伊布替尼联合利妥昔单抗治疗华氏巨球蛋白血症的 3 期临床试验。
Phase 3 Trial of Ibrutinib plus Rituximab in Waldenström's Macroglobulinemia.
机构信息
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.).
出版信息
N Engl J Med. 2018 Jun 21;378(25):2399-2410. doi: 10.1056/NEJMoa1802917. Epub 2018 Jun 1.
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 .).
背景
单药伊布替尼在复发性华氏巨球蛋白血症（一种罕见的 B 细胞淋巴瘤）患者中显示出显著的活性。我们评估了在这些患者中，伊布替尼联合利妥昔单抗与安慰剂联合利妥昔单抗相比的疗效，包括未接受过治疗的患者和疾病复发的患者。
方法
我们随机分配了 150 名有症状的患者接受伊布替尼联合利妥昔单抗或安慰剂联合利妥昔单抗治疗。主要终点是无进展生存期，由独立审查委员会评估。关键次要终点为缓解率、从基线开始的持续血液学改善和安全性。骨髓样本评估了 MYD88 和 CXCR4 的突变状态。
结果
在 30 个月时，伊布替尼-利妥昔单抗组的无进展生存率为 82%，而安慰剂-利妥昔单抗组为 28%（进展或死亡的风险比，0.20；P<0.001）。伊布替尼-利妥昔单抗组的获益与 MYD88 或 CXCR4 基因型无关。伊布替尼-利妥昔单抗组的主要缓解率高于安慰剂-利妥昔单抗组（72% vs. 32%，P<0.001）。更多患者接受伊布替尼-利妥昔单抗治疗后血红蛋白水平持续升高（73% vs. 41%，P<0.001）。伊布替尼-利妥昔单抗最常见的任何级别不良反应包括输注相关反应、腹泻、关节痛和恶心。伊布替尼-利妥昔单抗组比安慰剂-利妥昔单抗组更常见的 3 级或更高级别的不良反应包括心房颤动（12% vs. 1%）和高血压（13% vs. 4%）；更常见的不良反应包括输注反应（1% vs. 16%）和任何级别 IgM 爆发（8% vs. 47%）。两组试验的主要出血率相同（4%）。
结论
在华氏巨球蛋白血症患者中，与安慰剂联合利妥昔单抗相比，伊布替尼联合利妥昔单抗显著提高了无进展生存率，无论是在未接受过治疗的患者中还是在疾病复发的患者中。心房颤动和高血压在伊布替尼-利妥昔单抗组更为常见，而输注反应和 IgM 爆发在安慰剂-利妥昔单抗组更为常见。（由 Pharmacyclics 和 Janssen Research and Development 资助；ClinicalTrials.gov 编号，NCT02165397）。
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