Methods of determining acute myeloid leukemia response to treatment with farnesyltransferase inhibitors

Abstract

The disclosed method rapidly identifies with desired accuracy AML patients, including elderly AML patients, likely to respond to treatment with a combination of a farnesyltransferase inhibitor and one or more of etoposide, teniposide, tamoxifen, sorafenib, paclitaxel, temozolomide, topotecan, trastuzumab and cisplatinum. In an embodiment, the improvements include the use of whole blood rather than the customary bone marrow sample, thus making the assay more accurate, rapid, less intrusive, less expensive as well as less painful. The method includes evaluation of a two-gene expression ratio (RASGRP1 :APTX), which with a corresponding threshold, provides sufficient accuracy for predicting the response to the combination treatment. In the preferred embodiment the combination treatment combines tipifarnib (Rl 15777, ZARNESTRA TM ) with etoposide. Further, the elderly AML patients identified as being likely responsive to the combination treatment with tipinifarb and etoposide have a complete recovery rate comparable to the best therapy available for younger patients.

Description

Background technique [0001] The prevalence of acute myelogenous leukemia (AML) in the United States is low at about 50,000 patients, which is considered to be well below the 200,000 prevalence requirement for the definition of an orphan disease in the United States. Acute myeloid leukemia is more prevalent in older adults and tends to be more difficult to treat. Elderly patients, usually defined as patients at least 60 years old (although some classifications require patients to be at least 65 or even 70 years old) die from the disease at high rates. The average response rate and survival rate of elderly acute myelogenous leukemia patients are 30% to 50%, and the median recurrence-free survival (RFS) of complete remission is only 9 to 12 months. Few elderly patients live past two years. [0002] Therapeutic management of elderly patients with acute myeloid leukemia faces many challenges. Although about seventy percent (70%) of patients achieve remission with conventional in...

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Problems solved by technology

Furthermore, no clinical studies have yet demonstrated an association between RAS mutations and FTI efficacy, as noted in U.S. Patent Publication No. 20070048782, which is incorporated herein by reference

In fact, although early clinical studies of FTI focused on cancers exhibiting high rates of RAS mutations, response rates in these trials were very low

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