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The ongoing outbreak of Coronavirus Disease 2019 (COVID-19) is hitting the world hard, but the relationship between coagulation disorders and COVID-19 is still not clear. This study aimed to explore whether early coagulation tests can predict risk stratification and prognosis. PubMed, Web of Science, Cochrane Library, and Scopus were searched electronically for relevant research studies published up to March 24, 2020, producing 24 articles for the final inclusion. The pooled standard mean difference (SMD) of coagulation parameters at admission were calculated to determine severe and composite endpoint conditions (ICU or death) in COVID-19 patients. Meta-analyses revealed that platelet count was not statistically related to disease severity and composite endpoint; elevated D-dimer correlated positively with disease severity (SMD 0.787 (0.277-1.298), P= 0.003, I2= 96.7%) but had no significant statistical relationship with composite endpoints. Similarly, patients with prolonged prothrombin time (PT) had an increased risk of ICU and increased risk of death (SMD 1.338 (0.551-2.125), P = 0.001, I2 = 92.7%). Besides, increased fibrin degradation products (FDP) and decreased antithrombin might also mean the disease is worsening. Therefore, early coagulation tests followed by dynamic monitoring is useful for recognizing coagulation disorders accompanied by COVID-19 and guiding timely therapy to improve prognosis.

Background BCMA-specific chimeric antigen receptor-T cells (CAR-Ts) have exhibited remarkable efficacy in refractory or relapsed multiple myeloma (RRMM); however, primary resistance and relapse exist with single-target immunotherapy. Bispecific CARs are proposed to mitigate these limitations. Methods We constructed a humanized bispecific BM38 CAR targeting BCMA and CD38 and tested the antimyeloma activity of BM38 CAR-Ts in vitro and in vivo. Twenty-three patients with RRMM received infusions of BM38 CAR-Ts in a phase I trial. Results BM38 CAR-Ts showed stronger in vitro cytotoxicity to heterogeneous MM cells than did T cells expressing an individual BCMA or CD38 CAR. BM38 CAR-Ts also exhibited potent antimyeloma activity in xenograft mouse models. In the phase I trial, cytokine release syndrome occurred in 20 patients (87%) and was mostly grade 1–2 (65%). Neurotoxicity was not observed. Hematologic toxicities were common, including neutropenia in 96% of the patients, leukopenia in 87%, anemia in 43% and thrombocytopenia in 61%. At a median follow-up of 9.0 months (range 0.5 to 18.5), 20 patients (87%) attained a clinical response and minimal residual disease-negativity (≤ 10–4 nucleated cells), with 12 (52%) achieving a stringent complete response. Extramedullary plasmacytoma was eliminated completely in 56% and partially in 33% and of 9 patients. The median progression-free survival was 17.2 months. Two relapsed patients maintained BCMA and CD38 expression on MM cells. Notably, BM38 CAR-Ts cells were detectable in 77.8% of evaluable patients at 9 months and 62.2% at 12 months. Conclusion Bispecific BM38 CAR-Ts were feasible, safe and significantly effective in patient with RRMM. Trial registration: Chictr.org.cn ChiCTR1800018143.

In this study, we used plasma factor V activity and parameters of the thrombin generation test to discuss their diagnostic and prognostic value for disseminated intravascular coagulation (DIC) in patients with hematological malignancies. A total of 164 patients who were diagnosed with hematological malignancies in the Department of Hematology, Union Hospital, between Apr. 2014 and Dec. 2014 were enrolled in this study. There were 131 patients in the study group and 33 patients in the control group in terms of the laboratory results for DIC. The patients in the study group were divided into a DIC subgroup (n=59) and a non-DIC subgroup (n=72) based on the International Society of Thrombosis and Hemostasis (ISTH) Integral System, and they were divided into four subgroups [score ≤3 (n=35), score=4 (n=37), score=5 (n=47), and score ≥6 (n=12)] according to ISTH scores. Using 28-day mortality as the endpoint, the patients in the study group were divided into a survival subgroup (n=111) and a non-survival subgroup (n=20). The results showed that the plasma factor V activity was significantly weaker, and lag time and time to peak were significantly shorter in the study group than in the control group (P

Background: T cell receptor(TCR)-engineered T cell therapy, by replacing the antigen recognition domain of TCR with an antibody-derived Fab fragment, is another active field of cellular immunotherapy for cancer. We previously developed a human anti-CD19 antibody (ET190L1), and found that ET190L1-TCR-T cells maintained comparable anti-tumor potency with less cytokine release to CD28-costimulated ET190L1-CAR and CD137-based CTL019 T cells (Cell Discov. 2018 Nov 20;4:62.). ET019003-T cells are novel anti-CD19 γδ TCR-T cells generated based on ET190L1-TCR-T cells by adding an independent chimeric signaling receptor(CSR) to further promote T cell activation and reduce cytokine release (Figure 1A). We report outcomes for adult patients with relapsed or refractory diffuse large B-cell lymphoma (RR DLBCL) treated with ET019003-T cells. Methods: Our first-in-human, single-center, phase 1 study (NCT04014894) was designed to evaluate the safety and efficacy of ET019003-T cells in patients with CD19 + malignancies, of whom 8 with RR DLBCL are reported here. Eligible patients must have (1) histologically confirmed DLBCL; (2) CD19 + on malignant cells by IHC; (3) refractory disease as defined in the SCHOLAR-1 study, or recurrent disease within 6 months or at least 2 times after CR; (4) prior therapy including an anti-CD20 monoclonal antibody and an anthracycline. Patients with CNS lymphoma were eligible. Bridging therapy wasn't allowed after apheresis. Cyclophosphamide 250 mg/m 2 on day -5 and fludarabine 25 mg/m 2 on day -5 to -3 were used as the conditioning regimen. Planned dose levels were 2, 4x10 6 TCR+T cells/kg, and repeated infusions were allowed. Primary objectives were incidence of adverse events (AEs) and overall response rate(ORR). CRS and neurotoxicity were graded using the ASTCT criteria, and other AEs using CTCAE v5.0. Response was assessed per Lugano Criteria (Cheson 2014). Results: 8 pts (median age 50, range 33-71) received infusion of ET019003-T cells (6 at 2x10 6/kg, and 2 at 4x10 6/kg) and were included in the study analysis. Patient enrollment was ceased in June, 2020. Pt1 had primary CNS lymphoma, and 62.5% had stage 4 disease against Ann Arbor staging. MYC/BCL2/BCL6 triple expression was detected in 50% of pts, and double expression in 25%. Pts had received a median of 4.5 (range 2-8) prior lines of treatment, and 37.5% received prior PD-1 inhibitors, and 62.5% had primary refractory disease. 3 pts (37.5%) experienced grade 1 CRS that resolved spontaneously; 1(pt2) developed grade 3 neurotoxicity (dose-limiting toxicity), manifested by confusion, barylalia, tremor and agitation, which occurred after CRS and responded to corticosteroids. The most common AE was neutropenia (100%), and 62.5% were related to conditioning regimen; other hematologic AEs included thrombocytopenia (37.5%) and anemia (12.5%). Pt8 had pulmonary infection on day 15, and pt1 experienced viral encephalitis at 18 months, and both were manageable. As of July 20, 2021, median follow-up after infusion was 15 months (range 2-24.7). 6 pts(75%) achieved a clinical response, and 5(62.5%) reached CR, of whom 80% kept ongoing CR (all at 18+ months). 3 pts received a second infusion, pt5 for consolidation therapy after CR, and pt2 and pt7 for salvage therapy after disease progression, but response wasn't observed (Figure 1B). Pt1 with primary CNS lymphoma got continuing CR, without CRS or neurotoxicity (Figure 1C). The rate of overall survival, progression-free survival, and duration of response at 12 months was 87.5%, 62.5% and 66.7%, respectively. ET019003 cells showed striking peak expansion during 10-20 days post infusion as measured as ET019003+ cells per milliliter of PB by flow cytometry and copies per microgram of genomic DNA by qPCR, but poor expansion was observed in the second infusions (Figure 1D). ET019003 cells were detectable in cerebrospinal fluid of pt1, and continued to be detectable at 12+ months in PB of pt3 and pt5. Serum cytokine levels increased mildly post-infusion, except elevated IL-6 (>10 folds of upper limit of normal) in 3 pts (pt1 with a high baseline level, coinciding with onset of CRS and neurotoxicity of pt2, and concurrent with pulmonary infection of pt8). Conclusion: These data suggest ET019003-T cells had a good safety profile and could induce durable remission in patients with RR DLBCL, even with primary CNS lymphoma. γ/δ TCR-T cells may present a potential therapeutic option for these patients. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Background The development of mRNA sequencing has contributed greatly to the mechanism exploration in hematologic malignancies disease. With the advent of revolutionized single-cell mRNA sequencing (scRNA-seq), it is now possible to characterize every subset of expression programs and functional states in a comprehensive and unbiased manner. Here, we present a systematic evaluation of engineered chimeric antigen receptor T (CAR-T) products and patient bone marrow profiles in terms of primary resistance and severe cytokine release syndrome (CRS) at the single-cell level. Methods Using single-cell mRNA sequencing in conjunction with flow cytometry (FCM), we performed characterization of CD19-targeted CAR-T and mononuclear bone marrow cells from 4 on-trial B acute lymphoblastic leukemia (B-ALL) patients (NCT02965092). Bioinformatics analysis was utilized to explore diversity between patients with different grades of response or CRS. Basing on marker genes, CAR-T products were divided into four groups, which were double-positive T (DPT), CD4 positive T (CD4), CD8 positive T (CD8), and double-negative T (DNT) cells. Meanwhile, both the mononuclear bone marrow cells before and after CAR-T infusion were grouped into six clusters, which were B-ALL, stem, progenitor, B, T, and myeloid cells. The expression and enrichment analyses results were calculated by R (version 3.6.3) and then verified in a 22-sample conventional transcription sequencing cohort of the same clinical trial. Patient efficacy was assessed by the national comprehension cancer network guidelines version 2.2020 for acute lymphoblastic leukemia, and CRS was graded by CTCAE 5.0. Results By FCM detection, the variances of CAR-T infusion products between patients with different clinical outcomes were limited, and nor did mononuclear bone marrow cells. The scRNA sequencing results showed that distinct CAR-T and bone marrow cell subsets indicated differentiated expression in proliferation, cytotoxicity, and intercellular signaling pathways. Expression differentiation variances in CAR-T infusion products were minor than in mononuclear bone marrow cells. CD8+ CAR-T products of complete response (CR) patients were still significantly enriched in pathways such as cell killing (p adjust=0.0012), antigen processing and presentation (p adjust=0.0027), and cell cycle (p adjust=0.0231), exhibiting greater immune function when compared with no response patients. Also, DPT CAR-T products of the non-CRS patients were meaningfully enriched in negative regulation of cytokine production pathway (p adjust=0.0127) when compared with CRS ones. In mononuclear bone marrow cells, B-ALL cells before CAR-T treatment of CR patients presented negatively in cell-cycle (p adjust=0.0019), leading to a low malignant cell proliferation level; and stem-progenitor cells after CAR-T treatment of CR patients showed a stronger ability of neutrophil activation (p adjust Conclusions Through single-cell RNA-seq profiling and unbiased canonical pathway analyses, our results unveil heterogeneities in the cell cycle, immune phenotype, and metabolic profiles of subsets during CAR-T therapy, providing a mechanistic basis for ameliorating clinical outcomes and individualized management. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Background CAR T-cell therapy has shown remarkable efficacy for the treatment of hematologic malignancy. However, this novel adoptive cell therapy is associated with toxicities such as cytokine release syndrome (CRS), CAR-T related encephalopathy syndrome (CRES/ICANS) and infection. While as one of the most common toxicities after CAR T-cell therapy in the first month, infectious complications have not been systematically studied. we aim to explore the incidence, clinical and microbiological characteristics and identify high risk factors for infection in patients with ALL, NHL, and MM. The trial was registered on the Chinese Clinical Trial Registry (ChiCTR-OIC-17011180; ChiCTR1800018143). Methods 72 patients with ALL, 56 patients with NHL and 42 patients with MM from January 2016 to December 2020 are involved in the cohort and the baseline data and the clinical characteristics of infection are retrospectively analyzed within 28 days. Infections were defined as a microbiologic, histopathologic, corroborating laboratory, radiographic or clinical diagnosis, and classified as bacterial (bacteremia or site infection), viral (respiratory or other), or fungal (proven or probable). Infection severity was classified as mild, moderate, severe, life-threatening, or fatal. (Young et al.Biol Blood Marrow Transplant 2016; 22:359-70.)CRS was graded by ASTCT. We used univariate and stepwise multivariable Poisson regression to identify associations between baseline clinical characteristics and infection density, and Cox proportional hazards regression to assess high-risk factors for infection. Results Among 170 patients, a total of 119 infections occurred in 99 patients within 28 days, with a cumulative infection rate of 58.2%. The incidence of infection in ALL patients is higher than that of MM and NHL patients. Among 72 ALL patients, 46 (63.9%) patients developed infections, and among 42 MM patients, 24 patients (53.1%) developed infections. The difference in infections between these two groups of patients was statistically significant (Chi-Square test, P=0.038 78 patients had 98 bacterial infections and the cumulative incidence of bacterial infection was 45.9%. The cumulative incidence of viral infection was 8.24%, and fungal infection was 4.12%. Bacterial infections are the main types of infections in patients with different tumors, followed by viral infections, and finally fungal infections. There was no statistic significant difference in the severity of infection among different tumors, whether it was the number of patients or events (Kruskal-Wallis test, P=0.646 ,P=0.605） 75 infection events occurred in patients who were agranulocytosis, and 90% of patients with bloodstream infections had neutropenia at the time of infection. When agranulocytosis lasted for 28 days, the cumulative infection rate was 38.8%. 91 patients had both CRS and infection. The cumulative incidence of CRS and infection was 68.8% and 58.2%, respectively. Among patients with grade 3-4 CRS, 18 of 30 infections (60%) occurred after the peak of CRS. The adjusted baseline characteristic model showed that ALL patients, previous 30 days of infection history, refractory disease, ANC Conclusions Infection is one of the common complications of CAR-T cell therapy in patients with hematological malignancy. Bacterial infections occur in most patients regardless of the type of disease. ALL patients, previous 30 days of infection history，refractory disease, ANC Keywords：chimeric antigen receptor t cell；hematological malignancy； bacterial infection Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

High mobility group box 1(HMGB1) is a DNA-binding protein which can act as a proinflammatory cytokine when released by necrotic cells, monocytes or macrophages. It also plays a role in the coagulation activation and several tumors including leukemia. The objective of this study was to investigate the role of HMGB1 in the diagnosis of DIC with leukemia.89 subjects with leukemia in Wuhan Union Hospital were prospectively recruited. Among them, 83 cases were suspected of DIC, while the other 6 were the negative controls. Their clinical data, laboratory tests and plasma samples were collected or measured respectively. Accordingly, we made scores for these subjects by the Japanese Ministry of Health and Welfare (JMHW) criteria.This study demonstrated that the plasma levels of HMGB1 were higher in the DIC group than non-DIC (115.16 ng/ml vs. 63.94 ng/ml, p=0.003). The similar results were achieved in infected or non-infected groups. And along with the increase of DIC scores, the levels of HMGB1 increased gradually (p=0.006). In addition, HMGB1 was an independent factor in the diagnosis of DIC with leukemia(p0.05). The diagnostic sensitivity of HMGB1 was high (Se=90.32%), and there was a tendency of increased HMGB1 levels in the pre-DIC patients. Three of these six pre-DIC patients were diagnosed as DIC by the new revised scoring system which contained HMGB1. Finally, the HMGB1 levels were significantly higher in patients with organ failures (SOFA≥2) than those without (118.76 vs. 72.75, p=0.032).The increased plasma levels of HMGB1 were related tightly to the diagnosis and severity of DIC in leukemia patients. Furthermore, the diagnostic sensitivity of HMGB1 was high. So HMGB1 in plasma is a helpful molecular marker, and can be added in the scoring system for the early diagnosis of DIC with leukemia.

ObjectivesTo retrospectively validate the new Chinese DIC scoring system (CDSS).MethodsThis study retrospectively collected the information of 619 patients (371 cases with non-hematologic malignancies, 248 cases with hematologic malignancies) who suspected of DIC in Wuhan Union Hospital during 2013-4 to 2014-6. We validated CDSS by comparing it with three leading scoring systems, from International Society on Thrombosis and Haemostasis (ISTH), Japanese Association for Acute Medicine (JAAM) and Japanese Ministry of Health and Welfare (JMHW), and evaluated its prognostic value by 28 days mortality, APACHE II and SOFA score.ResultsIn non-hematologic malignancies, CDSS was more specific than JAAM (72.55% vs. 50.49%, pConclusionsWe are the first group to propose CDSS. It emphasized the values of the clinical manifestations, the rapidly declining platelet count, APTT in the diagnosis of DIC and used D-dimer as the fibrin-related maker. DIC with hematological malignancies was treated as a special part. In this study we can see that CDSS displayed an acceptable property for the diagnosis of DIC with appropriate sensitivity and specificity, and also had a good prognostic value for DIC patients.