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Programmed death-ligand 1 (PD-L1) is involved in immunosuppression in variety of tumours. Regulatory B cells (Bregs) are critical immune regulatory cells, and it has been demonstrated that the number of regulatory B cells in patients with acute myeloid leukaemia (AML) is much higher than that in healthy donors (HDs), which is linked to a poor prognosis. This study aimed to determine whether increased expression of PD-L1, including in Bregs, is associated with a worse prognosis in individuals with AML. The proportion of Bregs, PD-L1 expression in Bregs and PD-1 expression in T cells were determined using flow cytometry using patient samples from 21 newly diagnosed AML patients at different stages of treatment and 25 HDs. We confirmed PD-L1 expression in Bregs, and PD-1 expression in CD3

Introduction Genetic landscape, disease characteristics and clinical outcomes of young adults with myeloproliferative neoplasms (MPNs) were reported. However, data on patient-reported outcomes (PROs) in young adults with MPNs were rare. Methods We conducted a multicenter, cross-sectional study to compared the PROs in respondents with thrombocythemia (ET), polycythemia vera (PV) and myelofibrosis (MF) by age at survey, including the young group (18-40 years), middle-aged group (41-60 years), and elderly group (> 60 years). Results Of the 1664 respondents with MPNs, 349 (21.0%) were young including 244 (69.9%) with ET, 34 (9.7%) with PV and 71 (20.3%) with MF. In multivariate analyses the young groups with ET and MF were associated with the lowest MPN-10 scores among the 3 age groups; those with MF, highest proportion of reporting negative impact of disease and therapy on their daily life and work. The young groups with MPNs had the highest physical component summary scores, but the lowest mental component summary scores in those with ET. The young groups with MPNs were most concerned about fertility; those with ET, treatment-related adverse events and long-term efficacy of treatment. Conclusions We concluded that young adults with MPNs have different PROs compared with middle-aged and elderly patients.

Aim: To identify risk factors and establish a concise prognostic scoring system in patients with diffuse large B-cell lymphoma (DLBCL). Methods: A total of 131 DLBCL patients were enrolled with long-term follow-up who were treated in Shengjing Hospital of the China Medical University. The relationship between clinical parameters and outcomes was analyzed. Results: Multivariate analysis showed that patient age, BMI, CA125 and rituximab application were independent risk factors. Thereafter, a concise scoring system was established, and the new system could identify high-risk patients (p

Purpose Multiple myeloma (MM) is an incurable disease. This study focused on the expression of circular RNA circ_0069767 in MM and its influence on prognosis, in order to provide a potential target. Patients and methods Totally 66 MM patients participated in this research. Using RT-PCR method to determine the expression level of circ_0069767 in 66 sorted samples from multiple myeloma patients and 21 normal control bone marrow samples, Kaplan-Meier was applied for survival analysis. We constructed stable over-expressing circ_0069767 and silenced circ_0069767 cell lines and used MTS experiment to detect cell viability, transwell experiment to detect cell migration and invasion ability and flow cytometry to detect cell apoptosis. Dual luciferase experiment, qRT-PCR experiment and Western blot were used to explore miRNA and downstream genes. Results The expression of circ_0069767 in MM was significantly higher than that of the normal control group. Patients with high expression of circ_0069767 had longer PFS and OS. Cell function experiments showed that overexpression of circ_0069767 in MM cells led to decreased proliferation, migration and invasion, but increased apoptosis; meanwhile, knockdown of circ_0069767 caused opposite biological behaviors. Circ_0069767 by sponging miR-636 in MM cells regulates the expression of K-RAS while the K-RAS gene remained unmutated. Conclusion Circ_0069767 plays an antitumor role and its expression can be used as a reliable prognostic indicator for MM patients.

Background Acute myeloid leukemia (AML), an aggressive malignancy with poor prognosis, is the most common in adult leukemia. Long non-coding RNA (lncRNA) could affect the regulation of protein-coding genes, cell proliferation and apoptosis, tumor cell resistance to radio- and chemotherapy and pathological processes. Lnc00675 is a lncRNA also known as transmembrane protein 238 like (TMEM238L), which identified as a marker of tumor promoter and unfavorable prognosis in patients with pancreatic ductal adenocarcinoma, glioma and cervical cancer. However, the association between Lnc00675 and hematological tumors has not been previously reported. Methods Expression profile gene chip technology was used to screen for differentially expressed genes (DEGs) through comparing Lnc00675 overexpression and Lnc00675 downregulation. Gene ontology (GO) analysis was performed to identify the biologic implications of the DEGs. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis was performed to identify biologically important pathways associated with the DEGs. Cell Counting Kit-8 (CCK-8) assay and flow cytometric analysis were utilized to detect the cell proliferation rate and the cell apoptosis rate, respectively. Results Comparing Lnc00675 overexpression and Lnc00675 downregulation, a total of 866 and 1,115 DEGs were upregulated and downregulated, respectively. Bioinformatics analysis indicated that Lnc00675 might affect U937 cells proliferation and apoptosis through JAK-STAT signaling pathway and PI3K-Akt signaling pathway. The cell proliferation rate in si-Lnc00675 group was significantly lower than those of si-NC group and Lnc00675 group (P

We explored variables associated with patient-reported outcomes (PROs) including symptom burden, impact on daily life and work, obstacles during therapy, satisfaction level with therapy, and health-related quality of life in 1500 respondents with myeloproliferative neoplasms (MPNs) including essential thrombocythemia (ET), polycythemia vera (PV) and myelofibrosis (MF) in a multicenter, cross-sectional study across China, a representative of the developing countries. In multivariate analyses, urban household registration and higher education level were significantly-associated with no symptoms at diagnosis in respondents with ET or MF. CALR mutation was significantly-associated with lower MPN-10 scores in respondents with MF. Higher MPN-10 scores were significantly-associated with negative impact on daily life and work as well as lower satisfaction level in respondents with ET, PV and MF. Receiving ruxolitinib was significantly-associated with high satisfaction and satisfaction in respondents with MF. In addition, other demographics and clinical variables were also impacting PROs.

Human leukocyte antigen-E (HLA-E) has been putatively associated with the pathogenesis of multiple myeloma (MM). Our study first showed that HLA-E was differentially expressed on MM and normal plasma cells (39.27 ± 27.01 and 11.28 ± 0.79, respectively). Based on the median value of HLA-E expression, we further stratified MM patients into high and low-expression groups, and then found high expression of HLA-E was correlated with advanced ISS stage (p = 0.025) and high-risk cytogenetics risk stratification (p = 0.000) by the Pearson Chi-square test, suggesting that HLA-E could be considered as a biomarker for high-risk MM. Furthermore, peptide 3 (P3) from our previous study was confirmed to possess a high affinity to HLA-E positive MM cells. Taken together, HLA-E could be considered as a new marker and candidate treatment target for MM, while peptide P3 may act as a potential treatment choice for targeting MM cells.

Background ATG-010 (selinexor), a novel, oral selective inhibitor of nuclear export, inhibits exportin1. In preclinical and clinical studies, ATG-010 has demonstrated activity against multiple myeloma (MM). ATG-010 (80 mg biweekly) plus dexamethasone (20 mg biweekly) (Sd) has been approved by US FDA for treatment of patients (pts) with penta-refractory MM based on the STORM study. MARCH is a single arm, Phase 2 study to assess efficacy and safety of Sd in Chinese pts with RRMM. Methods Enrolled Chinese pts were previously treated with and refractory to PI, IMiD, and the last line of therapy. Sd was administered in 4-week cycles. The primary endpoint was overall response rate (ORR) per independent review committee. The total planned 82 pts provide -80% power to test against H0 of 15% ORR at one-sided α of 0.025. This abstract includes data from the first 60 treated pts. Results As of 13 Oct 2020, 18 (30%) of the 60 pts were on treatment. Median follow-up was 9.5 months (mo) (range: 1.9-12.8). Median age was 61 years (range 43-82; 42% > 65). Pts had received a median of 5 (range 1-16) prior MM regimens, with the following baseline risk factors: 72% R-ISS II/III, 70% cytogenetic abnormalities, 22% del (17p13),20% renal impairment, 15% prior CAR-T therapy, and 25% pre-treated with daratumumab (considered ‘triple-class exposed’). ORR was 26.7% (95% CI: 16.1, 39.7). Median duration of response (DOR) was 4.6 mo (95% CI: 1.42, NE). Median progression free survival was 3.7 mo (95% CI: 1.92, 4.66). Median overall survival (OS) was not reached; 9-mo OS rate was 68.5%. ORR was 33.3% in triple-class-exposed pts. Nine pts had prior CAR-T therapy with a median of 9 prior regimens (range 5-12). Among them, ORR was 44.4%, and median DOR was 3 mo (95% CI; 0.96, 4.63). Common treatment emergent adverse events (TEAEs) of any grade included: thrombocytopenia (87%), nausea (87%), leukopenia (85%), anemia (85%), lymphopenia (78%), neutropenia (73%), weight loss (72%), hyponatremia (65%), decreased appetite (63%), asthenia (62%)/fatigue (17%), hyperglycemia (53%), vomiting (52%), hypocalcemia (38%), hypokalemia (30%), diarrhea (30%), and pneumonia (27%). Common TEAEs of Grade ≥ 3 included: anemia (60%), thrombocytopenia (55%), leukopenia (42%), lymphopenia (42%), neutropenia (38%), hyponatremia (28%), and pneumonia (23%). Thirty pts (50%) had TESAEs, including (>3%): thrombocytopenia (15%), pneumonia (15%), anemia (6.7%), and hyponatremia (3.3%). Eight pts (13.3%) had TEAEs leading to treatment discontinuation, including (>2%): thrombocytopenia (5%) and pneumonia (3%). There were three fatal TEAEs: pneumonia, intracranial hemorrhage, and sudden death (1 each). Conclusions MM pts refractory to both IMiD and PI remain a high unmet medical need. The MARCH study confirms the efficacy of Sd in Chinese patients with a manageable safety profile. These data are consistent with the STORM trial and offer a new, oral therapeutic option for MM patients.

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

Background Epigenetic mechanisms play an important role in the chemoresistance of acute myeloid leukemia (AML). The clinical response to epigenetic modifier-based chemotherapy in patients with relapsed/refractory AML (r/r AML) is unclear. This multicenter clinical trial evaluated the safety and efficacy of epigenetic modifiers (chidamide and decitabine) in combination with aclarubicin, cytarabine, and granulocyte colony-stimulating factor (G-CSF) in patients with r/r AML. Results Adult patients with r/r AML were treated with chidamide, decitabine, cytarabine, aclarubicin, and G-CSF (CDCAG). The primary measures were overall response (OR), overall survival (OS), and safety. Next-generation sequencing was performed to analyze the correlation between gene mutations and response. A total of 93 patients with r/r AML were enrolled. Overall, 24 patients had a complete remission (CR) and 19 patients achieved CR with incomplete blood count recovery (CRi). The overall response rate (ORR) was 46.2%. The overall survival of these 43 patients who achieved CR/CRi was significantly longer than that of patients who failed to achieve remission (563 vs 152 days, P < 0.0001). Of the patients with mutations in epigenetic and transcription factor-related genes, but without internal tandem duplications in FMS-like tyrosine kinase3 (FLT3-ITDs), 55.6% achieved CR/CRi, whereas the ORR was 28.2% for patients with mutations in other genes. Conclusions The CDCAG regimen was well tolerated and effective in r/r AML. Patients with epigenetic and transcription factor-related gene mutations, but without FLT3-ITD mutations, may benefit from this regimen. Trial registration Clinical Trials, NCT02886559. Registered 01 September 2016

Multiple myeloma (MM) is a plasma cell malignancy that is currently incurable. Finding new targets and designing drugs are crucial for the treatment of MM. The two datasets (GSE6691 and GSE39754) are used to screen highly expressed antigen on MM cells. HLA-E was an ideal target for it was a hub gene, and also located in one of the key clusters. Highly expression of HLA-E mRNA on MM cells was also confirmed by real-time qPCR testing the MM patients' samples in Shengjing hospital. Crystal structure of HLA-E was obtained from Protein Data Bank (PDB ID: 3CDG) which was used to design targeting peptides with Molecular Operating Environment software. By analyzing interaction between CD94/NKG2A and HLA-E, a peptide with twelve amino acids was screened as a model peptide. Peptides library was constructed by randomly replaced non-key amino acid. Peptide-protein docking method was used to identify high affinity peptides. PEPTIDE 1-3 and model peptide were synthesized and identified the affinity to HLA-E by flow cytometer and confocal laser microscopy. At last, PEPTIDE3 (NALDEYCEDKNR) was found with the highest affinity. Taking all, HLA-E is a new treatment target, and PEPTIDE 3 is an ideal high affinity target-binding peptide candidate.

The covalently closed circular RNA has recently been proposed as a pivotal player in tumorigenesis. In the current study, we found that circ-CDYL was notably elevated in multiple myeloma tissue and plasma samples and had good diagnostic and prognostic efficacy. Functional assays showed that circ-CDYL enhanced the viability and DNA synthesis of multiple myeloma cells and inhibited apoptosis. Mechanically, cytoplasmic circ-CDYL was co-localized with miR-1180, and circ-CDYL absorbed miR-1180 to upregulate yes-associated protein (YAP), thereby facilitating multiple myeloma progression. Importantly, we further confirmed the existence of this circ-CDYL/miR-1180/YAP regulatory axis in vivo by using the xenograft tumor model. Taken together, our data demonstrate that circ-CDYL is novel promoter of multiple myeloma, and targeting circ-CDYL and its associated network implicates the therapeutic possibility for multiple myeloma patients. Impact statement Multiple myeloma (MM) is an extremely complex and heterogeneous disease, and its pathogenesis is poorly understood. Here, we described an important MM-related circular RNA (circRNA), circ-CDYL. It was remarkably increased in both MM cells and plasma. Depletion of circ-CDYL evidently stunted MM growth. Circ-CDYL could absorb miR-1180 and alleviated the repression of miR-1180 on YAP, leading to increased YAP expression, ultimately triggering MM uncontrolled growth. Therefore, our findings advance the understanding of MM pathogenesis, and also raise the possibility of considering circ-CDYL as a potential therapeutic intervention for MM.

PIWI-interacting RNA (piRNA) is a kind of non-coding single stranded RNA which plays major roles in epigenetic expressions, genome rearrangement, and regulation of gene and protein. Because piRNAs are abnormally expressed in various cancers, they can be used as novel biomarkers and therapeutic targets. However, the roles of piRNAs in cancer cell growth and survival are not well-known. Here, we are the first to provide evidence that PIWI-interacting RNA-004800 (piR-004800) is overexpressed in both exosomes from multiple myeloma (MM) patients' bone marrow supernatant and primary MM cells. The expression level of piR-004800 is positively correlated with the stages of MM, according to the international staging system (ISS). In MM cell lines, downregulation of piR-004800 induced apoptosis and autophagic cell death. This was accompanied by in vitro and in vivo inhibition of cell proliferation. Our previous study shows that sphingosine-1-phosphate receptor (S1PR) signaling pathway plays a crucial part in MM cell proliferation. In this study, we find that S1PR signaling pathway can regulate the PI3K/Akt/mTOR pathway through control of piR-004800 expressions. Taken together our data supports an oncogenic role for piR-004800 in MM, which sheds insight into a new mechanism that may lead to therapeutic targets in MM, an incurable plasma cell neoplasm.

Aims Multiple myeloma (MM) is the second hematological plasma cell malignany and sensitive to fingolimod (FTY720), a novel immunosuppressant. Previous study shows FTY720-induced apoptosis and autophagy can cause cell death in MM cells, however, the high death rate cannot fully be explained. The study aims to investigate further mechanism of how FTY720 kills MM cells. Materials and methods Experiments are performed on 25 human primary cell samples and two MM cell lines by flow cytometry, fluorescence microscopy, and transmission electron microscopy. Expressions of relative factors are tested by qRT-PCR or western blot. Key findings Ferroptosis-specific inhibitors, deferoxamine mesylate (DFOM) and ferropstatin-1 (Fer-1), reverse FTY720-induced cell death in MM cells. Glutathione peroxidase 4 (GPX4) and soluble carrier family 7 member 11 (SLC7A11), key regulators of ferroptosis, are highly expressed in primary MM cells and can be decreased by FTY720 at the mRNA and protein level in MM cells. In addition, FTY720 induces other characteristic changes of ferroptosis. Furthermore, FTY720 can dephosphorylate AMP-activated protein kinase subunit ɑ (AMPKɑ) at the Thr172 site by activating protein phosphatase 2A (PP2A) and reduce the expression of phosphorylated eukaryotic elongation factor 2 (eEF2), finally cause MM cell death. Using LB-100, a PP2A inhibitor, AICAR, an agonist of AMPK, and bafilomycin A1 (Baf-A1), an autophagy inhibitor, we discover that FTY720 induces ferroptosis and autophagy through the PP2A/AMPK pathway, and ferroptosis and autophagy can reinforce each other. Significance These results provide a new perspective on the treatment of MM.

In this study, the immunophenotype was retrospectively analyzed in 131 patients who received initial treatment for plasma cell myeloma (PCM) and the relationships of CD81 and CD117 with the clinicopathologic characteristics and prognosis were further evaluated. The Kaplan and Meier method and Cox regression survival analysis model were used to determine whether CD117 and CD81 were factors affecting the overall survival (OS) and progression‐free survival (PFS) of PCM patients. CD117 and CD81 positivity was demonstrated in 35.88% and 40.46% of the 131 patients, respectively. Kaplan‐Meier analysis showed that CD117 and CD81 were potential predictors of a patient's prognosis. Specifically, CD117(+) patients had longer PFS (P = 0.033) and OS (P = 0.002), while CD81(+) patients had shorter PFS (P = 0.001) and OS (P = 0.002). CD117(+) and CD81(−) patients had the longest PFS [P = 0.0183 compared to the CD117(−)CD81(−)/CD117(+)CD81(+) group; P = 0.0007 compared to the CD117(−)CD81(+) group] and the longest OS [P = 0.0331 compared to the CD117(−)CD81(−)/CD117(+)CD81(+) group; P = 0.0005 compared to the CD117(−)CD81(+) group]. Our results show that CD81 is an independent factor affecting the OS and PFS of PCM patients, and CD117 is an independent factor affecting the OS of PCM patients. CD117‐positive and CD81‐negative patients with PCM have a better prognosis.

PURPOSE To evaluate the use of 80 kVp and iterative model reconstruction (IMR) in lower extremity computed tomography angiography (CTA). MATERIALS AND METHODS Sixty patients were randomly assigned to Group A or Group B (both n=30) to further undergo CTA. Group A received Protocol 1 (P1) with 120 kVp, 180mAs, and 100mL of contrast agent with filtered back-projection (FBP). Group B received Protocol 2 (P2) and Protocol 3 (P3) with 80 kVp, 140mAs and 75mL of contrast agent with hybrid iterative reconstruction (P2) and IMR (P3). Mean intravascular attenuation (MIA), image noise, contrast-to-noise ratio (CNR), and signal-to-noise ratio (SNR) were compared. Radiologists assessed image quality on a 5-point scale, and radiation was compared between both groups. RESULTS Group A had 9 men and 21 women (mean age, 68.2±9.3 years [range: 53-85 years]), and Group B had 20 men and 10 women (mean age, 64.8±10.4 years [range: 37-81 years]). The MIA of P2 and P3 were significantly larger than that of P1 (P

Much progress has been made in understanding the mechanism of acute lymphocytic leukemia (ALL). However, for adult ALL, there is still a lack of an effective treatment. In the present study, we first used the Gene Expression Omnibus (GEO) database to identify differentially expressed genes (DEGs) between ALL cell lines and Hodgkin and non-Hodgkin cell lines. Then, the GEO database was also used to detect the DEGs in acute lymphoblastic leukemia (Reh) cells transfected with a normal control or a constitutively active variant of the IkB kinase β. Finally, we found that three key DEGs (CCL5, FSCN1, and HS3ST1) are involved in proliferation and apoptosis according to Gene Ontology (GO) and Kyoto Encyclopedia of Genes Genomes (KEGG) pathway analyses. Finally, we determined that all three target genes that participate in proliferation and apoptosis are regulated via the NF-kB signaling pathway.

Intrahepatic cholangiocarcinoma (ICC) is the second most common primary liver malignant tumor and has a poor prognosis. The prognostic factors associated with outcome remain poorly defined. In this study, we investigated the role of an important cell apoptosis initiator, Bcl-2 interacting mediator of cell death (Bim), by evaluating its expression and association with other clinicopathological features in ICCs. We analyzed 56 cases of ICC with clinical follow-up. The expression of Bim in ICC cells and other cellular components was evaluated by immunohistochemistry. Bim expression was considered up-regulated if Bim was detected in 10% or more of tumor cells. Of the 56 ICC samples, 19 (34%) had high Bim expression level, 15 (27%) were completely negative, and 22 (39%) were classified as low Bim expression (

Objective We undertook a single-center retrospective study to determine the relationship between CD9 and acute lymphoblastic leukemia (ALL). Materials and methods In total, 112 newly diagnosed patients in our center were enrolled in the study. Their clinical information was collected and the patients werefollowed over the course of the study. Flow cytometry was used to detect the expression of CD9. Results CD9 expression was more common in B cell acute lymphoblastic leukemia (B-ALL) and patients > 40 years old. CD9-positive patients exhibited a higher BCR-ABL fusion gene positive rate and higher neutrophil counts than CD9 negative patients (P= 0.004 and P= 0.004, respectively). Response to induction chemotherapy was not dependent on CD9 expression. CD9-positive patients had a lower 2-year overall survival rate than CD9-negative patients. Conclusion CD9 expression predicts some clinical characteristics and indicates an unfavorable prognosis in ALL patients.

Background: ATG-010 (selinexor) is a novel, oral selective inhibitor of nuclear export, which blocks exportin 1. US FDA has approved selinexor plus low dose dexamethasone (Sd) to treat patients (pts) with penta-refractory MM based on the STORM study. MARCH is a single arm, Phase 2, registrational study to assess efficacy and safety of Sd in Chinese pts with RRMM. Methods: Enrolled Chinese pts were previously refractory to PI, IMiD, and last line of therapy. ATG-010 (80mg) plus dexamethasone (20mg) was administered twice weekly. The primary endpoint was overall response rate (ORR) per independent review committee. The planned 82 pts would provide ~80% power to test against null hypothesis (H 0) of 15% ORR at one-sided α of 0.025 at the primary analysis, which is presented here. Results: As of 6 th May 2021, 9 (11%) of the 82 pts were still on treatment. Median follow-up was 10.6 months (mo) (range: 2.3-19.6). Median age was 60 years (39% ≥ 65yrs). Median duration from MM initial diagnosis was 3.2 years. A total of 61 pts (74.4%) had cytogenetic abnormalities (del(17p): 22.0%), 18 (22.0%) with baseline plasmacytoma, and 18 (22.0%) with creatinine clearance < 60ml/min. Median number of prior regimens were 5 (range 1-16); 23 pts (28.0%) had received daratumumab (triple-class exposure), 20 pts were triple-class refractory (TCR), and10 pts (12.2%) had undergone CAR-T therapy. ORR was 29.3% (95% CI: 19.7, 40.4), rejecting H 0, including 4 VGPR (very good partial response). Median duration of response (DOR) was 4.7 mo, median progression free survival (PFS) was 3.7 mo, and median overall survival (OS) was 13.2 mo. Among 20 TCR pts, ORR was 25.0% (95% CI:8.7, 49.1), mDOR 10.2 mo, mPFS 2.9 mo, and mOS 11.9 mo. Efficacy was evident in elderly pts (≥ 65yrs), with ORR 25% (95% CI: 11.5, 43.4) and mPFS 2.8 mo. Median OS and DOR were not reached. Sd also demonstrated a similar response rate in pts with high-risk cytogenetic abnormalities, with an ORR of 24.6% (95% CI: 14.5, 37.3). Efficacy of Sd was generally consistent across cytogenetic risk subgroups, including del (17p) pts with ORR 22.2% (95% CI: 6.4, 47.6), mDOR 3.8mo, and mPFS 2.9 mo. The most common non-hematologic treatment-emergent adverse events (TEAEs) of any grade included nausea (78%), hyponatremia (67.1%), weight loss (65.9%), decreased appetite (62.2%), asthenia (59.8%)/fatigue (15.9%), and vomiting (50.0%). The most common grade≥3 non-hematologic TEAE were hyponatremia (29.3%), pneumonia (26.8%), hypokalemia (12.2%) and asthenia (9.8%)/fatigue (2.4%). The most common grade≥3 hematologic TEAEs were anemia (57.3%), lymphopenia (76.8%), thrombocytopenia (51.2%), and neutropenia (40.2%). TESAE occurred in 54.9% of pts, with the most common being thrombocytopenia and pneumonia (14.6% each). TEAE led to death in 7 pts (8.5%). Elderly pts had no significantly increased risk of adverse events, however, given their limited physical state, drug exposure was shorter in the elderly subgroup (12.6 vs 16.1 weeks), suggesting more active supportive care is required. Conclusions: MM refractory to both IMiD and PI remains a high unmet medical need, especially in China. The MARCH study demonstrates statistically significant and clinically meaningful ORR with Sd in Chinese RRMM pts, and efficacy was consistent across subgroups, including the elderly and pts with high-risk cytogenetics. Adverse events were as expected and manageable with appropriate supportive care and dose modification. These data are compatible with the STORM study and offers a new, oral therapeutic option for MM patients. Disclosures Yu: Antengene Therapeutics Ltd.: Current Employment. Wang: Antengene Therapeutics Ltd.: Current Employment. Yang: Antengene Therapeutics Ltd.: Current Employment. Yu: Antengene Therapeutics Ltd.: Current Employment. Lynch: Antengene Therapeutics Ltd.: Current Employment.

The biofabrication of palladium nanoparticles (PdNPs) using aqueous leaf extract of Pelargonium graveolens is reported herein. The polyphenols present in the Pelargonium graveolens extract are mainly responsible for reduction and subsequent stabilization of formed PdNPs. UV-Visible spectroscopy (UV-Vis) absorption and reaction color change from yellow to brown indicated the formation of PdNPs. The as synthesized PdNPs were studied by using characterization techniques such as Fourier transform infrared spectroscopy (FTIR), Transmission electron microscopy (TEM), Energy dispersive spectroscopy (EDS), Zeta potential measurements and Selected area electron diffraction (SAED). FTIR analysis and Zeta potential measurements showed the capping of polyphenols onto the surface of PdNPs, which further responsible for preventing aggregation of PdNPs. TEM image showed that the PdNPs exists in the range from 50 to 150nm. Also, XRD pattern revealed the crystalline nature of as synthesized PdNPs. The in vitro cytotoxicity studies of Pelargonium graveolens extract capped PdNPs was conducted using human leukemia cell lines (K562) by following an MTT cell viability assay and is found that the cytotoxicity is dose dependent. Further, the synthesized PdNPs will open a new opportunities in the field of biomedicine. Also, the produced method is an alternative to the chemical synthetic approaches that are being used nowadays.

Live kinase B1 (LKB1) has been recognized as a tumor suppressor in many human cancers; however, LKB1 maintains self-renewal of hematopoietic stem cells (HSCs). The existence of leukemia stem cells (LSCs) is responsible for drug resistance and leukemia relapse. In acute myeloid leukemia (AML), CD34+CD38- fraction is the most enriched compartment for LSCs. We found that LKB1 was upregulated in CD34+CD38- AML cells. LKB1 downregulation suppressed the long-term proliferation of CD34+CD38- AML cells, induced CD34+CD38- AML cells into G2/M phase, and enhanced the sensitivity of CD34+CD38- AML cells to chemotherapy. Furthermore, LKB1 downregulation in CD34+CD38- AML cells inhibited tumor formation in NOD-SCID mice. Downregulation of LKB1 gene makes LSCs partly loose the characters as stem cells. Gene expression microarray showed that MAPK/ERK pathway was implicated in the regulation of CD34+CD38- AML cell proliferation by LKB1. Together, these findings demonstrate that LKB1 plays an important role in the maintenance of LSCs, which may be responsible for drug resistance and AML relapse.

BACKGROUND Regulatory B (Breg) cells are a group of B cells with immunomodulatory function, which mainly exert negative immunomodulatory function by secreting IL-10 and other cytokines. Due to their immunoregulatory properties, Breg cells may participate in the pathogenesis of acute myeloid leukemia (AML). This study was designed to explore the frequency of Breg cells and the relationship between the Breg cells and clinical data in patients with AML. MATERIAL AND METHODS A total of 46 (36 in peripheral blood, 10 in bone marrow) AML patients and 15 healthy donors (HD) were included for detection of Breg cells frequency by multicolor flow cytometry. All cases were divided into different groups according to FAB subtypes of leukemia, white blood cell count (WBC) levels, age, cytogenetic characteristics, and molecular abnormalities, and were compared the differences of Breg cell frequency. Survival curve analysis was performed to estimate the value of Breg cell frequency in prognosis among cases with AML. RESULTS We found that the frequency of Breg cells was higher in AML patients both in peripheral blood (PB) and in bone marrow (BM) compared with those in HDs. The AML patients with high WBC levels had higher Breg cell frequency compared with those with low WBC levels. Low-risk patients with had lower Breg cells frequency compared to the medium-risk patients. The patients with high WBC and high Breg cells frequency showed a shorter overall survival. Similarly, the overall survival of AML patients in the older group with high Breg cells frequency was significantly shorter than in the younger group with low Breg cell frequency. CONCLUSIONS For AML patients, the frequency of Breg cells was elevated, and high frequency of Breg cells may reveal poor prognosis.

Background: SAM domain- and HD domain-containing protein 1 (SAMHD1) is a cellular enzyme which is responsible for blocking replication in viruses and participates in the progression of many cancers. Objective: The aim of this study was to correlate the expression level of SAMHD1 with other apoptotic and autophagic genes in acute myeloid leukemia (AML) patients. Methods: In the present study, mRNA levels of SAMHD1 with other apoptotic and autophagic-related genes were evaluated in patients who were newly diagnosed with AML. Results: SAMHD1, Bcl-xl, Bax, Bak, XIAP, and cIAP1 were downregulated in the AML group compared to the non-AML group (p < 0.05). SAMHD1 expression did not correlate with the other genes, while most apoptotic genes were positively correlated with each other. SAMHD1 expression was not associated with the blood routine or blast percentage of the AML patients, while Bax, Bak, cIAP2, and LC3 were significantly correlated with white blood cells. No statistically significant differences were found between the studied genes and prognosis stratifications, but Bcl-xl, Bak, cIAP1, and Mcl-1, LC3 were expressed at lower levels in the unfavorable AML group compared to the controls. Conclusion: SAMHD1 and Bcl-xl, Bax, Bak, XIAP, and cIAP1 were downregulated in AML patients, while there were no significant differences in the clinical characteristics and prognosis with reference to SAMHD1 expression.

Chemotherapy resistance is still a primary clinical obstacle to the successful treatment of acute myeloid leukemia (AML). The underlying mechanisms of drug resistance are complicated and have not been fully understood. Here, we found that miR-199a-5p levels were significantly reduced in refractory/relapsed AML patients compared to those who achieved complete remission after chemotherapy. Consistently, miR-199a-5p was markedly decreased in Adriamycin-resistant AML K562/ADM cells in contrast with Adriamycin-sensitive K562 cells, and its decrement dramatically correlated with the chemoresistance of AML cells. Furthermore, we demonstrated that the basic and Adriamycin-induced autophagic activity in K562/ADM cells was higher than that in K562 cells. This inducible autophagy played a prosurvival role and contributed to the development of acquired drug resistance. Importantly, we investigated that miR-199a-5p could negatively regulate autophagy, at least in part, by inhibiting damage regulator autophagy modulator (DRAM1) expression at both the transcriptional and posttranscriptional level. miR-199a-5p bound directly to the 3′-UTR of DRAM1 mRNA which was a functional target of miR-199a-5p. Indeed, downregulation of DRAM1 gene by siRNA in K562/ADM cells resulted in autophagy suppression and chemosensitivity restoration. These results revealed that the miR-199a-5p/DRAM1/autophagy signaling represented a novel pathway regulating chemoresistance, indicating a potential therapeutic strategy for the intervention in drug-resistant AML.

Multiple myeloma (MM) is a malignant neoplasm of plasma, and exhibits several harmful effects including osteolytic injuries, hypercalcemia, and immune dysfunction. Many patients with MM succumb to the underlying malignancy. An S-phase kinase-related protein 2 (Skp2) inhibitor, designated SKPin C1, has been developed and confirmed to have an inhibitory effect on metastatic melanoma cells. This study aimed to determine the effect of SKPin C1 on MM. Normal B lymphocytes, THP-1 cells, and MM U266 and RPMI 8226 cells were exposed to various dosages of SKPin C1 for 48 h. Cell proliferation was determined by MTT, EdU staining, and cell cycle assays. Western blot assays were performed to assess intracellular protein levels of Skp2, p27, and cleaved caspase-3. The amount of ubiquitin attached to p27 was determined using an immunoprecipitation assay. The viability of U266 and RPMI 8226 cells was significantly inhibited by 10 μM SKPin C1 and the inhibitory effect was enhanced with increasing doses of SKPin C1. In contrast, 50 μM SKPin C1 only marginally decreased viability of normal B lymphocytes in 12 h. Skp2 and p27 expression in U266 and RPMI 8226 cells was higher and lower, respectively, than that in the normal B lymphocytes. Treatment with SKPin C1 or Skp2 knockdown increased p27 protein levels in U266 and RPMI 8226 cells by preventing p27 from being ubiquitinated, which slowed the cell cycle, inhibited cell proliferation, and triggered apoptosis. Therefore, this study suggested SKPin C1 as a potent inhibitor against aberrant proliferation and immortalization of MM.

e20002 Background: ATG-010 is a novel, oral selective inhibitor of nuclear export inhibiting exportin 1. In preclinical and clinical studies, ATG-010 has demonstrated activity against multiple myeloma (MM). ATG-010 (80 mg biweekly) plus dexamethasone (20 mg biweekly) (Sd) was approved by US FDA for treatment of patients (pts) with penta-refractory MM in 2019 based on the STORM study. MARCH is a single arm, Phase 2 study to assess efficacy and safety of Sd in Chinese pts with RRMM. Methods: Enrolled pts have been previously treated with and refractory to PI, IMiD, and the last line of therapy. Sd is administered in 4-week cycles. Primary endpoint is overall response rate (ORR) per independent review committee. The total planned enrollment of 82 pts provides ̃80% power to test against H0 of 15% ORR at one-sided α of 0.025. This abstract provides data from a planned analysis of the first 60 treated pts. Results: As of 13 Oct 2020, 18 (30%) of the 60 pts were on treatment. Median follow-up was 9.5 months (mo) (range: 1.9-12.8). Median age was 61 years (range 43-82; 42% > 65). Pts had received a median of 5 (range 1-16) prior MM regimens, with following baseline risk factors: 72% R-ISS II/III, 70% cytogenetic abnormalities, 22% del (17p13),20% renal impairment, 15% prior CAR-T therapy, and 25% pre-treated with daratumumab (considered ‘triple-class exposed’). ORR was 26.7% (95% CI: 16.1, 39.7). Median DOR was 4.6 mo (95% CI: 1.42, NE). Median PFS was 3.7 mo (95% CI: 1.92, 4.66). Median OS was not reached; 9-mo OS rate was 68.5%. ORR was 33.3% in triple-class-exposed pts, and 44.4% in pts with prior CAR-T. ORR was generally consistent across subgroups. Common TEAEs of any grade included: thrombocytopenia (87%), nausea (87%), leukopenia (85%), anemia (85%), lymphopenia (78%), neutropenia (73%), weight loss (72%), hyponatremia (65%), decreased appetite (63%), asthenia (62%)/fatigue (17%), hyperglycemia (53%), vomiting (52%), hypocalcemia (38%), hypokalemia (30%), diarrhea (30%), pneumonia (27%). Common TEAEs of Grade ≥ 3 included: anemia (60%), thrombocytopenia (55%), leukopenia (42%), lymphopenia (42%), neutropenia (38%), hyponatremia (28%), and pneumonia (23%). Thirty pts (50%) had TESAEs, including (> 3%): thrombocytopenia (15%), pneumonia (15%), anemia (6.7%), hyponatremia (3.3%). Eight pts (13.3%) had TEAEs leading to treatment discontinuation, including (> 2%): thrombocytopenia (5%) and pneumonia (3%). Three fatal TEAEs were pneumonia, intracranial hemorrhage and sudden death (1 each). Conclusions: In Chinese RRMM pts refractory to both IMiD and PI, with a highly unmet medical need, MARCH confirms the efficacy of Sd as a promising new oral therapeutic option with a manageable safety profile, which is consistent with STORM. Clinical trial information: NCT03944057.

Background Recent studies show that Liver X receptors (LXR) activation is involved in the regulation of tumor cell death in solid cancer via E2 factor (E2F) transcription factor or suppressor of cytokine signaling-3 (SOCS3) pathway. However, the effect of LXR activation on leukemic cell fate has not been tested. Methods Two human acute lymphoblastic leukemia (ALL) cell lines, Jurkat and SupT1, were cultured. Cells were transfected with small-interfering RNA (si-RNA) against SOCS3 and E2F family members (including E2F1, E2F2 and E2F3a) followed by treatment with LXR activator GW3965. The cellular biological behaviors, including proliferation, colony-forming ability and apoptosis were tested afterward. Results Activation of LXR by GW3965 significantly decreased the cell proliferation rates and colony-forming abilities in the Jurkat and SupT1 cells, but increased their apoptosis rates. Western blot assay show that GW3965 treatment dramatically up-regulated the SOCS3 protein in both cell lines, without affecting E2F1, E2F2 and F2F3a expression levels. SOCS3 inhibition by si-RNA transfection, instead of E2F1, E2F2 and F2F3a pathway inhibition, abolished the aforementioned effects of LXR activation on Jurkat and SupT1 cells. Conclusion Our finding suggests that LXR activation regulates leukemic cell fate and biological behavior via SOCS3 pathway, rather than E2F family members.

BACKGROUND To find economical and clinically available immune-related prognostic markers that could predict the overall survival (OS) of newly diagnosed multiple myeloma (NDMM) in the new drug era. MATERIAL AND METHODS Absolute lymphocyte count (ALC) and absolute monocyte count (AMC) were measured in routine blood samples from 102 patients with NDMM, and the lymphocyte-monocyte ratio (LMR) was derived. All the patients were receiving bortezomib-based chemotherapy as induction treatment. Log-rank testing was used for comparing the differences between groups. Univariate and multivariate tests were used to identify prognostic markers. RESULTS The median ALC and LMR values at diagnosis were 1.43×10⁹/L and 3.7, respectively, and served as the cutoff point. As prognostic factors, ALC, LMR, and a new staging system combining ALC and the ISS staging system (L-ISS) were expected to have a significant impact on predicting OS. Furthermore, multivariate analysis showed that ALC ≥1.43×10⁹/L (hazard ratio [HR]: 0.223; 95% confidence interval [CI]: 0.071-0.705; P=0.011), LMR ≥3.7 (HR: 0.363; 95% CI: 0.139-0.947; P=0.038), and L-ISS late stage (HR: 1.619; 95% CI: 1.065-2.743; P=0.027) were independent predictors for OS. CONCLUSIONS ALC and LMR can serve as surrogate markers for patients' antitumor immunity at the initial diagnosis of multiple myeloma. A new immune-related staging system, L-ISS, which combines ALC and the ISS staging system, can predict clinical outcomes in patients who are receiving bortezomib-based chemotherapy.

The present study aimed to investigate the effect of benzoxime on leukemia RBL-1 cell proliferation and a leukemic Sprague-Dawley rat model. Proliferation of RBL-1 cells was determined using an MTT assay. Sprague-Dawley rats were assigned randomly into three groups of 10 animals each, where the positive control group was administered an intravenous injection of normal saline, the negative control group was administered 1×106 RBL-1 cells and the treatment group was administered with 1×106 RBL-1 cells and then benzoxime (50 mg/kg/day) for 1 week. Increased dosage of benzoxime reduced RBL-1 cell viability from 92 at 2 µM to ٢١٪ at ١٢ µM after ٢٤ h. Benzoxime treatment prevented the loss of body weight in the rats with leukemia. Compared with the negative control rats, the body weight was determined to be significantly reduced (P