Division of Hematologic Malignancies, John Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD 21231-1000, USA.
Blood. 2012 Jan 5;119(1):55-63. doi: 10.1182/blood-2011-08-370825. Epub 2011 Oct 14.
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. Arm A (T 600 mg twice a day × 14 days, E 100 mg days 1-3 and 8-10) and arm B (T 400 mg twice a day × 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.
替皮法尼布（T）在新诊断为急性髓系白血病（AML）的老年患者中表现出适度的活性。基于临床前协同作用，T 加依托泊苷（E）的 1 期试验产生了 25%的完全缓解（CR）。我们为 84 名年龄在 70-90 岁之间（中位年龄 76 岁）、不适合常规化疗的成年人选择了两个可比剂量水平进行随机 2 期试验。A 臂（T 600mg 每日两次×14 天，E 100mg 第 1-3 天和第 8-10 天）和 B 臂（T 400mg 每日两次×14 天，E 200mg 第 1-3 天和第 8-10 天）产生了相似的 CR，但 B 臂毒性更大。总 CR 率为 25%，第 30 天死亡率为 7%。先前预测 T 反应的高 RASGRP1 和低 aprataxin（APTX）表达的 2 个基因特征。使用来自本研究中接受 T 加 E 治疗的 40 名患者亚组的 blast 进行的检测表明，RASGRP1/APTX 比值大于 5.2 的 AML 的 CR 率为 78%，阴性预测值为 87%。在接受常规化疗的 41 名患者中，该比值与结果无关。下一个基于 T 的临床试验将测试该 2 个基因特征前瞻性富集 T 反应者的能力。本研究在 www.clinicaltrials.gov 上注册为#NCT00602771。
