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.

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.

SF3B1基因突变形成了新骨髓增生异常综合征(MDS)亚型.MDS 国际预后工作组(international working group for the prognosis of myelodysplastic syndromes,IWG-PM)建议诊断标准:(1)血细胞减少;(2)SF3B1基因体细胞突变;(3)孤立性红系或多系病态造血(诊断不需要RS);(4)骨髓原始细胞＜5％和外周血原始细胞＜1％;(5)不符合WHO标准的孤立性del(5q)、MDS及骨髓增殖性肿瘤伴环状铁粒幼细胞伴血小板增多(MPN-RS-T)或其他MDS及MPN标准、原发性骨髓纤维化或其他MPN标准;(6)排除以下染色体异常:单体7;inv(3)或3q26异常(导致EVI1基因异常融合或过度表达),及复杂染色体核型(≥3个以上异常);(7)或共表达RUNX1或(和)EZH2基因突变.SF3B1突变型MDS预后较好,可通过luspatercept治疗脱离输血.

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 评估因肝肾功能异常不耐受强化免疫抑制治疗(IST)联合艾曲泊帕治疗的严重型再生障碍性贫血(SAA)患者,换用阿伐曲泊帕治疗的疗效及耐受性.方法 对2020年10月至2021年7月间江苏省人民医院收治的8例SAA,因肝肾功能异常不耐受IST联合艾曲泊帕,改用阿伐曲泊帕20 mg/d治疗,评估治疗前后血象变化、血栓事件、肝肾功能等指标.结果 阿伐曲泊帕中位治疗时间4(1～6)个月,1例完全缓解,3例部分缓解,2例血红蛋白及血小板改善,1例中性粒细胞及血小板改善,1例患者因治疗时间短未纳入疗效评估.中位起效时间68.5(28～107)d,自身对照显示中性粒细胞计数(P=0.004)、血红蛋白水平(P=0.005)及血小板计数(P=0.016)均较治疗前显著升高.阿伐曲泊帕治疗期间,所有患者无血栓事件发生,肝肾功能指标均维持正常范围内.结论 阿伐曲泊帕对IST联合艾曲泊帕不耐受的SAA患者有一定疗效,耐受性良好.