Efficacy and safety of plasmapheresis without plasma transfusion tandem with chemotherapy to treat multiple myeloma.

OBJECTIVES: This study evaluates the efficacy and safety of plasmapheresis without plasma transfusion tandem with chemotherapy in treating multiple myeloma (MM). METHOD: This retrospective study involves seventy-two patients, newly diagnosed with multiple myeloma, divided into two groups; one with plasmapheresis without plasma transfusion tandem with the chemotherapy group (Trial group), while the second was chemotherapy group (Control group). The levels of Plasma Globulin, ß2-microglobulin, Creatinine, Vascular endothelial growth factor (VEGF), and IL-6 were monitored after plasmapheresis, at initial diagnosis, and after four chemotherapy courses. Overall response rate of groups after four courses of chemotherapy was analyzed, and the adverse events were recorded. RESULTS AND DISCUSSION: The baseline data showed that sixty-seven percent of patients were at the ISS III stage and showed more severe renal insufficiency in the Trial group. The Plasma Globulin, ß2-microglobulin, VEGF and IL-6 levels were significantly different between the two groups during the initial diagnosis. After three times plasmapheresis, Plasma Globulin, ß2-microglobulin, VEGF, and IL-6 were significantly reduced in the plasmapheresis group. The Creatinine levels were also lowered, but the differences were not statistically significant. After four courses of chemotherapy, the levels of VEGF and IL-6 in the two groups were significantly reduced than the initial diagnosis; the differences were statistically considerable. No adverse events were found in the trial group as compared to the control group. CONCLUSION: Plasmapheresis reduces Globulin, ß2-microglobulin, serum VEGF and IL-6 levels in MM, improves renal functions, and releases some patients from dialysis dependence.

N6-Methyladenosine-Related lncRNAs Are Novel Prognostic Markers and Predict the Immune Landscape in Acute Myeloid Leukemia.

Background: Acute myelocytic leukemia (AML) is one of the hematopoietic cancers with an unfavorable prognosis. However, the prognostic value of N 6-methyladenosine-associated long non-coding RNAs (lncRNAs) in AML remains elusive. Materials and Methods: The transcriptomic data of m6A-related lncRNAs were collected from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) database. AML samples were classified into various subgroups according to the expression of m6A-related lncRNAs. The differences in terms of biological function, tumor immune microenvironment, copy number variation (CNV), and drug sensitivity in AML between distinct subgroups were investigated. Moreover, an m6A-related lncRNA prognostic model was established to evaluate the prognosis of AML patients. Results: Nine prognosis-related m6A-associated lncRNAs were selected to construct a prognosis model. The accuracy of the model was further determined by the Kaplan-Meier analysis and time-dependent receiver operating characteristic (ROC) curve. Then, AML samples were classified into high- and low-risk groups according to the median value of risk scores. Gene set enrichment analysis (GSEA) demonstrated that samples with higher risks were featured with aberrant immune-related biological processes and signaling pathways. Notably, the high-risk group was significantly correlated with an increased ImmuneScore and StromalScore, and distinct immune cell infiltration. In addition, we discovered that the high-risk group harbored higher IC50 values of multiple chemotherapeutics and small-molecule anticancer drugs, especially TW.37 and MG.132. In addition, a nomogram was depicted to assess the overall survival (OS) of AML patients. The model based on the median value of risk scores revealed reliable accuracy in predicting the prognosis and survival status. Conclusion: The present research has originated a prognostic risk model for AML according to the expression of prognostic m6A-related lncRNAs. Notably, the signature might also serve as a novel biomarker that could guide clinical applications, for example, selecting AML patients who could benefit from immunotherapy.

COVID-19 in persons with chronic myeloid leukaemia.

We studied by questionnaire 530 subjects with chronic myeloid leukaemia (CML) in Hubei Province during the recent SARS-CoV-2 epidemic. Five developed confirmed (N = 4) or probable COVID-19 (N = 1). Prevalence of COVID-19 in our subjects, 0.9% (95% Confidence Interval, 0.1, 1.8%) was ninefold higher than 0.1% (0, 0.12%) reported in normals but lower than 10% (6, 17%) reported in hospitalised persons with other haematological cancers or normal health-care providers, 7% (4, 12%). Co-variates associated with an increased risk of developing COVID-19 amongst persons with CML were exposure to someone infected with SARS-CoV-2 (P = 0.037), no complete haematologic response (P = 0.003) and co-morbidity(ies) (P = 0.024). There was also an increased risk of developing COVID-19 in subjects in advanced phase CML (P = 0.004) even when they achieved a complete cytogenetic response or major molecular response at the time of exposure to SARS-CoV-2. 1 of 21 subjects receiving 3rd generation tyrosine kinase-inhibitor (TKI) developed COVID-19 versus 3 of 346 subjects receiving imatinib versus 0 of 162 subjects receiving 2nd generation TKIs (P = 0.096). Other co-variates such as age and TKI-therapy duration were not significantly associated with an increased risk of developing COVID-19. Persons with these risk factors may benefit from increased surveillance of SARS-CoV-2 infection and possible protective isolation.

NPAS2 regulates proliferation of acute myeloid leukemia cells via CDC25A-mediated cell cycle progression and apoptosis.

Promoted proliferation and associated suppression of apoptosis at various stages of myeloid differentiation are well-known features of acute myeloid leukemia (AML), but understanding of the molecular processes involved remains limited. As a crucial circadian agent, neuronal PAS domain protein 2 (NPAS2) is widely recognized as a promising predictor of clinical outcome in various malignancies. Nevertheless, the understanding of its influence on AML is insufficient. Using KD cells and expression assays, we carried out detailed investigation of the role of NPAS2 in AML in vivo and in vitro. Firstly, we found that NPAS2 expression was elevated in AML cells both in vivo and in vitro. NPAS2 knockdown via lentiviral infection clearly suppressed proliferation of MV4-11 and MOLM-14 cells. Additionally, NPAS2 knockdown caused G1/S cell cycle arrest (CCA), which inhibited CDC25A expression. Moreover, NPAS2 knockdown promoted cell death, as evidenced by increased caspase-3 cleavage, and change in Bcl2/Bax production. Excessive CDC25A expression eliminated G1/S CCA triggered by NPAS2 knockdown and death of NPAS2 knocked down MOLM and MV4-11 cells. The expression of CDC25A was stabilized by NPAS2, which induced cell cycle progression and participated in suppression of cell death by modulating caspase-3 cleavage, and expression of Bcl2/Bax. We therefore indicated NPAS2 to be a crucial modulator of survival as well as proliferation. Our research sheds light on the etiology of the proliferation of promyelocytes modulated via NPAS2 with regard to AML.

Effects and Predictive Factors of Immunosuppressive Therapy Combined with Umbilical Cord Blood Infusion in Patients with Severe Aplastic Anemia.

PURPOSE: To investigate the efficacy and safety of umbilical cord blood (UCB) infusion (UCBI) plus immunosuppressive therapy (IST) treatment in comparison to IST treatment, as well as predictive factors for clinical responses, in severe aplastic anemia (SAA) patients. MATERIALS AND METHODS: Totally, 93 patients with SAA were enrolled in this cohort study. In the IST group, rabbit antithymocyte globulin (r-ATG) combined with cyclosporine A (CsA) was administered, while in the IST+UBCI group, r-ATG, CsA, and UCB were used. RESULTS: After 6 months of treatment, UCBI+IST achieved a higher complete response (CR) rate (p=0.002) and an elevated overall response rate (ORR) (p=0.004), compared to IST. Regarding hematopoietic recovery at month 6, platelet responses in the UCBI+IST group were better than those in the IST group (p=0.002), and UCBI+IST treatment facilitated increasing trends in absolute neutrophil count (ANC) response (p=0.056). Kaplan-Meier curves illuminated UCBI+IST achieved faster ANC response (p<0.001) and platelet response (p<0.001), compared with IST therapy. There was no difference in overall survival (OS) between the two groups (p=0.620). Furthermore, logistic regression analysis demonstrated that UCBI+IST was an independent predicting factor for both CR (p=0.001) and ORR (p<0.001), compared to IST; meanwhile, very severe aplastic anemia (VSAA) and ANC could predict clinical responses as well. However, Cox proportional hazard regression indicated that VSAA (p=0.003), but not UCBI+IST, affected OS. Safety profiles showed that UCBI+IST therapy did not elevate adverse events, compared with IST treatment. CONCLUSION: UCBI+IST achieved better clinical responses and hematopoietic recovery than IST, and was well tolerated in SAA patients.

[Detection of alloantibodies against Factor VIII in plasma of patients with hemophilia A and its relationship with Factor VIIIC domain].

This study was purposed to detect the alloantibodies against Factor VIII (FVIII) by ELISA for estimating the incidence of the alloantibodies against Factor VIII (FVIII) in patients with hemophilia A, and to investigate the relationship between factor VIIIC domain and alloantibodies. Total of 140 patients with hemophilia A and 80 normal controls were enrolled in this study, among them plasma FVIII level of 84 patients was less than 1%, plasma FVIII level of 34 patients was between 1% and 5%, and plasma FVIII level of 22 patients was more than 5%. All patients were treated with plasma-derived FVIII concentrate or plasma before. The ELISA plate was coated with McAb (SZ-132) against FVIII prepared in our laboratory, then human recombinant FVIII concentrates were applied. After incubation in room temperature for 2 hours, diluted plasma samples and HRP-conjugated goat anti-human IgG were added successively, finally A490 was recorded. The threshold of alloantibody of patient plasma was set as mean value>3 SD more than control. The plate was coated with antibody against His, then human recombinant FVIII-C1C2 prepared in our laboratory was added. After incubation in room temperature for 2 hours, diluted plasma samples and HRP-conjugated goat anti-human IgG were added successively, finally A490 were recorded. The threshold was set as the mean value>3 SD more than control. The results showed that the alloantibodies against FVIII were found in 56 patients (40%) by ELISA, and 82.1% (46/56) of this kind of alloantibody could interact with the C domain of FVIII. It is concluded that C domain of FVIII is one of the primary binding sites for the alloantibodies against FVIII in Chinese patients with hemophilia A.

[Plasma concentrations of vascular endothelial growth factor and tissue factor in children with acute lymphoblastic leukemia].

OBJECTIVE: To detect plasma concentrations of vascular endothelial cell growth factor (VEGF) and tissue factor (TF) in children with acute lymphoblastic leukemia (ALL) and explore their clinical significance in ALL. METHODS: Thirty-three children with newly diagnosed ALL, including 18 cases of low risk, 7 cases of moderate risk and 8 cases of high risk, were enrolled in this study. Twenty-five patients received a complete remission and 8 cases were in non-remission after conventional remission induction chemotherapy. Plasma concentrations of VEGF and TF in the patients were detected using ELISA before and after treatment. Sixteen healthy children served as normal control group. RESULTS: Plasma concentrations of VEGF and TF in ALL patients before treatment were significantly higher than those in normal controls (P < 0.01). Plasma concentrations of VEGF and TF in the non-remission group before treatment were significantly higher than those in the remission group (P < 0.05) and the control group (P < 0.01). After treatment the plasma concentrations of VEGF and TF in the non-remission group were not significantly reduced and higher than those in the remission and the control groups (P < 0.01). There were significant differences in plasma concentrations of VEGF and TF among the low-risk, moderate-risk and high-risk groups before and after treatment (P < 0.05). Plasma concentrations of VEGF and TF in the high risk group were not significantly reduced after treatment and higher than those in the control group (P < 0.01). A linear correlation was noted between plasma VEGF and TF concentrations in ALL patients before treatment (r=0.50, P < 0.01). CONCLUSIONS: VEGF and TF play an important role in the development of ALL and may be useful to the evaluation of the severity and the outcome in ALL.

[The effect of HGF on graft-versus-host disease and graft-versus-leukemia after allogeneic bone marrow transplantation in acute lymphoblastic leukemia mice].

OBJECTIVE: To investigate the effect of hepatocyte growth factor (HGF) on graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL) after allogeneic bone marrow transplantation (allo-BMT) and related mechanism in acute lymphoblastic leukemia (ALL) mice. METHODS: Twenty nude mice were randomly divided into control (group A) and test (group B) groups for monitoring relapse, and 20 BALB/c mice into control (group C) and test (group D) groups for GVHD. HGF as injected from day 0 to day 7 after BMT for groups B and D, while PBS for A and C. CD4(+) and CD8(+) T cell were evaluated by flow cytometry. The survival of mice after BMT was recorded. The level of tumor necrosis factor-alpha (TNF-alpha) was evaluated by ELISA. RESULTS: The median past-BMT survival were 7.00 +/- 1.58, 9.00 +/- 1.58, 11.00 +/- 3.95 and 24.00 +/- 13.44 days for groups A, B, C, D, respectively, being prolonged in group D. HGF could decrease the quantity of CD4(+) T cells [group D (10.39 +/- 1.15)% vs group C (13.50 +/- 1.80)%, P < 0.01] and increase CD8(+) T cell [group D (12.25 +/- 2.85)% vs group C (6.12 +/- 1.99)%, P < 0.01], decrease the level of TNF-alpha in transplanted ALL mice [group D (112.10 +/- 18.99) pg/ml vs group C (143.90 +/- 25.35) pg/ml, P < 0.01] and reduce the degree of GVHD. CONCLUSION: HGF could alleviate post-allo-BMT GVHD but retain GVL effect.

[Effects of HGF on GVHD and Th1/Th2-related cytokines in ALL mice after allo-BMT].

To observe the effects of hepatocyte growth factor (HGF) on graft-versus-host disease (GVHD) and Th1/Th2 related cytokines in mice with acute lymphoblastic leukemia (ALL) after allogenic bone marrow transplantation (allo-BMT), BALB/c mice were conditioned by total body irradiation with 11 Gy and then were transplanted with allogeneic bone marrow after establishing ALL model. BALB/c mice were divided into groups A and B. The mice of group A were injected subcutaneously with HGF from day 0 to 7 after allo-BMT, and the mice of group B were injected subcutaneously with PBS from day 0 to 7 after allo-BMT. The symptoms of GVHD and the GVHD pathological changes of liver and small intestine and skin were observed. The serum levels of both IFN-gamma and IL-4 were determined by ELISA. The results showed that the score of GVHD in group A was lower than that in group B (P < 0.05). The levels of IFN-gamma in both groups A and B were all higher than that in normal group (P < 0.05 and P < 0.001, respectively), However, the level of IFN-gamma in group A was lower than that in group B (P < 0.01). The levels of IL-4 in both group A and B were all lower than that in normal group (P < 0.05), but the level of IL-4 in group A was higher than that in group B (P < 0.05). It is concluded that HGF can alleviates the severity of GVHD, because of its balancing the Th1/Th2-related cytokines after allo-BMT.