期刊
BLOOD
卷 119, 期 1, 页码 55-63出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2011-08-370825
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资金
- National Cancer Institute [U01 CA70095]
- National Cancer Institute Cancer Center [2P30 CA06973-46]
- National Center for Research Resources [UL1 RR025005]
- Leukemia Lymphoma Society (White Plains, NY) [6047-08]
- Dr Robert E. Fischell in memory of his late wife Marian
Tipifarnib (T) exhibits modest activity in elderly adults with newly diagnosed acute myelogenous leukemia (AML). Based on preclinical synergy, a phase 1 trial of T plus etoposide (E) yielded 25% complete remission (CR). We selected 2 comparable dose levels for a randomized phase 2 trial in 84 adults (age range, 70-90 years; median, 76 years) who were not candidates for conventional chemotherapy. ArmA(T 600 mg twice a day x 14 days, E 100 mg days 1-3 and 8-10) and arm B (T 400 mg twice a day x 14 days, E 200 mg days 1-3 and 8-10) yielded similar CR, but arm B had greater toxicity. Total CR was 25%, day 30 death rate 7%. A 2-gene signature of high RASGRP1 and low aprataxin (APTX) expression previously predicted for T response. Assays using blasts from a subset of 40 patients treated with T plus E on this study showed that AMLs with a RASGRP1/APTX ratio of more than 5.2 had a 78% CR rate and negative predictive value 87%. This ratio did not correlate with outcome in 41 patients treated with conventional chemotherapies. The next T-based clinical trials will test the ability of the 2-gene signature to enrich for T responders prospectively. This study is registered at www.clinicaltrials.gov as #NCT00602771. (Blood. 2012; 119(1): 55-63)
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