Study On Gene Mutations In Chinese With Primary Myelofibrosis Study On Cytogenetics In Chinese With Primary Myelofibrosis Serum Ferritin Is An Independent Prognostic Factor In Chinese With Myelodysplastic Syndromes (MDS) Classified As IPSS Intermediate-1

Object To investigate ASXL1, IDH1/2, SRSF2, CALR, MPL mutations in patients with primary myelofibrosis (PMF) and clinical significance of these mutations.Methods A retrospective study on484PMF cases was performed according to2008World Health Organization (WHO) diagnostic criteria. Identification of the gene (exonl2of ASXL1, exon4of IDH1, exon4of IDH2, exonl of SRSF2, exon9of CALR, exon10of MPL) mutations were detected by direct sequencing and classification of mutation types by sequencing followed by plasmid cloning.The clinical and laboratory features were compared among the patients with gene mutation and those with wild type.Results Among127Chinese with PMF,38subjects displayed gene muation except for JAK2V617F mutation, including36(28%) with ASXL1mutation,2(2%) with SRSF2mutation and no subject with IDH1/2muations. The patients with ASXL1mutations were all heterozygous. The types of gene mutation included frameshift and nonsense mutations, G646Ffs*12was most frequent. Compared with subjects without ASXL1mutation, subjects with ASXL1mutation had higher WBC level (P=0.004), more obvious splenomagly (P=0.001) and were likely to be older than65yr and had abnormal karyotype. There was no significant difference in hemoglobin concentrations, PLT level, percentage of blasts in peripheral blood, frequency of JAK2V617F mutation, cytogenetic categories according to DIPSS-plus, risk groups according to DIPSS, DIPSS-Chinese and DIPSS-plus. Among357subjects with PMF, CALR mutations were detected in76subjects (21%), JAK2V617F mutations in178(50%) and MPL mutation in11(3%). The patients with CALR mutations were all heterozygous. The types of gene mutation were all frameshift mutation, including26(34%) type-1(L367fs*46) and47(62%) type-2(K385fs*47) mutations. Subjects with type-2CALR mutations had lower hemoglobin concentrations (P=0.001), lower WBC levels (P<0.001), higher percent blood blasts (P=0.009), higher conventional (P<0.001) and Chinese-adjusted DIPSS scores (P<0.001), compared with subjects with JAK2mutations, These subjects were also likely to have abnormal platelet levels (<100x109/L; P=0.01or>450x109/L; P=0.042) and no splenomegaly (P=0.004). Subjects with type-2CALR mutation had briefer overall survival than those with JAK2V617F mutations.In multivariate analyses type-2CALR mutation or no detectable mutation was an independent high-risk factor for survival adjusted for DIPSS-Chinese.Conclusion ASXL1mutation is frequent gene mutaion in epigenetic regulator but not a unfavorable prognostic factor in Chinese with PMF. CALR mutations are frequent in Chinese with PMF lacking mutations in JAK2or MPL. Subjects with type-2CALR mutation have briefer overall survival than those with JAK2V617F mutations. In multivariate analyses type-2CALR mutation is an independent high-risk factor for survival adjusted for DIPSS-Chinese. Objective To investigate the prognostic value of cytogenetical abnormality in Chinese with primary myelofibrosis (PMF)Methods439PMF patients with evaluable karyotye were retrospectively analyzed. Kaplan-Meier method, Log-rank test and COX regression model were used to evaluate factors that influence the prognosis.Results Among the439PMF patients,123displayed an abnormal karyotype, including24(20%) with complex karyotype,15(12%) with monosomal karytype,21(17%) with sole trisomy8,15(12%) with sole del(20q) and9(7%)with sole del(13q).14(58%) of complex karyotype also met criteria for monosomal karyotpe. Among123subjects with abnormal karytpe, compared to subjects without complex karytpe, subjects with complex karyotype were likely to display anemia (P=0.016), but there was no significant differences in age, gender, WBC and PLT level, percentage of blasts in peripheral blood, splenomegaly, constitutional symptoms and DIPSS risk groups. There was no significant difference in age, gender, HGB, WBC and PLT level, percentage of blasts in peripheral blood, splenomegaly, constitutional syndrome and DIPSS risk groups between subjects with monosomal karyotype and thoses without monosomal karyotype. In univariable survival analysis, abnormal karyotype, unfavorable karyotpe according to DIPSS plus, complex karyotype and monosomal karyotype were unfavorable prognostic factor (P=0.007,0.022,0.032,0.034). In multivariable analysis, monosomal karyotye was independent unfavorable prognostic factor adjusted for DIPSS-Chinese (P=0.003, HR3.339,95%CI1.514-7.367).Conclusion Among Chinese with PMF, percentage of subjects with abnormal karyotype is less than reported in persons with PMF of European descent. Complex karyotype, sole trisomy8, sole del(20q) and sole del(13q) arefrequent abnormalities. Monosomal karyotye is an independent unfavorable prognostic factor adjusted for DIPSS-Chinese Objective To investigate the prognostic factor of in Chinese with myelodysplastic syndromes (MDS) classified as IPSS intermediate-1Methods We studied prognostic variables in191Chinese subjects with MDS intermediate-1(INT-1) in the IPSS.Results Like the IPSS-R, we found serum ferritin level>500μg/L at diagnosis was a strong independent predictor of survival. Although baseline serum ferritin level was inversely correlated with baseline hemoglobin, it was serum ferritin, not baseline hemoglobin level that was significantly-correlated with survival in Chinese subjects. These data were not biased by the IPSS-R as they were generated before it’s publication. Based on these data a new prognostic scoring system including ECOG performance score, absolute neutrophil level (ANC), serum ferritin, percentage of bone marrow blasts and poor karyotye was developed for Chinese with IPSS INT-1MDS.Conclusions This revised scoring system identified a subgroup of Chinese with MDS and INT-1IPPS who have a poor prognosis and may benefit from more intensive therapy.