Jih-Luh Tang

AML1/RUNX1 Mutations in 470 Adult Patients with De Novo Acute Myeloid Leukemia: Prognostic Implication and Interaction with Other Gene Alterations.

Somatic mutation of the AML1/RUNX1(RUNX1) gene is seen in acute myeloid leukemia (AML) M0 subtype and in AML transformed from myelodysplastic syndrome, but the impact of this gene mutation on survival in AML patients remains unclear. In this study, we sought to determine the clinical implications of RUNX1 mutations in 470 adult patients with de novo non-M3 AML. Sixty-three distinct RUNX1 mutations were identified in 62 persons (13.2%); 32 were in N-terminal and 31, C-terminal. The RUNX1 mutation was closely associated with male sex, older age, lower lactic dehydrogenase value, French-American-British M0/M1 subtypes, and expression of HLA-DR and CD34, but inversely correlated with CD33, CD15, CD19, and CD56 expression. Furthermore, the mutation was positively associated with MLL/PTD but negatively associated with CEBPA and NPM1 mutations. AML patients with RUNX1 mutations had a significantly lower complete remission rate and shorter disease-free and overall survival than those without the mutation. Multivariate analysis demonstrated that RUNX1 mutation was an independent poor prognostic factor for overall survival. Sequential analysis in 133 patients revealed that none acquired novel RUNX1 mutations during clinical courses. Our findings provide evidence that RUNX1 mutations are associated with distinct biologic and clinical characteristics and poor prognosis in patients with de novo AML.

Distinct clinical and biologic characteristics in adult acute myeloid leukemia bearing the isocitrate dehydrogenase 1 mutation

Mutations of nicotinamide adenine dinucleotide phosphate-dependent isocitrate dehydrogenase gene (IDH1) have been identified in patients with gliomas. Recent genome-wide screening also revealed IDH1 mutation as a recurrent event in acute myeloid leukemia (AML), but its clinical implications in AML are largely unknown. We analyzed 493 adult Chinese AML patients in Taiwan and found 27 patients (5.5%) harboring this mutation. IDH1 mutation was strongly associated with normal karyotype (8.4%, P = .002), isolated monosomy 8 (P = .043), NPM1 mutation (P < .001), and French-American-British M1 subtype (P < .001), but inversely associated with French-American-British M4 subtype (P = .030) and expression of HLA-DR, CD13, and CD14 (P = .002, .003, and .038, respectively). There was no impact of this mutation on patient survival. Sequential analysis of IDH1 mutation was performed in 130 patients during follow-ups. None of the 112 patients without IDH1 mutation at diagnosis acquired this mutation at relapse. In all 18 IDH1-mutated patients studied, the mutation disappeared in complete remission; the same mutation reappeared in all 11 samples obtained at relapse. We conclude that IDH1 is associated with distinct clinical and biologic characteristics and seems to be very stable during disease evolution.

TET2 mutation is an unfavorable prognostic factor in acute myeloid leukemia patients with intermediate-risk cytogenetics.

The studies concerning clinical implications of TET2 mutation in patients with primary acute myeloid leukemia (AML) are scarce. We analyzed TET2 mutation in 486 adult patients with primary AML. TET2 mutation occurred in 13.2% of our patients and was closely associated with older age, higher white blood cell and blast counts, lower platelet numbers, normal karyotype, intermediate-risk cytogenetics, isolated trisomy 8, NPM1 mutation, and ASXL1 mutation but mutually exclusive with IDH mutation. TET2 mutation is an unfavorable prognostic factor in patients with intermediate-risk cytogenetics, and its negative impact was further enhanced when the mutation was combined with FLT3-ITD, NPM1-wild, or unfavorable genotypes (other than NPM1(+)/FLT3-ITD(-) or CEBPA(+)). A scoring system integrating TET2 mutation with FLT3-ITD, NPM1, and CEBPA mutations could well separate AML patients with intermediate-risk cytogenetics into 4 groups with different prognoses (P < .0001). Sequential analysis revealed that TET2 mutation detected at diagnosis was frequently lost at relapse; rarely, the mutation was acquired at relapse in those without TET2 mutation at diagnosis. In conclusion, TET2 mutation is associated with poor prognosis in AML patients with intermediate-risk cytogenetics, especially when it is combined with other adverse molecular markers. TET2 mutation appeared to be unstable during disease evolution.

Efficacy and safety of dasatinib in imatinib-resistant or -intolerant patients with chronic myeloid leukemia in blast phase

Dasatinib is an inhibitor of BCR-ABL and SRC-family kinases for patients with imatinib-resistant or -intolerant chronic myelogenous leukemia (CML). In this international phase II trial, dasatinib was administered orally (70 mg twice daily) to patients with myeloid blast phase (MBP, n=109) or lymphoid blast phase (LBP, n=48) CML. After a minimum follow-up of 12 months (range 0.03–20.7 months), major hematologic responses were induced in 34% (MBP-CML) and 35% (LBP-CML) of patients. Major cytogenetic responses were attained in 33% (MBP-CML) and 52% (LBP-CML) of patients and complete cytogenetic responses were attained in 26 and 46%, respectively. Median progression-free survival was 6.7 (MBP-CML) and 3.0 (LBP-CML) months. Median overall survival was 11.8 (MBP-CML) and 5.3 (LBP-CML) months. Overall, dasatinib had acceptable tolerability. Fluid retention events were more frequent in the MBP-CML than the LBP-CML cohort: pleural effusion occurred in 36 and 13% (all grades) and 15 and 6% (grades 3/4), respectively. Other non-hematologic side effects were primarily grade 1/2; grade 3/4 events were recorded in ⩽6% of patients, except febrile neutropenia (15%). Cytopenias were noted in the majority of patients, and were manageable with dose interruptions/reductions. Dasatinib is associated with a promising rate of response in this high-risk population.

Characterization of CEBPA Mutations in Acute Myeloid Leukemia: Most Patients with CEBPA Mutations Have Biallelic Mutations and Show a Distinct Immunophenotype of the Leukemic Cells

Purpose: The transcription factor CCAAT/enhancer binding protein α, encoded by the CEBPA, is crucial for the differentiation of immature granulocytes. Mutation of the CEBPA may play an important role in leukemogenesis and prognosis. We sought to characterize the CEBPA mutation in acute myeloid leukemia (AML) and to clarify if there is a distinct immunophenotype for leukemic cells with the mutation. Experiment Design: One hundred and four patients with de novo AML were evaluated for the CEBPA mutation and immunophenotype of the leukemic cells. Results: Twenty-two distinct mutations were identified in 16 (15%) of 104 AML patients. Fourteen patients had biallelic mutations, mostly involving both the NH2-terminal TAD1 region and the COOH-terminal basic leucine zipper domain (bZIP). The mutations in the bZIP region were always tandem duplications and were located at hot-spot regions for topoisomerase II sites. Sequential study of the CEBPA mutations showed that the mutations disappeared at complete remission but the same mutations reappeared at relapse. None of the patients developed novel mutations during the follow-up period. Patients with CEBPA mutations had significantly higher incidences of CD7 (73%), CD15 (100%), CD34 (93%), and HLA-DR (93%) expression on the leukemic cells. Conclusion: These data revealed that most AML with CEBPA mutations were associated with an immunophenotype of HLA-DR+CD7+CD13+CD14−CD15+CD33+CD34+. The close relationship of CEBPA mutations with the leukemia status of the patients and the concordance of mutation in presenting and relapse samples implicate the CEBPA mutation as a potential marker for monitoring minimal residue disease.

Nucleophosmin mutations in De novo acute myeloid leukemia : The age-dependent incidences and the stability during disease evolution

Nucleophosmin (NPM) mutations have been found in a significant proportion of adults with de novo acute myeloid leukemia (AML), especially in those of a normal karyotype. These results provide a basis for studies of the pathogenesis in this specific subgroup of AML. In this study, NPM mutations were analyzed in 173 Chinese patients of de novo AML, including adults and children. We found that NPM mutations were present in 19.1% of the overall population and 40.3% of those with a normal karyotype. Adults had a significantly higher incidence of NPM mutations than children [32 of 126 (25.4%) versus 1 of 47 (2.1%), P < 0.001]. NPM mutations were closely associated with normal karyotype (P < 0.001) and internal tandem duplication of FLT3 (P = 0.002), but negatively associated with CEBPA mutations (P = 0.032) and expression of CD34 (P < 0.001) and HLA-DR (P = 0.003). Serial analyses of NPM mutations showed the mutation disappeared at complete remission, but the same mutation reappeared at relapse, except for one who lost the mutation at the second relapse, when new cytogenetic abnormalities emerged. None acquired novel mutations during the follow-up period. In conclusion, NPM mutations occur in an age-dependent fashion. Moreover, the findings that NPM mutations are stable during disease evolution and closely associated with disease status make it a potential marker for monitoring minimal residual disease.

Distinct clinical and biological features of de novo acute myeloid leukemia with additional sex comb-like 1 (ASXL1) mutations

Mutations in the additional sex comb-like 1 (ASXL1) gene were recently shown in various myeloid malignancies, but they have not been comprehensively investigated in acute myeloid leukemia (AML). In this study, we analyzed ASXL1 mutations in exon 12 in 501 adults with de novo AML. ASXL1 mutations were detected in 54 patients (10.8%), 8.9% among those with normal karyotype and 12.9% among those with abnormal cytogenetics. The mutation was closely associated with older age, male sex, isolated trisomy 8, RUNX1 mutation, and expression of human leukocyte antigen-DR and CD34, but inversely associated with t(15;17), complex cytogenetics, FLT3-internal tandem duplication, NPM1 mutations, WT1 mutations, and expression of CD33 and CD15. Patients with ASXL1 mutations had a shorter overall survival than patients without, but the mutation was not an independent adverse prognostic factor in multivariate analysis. Sequential analyses showed that the original ASXL1 mutations were lost at relapse and/or refractory status in 2 of the 6 relapsed ASXL1-mutated patients studied, whereas 2 of the 109 ASXL1-wild patients acquired a novel ASXL1 mutation at relapse. In conclusion, AML bearing ASXL1 mutations showed distinct clinical and biological features. The ASXL1 mutation status can change during disease evolution in a few patients.

DNMT3A mutations in acute myeloid leukemia: stability during disease evolution and clinical implications

DNMT3A mutations are associated with poor prognosis in acute myeloid leukemia (AML), but the stability of this mutation during the clinical course remains unclear. In the present study of 500 patients with de novo AML, DNMT3A mutations were identified in 14% of total patients and in 22.9% of AML patients with normal karyotype. DNMT3A mutations were positively associated with older age, higher WBC and platelet counts, intermediate-risk and normal cytogenetics, FLT3 internal tandem duplication, and NPM1, PTPN11, and IDH2 mutations, but were negatively associated with CEBPA mutations. Multivariate analysis demonstrated that the DNMT3A mutation was an independent poor prognostic factor for overall survival and relapse-free survival in total patients and also in normokaryotype group. A scoring system incorporating the DNMT3A mutation and 8 other prognostic factors, including age, WBC count, cytogenetics, and gene mutations, into survival analysis was very useful in stratifying AML patients into different prognostic groups (P < .001). Sequential study of 138 patients during the clinical course showed that DNMT3A mutations were stable during AML evolution. In conclusion, DNMT3A mutations are associated with distinct clinical and biologic features and poor prognosis in de novo AML patients. Furthermore, the DNMT3A mutation may be a potential biomarker for monitoring of minimal residual disease.

Treatment outcome and pattern of failure in 77 patients with sinonasal natural killer/T-cell or T-cell lymphoma.

Sinonasal natural killer (NK)/T‐cell or T‐cell lymphoma behaves quite differently from other lymphomas. The objective of this study was to investigate clinical features, treatment outcomes, and failure patterns in patients with this type of sinonasal lymphoma.

Methylation of the p15INK4B gene in myelodysplastic syndrome: it can be detected early at diagnosis or during disease progression and is highly associated with leukaemic transformation

To investigate the time sequence of occurrence of p15INK4B gene methylation in myelodysplastic syndrome (MDS) and its correlation with leukaemic transformation and survival of patients, the methylation status of the p15INK4B promoter region was analysed in 50 patients and was serially studied in 22 of them. Of the 50 patients, 17 (34%) showed p15INK4B gene methylation, first demonstrated at diagnosis or during follow‐up. When FAB subtypes at the time of study were used in the analysis, the incidence of p15INK4B methylation in each risk group of MDS remained stable throughout the course: 0% for low‐risk MDS [refractory anaemia (RA) and RA with ring sideroblasts] and from 23% at diagnosis to 30% for high‐risk MDS [RA with excess of blasts (RAEB), RAEB in transformation and chronic myelomonocytic leukaemia] respectively. The incidence of p15INK4B methylation rose to 60% at initial study and, finally, to 75% in cases of acute myeloid leukaemia (AML) evolved from MDS. Most patients (69%) with p15INK4B methylation showed disease progression to AML; it could be detected before, at the time or after the diagnosis of leukaemic transformation. p15INK4B methylation in MDS patients implicated a shorter survival time in univariate analyses, but its prognostic significance disappeared in multivariate analyses. In conclusion, p15INK4B methylation can be detected early at the diagnosis of MDS or acquired during disease progression. It may play an important role in the pathogenesis of some high‐risk MDS and is related to leukaemic transformation of MDS.