Phase 3 Trial of Ibrutinib plus Rituximab in Waldenström's Macroglobulinemia

iNNOVATE Study Group and the European Consortium for Waldenström’s Macroglobulinemia

Research output: Contribution to journalArticle

Abstract

BACKGROUND: Single-agent ibrutinib has shown substantial activity in patients with relapsed Waldenström's macroglobulinemia, a rare form of B-cell lymphoma. We evaluated the effect of adding ibrutinib to rituximab in patients with this disease, both in those who had not received previous treatment and in those with disease recurrence.

METHODS: We randomly assigned 150 symptomatic patients to receive ibrutinib plus rituximab or placebo plus rituximab. The primary end point was progression-free survival, as assessed by an independent review committee. Key secondary end points were response rates, sustained hematologic improvement from baseline, and safety. The mutational status of MYD88 and CXCR4 was assessed in bone marrow samples.

RESULTS: At 30 months, the progression-free survival rate was 82% with ibrutinib-rituximab versus 28% with placebo-rituximab (hazard ratio for progression or death, 0.20; P<0.001). The benefit in the ibrutinib-rituximab group over that in the placebo-rituximab group was independent of the MYD88 or CXCR4 genotype. The rate of major response was higher with ibrutinib-rituximab than with placebo-rituximab (72% vs. 32%, P<0.001). More patients had sustained increases in hemoglobin level with ibrutinib-rituximab than with placebo-rituximab (73% vs. 41%, P<0.001). The most common adverse events of any grade with ibrutinib-rituximab included infusion-related reactions, diarrhea, arthralgia, and nausea. Events of grade 3 or higher that occurred more frequently with ibrutinib-rituximab than with placebo-rituximab included atrial fibrillation (12% vs. 1%) and hypertension (13% vs. 4%); those that occurred less frequently included infusion reactions (1% vs. 16%) and any grade of IgM flare (8% vs. 47%). The major hemorrhage rate was the same in the two trial groups (4%).

CONCLUSIONS: Among patients with Waldenström's macroglobulinemia, the use of ibrutinib-rituximab resulted in significantly higher rates of progression-free survival than the use of placebo-rituximab, both among those who had received no previous treatment and among those with disease recurrence. Atrial fibrillation and hypertension were more common with ibrutinib-rituximab, whereas infusion reactions and IgM flare were more common with placebo-rituximab. (Funded by Pharmacyclics and Janssen Research and Development; ClinicalTrials.gov number, NCT02165397 .).

Original languageEnglish
Pages (from-to)2399-2410
Number of pages12
JournalThe New England journal of medicine
Volume378
Issue number25
DOIs
Publication statusPublished - Jun 21 2018
Externally publishedYes

Fingerprint

Waldenstrom Macroglobulinemia
Placebos
Disease-Free Survival
Rituximab
PCI 32765
Atrial Fibrillation
Immunoglobulin M
Hypertension
Recurrence

Keywords

  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Combined Chemotherapy Protocols/adverse effects
  • Atrial Fibrillation/chemically induced
  • Disease-Free Survival
  • Female
  • Hemoglobins/analysis
  • Humans
  • Immunoglobulin M/blood
  • Infusions, Intravenous/adverse effects
  • Male
  • Middle Aged
  • Pyrazoles/administration & dosage
  • Pyrimidines/administration & dosage
  • Rituximab/administration & dosage
  • Survival Analysis
  • Waldenstrom Macroglobulinemia/blood

Cite this

iNNOVATE Study Group and the European Consortium for Waldenström’s Macroglobulinemia (2018). Phase 3 Trial of Ibrutinib plus Rituximab in Waldenström's Macroglobulinemia. The New England journal of medicine, 378(25), 2399-2410. https://doi.org/10.1056/NEJMoa1802917

Phase 3 Trial of Ibrutinib plus Rituximab in Waldenström's Macroglobulinemia. / iNNOVATE Study Group and the European Consortium for Waldenström’s Macroglobulinemia.

In: The New England journal of medicine, Vol. 378, No. 25, 21.06.2018, p. 2399-2410.

Research output: Contribution to journalArticle

iNNOVATE Study Group and the European Consortium for Waldenström’s Macroglobulinemia 2018, 'Phase 3 Trial of Ibrutinib plus Rituximab in Waldenström's Macroglobulinemia', The New England journal of medicine, vol. 378, no. 25, pp. 2399-2410. https://doi.org/10.1056/NEJMoa1802917
iNNOVATE Study Group and the European Consortium for Waldenström’s Macroglobulinemia. Phase 3 Trial of Ibrutinib plus Rituximab in Waldenström's Macroglobulinemia. The New England journal of medicine. 2018 Jun 21;378(25):2399-2410. https://doi.org/10.1056/NEJMoa1802917
iNNOVATE Study Group and the European Consortium for Waldenström’s Macroglobulinemia. / Phase 3 Trial of Ibrutinib plus Rituximab in Waldenström's Macroglobulinemia. In: The New England journal of medicine. 2018 ; Vol. 378, No. 25. pp. 2399-2410.
@article{9b38c9fb536a405499d4f09c1bf1537a,
title = "Phase 3 Trial of Ibrutinib plus Rituximab in Waldenstr{\"o}m's Macroglobulinemia",
abstract = "BACKGROUND: Single-agent ibrutinib has shown substantial activity in patients with relapsed Waldenstr{\"o}m's macroglobulinemia, a rare form of B-cell lymphoma. We evaluated the effect of adding ibrutinib to rituximab in patients with this disease, both in those who had not received previous treatment and in those with disease recurrence.METHODS: We randomly assigned 150 symptomatic patients to receive ibrutinib plus rituximab or placebo plus rituximab. The primary end point was progression-free survival, as assessed by an independent review committee. Key secondary end points were response rates, sustained hematologic improvement from baseline, and safety. The mutational status of MYD88 and CXCR4 was assessed in bone marrow samples.RESULTS: At 30 months, the progression-free survival rate was 82{\%} with ibrutinib-rituximab versus 28{\%} with placebo-rituximab (hazard ratio for progression or death, 0.20; P<0.001). The benefit in the ibrutinib-rituximab group over that in the placebo-rituximab group was independent of the MYD88 or CXCR4 genotype. The rate of major response was higher with ibrutinib-rituximab than with placebo-rituximab (72{\%} vs. 32{\%}, P<0.001). More patients had sustained increases in hemoglobin level with ibrutinib-rituximab than with placebo-rituximab (73{\%} vs. 41{\%}, P<0.001). The most common adverse events of any grade with ibrutinib-rituximab included infusion-related reactions, diarrhea, arthralgia, and nausea. Events of grade 3 or higher that occurred more frequently with ibrutinib-rituximab than with placebo-rituximab included atrial fibrillation (12{\%} vs. 1{\%}) and hypertension (13{\%} vs. 4{\%}); those that occurred less frequently included infusion reactions (1{\%} vs. 16{\%}) and any grade of IgM flare (8{\%} vs. 47{\%}). The major hemorrhage rate was the same in the two trial groups (4{\%}).CONCLUSIONS: Among patients with Waldenstr{\"o}m's macroglobulinemia, the use of ibrutinib-rituximab resulted in significantly higher rates of progression-free survival than the use of placebo-rituximab, both among those who had received no previous treatment and among those with disease recurrence. Atrial fibrillation and hypertension were more common with ibrutinib-rituximab, whereas infusion reactions and IgM flare were more common with placebo-rituximab. (Funded by Pharmacyclics and Janssen Research and Development; ClinicalTrials.gov number, NCT02165397 .).",
keywords = "Adult, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols/adverse effects, Atrial Fibrillation/chemically induced, Disease-Free Survival, Female, Hemoglobins/analysis, Humans, Immunoglobulin M/blood, Infusions, Intravenous/adverse effects, Male, Middle Aged, Pyrazoles/administration & dosage, Pyrimidines/administration & dosage, Rituximab/administration & dosage, Survival Analysis, Waldenstrom Macroglobulinemia/blood",
author = "{iNNOVATE Study Group and the European Consortium for Waldenstr{\"o}m’s Macroglobulinemia} and Dimopoulos, {Meletios A} and Alessandra Tedeschi and Judith Trotman and Ram{\'o}n Garc{\'i}a-Sanz and David Macdonald and Veronique Leblond and Beatrice Mahe and Charles Herbaux and Constantine Tam and Lorella Orsucci and Palomba, {M Lia} and Matous, {Jeffrey V} and Chaim Shustik and Efstathios Kastritis and Treon, {Steven P} and Jianling Li and Zeena Salman and Thorsten Graef and Christian Buske",
year = "2018",
month = "6",
day = "21",
doi = "10.1056/NEJMoa1802917",
language = "English",
volume = "378",
pages = "2399--2410",
journal = "New England Journal of Medicine",
issn = "0028-4793",
publisher = "Massachussetts Medical Society",
number = "25",

}

TY - JOUR

T1 - Phase 3 Trial of Ibrutinib plus Rituximab in Waldenström's Macroglobulinemia

AU - iNNOVATE Study Group and the European Consortium for Waldenström’s Macroglobulinemia

AU - Dimopoulos, Meletios A

AU - Tedeschi, Alessandra

AU - Trotman, Judith

AU - García-Sanz, Ramón

AU - Macdonald, David

AU - Leblond, Veronique

AU - Mahe, Beatrice

AU - Herbaux, Charles

AU - Tam, Constantine

AU - Orsucci, Lorella

AU - Palomba, M Lia

AU - Matous, Jeffrey V

AU - Shustik, Chaim

AU - Kastritis, Efstathios

AU - Treon, Steven P

AU - Li, Jianling

AU - Salman, Zeena

AU - Graef, Thorsten

AU - Buske, Christian

PY - 2018/6/21

Y1 - 2018/6/21

N2 - BACKGROUND: Single-agent ibrutinib has shown substantial activity in patients with relapsed Waldenström's macroglobulinemia, a rare form of B-cell lymphoma. We evaluated the effect of adding ibrutinib to rituximab in patients with this disease, both in those who had not received previous treatment and in those with disease recurrence.METHODS: We randomly assigned 150 symptomatic patients to receive ibrutinib plus rituximab or placebo plus rituximab. The primary end point was progression-free survival, as assessed by an independent review committee. Key secondary end points were response rates, sustained hematologic improvement from baseline, and safety. The mutational status of MYD88 and CXCR4 was assessed in bone marrow samples.RESULTS: At 30 months, the progression-free survival rate was 82% with ibrutinib-rituximab versus 28% with placebo-rituximab (hazard ratio for progression or death, 0.20; P<0.001). The benefit in the ibrutinib-rituximab group over that in the placebo-rituximab group was independent of the MYD88 or CXCR4 genotype. The rate of major response was higher with ibrutinib-rituximab than with placebo-rituximab (72% vs. 32%, P<0.001). More patients had sustained increases in hemoglobin level with ibrutinib-rituximab than with placebo-rituximab (73% vs. 41%, P<0.001). The most common adverse events of any grade with ibrutinib-rituximab included infusion-related reactions, diarrhea, arthralgia, and nausea. Events of grade 3 or higher that occurred more frequently with ibrutinib-rituximab than with placebo-rituximab included atrial fibrillation (12% vs. 1%) and hypertension (13% vs. 4%); those that occurred less frequently included infusion reactions (1% vs. 16%) and any grade of IgM flare (8% vs. 47%). The major hemorrhage rate was the same in the two trial groups (4%).CONCLUSIONS: Among patients with Waldenström's macroglobulinemia, the use of ibrutinib-rituximab resulted in significantly higher rates of progression-free survival than the use of placebo-rituximab, both among those who had received no previous treatment and among those with disease recurrence. Atrial fibrillation and hypertension were more common with ibrutinib-rituximab, whereas infusion reactions and IgM flare were more common with placebo-rituximab. (Funded by Pharmacyclics and Janssen Research and Development; ClinicalTrials.gov number, NCT02165397 .).

AB - BACKGROUND: Single-agent ibrutinib has shown substantial activity in patients with relapsed Waldenström's macroglobulinemia, a rare form of B-cell lymphoma. We evaluated the effect of adding ibrutinib to rituximab in patients with this disease, both in those who had not received previous treatment and in those with disease recurrence.METHODS: We randomly assigned 150 symptomatic patients to receive ibrutinib plus rituximab or placebo plus rituximab. The primary end point was progression-free survival, as assessed by an independent review committee. Key secondary end points were response rates, sustained hematologic improvement from baseline, and safety. The mutational status of MYD88 and CXCR4 was assessed in bone marrow samples.RESULTS: At 30 months, the progression-free survival rate was 82% with ibrutinib-rituximab versus 28% with placebo-rituximab (hazard ratio for progression or death, 0.20; P<0.001). The benefit in the ibrutinib-rituximab group over that in the placebo-rituximab group was independent of the MYD88 or CXCR4 genotype. The rate of major response was higher with ibrutinib-rituximab than with placebo-rituximab (72% vs. 32%, P<0.001). More patients had sustained increases in hemoglobin level with ibrutinib-rituximab than with placebo-rituximab (73% vs. 41%, P<0.001). The most common adverse events of any grade with ibrutinib-rituximab included infusion-related reactions, diarrhea, arthralgia, and nausea. Events of grade 3 or higher that occurred more frequently with ibrutinib-rituximab than with placebo-rituximab included atrial fibrillation (12% vs. 1%) and hypertension (13% vs. 4%); those that occurred less frequently included infusion reactions (1% vs. 16%) and any grade of IgM flare (8% vs. 47%). The major hemorrhage rate was the same in the two trial groups (4%).CONCLUSIONS: Among patients with Waldenström's macroglobulinemia, the use of ibrutinib-rituximab resulted in significantly higher rates of progression-free survival than the use of placebo-rituximab, both among those who had received no previous treatment and among those with disease recurrence. Atrial fibrillation and hypertension were more common with ibrutinib-rituximab, whereas infusion reactions and IgM flare were more common with placebo-rituximab. (Funded by Pharmacyclics and Janssen Research and Development; ClinicalTrials.gov number, NCT02165397 .).

KW - Adult

KW - Aged

KW - Aged, 80 and over

KW - Antineoplastic Combined Chemotherapy Protocols/adverse effects

KW - Atrial Fibrillation/chemically induced

KW - Disease-Free Survival

KW - Female

KW - Hemoglobins/analysis

KW - Humans

KW - Immunoglobulin M/blood

KW - Infusions, Intravenous/adverse effects

KW - Male

KW - Middle Aged

KW - Pyrazoles/administration & dosage

KW - Pyrimidines/administration & dosage

KW - Rituximab/administration & dosage

KW - Survival Analysis

KW - Waldenstrom Macroglobulinemia/blood

U2 - 10.1056/NEJMoa1802917

DO - 10.1056/NEJMoa1802917

M3 - Article

C2 - 29856685

VL - 378

SP - 2399

EP - 2410

JO - New England Journal of Medicine

JF - New England Journal of Medicine

SN - 0028-4793

IS - 25

ER -