Liwei Fang

TET2, ASXL1 and EZH2 mutations in Chinese with myelodysplastic syndromes

Somatic mutations of epigenetic gene regulators are common in patients with myelodysplastic syndromes (MDS) and correlate with some clinical and laboratory features. We studied mutations in TET2, ASXL1 and EZH2 in 153 Chinese patients with MDS. TET2 mutations were detected in 35 patients (23%), ASXL1 in 33 patients (22%) and EZH2 in 8 (5%). ASXL1 mutations were associated with increased colony formation of BFU-E, CFU-E and CFU-GM (P-values, 0.049, 0.011 and 0.006). EZH2 mutations were common in patients with poor IPSS cytogenetics (P=0.001) and in patients in the IPSS intermediate-2/high-risk cohorts (P=0.06). In uni- but not multi-variate analyses, mutated TET2 was associated with longer survival (P=0.044) whereas EZH2 mutations were associated with an increased risk of transformation to acute myeloid leukemia (AML; P=0.039). These data suggest ASXL1 mutations might results in dominance of the mutant clone in Chinese with MDS whereas EZH2 mutations might predict an increased risk of transformation to AML.

Serum iron metabolism and erythropoiesis in patients with myelodysplastic syndrome not receiving RBC transfusions

Dysregulation of hepcidin, a key iron regulating hormone, is important in the pathogenesis of iron overload in patients with myelodysplatic syndrome (MDS). However, most studies of hepcidin levels are complicated by concomitant RBC transfusions. To evaluate the relationship between iron metabolism and erythropoiesis, we measured serum levels of hepcidin, growth-differentiation factor-15 (GDF15) and other markers of erythropoiesis in 107 subjects with MDS not receiving RBC transfusions. Patients with MDS had significantly higher levels of hepcidin than normals. However, their hepcidin-ferritin ratio was markedly decreased compared to normals (P<0.001) and varied substantially between MDS subtypes (P=0.011). GDF15 levels positively correlated with percent of bone marrow erythroblasts (P<0.001), soluble transferrin receptor (sTfR) (P=0.018), and also with transferrin saturation (ISAT) (P=0.038). The hepcidin-ferritin ratio negatively correlated with serum erythropoietin (EPO) levels (P<0.001), and also with GDF15 levels (P=0.014). Colony forming cells (CFC) were evaluated in 70 subjects. Those with serum ferritin (SF) levels <500 ng/ml had significantly more BFU-E than subjects with SF ≥ 500 ng/L (P=0.007), but numbers of granulocyte/macrophage-colony-forming cells (CFU-GM) were similar (P=0.190). Our data indicate serum hepcidin levels are inappropriately low in patients MDS not receiving RBC transfusions. GDF15 levels correlated with low hepcidin levels and may contribute to iron overload in this setting. Iron overload may in turn suppress erythropoiesis by imparing the proliferative capacity of the erythroid progenitor cells.

Clinical importance of SF3B1 mutations in Chinese with myelodysplastic syndromes with ring sideroblasts

Recent studies report SF3B1 mutations in about 20% of persons of European descent with myelodysplastic syndromes (MDS). Mutations are especially common in persons with ring sideroblasts (RS). SF3B1 mutation state was determined in 104 Chinese with MDS-RS. SF3B1 mutations were found in 55 subjects (53%) including 25 of 39 with refractory anemia and RS (RARS), 26 of 45 (58%) of those with refractory cytopenia with multi-lineage dysplasia and RS (RCMD-RS), 3 of 6 with refractory anemia with excess blasts-1-RS (RAEB1-RS) and 1 of 14 with RAEB2-RS. There were significant correlations between SF3B1 mutation state and platelet levels (P=0.007), mean RBC corpuscular volume (MCV; (P<0.001), proportion of RS (P<0.001) and percent bone marrow erythroblasts (P=0.012) and myeloblasts (P=0.044). Multivariate analyses using a Cox proportional hazards regression model including sex, age, SF3B1 mutation state, hemoglobin concentration, absolute neutrophil level, platelet level, MCV, international prognostic scoring system (IPSS) cytogenetics category, WHO morphologic category and treatment showed SF3B1 mutation state to independently predict survival. These data increase our knowledge of the impact of SF3B1 mutations in persons with MDS. They indicate a similar favorable impact of SF3B1 mutation on survival in Chinese with MDS as reported for persons of European descent.

Monosomal karyotype is an independent predictor of survival in patients with higher-risk myelodysplastic syndrome.

A monosomal karyotype (MK) correlates with poor survival in patients with acute myeloid leukemia, although whether this is also the case in patients with myelodysplastic syndrome (MDS) remains controversial. Some studies report a correlation between a MK and a worse survival, whereas others claim that this correlation arises because of a confounding effect between a MK and a complex karyotype (CK). To address this question, we analyzed the clinical data and karyotypes of 610 adults with MDS. A MK was identified in 60 patients, of whom 55 (92%) also fulfilled the criteria for a CK. Conversely, a CK was found in 85 patients, of whom 55 (65%) also had a MK. To determine the impact of a MK on survival, 464 patients who received nonintensive therapies for MDS were analyzed separately. Patients with a MK demonstrated worse survival than those without a MK in univariate analyses (median, 8 months [95% CI, 3–12 months] versus 83 months [63–103 months]; P < 0.001). This effect was observed predominately in the cohorts of higher‐risk patients according to the Revised International Prognostic Scoring System and the World Health Organization Prognostic Scoring System (HR [hazard ratio] 3.94 [1.97–7.89]; P < 0.001 and 4.937 [2.45–9.94]; P < 0.001, respectively) and surpassed the impact of a CK in the final survival models. Our data suggest that the addition of MK as a binary variable could improve the predictive accuracy of current models to estimate the survival of patients with MDS. Am. J. Hematol. 89:E163–E168, 2014.

Cyclosporin A and thalidomide in patients with myelodysplastic syndromes: Results of a pilot study

We reported 37 patients with myelodysplastic syndromes (MDS) of refractory cytopenia with multilineage dysplasia or refractory anemia with excess blasts who were treated with cyclosporin A (CyA)/thalidomide combination therapy. Of them, 19 patients (19/37, 51.4%) achieved a hematologic improvement and erythroid response (HI-E); 9 patients (9/29, 31.0%) achieved hematologic improvement and platelet response (HI-P) and 7 patients (7/33, 21.2%) achieved hematologic improvement and neutrophil response (HI-N). 15 of 32 (46.9%) transfusion-dependent patients achieved independence from transfusion. The median response duration of HI-E, HI-P and HI-N were 88 (4-108) weeks, 78 (8-84+) weeks and 78 (10-84+) weeks, respectively. Some patients presented with I or II grade hepatic or nephritic impairment, constipation, lethargy, dizziness, edema, rash or sense of numbness. Therefore, CyA combined with thalidomide appears to be useful and is relatively well-tolerated for patients with MDS.

Cytogenetic studies and their prognostic contribution in 565 Chinese patients with primary myelofibrosis

To study the feature and prognostic contribution of cytogenetic information in Chinese patients with primary myelofibrosis (PMF), we analyzed cytogenetic data from 565 patients with PMF. One hundred and sixty‐two subjects (29%) had abnormal karyotypes, including trisomy 8 (45; 28%), deletion of 20q (25; 15%), deletion of 13q (13; 8%), deletion of 11q (12; 7%), and abnormal chromosome 1 (21; 13%); balanced translocations (14; 9%); a complex karyotype (CK; 30; 19%), and a monosomal karyotype (MK; 19; 12%). Using these data, we showed that the Dynamic International Prognostic Scoring System (DIPSS)‐plus, which includes cytogenetic information, is a better survival predictor than the DIPSS. We next used our data to construct the following two cytogenetic‐based cohorts: (1) favorable karyotype—subjects with a normal karyotype, a CK that is not a MK, +8 only or a balanced translocation only and (2) unfavorable karyotype—all others. The median survival times were not reached and were 52 month (95% CI, 32–72 months; P = 0.01) in patients with favorable and unfavorable karyotypes, respectively. These data provided the detailed cytogenetic information in Chinese patients with PMF and confirmed the impact of cytogenetic abnormalities on survival in Chinese patients. Am. J. Hematol. 89:1043–1046, 2014.

Clinical features and biological implications of different U2AF1 mutation types in myelodysplastic syndromes

U2AF1 mutations (U2AF1MT) occur commonly in myelodysplastic syndromes (MDS) without ring sideroblasts. The aim of this study was to investigate the clinical and biological implications of different U2AF1 mutation types in MDS. We performed targeted gene sequencing in a cohort of 511 MDS patients. Eighty‐six patients (17%) were found to have U2AF1MT, which occurred more common in younger patients (P = .001) and represented ancestral lesions in a substantial proportion (71%) of cases. ASXL1MT and isolated +8 were significantly enriched in U2AF1MT‐positive cases, whereas TP53MT, SF3B1MT, and complex karyotypes were inversely associated with U2AF1MT. U2AFS34 subjects were enriched for isolated +8 and were inversely associated with complex karyotypes. U2AF1MT was significantly associated with anemia, thrombocytopenia, and poor survival in both lower‐risk and higher‐risk MDS. U2AF1S34 subjects had more frequently platelet levels of <50 × 109/L (P = .043) and U2AF1Q157/U2AF1R156 subjects had more frequently hemoglobin concentrations at <80 g/L (P = .008) and more often overt fibrosis (P = .049). In conclusion, our study indicates that U2AF1MT is one of the earliest genetic events in MDS patients and that different types of U2AF1MT have distinct clinical and biological characteristics.

The usefulness of mutational data on prognosis of myelodysplastic syndromes: alone or incorporated into the IPSS-R?

Additional Supporting Information may be found in the online version of this article: Data S1. Supplemental information regarding study cohort, sample collection, cytogenetic analysis, cytokine and chemokine level evaluation and statistical analysis. Table SI. Correlation between main clinical features at SMM diagnosis and progression to active MM (univariate analysis). Table SII. Correlation between median BM levels of cytokines in SMM patients and progression to active MM (univariate analysis).

Bone marrow fibrosis grade is an independent risk factor for overall survival in patients with primary myelofibrosis

Bone marrow fibrosis grade is an independent risk factor for overall survival in patients with primary myelofibrosis

Long-term outcomes of imatinib in patients with FIP1L1/ PDGFRA associated chronic eosinophilic leukemia: experience of a single center in China

Background The FIP1L1/PDGFRA (F/P) fusion gene is the most common clonal genetic abnormality of chronic eosinophilic leukemia (CEL). Tyrosine kinase inhibitors (TKI), such as imatinib, have been demonstrated to be effective therapies for F/P mutated disease. The aim of this study was to analyze the treatment response and long term prognosis in patients with F/P mutated CEL. Methods The clinical features and treatment responses of 33 consecutive patients with F/P mutated CEL between August 2006 and October 2014 were analyzed. The 33 cases received imatinib therapy at an initial dose of 100 mg/day (30 patients) or 200 mg/day (3 patients); the maintenance dose depended on the response condition and patient willingness. Through the follow up, the molecular responses were regularly monitored. Results With a median follow up of 64 months, 94% of the 33 patients with F/P mutated CEL achieved a complete hematologic remission (CHR), and 97% achieved a complete molecular remission (CMR) after a median of 3 (1.5-12) months. Twenty-four cases received maintenance therapy, with a median CMR duration of 43 (5-88) months. Imatinib therapy was discontinued in 8 cases, including 4 cases who experienced relapse, and 4 patients who maintained CHR or CMR after discontinuing therapy with a median time of 47 (2-74) months. One case exhibited primary resistance with a PDGFRA T674I mutation. Conclusions F/P mutated CEL has an excellent long-term prognosis following imatinib therapy. A 100 mg daily dose of imatinib is sufficient to induce remission, and a single 100 mg weekly dose maintains a durable remission. A subgroup of patients may maintain a durable remission after discontinuing therapy with a CMR.