Dana-Farber Cancer Institute, Boston, MA.
Hôpital Saint-Louis, Université Paris Diderot, Paris, France.
J Clin Oncol. 2021 Jan 1;39(1):48-56. doi: 10.1200/JCO.20.01895. Epub 2020 Oct 27.
Patients with lower-risk (LR) myelodysplastic syndromes (MDS) who are RBC transfusion dependent and have experienced relapse after or are refractory to erythropoiesis-stimulating agent (ESA) have limited treatment options. High telomerase activity and human telomerase reverse-transcription expression in clonal hematopoietic cells have been reported in patients with MDS. Imetelstat, a first-in-class competitive inhibitor of telomerase enzymatic activity, targets cells with active telomerase. We report efficacy, safety, and biomarker data for patients with LR MDS who are RBC transfusion dependent and who were relapsed/refractory to ESAs.
In this two-part phase II/III study (MDS3001), the primary end point was 8-week RBC transfusion independence (TI) rate, with key secondary end points of 24-week RBC TI rate, TI duration, and hematologic improvement-erythroid.
Data from the phase II part of the study are reported. Of 57 patients enrolled and treated (overall population), 38 were non-del(5q) and hypomethylating agent and lenalidomide naïve (subset population). The 8- and 24-week RBC TI rates in the overall population were 37% and 23%, respectively, with a median TI duration of 65 weeks. In the subset population, 8- and 24-week RBC TI rates were 42% and 29%, respectively, with a median TI duration of 86 weeks. Eight-week TI rate was observed across all subgroups evaluated. Cytogenetic and mutational data revealed a reduction of the malignant clones, suggesting disease modification activity. The most common adverse events were cytopenias, typically reversible within 4 weeks.
Imetelstat treatment results in a meaningful, durable TI rate across a broad range of heavily transfused patients with LR MDS who are ineligible for or relapsed/refractory to ESAs. Biomarker analyses indicated effects on the mutant malignant clone.
需要输血的低危（LR）骨髓增生异常综合征（MDS）且红细胞生成刺激剂（ESA）治疗后复发或耐药的患者，其治疗选择有限。有报道称，MDS 患者的克隆造血细胞中存在高端粒酶活性和人端粒酶逆转录酶表达。imetelstat 是一种首创的端粒酶酶活性的竞争性抑制剂，靶向具有活跃端粒酶的细胞。我们报告了依赖输血且对 ESA 复发/耐药的 LR MDS 患者的疗效、安全性和生物标志物数据。
在这项两部分的 2 期/3 期研究（MDS3001）中，主要终点是 8 周红细胞输血独立性（TI）率，关键次要终点为 24 周 RBC TI 率、TI 持续时间和血液学改善-红细胞。
报告了研究的 2 期部分的数据。在纳入并治疗的 57 例患者（总体人群）中，38 例非 del(5q)和低甲基化药物及来那度胺初治（亚组人群）。总体人群的 8 周和 24 周 RBC TI 率分别为 37%和 23%，TI 持续时间中位数为 65 周。在亚组人群中，8 周和 24 周 RBC TI 率分别为 42%和 29%，TI 持续时间中位数为 86 周。在评估的所有亚组中均观察到 8 周 TI 率。细胞遗传学和突变数据显示恶性克隆减少，提示疾病修饰活性。最常见的不良反应是细胞减少症，通常在 4 周内可逆。
imetelstat 治疗可使广泛的依赖输血的 LR MDS 患者获得有意义的、持久的 TI 率，这些患者不适合或对 ESA 复发/耐药。生物标志物分析表明其对突变恶性克隆有影响。
