BackgroundAcute promyelocytic leukemia is a cytogenetically well defined entity. Nevertheless, some features observed at diagnosis are related to a worse outcome of the patients.MethodsIn a prospective study, we analyzed peripheral (PB) leukocyte count, immunophenotype, methylation status of CDKN2B, CDKN2A and TP73; FLT3 and NPM1 mutations besides nuclear chromatin texture characteristics of the leukemic cells. We also examined the relation of these features with patient’s outcome.ResultsAmong 19 cases, 4 had a microgranular morphology, 7 presented PB leukocytes >10x109/l, 2 had FLT3-ITD and 3 had FLT3-TKD (all three presenting a methylated CDKN2B). NPM1 mutation was not observed. PB leukocyte count showed an inverse relation with standard deviation of gray levels, contrast, cluster prominence, and chromatin fractal dimension (FD). Cases with FLT3-ITD presented a microgranular morphology, PB leukocytosis and expression of HLA-DR, CD34 and CD11b. Concerning nuclear chromatin texture variables, these cases had a lower entropy, contrast, cluster prominence and FD, but higher local homogeneity, and R245, in keeping with more homogeneously distributed chromatin. In the univariate Cox analysis, a higher leukocyte count, FLT3-ITD mutation, microgranular morphology, methylation of CDKN2B, besides a higher local homogeneity of nuclear chromatin, a lower chromatin entropy and FD were associated to a worse outcome. All these features lost significance when the cases were stratified for FLT3-ITD mutation. Methylation status of CDNK2A and TP73 showed no relation to patient’s survival.Conclusionin APL, patients with FLT3-ITD mutation show different clinical characteristics and have blasts with a more homogeneous chromatin texture. Texture analysis demonstrated that FLTD-ITD was accompanied not only by different cytoplasmic features, but also by a change in chromatin structure in routine cytologic preparations. Yet we were not able to detect chromatin changes by nuclear texture analysis of patients with the FTLD-TKD or methylation of specific genes.
4850 Introduction: The WHO 2008 classification of acute myeloid leukemia (AML) is based on morphology, cytogenetics and molecular features. Among them, mutations and internal tandem duplications of FLT3 in AML with a normal karyotype have been associated to a poor prognosis. Mutated NPM1 in the absence of FLT3-ITD is associated to a favorable. On the other hand, variables of nuclear chromatin texture have been described as independent risk factors in several malignancies (ALL, melanoma and multiple myeloma). Aim: To compare the influence on overall survival of the chromatin fractal dimension and molecular features in adult patients with AML. Patients and Methods: We analyzed 106 consecutive cases diagnosed at our Institution between 2007 and 2009. Diagnosis was made by bone marrow (BM) cytology and karyotype, and cases were classified by WHO criteria. Genomic DNA was extracted by phenol-chloroform. Genotyping was made with the MegaBACE 1000 equipment and analyzed in the Fragment Profiler v1.2. For detection of the FLT3-TKD mutation, genomic DNA was amplified by PCR followed by restriction analysis. Blasts from the diagnostic BM cytology were digitalized, segmented and nuclear morphometric variables were examined. Their influence on overall survival was analyzed in the Cox model. Results: Median age: 52 years; peripheral blood (PB) leukocytes: 24.0×109/l (0.7-281.3). In the univariate analysis were significant: PB leukocyte count (p=0.005), low-risk karyotype (p=0.002), FLT3 ITD+ (p=0.002), FLT3+NPM1- (p=0.029) and “goodness of fit” (R245) of the chromatin fractal dimension (Minkowski) (p=0.03). Age, fractal dimension and methylation status of p15, p16, p57, p73, ER and MDR1 were not significant. In the multivariate analyses including age, PB leukocytes, R245 and mutations, high leukocyte counts (p=0.03) and low R245 (p=0.01) were independent unfavorable and FLT3-NPM1- (p=0.04) and FLT3-NPM1+ (p=0.02) were favorable prognostic variables. Conclusions: The blast chromatin texture measured by R245 was an independent prognostic factor together with known risk variables in AML. Supported by: FAPESP and CNPq Disclosures: No relevant conflicts of interest to declare.
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