Long-Term Follow-up of Previously Treated Patients Who Received Ibrutinib for Symptomatic Waldenstrom's Macroglobulinemia: Update of Pivotal Clinical Trial
Long-Term Follow-up of Previously Treated Patients Who Received Ibrutinib for Symptomatic Waldenstrom's Macroglobulinemia: Update of Pivotal Clinical Trial
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对接受依鲁替尼治疗症状性华氏巨球蛋白血症的既往治疗患者的长期随访：关键临床试验的更新
DOI：
10.1182/blood.v130.suppl_1.2766.2766
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发表时间：
2017
期刊：
影响因子：
20.3
通讯作者：
R. Advani
中科院分区：
文献类型：
--
作者：
S. Treon;K. Meid;J. Gustine;K. Bantilan;T. Dubeau;Patricia Severns;Guang Yang;Lian Xu;C. Patterson;I. Ghobrial;J. Laubach;Z. Hunter;J. Castillo;M. Palomba;R. Advani
MyD88突变存在于95%的WM患者中，并通过Bruton9s酪氨酸激酶和造血细胞激酶触发恶性细胞生长，这两个酶都是伊布鲁替尼的靶点。CXCR4突变在30%-40%的先前接受治疗的西医患者中被发现，并在体外对伊布鲁替尼产生耐药性。因此，我们进行了一项前瞻性研究，检查了先前治疗的西医患者中伊布鲁替尼的活性(Treon等人，《新英格兰医学杂志》2015)。结果表明，伊布鲁替尼在以前治疗的西医患者中非常活跃，并支持FDA和EMA首次批准用于治疗西医的药物。在此，我们提供这项研究的长期随访。研究对象为63名既往至少接受过一次治疗的有症状西医患者。基线特征如下：中位年龄63岁(44~86岁)，男性48例(76%)，IPSSWM评分低(n=14；22%)、中(n=27；43%)、高(n=22；35%)，血清Ig M中位数为3,520(范围724~8,390 mg/dL)，血红蛋白中位数10.5(范围8.2~13.8g/dL)，血清B2M中位数3.9(1.3~14.2 mg/L)，腺病及GT 1.5 cm(n=37；59%)；15 cm(n=7；11%)，骨髓病变累及中位数为60%(3~95%)。既往治疗的中位数为2例(范围1-9)，25例(40%)患者对既往治疗无效。分别对63名和62名患者进行了MyD88和CXCR4基因分型，如表1所示。患者开始服用伊布鲁替尼420 mg/d，并允许降低毒性剂量。患者接受40个月的伊布鲁替尼方案管理，此后过渡到商业供应。患者可以同意在商业药物供应40个月后继续随访进行反应评估。伊布鲁替尼在病情进展或不耐受之前一直服用。使用伊布鲁替尼的中位时间为46.6个月(0.5-60个月)。随着治疗时间的延长，患者的分类反应有所改善。总体和主要(>；PR)应答率分别为90.4%和77.7%，不受既往治疗路线或复发或难治状态的影响。17例(27%)患者获得VGPR。没有观察到完全的反应。在最佳反应时，血清IgM水平中值从3520 mg/dL降至821 mg/dL(p 3000 mg/dL)，而最佳反应时患者中有4/63(6%)(p图1显示了所有研究参与者(A)以及由MYD88和CXCR4突变状态(B)分型的患者的Kaplan Meier无进展存活率(PFS)曲线。中位研究随访47.1个月，MYD88MutCXCR4WT患者的中位PFS尚未达到。相比之下，MYD88MutCXCR4Mut患者的中位PFS为45个月，MYD88WTCXCR4WT患者的中位PFS为21个月(3向比较对数等级p=0.0093)。三名患者因病情恶化而死亡。至少可能与方案治疗有关的不良事件(2级)在方案治疗期间5%的患者如下：贫血4例；房颤6例；胃肠道反流病5例；高血压5例；中性粒细胞减少14例；肺炎6例；皮肤感染3例；血小板减少9例。7例(11%)在服用伊布鲁替尼时发生房性心律失常[1级1例，2级5例，3级1例]。其中6名患者继续接受伊布鲁替尼治疗房性心律失常。4例患者因不良反应退出常规治疗：房颤1例，与药物治疗无关的感染1例，操作相关性血肿1例，血小板减少1例。这项关键研究的长期随访结果证实，伊布鲁替尼对有症状的复发和难治性西医患者非常有效，并产生持久的反应。延长伊布鲁替尼治疗时间与分类反应的改善有关，包括达到VGPR。在该患者群体中，MYD88和CXCR4突变状态会影响ibrutinib的反应活性和PFS。(ClinicalTrials.gov编号，NCT01614821。)披露Treon：药典：咨询，研究资金。劳巴赫：诺华、武田、Celgene：咨询；诺华、武田、Celgene、Onyx：研究资金。卡斯蒂略：药典：咨询，研究资助；艾伯维：研究资助；千禧年：研究资助；扬森：咨询，研究资助。Palomba：默克：咨询公司。Advani：药典：咨询；药典：研究资助；Janssen：研究资助；Infinity：研究资助；Juno治疗：咨询；Agensys：研究资助；Celgene：研究资助；NanoString：咨询；Cell Medica：研究资助；Genentech：研究资助；默克：研究资助；百时美施贵宝：咨询，研究资助；Gilead：咨询；西雅图遗传学：研究资助；拜耳医疗制药：研究资助；47：研究资助；Spectrum：咨询；Sutro：咨询；Regeneron：研究资助；千禧：研究资助；Kura：研究资助。
MYD88 mutations are present in 95% of WM patients and trigger malignant cell growth through Bruton9s Tyrosine Kinase and Hematopoietic Cell Kinase, both targets of ibrutinib. CXCR4 mutations are found in 30-40% of previously treated WM patients and confer in vitro resistance to ibrutinib. We therefore performed a prospective study that examined the activity of ibrutinib in previously treated WM patients (Treon et al, NEJM 2015). The findings showed that ibrutinib was highly active in previously treated WM patients and supported the first ever FDA and EMA drug approval for the treatment of WM. Herein, we provide a long-term follow-up of this study. Sixty-three symptomatic WM patients who received at least one prior therapy were enrolled. Their baseline characteristics were as follows: median age 63 (range 44-86 yrs); 48 (76%) were male, IPSSWM scores were low (n=14; 22%), intermediate (n=27; 43%), and high (n=22; 35%); median serum IgM was 3,520 (range 724-8,390 mg/dL); median hemoglobin level was 10.5 (range 8.2-13.8 g/dL); median serum B2M level was 3.9 (1.3-14.2 mg/L); adenopathy >1.5 cm (n=37; 59%); splenomegaly >15 cm (n=7; 11%), and median bone marrow disease involvement was 60% (range 3-95%). The median prior therapies was 2 (range 1-9), and 25 (40%) patients were refractory to their previous therapy. MYD88 and CXCR4 genotyping was performed for 63 and 62 patients, respectively and is shown in Table 1. Patients were initiated on 420 mg a day of ibrutinib, and dose de-escalation for toxicity was permitted. Patients received protocol administered ibrutinib for 40 months, and transitioned to commercial supply thereafter. Patients could consent to continue follow-up for response assessment after 40 months on commercial drug supply. Ibrutinib was administered until progression or intolerance. The median time on ibrutinib was 46.6 (range 0.5-60 months). Improvements in categorical responses occurred with prolonged treatment. The overall and major (>PR) response rates were 90.4% and 77.7%, respectively, and were not impacted by prior lines of therapy or relapsed or refractory status. Seventeen (27%) patients achieved a VGPR. No complete responses were observed. At best response, median serum IgM level declined from 3,520 to 821 mg/dL (p 3,000 mg/dL versus 4/63 (6%) patients at best response (p Figure 1 shows the Kaplan Meier curves for progression free survival (PFS) for all study participants (A), and those genotyped by MYD88 and CXCR4 mutation status (B). With a median study follow-up of 47.1 months, the median PFS for patients with MYD88MutCXCR4WT has not been reached. By comparison, the median PFS was 45 months for patients with MYD88MutCXCR4Mut, and 21 months for those with MYD88WTCXCR4WT (Log-rank p=0.0093 for 3-way comparison). Three patients died due to disease progression. Adverse events (Grade >2) that were at least possibly related to protocol therapy in >5% of patients during protocol therapy were as follows: anemia (n=4); atrial fibrillation (n=6); GERD (n=5); hypertension (n=5); neutropenia (n=14); pneumonia (n=6); skin infection (n=3); thrombocytopenia (n=9). Seven patients (11%) had atrial arrhythmia [Grade 1 (n=1); Grade 2 (n=5); Grade 3 (n=1)] on ibrutinib. Six of these patients continued ibrutinib with medical management for their atrial arrhythmia. Four patients came off protocol therapy for toxicity: atrial fibrillation (n=1); infection not related to drug therapy (n=1), procedure related hematoma (n=1), and thrombocytopenia (n=1). The findings from the long-term follow-up of this pivotal study confirm that ibrutinib is highly active in symptomatic patients with relapsed and refractory WM, and produces durable responses. Prolonged ibrutinib therapy is associated with improvements in categorical responses, including attainment of VGPR. Ibrutinib response activity and PFS are impacted by MYD88 and CXCR4 mutation status in this patient population. (ClinicalTrials.gov number, NCT01614821.) Disclosures Treon: Pharmacyclics: Consultancy, Research Funding. Laubach: Novartis, Takeda, Celgene: Consultancy; Novartis, Takeda, Celgene, Onyx: Research Funding. Castillo: Pharmacyclics: Consultancy, Research Funding; Abbvie: Research Funding; Millennium: Research Funding; Janssen: Consultancy, Research Funding. Palomba: Merck: Consultancy. Advani: Pharmacyclics: Consultancy; Pharmacyclics: Research Funding; Janssen: Research Funding; Infinity: Research Funding; Juno Therapeutics: Consultancy; Agensys: Research Funding; Celgene: Research Funding; Nanostring: Consultancy; Cell Medica: Research Funding; Genentech: Research Funding; Merck: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Gilead: Consultancy; Seattle Genetics: Research Funding; Bayer Healthcare Pharmaceuticals: Research Funding; FortySeven: Research Funding; Spectrum: Consultancy; Sutro: Consultancy; Regeneron: Research Funding; Millennium: Research Funding; Kura: Research Funding.