Use of arsenic trioxide in haematological malignancies: insight into the clinical development of a novel agent.

摘要

BACKGROUND: Arsenic trioxide delivers high rates of complete clinical remission in patients with relapsed/refractory acute promyelocytic leukaemia (APL), and is associated with high rates of molecular remission as indicated by PCR negativity for the PML-RARalpha gene. OBJECTIVE: Mitochondria are considered to be the primary intracellular target of arsenic trioxide, and preclinical and mechanistic studies suggest that this agent may have broad applicability in haematological and other malignancies. Investigations of this agent are ongoing in a range of haematological malignancies, and studies in newly diagnosed APL, acute myeloid leukaemia (AML), myelodysplastic syndromes (MDS), multiple myeloma (MM) and chronic myelogenous leukaemia (CML) are reviewed here using published articles and presentations at international congresses to June 2004. Medline was used to source published preclinical and clinical data, and abstract databases and publications from relevant major international haematology/oncology congresses were searched to source updates of preclinical and clinical trial data. FINDINGS: Accumulating data indicate that arsenic trioxide may be a useful addition to the therapeutic regimens that have been so successful in treating newly diagnosed APL, and investigations are ongoing to incorporate this agent into the first-line APL treatment paradigm. Preliminary data from clinical studies indicate that arsenic trioxide has clinical activity as a single agent in MDS and MM, and combination therapies are being investigated. In MM, the combination regimens under study incorporate ascorbic acid, which can enhance the efficacy of arsenic trioxide by reducing intracellular glutathione concentrations. In CML, arsenic trioxide is being investigated in combination with imatinib mesylate in patients who have failed initial imatinib treatment. In AML, although results with single-agent arsenic trioxide were not encouraging, treatment using arsenic trioxide in combination with ascorbic acid is a proposed strategy inelderly patients not able to withstand intensive chemotherapy. CONCLUSION: This versatile agent has a predictable and manageable safety profile and avoids many of the severe toxicities associated with conventional chemotherapies. Ongoing clinical studies will help to define the role of arsenic trioxide in the treatment of haematological malignancies.