First-generation tyrosine-kinase inhibitors: the role of combination therapy

作者：Guilhot F^*

来源：Oncologie, 2012, 14(10-11): 583-588.

DOI：10.1007/s10269-012-2222-1

• Chronic myeloid leukemia
• Tyrosine-kinase inhibitors
• Leukemic stem cells
• Interferon

Chronic myeloid leukemia (CML) is a malignant disorder in which the immune system has been described as important for the graft versus leukemia effect after stem cell transplantation. With imatinib at a dose of 400 mg, the current treatment of chronic phase CML does not eradicate the leukemic stem cells. Most of the patients in molecular response remain with leukemic stem cells responsible for relapse if the treatment is discontinued. Recent studies have suggested that interferon may be useful in order to eradicate the quiescent stem cells. The second-generation inhibitors like dasatinib, nilotinib or bosutinib do not eliminate either the stem cells; this leads to the conclusion that either there is a persistence of leukemic stem cells or there is a general phenomenon with TKI. The mechanisms of resistance include high activities of Bcr-Abl and CrkLPhospho, a weak expression ofOCT-1 and high levels of proteins ABCB1 and ABCG2. However, two scientific groups have recently demonstrated the value of interferon alpha as a molecule that may stimulate the turnover and proliferation of hematopoietic stem cells in vivo. This new approach to understanding the mechanism of action of interferon alpha on hematopoietic stem cells supports the use of combination therapy of TKI plus interferon.

• 出版日期2012-10