Current status of diagnosis and treatment of chronic lymphocytic leukemia in China: A national multicenter survey research / 中华血液学杂志

Objective: To understand the current status of diagnosis and treatment of chronic lymphocytic leukemia (CLL) /small lymphocytic lymphoma (SLL) among hematologists, oncologists, and lymphoma physicians from hospitals of different levels in China. Methods: This multicenter questionnaire survey was conducted from March 2021 to July 2021 and included 1,000 eligible physicians. A combination of face-to-face interviews and online questionnaire surveys was used. A standardized questionnaire regarding the composition of patients treated for CLL/SLL, disease diagnosis and prognosis evaluation, concomitant diseases, organ function evaluation, treatment selection, and Bruton tyrosine kinase (BTK) inhibitor was used. Results: ①The interviewed physicians stated that the proportion of male patients treated for CLL/SLL is higher than that of females, and the age is mainly concentrated in 61-70 years old. ②Most of the interviewed physicians conducted tests, such as bone marrow biopsies and immunohistochemistry, for patient diagnosis, in addition to the blood test. ③Only 13.7% of the interviewed physicians fully grasped the initial treatment indications recommended by the existing guidelines. ④In terms of cognition of high-risk prognostic factors, physicians' knowledge of unmutated immunoglobulin heavy-chain variable and 11q- is far inferior to that of TP53 mutation and complex karyotype, which are two high-risk prognostic factors, and only 17.1% of the interviewed physicians fully mastered CLL International Prognostic Index scoring system. ⑤Among the first-line treatment strategy, BTK inhibitors are used for different types of patients, and physicians have formed a certain understanding that BTK inhibitors should be preferentially used in patients with high-risk factors and elderly patients, but the actual use of BTK inhibitors in different types of patients is not high (31.6%-46.0%). ⑥BTK inhibitors at a reduced dose in actual clinical treatment were used by 69.0% of the physicians, and 66.8% of the physicians had interrupted the BTK inhibitor for >12 days in actual clinical treatment. The use of BTK inhibitors is reduced or interrupted mainly because of adverse reactions, such as atrial fibrillation, severe bone marrow suppression, hemorrhage, and pulmonary infection, as well as patients' payment capacity and effective disease progression control. ⑦Some differences were found in the perceptions and behaviors of hematologists and oncologists regarding the prognostic assessment of CLL/SLL, the choice of treatment options, the clinical use of BTK inhibitors, etc. Conclusion: At present, a gap remains between the diagnosis and treatment of CLL/SLL among Chinese physicians compared with the recommendations in the guidelines regarding the diagnostic criteria, treatment indications, prognosis assessment, accompanying disease assessment, treatment strategy selection, and rational BTK inhibitor use, especially the proportion of dose reduction or BTK inhibitor discontinuation due to high adverse events.

Efficacy and Safety of Decitabine Combined with Modified CAG Regimen in Patients Aged ≥ 70 Years with Newly Diagnosed Acute Myeloid Leukemia / 中国实验血液学杂志

OBJECTIVE@#To evaluate the clinical efficacy and safety of decitabine combined with modified CAG regimen (D-CAG regimen) in patients aged ≥70 years with newly diagnosed acute myeloid leukemia (AML).@*METHODS@#The clinical data of 59 AML patients (≥70 years old) who were newly diagnosed and treated in the Hematology Department of the First Affiliated Hospital of Nanjing Medical University from November 2010 to June 2021 were retrospectively analyzed.@*RESULTS@#Among the 59 AML patients, 28 were males and 31 were females, with a median age of 74 (70-86) years. The complete remission (CR) rate was 69.4% (34/49), and the median duration of CR was 10.7 (0.6-125.4) months after 2 courses of D-CAG treatment. According to the British Medical Research Council (MRC) classification, there was only one patient in the favorable-risk group, and the CR rate was 71.8% (28/39) in the intermediate-risk group, and 55.6% (5/9) in the adverse-risk group, respectively. There was no statistical difference in the CR rate between the intermediate-risk and adverse-risk group. Referring to ELN 2017 genetic risk classification, CR rate was 88.2% (15/17) in the favorable-risk group, 45.5% (5/11) in the intermediate-risk group, and 66.7% (14/21) in the adverse-risk group. There was no significant difference in CR rate between the favorable-risk and adverse-risk categories, but both were significantly higher than that in the intermediate-risk group (P <0.05). Next-generation sequencing (NGS) analysis showed that 11 gene mutations with a frequency of more than 10%, including TET2 mutation (35.6%), ASXL1 mutation (30.5%), NPM1 mutation (28.8%), FLT3-ITD mutation (27.1%), DNMT3A mutation (22.0%), IDH1 mutation (15.3%), CEBPA single mutation (13.6%), TP53 mutation (13.6%), IDH2 mutation (11.9%), RUNX1 mutation (11.9%), and NRAS mutation (10.2%). There were no statistical differences in mutation frequency of these 11 genes between CR group and non-CR group. Compared with normal karyotypes, patients with complex karyotypes were more likely to develop TP53 mutations (P <0.001), while FLT3-ITD and DNMT3A mutations were more likely to occur in patients with normal karyotypes (P =0.04, P =0.047). The median follow-up, overall survival (OS), and event-free survival (EFS) of all the patients was 11.7 (1.5-128.2) months, 12.3 (1.5-128.2) months, and 8.5 (1.5-128.2) months, respectively. The median OS and EFS of CR patients were 19.8 and 13.3 months, respectively, which were significantly longer than 6.4 and 5.7 months in patients experiencing treatment failure (P < 0.001, P =0.009). In regard to genes with mutation frequency >10%, there were no statistical differences in CR rate, median OS, and median EFS between mutated and wild-type patients by Chi-square test and survival analysis. Univariate analysis showed that age, hemoglobin, lactate dehydrogenase, cytogenetics and CR were factors affecting prognosis, while multivariate analysis showed that only CR failure was an independent adverse prognostic factor for OS. The major adverse reactions to D-CAG regimen were grade 3-4 myelosuppression, pulmonary infection, and fever (infection focus was not identified).@*CONCLUSION@#D-CAG regimen is safe and effective in the treatment of AML patients ≥70 years old, and can partially improve the prognosis of elderly and high-risk patients.

Analysis of Long-Term Prognostic Factors Based on Nutritional Status in Patients with Multiple Myeloma / 中国实验血液学杂志

OBJECTIVE@#To explore the prognostic factors of patients with multiple myeloma (MM) based on nutritional status.@*METHODS@#The Controlling Nutritional Status (CONUT) score and clinical parameters at diagnosis of 203 newly diagnosed MM patients hospitalized in the department of hematology, Wuxi People's Hospital from January 1, 2007 to June 30, 2019 were analyzed retrospectively. The best cut-off value was determined by ROC curve, and the patients were divided into high CONUT group (>6.5 points) and low CONUT group (≤6.5 points); through COX regression multivariate analysis of overall survival (OS) time, CONUT, ISS stage, LDH and treatment response were selected for multiparameter prognostic stratification.@*RESULTS@#The OS of MM patients in high CONUT group was shorter. The low-risk group (≤2 points) of the multiparameter risk stratification had longer OS time and progression-free survival (PFS) time compared with the high-risk group (>2 points), and it was also effective for different age or karyotype subgroups, new drug groups containing bortezomib and transplant-ineligible subgroup.@*CONCLUSION@#The risk stratification of MM patients based on CONUT, ISS stage, LDH and treatment response is worthy of clinical application.

The Risk and Survival Analysis of Multiple Malignancies in Hematologic Malignancy Patients: A Single Chinese Center Retrospective Study, 2009 through 2017 / 中国实验血液学杂志

OBJECTIVE@#To explore the risk and location of multiple malignancies in patients with hematologic malignancies who were followed up for 9 years in Jiangsu Province Hospital and to evaluate the impact of the second primary malignancy on survival of patients.@*METHODS@#The incidence and survival of multiple malignancies in 7 921 patients with hematologic malignancies from 2009 to 2017 were analyzed retrospectively.@*RESULTS@#A total of 180 (2.3%, 180/7 921) patients developed second malignancy, of whom 58 patients were diagnosed with hematologic malignancies as the first primary malignancy, and 98 patients developed hematologic malignancies as second primary malignancy, and the other 24 cases were diagnosed with the second malignancy within 6 months after the first primary malignancy was diagnosed, which was difined as multiple malignancies occurring simultaneously. In 180 patients, 18 cases developed two hematologic malignancies successively, and 11 patients developed more than 3 primary cancers (among them, 2 female patients were diagnosed with 4 primary cancers). Patients with lymphoma and multiple myeloma (MM) as the second primary malignancy had poorer survival than patients with lymphoma and MM as the first primary malignancy. Patients with chronic myeloid leukemia as the second primary malignancy were also associated with inferior overall survival.@*CONCLUSION@#In this study, 2.3% of hematologic malignancy patients had multiple mali-gnancies, lymphoma and MM as the second primary malignancy had poor survival.

Prognostic significance of serum immunoglobulin paraprotein in mucosa-associated lymphoid tissue (MALT) lymphoma.

To assess the prognostic significance of immunoglobulin (Ig) paraproteinaemia in mucosa-associated lymphoid tissue (MALT) lymphoma, 218 patients diagnosed with MALT lymphoma were enrolled in this study. Serum Ig paraprotein was detected in 42 of 218 patients (19.3%), mostly IgM-K (15, 35.7%), followed by IgM-L and IgG-L. Advanced age (p = 0.025), poor Eastern Cooperative Oncology Group performance status (p = 0.014), bone marrow involvement (p = 0.019), B symptoms (p = 0.039), advanced disease stage (III-IV) (p < 0.0001), elevated serum ß2-microglobulin level (p < 0.0001), multiple extranodal sites of involvement (p < 0.0001), nodal involvement (p < 0.0001), systemic therapy (p < 0.0001) and higher MALT-lymphoma International Prognostic Index (MALT-IPI) scores (p = 0.001) were significantly associated with the presence of serum Ig paraprotein. Multivariate Cox regression analysis showed that Ig paraproteinaemia was an independent prognostic predictor for inferior progression-free survival (PFS) and overall survival. A new prognostic index based on MALT-IPI and Ig paraproteinaemia, as assessed using receiver operating characteristic curves and the area under the curve statistics, showed better discriminative ability than MALT-IPI in predicting PFS. In conclusion, Ig paraproteinaemia was a promising prognostic predictor for MALT lymphoma. Ig paraproteinaemia together with MALT-IPI might contribute to optimising therapeutic management in clinical practice.

Influence of the number of high-risk cytogenetic abnormalities on the clinical characteristics and prognosis in 360 patients with newly diagnosed multiple myeloma / 中华血液学杂志

Objective: To investigate the influence of the number of high-risk cytogenetic abnormalities (HRCA) on the clinical characteristics and prognosis of patients with newly diagnosed multiple myeloma (MM) . Methods: A total of 360 patients with newly diagnosed MM admitted to Jiangsu Province Hospital between November 2013 and September 2020 were included in this study. Cytoplasmic light chain immunofluorescence with fluorescence in situ hybridization (cIg-FISH) was used to detect HRCA. Cytogenetic abnormalities were combined with clinical characteristics and outcomes for further analysis. Results: Among the 360 patients, 120 patients (33.3%) presented with no HRCAs, and 175 (48.6%) , 61 (16.9%) , and four (1.1%) patients had one, two, and three HRCA (s) , respectively. Patients were divided into three groups, including the no-HRCA group, one-HRCA group, and ≥two-HRCA group, according to the number of HRCAs. There were significant differences in the R-ISS stage, hemoglobin level, albumin level, and the proportion of bone marrow plasma cells among the three groups (P<0.05) . The COX proportional-hazards model identified extramedullary disease (P=0.018) , HRCA ≥ 2 (P=0.001) , and absence of autologous hematopoietic stem cell transplantation (P<0.001) as independent risk factors for progression free survival (PFS) and identified lactate dehydrogenase (LDH) level ≥ 220 U/L (P<0.001) , HRCA ≥2 (P=0.001) , and absence of autologous hematopoietic stem cell transplantation (P=0.005) as independent risk factors for overall survival (OS) . The median PFS was 28 months, 22 months, and 14 months (P=0.005) for the three cohorts, and their OS was not reached,60 months, and 30 months (P=0.001) , respectively. Conclusions: HRCA ≥ 2 is an independent risk factor for decreased survival in patients with newly diagnosed MM. More HRCAs result in heavier tumor burden, as well as a higher risk of disease progression and death.

Untargeted and Targeted Metabolomics Reveal the Underlying Mechanism of Aspirin Eugenol Ester Ameliorating Rat Hyperlipidemia via Inhibiting FXR to Induce CYP7A1.

Hyperlipidemia is an important lipid disorder and a risk factor for health. Aspirin eugenol ester (AEE) is a novel synthetic compound which is made up of two chemical structural units from aspirin and eugenol. Therapeutic effect of AEE on hyperlipidemia has been confirmed in animal model. But the action mechanism of AEE on hyperlipidemia is still poorly understood. In this study, we investigated the effects of AEE on liver and feces metabolic profile through UPLC-Q-TOF/MS-based untargeted metabolomics in hyperlipidemia hamster induced with high fat diet (HFD), and the effects of AEE on the expression of genes and proteins related to cholesterol and bile acid (BA) in HFD-induced hyperlipidemia SD rat. The concentrations of 26 bile acids (BAs) in the liver from hyperlipidemia SD rat were also quantified with the application of BA targeted metabolomics. The results of untargeted metabolomics showed that the underlying mechanism of AEE on hyperlipidemia was mainly associated with amino acid metabolism, glutathione metabolism, energy metabolism, BA metabolism, and glycerophospholipid metabolism. AEE induced the expression of the BA-synthetic enzymes cholesterol 7α-hydroxylase (CYP7A1) by the inhibition of BA nuclear receptor farnesoid X receptor (FXR) in liver, which resulted in accelerating the conversion of cholesterol into bile acids and excrete in feces. The results of BA targeted metabolomics showed that AEE elevated the glycine-conjugated BA level and decreased the tauro-conjugated BA level. In conclusion, this study found that AEE decreased FXR and increased CYP7A1 in the liver, which might be the possible molecular mechanisms and targets of AEE for anti-hyperlipidemia therapies.

Research Progress on Prognostic Factors of Multiple Myeloma--Review / 中国实验血液学杂志

At present, multiple myeloma (MM) still can not be cured, so it is particularly important to study the prognostic factors of MM. Recently, based on the characteristics of tumor or host, the complete disease staging systems, such as Mayor mSMART and frailty scoring system have been updated. Other independent prognostic factors, such as minimal residual disease, circulating tumor DNA, red blood cell distribution width, lymphocyte ratio and thymidine kinase 1 are of great value in evaluating the prognosis of MM from different perspectives. The comprehensive study about these prognostic factors is helpful to identify patients with high-risk MM to guide treatment and hopefully improves the quality of life of patients. In this review, the latest research progress of prognostic factors for MM is summarized briefly.

A Retrospective Analysis of TKI Discontinuation in Patients with CML / 中国实验血液学杂志

OBJECTIVE@#To investigate the clinical characteristics of the patients with chronic myeloid leukemia (CML) discontinued tyrosine kinase inhibitors (TKI) therapy and the outcome of the patients.@*METHODS@#35 cases of CML patients experienced initiative discontinuation of TKI therapy in our hospital from June 1st 2015 to December 31th 2019 were retrospectively analyzed. The TFR of the patients and the factors affecting it were analyzed.@*RESULTS@#The median duration of TKI administration was 72 (range 35-173) months in the 35 patients. Among these patients, 8 had experienced TKI dose reduction or suspension. All the enrolled patients have achieved at least MMR. The median time for these patients achieving MMR was 15 (range 3-75) months after administration of TKI, and for MMR maintenance before TKI suspension was 55 (range 13-164) months. After TKI withdrawal the median follow up time was 20.3 (range 3-57.9) months, 22 out of 35 patients kept TFR, among them, 2 （5.71%） patients restarted TKI after 12 month suspension, and maintained MMR during suspension. 13 （37.1%）patients lost MMR, among them, 9 patients restarted TKI treatment, and 5 of them achieved MR4.0 after the median duration of 3(2-5) month. No patients were found to have disease progression. The estimated TFR rate was 57.8% and 51.8% at 12 and 24 months after discontinuation, respectively. Other clinical characteristic related to relapse were also analyzed, including the cumulative TKI administration duration, cumulative MMR duration, time to achieve MMR, median age at diagnosis, risk stratification by Sokal score, TKI dose reduction and discontinuation history, and second-generation TKI administration before stopping TKI, however, no statistical difference was found.@*CONCLUSION@#TKI discontinuation is practical for CML patients in our center.

The Clinical and Laboratory Characteristics of Adult Langerhans Cell Histiocytosis Patients and the Influencing Factors of Prognosis / 中国实验血液学杂志

OBJECTIVE@#To observe the clinical and laboratory characteristics of adult Langerhans cell histiocytosis(LCH) patients and to analyze the influencing factors of its prognosis.@*METHODS@#The clinical and laboratory charac-teristics of 38 adult LCH patients treated in our hospital from January 2010 to August 2019 were retrospective analyzed, and the clinical prognosis of the patients was analyzed.@*RESULTS@#The median age of 38 patients was 41 (21-65) years old, and the ratio of male and female was about 2∶1. Among 38 patients, 44.7% (17/38) were involved in multiple systems, and 31.6% (12/38) were involved in high-risk organs (including liver, lung, hematopoietic system or spleen). The bone involvement was the most common (21/38, 55.3%), and the most common clinical symptom was pain (19/38, 50.0%). The result of laboratory showed that anemia (4/38，10.5%), thrombocytopenia (1/38，2.6%), neutropenia (2/38，5.3%), lymphopenia (6/38，15.8%), monocytosis (11/38，28.9%), C-reactive protein increasing (6/21，28.6%), erythrocyte sedimentation rate increasing (10/18, 55.3%), and ferritin protein increasing (9/17, 55.3%). The median follow-up time was 53 months, and a total of 5 patients were died. The 10-year overall survival rate of patients with single-system involvement was 100%, which was significantly higher than that of patients with multiple-system involvement (70.1%) (P=0.0078). The prognosis of patients without risk-organ involvement was better than that of patients with risk-organ involvement (10-year overall survival rate: 100% vs 60.6%) (P=0.0007). Further analysis showed that in addition to multiple-system involvement and risk-organ involvement, the increase of peripheral blood monocyte cells and the increase of ferritin protein were also associated with poorer prognosis of the patients.@*CONCLUSION@#The multiple system involve-ment and risk-organ involvement, the increasing of monocyte cells and the increasing of ferritin protein were the independent risk factors of adult LCH patients.

Expression and Prognostic Value of MiR-155 in Patients with Chronic Lymphocytic Leukemia / 中国实验血液学杂志

OBJECTIVE@#To explore the expression of miR-155 in patients with chronic lymphocytic leukemia (CLL) and its correlation with the clinical and biological features in CLL.@*METHODS@#The expression of miR-155 was detected by quantitative real time polymerase chain reaction (qRT-PCR) in the peripheral mononuclear cells collected from 73 CLL patients and CD19 positive B cells collected from 60 healthy controls, respectively. The expression of miR-155 in CLL patients was compared with the healthy controls, and the correlation of miR-155 expression with the clinical characteristics of CLL patients such as age, sex, Binet stage, cytogenetic and molecular genetic, as well as the relationship of miR-155 expression level with time to treatment (TTT) and overall survival (OS) was further analysed.@*RESULTS@#The expression of miR-155 was significantly elevated in CLL patients compared with the healthy controls. Further analysis showed that miR-155 expression decreased in the patients with the mutated immunoglobulin heavy chian variable region (IGHV) as compared with the patients unmutated (P＜0.05), and its expression was significant higher in the IGHV-39 family (P＜0.05). Fluorescence in situ hybridization (FISH) showed that the expression of miR-155 increased in patients with P53 mmutation/deletion and ATM deletion (P＜0.05). However, OS and TTT were not different between the patients with high and low expression of miR-155.@*CONCLUSION@#MiR-155 is increasingly expresses in CLL patients and correlates with poor prognosis, suggesting its important role in the genesis and progress of CLL.

Distribution of Natural Killer Cell in Patients with Newly Diagnosed Myelodysplastic Syndromes and Its Correlation with Prognosis / 中国实验血液学杂志

OBJECTIVE@#To investigate the distribution of peripheral blood lymphocytes and natural killer (NK) cells, and its influence on the prognosis of patients with myelodysplastic syndromes (MDS).@*METHODS@#The lymphocytes proportion, absolute lymphocyte counts (ALC), NK cell proportion and absolute NK cell counts (ANKC) as well as the related data of 95 MDS patients diagnosed between 2013 and 2017 analyzed retrospectively. The correlation of ALC and ANKC with prognosis was also analyzed.@*RESULTS@#As compared with low ALC patients, MDS patients with ALC≥0.885×10/L had a higher overall response rate (66.7% vs 35.8%) (P＜0.01). The ALC of effective patients after treatment significatitly increased in compaison of ALC at diagnosis. Multivariate analysis indicated that patients with ALC≥0.885×10/L had long overall survival (OS) time in comparison with patients with low level (16.4 vs 12.4 months) (P＜0.05). The OS time of patients with ANKC≥0.110×10/L was shorter in comparison with patients with low level (10.9 vs 16.3 months) (P＜0.01). Otherwise, blast, cytogenetic risks and treatment response were also independent risk factors of MDS (P＜0.05). Revised International Prognostic Scoring System (IPSS-R) combined with ANKC could improve predictive accuracy of IPSS-R alone (AUC 0.718 vs 0.674) (P＜0.05).@*CONCLUSION@#Lymphocytes and NK cells are important for the prognosis evaluation of MDS patients.

Diabetes Mellitus Is Associated with Inferior Prognosis in Patients with Chronic Lymphocytic Leukemia: A Propensity Score-Matched Analysis / Journal of the Korean Cancer Association, 대한암학회지

Purpose@#Diabetes mellitus (DM) is associated with elevated cancer risk and poor survival outcome in malignancies. The objective of this study was to evaluate the prognostic value of preexisting DM in chronic lymphocytic leukemia (CLL). @*Materials and Methods@#Six hundred and thirty-three subjects with newly-diagnosed CLL between 2007 and 2016 were recruited. Propensity score-matched method was performed to balance baseline characteristics and eliminate possible bias. Univariate and multivariate Cox regression analyses screened the independent risk indicators for time-to-first-treatment (TTFT) and cancer-specific survival (CSS) of CLL. Receiver operator characteristic curves and the corresponding areas under the curve assessed the predictive accuracy of CLL–International Prognostic Index (IPI) together with DM. @*Results@#The results showed that 111 patients had pre-existing DM. In the propensity-matched cohort, DM was correlated with inferior TTFT and CSS in CLL patients, and it was an independent prognostic factor for both CSS and TTFT. Pre-diabetics also shared undesirable prognostic outcome compared with patients with no diabetic tendency, and a positive association between longer diabetic duration and poorer prognosis of CLL was identified. DM as one additional point to CLL-IPI had larger area under the curve compared with CLL-IPI alone in CSS prediction and could improve the prognostic capacity of CLL-IPI. @*Conclusion@#Pre-existing DM was found to be a valuable prognostic predictor and could help predict life expectancy and build refined prognostication models for CLL.

EBV-miR-BHRF1-1 Targets p53 Gene: Potential Role in Epstein-BarrVirus Associated Chronic Lymphocytic Leukemia / Journal of the Korean Cancer Association, 대한암학회지

Purpose@#The purpose of this study was to investigate the prognostic impact of Epstein-Barr virus(EBV)–microRNA (miRNA, miR)-BHRF1-1 with chronic lymphocytic leukemia (CLL) as wellas role of EBV-miR-BHRF1-1 in p53 gene. @*Materials and Methods@#Quantitative reverse transcription–polymerase chain reaction and western blotting wereused to quantify EBV-miR-BHRF1-1 and p53 expression in cultured CLL. @*Results@#p53 aberration was associated with the higher expression level of EBV-miR-BHRF1-1 (p <0.001) which was also an independent prognostic marker for overall survival (p=0.028;hazard ratio, 5.335; 95% confidence interval, 1.193 to 23.846) in 97 newly-diagnosed CLLpatients after adjusted with International Prognostic Index for patients with CLL. We identifiedEBV-miR-BHRF1-1 as a viral miRNA regulator of p53. EBV-miR-BHRF1-1 repressedluciferase reporter activity by specific interaction with the seed region within the p53 3-untranslated region. Discordance of p53 messenger RNA and protein expression wasassociated with high EBV-miR-BHRF1-1 levels in CLL patients and cell lines. EBV-miR-BHRF1-1 inhibition upregulated p53 protein expression, induced cell cycle arrest and apoptosisand decreased cell proliferation in cell lines. EBV-miR-BHRF1-1 mimics downregulated p53protein expression, decreased cell cycle arrest and apoptosis, and induced cell proliferationin cell lines. @*Conclusion@#This study supported the role of EBV-miR-BHRF1-1 in p53 regulation in vitro. Our resultssupport the potential of EBV-miR-BHRF1-1 as a therapeutic target in EBV-associated CLLwith p53 gene aberration.

Roles of PET/CT in Predicting the Prognosis of Diffuse Large B Cell Lymphoma Patients Treated with Chimeric Antigen Receptor T Cell Therapy / 中国实验血液学杂志

OBJECTIVE@#To investigate the prognosis prediction value of PET/CT in DLBCL patients treated with CAR-T therapy.@*METHODS@#The effects of PET/CT were retrospectively explored on 13 R/R DLBCL patients who were treated with CAR-T therapy. Parameters reflecting tumor metabolic burden, such as metabolic tumor volume (MTV) and total lesion glycolysis (TLG) were measured before and after CAR-T treatment.@*RESULTS@#Patients with larger baseline MTV or longer sum of longest diameters showed shorter overall survival (OS) time than those with low tumor burden. Patients achieved complete remission (CR), partial remission (PR) and minor remission (MR) determined by response evaluation criteria in lymphoma (RECIL) in 12 weeks showed progression-free survival and OS time superior to those of patients with no remission. In addition, it was found that 2 patients with residual masses classified as PR by contrast-enhanced CT of patients were evaluated as complete metabolic response by PET/CT imaging.@*CONCLUSION@#PET/CT shows a great value in the evaluation of prognosis and response in CAR-T-treated R/R DLBCL patients.

Efficacy and safety of alirocumab versus ezetimibe in high cardiovascular risk Chinese patients with hyperlipidemia: ODYSSEY EAST Study-Chinese sub-population analysis / 中华心血管病杂志

Objective: To compare the efficacy and safety profile of alirocumab (PCSK9 inhibitor) versus ezetimibe on top of maximally tolerated statin dose in high cardiovascular risk Chinese patients with hyperlipidemia. Methods: The ODYSSEY EAST study was a randomized, double-blinded, double dummy, active-control, parallel group, multi-centers clinical trial, the Chinese sub-population included 456 patients with hyperlipidemia and high cardiovascular risk on maximally tolerated statin dose. Patients were randomized (2∶1) to receive the subcutaneous injection of alirocumab (75 mg Q2W; with dose up titration to 150 mg Q2W at week 12 if low-density lipoprotein cholesterol (LDL-C) was ≥1.81 mmol/L at week 8) or the oral administration of ezetimibe (10 mg daily) for 24 weeks. The primary endpoint was percentage change in calculated LDL-C from baseline to week 24. Key secondary efficacy endpoints included percentage change from baseline to week 12 or 24 in LDL-C (week 12) and other lipid parameters, including apolipoprotein (Apo) B, non-high-density lipoprotein cholesterol (non-HDL-C), TC, lipoprotein(a) (Lp(a)), HDL-C, fasting triglycerides (TG), and Apo A1, and the proportion of patients reaching LDL-C<1.81 mmol/L at week 24. Safety profile of therapeutic drugs was also assessed during the treatment period. Results: The mean age of 456 Chinese patients was (59.5±10.9) years, 341(74.8%) patients were male, 303 patients (66.4%) in alirocumab group and 153 patients (33.5%) in ezetimibe group. Demographic characteristics, disease characteristics, and lipid parameters at baseline were similar between the two groups. LDL-C was reduced more from baseline to week 12 and 24 in alirocumab group versus ezetimibe group, the difference of their least-squares mean (standard error) percent change were(-35.2±2.2)% and (-36.9±2.5)% (both P<0.001). At 12 weeks, alirocumab had significant reduction on Lp(a), Apo B, total cholesterol and non HDL-C, the difference of their least-squares mean (standard error) percent change were (-40.3±2.8)%, (-27.7±1.8)%, (-19.6±1.5)% and (-27.7±1.9)%, respectively (all P<0.001). At 24 weeks, the percent of patients who reached LDL-C<1.81 mmol/L and LDL-C<1.42 mmol/L was significantly higher in alirocumab group (85.3% and 70.5%) than in ezetimibe group (42.2% and 17.0%, both P<0.001), and alirocumab use was also associated with significant reduction on Lp(a), Apo B, total cholesterol and non HDL-C, the difference of their least-squares mean (standard error) percent change were (-37.2±2.8)%, (-29.1±2.0)%, (-21.6±1.6)% and (-29.6±2.2)%, respectively (all P<0.001). The incidence of treatment related adverse events was similar between the two treatment groups (223/302 patients (73.8%) in alirocumab group and 109/153 patients (71.2%) in ezetimibe group). Respiratory infection, urinary infection, dizziness and local injection-site reactions were the most frequently reported adverse events. Conclusions: In high cardiovascular risk patients with hyperlipidemia from China on maximally tolerated statin dose, the reduction of LDL-C induced by alirocumab is more significant than that induced by ezetimibe. Both treatments were generally safe during the observation period of study.

Characteristics and Clinical Significance of RAG1 Expression in Adult B-Cell Acute Lymphoblastic Leukemia / 中国实验血液学杂志

OBJECTIVE@#RAG1 plays important roles in lymphopoiesis and immune system, its dysfunction may result in the malignancies of hemopoietic system. The aim of this study was to investigate the characteristics of RAG1 expression in adult B-cell acute lymphoblastic leukemia (B-ALL), and to analyze the clinical significances.@*METHODS@#Quantitative PCR (q-PCR) was performed to evaluate the expression of RAG1 in 104 newly diagnosed, 22 relapsed adult B-ALL patients and 30 normal controls, the clinical significances of RAG1 expression were analyzed.@*RESULTS@#Compared with normal controls, newly diagnosed and relapsed adult B-ALL patients showed higher RAG1 expression level (3.94 vs 1.23) (P＜0.01), (5.86 vs 1.23) (P＜0.01). The analysis of paired simples from 6 cases of newly diagnosed and relapsed B-ALL showed that the expression level of RAG1 at relapse was significantly higher than that at new diagnosis (13.65 vs 2.31) (P＜0.01). The RAG1 expression level in IK6 positive patients was higher than that in IK6 negative patients (5.30 vs 2.11) (P＜0.05). The ratio of patients with LDH＞1 000 U/L in RAG1 high expression group was higher than that in RAG1 low expression group (42.2% vs 20.5%) (P＜0.05).@*CONCLUSION@#RAG1 up-regulation may play an important role in the development of adult B-ALL especially when relapsed, which may also take part in the formation of Ik6. Monitoring RAG1 expression may provide a new method to evaluate the prognosis of adult B-ALL patients.

Presence of serum antinuclear antibodies correlating unfavorable overall survival in patients with chronic lymphocytic leukemia / 中华医学杂志(英文版)

BACKGROUND@#Serum antinuclear antibodies (ANAs) are positive in some patients with chronic lymphocytic leukemia (CLL), but the prognostic value of ANAs remains unknown. The aim of this study was to evaluate the role of ANAs as a prognostic factor in CLL.@*METHODS@#This study retrospectively analyzed clinical data from 216 newly diagnosed CLL subjects with ANAs test from 2007 to 2017. Multivariate Cox regression analyses were used to screen the independent prognostic factors related to time to first treatment (TTFT), progression free survival (PFS) and overall survival (OS). Receiver operator characteristic curves and area under the curve (AUC) were utilized to assess the predictive accuracy of ANAs together with other independent factors for OS.@*RESULTS@#The incidence of ANAs abnormality at diagnosis was 13.9%. ANAs positivity and TP53 disruption were independent prognostic indicators for OS. The AUC of positive ANAs together with TP53 disruption was 0.766 (95% confidence interval [CI]: 0.697-0.826), which was significantly larger than that of either TP53 disruption (AUC: 0.706, 95% CI: 0.634-0.772, P = 0.034) or positive ANAs (AUC: 0.595, 95% CI: 0.520-0.668, P < 0.001) in OS prediction. Besides, serum positive ANAs as one additional parameter to CLL-international prognostic index (IPI) obtained superior AUCs in predicting CLL OS than CLL-IPI alone.@*CONCLUSION@#This study identified ANAs as an independent prognostic factor for CLL, and further investigations are needed to validate this finding.

Prognostic Value of Red Blood Cell Distribution Width in Senile Potients with Non-trans planted Multiple Myeloma / 中国实验血液学杂志

OBJECTIVE@#To investigate the prognostic value of red blood cell distribution width (RDW) in senile patients with non-transplanted multiple myeloma (MM).@*METHODS@#The RDW and clinical parameters such as β-2 microglobulin, creatiain, LDH and so on at diagnosis of 99 newly diagnosed senile MM patients were analysed retrospectively. The 99 patients were treated with chemotherapeutic regimens with or without bertezomib. The patients were divided into 2 groups: high (≥17.95%) and low (<17.95%) RDW groups according to ROC curve, then the prognosis of patients was compared between high and low RDW groups.@*RESULTS@#The levels of hemoglobin and C-reactive protein in high RDW group were lower than those in low RDW group, while the ratio of myeloma cells in high RDW group was higher than that in low RDW group. The unvariate and multivariate analyses in patients trented with chemotherapeutic regimen without bertezomib showed that the overall survival (OS) and progress free survival (PFS) time were shorter, while the high RDW group demonstrated the showter PFS in patients treated with chemotherapeutic regimen including bortezomib.@*CONCLUSION@#he RDW as a simple and easly available biomarker, suggests unfavorable prognosis for senile patients with non-transplanted MM; however the prognosis shows a certain difference on the basis of different chemotherapeutic regimens.

Clinical Analysis of 37 Patients with Primary Tonsil Diffuse Large B Cell Lymphoma / 中国实验血液学杂志

OBJECTIVE@#To investigate the clinical manifestation, immunophenotypes and prognostic factors of patients with primary tonsil afftive large B cell lymphoma ( PT-DLBCL ).@*METHODS@#The clinical data including clinical characterstics, typing, staging, treatment efficacy and prognostic factors of PT-DLBCL patients were collected and analyzed restrospectively.@*RESULTS@#Out of 36 cases with the detinite cell origin, 24 cases (66.7%) were detecmined as the type of germinal center B-cell (GCB) and 12 cases (33.3%) was non-germinal center B-cell (non-GCB), 15 (40.5%) out of 37 cases were in Ann Arbor stage Ⅰ, and 22 (59.5%) in stage Ⅱ. With the median follow-up of 44 (10-101) months, 2 cases (5.4%) failed to be followed-up, after treatment for 6 (3-8) cycles 35 patients were evaluated. Among them 26 cases (74.3%) reached to complete remission (CR), 8 cases (22.9%) to partial remission ( PR ), and 1 (2.8%) to stable disease (SD). Both the 3 years and 5 years progression-free survival ( PFS ) were 82.5%, and both 3 and 5 years overall survival (OS) were 95.5%. 5 cases (13.5%) received radiotherapy. The patients aged＞60 ( P＜0.05 ) or aged＞70 (P＜0.05) had shorter PFS than younger patients. The patients with increased lactic dehydrogenase ( LDH ) level (P＜0.01) and without rituximab (R) (P＜0.05) in the treatment regimen had relatively short OS.@*CONCLUSION@#The patients sensitive to chemotherapy and/or radiotherapy have a good prognosis. Most of the patients can obtain long-term survival after treatment. The effect of combined immunotherapy are better than that of the simple chemotherapy.