Incidence of Second Malignancies of Chronic Myeloid Leukemia During Treatment With Tyrosine Kinase Inhibitors.

BACKGROUND: Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of chronic myeloid leukemia (CML) by providing patients with long-term survival. Although most patients who receive TKI treatment have shown satisfactory tolerance, second malignancies (SMs) should not be ignored because of lifetime treatment. We designed a retrospective study to evaluate the incidence and possible risk factors of SMs in CML patients treated with TKIs. PATIENTS AND METHODS: Records of 223 patients with Philadelphia chromosome-positive CML treated with imatinib were reviewed to investigate frequencies and characteristics of SMs. The data of SMs were compared with the number expected from the National Central Cancer Registry. The possible risk factors of SM in CML patients treated with TKIs were also evaluated using Poisson regression in this study. RESULTS: After a median follow-up of 64 months (range, 4-253 months) from CML diagnosis, 7 patients (3.14%) developed 6 different SMs including colon, stomach, breast, kidney, cervical, and lymphonodus tissue. The risk of second cancer was higher than expected (observed-to-expected ratio, 2.45; 95% confidence interval, 1.17-5.14; P = .018). No associated elements were found in terms of influencing the incidence of SM in CML patients treated with TKIs. CONCLUSION: We found patients with CML treated with TKIs had a higher relative incidence of SM compared with the expected incidence among the general Chinese population. However, the correlations between second cancer and the potential risk factors including the length of exposure and cumulative dose of TKIs were not found in this study.

Impact of Chemotherapy Delay on Overall Survival for AML with IDH1/2 Mutations: A Study in Adult Chinese Patients.

The effect of time from diagnosis to treatment (TDT) on overall survival of patients with acute myeloid leukemia (AML) remains obscure. Furthermore, whether chemotherapy delay impacts overall survival (OS) of patients with a special molecular subtype has not been investigated. Here, we enrolled 364 cases of AML to assess the effect of TDT on OS by fractional polynomial regression in the context of clinical parameters and genes of FLT3ITD, NPM1, CEBPA, DNMT3a, and IDH1/2 mutations. Results of the current study show IDH1/2 mutations are associated with older age, M0 morphology, an intermediate cytogenetic risk group, and NPM1 mutations. TDT associates with OS for AML patients in a nonlinear pattern with a J shape. Moreover, adverse effect of delayed treatment on OS was observed in patients with IDH1/2 mutations, but not in those with IDH1/2 wildtype. Therefore, initiating chemotherapy as soon as possible after diagnosis might be a potential strategy to improve OS in AML patients with IDH1/2 mutations.

High IDH1 expression is associated with a poor prognosis in cytogenetically normal acute myeloid leukemia.

The prognostic value of IDH1 mutations has been systematically evaluated in acute myeloid leukemia (AML) patients recently. However, the role of IDH1 expression in AML is still under exploration. To investigate the clinical significance, we analyzed the IDH1/2 expression in 320 patients with cytogenetically normal AML (CN-AML) by quantitative real-time reverse-transcription polymerase chain reaction. High expression of IDH1 was predominant in patients with FLT3-ITD and DNMT3A mutations and less prevalent in cases with CEBPA double allele mutations. Strong association was observed between high IDH1 expression and low expression of microRNA 181 family. Prognosis was adversely affected by high IDH1 expression, with shorter overall survival and event-free survival in the context of clinical characteristics, including age, WBC count, and gene mutations of NPM1, FLT3-ITD, CEBPA, IDH1, IDH2 and DNMT3A in CN-AML. Moreover, the clinical outcome of IDH1 expression in terms of overall survival, event-free survival and complete remission rate still remained in multivariate models in CN-AML. Importantly, the prognostic value was validated using the published microarray data from 79 adult patients treated according to the German AMLCG-1999 protocol. Our results demonstrated that high IDH1 expression is associated with a poor prognosis of CN-AML.

[Expression of BCL2L12 gene in de novo acute myeloid leukemia and its clinical implications].

OBJECTIVE: To explore the expression of BCL2L12 gene and its clinical significance for de novo acute myeloid leukemia (AML). METHODS: Real-time quantitative PCR (RQ-PCR) was employed to measure the expression of BCL2L12 gene in 134 patients with de novo AML. The results were correlated with clinical features of patients. RESULTS: BCL2L12 gene transcript was determined for 134 AML patients and 49 healthy controls, with the median levels measured 0.1029 (0.0119-26.4090) and 0.2677 (0.0173-1.2858), respectively. There was a significant difference in the strength of BCL2L12 gene expression between patients and normal controls (P < 0.01). Those with lower BCL2L12 expression levels had a higher FLT3-ITD mutation rate compared with those with higher levels (27% vs. 5%, P = 0.036). Relapsed or refractory AML patients had lower expression compared with newly diagnosed patients (0.0873 vs. 0.1359, P = 0.014). There was no difference in overall survival (OS) between patients with higher and lower expression levels. However, for AML patients with a normal karyotype, the OS for those with lower expression was significant shorter (P = 0.037). CONCLUSION: De novo AML patients have a lower level of BCL2L12 gene expression. AML patients with lower BCL2L12 expression have a higher FLT3-ITD mutation rate, and most of them are relapse or refractory patients. In addition, among patients with a normal karyotype, those with a lower BCL2L12 expression have a shorter OS. Therefore, expression of the BCL2L12 gene may be used as a prognostic marker for AML patients with a normal karyotype.

[Karyotypic analysis and prognosis for 41 patients with chronic myelomonocytic leukemia].

OBJECTIVE: To analyze cytogenetic features of chronic myelomonocytic leukemia (CMML) patients and explore the relationship between cytogenetic characteristics and prognosis. METHODS: Clinical and laboratory data of 41 CMML patients were analyzed. RESULTS: The majority of CMML patients were middle-aged males. According to WHO classification, 17 (41.5%) patients were diagnosed as CMML-Ⅰ and 24 (58.5%) were diagnosed as CMML-Ⅱ. 14 (34%) of CMML patients harbored abnormal karyotypes and +8 was the most common. CMML-Ⅰpatients with abnormal karyotypes were older than those with normal karyotypes. CMML-Ⅱ patients with normal karyotypes had higher lymphocyte counts than those with abnormal karyotypes. Of 29 patients who had follow-up data, 26 died, with the median survival time being 4 (1-13) months. The median survival of patients with normal and abnormal karyotypes were 4.5 and 3.8 months, respectively (P=0.408). The median survival of CMML-Ⅰ patients with abnormal karyotypes was shorter than those with normal karyotypes (3 and 17 months, P=0.015), but no significant difference was found between the median survival of the two groups of CMML-Ⅱ patients (2.9 and 5.8 months, P=0.629). CONCLUSION: +8 has been the most common abnormal karyotype in CMML patients. The abnormal karyotype can be regarded as an indicator of poor prognosis for CMML-Ⅰ patients. Regardless of their karyotypes, CMML-Ⅱ patients have even poorer prognosis.

[Relationship between clinical characteristics and myelodysplastic syndrome patients with isocitrate dehydrogenase gene mutations].

OBJECTIVE: To assess the prevalence and clinical characteristics of isocitrate dehydrogenase 1 and 2 (IDH 1 and IDH2) gene mutations in myelodysplastic syndrome (MDS) patients. METHODS: Pretreatment bone marrow specimens were enriched for mononuclear cells in 108 adult patients with de novo MDS from January 2006 to August 2012. Genomic DNA was extracted from mononuclear cells. And PCR and direct sequencing were performed to sequence exon 4 of IDH gene. RESULTS: IDH mutations were discovered in 11 MDS patients (10.19%, 11/108) and all were heterozygous. The frequencies of IDH1 and IDH2 mutations were 5.56% (6/108) and 4.63% (5/108) respectively. Only one type of IDH1 mutation (c.394C→, p.R132C) was identified in our cohort. All IDH2 mutations caused the changes of R140 (c.419G→A, p.R140Q). However IDH2 R172 mutation was not detected. The combined mutations of IDH1 and IDH2 were not simultaneously observed in the same patient. The prevalence of IDH mutation was higher in advanced-stage MDS than those early-stage MDS patients. Mutated and wild-type groups had significantly difference in bone marrow blast percentage (median 12.5% vs 6.0%, P = 0.013) at diagnosis, but not in white blood cell count, hemoglobin level and platelet count, etc. In the normal karyotype group, the frequencies of IDH mutations were as similar as those in the abnormal karyotype group (10.61% (7/66) vs 10.00% (4/40), P > 0.05). The median follow-up time was 472 d, our data indicated that IDH mutations were correlated with poor overall survival (median time 512 vs 740 d, P = 0.017). IDH mutations were also an inferiorly predictive factor in the intermediate-1 group patients of International Prognostic Scoring System (IPSS) (median survival time 512 d vs not reached, P = 0.038). There was also better efficacies than other treatments in IDH mutation positive patients (median survival time 623 vs 165 d, P = 0.049). CONCLUSIONS: IDH mutation is a vital biomarker for better risk stratification of MDS patients with and improving IPSS. Hypomethylation agents may be effective for treating IDH mutation positive patients.

[Establishment of a rapid and easy method for simultaneous detection of FLT3-ITD and NPM1 gene mutations in acute myeloid leukemia].

OBJECTIVE: To establish a stable, rapid multiplex PCR assay combined with PAGE gel electrophoresis for simultaneously detecting FLT3-ITD and NPM1 mutations in acute myeloid leukemia (AML). METHODS: Capillary electrophoresis (CE) and PAGE gel electrophoresis were simultaneously used to analyze FLT3-ITD and NPM1 mutations in 117 de novo AML patients with normal cytogenetic findings. RESULTS: For certain mutations, the length of mutated double-stranded DNA is longer than wild-type DNA. Since FLT3-mut (420 bp) is longer than FLT3-wt (327-332 bp), and NPM1-mut (172 bp) is longer than NPM1-wt (168 bp), heteroduplex will move more slowly during PAGE gel electrophoresis than homoduplex. Therefore the mutations may be detected. A total of 117 CN-AML patients were analyzed with CE and PAGE gel electrophoresis, and the results were identical, which included 18 (15.4%) patients with FLT3-ITD+/NPM1-, 19 (16.2%) patients with FLT3-ITD+/NPM1+, 25 (21.4%) patients with FLT3-ITD-/NPM1+, and 55 (47.0%) patients with FLT3-ITD-/NPM1-. CONCLUSION: Both types of electrophoresis assays may provide a rapid and handy assay for simultaneous detection of FLT3-ITD and NPM1 mutations. CE is relatively sensitive, stable; while PAGE electrophoresis is relatively simple, cheap, and reliable, which may be suitable for primary hospitals and preliminary screening.

[Expression level of CDX2 gene in acute myeloid leukemia and its clinical significance].

OBJECTIVE: To explore the expression and clinical significance of Caudal-type homeobox transcription factor 2 (CDX2) gene in acute myeloid leukemia (AML) patients. METHOD: Real time quantitative PCR (RQ-PCR) was used to test the expression level of CDX2 gene in 108 de novo AML patients and the clinical features of these patients were analyzed. RESULTS: CDX2 gene transcript levels were detectable in bone marrow mononuclear cells from 108 AML patients and 7 healthy donors, the median expression level were 1179.44 (range 14.15 - 867 961.10) and 105.30 (range 22.30 - 453.11). There was a statistically significant difference in expression level of CDX2 gene between the AML patients and normal donor (P < 0.01). All 14 patients with FLT3-ITD(+) were in CDX2 gene higher expression group (P = 0.018), including 10 patients with normal karyotype. In the 83 treated AML patients (P = 0.046) and 57 higher WBC count (≥ 10×10(9)/L, P = 0.048) patients, the higher expression level of CDX2 gene was associated with lower complete remission (CR) rates. CONCLUSIONS: Higher expression level of CDX2 gene was seen mostly in AML patients with FLT3-ITD mutation and with lower CR rates. CDX2 gene might be a prognostic molecular marker in AML patients with normal karyotype.