Abstract:
Imatinib is the standard of care in chronic meloid leukemia (CML) therapy. However, imatinib is not curative since most patients who discontinue therapy relapse indicating that leukemia initiating cells (LIC) are resistant. Interferon alpha (IFN) induces hematologic and cytogenetic remissions and interestingly, improved outcome was reported with the combination of interferon and imatinib. Arsenic trioxide was suggested to decrease CML LIC. We investigated the effects of arsenic and IFN on human CML cell lines or primary cells and the bone marrow retroviral transduction-transplantation murine CML model. In vitro, the combination of arsenic and IFN inhibited proliferation and activated apoptosis. Importantly, arsenic and IFN synergistically reduced the clonogenic activity of primary bone marrow cells derived from CML patients. Finally, in vivo, combined interferon and arsenic treatment, but not single agents, prolonged the survival of primary CML mice. Importantly, the combination severely impaired engraftment into untreated secondary recipients, with some recipients never developing the disease, demonstrating a dramatic decrease in CML LIC activity. Arsenic-IFN effect on CML LIC activity was significantly superior to that of imatinib. These results support further exploration of this combination, alone or with imatinib aiming at achieving CML eradication rather than long-term disease control. What's new? The tyrosine kinase inhibitor imatinib has become the standard therapy for Chronic Myeloid Leukemia (CML). However, imatinib is not curative since most patients who discontinue therapy relapse, indicating that leukemia initiating cells are resistant. Here the authors demonstrated that arsenic and interferon alpha (IFN) inhibited the clonogenic activity of human primary CML cells. In a murine CML model, arsenic-IFN sharply diminished transplantation of CML cells, pointing to exhaustion of CML initiating cells. These studies plea for clinical exploration of this combination, knowing that IFN and arsenic have both previously shown clinical activity in CML, alone or in combination with imatinib. © 2013 UICC.