title: Cytogenetic heterogeneity negatively impacts outcomes in patients with acute myeloid leukemia.
abstract: Clonal heterogeneity is a hallmark of malignant transformation. In acute myeloid leukemia, acquired cytogenetic abnormalities are important independent predictors of initial response to therapy, remission duration, and overall survival. However, whether the presence of multiple cytogenetically characterized clones affects outcomes in acute myeloid leukemia is still not well defined. The aim of this study was to assess the prognostic impact of cytogenetic clonal heterogeneity in acute myeloid leukemia. This analysis included 1403 newly diagnosed acute myeloid leukemia patients fit for intensive chemotherapy, aged between 15 and 88 years, enrolled on Southwest Oncology Group protocols. The presence of multiple cytogenetic clones was found in 164 (24%) patients with abnormal karyotype. The proportion of patients with clonal heterogeneity increased with age, being present in 20% of patients under 40 years of age, but in 30% of those aged over 70 years (P=0.03). Clonal heterogeneity was significantly more common in association with unfavorable karyotype. Clonal heterogeneity was associated with decreased response rates and inferior event-free, relapse-free and overall survival, and was confirmed as an independent predictor of poor prognosis in multivariable analysis. Subgroup analysis showed that clonal heterogeneity adds prognostic information particularly in the unfavorable karyotype group. Our results confirm the negative prognostic impact of clonal heterogeneity in acute myeloid leukemia patients with abnormal karyotype. (clinicaltrials.gov identifiers: 014343329; 01338974; 00899171; 1059734; 01059734; 00899743; 0143329; 00023777; 00085709; 01360125; 00004217).
authors.affiliation: Stanford University School of Medicine, Stanford, CA brunom@stanford.edu.
authors.forename: Bruno C
authors.initials: BC
authors.lastname: Medeiros
authors.affiliation: Southwest Oncology Group Statistical Center, Seattle, WA Fred Hutchinson Cancer Research Center, Seattle, WA.
authors.forename: Megan
authors.initials: M
authors.lastname: Othus
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, WA University of Washington, Seattle, WA.
authors.forename: Min
authors.initials: M
authors.lastname: Fang
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, WA University of Washington, Seattle, WA.
authors.forename: Frederick R
authors.initials: FR
authors.lastname: Appelbaum
authors.affiliation: The University of Alabama at Birmingham, USA.
authors.forename: Harry P
authors.initials: HP
authors.lastname: Erba
mesh_terms: D059786:Abnormal Karyotype; D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use; D002999:Clone Cells; D005260:Female; D018740:Genetic Heterogeneity; D006801:Humans; D007621:Karyotyping; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis* / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D016019:Survival Analysis
chemical_list: D000970:Antineoplastic Agents