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N Engl J Med. 2018 Jun 21;378(25):2399-2410. doi: 10.1056/NEJMoa1802917. Epub 2018 Jun 1.

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

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From the National and Kapodistrian University of Athens School of Medicine, Athens (M.A.D., E.K.); ASST Grande Ospedale Metropolitano Niguarda, Milan (A.T.), and Città della Salute Hospital and University, Turin (L.O.) - both in Italy; Concord Hospital, University of Sydney, Concord, NSW (J.T.), and Peter MacCallum Cancer Centre and St. Vincent's Hospital, Melbourne, VIC (C.T.) - both in Australia; Hospital Universitario de Salamanca, Salamanca, Spain (R.G.-S.); Ottawa Hospital, University of Ottawa, Ottawa (D.M.), and Royal Victoria Hospital at McGill University Health Centre, Montreal (C.S.) - both in Canada; Département d'Hématologie, Hôpital Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Université Pierre et Marie Curie, Paris (V.L.), Centre Hospitalier Universitaire de Nantes, Nantes (B.M.), and Centre Hospitalier Régional Universitaire de Lille, Institute of Hematolog-Tranfusion, Lille (C.H.) - all in France; Memorial Sloan Kettering Cancer Center, New York (M.L.P.); Colorado Blood Cancer Institute, Denver (J.V.M.); Dana-Farber Cancer Institute, Boston (S.P.T.); Pharmacyclics, Sunnyvale, CA (J.L., Z.S., T.G.); and Comprehensive Cancer Center Ulm, Institute of Experimental Cancer Research, Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany (C.B.).



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.


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.


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%).


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; number, NCT02165397 .).

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