期刊
CANCER
卷 124, 期 13, 页码 2758-2765出版社
WILEY
DOI: 10.1002/cncr.31398
关键词
acute myeloid leukemia (AML); biomarker; cytarabine; idarubicin; indisulam; relapsed; refractory
类别
资金
- Eisai Pharmaceuticals
- University of Texas MD Anderson Cancer Center Support Grant [CA016672]
- University of Texas MD Anderson Cancer Center Leukemia Specialized Programs of Research Excellence grant from the National Cancer Institute [SPORE CA100632]
BACKGROUND: Indisulam possesses anticancer properties through down-regulation of various cell-cycle checkpoint molecules, thereby blocking the phosphorylation of retinoblastoma protein and inducing p53 and p21. Indisulam exhibits synergy with nucleoside analogs and topoisomerase inhibitors. METHODS: The authors designed a phase 2 study of indisulam in combination with idarubicin and cytarabine in patients who had relapsed/refractory acute myeloid leukemia AML and high-risk myelodysplastic syndrome. In stage 1, patients received intravenous indisulam at 400mg/m(2) on days 1 and 8 of a 28-day cycle. If they had no response, then patients received same dose schedule of indisulam followed by intravenous idarubicin 8mg/m(2) daily for 3 days and cytarabine 1.0 g/m(2) over 24 hours daily on days 9 through 12 (for those aged< 60 years) or days 9 through 11 (for those aged> 60 years) of a 28-day cycle. Primary endpoints included the overall response rate, and secondary objectives included overall survival. RESULTS: Forty patients were enrolled. Of the 37 evaluable patients, 31 received indisulam with chemotherapy. Of these, 11 (35%) responded for a median duration of 5.3 months. The estimated 1-year overall survival rate was 51% for responders compared with 8 % for nonresponders (P<. 001). The most common grade >= 3 nonhematologic toxicities were electrolyte abnormalities (50%) and febrile neutropenia (28%). CONCLUSIONS: The combination of indisulam with idarubicin and cytarabine yielded a 35% response rate in heavily pretreated patients with AML. With emerging data identifying the expression of DCAF15 (DDB1 and CUL4-associated factor 15) as a potential biomarker for activity, the combination of indisulam with idarubicin and cytarabine should be studied in a biomarker-driven trial or in patients who have splicing factor mutations. (C) 2018 American Cancer Society.
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