Several new approaches to improvement of alpha interferon therapy in chronic myelogenous leukaemia

Several basic experimental and clinical studies were carried out in an attempt to improve the efficacy of alpha interferon therapy for chronic myelogenous leukaemia (CML). First, the combined use of hydroxyurea (HU) and interferon (500-1000 mg daily) in interferon-resistant cases facilitated maintenance of reduced leucocyte production, or a reduction in the dose of interferon, although suppression of Philadelphia chromosome (Ph1)-positive clones was not observed in most cases. In order to try and decrease the rate of lymphoblastic crisis during the course of interferon therapy, we recently added methotrexate (MTX) (10-15 mg, weekly) to the treatment protocol. Since then, no lymphoblastic crisis has been observed. Second, the in vitro expression of alpha interferon-stimulated gene (ISG) mRNA was shown to be markedly decreased in granulocytes of one representative interferon-resistant case, compared to that in granulocytes of the three interferon-sensitive cases. Interestingly, it was found that the transcriptional activity in this case became almost normal when the blood granulocytes were controlled by the addition of HU. These findings suggest that the in vitro transcriptional assay of ISG mRNA may be clinically useful for predicting alpha interferon efficacy. Third, when genetically manipulated, alpha interferon-producing NIH/3T3 cells were co-transplanted using diffusion chambers into nude mice bearing a CML cell line, KU812, the CML tumour growth was shown to be markedly suppressed. This experimental model for alpha interferon replacement gene therapy suggests some directions for future studies on interferon therapy.