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Blood, 15 November 2005, Vol. 106, No. 10, pp. 3331-3332. 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 HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Litzow, M. R. Search for Related Content PubMed Articles by Litzow, M. R. Related Collections Related Article in Blood Online Social Bookmarking                   What's this? Next Article  TRANSPLANTATION Comment on Gale et al, page 3658 More flitting about FLT3 Mark R. Litzow MAYO CLINIC COLLEGE OF MEDICINE An elegant analysis of FLT3 mutational status in a large cohort of acute myeloid leukemia patients assesses the role of transplantation for these poor-prognosis patients. The FMS-like tyrosine kinase 3 (FLT3) is expressed on the cell surface of hematopoietic progenitors and its ligand can be found in either a soluble form or a membrane-bound form on bone marrow stromal cells. In 1996, it was reported that an internal tandem duplication (ITD) of base pairs within the juxtamembrane coding portion or point mutations in the second kinase domain (KDM) could result in constitutive activation of the gene in acute myeloid leukemia (AML) patients (see figure). These abnormalities are seen in up to 30% of patients with AML and especially in those with normal cytogenetics and with acute promyelocytic leukemia, making it one of the most frequently identified molecular abnormalities in AML.1 To assess the significance of these mutations, large observational studies of cohorts of AML patients were evaluated to determine the frequency of FLT3 mutations and its impact on prognosis. A meta-analysis of 4 of the largest series has confirmed that FLT3 mutations have an adverse impact on disease-free and overall survival in patients with AML.2 In clinical practice, a frequent approach to patients with poor prognostic AML is to offer allogeneic stem cell transplantation (SCT) in the hopes that the graft-versus-leukemia effect can overcome the high rate of relapse in these patients. However, a subset analysis of large trials examining different modes of consolidation therapy for patients with AML including chemotherapy or SCT has not born out that allogeneic SCT can overcome the adverse prognosis.3 Gale and colleagues from the Medical Research Council (MRC) of the United Kingdom have now addressed the issue of whether patients with AML with a FLT3/ITD have an improved outcome if they undergo SCT compared with patients receiving chemotherapy. Patient material from the MRC AML-10 and -12 trials was retrospectively analyzed for an FLT3/ITD mutation, and patient outcomes were compared depending on the type of therapy received. Patients with FLT3/KDM were not included in this study, although it appears that these patients have a similar prognosis to patients with an ITD.2 As one might predict, the relapse rate in FLT/ITD+ patients receiving either an autograft or an allograft compared with chemotherapy was lower, but these lower relapse rates did not translate into an overall survival advantage. Though in the allografted patients there was a suggestion that allografting reduced the risk of relapse, the authors rightly point out that these data may be subject to bias based on the retrospective nature of the study and relatively small numbers. This trend of a reduced relapse risk was not born out in the donor–versus–no donor analysis. Thus, while it is not clear from this study that SCT is uniquely effective in patients who are FLT3/ITD+, SCT clinicians may still want to take FLT/ITD or KDM status into account when deciding whether a patient should undergo transplantation given the overall poorer prognosis of these patients and lack of good alternative therapies at the present time. View larger version (49K): [in this window] [in a new window]   A schematic diagram of the FLT3 receptor tyrosine kinase showing the location of the internal tandem duplication of genes within the juxtamembrane domain and point mutations and gene insertions in the second kinase domain. Illustration by Kenneth Probst.   Several inhibitors of FLT3 have entered clinical trials and demonstrated leukemic cytoreduction, although most responses have been modest.4 These modest responses have raised the question as to how central a role FLT3 mutations play in the leukemogenesis of AML. The presence of an FLT3 mutation in AML patients is sometimes not stable between diagnosis and relapse and suggests the possibility that these mutations may be secondary rather than primary events.5 The FLT3 small molecule inhibitors described in the preceding paragraph are currently being studied in combination with chemotherapy in patients with AML, and it is hoped that these studies will improve the response rate in these poor-prognosis patients. References Naoe T, Kiyoi H. Normal and oncogenic FLT3. Cell Mol Life Sci. 2004;61: 2932-2938.[CrossRef][Medline] [Order article via Infotrieve] Yanada M, Matsuo K, Suzuki T, Kiyoi H, Naoe T. Prognostic significance of FLT3 internal tandem duplication and tyrosine kinase domain mutations for acute myeloid leukemia: a meta-analysis. Leukemia. 2005;19: 1345-1349.[CrossRef][Medline] [Order article via Infotrieve] Grimwade D, Walker H, Oliver F, et al. The importance of diagnostic cytogenetics on outcome in AML: analysis of 1,612 patients entered into the MRC AML 10 trial: the Medical Research Council Adult and Children's Leukaemia Working Parties. Blood. 1998;92: 2322-2333.[Abstract/Free Full Text] Stone RM, DeAngelo DJ, Klimek V, et al. Patients with acute myeloid leukemia and an activating mutation in FLT3 respond to a small-molecule FLT3 tyrosine kinase inhibitor, PKC412. Blood. 2005;105: 54-60.[Abstract/Free Full Text] Kottaridis PD, Gale RE, Langabeer SE, Frew ME, Bowen DT, Linch DC. Studies of FLT3 mutations in paired presentation and relapse samples from patients with acute myeloid leukemia: implications for the role of FLT3 mutations in leukemogenesis, minimal residual disease detection, and possible therapy with FLT3 inhibitors. Blood. 2002;100: 2393-2398.[Abstract/Free Full Text] CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: No evidence that FLT3 status should be considered as an indicator for transplantation in acute myeloid leukemia (AML): an analysis of 1135 patients, excluding acute promyelocytic leukemia, from the UK MRC AML10 and 12 trials Rosemary E. Gale, Robert Hills, Panagiotis D. Kottaridis, Sivatharsini Srirangan, Keith Wheatley, Alan K. Burnett, and David C. Linch Blood 2005 106: 3658-3665. [Abstract] [Full Text] [PDF] This article has been cited by other articles: A. J. Mead, D. C. Linch, R. K. Hills, K. Wheatley, A. K. Burnett, and R. E. Gale FLT3 tyrosine kinase domain mutations are biologically distinct from and have a significantly more favorable prognosis than FLT3 internal tandem duplications in patients with acute myeloid leukemia Blood, August 15, 2007; 110(4): 1262 - 1270. [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 HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Litzow, M. R. Search for Related Content PubMed Articles by Litzow, M. R. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?

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