A five-year follow-up clinical study of the B cell maturation antigen chimeric antigen receptor-T cell therapy HDS269B in patients with relapsed or refractory multiple myeloma.

PURPOSE: This study aimed to report the five-year clinical outcomes of anti-B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR)-T cell (HDS269B) therapy in relapsed/refractory multiple myeloma (RRMM) patients, including those with poor performance status (Eastern Cooperative Oncology Group [ECOG] 3-4), and to identify factors influencing long-term outcomes. METHODS: Forty-nine RRMM patients enrolled from 2016 to 2020 received HDS269B (9×106 cells/kg) after receiving a conditioning chemotherapy consisting of cyclophosphamide and fludarabine. The overall response, long-term outcomes, and safety were assessed, as were their associations with clinical and disease characteristics. RESULTS: With a median follow-up of 59.0 months, the overall response rate was 77.55%. The median progression-free survival (PFS) and overall survival (OS) were 9.5 months (95% confidence interval [CI], 5.01-13.99) and 20.0 months (95% CI, 11.26-28.74), respectively. The 5-year PFS and OS rates were 21.3% (95% CI, 12.3%-36.7%) and 34.1% (95% CI, 22.7%-51.3%), respectively. Patients with ECOG 0-2 had marked longer survival, with a median PFS of 11.0 months and median OS of 41.8 months. Early minimal residual disease negativity, and higher and persistent CAR-T cell expansion and absence of extramedullary disease were associated with better survival outcomes. No new CAR-T cell therapy associated toxicities were observed. Importantly, ECOG 0-2, prior therapy lines <4, and CAR-T cell persistence at ≥6 months were independently associated with longer OS. CONCLUSIONS: HDS269B is effective and safe, especially for patients with ECOG 0-2. Early CAR-T cell intervention may improve prognosis in patients with RRMM.

Matrine induces autophagic cell death by triggering ROS/AMPK/mTOR axis and apoptosis in multiple myeloma.

Despite significant advancements in multiple myeloma (MM) treatment in recent years, most patients will eventually develop resistance or experience relapse. Matrine, a primary active compound of traditional Chinese medicinal herb Sophora flavescens Ait, has been found to have anti-tumor properties in various types of malignant tumors. Whether autophagy plays a crucial role in the anti-MM effect of matrine remain unknown. Herein, we found that matrine could trigger apoptosis and cell cycle arrest, and meanwhile induce autophagy in MM cells in vitro. We further ascertained the role of autophagy by using ATG5 siRNA or the autophagy inhibitor spautin-1, which partially reversed matrine's inhibitory effect on MM cells. Conversely, the combination of matrine with the autophagy inducer rapamycin enhanced their anti-tumor activity. These findings suggest that autophagy induced by matrine can lead to cell death in MM cells. Further mechanism investigation revealed that matrine treatment increased the levels of reactive oxygen species (ROS) and AMPKα1 phosphorylation and decreased the phosphorylation of mTOR in MM cells. Additionally, co-treatment with AMPKα1 siRNA or the ROS scavenger N-acetyl-1-cysteine weakened the increase in autophagy that was induced by matrine. Finally, we demonstrated a synergistic inhibitory effect of matrine and rapamycin against MM in a xenograft mouse model. Collectively, our findings provided novel insights into the anti-MM efficacy of matrine and suggest that matrine induces autophagy by triggering ROS/AMPK/mTOR axis in MM cells, and combinatorial treatment of matrine and rapamycin may be a promising therapeutic strategy against MM.

Identification and validation of a platelet-related signature for predicting survival and drug sensitivity in multiple myeloma.

Background: Significant progress has been achieved in the management of multiple myeloma (MM) by implementing high-dose therapy and stem cell transplantation. Moreover, the prognosis of patients has been enhanced due to the introduction of novel immunomodulatory drugs and the emergence of new targeted therapies. However, predicting the survival rates of patients with multiple myeloma is still tricky. According to recent researches, platelets have a significant impact in affecting the biological activity of tumors and are essential parts of the tumor microenvironment. Nonetheless, it is still unclear how platelet-related genes (PRGs) connect to the prognosis of multiple myeloma. Methods: We analyzed the expression of platelet-related genes and their prognostic value in multiple myeloma patients in this study. We also created a nomogram combining clinical metrics. Furthermore, we investigated disparities in the biological characteristics, immunological microenvironment, and reaction to immunotherapy, along with analyzing the drug susceptibility within diverse risk groups. Results: By using the platelet-related risk model, we were able to predict patients' prognosis more accurately. Subjects in the high-risk cohort exhibited inferior survival outcomes, both in the training and validation datasets, as compared to those in the low-risk cohort (p < 0.05). Moreover, there were differences in the immunological microenvironments, biological processes, clinical features, and chemotherapeutic drug sensitivity between the groups at high and low risk. Using multivariable Cox regression analyses, platelet-related risk score was shown to be an independent prognostic influence in MM (p < 0.001, hazard ratio (HR) = 2.001%, 95% confidence interval (CI): 1.467-2.730). Furthermore, the capacity to predict survival was further improved when a combined nomogram was utilized. In training cohort, this outperformed the predictive value of International staging system (ISS) alone from a 5-years area under curve (AUC) = 0.668 (95% CI: 0.611-0.725) to an AUC = 0.721 (95% CI: 0.665-0.778). Conclusion: Our study revealed the potential benefits of PRGs in terms of survival prognosis of MM patients. Furthermore, we verified its potential as a drug target for MM patients. These findings open up novel possibilities for prognostic evaluation and treatment choices for MM.

Prognostic significance of ß2-microglobulin decline index in multiple myeloma.

Purpose: To assess the prognostic significance of ß2-microglobulin decline index (ß2M DI) in multiple myeloma (MM). Methods: 150 MM patients diagnosed with MM were enrolled in this study. Cox proportional hazards model was used to analyze the uni- and multivariate prognosis in training cohort (n=105). A new combined prognostic model containing ß2M DI was built up based on the data in training cohort. The validation group was used to verify the model. Results: ß2M DI showed significant correlation with prognosis in both uni- and multivariate analyses and had a good correlation with complete response (CR) rate and deep remission rate. The ROC and calibration curves in validation cohort (n=45) indicated a good predictive performance of the new model. Based on the median risk score of the training group, we classified patients into high- and low- risk groups. In both training and validation groups, patients in the low-risk group had longer overall survival (OS) time than that in the high-risk group (p<0.05). Conclusion: ß2M DI is a good predictive index for predicting treatment response and survival time in MM patients. The prognostic model added with ß2M DI showed a better correlation with OS.

Clinical characteristics and outcomes of COVID-19 infection in Chinese patients with hematologic malignancies in the Omicron era.

Patients with hematologic malignancies are often immunodeficient and therefore have a higher risk of severe symptoms from coronavirus disease 2019 (COVID-19). We retrospectively examined a cohort of 289 patients from 16 hospitals in Zhejiang Province who had hematologic malignancies and COVID-19 during a period when the Omicron variant was predominant. Univariate analysis showed that some clinical characteristics, including elder age (P = 0.014), multiple comorbid conditions (P = 0.011), and receipt of active antineoplastic therapy (P = 0.018) were associated with an increased risk of severe COVID-19. Patients with severe/critical COVID-19 had significantly lower levels of lymphocytes and serum albumin, and significantly higher levels of D-dimer, lactate dehydrogenase, C-reactive protein, and interleukin-6 (all P < 0.05). Fifty-four patients (18.7%) had symptoms lasting ≥3 weeks, suggesting that persistent long-term COVID-19 infection is likely present in a significant proportion of patients. Receipt of the inactivated vaccine was unrelated to disease severity (P = 0.143), which indicated that many patients with hematologic malignancies may not have effective humoral immunity to inactivated vaccines.

Significance of alkaline Phosphatase After Chimeric Antigen Receptor T Cell Therapy in Multiple Myeloma.

BACKGROUND: The inexpensive and readily available biomarkers for cytokine release syndrome (CRS) grading and prognosis assessment in chimeric antigen receptor (CAR)-T therapy are currently lacking. This study examined the significance of alkaline phosphatase (ALP) after CAR-T therapy in patients with relapsed/refractory multiple myeloma (MM). METHODS: This cohort study included 27 patients with relapsed/refractory MM who were treated with CAR-T cells between December 2017 and October 2021. Patients were classified into 2 groups: normal ALP group (peak ALP <125 U/L, n = 10) and high ALP group (peak ALP ≥125 U/L, n = 17). RESULTS: Within 1 month of CAR-T cell infusion, the incidence of ALP increases was 63%. We found that ALP levels began to rise in the second week, peaked in the third and fourth weeks, and began to decline in the second month. Moreover, the ALP levels in previous chemotherapy-responsive period were significantly lower than those after CAR-T therapy. Statistical analysis found that patients with increased ALP exhibited higher alanine aminotransferase and aspartate aminotransferase levels, higher and longer CAR-T cell proliferation, more serious CRS, higher cytokine and ferritin levels, and higher initial response rates. In addition, the duration of ALP increase was parallel to the duration of CAR-T expansion. Multivariable Cox-regression analysis showed that peak ALP was the independent predictor for progression-free survival (PFS) (HR = 0.029, 95% CI: 0.002-0.369). CONCLUSIONS: Our results suggest that the ALP levels after CAR-T therapy could serve as a suitable biomarker for monitoring CAR-T cell proliferation, CRS grading, and prognosis in patients with MM.

Comprehensive analysis of ferroptosis-related genes in immune infiltration and prognosis in multiple myeloma.

Background: One particular type of cellular death that is known as ferroptosis is caused by the excessive lipid peroxidation. It is a regulated form of cell death that can affect the response of the tumor cells. Currently, it is not known if the presence of this condition can affect the prognosis of patients with multiple myeloma (MM). Methods: In this study, we studied the expression differences and prognostic value of ferroptosis-related genes (FRGs) in MM, and established a ferroptosis risk scoring model. In order to improve the prediction accuracy and clinical applicability, a nomogram was also established. Through gene enrichment analysis, pathways closely related to high-risk groups were identified. We then explored the differences in risk stratification in drug sensitivity and immune patterns, and evaluated their value in prognostic prediction and treatment response. Lastly, we gathered MM cell lines and samples from patients to confirm the expression of marker FRGs using quantitative real-time PCR (qRT-PCR). Results: The ability to predict the survival of MM patients is a challenging issue. Through the use of a risk model derived from ferroptosis, we were able to develop a more accurate prediction of the disease's prognosis. They were then validated by a statistical analysis, which showed that the model is an independent factor in the prognosis of MM. Patients of high ferroptosis risk scores had a much worse chance of survival than those in the low-risk groups. The calibration and power of the nomogram were also strong. We noted that the link between the ferroptosis risk score and the clinical treatment was suggested by the FRG's significant correlation with the immune checkpoint genes and the medication sensitivity. We validated the predictive model using qRT-PCR. Conclusion: We demonstrated the association between FRGs and MM, and developed a new risk model for prognosis in MM patients. Our study sheds light on the potential clinical relevance of ferroptosis in MM and highlights its potential as a therapeutic target for patients with this disease.

A novel glycolysis-related gene signature for predicting the prognosis of multiple myeloma.

Background: Metabolic reprogramming is an important hallmark of cancer. Glycolysis provides the conditions on which multiple myeloma (MM) thrives. Due to MM's great heterogeneity and incurability, risk assessment and treatment choices are still difficult. Method: We constructed a glycolysis-related prognostic model by Least absolute shrinkage and selection operator (LASSO) Cox regression analysis. It was validated in two independent external cohorts, cell lines, and our clinical specimens. The model was also explored for its biological properties, immune microenvironment, and therapeutic response including immunotherapy. Finally, multiple metrics were combined to construct a nomogram to assist in personalized prediction of survival outcomes. Results: A wide range of variants and heterogeneous expression profiles of glycolysis-related genes were observed in MM. The prognostic model behaved well in differentiating between populations with various prognoses and proved to be an independent prognostic factor. This prognostic signature closely coordinated with multiple malignant features such as high-risk clinical features, immune dysfunction, stem cell-like features, cancer-related pathways, which was associated with the survival outcomes of MM. In terms of treatment, the high-risk group showed resistance to conventional drugs such as bortezomib, doxorubicin and immunotherapy. The joint scores generated by the nomogram showed higher clinical benefit than other clinical indicators. The in vitro experiments with cell lines and clinical subjects further provided convincing evidence for our study. Conclusion: We developed and validated the utility of the MM glycolysis-related prognostic model, which provides a new direction for prognosis assessment, treatment options for MM patients.

Identification and validation of a novel cuproptosis-related gene signature in multiple myeloma.

Background: Cuproptosis is a newly identified unique copper-triggered modality of mitochondrial cell death, distinct from known death mechanisms such as necroptosis, pyroptosis, and ferroptosis. Multiple myeloma (MM) is a hematologic neoplasm characterized by the malignant proliferation of plasma cells. In the development of MM, almost all patients undergo a relatively benign course from monoclonal gammopathy of undetermined significance (MGUS) to smoldering myeloma (SMM), which further progresses to active myeloma. However, the prognostic value of cuproptosis in MM remains unknown. Method: In this study, we systematically investigated the genetic variants, expression patterns, and prognostic value of cuproptosis-related genes (CRGs) in MM. CRG scores derived from the prognostic model were used to perform the risk stratification of MM patients. We then explored their differences in clinical characteristics and immune patterns and assessed their value in prognosis prediction and treatment response. Nomograms were also developed to improve predictive accuracy and clinical applicability. Finally, we collected MM cell lines and patient samples to validate marker gene expression by quantitative real-time PCR (qRT-PCR). Results: The evolution from MGUS and SMM to MM was also accompanied by differences in the CRG expression profile. Then, a well-performing cuproptosis-related risk model was developed to predict prognosis in MM and was validated in two external cohorts. The high-risk group exhibited higher clinical risk indicators. Cox regression analyses showed that the model was an independent prognostic predictor in MM. Patients in the high-risk group had significantly lower survival rates than those in the low-risk group (p < 0.001). Meanwhile, CRG scores were significantly correlated with immune infiltration, stemness index and immunotherapy sensitivity. We further revealed the close association between CRG scores and mitochondrial metabolism. Subsequently, the prediction nomogram showed good predictive power and calibration. Finally, the prognostic CRGs were further validated by qRT-PCR in vitro. Conclusion: CRGs were closely related to the immune pattern and self-renewal biology of cancer cells in MM. This prognostic model provided a new perspective for the risk stratification and treatment response prediction of MM patients.

Combined inhibition of XIAP and autophagy induces apoptosis and differentiation in acute myeloid leukaemia.

Perturbations in autophagy, apoptosis and differentiation have greatly affected the progression and therapy of acute myeloid leukaemia (AML). The role of X-linked inhibitor of apoptosis (XIAP)-related autophagy remains unclear in AML therapeutics. Here, we found that XIAP was highly expressed and associated with poor overall survival in patients with AML. Furthermore, pharmacologic inhibition of XIAP using birinapant or XIAP knockdown via siRNA impaired the proliferation and clonogenic capacity by inducing autophagy and apoptosis in AML cells. Intriguingly, birinapant-induced cell death was aggravated in combination with ATG5 siRNA or an autophagy inhibitor spautin-1, suggesting that autophagy may be a pro-survival signalling. Spautin-1 further enhanced the ROS level and myeloid differentiation in THP-1 cells treated with birinapant. The mechanism analysis showed that XIAP interacted with MDM2 and p53, and XIAP inhibition notably downregulated p53, substantially increased the AMPKα1 phosphorylation and downregulated the mTOR phosphorylation. Combined treatment using birinapant and chloroquine significantly retarded AML progression in both a subcutaneous xenograft model injected with HEL cells and an orthotopic xenograft model injected intravenously with C1498 cells. Collectively, our data suggested that XIAP inhibition can induce autophagy, apoptosis and differentiation, and combined inhibition of XIAP and autophagy may be a promising therapeutic strategy for AML.

MicroRNA-143 acts as a tumor suppressor through Musashi-2/DLL1/Notch1 and Musashi-2/Snail1/MMPs axes in acute myeloid leukemia.

BACKGROUND: The previous studies have revealed that abnormal RNA-binding protein Musashi-2 (MSI2) expression is associated with cancer progression through post-transcriptional mechanisms, however mechanistic details of this regulation in acute myeloid leukemia (AML) still remain unclear. Our study aimed to explore the relationship between microRNA-143 (miR-143) and MSI2 and to clarify their clinical significance, biological function and mechanism. METHODS: Abnormal expression of miR-143 and MSI2 were evaluated in bone marrow samples from AML patients by quantitative real time-PCR. Effects of miR-143 on regulating MSI2 expression were investigated using luciferase reporter assay. Functional roles of MSI2 and miR-143 on AML cell proliferation and migration were determined by CCK-8 assay, colony formation, and transwell assays in vitro and in mouse subcutaneous xenograft and orthotopic transplantation models in vivo. RNA immunoprecipitation, RNA stability measurement and Western blotting were performed to assess the effects of MSI2 on AML. RESULTS: We found that MSI2 was significantly overexpressed in AML and exerted its role of promoting AML cell growth by targeting DLL1 and thereby activating Notch signaling pathway. Moreover, we found that MSI2 bound to Snail1 transcript and inhibited its degradation, which in turn upregulated the expression of matrix metalloproteinases. We also found that MSI2 targeting miR-143 is downregulated in AML. In the AML xenograft mouse model, overexpression of MSI2 recapitulated its leukemia-promoting effects, and overexpression of miR-143 partially attenuated tumor growth and prevented metastasis. Notably, low expression of miR-143, and high expression of MSI2 were associated with poor prognosis in AML patients. CONCLUSIONS: Our data demonstrate that MSI2 exerts its malignant properties via DLL1/Notch1 cascade and the Snail1/MMPs axes in AML, and upregulation of miR-143 may be a potential therapeutic approach for AML.

Aging-related genes related to the prognosis and the immune microenvironment of acute myeloid leukemia.

BACKGROUND: Acute myeloid leukemia (AML), one of the common malignancies of the hematologic system, has progressively increased in incidence. Aging is present in both normal tissues and the tumor microenvironment. However, the relationship between senescence and AML prognosis is still not elucidated. METHODS: In this study, RNA sequencing data of AML were obtained from TCGA, and prognostic prediction models were established by LASSO-Cox analysis. Differences in immune infiltration between the different risk groups were calculated using the CIBERSORT and ESTIMATE scoring methods. The KEGG and GO gene enrichment and GSEA enrichment were also used to enrich for differential pathways between the two groups. Subsequently, this study collected bone marrow samples from patients and healthy individuals to verify the differential expression of uncoupling protein 2 (UCP2) in different populations. Genipin, a UCP2 protein inhibitor, was also used to examine its effects on proliferation, cell cycle, and apoptosis in AML cell lines in vitro. RESULTS: It showed that aging-related genes (ARGs) expression was correlated with prognosis. And there was a significant difference in the abundance of immune microenvironment cells between the two groups of patients at high risk and low risk. Subsequently, UCP2 expression was found to be elevated in AML patients. Genipin inhibits UCP2 protein and suppresses the proliferation of AML cell lines in vitro. CONCLUSION: ARGs can be used as a predictor of prognosis in AML patients. Moreover, suppressing UCP2 can reduce the proliferation of AML cell lines, alter their cell cycle, and promote apoptosis in vitro.

Efficacy of Surgery in Patients with Stage I Primary Parotid Gland Lymphoma: A Population-Based Study.

Background: Limited and controversial evidence is available on the efficacy of surgery for patients with stage I primary parotid gland lymphoma. Thus, we aimed to investigate whether surgery can enhance the prognosis of patients with stage I primary parotid gland lymphoma using large sample data. Methods: From 1998 to 2015, we searched the Surveillance, Epidemiology, and End Results (SEER) program database and extracted information regarding patients with stage I primary parotid gland lymphoma; we classified these patients into surgery and nonsurgery groups. We calculated overall survival (OS) and cancer-specific survival (CSS) using Kaplan-Meier curves and log-rank testing. Propensity score matching (PSM) analysis was also used to further account for confounding variables before comparing the OS and CSS again. We used the COX proportional hazard regression model in both multivariate and univariate analyses. Results: We enrolled 918 patients with stage I primary parotid gland lymphoma, among which 656 (71.5%) patients underwent surgery. Before PSM, the surgery group had better OS (hazard ratio (HR) = 0.673, 95% confidence interval (CI): 0.519-0.873, and p=0.003) and CSS (HR = 0.595, 95% CI: 0.403-0.879, and p=0.008) than the nonsurgery group. After PSM, surgery was still a beneficial factor for OS (HR = 0.569, 95% CI: 0.399-0.810, and p=0.002) and CSS (HR = 0.384, 95% CI: 0.220-0.669, and p=0.001). Furthermore, in univariate and multivariate analyses, total parotidectomy significantly increased OS (p=0.001 and p=0.021, respectively) and CSS (p=0.001 and p=0.037, respectively). Conclusions: In summary, the prognosis of patients with stage I primary parotid gland lymphoma can be significantly improved by surgery. Moreover, total parotidectomy was a protective factor for OS and CSS before and after PSM analysis, suggesting that surgery acts as a significant component in multimodal therapy for early primary parotid gland lymphoma.

A review of the therapeutic role of the new third-generation TKI olverembatinib in chronic myeloid leukemia.

Several tyrosine kinase inhibitors (TKIs) have been developed as targeted therapies to inhibit the oncogenic activity of several tyrosine kinases in chronic myeloid leukemia (CML), acute lymphoid leukemia (ALL), gastrointestinal stromal tumor (GIST), and other diseases. TKIs have significantly improved the overall survival of these patients and changed the treatment strategy in the clinic. However, approximately 50% of patients develop resistance or intolerance to imatinib. For second-generation TKIs, approximately 30%-40% of patients need to change therapy by 5 years when they are used as first-line treatment. Clinical study analysis showed that the T315I mutation is highly associated with TKI resistance. Developing new drugs that target the T315I mutation will address the dilemma of treatment failure. Olverembatinib, as a third-generation TKI designed for the T315I mutation, is being researched in China. Preliminary clinical data show the safety and efficacy in treating CML patients harboring the T315I mutation or who are resistant to first- or second-line TKI treatment. Herein, we review the characteristics and clinical trials of olverembatinib. We also discuss its role in the management of CML patients.

A novel 10-gene ferroptosis-related prognostic signature in acute myeloid leukemia.

Acute myeloid leukemia (AML) is one of the most common hematopoietic malignancies and exhibits a high rate of relapse and unfavorable outcomes. Ferroptosis, a relatively recently described type of cell death, has been reported to be involved in cancer development. However, the prognostic value of ferroptosis-related genes (FRGs) in AML remains unclear. In this study, we found 54 differentially expressed ferroptosis-related genes (DEFRGs) between AML and normal marrow tissues. 18 of 54 DEFRGs were correlated with overall survival (OS) (P<0.05). Using the least absolute shrinkage and selection operator (LASSO) Cox regression analysis, we selected 10 DEFRGs that were associated with OS to build a prognostic signature. Data from AML patients from the International Cancer Genome Consortium (ICGC) cohort as well as the First Affiliated Hospital of Wenzhou Medical University (FAHWMU) cohort were used for validation. Notably, the prognostic survival analyses of this signature passed with a significant margin, and the riskscore was identified as an independent prognostic marker using Cox regression analyses. Then we used a machine learning method (SHAP) to judge the importance of each feature in this 10-gene signature. Riskscore was shown to have the highest correlation with this 10-gene signature compared with each gene in this signature. Further studies showed that AML was significantly associated with immune cell infiltration. In addition, drug-sensitive analysis showed that 8 drugs may be beneficial for treatment of AML. Finally, the expressions of 10 genes in this signature were verified by real-time quantitative polymerase chain reaction. In conclusion, our study establishes a novel 10-gene prognostic risk signature based on ferroptosis-related genes for AML patients and FRGs may be novel therapeutic targets for AML.

The correlation factors and prognostic significance of coagulation disorders after chimeric antigen receptor T cell therapy in hematological malignancies: a cohort study.

Background: Along with cytokine release syndrome (CRS) and neurotoxicity, coagulation disorder is a common early complication of chimeric antigen receptor (CAR)-T cell therapy. However, the mechanisms and prognostic significance of CAR-T-related coagulation disorders are not fully known. This study explored the possible correlation factors and prognostic significance of coagulation disorders after CAR-T cell infusion in patients with relapsed/refractory hematological malignancies. Methods: This cohort study included 56 patients with relapsed/refractory hematological malignancies who were treated with CAR-T cells between April 2017 and February 2022. The median follow-up was 26.8 months. Coagulation disorders were defined as the abnormality in at least one coagulation parameters, including prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT), fibrinogen, and D-dimer. The correlation factors of coagulation disorders were analyzed using Wilcoxon rank-sum test, Fisher's exact test, paired t-test and Spearman correlation coefficient. The prognostic significance of coagulation disorders was analyzed using Kaplan-Meier method and stepwise multivariate Cox regression model. Results: The incidence of coagulation disorders was 59% within 1 month of CAR-T cell infusion. PT prolongation, APTT prolongation, TT prolongation, and D-dimer increase peaked at a median of 6-9 days, and fibrinogen decreased to its lowest value at a median of 12 days. Coagulation disorders in patients with severe CRS were more significant (P<0.001). Abnormality of coagulation parameters was closely related to cytokines, CAR-T cells, liver function parameters, and von Willebrand Factor (VWF) in both peak level and peak time (P<0.05). Statistical analysis showed that coagulation disorders were associated with higher initial response rates (TT, P=0.006; D-dimer, P=0.010) and also longer progression-free survival (PFS) (PT, P=0.017; APTT, P=0.018; TT, P=0.001; Fibrinogen, P=0.003; D-dimer, P<0.001) in CAR-T therapy, with TT prolongation (HR =0.279, 95% CI: 0.099-0.782, P=0.015) and D-dimer increase (HR =0.218, 95% CI: 0.087-0.548, P=0.001) independent predictors for PFS. Conclusions: The protection of liver and endothelial cells may reduce CAR-T-related coagulation disorders. Further, coagulation disorders occurring within 1 month of CAR-T cell infusion can serve as a new predictor for prognosis in patients with hematological malignancies.

Long term complete response of advanced hepatocellular carcinoma to glypican-3 specific chimeric antigen receptor T-Cells plus sorafenib, a case report.

The clinical efficacy of current therapies for Hepatocellular carcinoma (HCC) are unsatisfactory. In recent years, chimeric antigen receptor (CAR) T-cell therapies have been developed for solid tumors including advanced HCC (aHCC), but limited progress has been made. Glypican-3 is a promising immunotherapeutic target for HCC since it is specifically highly expressed in HCC. A previous study indicated that GPC3-targeted CAR T-(CAR-GPC3) cells were well-tolerated and had prolonged survival for HCC patients and that Sorafenib could increase the antitumor activities of CAR-GPC3 T-cells against HCC in mouse models. Here, we report a patient with aHCC who achieved a complete response (CR) and a long survival period after the combination therapy of CAR-GPC3 T-cell plus sorafenib. A 60-year-old Asian male diagnosed with hepatitis B virus (HBV) related HCC developed liver recurrence and lung metastasis after liver tumor resection and trans-arterial chemoembolization therapy. The patient also previously received microwave ablation therapy for lung metastasis. After the enrollment, the patient underwent leukapheresis for CAR-GPC3 T-cells manufacturing. Seven days after leukapheresis, the patient started to receive 400 mg of Sorafenib twice daily. The patient received 4 cycles of CAR-GPC3 T cells (CT011) treatment and each cycle was divided into two infusions. Prior to each cycle of CT011 treatment, lymphodepletion was performed. The lymphodepletion regimen was cyclophosphamide 500 mg/m2/day for 2 to 3 days, and fludarabine 20-25 mg/m2/day for 3 to 4 days. A total of 4×109 CAR-GPC3 T cells were infused. The CT011 plus Sorafenib combination therapy was well tolerated. All the ≥ grade 3 AEs were hematological toxicities which were deemed an expected event caused by the preconditioning regimen. This patient obtained partial responses from the 3rd month and achieved CR in the 12th month after the first cycle of CT011 infusion according to the RECIST1.1 assessment. The tumor had no progression for more than 36 months and maintained the CR status for more than 24 months after the first infusion.

Pneumocystis jirovecii pneumonia in non-Hodgkin's lymphoma after rituximab-based chemotherapy: a case series.

Background: The incidence of Pneumocystis jirovecii pneumonia (PCP) has been increasing in patients with hematologic malignancies due to the use of glucocorticoid therapy and immunosuppressive medication. The reports of PCP in non-Hodgkin's lymphoma (NHL) after rituximab-based chemotherapy are still rare. We reported a case series of PCP in NHL to show the clinical features and prognosis in those patients. Methods: We conducted a retrospective review of 15 NHL patients who developed PCP after rituximab-based chemotherapy during June 30, 2014 to June 1, 2020. We analyzed the laboratory and radiographic findings for those patients through descriptive statistics analysis. Results: The study revealed that PCP in NHL patients was complicated by chemotherapy after about 4 courses (range, 2 to 6 courses). Most patients had a standard lymphocyte count before treatment, and 14 of 15 patients (93.3%) had lymphopenia at the time of diagnosis of PCP. In addition to typical symptoms such as fever and dyspnea at the diagnosis of PCP, most patients had abnormal laboratory indexes such as marked elevations of C-reactive protein (CRP) and lactic dehydrogenase (LDH) both before and at the time of diagnosis. The (1,3)-ß-D-glucan test was also revealed as a sensitive index for PCP. Bilateral ground-glass opacity was detected in 14 cases through computed tomography (CT) scans. Positive results of microbiological testing were observed in 7 cases; sputum culture was positive in 3 and next-generation sequencing (NGS) was positive in 3 of these 7 patients, and the other case was positive in both sputum culture and NGS. Patients received high-dose trimethoprim/sulfamethoxazole (TMP/SMZ), caspofungin, and steroids as the treatment for PCP. Ventilatory support was required by 3 patients, so they were admitted to the intensive care unit (ICU), and 1 patient died from PCP. Conclusions: Dynamic monitoring of CRP, LDH, and (1,3)-ß-D-glucan test during the treatment of NHL may have a predictive value for the diagnosis of PCP. Additionally, we should use NGS as a rapid and sensitive method for the early diagnosis of PCP. When patients are classified as 'probable PCP', early and effective treatment has obvious significance to improve the prognosis.