Brentuximab vedotin as consolidation therapy after autologous stem-cell transplantation in patients with Hodgkin's lymphoma at risk of relapse or progression (AETHERA)

A randomised, double-blind, placebo-controlled, phase 3 trial

Craig Moskowitz, Auayporn Nademanee, Tamas Masszi, Edward Agura, Jerzy Holowiecki, Muneer H. Abidi, Andy I. Chen, Patrick Stiff, Alessandro M. Gianni, Angelo Carella, Dzhelil Osmanov, Veronika Bachanova, John Sweetenham, Anna Sureda, Dirk Huebner, Eric L. Sievers, Andy Chi, Emily K. Larsen, Naomi N. Hunder, Jan Walewski

Research output: Contribution to journalArticle

297 Citations (Scopus)

Abstract

Background High-dose therapy followed by autologous stem-cell transplantation is standard of care for patients with relapsed or primary refractory Hodgkin's lymphoma. Roughly 50% of patients might be cured after autologous stem-cell transplantation; however, most patients with unfavourable risk factors progress after transplantation. We aimed to assess whether brentuximab vedotin improves progression-free survival when given as early consolidation after autologous stem-cell transplantation. Methods We did this randomised, double-blind, placebo-controlled, phase 3 trial at 78 sites in North America and Europe. Patients with unfavourable-risk relapsed or primary refractory classic Hodgkin's lymphoma who had undergone autologous stem-cell transplantation were randomly assigned, by fixed-block randomisation with a computer-generated random number sequence, to receive 16 cycles of 1·8 mg/kg brentuximab vedotin or placebo intravenously every 3 weeks, starting 30-45 days after transplantation. Randomisation was stratified by best clinical response after completion of salvage chemotherapy (complete response vs partial response vs stable disease) and primary refractory Hodgkin's lymphoma versus relapsed disease less than 12 months after completion of frontline therapy versus relapse 12 months or more after treatment completion. Patients and study investigators were masked to treatment assignment. The primary endpoint was progression-free survival by independent review, defined as the time from randomisation to the first documentation of tumour progression or death. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01100502. Findings Between April 6, 2010, and Sept 21, 2012, we randomly assigned 329 patients to the brentuximab vedotin group (n=165) or the placebo group (n=164). Progression-free survival by independent review was significantly improved in patients in the brentuximab vedotin group compared with those in the placebo group (hazard ratio [HR] 0·57, 95% CI 0·40-0·81; p=0·0013). Median progression-free survival by independent review was 42·9 months (95% CI 30·4-42·9) for patients in the brentuximab vedotin group compared with 24·1 months (11·5-not estimable) for those in the placebo group. We recorded consistent benefit (HR <1) of brentuximab vedotin consolidation across subgroups. The most frequent adverse events in the brentuximab vedotin group were peripheral sensory neuropathy (94 [56%] of 167 patients vs 25 [16%] of 160 patients in the placebo group) and neutropenia (58 [35%] vs 19 [12%] patients). At time of analysis, 28 (17%) of 167 patients had died in the brentuximab vedotin group compared with 25 (16%) of 160 patients in the placebo group. Interpretation Early consolidation with brentuximab vedotin after autologous stem-cell transplantation improved progression-free survival in patients with Hodgkin's lymphoma with risk factors for relapse or progression after transplantation. This treatment provides an important therapeutic option for patients undergoing autologous stem-cell transplantation. Funding Seattle Genetics and Takeda Pharmaceuticals International.

Original languageEnglish (US)
Pages (from-to)1853-1862
Number of pages10
JournalThe Lancet
Volume385
Issue number9980
DOIs
StatePublished - Jan 1 2015
Externally publishedYes

Fingerprint

Stem Cell Transplantation
Hodgkin Disease
Placebos
Recurrence
Disease-Free Survival
Therapeutics
Random Allocation
Transplantation
cAC10-vcMMAE
Intention to Treat Analysis
Peripheral Nervous System Diseases
Standard of Care
North America
Neutropenia
Documentation

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Brentuximab vedotin as consolidation therapy after autologous stem-cell transplantation in patients with Hodgkin's lymphoma at risk of relapse or progression (AETHERA) : A randomised, double-blind, placebo-controlled, phase 3 trial. / Moskowitz, Craig; Nademanee, Auayporn; Masszi, Tamas; Agura, Edward; Holowiecki, Jerzy; Abidi, Muneer H.; Chen, Andy I.; Stiff, Patrick; Gianni, Alessandro M.; Carella, Angelo; Osmanov, Dzhelil; Bachanova, Veronika; Sweetenham, John; Sureda, Anna; Huebner, Dirk; Sievers, Eric L.; Chi, Andy; Larsen, Emily K.; Hunder, Naomi N.; Walewski, Jan.

In: The Lancet, Vol. 385, No. 9980, 01.01.2015, p. 1853-1862.

Research output: Contribution to journalArticle

Moskowitz, C, Nademanee, A, Masszi, T, Agura, E, Holowiecki, J, Abidi, MH, Chen, AI, Stiff, P, Gianni, AM, Carella, A, Osmanov, D, Bachanova, V, Sweetenham, J, Sureda, A, Huebner, D, Sievers, EL, Chi, A, Larsen, EK, Hunder, NN & Walewski, J 2015, 'Brentuximab vedotin as consolidation therapy after autologous stem-cell transplantation in patients with Hodgkin's lymphoma at risk of relapse or progression (AETHERA): A randomised, double-blind, placebo-controlled, phase 3 trial', The Lancet, vol. 385, no. 9980, pp. 1853-1862. https://doi.org/10.1016/S0140-6736(15)60165-9
Moskowitz, Craig ; Nademanee, Auayporn ; Masszi, Tamas ; Agura, Edward ; Holowiecki, Jerzy ; Abidi, Muneer H. ; Chen, Andy I. ; Stiff, Patrick ; Gianni, Alessandro M. ; Carella, Angelo ; Osmanov, Dzhelil ; Bachanova, Veronika ; Sweetenham, John ; Sureda, Anna ; Huebner, Dirk ; Sievers, Eric L. ; Chi, Andy ; Larsen, Emily K. ; Hunder, Naomi N. ; Walewski, Jan. / Brentuximab vedotin as consolidation therapy after autologous stem-cell transplantation in patients with Hodgkin's lymphoma at risk of relapse or progression (AETHERA) : A randomised, double-blind, placebo-controlled, phase 3 trial. In: The Lancet. 2015 ; Vol. 385, No. 9980. pp. 1853-1862.
@article{dd70792f96e54b4b86dd950ab0e2f5d0,
title = "Brentuximab vedotin as consolidation therapy after autologous stem-cell transplantation in patients with Hodgkin's lymphoma at risk of relapse or progression (AETHERA): A randomised, double-blind, placebo-controlled, phase 3 trial",
abstract = "Background High-dose therapy followed by autologous stem-cell transplantation is standard of care for patients with relapsed or primary refractory Hodgkin's lymphoma. Roughly 50{\%} of patients might be cured after autologous stem-cell transplantation; however, most patients with unfavourable risk factors progress after transplantation. We aimed to assess whether brentuximab vedotin improves progression-free survival when given as early consolidation after autologous stem-cell transplantation. Methods We did this randomised, double-blind, placebo-controlled, phase 3 trial at 78 sites in North America and Europe. Patients with unfavourable-risk relapsed or primary refractory classic Hodgkin's lymphoma who had undergone autologous stem-cell transplantation were randomly assigned, by fixed-block randomisation with a computer-generated random number sequence, to receive 16 cycles of 1·8 mg/kg brentuximab vedotin or placebo intravenously every 3 weeks, starting 30-45 days after transplantation. Randomisation was stratified by best clinical response after completion of salvage chemotherapy (complete response vs partial response vs stable disease) and primary refractory Hodgkin's lymphoma versus relapsed disease less than 12 months after completion of frontline therapy versus relapse 12 months or more after treatment completion. Patients and study investigators were masked to treatment assignment. The primary endpoint was progression-free survival by independent review, defined as the time from randomisation to the first documentation of tumour progression or death. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01100502. Findings Between April 6, 2010, and Sept 21, 2012, we randomly assigned 329 patients to the brentuximab vedotin group (n=165) or the placebo group (n=164). Progression-free survival by independent review was significantly improved in patients in the brentuximab vedotin group compared with those in the placebo group (hazard ratio [HR] 0·57, 95{\%} CI 0·40-0·81; p=0·0013). Median progression-free survival by independent review was 42·9 months (95{\%} CI 30·4-42·9) for patients in the brentuximab vedotin group compared with 24·1 months (11·5-not estimable) for those in the placebo group. We recorded consistent benefit (HR <1) of brentuximab vedotin consolidation across subgroups. The most frequent adverse events in the brentuximab vedotin group were peripheral sensory neuropathy (94 [56{\%}] of 167 patients vs 25 [16{\%}] of 160 patients in the placebo group) and neutropenia (58 [35{\%}] vs 19 [12{\%}] patients). At time of analysis, 28 (17{\%}) of 167 patients had died in the brentuximab vedotin group compared with 25 (16{\%}) of 160 patients in the placebo group. Interpretation Early consolidation with brentuximab vedotin after autologous stem-cell transplantation improved progression-free survival in patients with Hodgkin's lymphoma with risk factors for relapse or progression after transplantation. This treatment provides an important therapeutic option for patients undergoing autologous stem-cell transplantation. Funding Seattle Genetics and Takeda Pharmaceuticals International.",
author = "Craig Moskowitz and Auayporn Nademanee and Tamas Masszi and Edward Agura and Jerzy Holowiecki and Abidi, {Muneer H.} and Chen, {Andy I.} and Patrick Stiff and Gianni, {Alessandro M.} and Angelo Carella and Dzhelil Osmanov and Veronika Bachanova and John Sweetenham and Anna Sureda and Dirk Huebner and Sievers, {Eric L.} and Andy Chi and Larsen, {Emily K.} and Hunder, {Naomi N.} and Jan Walewski",
year = "2015",
month = "1",
day = "1",
doi = "10.1016/S0140-6736(15)60165-9",
language = "English (US)",
volume = "385",
pages = "1853--1862",
journal = "The Lancet",
issn = "0140-6736",
publisher = "Elsevier Limited",
number = "9980",

}

TY - JOUR

T1 - Brentuximab vedotin as consolidation therapy after autologous stem-cell transplantation in patients with Hodgkin's lymphoma at risk of relapse or progression (AETHERA)

T2 - A randomised, double-blind, placebo-controlled, phase 3 trial

AU - Moskowitz, Craig

AU - Nademanee, Auayporn

AU - Masszi, Tamas

AU - Agura, Edward

AU - Holowiecki, Jerzy

AU - Abidi, Muneer H.

AU - Chen, Andy I.

AU - Stiff, Patrick

AU - Gianni, Alessandro M.

AU - Carella, Angelo

AU - Osmanov, Dzhelil

AU - Bachanova, Veronika

AU - Sweetenham, John

AU - Sureda, Anna

AU - Huebner, Dirk

AU - Sievers, Eric L.

AU - Chi, Andy

AU - Larsen, Emily K.

AU - Hunder, Naomi N.

AU - Walewski, Jan

PY - 2015/1/1

Y1 - 2015/1/1

N2 - Background High-dose therapy followed by autologous stem-cell transplantation is standard of care for patients with relapsed or primary refractory Hodgkin's lymphoma. Roughly 50% of patients might be cured after autologous stem-cell transplantation; however, most patients with unfavourable risk factors progress after transplantation. We aimed to assess whether brentuximab vedotin improves progression-free survival when given as early consolidation after autologous stem-cell transplantation. Methods We did this randomised, double-blind, placebo-controlled, phase 3 trial at 78 sites in North America and Europe. Patients with unfavourable-risk relapsed or primary refractory classic Hodgkin's lymphoma who had undergone autologous stem-cell transplantation were randomly assigned, by fixed-block randomisation with a computer-generated random number sequence, to receive 16 cycles of 1·8 mg/kg brentuximab vedotin or placebo intravenously every 3 weeks, starting 30-45 days after transplantation. Randomisation was stratified by best clinical response after completion of salvage chemotherapy (complete response vs partial response vs stable disease) and primary refractory Hodgkin's lymphoma versus relapsed disease less than 12 months after completion of frontline therapy versus relapse 12 months or more after treatment completion. Patients and study investigators were masked to treatment assignment. The primary endpoint was progression-free survival by independent review, defined as the time from randomisation to the first documentation of tumour progression or death. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01100502. Findings Between April 6, 2010, and Sept 21, 2012, we randomly assigned 329 patients to the brentuximab vedotin group (n=165) or the placebo group (n=164). Progression-free survival by independent review was significantly improved in patients in the brentuximab vedotin group compared with those in the placebo group (hazard ratio [HR] 0·57, 95% CI 0·40-0·81; p=0·0013). Median progression-free survival by independent review was 42·9 months (95% CI 30·4-42·9) for patients in the brentuximab vedotin group compared with 24·1 months (11·5-not estimable) for those in the placebo group. We recorded consistent benefit (HR <1) of brentuximab vedotin consolidation across subgroups. The most frequent adverse events in the brentuximab vedotin group were peripheral sensory neuropathy (94 [56%] of 167 patients vs 25 [16%] of 160 patients in the placebo group) and neutropenia (58 [35%] vs 19 [12%] patients). At time of analysis, 28 (17%) of 167 patients had died in the brentuximab vedotin group compared with 25 (16%) of 160 patients in the placebo group. Interpretation Early consolidation with brentuximab vedotin after autologous stem-cell transplantation improved progression-free survival in patients with Hodgkin's lymphoma with risk factors for relapse or progression after transplantation. This treatment provides an important therapeutic option for patients undergoing autologous stem-cell transplantation. Funding Seattle Genetics and Takeda Pharmaceuticals International.

AB - Background High-dose therapy followed by autologous stem-cell transplantation is standard of care for patients with relapsed or primary refractory Hodgkin's lymphoma. Roughly 50% of patients might be cured after autologous stem-cell transplantation; however, most patients with unfavourable risk factors progress after transplantation. We aimed to assess whether brentuximab vedotin improves progression-free survival when given as early consolidation after autologous stem-cell transplantation. Methods We did this randomised, double-blind, placebo-controlled, phase 3 trial at 78 sites in North America and Europe. Patients with unfavourable-risk relapsed or primary refractory classic Hodgkin's lymphoma who had undergone autologous stem-cell transplantation were randomly assigned, by fixed-block randomisation with a computer-generated random number sequence, to receive 16 cycles of 1·8 mg/kg brentuximab vedotin or placebo intravenously every 3 weeks, starting 30-45 days after transplantation. Randomisation was stratified by best clinical response after completion of salvage chemotherapy (complete response vs partial response vs stable disease) and primary refractory Hodgkin's lymphoma versus relapsed disease less than 12 months after completion of frontline therapy versus relapse 12 months or more after treatment completion. Patients and study investigators were masked to treatment assignment. The primary endpoint was progression-free survival by independent review, defined as the time from randomisation to the first documentation of tumour progression or death. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01100502. Findings Between April 6, 2010, and Sept 21, 2012, we randomly assigned 329 patients to the brentuximab vedotin group (n=165) or the placebo group (n=164). Progression-free survival by independent review was significantly improved in patients in the brentuximab vedotin group compared with those in the placebo group (hazard ratio [HR] 0·57, 95% CI 0·40-0·81; p=0·0013). Median progression-free survival by independent review was 42·9 months (95% CI 30·4-42·9) for patients in the brentuximab vedotin group compared with 24·1 months (11·5-not estimable) for those in the placebo group. We recorded consistent benefit (HR <1) of brentuximab vedotin consolidation across subgroups. The most frequent adverse events in the brentuximab vedotin group were peripheral sensory neuropathy (94 [56%] of 167 patients vs 25 [16%] of 160 patients in the placebo group) and neutropenia (58 [35%] vs 19 [12%] patients). At time of analysis, 28 (17%) of 167 patients had died in the brentuximab vedotin group compared with 25 (16%) of 160 patients in the placebo group. Interpretation Early consolidation with brentuximab vedotin after autologous stem-cell transplantation improved progression-free survival in patients with Hodgkin's lymphoma with risk factors for relapse or progression after transplantation. This treatment provides an important therapeutic option for patients undergoing autologous stem-cell transplantation. Funding Seattle Genetics and Takeda Pharmaceuticals International.

UR - http://www.scopus.com/inward/record.url?scp=84929510996&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84929510996&partnerID=8YFLogxK

U2 - 10.1016/S0140-6736(15)60165-9

DO - 10.1016/S0140-6736(15)60165-9

M3 - Article

VL - 385

SP - 1853

EP - 1862

JO - The Lancet

JF - The Lancet

SN - 0140-6736

IS - 9980

ER -