Initial treatment for patients with chronic myeloid leukemia

Abstract

The first-line treatment of chronic myeloid leukemia is based on the three currently available tyrosine kinase inhibitors (TKIs), namely imatinib, nilotinib and dasatinib. Nilotinib and dasatinib are more potent, and it is predicted that, in comparison with imatinib, they can reduce the risk of progression and increase the number of the patients who can discontinue the treatment without relapsing. Other TKIs are still being developed and may help to improve treatment options further on. Hydroxyurea has no longer a role. Allogeneic stem cell transplantation is the treatment of choice for the advanced phases, and in case of resistance to at least two TKIs.Leukemia Supplements (2012) 1, S37--S39; doi:10.1038/leusup.2012.21Keywords: chronic myeloid leukemia; BCR-ABL; Philadelphia chromosome; imatinib; nilotinib; dasatinib The initial treatment of Philadelphia-positive (Ph þ ), BCR-ABL þ chronic myeloid leukemia (CML) is based on tyrosine kinase inhibitors (TKI), a class of small molecules that can inhibit the phosphorylative function of the proteins that are coded by the BCR-ABL fusion gene on chromosome 22q. 1--4 These proteins are located in the cytoplasm, where they activate a number of downstream signals of proliferation and survival, resulting in the transformation of normal hematopoietic stem cells to leukemic cells. The Ph þ leukemic stem and progenitor cells on one hand proliferate and mature, expanding the myeloid tissue in the bone marrow and in the spleen, and causing leukocytosis, whereas on the other hand, they are genetically unstable and develop a number of secondary genomic lesions, leading to the progression from chronic to accelerated and blastic phase. 1--4 Therefore, the first goal of treatment is to prevent progression, and the second one is to eliminate the leukemic clone. Achieving the first goal may be sufficient to ensure a normal survival. Achieving the second goal may be necessary to cure the disease and discontinue the treatment safely. Both goals can be achieved with TKIs, although achieving the second goal may require other agents. TYROSINE KINASE INHIBITORSThe TKIs are a class of small molecules that have been designed with the purpose of inhibiting the phosphorylative activity of the TK. Several TKIs are able to inhibit the BCR-ABL proteins, although none is truly specific, because they inhibit other TKs as well. The TKIs that have been selected and registered so far for their activity on BCR-ABL, then for the treatment of CML, both first-line and second-line treatment, are as follows:Imatinib (Glivec or Gleevec, Novartis Pharma) 2,5 Nilotinib (Tasigna, Novartis Pharma) 2,6 Dasatinib (Sprycel, Bristol-Myers Squibb) 2,7 Another compound (Bosutinib, Pfizer) has already been tested in first-line and second-line treatment. 8 A fifth compound (Ponatinib, Ariad) has been tested in second-line and third-line treatment. 9 Imatinib, first of the class, was introduced more than 10 years ago. With imatinib, the complete hematologic response rate is close to 100%, the complete cytogenetic respon...