伊马替尼在原发性血小板增多症患者中的应用。

Telomerase Inhibitor Imetelstat in Patients with Essential Thrombocythemia.

机构信息

From the Department of Hematology, University Hospital of Bern and University of Bern, Bern, Switzerland (G.M.B., E.O.L., M.D.); the Department of Hematology, School of Medicine, Cardiff University, Cardiff, United Kingdom (O.G.O.); Upstate Oncology Associates, Greenville, SC (G.S.); the Section of Hematology and Oncology, University of Chicago, Chicago (O.O.); the Divisions of Hematologic Malignancies and Hematology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore (M.A.M.); the Department of Hematology, University Hospital Essen, Essen, Germany (A.R.); and Geron, Menlo Park (B.B., M.S.), and the Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Gehr Family Center for Leukemia Research, Duarte (D.S.S.) - both in California.

出版信息

N Engl J Med. 2015 Sep 3;373(10):920-8. doi: 10.1056/NEJMoa1503479.

DOI:10.1056/NEJMoa1503479

PMID:26332546

Abstract

BACKGROUND

Imetelstat, a 13-mer oligonucleotide that is covalently modified with lipid extensions, competitively inhibits telomerase enzymatic activity. It has been shown to inhibit megakaryocytic proliferation in vitro in cells obtained from patients with essential thrombocythemia. In this phase 2 study, we investigated whether imetelstat could elicit hematologic and molecular responses in patients with essential thrombocythemia who had not had a response to or who had had unacceptable side effects from prior therapies.

METHODS

A total of 18 patients in two sequential cohorts received an initial dose of 7.5 or 9.4 mg of imetelstat per kilogram of body weight intravenously once a week until attainment of a platelet count of approximately 250,000 to 300,000 per cubic millimeter. The primary end point was the best hematologic response.

RESULTS

Imetelstat induced hematologic responses in all 18 patients, and 16 patients (89%) had a complete hematologic response. At the time of the primary analysis, 10 patients were still receiving treatment, with a median follow-up of 17 months (range, 7 to 32 [ongoing]). Molecular responses were seen in 7 of 8 patients who were positive for the JAK2 V617F mutation (88%; 95% confidence interval, 47 to 100). CALR and MPL mutant allele burdens were also reduced by 15 to 66%. The most common adverse events during treatment were mild to moderate in severity; neutropenia of grade 3 or higher occurred in 4 of the 18 patients (22%) and anemia, headache, and syncope of grade 3 or higher each occurred in 2 patients (11%). All the patients had at least one abnormal liver-function value; all persistent elevations were grade 1 or 2 in severity.

CONCLUSIONS

Rapid and durable hematologic and molecular responses were observed in patients with essential thrombocythemia who received imetelstat. (Funded by Geron; ClinicalTrials.gov number, NCT01243073.).

摘要

背景

伊美替萨（imetelstat）是一种带有脂质延伸的 13 个核苷酸寡聚物，它可以竞争性抑制端粒酶的酶活性。它已被证明可以抑制体外从原发性血小板增多症患者中获得的巨核细胞增殖。在这项 2 期研究中，我们研究了伊美替萨是否可以在对先前治疗无反应或无法耐受的原发性血小板增多症患者中引起血液学和分子反应。

方法

两个连续队列的 18 名患者最初每周一次静脉注射 7.5 或 9.4mg/kg 的伊美替萨，直到血小板计数达到每立方毫米约 250,000 至 300,000 为止。主要终点是最佳血液学反应。

结果

伊美替萨诱导了所有 18 名患者的血液学反应，16 名患者（89%）有完全血液学反应。在主要分析时，10 名患者仍在接受治疗，中位随访时间为 17 个月（范围，7 至 32[持续]）。在 8 名 JAK2 V617F 突变阳性的患者中观察到分子反应（88%；95%置信区间，47%至 100%）。CALR 和 MPL 突变等位基因负担也降低了 15%至 66%。治疗期间最常见的不良反应为轻至中度；18 名患者中有 4 名（22%）发生 3 级或更高级别的中性粒细胞减少症，2 名（11%）各发生 3 级或更高级别的贫血、头痛和晕厥。所有患者至少有一个肝功能值异常；所有持续性升高均为 1 级或 2 级。