Dual inhibition of ras and bcr-abl signalling pathways in chronic myeloid leukaemia: A phase I/II study in patients in complete haematological remission

Abstract

Zoledronic acid inhibits the prenylation of ras-related proteins downstream of bcr-abl and preclinical studies have shown augmentation of the inhibitory effects of imatinib in BCR-ABL expressing cells. A Phase I/II study was designed to assess the safety and efficacy of the addition of zoledronic acid to imatinib in patients with chronic myeloid leukaemia (CML) with a suboptimal response to imatinib alone. Ten patients with CML who had been treated with imatinib for at least 2 years and had achieved and maintained a complete haematological response were included. Zoledronic acid was administered intravenously on one occasion every 28 d. The initial dose of 4 mg was given for three consecutive months; in the absence of significant toxicity and/or response the dose was escalated to 8 mg for an additional 3 months. Efficacy was assessed by serial monitoring of blood levels of BCR-ABL transcripts and bone marrow cytogenetics. Addition of zoledronic acid to imatinib caused no haematological toxicity. There were no grade III or IV non-haematological adverse effects. Grade I fatigue, hypocalcaemia and fever were common side effects. No responses were demonstrated after 6 months on the combination. © 2007 The Authors.