Guowei Lin

Prospective study of 174 de novo acute myelogenous leukemias according to the WHO classification: subtypes, cytogenetic features and FLT3 mutations

Abstract:  We report a prospective study of 174 unselected adult de novo acute myeloid leukemia (AML) cases diagnosed using the WHO classification. Of those, 57 (33%) were AML with recurrent cytogenetic abnormalities, 41 were (24%) AML with multilineage dysplasia, 74 (42%) were AML not otherwise categorized, and two were acute leukemias of ambiguous lineage. Clonal cytogenetic abnormalities were detected in 64% of the WHO AML cases with t(15;17) (15%), t(8;21) (12%), +8 (11%), −7/del7q (8%) and del9q (5%) being the most common ones. The FLT3/ITD mutations (FMS‐like tyrosine kinase 3/internal tandem duplication) were observed in 12% of the WHO AML cases, which is much lower than ones in the literature, while the 6% incidence of the FLT3‐activating loop mutations (either FLT3/D835 or FLT3/I836) was comparable with others. Both mutations were associated with leukocytosis. Our study also suggests that the FLT3 mutations are biomarkers independent of cytogenetic characteristics.

Case–control study of risk factors of myelodysplastic syndromes according to World Health Organization classification in a Chinese population†

Risk factors of mydelodysplastic syndromes (MDS) remain largely unknown. We conducted a hospital‐based case–control study consisting of 403 newly diagnosed MDS patients according to World Health Organization classification and 806 individually gender and age‐matched patient controls from 27 major hospitals in Shanghai, China, to examine relation of lifestyle, environmental, and occupational factors to risk of MDS. The study showed that all MDS (all subtypes combined) risk factors included anti tuberculosis drugs [odds ratio (OR)adj = 3.15; 95% confidence interval (CI) = 1.22–8.12] as an independent risk factor, benzene (ORadj = 3.73; 95% CI = 1.32–10.51), hair dye use (OR = 1.46; 95% CI = 1.03–2.07), new building and renovations (OR = 1.69; 95% CI = 1.11–2.00), pesticides (OR = 2.16; 95% CI = 1.22–3.82), and herbicides (OR = 5.33; 95% CI = 1.41–20.10) as relative risk factors. Risk factors of MDS subtype refractory cytopenia with multiple dysplasia (RCMD) were benzene (ORadj = 5.99; 95% CI = 1.19–30.16) and gasoline (ORadj = 11.44; 95% CI = 1.31–100.03) as independent risk factors, and traditional Chinese medicines (OR = 2.17; 95% CI = 1.15–4.07), pesticides (OR = 2.92; 95% CI = 1.37–6.25), and herbicides (OR = 12.00; 95% CI = 1.44–99.67) as relative risk factors. Smoking tobacco was significantly associated with refractory anemia with excess of blasts (RAEB) (ORadj = 2.43; 95% CI = 1.02–5.77). Education is shown as an independent protective factor against all MDS (ORadj = 0.90; 95% CI = 0.83–0.99) and RCMD (ORadj = 0.89; 95% CI = 0.79–0.99). These findings suggest that multiple modifiable behavioral, environmental, and occupational factors play a role in MDS etiology, and various MDS subtypes may have different susceptibility. Am. J. Hematol. 86:163–169, 2011.

ID4 methylation predicts high risk of leukemic transformation in patients with myelodysplastic syndrome

Epigenetic gene silencing due to promoter methylation is observed in human cancers like acute myeloid leukemia (AML). Little is known about aberrant methylation in myelodysplastic syndrome (MDS), a heterogeneous clonal stem cell disorder with a approximately 30% risk of transformation into secondary AML. Recent evidence demonstrated that ID4, a negative regulator of transcription, may act as a tumor-suppressor gene. To clarify the role of ID4 in MDS, we employed methylation-specific PCR (MSP) to examine the methylation status of ID4 in 144 adult de novo MDS patients. We found that ID4 methylation was present in 35.4% (n=51) of these MDS patients and methylaiton was correlated significantly with World Health Organization (WHO) subtypes and International Prognostic Scoring System (IPSS) risk groups. Patients with advanced stages of WHO subtypes (45.8% vs. 21.3%, P=0.002) and higher risk IPSS subgroups (45.7% vs. 26.0%, P=0.014) exhibited a significantly higher frequency of ID4 methylation. The median survival of patients with ID4 methylation was shorter than patients without ID4 methylation (12.2 months vs. 26.9 months, P=0.005). Multivariate analysis indicated that ID4 methylation status was the independent factor that impacted leukemia-free survival (LFS). Disease in patients with ID4 methylation progressed more rapidly than those without ID4 methylation (P=0.047, HR=2.11). Our results suggest that ID4 may be a therapeutic target in MDS.

Cytogenetic evolution correlates with poor prognosis in myelodysplastic syndrome

Clonal chromosomal abnormalities are observed in 30-50% of primary myelodysplastic syndrome (MDS) patients. Although the prognostic relevance of cytogenetics is generally appreciated, the prognostic value of cytogenetic evolution has rarely been evaluated. In this study, we retrospectively analyzed cytogenetic features at diagnosis and during follow-up in 85 patients with primary MDS. Cytogenetic evolution occurred in 18 of the 85 patients (21%), with chromosomes 8, 5, and 1 most often involved. Patients with higher levels of marrow blasts (P = 0.034), more advanced stages of World Health Organization (WHO) subtypes (44% vs. 16%, P = 0.035), and higher risk International Prognostic Scoring System (IPSS) subgroups (47% vs. 16%, P = 0.021) had higher incidences of developing cytogenetic evolution. Furthermore, the median survival of patients in the group with cytogenetic evolution was 25.8 months, compared with 45.4 months for patients in the group without cytogenetic evolution (P = 0.01). The same result was also found for time to progression: patients with cytogenetic evolution progressed more rapidly than those without cytogenetic evolution (P = 0.007). Knowledge of cytogenetic evolution offers useful information for clinicians to make more accurate prognostic assessments for patients with MDS.

Prospective analysis of clinical and cytogenetic features of 435 cases of MDS diagnosed using the WHO (2001) classification: a prognostic scoring system for predicting survival in RCMD

We characterized the prevalence, clinical and cytogenetic characteristics and survival of 435 patients diagnosed with de novo MDS in a single laboratory according to WHO criteria, and compared the utility of different scoring systems to predict survival for individual subtypes of MDS. The mean follow-up period was 25.1 (5.5–53.2) months. Our results confirm major differences in the age-distribution and prevalence of individual subtypes of MDS between Asian and Western patients with a median age of 58 years and a predominance of RCMD (69.9%). Survival rates were similar to those reported in the West: the 3-year survival rate for MDS was 46.7% with a median survival time for RCMD of 38 months and RAEB, 10 months. We found that the IPSS and WPSS scoring systems, which are weighted heavily by blast cell count and karyotype, were not independent predictors for survival in RCMD patients. Multivariate analysis demonstrated that a scoring system based on age (≥60 years), ANC (<1.0 × 109/L), Hb (<90 g/L), number of cytopenias and complex karyotype is a more useful predictor of survival in RCMD.

Characterization of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) in Shanghai, China: Molecular and cytogenetic characteristics, IgV gene restriction and hypermutation patterns

The clinical, cytogenetic and molecular features of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), a disease previously considered to be rare in Asia, were examined in consecutive series of 70 cases diagnosed by our laboratory over a 30-month period. Clonal abnormalities were observed in 80% of CLL/SLL cases using a combination of conventional cytogenetic and fluorescence in situ hybridization (FISH) analysis. Those involving 14q32/IGH were the most frequent (24 cases), followed by trisomy 12 and 11q abnormalities. IgV(H) gene usage was non-random with over-representation of V(H)4-34, V(H)3-23 and a previously unreported increase in V(H)3-48 gene use. Somatic hypermutation (SHM) of IgV(H) germline sequences was observed in 56.5% of cases with stereotyped patterns of SHM observed in V(H)4-34 heavy chain complimentary-determining (HCDR1) and framework region CFR2 sequences. These findings in a Chinese population suggest subtle geographical differences in IgV(H) gene usage while the remarkably specific pattern of SHM suggest that a relatively limited set of antigens may be involved in the development of this disease worldwide. IgV(H) gene mutation status was a significant predictor of initial survival in CLL/SLL. However, an influence of karyotype on prognosis was not observed.

Analyses on clinical characteristic and prognoses of 41 patients with chronic myelomonocytic leukemia in China.

PURPOSE To investigate clinical characteristic and prognostic factors for chronic myelomonocytic leukemia (CMML). METHODS A retrospective cohort study was used in the research. We investigated clinical and laboratory characteristics of CMML patients and survival status. Patients were followed up regularly through out the course of the research. RESULTS Forty-one cases were diagnosed as CMML, including 27 male and 14 female patients. Median WBC was 13.7 x 10(9)/L. Five patients had leukocytopenia (1.92-3.46 x 10(9)/L). Median monocyte count in the peripheral blood was 2.13 x 10(9)/L. All patients presented with bone marrow dysplasia, and most showed hyperplasia, except 3 cases. Abnormal chromosome was detected in 34% cases. Median survival time for CMML-1 and CMML-2 was 20 and 12 months, respectively, but there were no statistical significance of survival duration between them. Univariable analysis showed that age (>60 years), neutrophil count (<2.0 x 10(9)/L), lymphocyte count (<1.0 x 10(9)/L), mature monocyte count (>or=5 x 10(9)/L) and anemia (Hb<60 g/L) were associated with poor prognosis for CMML. There was no statistical significance in LDH, gender, and abnormal chromosome for survival time. Only lymphocyte count and neutrophil count in peripheral blood were independent prognostic factors for CMML after multivariate analysis. CONCLUSION CMML mainly occurs in elderly patients. Although most patients have leukocytosis and monocytosis at diagnosis, few cases show leucopenia and monocytopenia. Age, neutrophil, lymphopenia, monocytosis, and severe anemia are associated with inferior prognosis of CMML. Lymphocyte<1.0 x 10(9)/L and neutrophil count<2.0 x 10(9)/L are adversely independent prognostic factors for CMML.

Chromosome abnormalities in diffuse large B-cell lymphomas: analysis of 231 Chinese patients.

Genome instability is a hallmark of cancer. Diffuse large B‐cell lymphoma (DLBCL) is the most common form of non‐Hodgkin lymphoma with high levels of chromosomal aberrations. The purpose of this study was to characterize chromosomal aberrations in Chinese DLBCL patients and to compare chromosomal abnormalities between germinal centre B‐cell‐like (GCB) and non‐GCB subgroups. Fluorescence in situ hybridization, G‐band cytogenetics and immunohistochemistry were performed in 231 cases of de novo DLBCL. We demonstrated that the rate of abnormal and complex karyotypes was 89.1% (139/156) and 92.8% (129/139), respectively. We found a total of 490 structural chromosomal aberrations, including 96 frequent and recurring structural alterations. Most importantly, we identified several rare or novel chromosomal alterations: eight gains (5, 13, 14q, 17, 19p, 20, 21p, Y), one loss (21) and three recurrent translocations [t(7;15)(q22;q22), t(3;20)(p24;q13.1), t(2;3)(q21;q25)]. Moreover, the frequent recurrent genomic imbalance between GCB and non‐GCB subgroups was different. Finally, we discovered two cases of concurrent IGH‐BCL6 and MYC rearrangements. The rate of abnormal karyotypes in DLBCL patients of Chinese descent was similar to that of Western countries, but some common karyotypes were different, as were the abnormal karyotypes of GCB and non‐GCB subgroups. Our discovery of rare and novel abnormal karyotypes may represent unique chromosomal alterations in Chinese DLBCL patients. Copyright

Analysis of clinical characteristics of 516 patients with non-Hodgkin's lymphoma in Shanghai area

Abstract The aim was to determine the clinical and cytogenetic characteristics of non-Hodgkins lymphoma (NHL) in Shanghai. A retrospective analysis was conducted in 516 patients with NHL. Patient clinical data, including age, sex, diagnosis, immunophenotypes, and karyotypes, were collected. The median age was 58 years. There was a male predominance in all NHL, except extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue. Patients with B cell NHL (1.5%) expressed CD3. T cell NHL patients (11.5%) expressed CD20. Epstein–Barr virus latent integral membrane protein 1, BCL6, CD10, Bcl-2, CD68, myeloperoxidase, CD99, CD30, CD15, and CD43 were present in various types of NHL. Complex karyotypes accounted for 92.3% of the 73.7% patients with abnormal karyotypes. Immunoglobin heavy chain gene translocation was present in 60.3% of B cell and 23.7% of T/NK cell neoplasms. Understanding the complex clinicopathological and molecular features of NHL may help with prognosis and serve as targets for treatments.

Bone marrow blasts level predicts prognosis in patients with refractory cytopenia with multilineage dysplasia

Objectives:  Current prognostic models for myelodysplastic syndrome (MDS) do not consider the prognostic value of a bone marrow blast level that is <5%. Exploring the prognostic value of the International Prognostic Scoring System (IPSS) and a marrow blast level that is <5% may lead to better risk‐adapted therapeutic strategies.