Multifaceted Approach to the Treatment of Bcr-Abl-Positive Leukemias

Abstract

Bcr-Abl-positive leukemias include chronic myelogenous leukemia (CML), both myeloid and lymphoid blast-phase CML, and some cases of acute lymphoblastic leukemia. The chimeric bcr-abl gene codes for a tyrosine kinase that is constitutively activated in the leukemic cells and plays the central role in leukemogenesis. Hematologic malignancies, including Bcr-Abl-positive leukemias, also frequently have overactivity of the Ras signaling pathway, leading to abnormal transduction of growth and survival signals. New and investigational therapeutic options that target these specific molecular defects of leukemic cells include the tyrosine kinase inhibitor imatinib mesylate (STI571) and farnesyltransferase inhibitors (R115777, SCH66336), which block localization of Ras proteins to the cell membrane. While single-agent therapy with these new agents may produce hematologic and cytogenetic remissions in patients with Bcr-Abl-positive leukemias, molecular remissions are less common, and resistance may develop. Therefore, the development of a multifaceted therapeutic approach to these leukemias is of great interest. Arsenic trioxide (ATO), which has significant activity in patients with relapsed and refractory acute promyelocytic leukemia, is a potential addition to the therapeutic arsenal. While some of the molecular activities of ATO are specific to acute promyelocytic leukemia, arsenicals also have a broad variety of antineoplastic properties that may be useful in combination therapy with agents that target specific molecular defects of Bcr-Abl-positive leukemias.