Addition of eltrombopag (E-PAG) to intensive immunosuppressive therapy (IST) contributes to restoring hematopoiesis in patients with severe aplastic anemia (SAA). Used at relatively low doses in the East Asian population, the efficacies of E-PAG and the predictors for efficacy are not clear. We conducted a retrospective, multicenter study to analyze the efficacy and the possible predicting factors at 6 months in 58 adult SAA patients with rabbit ATG-based IST and E-PAG. The response rate and complete response rate at 6 months were 76% and 21%, respectively. The baseline reticulocyte percentage [area under a curve (AUC)=0.798, 95% confidence interval (CI) 0.640-0.956, P=0.006], absolute reticulocyte count (ARC) (AUC =0.808, 95%CI 0.647-0.970, P=0.004), red cell distribution width – coefficient of variation (RDW-CV) (AUC=0.722, 95%CI 0.494-0.950, P=0.040), and absolute lymphocyte count (ALC) (AUC=0.706, 95%CI 0.522-0.890, P=0.057) were highly predictive of response at 6 months. The tipping values of reticulocyte percentage, ARC, RDW-CV, and ALC were 0.45%, 7.36×109/L, 11.75%, and 1.06×109/L, respectively. The sensitivity and specificity of reticulocyte percentages were 81.6% and 66.7%; ARC were 86.8% and 66.7%, RDW-CV were 94.7% and 55.6%; ALC were 55.3% and 88.9%. At a median follow-up of 15.5 months, the 2-year cumulative overall survival was 92%. The baseline reticulocyte percentage, ARC, RDW-CV, and ALC were potential factors in predicting a favorable effect of rabbit-ATG based IST plus E-PAG in SAA patients of East Asia (ChiCTR2100045895).Clinical Trial Registrationhttp://www.chictr.org.cn/edit.aspx?pid=125480&htm=4, identifier ChiCTR2100045895.

目的 探讨不同减低剂量地西他滨治疗骨髓增生异常综合征(MDS)的临床疗效和安全性.方法 2017年1月至2020年12月于南京医科大学第一附属医院,68例MDS患者前瞻性随机分为2组给予不同减低剂量地西他滨皮下注射,低剂量组:20mg/m2,3d,d1～3;超低剂量组:5～7mg/m2,6d,d1～3,d8,d15,d22;每6周为一个疗程.结果 低剂量组的总反应率(ORR)和血液学改善(HI)均优于超低剂量组(60.0％比24.2％,P=0.003;37.1％比15.2％,P=0.04);两组间完全缓解(CR)、部分缓解(PR)、骨髓完全缓解(mCR)分别为2.9％比3.0％(P=0.966),5.7％比0(P=0.163),14.3％比6.1％(P=0.265).IPSSR分组较低危组和较高危组患者在低剂量组的ORR均优于超低剂量组(60.0％比16.7％,P=0.023;60.0％比28.6％,P=0.043).低剂量组等位基因突变频率(VAF)下降程度高于超低剂量组(15.49％比5.98％,P=0.042).多因素分析显示,地西他滨剂量(OR 0.287,P=0.036),女性(OR 6.855,P=0.002)及 IPSSR 分组(OR 1.222,P=0.043)为影响疗效的相关因素.两组出现Ⅲ～Ⅳ级骨髓抑制(15.2％比25.7％,P=0.280)及感染性发热(36.4％比20.0％,P=0.133)的比例相当,而低剂量组肺部感染比例明显低于超低剂量组(8.6％比33.3％,P=0.012).中位随访时间16个月(2～54个月),两组的转白率(24.2％比20.0％,P=0.673),中位转白时间(5.5个月比6.0个月,P=0.879)及中位生存时间(11个月比11个月,P=0.925)比较差异无统计学意义.结论 地西他滨剂量降至极低水平后疗效不佳,女性患者效果优于男性.

目的:探讨芦可替尼治疗SF3B1基因突变的骨髓增生异常综合征（MDS）/骨髓增殖性肿瘤（MPN）伴环状铁粒幼细胞增多和血小板增多（RS-T）、骨髓纤维化（MF）的难治性贫血效果。方法:回顾性分析南通大学附属建湖医院收治的1例SF3B1基因突变MPN/MDS-RS-T伴MF难治性贫血患者的临床资料，并进行文献复习。结果:该患者2016年9月开始先后予以沙利度胺联合糖皮质激素、地西他滨、来那度胺联合糖皮质激素治疗，均无效，严重依赖红细胞输注。2019年10月给予芦可替尼15 mg，2次/d，治疗2周后患者血红蛋白上升，随访3个月后血红蛋白依然稳定，脱离红细胞输注。结论:芦可替尼对SF3B1基因突变的MPN/MDS-RS-T伴MF难治性贫血患者可能有效，值得进一步积累病例进行探索。

Objective:To investigate the changes of related indicators of right heart hypofunction in patients with primary myelofibrosis (PMF).Methods:The clinical data of 55 PMF patients in the Second People's Hospital of Lianyungang in Jiangsu Province and Jiangsu Province Hospital from January 2015 to August 2019 were retrospectively analyzed. The differences in right heart function-related echocardiographic indexes and biochemical indexes between pre-fibrosis/early stage fibrosis patients and obvious stage fibrosis patients were compared. Single factor linear regression method was used to analyze the correlations of pulmonary artery pressure with biochemical indexes.Results:The hemoglobin level [119 g/L (47-224 g/L) vs. 78 g/L (33-182 g/L)] and platelet count [233×10 12/L (5×10 12/L-984×10 12/L) vs. 117×10 12/L (7×10 12/L-731×10 12/L)] of patients in the pre-fibrosis/early stage fibrosis group were higher than those in the obvious stage fibrosis group, and the differences were statistically significant (both P<0.05). Among 22 patients with complete results of cardiac ultrasound, 90.9% (20/22) patients had increased pulmonary artery pressure, 72.7% (16/22) patients had increased left atrial diameter, and 90.9% (20/22) patients had increased right ventricular diastolic diameter. There were no patients with abnormal ejection fraction. The pulmonary artery pressure [48 mmHg (46-90 mmHg) vs. 33 mmHg (20-50 mmHg) (1 mmHg = 0.133 kPa)], left ventricular diastolic diameter [46 mm (36-50 mm) vs. 47 mm (43-53 mm)] and fractional shortening rate [38.1% (36.0%-38.9%) vs. 35.4% (32.7%-37.8%)] of patients in the pre-fibrosis/early stage fibrosis group were higher than those in the obvious stage fibrosis group, and the differences were statistically significant (all P < 0.05). The pulmonary artery pressure of patients had positive correlations with age ( r = 0.590), serum ferritin (SF) ( r = 0.608), lactate dehydrogenase (LDH) ( r = 0.711) and soluble growth-stimulating expression gene 2 (ST-2) ( r = 0.580)(all P<0.05), and had negative correlation with platelet count ( r = -0.596, P = 0.003). Conclusion:PMF patients are prone to right heart hypofunction, the pulmonary artery pressure is higher in older patients and patients with high SF, LDH and ST-2 levels and low platelet count.

Abstract Background Large granular lymphocyte leukemia associated pure red cell aplasia (LGLL-PRCA) accounts for a significant portion of secondary PRCA. Cyclosporine (CsA) and cyclophosphamide (CTX) are the main immunosuppressive agents used in treating LGLL-PRCA [1]. Considering the cytotoxicity of CTX, CsA may be proposed as first-line therapy [2]. However, because of the rarity of LGLL-PRCA, long-term responses and relapse rates after CsA and CTX therapy are largely unknown. Methods and results From September 2009 to December 2020, we selected 65 uniformly diagnosed LGLL-PRCA and analyzed clinical features and treatment outcomes of CsA and CTX. In the present study, 43.1% harbored neutropenia (<1.5×10 9/L) and only 1 patient had spondyloarthritis (Table 1). Besides, we found that 9.2% developed recurrent oral ulcer and 18.5% had reduced serum complemet C3 level, both of which were related to abnormal immune status. In our cohort, 44 patients received CsA therapy and 21 patients received CTX therapy. 53.8% (35/65) obtained erythroid lineage response and 26.2% (17/65) achieved complete response. CTX produced higher response rate (81.0% vs 40.9%, P=0.002) and complete response rate (47.6% vs 15.9%, P=0.007) than CsA. We further analyzed related factors influencing efficacy by Binary-Logistic multivariate regression model and found that higher response rate was mainly related to CTX therapy (P=0.02) (Table 2). We detected STAT3 and STAT5b gene in 50 cases. None of the patients had STAT5b mutation and 14 patients had STAT3 mutation. 12 of 14 mutation cases were non-elderly patients (<60 years ). For younger patients, STAT3 mutation was more frequent (85.7% vs 22.2%, P<0.01). In STAT3 mutation group, patients appeared to respond better to CTX than CsA (83.3% vs 37.5%, P=0.138). Up to the last follow-up, 11 patients treated with CsA recurred after CsA reduction or discontinuation, with a median relapse time of 10 (3~80) months after remission. Only 1 patient relpsed after the discontinuation of CTX due to neutropenia and returned to remission status after CTX retreatment. In our research, CsA had higher recurrence rate than CTX without statistical significance (25.0% vs 4.8%, P=0.104). Discussion CsA may be proposed as first-line therapy for LGLL-PRCA [2,3]. CTX also appears to be a good treatment choice, but CTX should not be used for more than 12 months since associated toxicities and the risk for developing myelodysplastic syndromes and acute myeloid leukemia. Therefore, it is necessary to compare the efficacy of CsA or CTX in the treatment of LGLL-PRCA. Deep sequencing analyses of residuals LGLL clones reveals that CTX could eradicate LGLL clones, providing durable response, low relapse rate, whereas CsA is associated with the persistence of leukemic clones, and high frequency of relapse [4]. Our results show that the response rate of CTX is higher than CsA (P=0.02), and the probability of recurrence is relatively low (25.0% vs 4.8%, P=0.104). This is consistent with the results of previous study by Rajala [4]. It was important to note that patients with STAT3 mutations are more likely to respond to MTX [5]. Our study showed that the response rate for CTX was 83.3% in patients with STAT3 mutations, which was seemingly higher than CsA (37.5%), although remained statistically insignificant (P=0.138) that might be due to small number of cases. Conclusions The results of the current study may reflect the real world experience of LGLL-PRCA in whom treated by CTX or CsA, may be limited by its retrospective nature, small cohorts. In preliminary conclusion, LGLL-PRCA could acquired better response to CTX than CsA. Besides, CTX may reduce relapse. References 1. Means RT Jr. Pure red cell aplasia. Blood, 2016, 128(21): 2504~9. 2. Moignet A, Lamy T. Latest Advances in the Diagnosis and Treatment of Large Granular Lymphocytic Leukemia. Am Soc Clin Oncol Educ Book, 2018, 38: 616~25. 3. Go RS, Tefferi A, Li CY, et al. Lymphoproliferative disease of granular T lymphocytes presenting as aplastic anemia. Blood, 2000, 96(10):3644~6. 4. Rajala HLM, Olson T, Clemente MJ, et al. The analysis of clonal diversity and therapy responses using STAT3 mutations as a molecular marker in large granular lymphocytic leukemia. Haematologica, 2015, 100: 91~9. 5. Loughran TP, Zickl L, Olson TL, et al. Immunosuppressive therapy of LGL leukemia: prospective multicenter phase II study by the Eastern Cooperative Oncology Group (E5998). Leukemia, 2015, 29(4): 886~94. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Prospective trials showed the clinical efficacy of eltrombopag in refractory/relapsed aplastic anemia (AA), with up to 40% hematologic improvement [1]. Moreover, eltrombopag was combined with frontline immunosupressive therapy (IST) consisited of antithymocyte immunoglobulin (ATG) and cyclosporin (CsA), with an overall response rate exceeding 80% [2]. The metabolism of eltrodopag is different in disparate population. Currently, the recommended dose is 75 mg/d for East Asian populations [2], Pretreatment clinical and laboratory characteristics predicting eltrombopag response are still unclear in severe AA (SAA) patients of real-world in East Asian.

目的:探讨阿伐曲泊帕对仑伐替尼相关重型再生障碍性贫血（SAA）的疗效及安全性。方法:回顾性分析南京医科大学第一附属医院收治的1例仑伐替尼相关SAA患者的临床资料。总结治疗过程，分析阿伐曲泊帕治疗结果，并进行文献复习。结果:该例SAA患者肝癌骨转移后使用仑伐替尼和短程局部放疗后出现骨髓衰竭，确诊SAA。应用他克莫司、西罗莫司后血象无改善。接受阿伐曲泊帕40 mg/d治疗4周后，三系造血恢复，脱离输血。结论:阿伐曲泊帕成功治疗1例仑伐替尼相关SAA，耐受性良好，值得临床继续积累相关病例。

目的:评估小剂量利妥昔单抗靶向控制循环B淋巴细胞数量治疗难治性自身免疫性溶血性贫血(AIHA)的疗效及不良反应.方法:2014-10-2019-09期间31例难治性AIHA接受利妥昔单抗100mg,每周1次,连续使用至外周循环中CD19+细胞降低至流式细胞仪常规检测下限0.1％.结果:经中位2个疗程(1～4个疗程)的利妥昔单抗治疗,患者循环CD19细胞比例降至0.1％以下,总体有效率87.1％(27/31).输注相关不良反应1例(3.2％),1周内发生感染2例(6.5％).中位无复发生存时间13个月(2～26个月).结论:小剂量利妥昔单抗治疗AIHA,疗效佳且不良反应较少,值得临床进一步探索.

目的:了解皮下注射小剂量地西他滨治疗骨髓增生异常综合征(MDS)的疗效,并进行药物经济学分析.方法:采用临床研究NCT02779569的病例资料,收集59例MDS患者,根据地西他滨给药方案不同分为皮下注射组和静脉注射组.比较两组疗效、不良反应发生情况,并进行药物经济学分析.结果:两组有效率差异无统计学意义(47.5％ vs.36.8％,P＞0.05),但皮下注射组感染发生率显著低于静脉注射组(P＜0.05),且床位费用、地西他滨药费、输注红细胞和血小板的费用,以及总药费、不良反应处理费用、总住院费等各项指标均显著低于静脉注射组(P＜0.001).采用最小成本分析,提示皮下注射经济学效果较优.结论:地西他滨小剂量皮下注射与传统静脉注射相比,疗效相当,但感染发生率低,各项成本明显降低,药物经济学效果较优,值得临床推广.

OBJECTIVE:To investigate the clinical characteristics, laboratorial and bone marrow pathological features of primary thrombocytopenia (ET) patients with different mutations of CALR, JAK2 and MPL genes.METHODS:The chinical data of 120 cases of ET in Jiangsu provincial people's hospital/ The First Affiliated Hospital of Nanjing Medical University from January 2015 to December 2017 were collected and analyzed, including 76 cases with JAK2 gene mutation, 40 cases with CALR gene mutation, 2 cases with MPL gene mutations, 2 cases without gene mutation.RESULTS:Among the ET patients, compared with the JAK2 gene mutation, CALR gene mutation showed statistically significant deareament of white blood cells and hemoglobin (P=0.001, P=0.01) and the male platelets in CALR group showed significant increament (P=0.04). Fourthermore, the average number of megakaryocytes and its cluster numbers in each hight power field of vision showed statistically significant decreament in CALR group as compared with JAK2 group (P=0.001, P=0.001), and thrombotic events in CALR group were signicantly lower than those in JAK2 group (7.5% vs 18.4%) (P=0.03).CONCLUSION:Mutations of CALR, JAK2 have different clinical characteristics and blood pathological changes of Chinese ET patients, and their clinical significance is worth to explore.

Objective:To investigate the effect of rapamycin in treatment of tyrosine kinase inhibitor (TKI)-resistant chronic myelogenous leukemia (CML) without ABL mutation.Methods:Flow cytometry was used to detect the positive expressions of p-mTOR and p-S6 in CD33 positive cells of 2 CML patients with TKI resistance in Jiangsu Province Hospital, and the influence of rapamycin on the positive expressions of p-mTOR and p-S6 in vitro.Results:Rapamycin in vitro inhibited the positive expressions of p-mTOR and p-S6 in CD33 positive cells. After 3 months of oral administration of rapamycin, the positive expressions of p-mTOR and p-S6 in CD33 positive cells were decreased, and the copy number of BCR-ABL fusion gene was also decreased simultaneously.Conclusion:Part of the resistance of CML patients to TKI may be related to the activation of intracellular signaling pathway of mTOR.

目的 评价兔抗人胸腺细胞免疫球蛋白(anti-thymocyte globulin,ATG)联合环孢素A(cyclosporine,CsA)强化免疫抑制治疗(intensive immunosuppressive therapy,IIST)中性粒细胞为0的成人再生障碍性贫血的疗效.方法 回顾性分析2014年1月至2018年3月国内三家医院86例接受IIST的重型再生障碍性贫血(severe aplastic anemia,SAA)临床资料.将免疫抑制治疗前中性粒细胞为0的SAA定义为暴发型再生障碍性贫血(fulminant aplastic anemia,FAA),与SAA、极重型再生障碍性贫血(very SAA,vSAA)比较对IIST的疗效.结果 86例患者中,FAA 19例,vSAA 23例,SAA 44例.3个月总有效率分别为21.1％,56.5％和54.5％,6个月总有效率分别为42.1％,60.9％和72.7％.FAA组患者3个月的有效率明显低于vSAA和SAA组(21.1％ vs.56.5％,P=0.032;21.1％ vs.54.5％,P=0.023),6个月的有效率明显低于SAA组(42.1％ vs.72.7％,P=0.028),疗效与中性粒细胞计数显著相关(P=0.019).三组的中位起效时间分别为17.0个月,4.0个月和3.0个月,FAA组慢于vSAA组、SAA组(P =0.031,P=0.001).FAA组患者总生存率明显低于vSAA和SAA组(63.2％,91.3％和95.5％,P=0.001),生存率与中性粒细胞计数及疗效显著相关(P=0.026,P=0.010).结论 中性粒细胞为0的成人FAA临床预后严重不良,需要探索新的治疗方案.

目的 评估不同治疗方案治疗成人获得性纯红细胞再生障碍(PRCA)的疗效.方法 回顾性分析2009年10月至2019年7月南京医科大学第一附属医院收治的100例PRCA患者的临床资料、治疗方案及疗效相关因素.结果 100例患者中原发性PRCA60例;继发性PRCA40例,其中最常见的继发性疾病是大颗粒淋巴细胞白血病(28例,70.0％),其次是胸腺瘤(6例,15.0％).接受糖皮质激素治疗18例,环孢菌素治疗70例,其他免疫抑制剂治疗12例,有效率分别为66.7％、71.4％、50%(P=0.336),完全缓解率分别为22.2％、34.9％、16.7％(P=0.408).原发性PRCA有效率高于继发性PRCA患者(78.3％ vs.52.5％,P=0.007).大颗粒淋巴细胞白血病相关PRCA有效率低于原发PRCA(46.4％ vs.79.3％,P=0.003).环孢菌素治疗患者中,原发性PRCA疗效高于继发性PRCA(85.7％ vs.50.0％,P=0.001)及大颗粒淋巴细胞白血病相关PRCA(85.7％ vs.42.1％,P=0.000).Logistic回归分析亦提示治疗有效率与继发(OR=3.30,95％CI 1.32 ～ 8.25,P=0.025)及大颗粒淋巴细胞白血痛相关PRCA (0R=4.506,95％CI 1.59～12.78,P=0.005)有关.结论 不同治疗方案对PRCA的治疗有效率相似,原发性PRCA较继发性PRCA对环孢菌素反应性更好,大颗粒淋巴细胞白血病相关PRCA治疗有效率较差.