PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma

Stephen Maxted Ansell, Alexander M. Lesokhin, Ivan Borrello, Ahmad Halwani, Emma C. Scott, Martin Gutierrez, Stephen J. Schuster, Michael M. 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

Research output: Contribution to journalArticle

1612 Citations (Scopus)

Abstract

BACKGROUND: Preclinical studies suggest that Reed-Sternberg cells exploit the programmed death 1 (PD-1) pathway to evade immune detection. In classic Hodgkin's lymphoma, alterations in chromosome 9p24.1 increase the abundance of the PD-1 ligands, PD-L1 and PD-L2, and promote their induction through Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling. We hypothesized that nivolumab, a PD-1-blocking antibody, could inhibit tumor immune evasion in patients with relapsed or refractory Hodgkin's lymphoma.

METHODS: In this ongoing study, 23 patients with relapsed or refractory Hodgkin's lymphoma that had already been heavily treated received nivolumab (at a dose of 3 mg per kilogram of body weight) every 2 weeks until they had a complete response, tumor progression, or excessive toxic effects. Study objectives were measurement of safety and efficacy and assessment of the PDL1 and PDL2 (also called CD274 and PDCD1LG2, respectively) loci and PD-L1 and PD-L2 protein expression.

RESULTS: Of the 23 study patients, 78% were enrolled in the study after a relapse following autologous stem-cell transplantation and 78% after a relapse following the receipt of brentuximab vedotin. Drug-related adverse events of any grade and of grade 3 occurred in 78% and 22% of patients, respectively. An objective response was reported in 20 patients (87%), including 17% with a complete response and 70% with a partial response; the remaining 3 patients (13%) had stable disease. The rate of progression-free survival at 24 weeks was 86%; 11 patients were continuing to participate in the study. Reasons for discontinuation included stem-cell transplantation (in 6 patients), disease progression (in 4 patients), and drug toxicity (in 2 patients). Analyses of pretreatment tumor specimens from 10 patients revealed copy-number gains in PDL1 and PDL2 and increased expression of these ligands. Reed-Sternberg cells showed nuclear positivity of phosphorylated STAT3, indicative of active JAK-STAT signaling.

CONCLUSIONS: Nivolumab had substantial therapeutic activity and an acceptable safety profile in patients with previously heavily treated relapsed or refractory Hodgkin's lymphoma. (Funded by Bristol-Myers Squibb and others; ClinicalTrials.gov number, NCT01592370.).

Original languageEnglish (US)
Pages (from-to)311-319
Number of pages9
JournalThe New England journal of medicine
Volume372
Issue number4
DOIs
StatePublished - Jan 22 2015

Fingerprint

Hodgkin Disease
Reed-Sternberg Cells
Janus Kinases
Stem Cell Transplantation
Drug-Related Side Effects and Adverse Reactions
Transducers
nivolumab
Tumor Escape
Ligands
Safety
Recurrence
Blocking Antibodies
Poisons
Disease-Free Survival
Disease Progression
Neoplasms
Chromosomes
Body Weight

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Ansell, S. M., Lesokhin, A. M., Borrello, I., Halwani, A., Scott, E. C., Gutierrez, M., ... Armand, P. (2015). PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma. The New England journal of medicine, 372(4), 311-319. https://doi.org/10.1056/NEJMoa1411087

PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma. / Ansell, Stephen Maxted; Lesokhin, Alexander M.; Borrello, Ivan; Halwani, Ahmad; Scott, Emma C.; Gutierrez, Martin; Schuster, Stephen J.; Millenson, Michael M.; Cattry, Deepika; Freeman, Gordon J.; Rodig, Scott J.; Chapuy, Bjoern; Ligon, Azra H.; Zhu, Lili; Grosso, Joseph F.; Kim, Su Y oung; Timmerman, John M.; Shipp, Margaret A.; Armand, Philippe.

In: The New England journal of medicine, Vol. 372, No. 4, 22.01.2015, p. 311-319.

Research output: Contribution to journalArticle

Ansell, SM, Lesokhin, AM, Borrello, I, Halwani, A, Scott, EC, Gutierrez, M, Schuster, SJ, Millenson, MM, Cattry, D, Freeman, GJ, Rodig, SJ, Chapuy, B, Ligon, AH, Zhu, L, Grosso, JF, Kim, SYO, Timmerman, JM, Shipp, MA & Armand, P 2015, 'PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma', The New England journal of medicine, vol. 372, no. 4, pp. 311-319. https://doi.org/10.1056/NEJMoa1411087
Ansell, Stephen Maxted ; Lesokhin, Alexander M. ; Borrello, Ivan ; Halwani, Ahmad ; Scott, Emma C. ; Gutierrez, Martin ; Schuster, Stephen J. ; Millenson, Michael M. ; Cattry, Deepika ; Freeman, Gordon J. ; Rodig, Scott J. ; Chapuy, Bjoern ; Ligon, Azra H. ; Zhu, Lili ; Grosso, Joseph F. ; Kim, Su Y oung ; Timmerman, John M. ; Shipp, Margaret A. ; Armand, Philippe. / PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma. In: The New England journal of medicine. 2015 ; Vol. 372, No. 4. pp. 311-319.
@article{a19cf1bb05dd4aee9186c569671d8924,
title = "PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma",
abstract = "BACKGROUND: Preclinical studies suggest that Reed-Sternberg cells exploit the programmed death 1 (PD-1) pathway to evade immune detection. In classic Hodgkin's lymphoma, alterations in chromosome 9p24.1 increase the abundance of the PD-1 ligands, PD-L1 and PD-L2, and promote their induction through Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling. We hypothesized that nivolumab, a PD-1-blocking antibody, could inhibit tumor immune evasion in patients with relapsed or refractory Hodgkin's lymphoma.METHODS: In this ongoing study, 23 patients with relapsed or refractory Hodgkin's lymphoma that had already been heavily treated received nivolumab (at a dose of 3 mg per kilogram of body weight) every 2 weeks until they had a complete response, tumor progression, or excessive toxic effects. Study objectives were measurement of safety and efficacy and assessment of the PDL1 and PDL2 (also called CD274 and PDCD1LG2, respectively) loci and PD-L1 and PD-L2 protein expression.RESULTS: Of the 23 study patients, 78{\%} were enrolled in the study after a relapse following autologous stem-cell transplantation and 78{\%} after a relapse following the receipt of brentuximab vedotin. Drug-related adverse events of any grade and of grade 3 occurred in 78{\%} and 22{\%} of patients, respectively. An objective response was reported in 20 patients (87{\%}), including 17{\%} with a complete response and 70{\%} with a partial response; the remaining 3 patients (13{\%}) had stable disease. The rate of progression-free survival at 24 weeks was 86{\%}; 11 patients were continuing to participate in the study. Reasons for discontinuation included stem-cell transplantation (in 6 patients), disease progression (in 4 patients), and drug toxicity (in 2 patients). Analyses of pretreatment tumor specimens from 10 patients revealed copy-number gains in PDL1 and PDL2 and increased expression of these ligands. Reed-Sternberg cells showed nuclear positivity of phosphorylated STAT3, indicative of active JAK-STAT signaling.CONCLUSIONS: Nivolumab had substantial therapeutic activity and an acceptable safety profile in patients with previously heavily treated relapsed or refractory Hodgkin's lymphoma. (Funded by Bristol-Myers Squibb and others; ClinicalTrials.gov number, NCT01592370.).",
author = "Ansell, {Stephen Maxted} and Lesokhin, {Alexander M.} and Ivan Borrello and Ahmad Halwani and Scott, {Emma C.} and Martin Gutierrez and Schuster, {Stephen J.} and Millenson, {Michael M.} and Deepika Cattry and Freeman, {Gordon J.} and Rodig, {Scott J.} and Bjoern Chapuy and Ligon, {Azra H.} and Lili Zhu and Grosso, {Joseph F.} and Kim, {Su Y oung} and Timmerman, {John M.} and Shipp, {Margaret A.} and Philippe Armand",
year = "2015",
month = "1",
day = "22",
doi = "10.1056/NEJMoa1411087",
language = "English (US)",
volume = "372",
pages = "311--319",
journal = "New England Journal of Medicine",
issn = "1533-4406",
publisher = "Massachussetts Medical Society",
number = "4",

}

TY - JOUR

T1 - PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma

AU - Ansell, Stephen Maxted

AU - Lesokhin, Alexander M.

AU - Borrello, Ivan

AU - Halwani, Ahmad

AU - Scott, Emma C.

AU - Gutierrez, Martin

AU - Schuster, Stephen J.

AU - Millenson, Michael M.

AU - Cattry, Deepika

AU - Freeman, Gordon J.

AU - Rodig, Scott J.

AU - Chapuy, Bjoern

AU - Ligon, Azra H.

AU - Zhu, Lili

AU - Grosso, Joseph F.

AU - Kim, Su Y oung

AU - Timmerman, John M.

AU - Shipp, Margaret A.

AU - Armand, Philippe

PY - 2015/1/22

Y1 - 2015/1/22

N2 - BACKGROUND: Preclinical studies suggest that Reed-Sternberg cells exploit the programmed death 1 (PD-1) pathway to evade immune detection. In classic Hodgkin's lymphoma, alterations in chromosome 9p24.1 increase the abundance of the PD-1 ligands, PD-L1 and PD-L2, and promote their induction through Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling. We hypothesized that nivolumab, a PD-1-blocking antibody, could inhibit tumor immune evasion in patients with relapsed or refractory Hodgkin's lymphoma.METHODS: In this ongoing study, 23 patients with relapsed or refractory Hodgkin's lymphoma that had already been heavily treated received nivolumab (at a dose of 3 mg per kilogram of body weight) every 2 weeks until they had a complete response, tumor progression, or excessive toxic effects. Study objectives were measurement of safety and efficacy and assessment of the PDL1 and PDL2 (also called CD274 and PDCD1LG2, respectively) loci and PD-L1 and PD-L2 protein expression.RESULTS: Of the 23 study patients, 78% were enrolled in the study after a relapse following autologous stem-cell transplantation and 78% after a relapse following the receipt of brentuximab vedotin. Drug-related adverse events of any grade and of grade 3 occurred in 78% and 22% of patients, respectively. An objective response was reported in 20 patients (87%), including 17% with a complete response and 70% with a partial response; the remaining 3 patients (13%) had stable disease. The rate of progression-free survival at 24 weeks was 86%; 11 patients were continuing to participate in the study. Reasons for discontinuation included stem-cell transplantation (in 6 patients), disease progression (in 4 patients), and drug toxicity (in 2 patients). Analyses of pretreatment tumor specimens from 10 patients revealed copy-number gains in PDL1 and PDL2 and increased expression of these ligands. Reed-Sternberg cells showed nuclear positivity of phosphorylated STAT3, indicative of active JAK-STAT signaling.CONCLUSIONS: Nivolumab had substantial therapeutic activity and an acceptable safety profile in patients with previously heavily treated relapsed or refractory Hodgkin's lymphoma. (Funded by Bristol-Myers Squibb and others; ClinicalTrials.gov number, NCT01592370.).

AB - BACKGROUND: Preclinical studies suggest that Reed-Sternberg cells exploit the programmed death 1 (PD-1) pathway to evade immune detection. In classic Hodgkin's lymphoma, alterations in chromosome 9p24.1 increase the abundance of the PD-1 ligands, PD-L1 and PD-L2, and promote their induction through Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling. We hypothesized that nivolumab, a PD-1-blocking antibody, could inhibit tumor immune evasion in patients with relapsed or refractory Hodgkin's lymphoma.METHODS: In this ongoing study, 23 patients with relapsed or refractory Hodgkin's lymphoma that had already been heavily treated received nivolumab (at a dose of 3 mg per kilogram of body weight) every 2 weeks until they had a complete response, tumor progression, or excessive toxic effects. Study objectives were measurement of safety and efficacy and assessment of the PDL1 and PDL2 (also called CD274 and PDCD1LG2, respectively) loci and PD-L1 and PD-L2 protein expression.RESULTS: Of the 23 study patients, 78% were enrolled in the study after a relapse following autologous stem-cell transplantation and 78% after a relapse following the receipt of brentuximab vedotin. Drug-related adverse events of any grade and of grade 3 occurred in 78% and 22% of patients, respectively. An objective response was reported in 20 patients (87%), including 17% with a complete response and 70% with a partial response; the remaining 3 patients (13%) had stable disease. The rate of progression-free survival at 24 weeks was 86%; 11 patients were continuing to participate in the study. Reasons for discontinuation included stem-cell transplantation (in 6 patients), disease progression (in 4 patients), and drug toxicity (in 2 patients). Analyses of pretreatment tumor specimens from 10 patients revealed copy-number gains in PDL1 and PDL2 and increased expression of these ligands. Reed-Sternberg cells showed nuclear positivity of phosphorylated STAT3, indicative of active JAK-STAT signaling.CONCLUSIONS: Nivolumab had substantial therapeutic activity and an acceptable safety profile in patients with previously heavily treated relapsed or refractory Hodgkin's lymphoma. (Funded by Bristol-Myers Squibb and others; ClinicalTrials.gov number, NCT01592370.).

UR - http://www.scopus.com/inward/record.url?scp=84925221855&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84925221855&partnerID=8YFLogxK

U2 - 10.1056/NEJMoa1411087

DO - 10.1056/NEJMoa1411087

M3 - Article

VL - 372

SP - 311

EP - 319

JO - New England Journal of Medicine

JF - New England Journal of Medicine

SN - 1533-4406

IS - 4

ER -