Reply to V. Pitini et al

Abstract

We appreciate the comments by Pitini et al highlighting the interesting mechanisms of action of interferon alfa (IFN) that supplement the activity of tyrosine kinase inhibitors in the treatment of chronic myeloid leukemia (CML). As monotherapy, IFNinduces heterogeneous responses in CML, with up to 80% of early chronic-phase patients achieving hematologic remission but only 8% to 30% achieving complete cytogenetic remission. Although response correlates with Euro and Sokal risk scores, the molecular basis for heterogeneous responses and indeed more broadly the mechanism of response to IFNremain poorly understood. Recent evidence suggested that IFNmay sensitize dormant stem cells to imatinib-induced apoptosis by inducing their cell cycle entry. This observation, which was discussed in our report, was made using short courses of high-dose IFNfollowed by fluorouracil in a non-CML mouse model. Hematopoietic stem cells (HSCs) respond to IFNtreatment by the increased phosphorylation of STAT1 and PKB/Akt, the expression of IFN target genes, and the upregulation of stem cell antigen-1 (Sca-1). In HSCs lacking the IFN/ receptor, STAT1 and Sca-1 are insensitive to IFN stimulation. Conversely, HSCs chronically activated by IFN are rapidly outcompeted in repopulation assays. Whereas chronic activation of the IFN pathway in HSCs impairs their function, acute IFN treatment promotes the proliferation of dormant HSCs in vivo. The anti-CML mechanism exerted by IFN has classically been linked to the effects on immune cells, including cytotoxic T cells. In our study, patients were predominantly treated with pegylated IFN-2a in low doses, which results in a continuous exposure of normal and neoplastic cells to the drug. Although an additional stem-cell activation effect of permanent IFNadministration cannot be excluded, the effect should have disappeared after chronic administration during maintenance therapy. Thus, for the concept of maintenance therapy with IFNafter tyrosine kinase inhibitor induction, the stimulation effect on cytotoxic T cells is the dominant cause of response, which persists even after discontinuation of all therapy including IFN. Because the model by Essers et al suggests a new mode of action of IFN in cancer therapy, the appropriate demonstration of applicability to CML in vivo is pending. Our data suggest the predominance of an immunophenomenon, which will persist even after discontinuation of IFN. Beginning CML therapy with IFNfollowed by imatinib therapy was tested in the pilot phase of the German CML Study IV. This schedule will be able to test for the stem cell recruiting activity of IFN, which will be used to increase the efficacy of tyrosine kinase inhibitors.