Dual inhibition of ras and bcr-abl signalling pathways in chronic myeloid leukaemia: a phase I/II study in patients in complete haematological remission.
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.
Pavlu
Jiri
J
Department of Haematology, Imperial College at Hammersmith Hospital, Du Cane Road, London, UK.
Andreasson
Catharina
C
Chuah
Charles
C
Kaeda
Jaspal
J
Goldman
John M
JM
Apperley
Jane F
JF
Marin
David
D
D000328:Adult; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001549:Benzamides; D050071:Bone Density Conservation Agents / Q000008:administration & dosage / Q000627:therapeutic use; D020732:Cytogenetic Analysis; D004164:Diphosphonates / Q000008:administration & dosage / Q000627:therapeutic use; D004334:Drug Administration Schedule; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism*; D006801:Humans; D000068877:Imatinib Mesylate; D007093:Imidazoles / Q000008:administration & dosage / Q000627:therapeutic use; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D010879:Piperazines / Q000627:therapeutic use; D011743:Pyrimidines / Q000627:therapeutic use; D012074:Remission Induction; D015398:Signal Transduction / Q000187:drug effects*; D000077211:Zoledronic Acid; D018631:ras Proteins / Q000378:metabolism*
D000970:Antineoplastic Agents; D001549:Benzamides; D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D007093:Imidazoles; D010879:Piperazines; D011743:Pyrimidines; D000077211:Zoledronic Acid; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl; D018631:ras Proteins