Efficacy of STI571, an Abl tyrosine kinase inhibitor, in conjunction with other antileukemic agents against Bcr-Abl-positive cells

Chronic myelogenous leukemia (CML), a malignancy of a hematopoietic stem ce ll, is caused by the Bcr-Abl tyrosine kinase. STI571(formerly CGP 57148B), an Abl tyrosine kinase inhibitor, has specific in vitro antileukemic activi ty against Bcr-Abl-positive cells and is currently in Phase II clinical tri als. As it is likely that resistance to a single agent would be observed, c ombinations of STI571 with other antileukemic agents have been evaluated fo r activity against Bcr-Abl-positive cell lines and in colony-forming assays in vitro. The specific antileukemic agents tested included several agents currently used for the treatment of CML: interferon-alpha (IFN), hydroxyure a (HU), daunorubicin (DNR), and cytosine arabinoside (Ara-C). In proliferat ion assays that use Bcr-Abl-expressing cells lines, the combination of STI5 71 with IFN, DNR, and Ara-C showed additive or synergistic effects, whereas the combination of STI571 and HU demonstrated antagonistic effects. Howeve r, in colony-forming assays that use CML patient samples, all combinations showed increased antiproliferative effects as compared with STI571 alone. T hese data indicate that combinations of STI571 with IFN, DNR, or Ara-C may be more useful than STI571 alone in the treatment of CML and suggest consid eration of clinical trials of these combinations. (C) 2000 by The American Society of Hematology.