title: Improved prognostic significance of cytokine-induced proliferation in vitro in patients with de novo acute myeloid leukemia of intermediate risk: impact of internal tandem duplications in the Flt3 gene.
abstract: The heterogeneity of acute myeloid leukemia is reflected in many clinical, biological and genetic features that are used to predict the response to therapy. On the basis of chromosome aberrations patients can be stratified in groups reflecting either good or poor prognosis. However, the majority of patients fall in an 'intermediate risk' group. Internal tandem duplications in the hematopoietic growth factor receptor Flt3 have been shown to separate a subset of high risk patients from intermediate or low risk cases. In an attempt to further characterize the heterogeneity of prognosis among the cytogenetic intermediate risk group of AML, we investigated the overall survival, failure-free survival, initial therapy response and relapse rates of 103 patients with de novo AML in relation to autonomous proliferation and the proliferative response to a panel of 10 cytokines in a short-term thymidine incorporation assay. To exclude perturbation of the responses by other (known) risk factors our final intermediate risk population was comprised of patients with intermediate risk cytogenetics, having an age of 60 years of younger and not showing tandem duplications in the Flt3 gene. Among this intermediate risk group, only the responses to M-CSF and IL-1alpha were found to be predictive for therapy outcome. Results obtained by a 7-day culture with these cytokines revealed two subpopulations characterized by a good and a poor prognosis, respectively. The complete remission rates in these subpopulations were similar, but the relapse rates, failure-free survival and overall survival differed. If further study extends and supports our data, it should be considered to include these patients in the poor risk arms of treatment protocols and offer them intensified treatment or bone marrow transplantation.
authors.affiliation: Department of Hematology, Erasmus University, Rotterdam, The Netherlands.
authors.forename: W J
authors.initials: WJ
authors.lastname: Rombouts
authors.forename: B
authors.initials: B
authors.lastname: Löwenberg
authors.forename: W L
authors.initials: WL
authors.lastname: van Putten
authors.forename: R E
authors.initials: RE
authors.lastname: Ploemacher
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002455:Cell Division / Q000187:drug effects; D016207:Cytokines / Q000494:pharmacology*; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D020080:Tandem Repeat Sequences; D051941:fms-Like Tyrosine Kinase 3
chemical_list: D016207:Cytokines; D011518:Proto-Oncogene Proteins; C497970:FLT3 protein, human; D020794:Receptor Protein-Tyrosine Kinases; D051941:fms-Like Tyrosine Kinase 3