Pan Lj

Relationship between polymorphisms of tumor necrosis factor alpha gene and primary myelodysplastic syndromes

OBJECTIVEnTo investigate the association of single nucleus polymorphisms(SNP)of tumor necrosis factor alpha (TNF-α) gene (-308 G>A and -238 G>A genotypes) with susceptibility to primary myelodysplastic syndromes (MDS).nnnMETHODSnTwo SNPs (TNF-α-308 G>A,TNF-α-238 G>A) of TNF-α gene were detected by Taqman probes in 341 MDS patients and 365 unrelated-healthy controls.nnnRESULTSnCompared to healthy controls, the frequency of TNF-α-308 AA+AG genotype and A allele increased (18% vs 10%, P=0.015, 9% vs 5%, P=0.021, respectively) in refractory cytopenia with multilineage dysplasia (RCMD) patients. There was no correlation of TNF-α-308 G>A genotype and allele frequency between MDS and controls. No difference in the genotype and allele frequency of TNF-α-238 G>A were found between controls and MDS or the subtypes of MDS (P>0.05). We did not find any linkage between plasma level of TNF-α and TNF-α-308 G>A or TNF-α-238 G>A genotype. Statistic differences were observed between platelet count[58(1-611)×10⁹/L vs 90(7-352)×10⁹/L]and bone marrow blasts in MDS patients carrying TNF-α-308 G>A GG and AA+AG genotype (P=0.024, 0.019, respectively).nnnCONCLUSIONnTNF-α-308 G>A polymorphism was correlated with susceptibility to MDS-RCMD.

[Long-term outcomes of homoharringtonine, cytarabine, daunorubicin or idarubicin (HAD/HAI) as induction chemotherapy in de novo acute myeloid leukemia].

OBJECTIVEnTo estimate the long-term outcomes and the prognostic factors of homoharringtonine, cytarabine, daunorubicin or idarubicin (HAD/HAI) as induction chemotherapy in de novo acute myeloid leukemia (AML).nnnMETHODSnThe CR rate, overall survival (OS) rate, relapse free survival (RFS) rate were retrospectively assayed in 143 de novo AML patients who received the HAD/HAI induction chemotherapy. The outcomes were compared among prognostic groups according to world health organization (WHO) classification, genetic prognosis and initial white blood cell (WBC) count. The role of consolidation chemotherapy consisting of middle-dosage Ara-C (MD-Ara-C) on long term survival was evaluated.nnnRESULTSnOf 143 patients, 112 (78.3%) achieved CR after the first course of HAD/HAI induction treatment, and early death occurred in only one case. Notably, the CR rate of patients with an initial WBC count ≥100×10(9)/L was not significantly different from those with an initial WBC count<100× 10(9)/L (70.4% vs 80.2%, P=0.266). The CR rate for the patients with favorable, intermediate and unfavorable integrated genetics risk factors was 93.7%, 71.4% and 61.3%, respectively, the difference between groups was statistically significant (P=0.001). Patients with FLT3-ITD mutation obtained similar CR rate (70.6%) to that of patients with FLT3 wild type (79.3%, P=0.528).The estimated 5-year OS rate and 5-year RFS rate for all patients was 40.0% and 37.0%, respectively, with a median follow-up of 24 (range 1-104) months. The median survival time was 30 [95%CI (12, 48)] months. 5-year OS and 5-year RFS of the 96 patients who achieved CR after first course chemotherapy without undergoing allo-HSCT in complete remission was 47.0% and 38.0%, respectively. 5-year OS was significantly higher in MD-Ara-C consolidation group than in no MD-Ara-C consolidation group among CR patients without allo-HSCT (58.0%, 19.0%, respectively, P=0.004). In patients who obtained CR after first course and received MD-Ara-C consolidation without allo-HSCT, the 5-year OS of patients with hyperleukocytosis was not significantly lower than that of patients without hyperleukocytosis (55.5%, 58.8%, respectively,P=0.419). FLT3-ITD mutation patients showed similar 5-year OS to that of wild type FLT3 patients (51.4%, 60.2%, respectively, P=0.482). And furthermore, 5-year OS of favorable, intermediate and unfavorable integrated genetics groups were 59.1%, 62.5%, 51.9%, respectively (P=0.332) in this subgroup.nnnCONCLUSIONnHAD/HAI induction chemotherapy with sequential consolidation of MD-Ara-C could obtain satisfactory CR rate and long-term survival rate in de novo AML, especially for patients with hyperleukocytosis or FLT3-ITD mutation. It yet remains to be verified by large sample, prospective studies.目的 评价高三尖杉酯碱、阿糖胞苷、柔红霉素或去甲氧柔红霉素(HAD/HAI)方案诱导治疗初治急性髓系白血病(AML)患者的长期疗效并探讨其影响因素。 方法 观察HAD/HAI方案治疗1个疗程后初治143例AML患者的完全缓解(CR)、总生存(OS)及无复发生存(RFS)率，分析WHO 2008标准诊断分型、遗传学预后分组及初始WBC等因素对患者OS、RFS率的影响，评估中剂量阿糖胞苷(MD-Ara-C)巩固治疗在提高AML患者长期生存中的作用。 结果 143例患者中112例(78.3%)1个疗程获CR。仅1例患者在诱导化疗期早期死亡。高白细胞与非高白细胞组、FLT3-ITD突变型与野生型组患者CR率差异均无统计学意义(P值分别为0.266和0.528)。遗传学预后良好、中等、不良组患者CR率分别为93.7%、71.4％和61.3%，组间差异有统计学意义(P=0.001)。中位随访24(1~104)个月，中位生存时间为30(95%CI 12~48)个月。所有患者的5年OS率为40.0%，5年RFS率为37.0%。1个疗程CR后接受巩固治疗的患者为96例，5年OS率为47.0%，5年RFS率为38.0%；其中序贯含MD-Ara-C方案(71例)和序贯标准剂量Ara-C(25例)巩固治疗组患者的5年OS率差异有统计学意义(58.0％对19.0%，P=0.004)。在序贯含MD-Ara-C方案巩固治疗的患者中，高白细胞与非高白细胞组、FLT3-ITD突变型和野生型组患者的5年OS率差异均无统计学意义(P值分别为0.419和0.482)，遗传学预后良好、中等、不良组患者5年OS率差异无统计学意义(P=0.332)。 结论 HAD/HAI方案诱导化疗缓解后序贯含MD-Ara-C方案巩固治疗的策略对初治AML患者，特别是高白细胞患者，可望获得满意的长期生存率。

Prognostic evaluation of comorbidities in patients with myelodysplastic syndrome

目的 探讨合并疾病对骨髓增生异常综合征（MDS）患者预后的影响。 方法 回顾性分析676例连续入组有详细合并疾病评估的MDS患者临床资料并进行统计学分析。 结果 676例患者中395例（58.4%）伴有合并疾病（合并疾病组），281例（41.6%）不伴合并疾病（无合并疾病组）。两组患者≥60岁比例（32.4%对18.5%）、骨髓原始细胞比例中位数[0.035（0~0.190）对0.025（0~0.190）]、染色体核型异常比例（37.5%对35.9%）、分型诊断构成比和修正版国际预后积分系统（IPSS-R）分组比较，差异均有统计学意义（P值均<0.05）。多因素COX分析证实合并疾病为影响患者总生存（OS）的独立预后因素（HR=3.051，95%CI 2.018~4.612，P<0.001）。按MDS特异性合并疾病指数（MDS-CI）评分模型对伴有合并疾病的MDS患者进行危险度分组，低、中、高危患者中位OS时间分别为32（1~153）、19（2~85）、13（1~37）个月，而不伴有合并疾病的患者中位OS时间为96（1~166）个月，差异有统计学意义（P<0.001）。IPSS-R低危、中危及高危组患者根据MDS-CI模型进行再分组，各组患者OS时间比较差异均有统计学意义（P值均<0.01）。 结论 合并疾病是MDS患者独立于IPSS-R之外的预后影响因素。OBJECTIVEnTo discuss the impact of comorbidities on the outcomes of patients with MDS.nnnMETHODSnThe clinical characteristics of 676 MDS patients with detailed comorbidities evaluations was analyzed retrospectively.nnnRESULTSnThere were 395/676 cases (58.4%) with comorbidities (group 1), 281/676 cases (41.6%) without (group 2). Significant differences were seen in the distribution of age (≥ 60 y), bone marrow blasts, abnormal karyotype, WHO 2008 subtypes and IPSS-R risk cohorts (P<0.05) between the two groups. While gender, HGB concentrations, WBC levels, platelet levels and serum ferritin were not significantly different (P>0.05). Independent prognostic significance of comorbidities was seen in both uni-variate and multi-variate analyses (P<0.001). According to MDS-specific comorbidity index (MDS-CI), the median survival were 32(1-153) months, 19(2-85) months and 13(1-37) months in the low-risk, intermediate-risk and high-risk cohorts respectively, while 96(1-166) months in cohorts without any comorbidities, of which significant differences were seen (P<0.001). The MDS-CI allowed further stratification in the IPSS-R low-risk, intermediate-risk and high-risk cohorts (P<0.001).nnnCONCLUSIONnComorbidities provides prognostic stratification independently of IPSS-R for MDS patients.

[Long- term outcome of thalidomide and cyclosporine in patients with IPSS low/intermediate- 1 myelodysplastic syndromes].

OBJECTIVEnTo investigate the long- term outcome of cyclosporin A (CsA) combined with thalidomide regime for Chinese patients with IPSS low/intermediate- 1 myelodysplastic syndromes (MDS) without del（5q）and the predictive variables which could impact the response to the therapy.nnnMETHODSnSeventy-six MDS patients who were treated with these drugs at a single institute in China were retrospectively analyzed. The polymorphism of cereblon gene, rs1672753, was detected in patients of this cohort by PCR and direct sequencing.nnnRESULTSnA total of 53% of patients showed hematological improvement（HI）to the therapy. Thirty-one patients（31/73, 43%）achieved erythrocyte response（HI-E）; 15 patients（15/50, 30%）achieved neutrophil response（HI-N); 18 patients（18/58, 31%）achieved platelet response（HI-P). Twenty-seven of the 50 patients（46%）who were dependent on red blood cell transfusion achieved HI- E and became independent of transfusion. The median duration of response among the responders was 22 months (range, 1- 131 + months). Bone marrow blasts ≤2% was the only factor associated with longer response duration in univariate analysis （P=0.010）. There was no significant difference between the two groups of celeblon gene rs1672753 polymorphism either on the response rate or the response duration. The median survival of 67 patients without stem cell transplantation was 82 months. In multivariate analyses, factors significantly correlated with survival were IPSS-R（HR=3.461, 95%CI 1.126-10.639, P=0.030), age ≥ 60 y（HR=4.120, 95%CI 1.070-15.867, P=0.040）and HI-N（HR=7.733, 95%CI 1.007-59.396, P=0.049).nnnCONCLUSIONnCsA combined with thalidomide regime could improve the anemia symptom in low/int-1 risk MDS patients without del（5q）. The predictive value of cereblon gene polymorphism, rs1672753, could not be verified in this study.目的 评价环孢素（CsA）联合沙利度胺治疗国际预后积分系统（IPSS）低危／中危-1骨髓增生异常综合征（MDS）患者的远期疗效及预后影响因素。 方法 回顾性分析CsA联合沙利度胺治疗的76例IPSS低危／中危-1 MDS患者临床资料。采用PCR联合直接测序法检测患者cereblon基因rs1672753位点基因型。 结果 76例患者中，男48例，女28例，中位年龄41(18~70）岁。CsA联合沙利度胺治疗后，40例（53%）获得血液学改善（HI），其中红系反应（HI-E）率为43%（73例中31例），中性粒细胞反应（HI-N）率为30%（50例中15例），血小板反应（HI-P）率为31%（58例中18例）。59例红细胞输注依赖患者中27例（46%）获得HI-E并脱离输血。HI中位维持时间为22(1~131+）个月。单因素分析显示骨髓原始细胞≤2％的患者疗效持续时间更长（P=0.010）。cereblon基因rs1672753位点基因型与HI率及治疗反应的维持时间均无明显相关性（P值均>0.05）。67例未行造血干细胞移植患者中位生存时间为82（95% CI 38~126）个月。多因素分析显示IPSS-R分组（HR=3.461，95% CI 1.126~10.639，P= 0.030）、年龄≥60岁（HR=4.120，95% CI 1.070~15.867，P=0.040）以及HI-N（HR=7.733，95% CI 1.007~59.396，P=0.049）为影响患者生存时间的独立预后因素。 结论 CsA联合沙利度胺治疗能长期改善IPSS低危／中危-1 MDS患者贫血症状，不良反应轻。在此组患者中未能验证cereblon基因rs1672753位点基因型对疗效的预测价值。

[Comparison of low-dose thalidomide and prednisone combined with or without danazol for the treatment of primary myelofibrosis-associated anemia].

OBJECTIVEnTo observe the clinical effects of low-dose thalidomide (THAL) and prednisone (PRED) with or without danazol (DANA) in patients with primary myelofibrosis (PMF) associated anemia.nnnMETHODSnA cohort of 58 PMF patients with anemia (Hb<100 g/L) were retrospectively studied. Of them, 28 patients were treated with THAL and PRED (THAL-PRED group), and the rest with THAL, PRED and DANA (THAL-PRED-DANA group). The hematological response was assessed according to the modified criteria of the International Working Group in 2006, and the myelofibrosis degree was evaluated at 3 and 12 month after treatment.nnnRESULTSnThe total response rate was 56.9%(33/58) including 1.7% (1/58) partial remission (PR) and 55.2% (32/58) clinical improvement (CI). There was no statistical difference in the response rate between THAL-PRED and THAL-PREDDANA groups (50.0% vs 63.3%, P=0.306). However, the median response duration of clinical improvement, erythroid response (CI-E) and total response prolonged in THAL-PRED-DANA than THALPRED group (61.5w vs 22w, P=0.015; 75w vs 30w, P=0.007, respectively). Myelofibrosis degree at 3 and 12 months after treatment decreased significantly than before treatment (P=0.000 and 0.005, respectively). Side-effects in both groups were only grade 1-2.nnnCONCLUSIONnLow-dose THAL together with PRED appeared to be effective in the treatment of PMF-associated anemia, and the response duration would prolong significantly if combined with DANA.

[Clinical efficacy analysis of recombinant human erythropoietin in the treatment of lower-risk myelodysplastic syndromes].

OBJECTIVEnTo investigate the efficacy and impact factors in lower-risk [International prognostic scoring system (IPSS) low or intermediate-1 risk] myelodysplastic syndrome (MDS) patients treated with recombinant human erythropoietin (rhEPO) alone or in combination with recombinant human granulocyte colony- stimulating factor (rhG-CSF).nnnMETHODSnA total of 52 consecutive lower-risk MDS patients received subcutaneous injection of rhEPO alone or in combination with rhG-CSF at least 8 weeks, the rhEPO dose would be reduced slowly to stop or kept at minimum to maintain the response when the best efficacy achieved and maintained for 4 weeks. Their clinical features, efficacy, survival and the predictors of efficacy were analyzed retrospectively.nnnRESULTSnThe overall response rate was 51.9% (27/52) with 33.3%(9/27) achieving complete remission (CR) and 66.7%(18/27) achieving erythroid response (HI-E). In multivariate analysis, sEPO level (less than 500 U/L), BFU-E count (more than 25/10⁵ BMMNC), intermediate and high doses rhEPO±rhG-CSF therapy were independent predictors of better response. The median therapy period was 8(2-45) months and the median efficacy duration was 37(6-94) months (38 months for CR, 36 months for HI-E). Ten of the 27 responsive patients relapsed and 40% of them had disease progressions. Hemoglobin levels and karyotype affect response duration. Median overall survival was 47(6-114) months on a 37(6-114) months median follow-up. In multivariate analysis, ages (less than 60 years old), karyotype (good or intermediate) and response to rhEPO±rhG-CSF therapy may have a favorable survival impact on MDS.nnnCONCLUSIONnrhEPO, alone or in combination with rhG-CSF, is a useful drug for the treatment of anemia in lower-risk MDS patients and has favorable impact on life expectancy.

A study of prognostic value of cytogenetics in patients with primary myelofibrosis

OBJECTIVEnTo evaluate the prognostic value of cytogenetics in Chinese with primary myelofibrosis (PMF).nnnMETHODSnFour hundred and thirty-nine Chinese patients with PMF were retrospectively analyzed. The Kaplan-Meier method, the Log-rank test, the likelihood ratio test and the COX proportional hazards regression model were used to evaluate the prognostic scoring systems.nnnRESULTSnFour hundred and thirty-nine Chinese patients with PMF were analyzed with a median age of 56 years (range: 8-83), including 298 males and 141 females. The DIPSS-plus system could effectively evaluate prognosis in Chinese patients with PMF. There was significantly higher predictive power for survival for the DIPSS-plus group compared with the DIPSS group (P=0.006, -2 log-likelihood ratios of 989.5 and 1001.9 for the DIPSS-plus and DIPSS systems, respectively). Univariate analysis indicated that the patients with a normal karyotype, a complex karyotype that was not a monosomal karyotype, +8 only or a balanced translocation only had better survival. Following two cytogenetic risk categories were constructed: favorable karyotype including subjects with a normal karyotype, a complex karyotype that was not a monosomal karyotype, +8 only or a balanced translocation only and unfavorable karyotype included all others. The modified DIPSS-Chinese prognostic model was proposed by adopting cytogenetic categories and DIPSS- Chinese risk group. The median survival of patients classified in low risk (163 subjects), intermediate-1 risk (187 subjects), intermediate-2 risk (82 subjects) and high risk (7 subjects) were not reached, 74 (95% CI 42-106), 39 (95% CI 26-52) and 12(95% CI 1-25)months, respectively, and there was a statistically significant difference in overall survival among the four risk groups (P<0.01).nnnCONCLUSIONnThe DIPSS-plus had significantly higher predictive power than the DIPSS group in Chinese patients with PMF and the modified DIPSS-Chinese system based on the cytogenetic features of Chinese patients was proposed and worked well for prognostic indication.