Ivosidenib in Chinese patients with relapsed or refractory isocitrate dehydrogenase 1 mutated acute myeloid leukemia: a registry study.

Ivosidenib, an isocitrate dehydrogenase 1 (IDH1) inhibitor, has demonstrated clinical benefits in a pivotal study (AG120-C-001) in patients with IDH1-mutated (mIDH1) acute myeloid leukemia (AML). A registry study (CS3010-101: NCT04176393) was conducted to assess the pharmacokinetic (PK) characteristics, safety, and efficacy of ivosidenib in Chinese patients with relapsed or refractory (R/R) mIDH1 AML. Patients received ivosidenib 500 mg once daily for 28-day cycles until disease progression. Ten subjects underwent intensive PK/progressive disease (PD) assessments. All subjects had the clinical response assessed at screening, every 28 days through month 12, and then every 56 days. Between November 12, 2019, and April 2, 2021, 30 patients were enrolled; 26 (86.7%) had de novo AML and 18 (60.0%) were transfusion-dependent at baseline. Following single and repeated doses of ivosidenib, median time to maximum plasma concentration (T max) was 4.0 and 2.0 hours, respectively. The inter-individual variability of pharmacokinetic exposure was moderate to high (coefficient of variation [CV], 25%-53%). No obvious accumulation was observed after repeated doses at cycle 2 day 1. Regarding the clinical response, the CR + CRh rate was 36.7% (95% confidence interval [CI]: 19.9%-56.1%), the median duration of CR + CRh was 19.7 months (95% CI: 2.9 months-not reached [NR]), and median duration of response (DoR) was 14.3 months (95% CI: 6.4 months-NR). Consistent clinical benefits and safety of ivosidenib were consistently observed at the final data cutoff with median follow-up time 26.0 months, as compared with primary data cutoff, and the data from Chinese R/R mIDH1 AML patients were also consistent with results from pivotal study.

A Systematic Review on Password Guessing Tasks.

Recently, many password guessing algorithms have been proposed, seriously threatening cyber security. In this paper, we systematically review over thirty methods for password guessing published between 2016 and 2023. First, we introduce a taxonomy for classifying the existing methods into trawling guessing and targeted guessing. Second, we present an extensive benchmark dataset that can assist researchers and practitioners in successive works. Third, we conduct a bibliometric analysis to present trends in this field and cross-citation between reviewed papers. Further, we discuss the open challenges of password guessing in terms of diverse application scenarios, guessing efficiency, and the combination of traditional and deep learning methods. Finally, this review presents future research directions to guide successive research and development of password guessing.

Research Progress on Pyroptosis in Hematological Malignancies.

OPINION STATEMENT: Pyroptosis is a kind of programmed cell death dependent on the caspase pathway that is different from apoptosis and necrosis. Recent studies have shown that pyroptosis can be involved in the pathological processes of many diseases, such as cancers, atherosclerosis, diabetic nephropathy, and blood diseases. However, the specific mechanisms by which pyroptosis participates in the occurrence and development of hematological malignant tumors still need further exploration. This article reviews the characteristics of pyroptosis and the regulatory mechanisms promoting or inhibiting pyroptosis and discusses the role of pyroptosis in hematological malignant tumors, which could provide ideas for the clinical treatment of such tumors in the future.

Regulatory effects of IRF4 on immune cells in the tumor microenvironment.

The tumor microenvironment (TME) is implicated in tumorigenesis, chemoresistance, immunotherapy failure and tumor recurrence. Multiple immunosuppressive cells and soluble secreted cytokines together drive and accelerate TME disorders, T cell immunodeficiency and tumor growth. Thus, it is essential to comprehensively understand the TME status, immune cells involved and key transcriptional factors, and extend this knowledge to therapies that target dysfunctional T cells in the TME. Interferon regulatory factor 4 (IRF4) is a unique IRF family member that is not regulated by interferons, instead, is mainly induced upon T-cell receptor signaling, Toll-like receptors and tumor necrosis factor receptors. IRF4 is largely restricted to immune cells and plays critical roles in the differentiation and function of effector cells and immunosuppressive cells, particularly during clonal expansion and the effector function of T cells. However, in a specific biological context, it is also involved in the transcriptional process of T cell exhaustion with its binding partners. Given the multiple effects of IRF4 on immune cells, especially T cells, manipulating IRF4 may be an important therapeutic target for reversing T cell exhaustion and TME disorders, thus promoting anti-tumor immunity. This study reviews the regulatory effects of IRF4 on various immune cells in the TME, and reveals its potential mechanisms, providing a novel direction for clinical immune intervention.

Efficacy and safety of lenalidomide in diffuse large B-cell lymphoma: a meta-analysis of randomized controlled trials.

As an immunomodulatory agent with antitumor activity, lenalidomide has been evaluated for its value in diffuse large B-cell lymphoma (DLBCL). We performed a meta-analysis to gain a better understanding of the efficacy and safety of lenalidomide in DLBCL. PubMed, Cochrane Library, and Embase were searched up to March 2022 for potential studies. The pooled hazard ratio (HR) and relative risk (RR) with 95% confidence interval (CI) were estimated by the fixed/random effects model. Overall, 6 randomized controlled trials including 1938 patients were included. The complete response rate (CRR) of the group containing lenalidomide was 47.7% (95%CI 28.5-67.2%), which was higher than the 37.8% (95%CI 16.7-61.5%) of the control group without lenalidomide (RR = 1.11, 95%CI 1.03-1.20, P = 0.008). The overall estimation of survival showed a benefit for progression-free survival (PFS) (HR = 0.77, 95%CI 0.66-0.90, P = 0.001) but not overall survival (OS) or event-free survival (EFS). The lenalidomide group had a significant incidence of grade ≥ 3 hematological adverse events (AEs) involving neutropenia (RR = 1.56, 95%CI 1.15-2.11, P = 0.004) and febrile neutropenia (RR = 1.81, 95%CI 1.31-2.49, P < 0.001), with the incidence of neutropenia (48.3%, 95%CI 37.5-59.1%) being highest. In conclusion, addition of lenalidomide results in a higher CRR and better PFS but a higher incidence of grade ≥ 3 hematological AEs involving neutropenia and febrile neutropenia.

Decreased TCF1 and BCL11B expression predicts poor prognosis for patients with chronic lymphocytic leukemia.

T cell immune dysfunction is a prominent characteristic of chronic lymphocytic leukemia (CLL) and the main cause of failure for immunotherapy and multi-drug resistance. There remains a lack of specific biomarkers for evaluating T cell immune status with outcome for CLL patients. T cell factor 1 (TCF1, encoded by the TCF7 gene) can be used as a critical determinant of successful anti-tumor immunotherapy and a prognostic indicator in some solid tumors; however, the effects of TCF1 in CLL remain unclear. Here, we first analyzed the biological processes and functions of TCF1 and co-expressing genes using the GEO and STRING databases with the online tools Venny, Circos, and Database for Annotation, Visualization, and Integrated Discovery (DAVID). Then the expression and prognostic values of TCF1 and its partner gene B cell leukemia/lymphoma 11B (BCL11B) were explored for 505 CLL patients from 6 datasets and validated with 50 CLL patients from Henan cancer hospital (HNCH). TCF1 was downregulated in CLL patients, particularly in CD8+ T cells, which was significantly correlated with poor time-to-first treatment (TTFT) and overall survival (OS) as well as short restricted mean survival time (RMST). Function and pathway enrichment analysis revealed that TCF1 was positively correlated with BCL11B, which is involved in regulating the activation and differentiation of T cells in CLL patients. Intriguingly, BCL11B was highly consistent with TCF1 in its decreased expression and prediction of poor prognosis. More importantly, the combination of TCF1 and BCL11B could more accurately assess prognosis than either alone. Additionally, decreased TCF1 and BCL11B expression serves as an independent risk factor for rapid disease progression, coinciding with high-risk indicators, including unmutated IGHV, TP53 alteration, and advanced disease. Altogether, this study demonstrates that decreased TCF1 and BCL11B expression is significantly correlated with poor prognosis, which may be due to decreased TCF1+CD8+ T cells, impairing the effector CD8+ T cell differentiation regulated by TCF1/BCL11B.

Effects of ibrutinib on T-cell immunity in patients with chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL), a highly heterogeneous B-cell malignancy, is characterized by tumor microenvironment disorder and T-cell immune dysfunction, which play a major role in the proliferation and survival of CLL cells. Ibrutinib is the first irreversible inhibitor of Bruton's tyrosine kinase (BTK). In addition to targeting B-cell receptor (BCR) signaling to kill tumor cells, increasing evidence has suggested that ibrutinib regulates the tumor microenvironment and T-cell immunity in a direct and indirect manner. For example, ibrutinib not only reverses the tumor microenvironment by blocking cytokine networks and toll-like receptor signaling but also regulates T cells in number, subset distribution, T-cell receptor (TCR) repertoire and immune function by inhibiting interleukin-2 inducible T-cell kinase (ITK) and reducing the expression of inhibitory receptors, and so on. In this review, we summarize the current evidence for the effects of ibrutinib on the tumor microenvironment and cellular immunity of patients with CLL, particularly for the behavior and function of T cells, explore its potential mechanisms, and provide a basis for the clinical benefits of long-term ibrutinib treatment and combined therapy based on T-cell-based immunotherapies.

Efficacy and safety of blinatumomab in Chinese adults with Ph-negative relapsed/refractory B-cell precursor acute lymphoblastic leukemia: A multicenter open-label single-arm China registrational study.

OBJECTIVES: The prognosis for adults with relapsed/refractory (R/R) B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is poor. Blinatumomab is a CD3/CD19-directed BiTE® (bispecific T-cell engager) molecule approved globally for the treatment of BCP-ALL in adults and children. This multicenter open-label single-arm China registrational study evaluated the safety, efficacy, and pharmacokinetics of blinatumomab in Chinese adults with Philadelphia chromosome-negative (Ph-) R/R BCP-ALL (NCT03476239). METHODS: Patients aged ≥ 18 years were treated with up to 5 cycles of blinatumomab. The primary objective was to evaluate the hematological response rate (complete remission/complete remission with partial hematological recovery [CR/CRh]) within 2 cycles of blinatumomab. RESULTS: At the interim analysis (April 12, 2019), 90 patients (median age 31.5 years [range: 18-74]; 53.3% female; 77.8% with bone marrow blasts ≥ 50% at study entry) were enrolled at 23 study centers in China and had received blinatumomab. As of data cutoff, 43 patients (47.8%) continued the study. The CR/CRh rate within 2 cycles of blinatumomab was 45.6% (41/90 [CR, 37; CRh, 4]; 95% CI: 35.0-56.4). Median overall survival was 9.2 months (95% CI: 6.5-11.7); median relapse-free survival was 4.3 months (95% CI: 3.2-9.4). Mean serum concentration at steady-state and systemic clearance of blinatumomab in Chinese patients were within the range reported in adults from global clinical trials. No new safety risks were identified in Chinese patients. CONCLUSIONS: The efficacy and safety of blinatumomab in these heavily pre-treated Chinese patients with Ph- R/R BCP-ALL is comparable to that for patients within global clinical trials.

The different predictive effects of the intensity and proportion of CD20 expression on the prognosis of B-lineage acute lymphocyte leukemia.

The prognostic effects of the CD20 positivity have been studied extensively in B-lineage acute lymphocyte leukemia (B-ALL) patients, but the results remain controversial. The aim of this study is to investigate the different predictive effects of the intensity and proportion of CD20 expression on the prognosis for B-ALL patients by retrospective analysis. The mean fluorescence intensity (MFI) and percentage of CD20 on B-ALL cells from 206 patients with B-ALL were dynamically measured by flow cytometry, and their optimal cut-off values were determined using the receiver operating characteristic curve. Changes in MFI and percentage of CD20 at various time points and their relationship with prognosis were analyzed. We found that a low baseline CD20 MFI or high CD20 proportion was significantly associated with shorter 5-year overall survival and progression-free survival, and the combination of these two factors could more accurately predict worse survival for B-ALL patients. Furthermore, low CD20 MFI or a high CD20 proportion had different predictive effects for ALL patients with different clinical characteristics and could serve as an independent risk factor for adverse prognosis. There were significant decreases in both the intensity and proportion of CD20 after recurrence in the absence of rituximab treatment, particularly with CD20 intensity. Notably, the decrease of CD20 intensity after recurrence indicated a more shortened survival time. Finally, we conclude that a low intensity or high proportion of CD20 expression may be used as an indicator for inferior prognosis for B-ALL patients. CD20 intensity is more likely to be a more universal biomarker for worse prognosis.

A retrospective study on effectiveness of combined recombinant human interferon-α-1b, interleukin-2, and thalidomide for the treatment of acute myeloid leukemia in various disease states.

Background: Interferon-α-1b, interleukin-2 combined with thalidomide (ITI) improved the outcome and prognosis of some acute myeloid leukemia (AML) patients, but the cases was insufficient. This study observed the efficacy and safety of this regimen in the treatment of numbers of AML patients in various disease states. Methods: Starting in January 2014, patients with AML (n=188) were treated with ITI regimen, including 60 refractory/relapses patients in group A, 40 patients in group B remained minimal residual disease-positive (MRD) or changed from negative to positive again after consolidation therapy, and 88 patients in group C with initial complete remission of AML received the ITI treatment after routine consolidation therapy. Bone marrow, fusion gene and MRD were detected to judge the curative effect and the adverse reactions were observed. The remission rate, MRD status and long-term survival of three groups were analyzed. An AML mouse model was constructed to observe the anti-leukemia effect of the three drugs in vivo. Results: Sixty patients with primary AML who were unable to receive chemotherapy, or with relapsed/refractory AML, showed a total response rate of 28.3% (17/60) after receiving the ITI regimen. Forty patients with morphologically complete remission and MRD-positive achieved a response rate of 77.5% (31/40); the MRD converted to negative in 19 patients and was mitigated in 12 patients. Among 88 patients with initial complete remission, 11 failed to maintain the negative MRD, and the relapse rate was 12.5%, which was significantly lower than that of the non-maintenance treatment group (54.3%). In the mouse model, interferon, interleukin-2, and thalidomide exerted an anti-leukemia effect, prolonged the survival time of the mice, and the anti-leukemia effect was further enhanced after administration of the combination ITI regimen. Conclusions: For suitable patients, hematopoietic stem cell transplantation is still strong recommended. The ITI regimen may be an effective option for patients with AML who cannot tolerate conventional chemotherapy, including those with relapsed/refractory disease, those with a complete remission status but are MRD-positive, or those who require maintenance treatment after consolidation therapy. However, a rigorous clinical randomized controlled trial and more in-depth mechanism exploration are still needed to verify this conclusion.

Prognostic significance of the neutrophil-to-lymphocyte ratio in peripheral T-cell lymphoma: a meta-analysis.

The neutrophil-to-lymphocyte ratio (NLR) as an inflammatory marker may represent changes between inflammation and host immunity that affect the prognosis of peripheral T-cell lymphoma (PTCL). To comprehensively evaluate the NLR in PTCL, we performed a meta-analysis to investigate the relationship between the NLR and overall survival (OS) and progression-free survival (PFS). PubMed, Embase, Cochrane library, and China National Knowledge Infrastructure (CNKI) were searched for all relevant studies. Hazard ratios (HRs) and 95% confidence intervals (CIs) were obtained from each study. Heterogeneity among the included studies was checked to determine whether fixed or random effects model was used. In total, 8 studies with 921 patients were included for the meta-analysis. High NLR significantly correlated with worse OS (HR = 2.20, 95% CI 1.71-2.83, P < 0.05) regardless of region (Asian or non-Asian), sample size (< 60 or ≥ 60), median age (< 60 or ≥ 60), disease type, or cut-off value (NLR < 3.9 or NLR ≥ 3.9). In terms of PFS, the NLR had no prognostic impact for patients with PTCL (HR = 1.12, 95% CI 0.57-2.20, P = 0.742). Our findings suggest that PTCL patients with high NLR are more likely to have worse OS compared to those with low NLR. Therefore, the NLR can serve as a prognostic marker in PTCL.

Culturing adequate CAR-T cells from less peripheral blood to treat B-cell malignancies.

OBJECTIVE: Chimeric antigen receptor-modified T (CAR-T) cells have shown impressive results against relapsed/refractory B cell malignancies. However, the traditional manufacture of CAR-T cells requires leukapheresis to isolate large amounts of peripheral blood T cells, thus making some patients ineligible for the procedure. METHODS: We developed a simple method for CAR-T cell preparation requiring small volumes of peripheral blood. First, CD3+ T cells isolated from 50 mL peripheral blood from patients (B-cell malignancies) were stimulated with immobilized anti-CD3/RetroNectin in 6-well plates and then transduced with CAR-expressing lentiviral vector. After 4 d, the T cells were transferred to culture bags for large-scale CAR-T cell expansion. In vitro and animal experiments were performed to evaluate the activity of the manufactured CAR-T cells. Finally, 29 patients with B-cell acute lymphoblastic leukemia (B-ALL) and 9 patients with B-cell lymphoma were treated with the CAR-T cells. RESULTS: The CAR-T cells were expanded to 1-3 × 108 cells in 8-10 d and successfully killed B cell-derived malignant tumor cells in vitro and in vivo. For patients with B-ALL, the complete remission rate was 93% 1 month after CAR-T cell infusion; after 12 months, the overall survival (OS) and leukemia-free survival rates were 69% and 31%, respectively. For patients with lymphoma, the objective response rate (including complete and partial remission) was 78% 2 months after CAR-T cell infusion, and after 12 months, the OS and progression-free survival rates were 71% and 43%, respectively. Cytokine-release syndrome (CRS) occurred in 65.51% and 55.56% of patients with B-ALL and B-cell lymphoma, respectively; severe CRS developed in 20.69% of patients with B-ALL and in no patients with lymphoma. CONCLUSIONS: Our novel method can generate sufficient numbers of CAR-T cells for clinical use from 50-100 mL peripheral blood, thus providing an alternative means of CAR-T cell generation for patients ineligible for leukapheresis.

Combined use of interferon alpha-1b, interleukin-2, and thalidomide to reverse the AML1-ETO fusion gene in acute myeloid leukemia.

This study aims to explore the effect of the ITI (interferon alpha-1b, thalidomide, and interleukin-2) regimen on the AML1-ETO fusion gene in patients with t(8;21) acute myeloid leukemia (AML) who were in hematologic remission but positive for the AML1-ETO fusion gene. From September 2014 to November 2020; 20 patients with AML (15 from The Affiliated Cancer Hospital of Zhengzhou University, 4 from The First Affiliated Hospital; and College of Clinical Medicine of Henan University of Science and Technology, and 1 from Anyang District Hospital) with hematological remission but AML1-ETO fusion gene positivity were treated with different doses of the ITI regimen to monitor changes in AML1-ETO fusion gene levels. Twenty patients were treated with a routine dose of the ITI regimen, including 13 males and 7 females. The median patient age was 38 (14-70 years). The fusion gene was negative in 10 patients after 1 (0.5 ~ 8.6) month, significantly decreased in 4 patients after 2.8 (1 ~ 6) months, increased in 4 patients, and unchanged in 2 patients. The 4 patients with elevated levels of the fusion gene were treated with an increased dose of the ITI regimen, and all four patients became negative, for a total effective rate of 90%. The ITI regimen reduces AML1-ETO fusion gene levels in patients with AML who are in hematologic remission but are fusion gene-positive. Improvement was observed in patients' response to a higher dose administration, and patients tolerated the treatment well.

[CLAG Regimen Composed of Continuous Intravenous Infusion of Cladribine in the Treatment of Refractory/Relapsed Acute Myeloid Leukemia].

OBJECTIVE: To study the efficacy and safety of continuous intravenous infusion of 2-Chlorodeoxyadenosine (2-CdA) combined with high-dose cytarabine (Ara-C) and granulocyte colony-stimulating factor (G-CSF) (CLAG regiem) in the treatment of relapsed/refractory acute myeloid leukemia (AML). METHODS: Fifteen patients with refractory/relapsed AML hospitalized in 5 medical units such as Department of Hematology, the Affiliated Tumor Hospital of Zhengzhou University and received one course of CLAG regimen from June 2014 to August 2019 were analyzed retrospectively (specifically: cladribine 5 mg/M2, day 1 to day 5, continuous 24-hour intravenous infusion; Ara-C 2 g/M2, 1 time/day, day 1 to day 5, intravenous infusion; G-CSF 300 mg, 1 time/day, day 0 to day 5, subcutaneous injection). RESULTS: Among the 15 patients with refractory/relapsed AML, 9 males and 6 females, the median age was 35 (13-63) years old. FAB classification: 1 case of M1, 3 cases of M2a, 4 cases of M2b (including 1 case with extramedullary invasion), 1 case of M4 with extramedullary invasion, 5 cases of M5, 1 case of HAL; NCCN classification: 6 cases in intermediate risk group, 9 cases in high risk group; 8 cases refractory, 7 cases relapsed. The median time of pre-chemotherapy was 4 (2-8) (of which NO.15 had received 8 cycles of chemotherapy and received CLL1-CAR-T), and the median white blood cell count before chemotherapy was 12.27 (from 0.78 to 5.29)×109/L. After 1 course of treatment with CLAG regimen, 12 patients achieved complete remission (12/15, 80%), and the median duration of CR was 65 days (0-528) days. IV grade leukopenia and thrombocytopenia was found in all the patients after chemotherapy. The median duration of granulocytosis was 20 (14 to 33) days, and 1 patient died. Seven patients received allogeneic hematopoietic stem cell transplantation. The median EFS and OS time of 15 patients was 85 (19-558) days and 117 (19-558) days, respectively. CONCLUSION: The CLAG regimen consisting of continuous intravenous infusion of cladribine shows high CR in the treatment of AML patients, but the duration of CR is short, myelosuppression is sever, so that infection control is the key. Allogeneic hematopoietic stem cells transplantation should be performed as soon as possible after CR.

[Research Advances in the Treatment of B-Cell Acute Lymphoblastic Leukemia Based on Surface Antigen Expression --Review].

B-cell acute lymphoblastic leukemia (B-ALL) is a common malignant tumor in hematopoietic system. Although the remission rate of the patients with adult B-ALL is similar to those with childhood B-ALL, the rate of long-term disease-free survival (DFS) rate is significantly lower, once recurrence, the remission rate of routine chemotherapy is low and the prognosis is so poor. Based on the expression of tumor cell surface antigens(such as CD19, CD20 and CD22), the specific monoclonal antibodies, bispecific antibodies and chimeric antigen receptor T cells (CAR-T), and other targeted immunotherapy can greatly improve the efficacy of B-ALL patients, especially for patients with relapse and refractory. In this review, the progress of immunotherapy against B-ALL cell surface antigen is summarized briefly.

LINC00963 facilitates acute myeloid leukemia development by modulating miR-608/MMP-15.

Despite continuous improvements of AML therapy, the prognosis of AML patients remains unsatisfactory. Recently, lncRNAs have been reported to participate in the development of AML. Our data demonstrated that MMP15 and LINC00963 were upregulated and miR-608 was decreased in AML cells (THP-1, HL-60, HEL and MOLM-13) compared to HS-5 cells. RT-qPCR results showed that LINC00963 levels were higher in the serum and bone marrow of AML cases than in controls. Moreover, overexpression of LINC00963 promoted AML cell growth and EMT progression in both THP-1 and HL-60 cells. Furthermore, miR-608 levels were downregulated in the serum and bone marrow of AML cases compared with controls, and Pearson's correlation analysis indicated that LINC00963 was negatively correlated with miR-608 in the serum and bone marrow of AML samples. In addition, we demonstrated that LINC00963 sponged miR-608 expression and that MMP-15 was a target of miR-608 in AML cells. Finally, rescue experiments indicated that ectopic expression of LINC00963 accelerated cell growth and EMT development by modulating MMP-15. These data demonstrated that LINC00963 acted as an oncogene and may be a potential target for AML treatment.

Safety and efficacy of CAR-T cell targeting BCMA in patients with multiple myeloma coinfected with chronic hepatitis B virus.

BACKGROUND: Reactivation of hepatitis B virus (HBV) infection is a well-recognized complication in patients with chronic or resolved HBV infection undergoing anticancer therapy. There is a risk of HBV reactivation after infusion of chimeric antigen receptor (CAR) T cells for patients with refractory/relapsed (R/R) multiple myeloma (MM). METHODS: We administered B cell maturation antigen (BCMA) CAR-T cell by infusion to nine patients with R/R MM with chronic or resolved HBV infection. Patient serum was analyzed to determine the expression of five components of HBV and the copy number of HBV DNA. HBV reactivation was defined if a patient re-exhibited hepatitis B surface antigen (HBsAg) or HBV DNA regrowth after CAR-T therapy. RESULTS: In one patient who was HBsAg-positive, no HBV reactivation was observed during the follow-up period of 9.8 months after administration of anti-HBV drugs before and after CAR-T therapy. Among eight patients with MM who had resolved HBV infection, two patients administered prophylactic anti-HBV drugs did not exhibit HBV reactivation. Of the six patients who did not use prophylactic antiviral drugs, five did not exhibit HBV reactivation, while one showed recurrence of HBsAg without detection of HBV DNA or damage to liver function. The best objective response rate was 100%, and the progression-free survival (PFS) at 12 months was of 88.89% (median PFS was not observed). CONCLUSIONS: These findings showed that BCMA CAR-T cell therapy could be used in patients with R/R MM with chronic or resolved HBV infection and that antiviral drugs should be administered in these patients during CAR-T cell therapy.

The CXCR4 Antagonist, AMD3100, Reverses Mesenchymal Stem Cell-Mediated Drug Resistance in Relapsed/Refractory Acute Lymphoblastic Leukemia.

PURPOSE: To investigate the role of the CXCR4/CXCL12 axis in chemotherapy resistance in refractory/relapsed (R/R) ALL patients. METHODS: CXCR4 expression on ALL cells from newly diagnosed or R/R ALL patients were detected using flow cytometry. The CXCR4/CXCL12 signaling pathway was blocked by the CXCR4 inhibitor AMD3100 in a co-culture model of primary drug-resistant ALL cells and umbilical cord mesenchymal stem cells (UCMSCs). Surface CXCR4 expression, apoptosis rate, and apoptosis-related protein expression in primary ALL cells under various treatments were detected. RESULTS: Of the 37 ALL patients examined, CXCR4 expression was higher in R/R patients than that in those with newly diagnosed disease. Similarly, in in vitro co-cultures of drug-resistant ALL cells with UCMSCs, the expression of CXCR4 was increased in the presence of vincristine (VCR), but reduced when VCR was combined with the CXCR4 antagonist AMD3100. Additionally, the supernatants of ALL-UCMSC co-cultures contained high CXCL12 concentrations, which were upregulated by VCR and significantly decreased by the combination of VCR plus AMD3100. Furthermore, the apoptosis rate of ALL cells significantly decreased, Bax expression was downregulated, and Bcl-2 was upregulated when ALL was co-cultured with UCMSCs compared with ALL cells alone. With the addition of VCR, the apoptosis rate mildly increased, Bax was upregulated, and Bcl-2 was downregulated. Nevertheless, the above results were further intensified, particularly Bax expression, when VCR was combined with AMD3100. CONCLUSION: The CXCR4 antagonist could effectively reverse MSC-mediated drug resistance by blocking the CXCR4/CXCL12 axis and sensitizing leukemic cells from R/R ALL patients to chemotherapy drugs.