Sequential therapy with recombinant interferons gamma and alpha in patients with unfavorable prognosis of chronic myelocytic leukemia: Clinical responsiveness to recombinant ifn‐α correlates with the degree of receptor down‐regulation

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Abstract
Natural and recombinant interferons (IFNs) have already demonstrated therapeutic efficacy, including cytogenetic remissions, in patients with chronic myelocytic leukemia (CML). We investigated at the level of ligand-receptor interaction the question whether heterogeneity of receptor number or affinity might contribute to primary or secondary treatment failures in CML. We therefore analyzed IFN-γ and IFN-α receptor expression and regulation during treatment with recombinant IFN-γ and IFN-α in 15 patients with advanced CML. We found no difference in number or affinity of constitutively expressed IFN-γ receptors (mean 1,100) and, on average, a 30% reduction of IFN-α receptors (mean 750) on peripheral blood mononuclear cells (PBMNC) of patients with chronic or accelerated CML as compared to mature granulocytes and/or bone marrow cells of healthy controls, which express on average 1,050 and 1,100 IFN-γ and IFN-α receptors, respectively. While IFN-γ receptor expression on PBMNC is not influenced upon treatment with rIFN-γ, there is a substantial downregulation of IFN-α receptors in the course of rIFN-α therapy. Our data also show a differential pattern of receptor down-regulation between patients achieving complete hematologic remission (CHR) (4 out of 12) compared with patients with partial hematologic remission (PHR) and non-responders. We conclude that differences in IFN receptor number cannot explain primary or secondary treatment failures. However, the differential ligand induced downregulation of IFN-α receptors in patients achieving CHR compared to those with PHR or non-responders suggest a prospective value of IFN-α receptor determination.