Lijuan Li

Summary: Paroxysmal nocturnal haemoglobinuria (PNH) is a rare clonal disorder caused by PIG‐A mutations and characterized by complement‐mediated haemolysis. C5 inhibitors are recommended as first‐line therapy for PNH with high disease activity. We retrospectively analysed 57 patients treated with eculizumab or crovalimab. Luminex® liquid‐phase chip technology was used to detect changes in complement and cytokine levels in patients pre‐ and post‐treatment. Haemolysis control (LDH ≤ 1.5 × ULN) was achieved in 78.9% of patients, and 68.3% became transfusion‐independent. Mean haemoglobin rose from 76 to 99 g/L at week 24. Infections were the most common adverse events, but none were severe, and no discontinuations occurred. Post‐treatment, C5 and C5a levels increased significantly. Baseline levels of C5, C5a, C3, C1q, granulocyte colony‐stimulating factor (G‐CSF) and tumour necrosis factor‐α (TNF‐α) were higher in non‐responders than in responders or controls. Our findings confirm the efficacy and safety of C5 inhibitors in Chinese PNH patients and indicate that complement and cytokine profiles may serve as predictive biomarkers.

Background Myelodysplastic syndrome (MDS) is a type of heterogeneous myeloid clonal disorder usually diagnosed based on a combination of multiple laboratory examinations, including analysis of peripheral blood cells, bone marrow cell morphology and cytogenetics. However, there is a certain difficulty in cases with no distinct changes in hematology and marrow cell morphology. Methods We adopt flow cytometry to quantitatively analyze the immunophenotypic changes of marrow monocytes according to the surface antigens and their combinations at different differentiation stages, so as to study the changes of monocytes during differentiation in patients with bone marrow failure. In the meantime, the relationship between the immunophenotypic changes of marrow monocytes and IPSS-R score and prognosis of MDS patients was analyzed. Results Our results demonstrated disorders of maturation and differentiation of monocytes in patients with MDS and clonal cytopenias of undetermined significance as compared to those with aplastic anemia and healthy individuals. In addition, the differentiation abnormality gradually increased with the disease progression. Furthermore, CD300e expression was found to show significant associations with the clinical stage and disease progression of MDS, and the progression-free survival and AML-free survival were much longer in MDS patients highly expressing CD300e on monocytes. Conclusions CCUS and MDS patients have disorders of differentiation and maturation of monocytes, which tends to be more critical with MDS progression or transforms to AML. Moreover, high CD300e expression has the potential to be a favorable prognostic marker for MDS. This study provides important insights to the role of monocyte immunotyping in the diagnosis, differentiation and prognosis of MDS.

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of bone marrow cells originating from immature myeloid cells. They exert potent immunosuppressive activity and are closely associated with the development of various diseases such as malignancies, infections, and inflammation. In malignant tumors, MDSCs, one of the most dominant cellular components comprising the tumor microenvironment, play a crucial role in tumor growth, drug resistance, recurrence, and immune escape. Although the role of MDSCs in solid tumors is currently being extensively studied, little is known about their role in hematologic malignancies. In this review, we comprehensively summarized and reviewed the different roles of MDSCs in hematologic malignancies and hematopoietic stem cell transplantation, and finally discussed current targeted therapeutic strategies.Affiliation: Kindly check and confirm the processed affiliations are correct. Amend if any.correct

Myeloid‐derived suppressor cells (MDSC) induced cellular immune deficiency and bone marrow inflammatory microenvironment play an important role in the pathogenesis and progression of myelodysplastic syndrome (MDS), but the underlying mechanism remains unclear. Here, we revealed that immune checkpoint protein TIM3 and CEACAM1 were highly demonstrated on MDSC and CD8⁺ T cells in MDS patients. CD8⁺ T cells were reduced in number and function and presented a exhaustion state. The levels of pro‐inflammatory cytokines (IL‐1β, IL‐18) and CEACAM1 were raised in bone marrow supernatants and MDSC culture supernatants. Blocking or neutralizing TIM3/CEACAM1 and IL‐1β/IL‐18 partially reversed exhaustion of CD8⁺ T cells. Moreover, TIM3 correlated with NF‐κB /NLRP3 inflammatory pathway. The levels of NF‐κB/NLRP3/Caspase‐1/IL‐1β and IL‐18 were all increased in MDSC of MDS. Co‐culturing MDSC from MDS patients with rhCEACAM1 enhanced NF‐κB/NLRP3/Caspase‐1/IL‐1β and IL‐18 levels, whereas blocking TIM3 could partially reverse the above manifestations. These results indicated that TIM3/CEACAM1 pathway involved in CD8⁺ T cells exhaustion and might activate the NF‐κB/NLRP3/Caspase‐1 pathway in MDSC, increasing pro‐inflammatory cytokines secretion in MDS bone marrow microenvironment. This study provided a basis for applying immune checkpoint inhibitors that could simultaneously modulate pro‐inflammatory cytokine secretion and enhance anti‐tumour immune function in the treatment of MDS.

Background: We performed a retrospective analysis to investigate the clinical characteristics and therapeutic strategies of 20 refractory/recurrent PNH patients, including the clinical efficacy of chemotherapy treatment, safety, and survival.Methods: The clinical data of 20 classic PNH patients who were refractory/recurrent or had glucocorticoid dependence in our hospital were analyzed, including clinical manifestations, laboratory examinations, treatment efficacy, and survival.Results: Seventeen patients had a marked improvement in anemia after chemotherapy, 14 patients acquired blood transfusion independence, and the Hb of 3 patients increased to normal levels. Although 6 patients still needed blood transfusion, the transfusion interval was significantly prolonged. The percentages of LDH, TBIL, and RET, which are indicators of hemolysis, were significantly lower than those before chemotherapy. The dosage of adrenal glucocorticoids was reduced by more than half compared with that before chemotherapy.Conclusions: Chemotherapy can reduce PNH clones, promote normal hematopoiesis, and control hemolytic attack. It is a promising and widely used therapeutic method.

Background: The role of CD59 and fluorescently labeled aerolysin (FLAER) in acute myeloid leukemia (AML) remains unclear and requires further investigation. To explore the relationship between CD59, FLAER, and AML, we investigated CD59 and FLAER expression in AML and analyzed their relationship with clinical characteristics of AML patients.Methods: We employed flow cytometry (FCM) to analyze CD59 and FLAER expression in 161 AML patients at Tianjin Medical University General Hospital and evaluated its association with sex, white blood cell (WBC) count, platelet (PLT) count, thrombin time (TT), prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen (FIB), D‐Dimer(D‐D), and lactate dehydrogenase (LDH), followed by analyzing its connection with disease progression and complete remission (CR).Results: CD59 and FLAER deficiencies were identified in AML patients. Compared with CR group, non‐CR group patients revealed more CD59 and FLAER deficiency. Compared with non‐acute promyelocytic leukemia (M3) group, M3 group patients had more CD59 and FLAER deficiency. CD59⁻level in primordial cells of M3 patients was positively correlated with primordial cell ratio (r = 0.660,p = 0.003). Additionally, we discovered that the decline in CD59 and FLAER levels might be linked to higher D‐D and LDH in AML patients. The difference was statistically significant (p < 0.05).Conclusions: We demonstrated that the decline in CD59 and FLAER levels was associated with leukemia cell proliferation and abnormal coagulation function in AML, suggesting that they could serve as a predictor of AML coagulation dysfunction, particularly in M3.

Background and Aim: Many studies indicated that eltrombopag and romiplostim could improve hematopoietic function in patients with myelodysplastic syndromes (MDS), but their toxicity and efficacy were not known. This meta-analysis aimed to investigate the safety and efficacy of eltrombopag and romiplostim in MDS. Methods: A full-scale search strategy was used to search relevant published studies in PubMed, Embase, Web of Science, ClinicalTrials.gov and the Cochrane Library until January 2020 using a random-effects model and the pooled risk ratio (RR) with 95% confidence interval as the effect indicator. Statistical analyses were performed using RevMan 5.3. Results: This meta-analysis included eight studies comprising 1047 patients. A lower RR of overall response rate (ORR) (RR: 0.65; 95% CI, 0.47–0.9) and grade ≥3 bleeding events (RR: 0.36; 95% CI, 0.36–0.92) were observed after romiplostim and eltrombopag treatment compared with placebo. The pooled RR for the ORR and grade ≥3 bleeding events were 0.58 (95% CI: 0.41–0.83, P = 0.003) and 0.6 (95% CI: 0.37–0.96, P = 0.03) in eltrombopag, respectively. A lower ORR in intermediate- or high-risk MDS (RR: 0.63; 95% CI: 0.45–0.88, P = 0.006) was observed. No difference in mortality, serious adverse events, platelet transfusion, hematologic improvement, and AML transformation was observed. Conclusions: Thrombopoietin receptor agonists (TPO-RAs) romiplostim and eltrombopag were effective in reducing bleeding events, especially grade ≥3 bleeding events. However, it might reduce the ORR of MDS, especially in eltrombopag treatment group or high-risk MDS group. Due to the limited treatment of MDS and the poor response to the drug, this may be a selection method for MDS combined with fatal bleeding, although further research is needed to confirm the effectiveness of this approach.

Objective: Targeting immune checkpoints, such as PD-1, represents a promising approach for cancer immunotherapy, achieving long-term disease remission rates in numerous types of cancer. T cell immunoglobulin and ITIM domain (TIGIT) is a checkpoint receptor associated with the antitumor roles of NK and T cells. Notably, the blockade of TIGIT has been revealed as a potential promising approach in cancer immunotherapy. However, the therapeutic potential of blocking TIGIT in myelodysplastic syndrome (MDS) remains unclear and further research is required to reveal their role. Methods: Fresh peripheral blood (PB) and bone marrow (BM) were obtained from patients with MDS and healthy donors (HDs) at the Tianjin Medical University General Hospital between January 21 2018 and March 22 2019. The present study investigated the expression levels of TIGIT on NK and T cells using flow cytometry (FCM) and PCR. In addition, other checkpoint receptors, such as CD226 and PD-1, were also investigated. To determine the mechanisms of antitumor immunity, the functions of NK and T cells expressing TIGIT were determined. Results: TIGIT was found to be highly expressed on NK and T cells of the PB, where it was involved in disease progression and the immune escape of MDS. The high expression levels of TIGIT were associated with decreased NK and T cell function, and significantly lower secretions of activation factors, such as CD107a, IFN-γ and TNF-α. Notably, blocking TIGIT enhanced the antitumor effects of NK and T cells. Conclusion: The results of the present study suggested that targeting TIGIT alone or in combination with PD-1 may be a promising anticancer therapeutic strategy in MDS.