Abstract
BACKGROUND Single-agent ibrutinib has shown substantial activity in patients with relapsed Waldenstrom'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 Waldenstrom'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 language | English |
|---|---|
| Pages (from-to) | 2399-2410 |
| Number of pages | 12 |
| Journal | New England Journal of Medicine |
| Volume | 378 |
| Issue number | 25 |
| DOIs | |
| Publication status | Published - Jun 21 2018 |
| Externally published | Yes |
Bibliographical note
Funding Information:The trial was sponsored by Pharmacyclics and designed by the sponsor in collaboration with the investigators and Janssen Research and Development; the two companies provided funding for the trial. Janssen representatives had access to the data and were permitted a courtesy review of the manuscript but were otherwise not involved in the trial conduct. All the investigators and their research teams collected data. The sponsor confirmed the accuracy of the data and compiled the data for analysis. All the authors had full access to the data and analyses. The first author, the last author, and two authors who were employed by the sponsor wrote the first draft of the manuscript. Editorial support was provided by a professional medical writer who was funded by the sponsor. All the authors reviewed the manuscript and made the decision to submit it for publication and vouch for the accuracy and completeness of the data and analyses and for the adherence of the trial to the protocol (available with the full text of this article at NEJM.org). An independent review committee evaluated the response and disease progression in a blinded manner.
Publisher Copyright:
Copyright © 2018 Massachusetts Medical Society.
ASJC Scopus Subject Areas
- General Medicine
