Long Su

Cytogenetic and Genetic Mutation Features of de novo Acute Myeloid Leukemia in Elderly Chinese Patients

OBJECTIVES The present study aimed to examine the cytogenetic and genetic mutation features of acute myeloid leukemia (AML) in elderly Chinese patients. METHODS A retrospective analysis of cytogenetics and genetic mutations was performed in 113 cases (age range 50-82 years) with de novo AML. RESULTS The most frequent cytogenetic abnormality was t (15;17) (q22;q21), detected in 10.0% (n = 9) of successfully analyzed cases, followed by t (8;21) (q22;q22) in 8.89% (n = 8), and complex karyotypes in 5.56% (n = 5). Those with complex karyotypes included 4 cases (4.44%) of monosomal karyotypes. The frequencies of NPM1, FLT3-ITD, c-kit, and CEBPA mutations were 27.4% (31/113), 14.5% (16/110), 5.88% (6/102), and 23.3% (7/30), respectively. The complete remission rates of patients in low, intermediate, and high risk groups were 37.5%, 48.6%, and 33.3%, respectively (χ2 = 0.704, P = 0.703) based on risk stratification. CONCLUSION Cytogenetics and genetic mutations alone may not be sufficient to evaluate the prognoses of elderly AML patients. The search for a novel model that would enable a more comprehensive evaluation of this population is therefore imperative.

NPM1, FLT3-ITD, CEBPA, and c-kit mutations in 312 Chinese patients with de novo acute myeloid leukemia

Abstract Objectives To explore NPM1, FLT3-ITD, CEBPA, and c-kit mutations in patients with acute myeloid leukemia (AML) from Chinese population. Methods In this study, we retrospectively analyzed the prevalence and clinical profile of NPM1, FLT3-ITD, CEBPA, and c-kit mutations in 312 patients with de novo AML. Results The frequencies of NPM1, FLT3-ITD, c-kit, and CEBPA mutations were 15.4, 14.0, 7.64, and 25.6%, respectively. The occurrence rate of NPM1 mutations increased with age in patients younger than 60 years. NPM1, c-kit, and CEBPA mutations were all associated with French-American-British subtypes. Patients with NPM1 mutations and FLT3-ITD presented with higher peripheral white blood cell counts and marrow blast percentages. Conclusion Both this and previous studies may suggest low frequencies of NPM1 and FLT3-ITD mutations in AML patients from the Chinese population, and they may have a synergistic function in stimulating proliferation of leukemia cells.

Associations between age, cytogenetics, FLT3-ITD, and marrow leukemia cells identified by flow cytometry.

OBJECTIVES To explore the relationships between age, cytogenetic subgroups, molecular markers, and cells with leukemic aberrant immunophenotype in patients with acute myeloid leukemia (AML). METHODS In this study, we evaluated the correlations between age, cytogenetic subgroups (normal, balanced and unbalance karyotype), molecular mutations (NPM1, FLT3-ITD, and CEBPA mutations) and marrow leukemia cells (LC) identified by flow cytometry in 256 patients with de novo AML. RESULTS From age group 10-19 years to age group ≥ 60 years, the percentage of LC decreased from 67.0 ± 18.4% to 49.0 ± 25.1% (F = 2.353, P = 0.041). LC percentage was higher in patients with balanced karyotypes (65.7 ± 22.4%), than those with unbalanced karyotypes (46.0 ± 26.6%) (u = 3.444, P = 0.001) or a normal karyotype (49.9 ± 22.1%) (u = 5.093, P < 0.001). Patients with FLT3-ITD (64.3 ± 19.5%) had higher LC percentages compared with those without (54.2 ± 24.3%) (u = 2.794, P = 0.007). CONCLUSIONS Associations between age, cytogenetics, molecular markers, and marrow leukemia cells may offer beneficial information to understand the biology and pathogenesis of AML.

Age-Specific Distributions of Cytogenetic Subgroups of Acute Myeloid Leukemia: Data Analysis in a Chinese Population

Although some studies have reported relationships between cytogenetic subgroups, molecular markers and age in acute myeloid leukemia (AML), conclusions based on data from a Chinese population are lacking. In the present study, we evaluated 640 patients with de novo AML. The patients were divided into 8 age groups, i.e. 0–9, 10–19, 20–29, 30–39, 40–49, 50–59, 60–69 and ≥70 years, and were then classified into cytogenetic groups based on normal, balanced and unbalanced karyotypes [including both complex karyotypes (CKs) and monosomal karyotypes (MKs)]. Different age distributions were observed in these karyotype groups. The frequency of the normal karyotype increased with age from 6.67 to 58.33% (χ2 = 20.68, p = 0.001), whereas that of the balanced karyotypes decreased with age from 73.33 to 11.11% (χ2 = 48.22, p < 0.001). Furthermore, the occurrence of the unbalanced karyotypes and CKs also increased with age (p < 0.05). No age-specific distributions were observed for the MK subgroups and the different molecular markers (NPM1, FLT3-ITD and c-kit). The cytogenetic subtypes were also related to the French-American-British classification, peripheral blood white cell count and molecular markers. In conclusion, the different age profiles of the cytogenetic subtypes may implicate different mechanisms in the pathogenesis of AML, which may be beneficial for etiological research and the prevention of AML.

The Surface Molecular Signature of Leukemic Cells Is Associated with NPM1 Mutations and FLT3-ITD in Patients with de novo Acute Myeloid Leukemia

Certain molecular mutations are associated with signs of cell morphology and differentiation in acute myeloid leukemia (AML). However, only limited data are available for the detailed analysis of such correlations. In this study, AML patients were classified into 4 subsets according to CD34, HLA-DR and CD11c expression levels. Significantly low CD34 antigen expression was observed in nucleophosmin (NPM1)-mutated patients and in those with FMS-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD). No correlations were observed among NPM1 mutations, FLT3-ITD and monocytic morphology in patients without CD34 expression. Both NPM1 mutations and FLT3-ITD were absent in cluster IIb patients (CD34+CD11c-). The associations among NPM1 mutations, FLT3-ITD and the surface molecular signature of leukemic cells may offer beneficial information about the pathogenesis of AML.

Mutational spectrum of acute myeloid leukemia patients with double CEBPA mutations based on next-generation sequencing and its prognostic significance

The aim of this study was to profile the spectrum of genetic mutations in acute myeloid leukemia (AML) patients co-occurring with CEBPA double mutation (CEBPAdm). Between January 1, 2012, and June 30, 2017, 553 consecutive patients with de novo AML were screened for CEBPA mutations. Out of these, 81 patients classified as CEBPAdm were analyzed further by a sensitive next-generation sequencing assay for mutations in 112 candidate genes. Within the CEBPA gene itself, we found 164 mutations. The most common mutated sites were c.936_937insGAG (n = 11/164, 6.71%) and c.939_940insAAG (n = 11/164, 6.71%), followed by c.68dupC (n = 10/164, 6.10%). The most common co-occurring mutations were found in the CSF3R (n = 16/81, 19.75%), WT1 (n = 15/81, 18.52%), and GATA2 (n = 13/81, 16.05%) genes. Patients with CSF3R mutations had an inferior four-year relapse-free survival (RFS) than those with the wild-type gene (15.3% versus 46.8%, respectively; P = 0.021). Patients with WT1 mutations had an inferior five-year RFS compared with those without such mutations (0% versus 26.6%, respectively, P = 0.003). However, GATA2, CSF3R, WT1 mutations had no significant influence on the overall survival. There were some differences in the location of mutational hotspots within the CEBPA gene, as well as hotspots of other co-occurring genetic mutations, between AML patients from Chinese and Caucasian populations. Some co-occurring mutations may be potential candidates for refining the prognoses of AML patients with CEBPAdm in the Chinese population.

CEBPA mutations in patients with de novo acute myeloid leukemia: data analysis in a Chinese population

Background This study was aimed to explore the clinical characteristics and prognoses of acute myeloid leukemia (AML) patients with CEBPA mutations. Patients and methods Three hundred and forty-five patients with de novo AML were retrospectively analyzed with regard to CEBPA mutations, clinical characteristics, therapeutic responses, and long-term outcomes. Results CEBPA mutations were detected in 59 patients (17.10%), with 47 cases harboring double mutations and 12 cases harboring single mutations. In those with a normal karyotype (NK), 44 cases (25.29%) were detected with CEBPA mutations. The following characteristics were observed in CEBPA-mutated patients: most (66.10%) of them were M1 or M2; they presented with higher peripheral white blood cell counts (23.71 [12.6, 60.02] ×109/L versus 7.34 [2.38, 26.63] ×109/L; u=4.944, P<0.001) and higher hemoglobin levels (89.64±23.05 g/L versus 75.65±23.65 g/L; t=4.156, P<0.001) than those observed in patients without the mutation; and the expression of CD7 and HLA-DR was higher, whereas that of CD34 and CD56 was lower in patients with the mutation than in those without the mutation. Compared with those without the mutation, patients with CEBPA mutations had a superior complete remission rate (75.0% versus 56.54%; χ2=6.185, P=0.013) and superior overall survival (P=0.034). Conclusion The frequency of CEBPA mutations may be higher in Chinese patients with AML than has been reported in populations of western countries, and the presence of CEBPA mutations is an indication of favorable prognoses for these patients.

High-dose versus standard-dose daunorubicin in induction therapy for young patients with de novo acute myeloid leukaemia: a meta-analysis of randomised trials

Purpose: To compare the efficacy and safety of high-dose versus standard-dose daunorubicin for young patients with de novo acute myeloid leukaemia (AML) using meta-analysis. Methods: Two trials were taken from 2,481 full-text articles. Heterogeneity was assessed using the I2 index. Quality assessment was performed with the Cochrane Collaboration’s risk-of-bias tool. Results: The analysis showed that high-dose daunorubicin induction therapy was associated with higher complete remission (CR) rate (n = 965; RR = 1.80; 95% CI = 1.36–2.38; p < 0.0001; I2 = 0%) and improved overall survival (n = 1040; HR = 0.74; 95% CI = 0.63–0.87; p = 0.0003; I2 = 0%) compared with standard-dose daunorubicin. However, there was no significant interaction between treatment efficacy and prognostic category based on cytogenetics (favourable, intermediate and unfavourable) (p = 0.44, I2 = 0%). Conclusion: High-dose daunorubicin therapy could increase CR rate and improve long-term outcome for young patients with de novo AML. However, further study is needed to identify those who can benefit from high-dose daunorubicin.

Reduced serum retinol-binding protein levels in patients with de novo acute myeloid leukaemia

Abstract Retinol-binding protein (RBP) has been used as a nutritional index for children with acute myeloid leukaemia (AML) in previous studies. However, no studies have yet examined RBP levels in AML patients from all age groups. In this study, AML patients presented with lower RBP concentrations than healthy control subjects and patients with benign haematopathies. A negative association was observed between serum RBP level and peripheral white blood cell count in M4 and M5 AML patients. Moreover, patients carrying the FLT3-ITD mutation and young patients had lower RBP levels than those lacking this mutation and elderly patients. In conclusion, these observations suggest that aberrant retinol levels may be associated with AML.