Brentuximab Vedotin with Chemotherapy for Stage III or IV Hodgkin's Lymphoma

J. M. Connors, W. Jurczak, D. J. Straus, S. M. Ansell, W. S. Kim, A. Gallamini, A. Younes, S. Alekseev, A. Illes, M. Picardi, E. Lech-Maranda, Y. Oki, T. Feldman, P. Smolewski, K. J. Savage, N. L. Bartlett, J. Walewski, R. Chen, R. Ramchandren, P. L. ZinzaniD. Cunningham, A. Rosta, N. C. Josephson, E. Song, J. Sachs, R. Liu, H. A. Jolin, D. Huebner, J. Radford, ECHELON-1 Study Group, Andrea Mengarelli

Research output: Contribution to journalArticle

Abstract

BACKGROUND: Brentuximab vedotin is an anti-CD30 antibody-drug conjugate that has been approved for relapsed and refractory Hodgkin's lymphoma. METHODS: We conducted an open-label, multicenter, randomized phase 3 trial involving patients with previously untreated stage III or IV classic Hodgkin's lymphoma, in which 664 were assigned to receive brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine (A+AVD) and 670 were assigned to receive doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). The primary end point was modified progression-free survival (the time to progression, death, or noncomplete response and use of subsequent anticancer therapy) as adjudicated by an independent review committee. The key secondary end point was overall survival. RESULTS: At a median follow-up of 24.6 months, 2-year modified progression-free survival rates in the A+AVD and ABVD groups were 82.1% (95% confidence interval [CI], 78.8 to 85.0) and 77.2% (95% CI, 73.7 to 80.4), respectively, a difference of 4.9 percentage points (hazard ratio for an event of progression, death, or modified progression, 0.77; 95% CI, 0.60 to 0.98; P=0.04). There were 28 deaths with A+AVD and 39 with ABVD (hazard ratio for interim overall survival, 0.73 [95% CI, 0.45 to 1.18]; P=0.20) [corrected]. All secondary efficacy end points trended in favor of A+AVD. Neutropenia occurred in 58% of the patients receiving A+AVD and in 45% of those receiving ABVD; in the A+AVD group, the rate of febrile neutropenia was lower among the 83 patients who received primary prophylaxis with granulocyte colony-stimulating factor than among those who did not (11% vs. 21%). Peripheral neuropathy occurred in 67% of patients in the A+AVD group and in 43% of patients in the ABVD group; 67% of patients in the A+AVD group who had peripheral neuropathy had resolution or improvement at the last follow-up visit. Pulmonary toxicity of grade 3 or higher was reported in less than 1% of patients receiving A+AVD and in 3% of those receiving ABVD. Among the deaths that occurred during treatment, 7 of 9 in the A+AVD group were associated with neutropenia and 11 of 13 in the ABVD group were associated with pulmonary-related toxicity. CONCLUSIONS: 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. (Funded by Millennium Pharmaceuticals and Seattle Genetics; ECHELON-1 ClinicalTrials.gov number, NCT01712490 ; EudraCT number, 2011-005450-60 .).
Original languageEnglish
Pages (from-to)331-344
Number of pages14
JournalThe New England journal of medicine
Volume378
Issue number4
DOIs
Publication statusPublished - Jan 25 2018
Externally publishedYes

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Hodgkin Disease
Drug Therapy
Confidence Intervals
Dacarbazine
Vinblastine
Peripheral Nervous System Diseases
Neutropenia
Doxorubicin
Disease-Free Survival
Febrile Neutropenia
Lung
Survival
cAC10-vcMMAE
Bleomycin
Granulocyte Colony-Stimulating Factor
Advisory Committees
Therapeutics
Pharmaceutical Preparations
Anti-Idiotypic Antibodies
Survival Rate

Keywords

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Combined Chemotherapy Protocols/adverse effects/therapeutic use
  • Bleomycin/administration & dosage
  • Dacarbazine/administration & dosage
  • Disease-Free Survival
  • Doxorubicin/administration & dosage
  • Female
  • Follow-Up Studies
  • Hodgkin Disease/drug therapy/mortality
  • Humans
  • Immunoconjugates/administration & dosage/adverse effects
  • Immunologic Factors/administration & dosage/adverse effects
  • Male
  • Middle Aged
  • Neoplasm Staging
  • Neutropenia/chemically induced
  • Survival Rate
  • Vinblastine/administration & dosage
  • Young Adult

Cite this

Connors, J. M., Jurczak, W., Straus, D. J., Ansell, S. M., Kim, W. S., Gallamini, A., ... Mengarelli, A. (2018). Brentuximab Vedotin with Chemotherapy for Stage III or IV Hodgkin's Lymphoma. The New England journal of medicine, 378(4), 331-344. https://doi.org/10.1056/NEJMoa1708984 [doi]

Brentuximab Vedotin with Chemotherapy for Stage III or IV Hodgkin's Lymphoma. / Connors, J. M.; Jurczak, W.; Straus, D. J.; Ansell, S. M.; Kim, W. S.; Gallamini, A.; Younes, A.; Alekseev, S.; Illes, A.; Picardi, M.; Lech-Maranda, E.; Oki, Y.; Feldman, T.; Smolewski, P.; Savage, K. J.; Bartlett, N. L.; Walewski, J.; Chen, R.; Ramchandren, R.; Zinzani, P. L.; Cunningham, D.; Rosta, A.; Josephson, N. C.; Song, E.; Sachs, J.; Liu, R.; Jolin, H. A.; Huebner, D.; Radford, J.; Group, ECHELON-1 Study; Mengarelli, Andrea.

In: The New England journal of medicine, Vol. 378, No. 4, 25.01.2018, p. 331-344.

Research output: Contribution to journalArticle

Connors, JM, Jurczak, W, Straus, DJ, Ansell, SM, Kim, WS, Gallamini, A, Younes, A, Alekseev, S, Illes, A, Picardi, M, Lech-Maranda, E, Oki, Y, Feldman, T, Smolewski, P, Savage, KJ, Bartlett, NL, Walewski, J, Chen, R, Ramchandren, R, Zinzani, PL, Cunningham, D, Rosta, A, Josephson, NC, Song, E, Sachs, J, Liu, R, Jolin, HA, Huebner, D, Radford, J, Group, ECHELONS & Mengarelli, A 2018, 'Brentuximab Vedotin with Chemotherapy for Stage III or IV Hodgkin's Lymphoma', The New England journal of medicine, vol. 378, no. 4, pp. 331-344. https://doi.org/10.1056/NEJMoa1708984 [doi]
Connors JM, Jurczak W, Straus DJ, Ansell SM, Kim WS, Gallamini A et al. Brentuximab Vedotin with Chemotherapy for Stage III or IV Hodgkin's Lymphoma. The New England journal of medicine. 2018 Jan 25;378(4):331-344. https://doi.org/10.1056/NEJMoa1708984 [doi]
Connors, J. M. ; Jurczak, W. ; Straus, D. J. ; Ansell, S. M. ; Kim, W. S. ; Gallamini, A. ; Younes, A. ; Alekseev, S. ; Illes, A. ; Picardi, M. ; Lech-Maranda, E. ; Oki, Y. ; Feldman, T. ; Smolewski, P. ; Savage, K. J. ; Bartlett, N. L. ; Walewski, J. ; Chen, R. ; Ramchandren, R. ; Zinzani, P. L. ; Cunningham, D. ; Rosta, A. ; Josephson, N. C. ; Song, E. ; Sachs, J. ; Liu, R. ; Jolin, H. A. ; Huebner, D. ; Radford, J. ; Group, ECHELON-1 Study ; Mengarelli, Andrea. / Brentuximab Vedotin with Chemotherapy for Stage III or IV Hodgkin's Lymphoma. In: The New England journal of medicine. 2018 ; Vol. 378, No. 4. pp. 331-344.
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abstract = "BACKGROUND: Brentuximab vedotin is an anti-CD30 antibody-drug conjugate that has been approved for relapsed and refractory Hodgkin's lymphoma. METHODS: We conducted an open-label, multicenter, randomized phase 3 trial involving patients with previously untreated stage III or IV classic Hodgkin's lymphoma, in which 664 were assigned to receive brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine (A+AVD) and 670 were assigned to receive doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). The primary end point was modified progression-free survival (the time to progression, death, or noncomplete response and use of subsequent anticancer therapy) as adjudicated by an independent review committee. The key secondary end point was overall survival. RESULTS: At a median follow-up of 24.6 months, 2-year modified progression-free survival rates in the A+AVD and ABVD groups were 82.1{\%} (95{\%} confidence interval [CI], 78.8 to 85.0) and 77.2{\%} (95{\%} CI, 73.7 to 80.4), respectively, a difference of 4.9 percentage points (hazard ratio for an event of progression, death, or modified progression, 0.77; 95{\%} CI, 0.60 to 0.98; P=0.04). There were 28 deaths with A+AVD and 39 with ABVD (hazard ratio for interim overall survival, 0.73 [95{\%} CI, 0.45 to 1.18]; P=0.20) [corrected]. All secondary efficacy end points trended in favor of A+AVD. Neutropenia occurred in 58{\%} of the patients receiving A+AVD and in 45{\%} of those receiving ABVD; in the A+AVD group, the rate of febrile neutropenia was lower among the 83 patients who received primary prophylaxis with granulocyte colony-stimulating factor than among those who did not (11{\%} vs. 21{\%}). Peripheral neuropathy occurred in 67{\%} of patients in the A+AVD group and in 43{\%} of patients in the ABVD group; 67{\%} of patients in the A+AVD group who had peripheral neuropathy had resolution or improvement at the last follow-up visit. Pulmonary toxicity of grade 3 or higher was reported in less than 1{\%} of patients receiving A+AVD and in 3{\%} of those receiving ABVD. Among the deaths that occurred during treatment, 7 of 9 in the A+AVD group were associated with neutropenia and 11 of 13 in the ABVD group were associated with pulmonary-related toxicity. CONCLUSIONS: 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. (Funded by Millennium Pharmaceuticals and Seattle Genetics; ECHELON-1 ClinicalTrials.gov number, NCT01712490 ; EudraCT number, 2011-005450-60 .).",
keywords = "Adolescent, Adult, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols/adverse effects/therapeutic use, Bleomycin/administration & dosage, Dacarbazine/administration & dosage, Disease-Free Survival, Doxorubicin/administration & dosage, Female, Follow-Up Studies, Hodgkin Disease/drug therapy/mortality, Humans, Immunoconjugates/administration & dosage/adverse effects, Immunologic Factors/administration & dosage/adverse effects, Male, Middle Aged, Neoplasm Staging, Neutropenia/chemically induced, Survival Rate, Vinblastine/administration & dosage, Young Adult",
author = "Connors, {J. M.} and W. Jurczak and Straus, {D. J.} and Ansell, {S. M.} and Kim, {W. S.} and A. Gallamini and A. Younes and S. Alekseev and A. Illes and M. Picardi and E. Lech-Maranda and Y. Oki and T. Feldman and P. Smolewski and Savage, {K. J.} and Bartlett, {N. L.} and J. Walewski and R. Chen and R. Ramchandren and Zinzani, {P. L.} and D. Cunningham and A. Rosta and Josephson, {N. C.} and E. Song and J. Sachs and R. Liu and Jolin, {H. A.} and D. Huebner and J. Radford and Group, {ECHELON-1 Study} and Andrea Mengarelli",
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}

TY - JOUR

T1 - Brentuximab Vedotin with Chemotherapy for Stage III or IV Hodgkin's Lymphoma

AU - Connors, J. M.

AU - Jurczak, W.

AU - Straus, D. J.

AU - Ansell, S. M.

AU - Kim, W. S.

AU - Gallamini, A.

AU - Younes, A.

AU - Alekseev, S.

AU - Illes, A.

AU - Picardi, M.

AU - Lech-Maranda, E.

AU - Oki, Y.

AU - Feldman, T.

AU - Smolewski, P.

AU - Savage, K. J.

AU - Bartlett, N. L.

AU - Walewski, J.

AU - Chen, R.

AU - Ramchandren, R.

AU - Zinzani, P. L.

AU - Cunningham, D.

AU - Rosta, A.

AU - Josephson, N. C.

AU - Song, E.

AU - Sachs, J.

AU - Liu, R.

AU - Jolin, H. A.

AU - Huebner, D.

AU - Radford, J.

AU - Group, ECHELON-1 Study

AU - Mengarelli, Andrea

N1 - LR: 20180419; ClinicalTrials.gov/NCT01712490; ClinicalTrials.gov/NCT01712490; EudraCT/2011-005450-60; GR: P30 CA008748/CA/NCI NIH HHS/United States; JID: 0255562; 0 (Immunoconjugates); 0 (Immunologic Factors); 11056-06-7 (Bleomycin); 5V9KLZ54CY (Vinblastine); 7GR28W0FJI (Dacarbazine); 7XL5ISS668 (brentuximab vedotin); 80168379AG (Doxorubicin); CIN: N Engl J Med. 2018 Jan 25;378(4):392-394. PMID: 29224505; CIN: . PMID: 29671464; CIN: . PMID: 29671465; CIN: . PMID: 29671466; CIN: . PMID: 29671468; EIN: N Engl J Med. 2018 Mar 1;378(9):878. PMID: 29490175; NIHMS941383; 2017/12/12 06:00 [pubmed]; 2018/02/09 06:00 [medline]; 2017/12/12 06:00 [entrez]; ppublish

PY - 2018/1/25

Y1 - 2018/1/25

N2 - BACKGROUND: Brentuximab vedotin is an anti-CD30 antibody-drug conjugate that has been approved for relapsed and refractory Hodgkin's lymphoma. METHODS: We conducted an open-label, multicenter, randomized phase 3 trial involving patients with previously untreated stage III or IV classic Hodgkin's lymphoma, in which 664 were assigned to receive brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine (A+AVD) and 670 were assigned to receive doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). The primary end point was modified progression-free survival (the time to progression, death, or noncomplete response and use of subsequent anticancer therapy) as adjudicated by an independent review committee. The key secondary end point was overall survival. RESULTS: At a median follow-up of 24.6 months, 2-year modified progression-free survival rates in the A+AVD and ABVD groups were 82.1% (95% confidence interval [CI], 78.8 to 85.0) and 77.2% (95% CI, 73.7 to 80.4), respectively, a difference of 4.9 percentage points (hazard ratio for an event of progression, death, or modified progression, 0.77; 95% CI, 0.60 to 0.98; P=0.04). There were 28 deaths with A+AVD and 39 with ABVD (hazard ratio for interim overall survival, 0.73 [95% CI, 0.45 to 1.18]; P=0.20) [corrected]. All secondary efficacy end points trended in favor of A+AVD. Neutropenia occurred in 58% of the patients receiving A+AVD and in 45% of those receiving ABVD; in the A+AVD group, the rate of febrile neutropenia was lower among the 83 patients who received primary prophylaxis with granulocyte colony-stimulating factor than among those who did not (11% vs. 21%). Peripheral neuropathy occurred in 67% of patients in the A+AVD group and in 43% of patients in the ABVD group; 67% of patients in the A+AVD group who had peripheral neuropathy had resolution or improvement at the last follow-up visit. Pulmonary toxicity of grade 3 or higher was reported in less than 1% of patients receiving A+AVD and in 3% of those receiving ABVD. Among the deaths that occurred during treatment, 7 of 9 in the A+AVD group were associated with neutropenia and 11 of 13 in the ABVD group were associated with pulmonary-related toxicity. CONCLUSIONS: 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. (Funded by Millennium Pharmaceuticals and Seattle Genetics; ECHELON-1 ClinicalTrials.gov number, NCT01712490 ; EudraCT number, 2011-005450-60 .).

AB - BACKGROUND: Brentuximab vedotin is an anti-CD30 antibody-drug conjugate that has been approved for relapsed and refractory Hodgkin's lymphoma. METHODS: We conducted an open-label, multicenter, randomized phase 3 trial involving patients with previously untreated stage III or IV classic Hodgkin's lymphoma, in which 664 were assigned to receive brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine (A+AVD) and 670 were assigned to receive doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). The primary end point was modified progression-free survival (the time to progression, death, or noncomplete response and use of subsequent anticancer therapy) as adjudicated by an independent review committee. The key secondary end point was overall survival. RESULTS: At a median follow-up of 24.6 months, 2-year modified progression-free survival rates in the A+AVD and ABVD groups were 82.1% (95% confidence interval [CI], 78.8 to 85.0) and 77.2% (95% CI, 73.7 to 80.4), respectively, a difference of 4.9 percentage points (hazard ratio for an event of progression, death, or modified progression, 0.77; 95% CI, 0.60 to 0.98; P=0.04). There were 28 deaths with A+AVD and 39 with ABVD (hazard ratio for interim overall survival, 0.73 [95% CI, 0.45 to 1.18]; P=0.20) [corrected]. All secondary efficacy end points trended in favor of A+AVD. Neutropenia occurred in 58% of the patients receiving A+AVD and in 45% of those receiving ABVD; in the A+AVD group, the rate of febrile neutropenia was lower among the 83 patients who received primary prophylaxis with granulocyte colony-stimulating factor than among those who did not (11% vs. 21%). Peripheral neuropathy occurred in 67% of patients in the A+AVD group and in 43% of patients in the ABVD group; 67% of patients in the A+AVD group who had peripheral neuropathy had resolution or improvement at the last follow-up visit. Pulmonary toxicity of grade 3 or higher was reported in less than 1% of patients receiving A+AVD and in 3% of those receiving ABVD. Among the deaths that occurred during treatment, 7 of 9 in the A+AVD group were associated with neutropenia and 11 of 13 in the ABVD group were associated with pulmonary-related toxicity. CONCLUSIONS: 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. (Funded by Millennium Pharmaceuticals and Seattle Genetics; ECHELON-1 ClinicalTrials.gov number, NCT01712490 ; EudraCT number, 2011-005450-60 .).

KW - Adolescent

KW - Adult

KW - Aged

KW - Aged, 80 and over

KW - Antineoplastic Combined Chemotherapy Protocols/adverse effects/therapeutic use

KW - Bleomycin/administration & dosage

KW - Dacarbazine/administration & dosage

KW - Disease-Free Survival

KW - Doxorubicin/administration & dosage

KW - Female

KW - Follow-Up Studies

KW - Hodgkin Disease/drug therapy/mortality

KW - Humans

KW - Immunoconjugates/administration & dosage/adverse effects

KW - Immunologic Factors/administration & dosage/adverse effects

KW - Male

KW - Middle Aged

KW - Neoplasm Staging

KW - Neutropenia/chemically induced

KW - Survival Rate

KW - Vinblastine/administration & dosage

KW - Young Adult

U2 - 10.1056/NEJMoa1708984 [doi]

DO - 10.1056/NEJMoa1708984 [doi]

M3 - Article

VL - 378

SP - 331

EP - 344

JO - New England Journal of Medicine

JF - New England Journal of Medicine

SN - 0028-4793

IS - 4

ER -