given every 2 weeks was generally well tolerated by patients. At present, a phase 3 trial comparing brentuximab vedotin plus AVD to ABVD alone is ongoing (ClinicalTrials.gov, number NCT01712490) and will formally assess whether brentuximab vedotin plus AVD might redefine therapy in treatment-naive patients with Hodgkin's lymphoma. Funding Seattle Genetics Inc and Takeda Pharmaceuticals International Co.read more
Citations
More filters
Journal ArticleDOI
Brentuximab Vedotin with Chemotherapy for Stage III or IV Hodgkin’s Lymphoma
Joseph M. Connors,Wojciech Jurczak,David J. Straus,Stephen M. Ansell,Won Kim,Andrea Gallamini,Anas Younes,Sergey Alekseev,Árpád Illés,Marco Picardi,Ewa Lech-Marańda,Yasuhiro Oki,Tatyana Feldman,Piotr Smolewski,Kerry J. Savage,Nancy L. Bartlett,Jan Walewski,Robert T. Chen,Radhakrishnan Ramchandren,Pier Luigi Zinzani,David Cunningham,András Rosta,Neil C Josephson,Eric Song,Jessica A. Sachs,Rachael Liu,Hina Jolin,Dirk Huebner,John Radford +28 more
TL;DR: A+AVD had superior efficacy to ABVD in the treatment of patients with advanced‐stage Hodgkin's lymphoma, with a 4.9 percentage‐point lower combined risk of progression, death, or noncomplete response and use of subsequent anticancer therapy at 2 years.
Journal ArticleDOI
Chimeric antigen receptor T-cell therapies for lymphoma
TL;DR: Clinical efficacy and toxicity of CAR-T-cell therapies for lymphoma are reviewed, and their limitations and future directions with regard to toxicity management, CAR designs and CAR- t cells phenotypes, conditioning regimens, and combination therapies are discussed.
Journal ArticleDOI
Effects of antibody, drug and linker on the preclinical and clinical toxicities of antibody-drug conjugates
TL;DR: The toxicities reported for active and discontinued drugs are important to drive the rational design and improve the therapeutic index of ADCs of the future.
Journal ArticleDOI
Hodgkin lymphoma: A review and update on recent progress.
TL;DR: Alternative donor sources and reduced‐intensity conditioning have made allogeneic hematopoietic stem cell transplantation a viable option for more patients and future research will look to integrate novel strategies into earlier lines of therapy to improve the HL cure rate and minimize long‐term treatment toxicities.
Journal ArticleDOI
Non-Hodgkin lymphoma: diagnosis and treatment.
TL;DR: Non-Hodgkin lymphomas are a heterogeneous group of malignancies of the lymphoid system that have identified molecular and genetic markers of prognosis that may be used in the future to further refine treatment decisions.
References
More filters
Journal ArticleDOI
Revised response criteria for malignant lymphoma
Bruce D. Cheson,Beate Pfistner,Malik E. Juweid,Randy D. Gascoyne,Lena Specht,Sandra J. Horning,Bertrand Coiffier,Richard I. Fisher,Anton Hagenbeek,Emanuele Zucca,Steven T. Rosen,Sigrid Stroobants,T. Andrew Lister,Richard T. Hoppe,Martin Dreyling,Kensei Tobinai,Julie M. Vose,Joseph M. Connors,Massimo Federico,Volker Diehl +19 more
TL;DR: New guidelines incorporating PET, IHC, and flow cytometry for definitions of response in non-Hodgkin's and Hodgkin's lymphoma are presented and it is hoped that they will be adopted widely by study groups, pharmaceutical and biotechnology companies, and regulatory agencies to facilitate the development of new and more effective therapies to improve the outcome of patients with lymphoma.
Journal ArticleDOI
Results of a Pivotal Phase II Study of Brentuximab Vedotin for Patients With Relapsed or Refractory Hodgkin's Lymphoma
Anas Younes,Ajay K. Gopal,Scott E. Smith,Stephen M. Ansell,Joseph D. Rosenblatt,Kerry J. Savage,Radhakrishnan Ramchandren,Nancy L. Bartlett,Bruce D. Cheson,Sven de Vos,Andres Forero-Torres,Craig H. Moskowitz,Joseph M. Connors,Andreas Engert,Emily K. Larsen,Dana A. Kennedy,Eric L. Sievers,Robert T. Chen +17 more
TL;DR: The ADC brentuximab vedotin was associated with manageable toxicity and induced objective responses in 75% of patients with relapsed or refractory HL after autologous stem-cell transplantation (auto-SCT).
Journal ArticleDOI
Dose intensification with autologous bone-marrow transplantation in relapsed and resistant Hodgkin's disease: results of a BNLI randomised trial
Dc Linch,D. A. Winfield,Ah Goldstone,D. Moir,Barry W. Hancock,A. McMillan,Rajesh Chopra,Donald Milligan,GV Hudson +8 more
TL;DR: A randomised comparison of high-dose chemotherapy plus ABMT with the same drugs at lower doses not requiring bone-marrow rescue in patients with active Hodgkin's disease found that high doses facilitated by ABMT can lead to better disease-free survival.
Journal ArticleDOI
Aggressive conventional chemotherapy compared with high-dose chemotherapy with autologous haemopoietic stem-cell transplantation for relapsed chemosensitive Hodgkin's disease: a randomised trial
Norbert Schmitz,Beate Pfistner,M Sextro,M. Sieber,Angelo Michele Carella,Matthias Haenel,F. Boissevain,Reinhart Zschaber,P. Müller,Hartmut Kirchner,Andreas Lohri,Susanne Decker,Bettina Koch,Dirk Hasenclever,Anthony H. Goldstone,Volker Diehl +15 more
TL;DR: High-dose BEAM and transplantation of haemopoietic stem cells improves freedom from treatment failure in patients with chemosensitive first relapse of Hodgkin's disease irrespective of length of initial remission.
Journal ArticleDOI
Early Interim 2-[18F]Fluoro-2-Deoxy-D-Glucose Positron Emission Tomography Is Prognostically Superior to International Prognostic Score in Advanced-Stage Hodgkin's Lymphoma: A Report From a Joint Italian-Danish Study
Andrea Gallamini,Martin Hutchings,Luigi Rigacci,Lena Specht,Francesco Merli,Mads Hansen,Caterina Patti,Annika Loft,Francesco Di Raimondo,Francesco d'Amore,Alberto Biggi,Umberto Vitolo,Caterina Stelitano,R Sancetta,Livio Trentin,Stefano Luminari,Emilio Iannitto,Simonetta Viviani,Ivana Pierri,Alessandro Levis +19 more
TL;DR: PET-2 overshadows the prognostic value of IPS and emerges as the single most important tool for planning of risk-adapted treatment in advanced HL.
Related Papers (5)
Results of a Pivotal Phase II Study of Brentuximab Vedotin for Patients With Relapsed or Refractory Hodgkin's Lymphoma
Anas Younes,Ajay K. Gopal,Scott E. Smith,Stephen M. Ansell,Joseph D. Rosenblatt,Kerry J. Savage,Radhakrishnan Ramchandren,Nancy L. Bartlett,Bruce D. Cheson,Sven de Vos,Andres Forero-Torres,Craig H. Moskowitz,Joseph M. Connors,Andreas Engert,Emily K. Larsen,Dana A. Kennedy,Eric L. Sievers,Robert T. Chen +17 more
PD-1 Blockade with Nivolumab in Relapsed or Refractory Hodgkin's Lymphoma
Stephen M. Ansell,Alexander M. Lesokhin,Alexander M. Lesokhin,Ivan Borrello,Ahmad Halwani,Emma C. Scott,Martin Gutierrez,Stephen J. Schuster,Michael Millenson,Deepika Cattry,Gordon J. Freeman,Scott J. Rodig,Bjoern Chapuy,Azra H. Ligon,Lili Zhu,Joseph F. Grosso,Su Y oung Kim,John M. Timmerman,Margaret A. Shipp,Philippe Armand +19 more
Early Interim 2-[18F]Fluoro-2-Deoxy-D-Glucose Positron Emission Tomography Is Prognostically Superior to International Prognostic Score in Advanced-Stage Hodgkin's Lymphoma: A Report From a Joint Italian-Danish Study
Andrea Gallamini,Martin Hutchings,Luigi Rigacci,Lena Specht,Francesco Merli,Mads Hansen,Caterina Patti,Annika Loft,Francesco Di Raimondo,Francesco d'Amore,Alberto Biggi,Umberto Vitolo,Caterina Stelitano,R Sancetta,Livio Trentin,Stefano Luminari,Emilio Iannitto,Simonetta Viviani,Ivana Pierri,Alessandro Levis +19 more