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

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.