Objective:To investigate the efficacy and safety of combining venetoclax (VEN) with hypomethylated drugs (HMA) in the treatment of higher-risk (IPSS-R score >3.5) myelodysplastic syndromes (MDS) .Methods:From March 2021 to December 2022, forty-five MDS patients with intermediate and high risk were treated with VEN in combination with HMAs. Clinical data were collected and analyzed retrospectively, including gender, age, MDS subtype, IPSS-R score, treatment regimen, and efficacy, etc. Kaplan-Meier method and Cox regression model were used to analyze univariate and multivariate of survival prognosis.Results:①Forty-five patients with MDS, including ninety-one percent were classified as high or very high risk. According to the 2023 consensus proposal for revised International Working Group response criteria for higher-risk MDS, the overall response rate (ORR) was 62.2% (28/45), with the complete response rate (CR) was 33.3% (15/45). For twenty-five na?ve MDS, the ORR was 68% (17/25) and the CR rate was 32% (8/25). In nonfirst-line patients, the ORR and CR were 55% (11/20) and 35% (7/20) respectively. The median cycle to best response was 1 (1-4). ②With a median followup of 189 days, the median overall survival (OS) time was 499 (95% confidence interval, 287-711) days, and most patients died from disease progression. Responders had a significantly better median OS time than nonresponders (499 days vs 228 days, P<0.001). Multifactor analysis revealed that IPSS-R score and response to treatment were independent prognostic factors for OS; the presence of SETBP1 gene mutations was associated with a longer hospital stay (51.5 days vs 27 days, P=0.017) . Conclusions:There is clinical benefit of venetoclax in combination with hypomethylated agents in patients with higher-risk MDS, but adverse events such as severe hypocytopenia during treatment should be avoided.

Objective To observe the effects of different administration doses of dexmedetomidine on the circulatory system and stress response in patients undergoing extracorporeal coronary artery bypass grafting(OPCABG).Methods Ninety-six patients who underwent OPCABG in our hospital from October 2021 to October 2023 were selected and divided into two groups using simple randomization method.Group A was administered dexmedetomi-dine at a dose of 0.5 μg/kg over 10 minutes before anesthesia induction,followed by a maintenance dose of 0.5 μg/(kg·h)infused until the end of the surgery,while group B was administered dexmedetomidine at a dose of 0.8 μg/kg for 10 min before anesthesia induction,followed by a maintenance dose of 0.8 μg/(kg·h)until the end of the operation.The two groups were compared in terms of cardiac index(CI),heart rate,mean arterial pressure(MAP),intrathoracic blood volume index(ITBI),bispectral index(BIS),and systemic peripheral vascular resistance index(SVRI)before anesthesia started(T0),at the immediate moment of intubation(T1),at the immediate moment of the start of the surgery(T2),at the time of sawing of the sternum(T3),and at the immediate moment of extubation(T4).Additionally,the two groups were compared in terms of cortisol(Cor),Angiotensin Ⅱ(Ang Ⅱ)levels,safety and postoperative awakening time.Results The two groups showed no differences in operation time,anaesthesia time,bleeding and urine volume(P＞0.05),but group B demonstrated less intraoperative use of cisatracurium compared to group A(P＜0.05).At T0,the two groups showed no difference in heart rate and MAP(P＞0.05),but higher heart rate and MAP at T1 and T3 than at T0.Group A was observed to have higher heart rate and MAP at T4 than at T0,while group B showed no significant differences in heart rate and MAP at T4 com-pared to them at T0(P＞0.05).At T2 and T4,Group B showed significantly lower heart rate and MAP compared to group A(P＜0.05).At T0,the two group had no differences in terms of CI,CO,ITBI,and SVRI(P＞0.05).Both groups showed significantly lowered levels of CI,CO,ITBI,and SVRI at T1-T4 than at T0(P＜0.05),but demonstrated no differences in the levels of CI,CO,ITBI,SVRI at T0-T4(P＞0.05).At T0,both groups had no difference in BIS values(P＞0.05),but showed significantly decreased BIS values at T1-T4 compared with those at T0(P＜0.05).At T2-T4,group A showed significantly lower BIS values compared with group A(P＜0.05).The two groups had no difference in postoperative awakening time compared with group A(8.12±1.88 min vs.8.05±1.97 min,P＞0.05).Preoperatively,the two groups had no differences in Cor and Ang Ⅱ(P＞0.05).However,at 6 h postoperatively,both groups showed significantly elevated Cor and AngⅡ values compared to preoperatively(P＜0.05),and group B showed signifantly lower values of Cor and AngⅡ compared to group A(P＜0.05).The two groups had no difference in the adverse reactions(6.25%vs.8.33%,P＞0.05).Conclusion Dexmedetomidine administered at the dose of 0.8 μg/(k·h)rather than at the dose of 0.5 μg/(k·h)for managing OPCABG results in more stable hemodynamics during surgery,yielding better sedative effect,milder postoperative stress response,and no increase in adverse reactions.

Objective:To explore the risk factors in leukemia transformation (LT) in those with myelodysplastic syndromes (MDS) .Methods:From January 2012 to December 2020,data on 320 patients with newly diagnosed primary MDS were gathered from the MDS center. The clinical features and molecular characteristics are explored. Additionally, a retrospective analysis of risk factors for the development of acute leukemia from MDS was done.Results:The median follow-up was13.6 (0.4-107.3) months. 23.4% (75/320) of the MDS patients had LT group. Significant differences between the LT group and non-LT group can be seen in age ( P<0.001) , bone marrow blast percentage ( P<0.001) , bone marrow fibrosis ( P=0.046) , WHO classification ( P<0.001) , IPSS-R ( P<0.001) and IPSS-R karyotype group ( P=0.001) . The median number of mutation of LT group was 1 (1, 3) , that in non-LT group was 1 (0, 2) ,which had a statistical difference ( P=0.003) .At the time of the initial diagnosis of MDS, the LT group had higher rates of the TP53 mutation ( P=0.034) , DNMT3A mutation ( P=0.026) , NRAS mutation ( P=0.027) and NPM1 mutation ( P=0.017) . Compared with the mutations at first diagnosis and LT of six patients, the number of mutations increased and the variant allele frequencies (VAF) increased significantly in LT patients. Higher bone marrow blast percentage (Refer to <5% , 5% -10% : HR=4.587, 95% CI 2.214 to 9.504, P<0.001, >10% : HR=9.352, 95% CI 4.049 to 21.600, P<0.001) , IPSS-R cytogenetic risk groups ( HR=2.603, 95% CI 1.229-5.511, P=0.012) , DNMT3A mutation ( HR=4.507, 95% CI 1.889-10.753, P=0.001) , and NPM1 mutation ( HR=3.341, 95% CI 1.164-9.591, P=0.025) were all independently associated with LT in MDS patients, according to results of multivariate Cox regression. Conclusion:Bone marrow blast percentage, IPSS-R cytogenetic risk groups, DNMT3A mutation, and NPM1 mutation are independent risk factors in LT for MDS patients.

Objective:Diagnostic value assessment of sternal bone marrow cell morphology in patients with acquired hypocellular bone marrow failure syndromes (BMFS) characterized by normal cytogenetics.Methods:A total of 194 eligible patients with an acquired hypocellular BMFS pre-sternum diagnosis in Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Science & Peking Union Medical College from June 2014 to January 2019 were reviewed. Sternal bone marrow evaluation was performed, and a post-sternum diagnosis was made. Clinical characteristics and overall survival (OS) were then compared among patients with different post-sternum diagnosis. Binary logistic regression was used to develop a predictive scoring system.Results:In 152 patients with pre-sternum AA diagnosis, 29 patients with a pre-sternum idiopathic cytopenia of undetermined significance (ICUS) diagnosis, and 13 patients with a pre-sternum clonal cytopenia of undetermined significance (CCUS) diagnosis, sternal bone marrow evaluation resulted in a change of diagnosis to hypocellular myelodysplastic syndrome (hypo-MDS) in 42.8% (65/152) , 24.1% (7/29) , and 30.8% (4/13) , respectively. Patients with a post-sternum hypo-MDS diagnosis showed a significant difference in OS compared with patients with a post-sternum AA diagnosis ( P=0.005) . Patients with ICUS/CCUS showed no difference in OS compared with AA and hypo-MDS ( P=0.095 and P=0.480, respectively) . A 4-item predictive scoring system to identify hypocellular BMFS patients that need sternal bone marrow evaluation was developed, including age > 60 years old ( OR=6.647, 95% CI 1.954-22.611, P=0.002, 2 points) , neutrophil alkaline phosphatase score ≤ 160 ( OR=2.654, 95% CI 1.214-5.804, P=0.014, 1 point) , abnormal erythroid markers evaluated by flow cytometry on iliac bone marrow ( OR=6.200, 95% CI 1.165-32.988, P=0.032, 2 points) , and DAT (DNMT3A, ASXL1, TET2) genes mutation ( OR=4.809, 95% CI 1.587-14.572, P=0.005, 1 point) . The Akaike information criterin (AIC) was 186.1. Conclusion:Patients with a pre-sternum acquired hypocellular BMFS diagnosis characterized by normal cytogenetics may not reach accurate diagnostic categorization without sternal bone marrow cell morphology evaluation, which could be considered a diagnostic tool for this patient population. A predictive scoring system was developed, and when the total score is ≥ 2 points, sternal bone marrow evaluation should be performed for accurate diagnostic categorization that is critical to optimal patient care.

Objective:To evaluate the prognostic value of MIPSS70-plus in Chinese patients with primary myelofibrosis (PMF) .Methods:A total of 113 Chinese patients with PMF were retrospectively analyzed. The Kaplan-Meier method, Log-rank test, and Cox proportional hazard regression model were performed to evaluate the prognostic factors. The likelihood ratio test was used to evaluate the predictive power between MIPSS70-plus and DIPSS systems.Results:The median age of the Chinese patients was 55 (range: 20-70) years, including 71 males and 42 females. According to the standard of MIPSS70-plus system, 99 patients (79.6% ) had a favorable karyotype and 23 patients (20.4% ) had an unfavorable karyotype. JAK2V617F in 55.8% ( n=63) , CALR exon9 in 17.7% (including 15 CALR type 1 and 5 CALR type 2, n=20) , MPLW515 in 4.4% ( n=5) , and triple negative (no detectable JAK2, MPL, and CALR mutations) in 22.1% of patients in our cohort were found by target-specific next-generation sequencing approach. At least one high-molecular risk mutations were presented in 45.1% ( n=51) of patients, with ASXL1 in 38.9% ( n=44) , SRSF2 in 7.1% ( n=8) , IDH1/2 in 4.4% ( n=5) , and EZH2 in 3.5% ( n=4) of patients. A total of 28 patients (26.7% ) were in low risk, 20 (19.0% ) in intermediate risk, 41 (39.0% ) in high risk, and 16 (15.3% ) in very-high risk categories, which were delineated for the MIPSS70-plus model. A 2-year OS was 100% in low risk, 89.7% (95% CI 76.2% -100.0% ) in intermediate risk, 64.8% (95% CI 47.0% -82.6% ) in high risk, and 35.0% (95% CI 10.3% -59.7% ) in very-high risk categories, which had a significant difference ( P<0.001) . A significantly higher predictive power for survival of the MIPSS70-plus group was observed compared with the DIPSS group ( P=0.001, -2 log-likelihood ratios of 86.355 vs 95.990 for the MIPSS70-plus and DIPSS systems, respectively) . Conclusion:The MIPSS70-plus had significantly higher predictive power than the DIPSS.

Objective:To explore the outcome of cyclosporine A (CsA) combined with danazol with or without thalidomide regimen for myelodysplastic syndrome (MDS) with low-percentage bone marrow blasts and predictive factors for treatment response.Methods:Data of 115 subjects who were newly diagnosed with primary MDS with low-percentage bone marrow blasts and were treated with CsA combined with danazol with or without thalidomide from December 2011 to December 2019 in our center were collected. Their clinical features, efficacy, and predictive factors of efficacy were retrospectively analyzed. A model for predicting this response was developed.Results:A total of 55 subjects responded (47.8%) , including 11 complete responses and 44 hematologic improvements. Fifty-two patients (52/105, 49.5%) achieved erythrocyte response; 35 (35/86, 40.7%) , platelet response; and 14 (14/40, 35%) , neutrophil response. Of 29 subjects (24.1%) , 7 who were red blood cell (RBC) transfusion-dependent became independent of transfusion. The median response duration was 20 months (range, 3-84 months) . In the univariate analysis, patients <0 years had a higher response rate than those ≥60 years (52.5% vs 22.2%, P=0.018) . Contrarily, the response rate was substantially decreased in patients with RBC transfusion dependence compared with those without RBC transfusion dependence (24.1% vs 55.8%, P=0.003) , as well as in patients with the mutated U2AF1 compared with those with the wild-type U2AF1 (26.1% vs 53.2%, P=0.020) . In multivariable analyses, age <0 years ( OR=4.302, 95% CI 1.245-14.820, P=0.021) , RBC transfusion dependence ( OR=3.774, 95% CI 1.400-10.177, P=0.009) , and U2AF1 mutation ( OR=3.414, 95% CI 1.168-9.978, P=0.025) were significantly correlated with response. Variables that independently predicted the response were combined to generate the predictive model. According to the model, the overall response rates of patients with 0, 1, 2, and 3 risk factors were 65%, 30%-35%, 10%-15%, and 3%, respectively. Conclusion:CsA combined with danazol with or without thalidomide regimen could improve cytopenia symptoms in patients with MDS with low-percentage bone marrow blasts. At age <60 years, no transfusion dependence of RBC and wild-type U2AF1 mutation is a favorable prognostic factor.

Objective:To explore the relationship between symptom burden and hematologic responses after treatment with interferon and/or hydroxyurea in patients with polycythemia vera (PV) .Methods:Hematologic responses after continuous treatment with interferon and/or hydroxyurea for six months were evaluated in 190 patients with PV using the Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (MPN-10 score) . In all patients, the PV diagnosis was based on the 2016 World Health Organization diagnostic definitions.Results:The study cohort comprised 93 (48.9% ) male and 97 (51.1% ) female patients. The median age at the time of MPN-10 assessment was 60 (32-82) years. The median MPN-10 score of the entire cohort was 9 (range, 0-67) . The median MPN-10 score of patients treated with interferon plus hydroxyurea ( n=27) was 11 (0-67) , which was significantly higher than those of patients treated with interferon only ( n=64) (6[0-56], P=0.019) or hydroxyurea only ( n=99) (9[0-64], P=0.047) , whereas the median MPN-10 score was not significantly different between those treated with interferon only and hydroxyurea only ( P=0.421) . The rate of severe symptom burden (i.e., any single symptom burden score ≥ 7 and/or total score ≥ 44) was 28.9% (55/190) in the entire cohort, whereas the rate of severe symptom burden was not significantly different among the interferon only (23.4% ) , hydroxyurea only (29.3% ) , and interferon plus hydroxyurea (40.7% ) groups ( P>0.05 for all two-group comparisons) . When evaluating MPN-10 score, 37.4% (71/190) of the patients achieved complete hematologic remission (CHR) . Only 28.9% (55/190) patients had adequate disease control, defined as CHR without severe symptom burden. Reasons for inadequate disease control were evaluating blood counts alone, severe symptom burden alone, and evaluating blood counts accompanied with severe symptom burden in 42.1% (80/190) , 8.4% (16/190) , and 20.5% (39/190) of the patients, respectively. Compared to the patients with a platelet count ≤ 400×10 9/L, those with a platelet count > 400×10 9/L had a significantly higher rate of severe symptom burden (40.8% [20/49] vs 24.8% [35/141], P=0.044) and a higher median MPN-10 score (14[0-67] vs 7[0-56], P=0.038) . Platelet count > 400×10 9/L was associated with an increased risk of severe symptom burden (hazard ratio, 2.089; 95% confidence interval, 1.052-4.147, P=0.035) . Conclusions:Symptoms related to disease after treatment with interferon and/or hydroxyurea were rather universal in patients with PV. Some patients still experienced severe symptom burden despite achieving CHR. Platelet count > 400×10 9/L was associated with an increased risk of severe symptom burden in patients with PV treated with interferon and/or hydroxyurea.

Objective:To explore predictors of overall survival (OS) in Chinese patients with polycythemia vera (PV) .Methods:A total of 906 consecutive newly diagnosed patients with PV seen at the Blood Diseases Hospital, Chinese Academy of Medical Sciences, from June 2007 to February 2020 were included, and their data were collected. PV was diagnosed according to 2016 World Health Organization (WHO) diagnostic definitions. OS and prognostic factors were retrospectively analyzed.Results:Among the 906 patients, 439 were male (48.5%) and 467 were female (51.5%) . The median age was 57 years (range: 18-91 years) . 31.6% (276/874) of the patients had a thrombosis history at diagnosis, and 4.6% (25/541) of the patients had abnormal cytogenetics. The median follow-up was 54 months (95% confidence interval [ CI] 8-130 months) . The 5- and 10-year cumulative deaths were 5.8% (95% CI 4.8%-6.7%) and 11.1% (95% CI 9.3%-12.9%) , respectively. Univariate analysis showed that age ≥60 years, thrombosis history, white blood cells (WBC) ≥15×10 9/L, platelet (PLT) ≥450×10 9/L, and platelet distribution width (PDW) ≥15 fl significantly correlated with worse OS, and palpable spleen correlated with better OS. Multivariate analysis showed that age ≥60 years ( HR=4.3, 95% CI 2.1-9.2, P<0.001) and PDW ≥15 fl ( HR=2.1, 95% CI 1.1-4.0, P=0.023) were independent prognostic factors for worse OS. The 5-year cumulative death for patients with PDW ≥15 fl or PDW<15 fl was 8.6% (95% CI 5.9%-11.3%) or 4.4% (95% CI 3.4%-5.4%) , respectively. The 5-year cumulative death for patients defined as low-, intermediate-, and high-risk patients by international working group score system for PV (IWG-PV) were 0.8% (95 CI 0.2%-1.4%) , 4.0% (95% CI 2.7%-5.3%) , and 12% (95% CI 9.6%-14.4%) , respectively, with a significant difference among the three cohorts ( P<0.05) . PDW ≥ 15 fl significantly affected OS for intermediate- and high-risk patients ( HR=2.3, 95% CI 1.2-4.2, P=0.009) defined by IWG-PV score system, but not for low-risk patients ( HR=3.1, 95% CI 0.2-52.0, P=0.405) . Conclusions:Age ≥60 years and PDW ≥15 fl were independent prognostic factors for worse OS in PV. IWG-PV score system effectively predicted OS for Chinese patients with PV.

Objective:To explore the features and clinical significance of gene mutations in patients with myelodysplastic syndromes with ring sideroblasts (MDS-RS) .Methods:A total of 255 newly diagnosed primary MDS-RS patients were retrospectively reviewed from our center from January2001 to June 2019. SF3B1 gene mutations were detected by Sanger sequencing in 129 patients, and next generation sequencing (NGS) was performed in the other 126 patients using a set of selected 112-genes.Results:A total of 193 (75.7%) patients presented with SF3B1 mutation, predominantly mutant at amino acid position 700 (K700E) ( n=147, 76.2%) . Non-SF3B1 gene mutations were TET2 (16.7%) , ASXL1 (14.3%) , U2AF1 (11.1%) , TP53 (7.9%) , SETBP1 (6.3%) , and RUNX1 (6.3%) . RS 5%-<15% patients had a higher SETBP1 mutation frequency than RS≥15% patients (21.4% vs 4.5%, P=0.044) . Mutation frequencies of other genes were similar in both groups (all P>0.05) . SF3B1 variant allele frequencies (VAF) had positive correlation with marrow RS percentage but without statistical significance in RS 5%-<15% group ( P=0.078, r=0.486) . SF3B1 mutant patients presented with higher marrow RS percentage compared with wild-type patients[40.0% (15.0%-80.0%) vs 25.5% (15.0%-82.0%) , P<0.001], and SF3B1 VAF positively correlated with RS percentage ( P=0.009, rs=0.261) in RS≥15% group. Age, ANC, PLT, mean RBC corpuscular volume, RS percentage, IPSS-R cytogenetics, and IPSS-R risk score were significantly different between patients with SF3B1 mutations and wild-type SF3B1 (all P<0.05) . Multivariable survival analyses adjusted by age and IPSS-R cytogenetics revealed that SF3B1 mutation was an independent favorable prognostic factor ( HR=0.265, 95% CI 0.077-0.917, P=0.036) , and TP53 mutation was an adverse variable independent of SF3B1 mutation ( HR=6.272, 95% CI 1.725-22.809, P=0.005) . According to the mutant status of SF3B1 and TP53, MDS-RS patients were categorized into 4 groups, namely, with SF3B1 and TP53 mutation, with wild-type SF3B1 and TP53, with wild-type SF3B1 but TP53 mutation, and with SF3B1 mutation but wild-type TP53. There was a significant difference for OS among these 4 groups ( P<0.001) . The former 3 groups showed no significant difference in OS in multiple comparisons. However, the SF3B1 mutation but wild-type TP53 group had a better OS than wild-type SF3B1 but TP53 mutation group and wild-type SF3B1 and TP53 group, whereas a similar OS compared with SF3B1 and TP53 mutation group. Conclusion:SF3B1 mutations were prevalent in MDS-RS patients with the most common mutation at amino acid position 700 (K700E) . SF3B1 mutation was an independent favorable prognostic variable, whereas TP53 mutation was an independent adverse variable. SF3B1 mutation could coordinate with TP53 mutation for more sophisticated prognosis stratification in MDS-RS patients.

Objective:To explore the molecular features and prognostic value of RAS mutations in patients with myelodysplastic syndromes (MDS) .Methods:112-gene targeted sequencing was conducted to detect RAS mutations in 776 patients with newly diagnosed primary MDS from December 2011 to December 2018. The mutual exclusivity and co-occurrence in gene mutations and clonal architecture were explored. Moreover, the prognostic significance of RAS mutations in MDS was analyzed.Results:RAS gene mutations were found in 52 (6.7% ) cases, 38 (4.9% ) of whom harbored NRAS mutation, 18 (2.3% ) KRAS mutation, and 4 (0.5% ) both NRAS and KRAS mutations. All the NRAS mutations and 65% of the KRAS mutations were located in codons 12, 13, and 61. PTPN11, FLT3, U2AF1, RUNX1, WT1, ETV6, and NPM1 mutations were enriched in patients with RAS mutations ( Q<0.05) . Around 80% of RAS mutations represented subclonal lesions in patients who harbored at least two different mutations. Patients with RAS mutations were more frequently diagnosed with MDS with excess blast (MDS-EB) (82.7% vs. 35.2% , P<0.001) and had higher levels of white blood cell count (4.33×10 9/L vs. 2.71×10 9/L, P<0.001) , neutrophil absolute count (2.13×10 9/L vs. 1.12×10 9/L, P<0.001) , and bone marrow blast percentage (7% vs. 2% , P<0.001) but lower levels of platelet count (48×10 9/L vs. 62×10 9/L, P=0.048) . RAS mutations were correlated with higher-risk categories in the Revised International Prognostic Scoring System (IPSS-R) (71.1% vs. 37.9% , P<0.001) . The median overall survival of patients with NRAS mutations was shorter than the others ( P=0.011) , while the significance was lost in the multivariable model. Conclusion:RAS gene mutations always occurred in the late-stage MDS and co-occurred with other signal transduction- and transcription factor-related gene mutations. PTPN11, a RAS pathway-related gene, is an independent poor prognostic factor in MDS patients.