Two genes, tipifarnib, and AML

Karp and colleagues' study of tipifarnib plus etoposide for elderly adults with newly diagnosed AML in this issue of Blood can be divided into two sections: (1) evaluating two dosage schemes of the combined therapy and (2) the use of a two-gene ratio of high RASGRP1 and low APTX expression to predict which patients are most likely to benefit from tipifarnib based therapies.¹ 

The outcome of AML in elderly patients continues to be dismal, particularly for those patients who are not candidates for conventional high-dose therapy. These cases are often complex, with multiple comorbidities, less tolerance and less responsiveness to conventional chemotherapy, and possession of adverse prognostic features such as unfavorable cytogenetics and antecedent myelodysplastic syndrome at diagnosis; all predicting for a gloomy future.²  Elderly AML patients are in dire need of new and better therapeutic options.

Farnesyltransferase inhibitors (FTIs) are one of the alternative therapeutic options being explored for elderly AML. FTIs function by competitively inhibiting the addition of a farnesyl moiety to several important signaling molecules³  and thus target multiple pathways, including the RAS pathway implicated in the pathogenesis of solid and hematologic malignancies.^4,5 

Ras, a small farnesylated GTPase, is critical for many receptor-mediated pathways leading to MEK/ERK activation.²  The RAS family of genes is involved in the regulation of proliferation, differentiation, cell adhesion, and apoptosis of cells. The farnesyl group on RAS is essential for activation. Activation of RAS genes with or without activating mutations is frequent in MDS and AML.²  Targeted disruption of farnesyltransferase by FTIs leads to the inactivation of RAS function. Yet to be understood is the lack of correlation between RAS mutations and response to FTIs in clinical studies. Possibly this reflects RAS activation by alternative pathways.

Tipifarnib is an oral, very potent, and highly selective FTI with a relatively low toxicity profile.⁶  Single-agent tipifarnib has shown antileukemic activity in patients with MDS and refractory/poor risk AML⁷  However, a phase 3 study comparing single-agent tipifarnib to best supportive care including hydroxyurea in patients 70 years of age or older with untreated AML failed to demonstrate a survival advantage of tipifarnib.^5,8  Subsequently, based on evidence of in vitro synergy for tipifarnib with etoposide, a phase 1 trial combining these two agents in elderly poor-risk AML patients led to an improved CR rate of 25% across multiple dose levels of both drugs compared with 14% for single-agent tipifarnib.⁹  Disappointingly similar results were attained in the present phase 2 study of tipifarnib and etoposide at two dose schedules.¹ 

The most compelling portion of this study is the use of high RASGRP1 and low APTX gene expression to predict the clinical response to tipifarnib and etoposide. RASGRP1 is a guanine nucleotide exchange factor (GEF) that specifically activates RAS, and Aprataxin is a member of the histine triad family of nucleotide hydrolsases involved in the repair of DNA strand breaks.³  The two-gene expression ratio (RASGRP1/APTX) was identified by analyzing gene expression profiles in bone marrow samples from older patients with previously untreated AML in a phase 2 study of tipifarnib. The results were validated in an independent set of samples from relapsed or refractory AML with negative predictive and positive predictive values of 92% and 28%, respectively (odds ratio of 4.4). The two-gene signature also predicted for improved overall survival (154 vs 56 days; P < .001).³  Here, Karp and colleagues confirmed the two-gene signature correlated with clinical response in a cohort of the elderly AML patients treated with tipifarnib and etoposide. Patients with a RASGRP1:APTX ratio of ≥ 5.2 had a CR rate of 78% compared with those with a ratio of < 5.2 who had a CR rate of only 13%. The two-gene ratio did not correlate with outcome in other patients treated with conventional chemotherapy.¹ 

The report by Karp et al contains important information in the search for the most effective way to use tipifarnib in the treatment of elderly AML. Technologies such as microarray gene expression assays may be paving the way to a better understanding of which genetic lesions are involved in the biology of AML and drug resistance, and thus possibly allowing for a more effective and perhaps personalized selection of appropriate therapies. Further work needs to be done to clarify whether the two-gene signature expression ratio has utility for other classes of FTIs and whether a qPCR assay can be applied in clinical practice.