Thymocyte selection-associated high mobility box protein regulates T lymphocytes exhaustion in patients with myelodysplastic syndromes by inhibiting PI3K/AKT/mTOR pathway.

Myelodysplastic syndromes (MDS) patients often experience CD8+ T lymphocytes exhaustion, which plays a crucial role in the development of MDS. However, the specific role of thymocyte selection-associated high mobility box protein (TOX) in the CD8+ T lymphocytes exhaustion in MDS patients remains unclear. In this study, we investigated the role of TOX in CD8+ T lymphocytes exhaustion in patients with MDS. The expression of TOX, inhibitory receptors (IRs), and functional molecules in peripheral blood T lymphocytes of MDS patients and normal controls were detected using flow cytometry. Lentiviral transduction was used to create stable TOX-knockdown CD8+ T lymphocytes, and small interfering RNA (si-RNA) was used to knock down TOX in Jurkat cells. The expression of TOX was found to be significantly higher in CD8+ T lymphocytes of MDS patients compared to normal controls. This was associated with upregulated IRs and reduced expression of functional molecules such as Granzyme and Perforin. Myelodysplastic syndromes patients with higher TOX expression had poor clinical indicators and shorter survival. Knockdown of TOX using sh-RNA partially reverses the exhausted phenotype and enhances the lethality of CD8+ T lymphocytes. Moreover, the knockdown of TOX using si-RNA in Jurkat cells improved cell proliferation activity, down-regulated IRs and activated PI3K/AKT/mTOR signaling pathway. TOX promotes the exhaustion of CD8+ T lymphocytes by inhibiting PI3K/AKT/mTOR pathway, and targeted inhibition of TOX could partially restore the effector functions and activity of CD8+ T lymphocytes.

Single-institution experience of venetoclax combined with azacitidine in newly diagnosed acute myeloid leukemia patients.

To retrospectively analyze the efficacy and safety of venetoclax combined with azacitidine (VEN + AZA) in the treatment of elderly patients with acute myeloid leukemia. The clinical data for 57 AML patients treated with the VEN + AZA regimen from December 2019 to November 2022 in the Department of Hematology, General Hospital of Tianjin Medical University, were collected. Of the 57 patients included in this study, the mean age of onset was 69.89 (±8.88) years. The median follow-up time was 8.57 months, and the median OS time was 11.50 months. The ORR, CR rate, and MRD (<0.1%) negativity rate were 87.5%, 68.8%, and 58.3%, respectively. The median OS was longer in patients who achieved CR/CRi and who were MRD-negative than in those who did not. MRD negativity was less likely to be achieved in patients aged ≥75 years and with ECOG scores of ≥3. Compared to traditional intensive chemotherapy, MRD negative was achieved more quickly with VEN + AZA regimens in patients with newly diagnosed AML. Advanced age and ECOG score were risk factors for negative MRD. The dominant adverse reactions were hematological adverse events. VEN + AZA regimens in elderly unfit patients with previously untreated newly diagnosed AML have sufficient efficacy and safety.

Aponermin or placebo in combination with thalidomide and dexamethasone in the treatment of relapsed or refractory multiple myeloma (CPT-MM301): a randomised, double-blinded, placebo-controlled, phase 3 trial.

BACKGROUND: Aponermin, a circularly permuted tumor necrosis factor-related apoptosis-inducing ligand, is a potential death receptor 4/5-targeted antitumour candidate. Previous phase 1/2 studies have demonstrated the efficacy of aponermin in patients with relapsed or refractory multiple myeloma (RRMM). To confirm the superiority of aponermin plus thalidomide and dexamethasone (aponermin group) over placebo plus thalidomide and dexamethasone (placebo group) in RRMM, a randomized, double-blinded, placebo controlled phase 3 trial was performed. METHODS: Four hundred seventeen patients with RRMM who had previously received at least two regimens were randomly assigned (2:1) to receive aponermin, thalidomide, and dexamethasone or placebo, thalidomide, and dexamethasone. The primary endpoint was progression-free survival (PFS). Key secondary endpoints included overall survival (OS) and overall response rate (ORR). RESULTS: A total of 415 patients received at least one dose of trial treatment (276 vs. 139). The median PFS was 5.5 months in the aponermin group and 3.1 months in the placebo group (hazard ratio, 0.62; 95% confidence interval [CI], 0.49-0.78; P < 0.001). The median OS was 22.4 months for the aponermin group and 16.4 months for the placebo group (hazard ratio, 0.70; 95% CI, 0.55-0.89; P = 0.003). Significantly higher rates of ORR (30.4% vs. 13.7%, P < 0.001) and very good partial response or better (14.1% vs. 2.2%, P < 0.0001) were achieved in the aponermin group than in the placebo group. Treatment with aponermin caused hepatotoxicity in some patients, as indicated by the elevated alanine transaminase, aspartate transaminase, or lactate dehydrogenase levels (52.2% vs. 24.5%, 51.1% vs. 19.4% and 44.9% vs. 21.6%, respectively), mostly grade 1/2, transient and reversible. The main grade 3/4 adverse events included neutropenia, pneumonia and hyperglycemia. The incidence of serious adverse events was similar between the two groups (40.6% vs. 37.4%). There was no evidence that aponermin leads to hematological toxicity, nephrotoxicity, cardiotoxicity, or secondary tumors. CONCLUSIONS: Aponermin plus thalidomide and dexamethasone significantly improved PFS, OS and ORR with manageable side effects in RRMM patients who had received at least two prior therapies. These results support the use of aponermin, thalidomide, and dexamethasone as a treatment option for RRMM patients. TRIAL REGISTRATION: The trial was registered at http://www.chictr.org.cn as ChiCTR-IPR-15006024, 17/11/2014.

Interleukin 6 exacerbates the progression of warm autoimmune hemolytic anemia by influencing the activity and function of B cells.

To explore the effect of IL-6 on the activity and secretory function of B cells and analyze its effect on clinical indicators and efficacy in wAIHA patients. This study included 25 hemolytic wAIHA patients, 13 remission patients, and 10 HCs. Plasma levels of various cytokines were detected using CBA. PBMCs were extracted from 12 hemolytic wAIHA patients and divided into three wells, stimulation with IL-6 and IL-6 + tocilizumab, the blank control wells were also set. After 48 h of in vitro cell culture, percentage of CD5+CD80+, CD5-CD80+,CD5+CD86+,CD5-CD86+,CD5+IL-10+,CD5-IL-10+B cells were determined by flow-cytometry. Plasma levels of IL-6 and IL-10 in hemolytic episode group were significantly higher than that in HCs group (p = 0.0243; p = 0.0214). RBC and Hb levels were negatively correlated with IL-6 levels in wAIHA patients, while LDH levels were positively correlated.Therapeutic effects of glucocorticoid and duration of efficacy were also significantly correlated with IL-6 levels in wAIHA patients. After 48 h in vitro cell culture, percentages of CD80+/CD5+CD19+and CD80+/CD5-CD19+ cells in the IL-6 stimulation group were higher than those in blank control group (p = 0.0019; p = 0.0004), while CD86+/CD5+ CD19+ and CD86+/CD5-CD19+ cells were not statistically different before and after IL-6 stimulation. Percentage of IL-10+/CD5+ CD19+ cells in IL-6 stimulation group was lower than that in blank control (p = 0.0017) and IL-6 + toc (p = 0.0117) group. Percentage of IL-10+/CD5- CD19+cells in the IL-6 stimulation group was lower than that in the blank control group (p = 0.0223). Plasma levels of IL-6 were significantly elevated in hemolytic wAIHA patients and correlated with clinical indicators and efficacy. IL-6 promotes the activation of B cells. Although the results were not statistically significant, IL-6R antagonist tocilizumab may hopefully become a targeted therapy for wAIHA patients.

Genome-wide DNA methylation profiles analysis in primary warm autoimmune hemolytic anemia patients.

BACKGROUND: Autoimmune hemolytic anemia (AIHA) is caused by auto-antibodies, secreted by overactivated B cells, directed against self-red blood cells, resulting in hemolysis. It found that aberrant DNA methylation in B cells can induce the production of autoantibodies. Therefore, we attempted to explore if similar aberrant DNA methylation occur in AIHA patients. METHODS: A 49-year-old female wAIHA patient and a 47-year-old female healthy control (HC) were enrolled. Peripheral blood (PB) B cells DNA was extracted. After constructing genomic libraries, bisulfite genomic sequencing (BSP) and DNA methylation profiles were analyzed. BSP was verified using PB B cells from 10 patients with hemolysis, 10 patients with hemolytic remission, and 10 healthy controls (HCs) by Methylation-specific PCR. RESULTS: Total DNA methylation of whole-genome C bases (4.8%) and CG type bases (76.8%) in wAIHA patient were lower than those in the HC (5.3 and 82.5%, respectively) (p = 0.022 and p < 0.001). DNA methylation of C bases and CG type bases in whole-genome regulatory elements, such as coding sequence, up2Kb and down2Kb in the patient were also lower than those in the HC (p = 0.041, p = 0.038, and p = 0.029). 30,180 DNA-methylated regions (DMRs) on all 23 chromosomes were identified. DMR-related genes were mainly involved in the Rap1, phospholipase D, HIF-1, calcium, vascular endothelial growth factor (VEGF) and Ras signaling pathways. CONCLUSION: The DNA methylation spectrum of B cells in AIHA patients is different from that of HC, and the proportion of hypo-methylation regions is higher than that of HC. DMR-related genes are mainly related to some signaling pathways.

A new dosing regimen of ropeginterferon alfa-2b is highly effective and tolerable: findings from a phase 2 study in Chinese patients with polycythemia vera.

Ropeginterferon alfa-2b represents a new-generation pegylated interferon-based therapy and is administered every 2-4 weeks. It is approved for polycythemia vera (PV) treatment in the United States and Europe with a starting dose of 100 µg (50 µg for patients receiving hydoxyurea) and intra-patient dose titrations up to 500 µg at 50 µg increments, which took approximately 20 or more weeks to reach a plateau dose level. This study aimed to assess ropeginterferon alfa-2b at an alternative dosing regimen with a higher starting dose and quicker intra-patient dose titrations, i.e., the 250-350-500 µg schema, in 49 Chinese patients with PV with resistance or intolerance to hydroxyurea. The primary endpoint of the complete hematologic response rate at treatment weak 24 was 61.2%, which was notably higher than 43.1% at 12 months with the approved dosing schema. The JAK2V617F allele burden decreased from baseline to week 24 (17.8% ± 18.0%), with one patient achieving a complete molecular response. Ropeginterferon alfa-2b was well-tolerated and most adverse events (AEs) were mild or moderate. Common AEs included alanine aminotransferase and aspartate aminotransferase increases mostly at grade 1 or 2 levels. Patients did not present with jaundice or significant bilirubin level increase. No grade 4 or 5 AEs occurred. Seven patients (14.3%) experienced reversible, drug-related grade 3 AEs. No AEs led to treatment discontinuation. Ropeginterferon alfa-2b at the 250-350-500 µg regimen is highly effective and well-tolerated and can help patients achieve greater and rapid complete hematologic and molecular responses.Clinical Trial Registration: This trial is registered at ClinicalTrials.gov (Identifier: NCT05485948) and in China (China National Medical Products Administration Registration Number: CTR20211664).

Decitabine in patients with myelodysplastic syndromes: A multi-center, open-label, dose comparison trial.

BACKGROUND: The hypomethylating agent decitabine is the standard therapy for intermediate or high risk myelodysplastic syndrome (MDS). METHODS: In this trial, 191 adult patients with intermediate/high risk MDS (IPSS score ≥ 0.5) randomly received decitabine using a standard regimen (20 mg/m2 /day for 5 consecutive days; n = 94) or an extended regimen with lower daily dose (12 mg/m2 /day for 8 consecutive days; n = 97) every 4 weeks, for a total of 4 cycles. RESULTS: The median follow-up was 14 months (range 2-36). The primary end point of overall response rate in the intent-to-treat analysis was 41.5% and 38.1% in the standard and extended dosing arms, respectively (p = 0.660). Complete remission and marrow complete remission also did not differ between the two arms. Cytopenia was the most frequent adverse event (76.4%). The median duration of neutropenia per cycle did not differ between the two arms during the first two cycles, but significantly shorter in the extended dosing arm in the third cycle (8.5 vs. 15.5 days, p = 0.049) and in the fourth cycle (8 vs. 14 days, p = 0.294). CONCLUSION: The 5-day 20-mg/m2 /day and 8-day 12-mg/m2 /day decitabine regimens have similar efficacy and safety in patients with intermediate or high risk MDS.

Partial SAA patients benefit from delayed response of IST.

Introduction: Severe aplastic anemia(SAA)is a severe disease characterized by immune-mediated bone marrow failure and pancytopenia. Immunosuppressive therapy (ATG plus CsA, IST) is the standard treatment for patients who are not suitable for allogeneic hematopoietic stem cell transplantation (allo-HSCT). Some patients have a delayed response after 6 months of ATG, and unnecessary to be given secondary ATG or allo-HSCT. We attempted to distinguish patients who may get potential delayed response from those who were really not responsive to IST. Methods: We collected data from 45 SAA patients who were assessed no-response to IST at 6 months after rATG and failed to receive secondary ATG or allo-HSCT. Results: CsA plus eltrombopag (EPAG) group has an extra 75% response rate while CsA maintenance group has an extra 44% response rate at 12 months. ATG was applied within 30 days after diagnosis, ATG dosage was suffificient (ATG/lymphocyte ≥2), and absolute reticulocyte count (ARC) was ≥30×109 /L at 6 months, indicated patients could get delayed response and benefifit from CsA maintenance. Addition of EPAG could give an even better response. Otherwise, secondary ATG or allo-HSCT treatment were recommended to be given immediately. Clinical Trial Registration: https://www.chictr.org.cn/searchproj.aspx, identifier ChiCTR2300067615.

Iron metabolism abnormalities in autoimmune hemolytic anemia and Jianpishengxue keli can ameliorate hemolysis and improve iron metabolism in AIHA mouse models.

OBJECTIVE: Autoimmune hemolytic anemia (AIHA) is rare heterogeneous disorder characterized by red blood cell (RBC) destruction via auto-antibodies, and after RBC is destroyed, proinflammatory danger-associated molecular patterns including extracellular hemoglobin, heme, and iron which causing cell injury. And oxidative stress represents one of the most significant effects of chronic hemolysis. Jianpishengxue keli can improve the symptoms of anemia patients with kidney disease and tumors and are beneficial in promoting recovery from chronic inflammation. Therefore, it is presumed that Jianpishengxue keli can improve the symptoms of AIHA. We aimed to investigate iron metabolism in AIHA and effects of Jianpishengxue keli on AIHA murine model. METHODS: Nineteen hemolytic episode AIHA patients, 10 remission patients and 10 healthy controls (HCs) were enrolled in this study. Serum hepcidin, ferritin and other related indicators of iron metabolism were measured. Mouse models of AIHA were established and received high, medium, or low doses of Jianpishengxue keli by gavage daily for 14 and 28 days respectively. The level of RBCs, Hb, bilirubin, LDH, hepcidin, and the expression level of hepcidin mRNA, and hepatic ferroportin 1(FPN1) protein were evaluated. RESULTS: Serum hepcidin in hemolytic episode AIHA patients and remission patients were significantly higher than that in HCs (p = 0.0083 and p = 0.0473, respectively). Serum ferritin in hemolytic AIHA patients was significantly higher than that in HCs (p = 0.008). Serum transferrin saturation levels are increased in patients with AIHA[ (57.21 ± 8.96) %]. EPO in hemolytic group was higher than that in healthy control (p＜0.05). In AIHA mouse models, IBIL decreased after 14 days of high dose drug intervention. After 28 days, TBIL and IBIL both significantly decreased in all dose groups and LDH significantly decreased in the medium-and high-dose groups. Body weight improved, and the level of RBCs, Hb and hepcidin in the high-dose group returned to normal. After 14 and 28 days of intervention, hepatic hepcidin mRNA in all dose group significantly decreased. Hepatic FPN1 protein which were significantly lower in the AIHA mouse models, increased in all dose groups after drug intervention for 28 days. CONCLUSION: Iron metabolism abnormalities exists in AIHA patients and Jianpishengxue keli can ameliorate hemolysis and improve iron metabolism in AIHA mouse models.KEY MESSAGESIron metabolism abnormalities exists in hemolytic episode AIHA patients. Hepcidin and ferritin levels significantly elevated and also correlated with the severity of AIHA patients. Jianpishengxue keli can ameliorate hemolysis and prompt the recovery of AIHA.

Efficacy and quality of life of Romiplostim in adults and children with immune thrombocytopenia: A review.

BACKGROUND: To systematically evaluate the clinical efficacy, drug safety and health-related quality of life (HRQoL) of Romiplostim in adult and child immune thrombocytopenia (ITP) patients. METHODS: PubMed, EMBASE and Cohrane library databases were searched for all randomized controlled trials published until 2022, and the Review Manager 5.3 was used for meta-analysis. RESULTS: A total of 9 randomized controlled trials were included in this study. The results of meta-analysis showed that the total platelet response rate and long-term platelet response rate in treatment group were significantly higher than those in control group (P<0.05). There was no statistical significance in the side effects, serious side effects, bleeding events and serious bleeding events between 2 groups (P>0.05). Compared with control group, the HRQoL in ITP adults and children, and parents of ITP children had no statistical significance (P>0.05). CONCLUSION: Romiplostim has a certain clinical efficacy in ITP adults and children, and relatively small adverse drug reactions. The improvement of Romiplostim on HRQoL in ITP adults and children is not clear.

Bone marrow free immune checkpoints as a potential biomarker for differential diagnosis of acquired bone marrow failures.

OBJECTIVE: Clinically, to make a definite diagnosis of aplastic anemia (AA), idiopathic cytopenia of undetermined significance (ICUS) or myelodysplastic syndrome (MDS), they should be distinguished from each other. AA and ICUS have some incidence to transform into MDS. Immunosuppressive therapy (IST) is effective in AA and partial ICUS patients, while other ICUSs are more likely to progress to MDS without response to IST. To date, we neither found a technical method that could easily identify AA from hypoproliferative MDS, nor a simple parameter that could indicate ICUS with a response to IST. Here, we detected the concentration of free immune checkpoints in bone marrow supernatant of AA, ICUS, and MDS patients, analyzed the differences of immune status among these three diseases, to try to find a way to predict the response to IST in ICUSs. METHODS: Seventy-four novel patients were enrolled with newly diagnosed acquired bone marrow failure (including 29 AA patients, 11 ICUS patients, and 34 MDS patients), bone marrow supernatants were collected. Luminex liquid suspension array technology was used to measure the concentrations of 17 immune checkpoints to analyze the differences of immune status among these three diseases. RESULTS: The levels of 17 free immune checkpoints were elevated in MDS and showed a strong correlation with each other, followed by ICUS, and with the weakest in AA. By drawing the ROC curve, we found eight immune checkpoints, including sCD40, sCD86/B7-2, sCTLA-4, sGITR, sHVEM, sPD-1, sTIM-3, and sTLR-2, could easily distinguish AA from hypoproliferative MDS. ICUSs with lower concentrations of these eight free immune checkpoints predicted a better IST response. CONCLUSION: In conclusion, we found that there were notable differences in the immune status of AA, ICUS, and MDS. The concentrations of sCD40, sCD86/B7-2, sCTLA-4, sGITR, sHVEM, sPD-1, sTIM-3, and sTLR-2 could be used to identify AA and hypoproliferative MDS patients, as well as to distinguish ICUS patients who could benefit from IST.

Gut Microbiome and Plasma Metabolomic Analysis in Patients with Myelodysplastic Syndrome.

Myelodysplastic syndrome (MDS) is a heterogeneous group of clonal hematopoietic stem cell disorders. Studies have shown the involvement of an abnormal immune system in MDS pathogenesis. The gut microbiota are known to influence host immunity and metabolism, thereby contributing to the development of hematopoietic diseases. In this study, we performed gut microbiome and plasma metabolomic analyses in patients with MDS and healthy controls. We found that patients with MDS had a different gut microbial composition compared to controls. The gut microbiota in MDS patients showed a continuous evolutionary relationship from the phylum to the species level. At the species level, the abundance of Haemophilus parainfluenzae, Streptococcus luteciae, Clostridium citroniae, and Gemmiger formicilis increased, while that of Prevotella copri decreased in MDS patients compared to controls. Moreover, abundance of bacterial genera correlated with the percentage of lymphocyte subsets in patients with MDS. Metabolomic analysis showed that the concentrations of hypoxanthine and pyroglutamic acid were increased, while that of 3a,7a-dihydroxy-5b-cholestan was decreased in MDS patients compared to controls. In conclusion, gut microbiome and plasma metabolomics are altered in patients with MDS, which may be involved in the immunopathogenesis of the disease.

Ferritin Light Chain: A Candidate Autoantigen in Immuno-Related Pancytopenia.

The characteristic feature of immune-related pancytopenia (IRP) is autoantibody-mediated bone marrow (BM) damage and peripheral blood cytopenia. We found that the potential antigen of IRP was Ferritin light chain (FTL) by SEREX (serological analysis of recombinant cDNA expression libraries) in the previous study. In this study, we tried to explore the antigenic epitopes of FTL and verify its antigenicity in IRP. We found the possible FTL epitope: VNLYLQASYTYLSLG by phage random peptide library. Through ELISPOT, it was found that peptide VNLYLQASYTYLSLG can significantly stimulate the production of interleukin-4 and cannot stimulate the production of interferon-γ, which suggested that the peptide can obviously activate Th2 cells. Peptide-major histocompatibility complex tetramer elicited antigen-specific T cell responses. The expression levels of FTL were significantly increased in the patients with untreated IRP (P < 0.05). In conclusion, we found that FTL is the target antigen for some patients with IRP. The peptide of VNLYLQASYTYLSLG is an epitope of the target antigen. The target antigen is abnormally overexpressed on the membrane of BM cells, especially on the surface of CD34+ BM cells of patients with IRP. In addition, it is related to the severity of disease. These results provide a possible new target for the treatment of IRP in the future.

Lymphocyte Activation Gene 3 Single-Nucleotide Polymorphisms in Bone Marrow Failure Diseases.

Introduction: Lymphocyte activation gene 3 (LAG3) is an inhibitory checkpoint protein expressed on activated T effector, T regulatory, and natural killer cells. The main function of LAG3 is the regulation of immune homeostasis. Several studies have suggested its role in malignant and autoimmune diseases. The objective of this study was to explore the association between LAG3 single-nucleotide polymorphisms (SNPs) and bone marrow failure diseases. Methods: Sixty-two patients newly diagnosed with bone marrow failure diseases in the Hematology Department of Tianjin Medical University General Hospital between January 2019 and December 2020 and 16 healthy controls were enrolled in this study. SNPs in LAG3 were investigated by performing Sanger sequencing, and the association of the detected SNPs with bone marrow failure diseases was analyzed. Results: Eleven SNPs were identified. Among them, the frequency of LAG3 rs1941928301 (C>T) was statistically different among the groups (P = 0.013). It was higher in the myelodysplastic syndrome (MDS) group than that in the severe aplastic anemia (SAA) group (P = 0.004) and that in the healthy control group (P = 0.009). Conclusions: LAG3 rs1941928301 (C>T) might be associated with a higher risk of MDS. The detected LAG3 SNPs have no apparent effect on susceptibility to SAA and immune-related pancytopenia (IRP).

Abnormal expression of histone acetylases in CD8+ T cells of patients with severe aplastic anemia.

INTRODUCTION: We aimed to investigate the balance between the mRNA levels of histone acetyltransferases (HATs) and histone deacetylases (HDACs) in CD8+ T cells of patients with severe aplastic anemia (SAA). METHODS: Twenty untreated SAA patients, 18 remission SAA patients (R-SAA), and 22 normal controls were evaluated. The mRNA expression levels of HATs, HDACs, and IFNG in CD8+ T cells were measured by real-time quantitative reverse transcription polymerase chain reaction. RESULTS: Histone acetylase EP300 and CREBBP mRNA levels were significantly elevated in CD8+ T cells of SAA patients compared with the normal controls (both p < 0.05). No significant differences were observed in HDAC1 and HDAC7 mRNA between SAA patients and the normal controls. There was an obvious positive correlation between IFNG and EP300 (r = 0.5126, p < 0.01), and CREBBP (r = 0.4663, p < 0.05), respectively, in SAA and R-SAA patients. In addition, EP300 and CREBBP mRNA levels were clearly correlated with clinical parameters of peripheral blood and bone marrow in those patients. CONCLUSION: Our findings suggest that EP300 and CREBBP are increased in CD8+ T cells of SAA patients and are correlated with disease severity. The imbalances in HATs and HDACs may play a role in activating CD8+ T cells to promote the immune pathogenesis of SAA.

SARS-CoV-2 vaccine-induced immune thrombotic thrombocytopenia.

SARS-CoV-2 vaccines have been carefully developed and significantly alleviate the global pandemic. However, a rare but severe complication after vaccination of adenoviral vector vaccines has attracted worldwide attention. It is characterized by thrombosis at unusual sites (often cerebral or abdominal), thrombocytopenia, and the presence of antibodies against platelet factor 4 (PF4), termed vaccine-induced immune thrombotic thrombocytopenia (VITT). Its pathogenesis is similar to that of heparin-induced thrombocytopenia (HIT). VITT progresses rapidly and has a high mortality rate. Clinicians and the public should raise their vigilance to this disease so that accurate and timely treatment is provided.

Phagocytosis checkpoints on hematopoietic stem cells in patients with myelodysplastic syndromes.

BACKGROUND: The myelodysplastic syndrome (MDS) is a high-risk hemocytopenia easily converted to acute myeloid leukemia. CD47 plays an important role in regulating phagocytosis, and its role in the pathogenesis of MDS is unclear. METHODS: CD47 and PI3K/AKT/mTOR on CD34+ CD38- cells were detected by flow cytometry. NF-κB, PI3K, AKT, PTEN, and mTOR mRNA overexpressed in CD34+ CD38- CD47+ cells were performed by real-time quantitative transcriptase-polymerase chain reaction. Phagocytic capacity of macrophages was measured with carboxyfluorescein succinimidyl ester and fluorescent microspheres. Sorted CD34+ CD38- CD47+ cells were injected into NOD-Prkdcscid Il2rgnull mice. RESULTS: The expression of CD47 on CD34+ CD38- cells of the patients in high-risk MDS based on IPSS-R/WPSS score was higher than that in low-risk MDS and controls. The signaling pathway of PI3K/AKT/mTOR is active in CD34+ CD38- CD47+ cells of MDS patients. CD47 overexpressing CD34+ CD38- cells has antiphagocytosis. CD47 overexpressing leukemia stem cell (LSC) -transplanted mice has a short survival time. The macrophages originated from MDS might elicit a pro-tumor response in MDS by inhibiting phagocytosis. CONCLUSIONS: Phagocytosis checkpoints are impaired in MDS. High expression of CD47 on CD34+CD38- cells indicates poor clinical prognosis in MDS.

Efficacy and safety of GLS-010 (zimberelimab) in patients with relapsed or refractory classical Hodgkin lymphoma: A multicenter, single-arm, phase II study.

BACKGROUND: GLS-010 (zimberelimab) is a novel, fully human, anti-programmed death-1 monoclonal antibody that shows promising efficacy and safety in advanced solid tumors. This trial aimed to evaluate the efficacy and safety of GLS-010 (zimberelimab) in Chinese patients with relapsed or refractory classical Hodgkin lymphoma (r/r-cHL). METHODS: This phase II, single-arm, open-label, multicenter clinical trial was conducted at 24 centers in China and enrolled patients with r/r-cHL after two or more lines of therapy. The patients were administered intravenous GLS-010 (zimberelimab) (240 mg, once every 2 weeks) until progression, death, unacceptable toxicity, or consent withdrawal. The primary end-point was the objective response rate assessed by an independent radiology review committee (IRC). This study was registered (NCT03655483). RESULTS: Eighty-five patients were enrolled between August 2018 and August 2019. The median follow-up was 15.8 months. Seventy-seven patients (90.6%; 95% confidence interval [CI] 82.3-95.9) had an IRC-assessed objective response. The complete response rate was 32.9% (n = 28). The 12-month progression-free survival and overall survival rates were 78% (95% CI 67.5-85.6) and 99% (95% CI 91.9-99.8), respectively. Treatment-related adverse events (TRAEs) were observed in 92.9% of participants. Grade III or IV TRAEs occurred in 24 (28.2%) of the 85 participants. The most common grade III or IV TRAEs were abnormal hepatic function (5.9%), hyperuricemia (4.7%), decreased neutrophil count (3.5%), and increased weight (3.5%). Only one grade V AE, gastrointestinal infection, occurred. CONCLUSIONS: GLS-010 (zimberelimab) appears to be effective and safe for the treatment of Chinese patients with r/r-cHL. Long-term follow-up is required to confirm these clinical benefits.

[Inhibitory Effect of Ascorbic Acid on Myelodysplastic Syndrome Cells and Its Mechanism].

OBJECTIVE: To investigate the inhibitory effect of ascorbic acid single or combination of decitabine on tumor cells of myelodysplastic syndrome (MDS) and explore its related mechanism. METHODS: The human MDS cell lines SKM-1 and MUTZ-1 were treated with different concentrations of ascorbic acid, and the cell proliferation activity was detected by the CCK-8 assay. The reactive oxygen species (ROS) level, labile iron pool (LIP), cell cycle, and apoptosis of SKM-1 and MUTZ-1 cells were detected by flow cytometry. The control group, ascorbic acid monotherapy group, decitabine monotherapy group, and combination group of ascorbic acid and decitabine were set up, the cell proliferation activity and apoptosis were detected in each group. RESULTS: High-dose ascorbic acid could reduce the cell proliferation activity of SKM-1 (R=0.886, p=0.000) and MUTZ-1 (R=0.880, p=0.000). With the increase of ascorbic acid concentration, the ROS level in SKM-1 and MUTZ-1 cells increased (r=0.816, r=0.942), the proportion of cells stagnation in G2 phase increased (r=0.970, p=0.000; r=0.962, p=0.000), the proportion of surviving cells decreased (r=-0.966, p=0.000; r=-0.952, p=0.000), and the apoptosis cells significantly increased (r=0.966, p=0.000; r=0.958, p=0.000). Nevertheless, the level of LIP showed no significant changes. After the combined application of ascorbic acid and decitabine, MDS tumor cells showed decreased proliferative activity and increased apoptosis compared with single-agent ascorbic acid and decitabine group. CONCLUSION: High-dose ascorbic acid shows a cytotoxic effect on MDS tumor cells, inhibiting cell proliferation and increasing apoptosis. Ascorbic acid combined decitabine have a synergistic effect of anti-MDS tumor cells.