INTERFERON-ALPHA-2A - A REVIEW OF ITS PHARMACOLOGY AND THERAPEUTIC USE IN THE TREATMENT OF CHRONIC MYELOGENOUS LEUKEMIA

Interferons are intercellular signalling proteins which have antiviral, antitumour and immunomodulatory activities. Intereferon-alpha-2a is a recombinant product which has antiproliferative effects on haemopoietic progenitor cells and haematological cell lines in vitro. These properties have led to its evaluation in the treatment of chronic myelogenous leukaemia (CML), a myeloproliferative disorder resulting from neoplastic transformation of a pluripotential haemopoietic stem cell and characterised by the presence of a chromosomal marker the Philadelphia (Ph) chromosome, in the leukaemic cells. Clinical trials have demonstrated that interferon-alpha-2a (often given with or after cytoreductive chemotherapy), in common with other forms of interferon-alpha, can eliminate or reduce the proportion of Ph-positive cells in a number of patients with CML, as well as inducing haematological remission in the majority, of cases. Higher rates of cytogenetic response were achieved in small groups of patients who had relapsed following allogeneic bone marrow transplant (BMT) and those who received low-dose cytarabine in combination with interferon-alpha-2a. Interferon-alpha-2a was superior to conventional chemotherapy [hydroxycarbamide (hydroxyurea) or busulfan] in a randomised multicentre study in 322 patients; if achieved a greater number of major cytogenetic responses (19 vs 1% of patients), a greater delay in disease progression and longer overall survival (median 72 vs 52 months). However in another large comparative study interferon-alpha-2a or -2b was superior to busulfan, but not hydroxycarbamide, in prolonging survival. As with other types of interferon therapy, interferon-alpha-2a produces an acute influenza-like syndrome (fever, chills, myalgia, headache, arthralgia). Adverse effects during long term therapy include fatigue and anorexia (the most common events), and CNS disturbances. Serum neutralising antibodies to interferon-alpha-2a can usually be detected in around 20 to 25% of patients receiving the drug, but the clinical significance of this is unknown. Interferon-alpha therapy represents an important advance in the management of CML and is presently the only alternative to BMT (the preferred treatment option) for achieving long term complete cytogenetic remission and prolonging survival in this disease. Interferon-alpha-2a has been found to be effective in clinical trials and was superior to standard chemotherapy in one study. Although it appeared to be more effective than partially purified interferon-alpha, well-designed comparative studies are needed to demonstrate any differences in efficacy between different types of interferon-alpha. While only a small proportion of patients achieve long term cytogenetic remission with this agent and wider clinical experience is required, interferon-alpha-2a nevertheless can be considered a first-line therapy option in this disease, particularly in patients who cannot receive, or relapse following, BMT Further research is also required to evaluate combination therapy with interferon-alpha and other agents.