We analyzed
bone marrow from 67 patients from a phase 2 study of farnesyltransferase inhibition with tipifarnib (R115777, ZARNESTRA®), in older adults with previously untreated, poor-risk acute
myeloid leukemia (AML) for N-Ras mutations, global
gene expression, and / or quantitative PCR (qPCR) of specific genes.
Microarray profiling identified a two-
gene expression ratio (RASGRP1:APTX) which provided the greatest accuracy for predicting response to tipifarnib. We demonstrated that this classifier could predict response to tipifarnib in an independent set of 54 samples from relapsed or
refractory AML, with a NPV and PPV of 92% and 28%, respectively (
odds ratio of 4.4). Therefore, in both
newly diagnosed and relapsed or
refractory AML, this classifier improves the overall response rate by approximately 50% while maintaining a high NPV, and significantly improves patient
overall survival. The two-
gene classifier was also validated by qPCR in thirty AML samples from the same
clinical study demonstrating a negative
predictive value (NPV) and positive
predictive value (PPV) of 81% and 50%, respectively (
odds ratio of 4.3). These data indicate that a simple two-
gene expression assay may have utility in diagnosing a
population of AML patients who are more likely to respond to tipifarnib.