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Blood, 15 April 2007, Vol. 109, No. 8, pp. 3128. This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Goldman, J. Search for Related Content PubMed Articles by Goldman, J. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  CLINICAL TRIALS AND OBSERVATIONS Comment on Cortes et al, page 3207 Unraveling CML phase by phase John Goldman 1 IMPERIAL COLLEGE LONDON Dasatinib induces hematologic and cytogenetic responses in both myeloid and lymphoid blastic phase of CML regardless of the presence of BCR-ABL kinase domain mutations, and these responses are durable at least in the short term. Blastic transformation or blastic crisis of chronic myeloid leukemia (CML) is one of the most aggressive and intractable of leukemias, and it is therefore very encouraging to learn from the report by Cortes and colleagues published in this issue of Blood that dasatinib, one of the so-called second-generation tyrosine kinase (TK) inhibitors that includes also nilotinib, can induce major hematologic responses in about one third of patients treated previously with imatinib and complete cytogenetic responses in a similar proportion. These results are much better than might have been expected with classical cytotoxic drug combinations and shed some light on at least 4 questions that have fascinated CML aficionados over the years. First, do residual Ph-negative stem cells routinely survive in the marrow of patients after the onset of blastic transformation? The evidence here suggests that even in blastic transformation a significant number of presumably normal stem cells do survive and can reconstitute hematopoiesis if given the chance. Second, what role does the BCR-ABL fusion gene play in causing or maintaining the blastic subclone? It might have been assumed that the BCR-ABL fusion gene set the scene for progression of leukemia to blastic phase but then became operationally irrelevant. This seems not to be the case. The fact that some patients respond to dasatinib even after failing imatinib suggests (but does not prove) that the BCR-ABL gene still plays some crucial cooperative role in maintaining the blastic phase (though studies that showed resumption of the capacity of Bcr-Abl in vitro to phosphorylate Crkl might have been definitive). This would mean either that dasatinib, at least in this setting, is generally a much more powerful BCR-ABL inhibitor than imatinib, perhaps because of its less stringent binding requirements, or that other activated TKs, such as SRC or other SRC family kinases, which are targeted by dasatinib but not by imatinib, have substituted for BCR-ABL in maintaining the transformed leukemia.1 Third, why do some of the responses seem to be durable, although the follow-up is still relatively short? If dasatinib-resistant subclones were already present when the drug was started, one would have expected to see resistance developing quite quickly; if, however, resistant subclones had not yet developed and dasatinib completely or near-completely suppressed the whole population in which they would have been expected to occur, then the drug should control the leukemia for some time. One hopes this proves to be the case. And finally, what is the role of kinase domain mutations in "causing" resistance to TK inhibitors? An increasing body of evidence suggests that whereas some mutations are indubitably the cause of imatinib resistance, others seem merely to be epiphenomena.2 Dasatinib actually controls almost all mutant subclones,3,4 though not the notorious T315I. One might speculate therefore that it might for this reason be slightly more effective than imatinib for treating chronic-phase disease, but in "late" blastic phase disease resistance seems often to be due to mechanisms other than BCR-ABL kinase domain mutations. The challenge now must be to identify activated signal transduction pathways that maintain the blastic phenotype even when the BCR-ABL kinase remains fully suppressed. Footnotes The author declares no competing financial interests. REFERENCES Hu Y, Liu Y, Pelletier S, et al. Requirement for Src kinases Lyn, Hck and Fgr for BCR-ABL1-induced B-lymphoblastic leukemia but not chronic myeloid leukemia. Nat Genet 2004; 36:440–441.[CrossRef][Medline] [Order article via Infotrieve] Khorashad J, Anand M, Marin D, et al. The presence of a BCR-ABL mutant allele in CML does not always explain clinical resistance to imatinib. Leukemia 2006; 20:658–663.[CrossRef][Medline] [Order article via Infotrieve] Shah NP, Tran C, Lee FY, et al. Overriding imatinib resistance with a novel ABL kinase inhibitor. Science 2004; 305:399–401.[Abstract/Free Full Text] Bradeen H, Eide CA, O'Hare T, et al. Comparison of imatinib mesylate, dasatinib (BMS-354825), and nilotinib (AMN107) in N-ethyl-N-nitrosourea (ENU)-based mutagenic screen: high efficiency of drug combinations. Blood 2006; 108:2332–2338.[Abstract/Free Full Text] CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Dasatinib induces complete hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in blast crisis Jorge Cortes, Philippe Rousselot, Dong-Wook Kim, Ellen Ritchie, Nelson Hamerschlak, Steven Coutre, Andreas Hochhaus, Francois Guilhot, Giuseppe Saglio, Jane Apperley, Oliver Ottmann, Neil Shah, Philipp Erben, Susan Branford, Prasheen Agarwal, Ashwin Gollerkeri, and Michele Baccarani Blood 2007 109: 3207-3213. [Abstract] [Full Text] [PDF] This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Goldman, J. Search for Related Content PubMed Articles by Goldman, J. 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