医学
内科学
阿糖胞苷
粘膜炎
去甲柔比星
耐受性
胃肠病学
化疗
米托蒽醌
髓系白血病
耐火材料(行星科学)
肿瘤科
依托泊苷
诱导化疗
不利影响
物理
天体生物学
作者
Daniel J. DeAngelo,Brian A. Jonas,Jane L. Liesveld,Dale L. Bixby,Anjali S. Advani,Paula Marlton,John L. Magnani,Helen M. Thackray,Eric J. Feldman,Michael O'Dwyer,Pamela S. Becker
出处
期刊:Blood
[American Society of Hematology]
日期:2022-02-24
卷期号:139 (8): 1135-1146
被引量:19
标识
DOI:10.1182/blood.2021010721
摘要
Uproleselan (GMI-1271) is a novel E-selectin antagonist that disrupts cell survival pathways, enhances chemotherapy response, improves survival in mouse xenograft and syngeneic models, and decreases chemotherapy toxicity in vivo. A phase 1/2 study evaluated the safety, tolerability, and antileukemic activity of uproleselan (5-20 mg/kg) with MEC (mitoxantrone, etoposide, and cytarabine) among patients with relapsed/refractory (R/R) acute myeloid leukemia (AML). Among the first 19 patients, no dose-limiting toxicities were observed. The recommended phase 2 dose (RP2D) was 10 mg/kg twice daily. An additional 47 patients with R/R AML were treated with uproleselan at the RP2D plus MEC. At the RP2D, the remission rate (complete response [CR]/CR with incomplete count recovery [CRi]) was 41% (CR, 35%), and the median overall survival (OS) was 8.8 months. In a separate cohort, 25 newly diagnosed patients age ≥60 years received uproleselan at the RP2D plus cytarabine and idarubicin (7 + 3). In these frontline patients, the CR/CRi rate was 72% (CR, 52%), and the median OS was 12.6 months. The addition of uproleselan was associated with low rates of oral mucositis. E-selectin ligand expression on leukemic blasts was higher in patients with relapsed vs primary refractory AML and in newly diagnosed older patients with high-risk cytogenetics and secondary AML. In the R/R cohort, E-selectin expression >10% was associated with a higher response rate and improved survival. The addition of uproleselan to chemotherapy was well tolerated, with high remission rates, low induction mortality, and low rates of mucositis, providing a strong rationale for phase 3 randomized confirmatory studies. This trial was registered at www.clinicaltrials.gov as #NCT02306291.
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