bluuebunny/crossref_metadata_2025 huggingface dataset:
MDS-MSC Derived Exosomes Promote MDS Cells Malignant Proliferation through RIG-1/Isgs Pathway Via RN7SL1
Authors: Guo Juan , Wang Jianxiang , Chang Chunkang
Published: December 2023

The interactions between bone marrow stem cells (BM-MSCs) and myelodysplastic syndromes (MDS) cells perform a crucial role in MDS pathogenesis by secreting cytokines ,growth factors, and exosomes. Although BM-MSCs induced growth of MDS cells has been studied, the role of exosomes from MDS-derived MSC (MDS-MSC-EXO) in this action remains unclear. In our study, we investigate the effect of MDS-MSC-EXO on the viability, proliferation, migration, cellular apoptosis of MDS cell lines, such as MDS-L and SKM-1. Our data identified that MDS-MSC-EXO can promote proliferation, migration, and decrease cell apoptosis. Both LR-MDS-MSC and HR-MDS-MSC-derived exosomes increased MDS cell growth.Exosomes mediate local cell-to-cell communication by transferring mRNAs, miRNAs, and proteins. In our study, we found that MDS-MSC-EXO expressed higher unshielded RN7SL1,an endogenous RNA normally shielded by RNA binding proteins SRP9/14, than that from health controls (HC-MSC-EXO). MDS cloned cells expressed higher retinoic acid inducible gene-I (RIG-I) and interferon-stimulated genes (ISGs), such as ISG15, IFIT1 and IFITM1, which are the receptor and effector molecules of RN7SL1. Both MDS-MSC-EXO and exogenous RN7SL1 can promote MDS cloned cells proliferation and stimulate ISGs expression by activating RIG-1. RIG-I inhibitor can block this effect. We demonstrate that MDS-MSC may promote MDS cloned cell proliferation through RIG-ISGs signal activated by exosomes-derived RN7SL1. Overall, our studies provide new insights that MSC-EXO functions the crucial roles in mediating the progression of MDS via RIG-1/ISGs activation, and demonstrate novel targets of RN7SL1 to the pathogenesis of MDS.This study will provide new ideas for MDS treatment in the aspect of microenvironment.
G Protein-Coupled Receptor 183 Plays a Prognostic Factor in Acute Myeloid Leukemia By Regulating Immune Regulation
Authors: Li Fenglin , Chen Dong , Li Chen , Zhuang Haihui , Ye Peipei , Jin Jie , Lu Ying
Published: December 2023

CONCLUSION

G protein-coupled receptor 183 (GPR183) is a critical oligoheptameric transmembrane receptor that regulates cellular immune responses. Its malfunction causes a variety of immunological and inflammatory disorders. GPR183 overexpression enhances B cell migration from the germinal center and plays a significant role in the pathogenesis of Chronic myeloid leukemia. However, its prognostic value and regulatory role in AML are not clear. This study aimed to reveal the prognostic significance of GPR183 in AML and the mechanism of its regulatory role in AML.

The expression level of GPR183 in 300 deno AML patients was analyzed by RT-qPCR. Combined with the clinical characteristics and treatment response of patients, the expression characteristics and clinical prognostic significance of GPR183 in AML were analyzed. The regulatory function of GPR183 in AML was investigated using shRNA-targeted knockdown or over expression of GPR183 in AML, and the impact of knockdown of GPR183 on tumor burden and survival of AML mice was further confirmed in vivo using an AML mouse model. By using bioinformatics techniques, the potential regulatory mechanisms of GPR183's effects on AML cells were further examined and verified.

The expression level of GPR183 in AML cells was higher than that in normal samples, and its expression was significantly higher in older AML patients than in younger ones. By univariate and multivariate analyses, it was found that the high expression of GPR183 was an independent poor prognostic factor in AML patients for overall survival(OS) and eventfree survival(EFS), and the knockdown of GPR183 in AML cells could inhibit the proliferation of AML cells, promote apoptosis, and inhibit the migration of AML cells, and the in vivo model of AML mice showed that the knockdown of GPR183 could reduce the tumor load and prolong the survival of AML mice. Overexpression of GPR183 in AML cells promoted the growth and increased the drug resistance of AML drug. Single-gene GESA revealed that AML patients with high GPR183 expression had HALLMARK_ALLOGRAFT_REJECTION, HALLMARK_TNFA_SIGNALING_VIA_NFKB, HALLMARK_INFLAMMATORY_RESPONSE, HALLMARK_COMPLEMENT, and HALLMARK_CLEARING_VIA_NFKB, and HALLMARK_INFLAMMATORY_RESPONSE. COMPLEMENT, HALLMARK_IL6_JAK_STAT3_SIGNALING, and HALLMARK_IL2_STAT5_SIGNALING pathways were activated, and all of these top 5 activated pathways were associated with immune regulation.

GPR183 plays a prognostic factor in Acute Myeloid Leukemia by regulating

immune regulation
Comparison of Condensed to Standard Schedule of High Dose Cytarabine Consolidation for Acute Myeloid Leukemia in First Complete Remission
Authors: Solh Melhem M. , Kilby Kristen , Baron Jimena , Zhang Xu , Bashey Asad , Holland H Kent , Bachier-Rodriguez Lizamarie , Morris Lawrence , Solomon Scott R.
Published: December 2023

Background

Traditionally, acute myeloid leukemia (AML) consolidation therapy for patients less than 60 years old with low to intermediate risk disease has been treated with high dose cytarabine (HDAC) cycles given on days 1, 3, and 5 (HDAC-135). However, more recent publications have assessed alternative dosing, namely administering HDAC on days 1, 2, and 3 (HDAC-123). National Comprehensive Cancer Network (NCCN) Guidelines for AML discuss this alternative dosing for HDAC and do not recommend one over another. A prospective study found that there was no cumulative hematologic toxicity and no change in survival when comparing HDAC-123 to HDAC-135 5. As a result, Northside Hospital began using HDAC-123 in patients less than 60 years old for AML consolidation therapy. The purpose of this study was to assess the safety, efficacy, and health care resource consumption associated with HDAC-135 versus the condensed HDAC-123 regimen at Northside Hospital.

Methods

This single-center, retrospective study included patients with AML between 18 and 60 years old who received at least one cycle of HDAC-123 or HDAC-135 at Northside Hospital Atlanta's outpatient clinic from January 1, 2018 to January 1, 2023. The primary outcome was time to hematologic recovery of white blood cell (WBC), absolute neutrophil count (ANC), and platelets. Secondary endpoints were the amount of transfusions needed, incidence of documented infections, rate of hospital admission, and length of hospital stay.

Results

A total of 51 patients were included. Twenty one patients received a cumulative total of 39 cycles of HDAC-123 and 30 patients received a cumulative total of 57 cycles of HDAC-135. Overall, baseline characteristics were similar between groups although hemoglobin and hematocrit were significantly lower in the HDAC-123 group. In the HDAC-123 group compared to the HDAC-135 group, the median day of WBC recovery was 15 and 24 days, respectively (p < 0.001). The median day of ANC recovery was 16 and 28 days, respectively (p < 0.001). The median day of platelet recovery was 16 and 20 days, respectively (p < 0.001).

Conclusion

The results of this retrospective review support the findings of other studies. HDAC-123 demonstrated a significantly reduced time to WBC, ANC, and platelet recovery compared to HDAC-135. HDAC-123 was also was associated with lower rates of microbiologically documented infections but did require more RBC transfusions. HDAC-123 may be preferred over HDAC-135 for consolidation therapy in patients less than 60 years old.
A Novel Transgenic Mouse Model of Down Syndrome Acute Lymphoblastic Leukemia Identifies Targetable Vulnerabilities
Authors: Junco Jacob J. , Rashid Raushan , Terrell Maci , Alozie Michelle , Rochette Max , Zorman Barry , Sumazin Pavel , Rowland Lauren , Dettorre Gino , Powell Reid T. , Stephan Clifford C. , Davies Peter J. , Moczygemba Margie M. , Yang Jun J. , Rabin Karen R.
Published: December 2023

Background: Children with Down syndrome (DS) have a 10-fold increased risk of developing B-cell acute lymphoblastic leukemia (B-ALL), and they have poorer survival due to increased relapses and treatment-related mortality (TRM). Targeted therapies for DS-ALL are needed to improve anti-leukemic efficacy and reduce the risk of TRM. Mouse models and cell lines recapitulating DS-ALL are lacking, and may aid in identifying new targets for DS-ALL.

Methods: We used the Dp(16)1Yey (Dp16) mouse model of DS, which has a triplication of ~115 human chromosome 21 (Hsa21) orthologues. We introduced Kras G12D and Pax5 heterozygosity, both driven in B cells by CD19-Cre, in Dp16 and non-DS wild-type (WT) mice. We performed RNA-Sequencing (RNA-Seq) and gene set enrichment analysis (GSEA) to identify differentially regulated signaling pathways in Dp16 and WT B-ALL blasts. We cultured B-ALL blasts from mice to generate immortal cell lines. We tested the chemosensitivity of Dp16 and WT B-ALL cell lines with 35 agents with known efficacy in hematologic malignancies, and with 481 anti-cancer compounds used in the Cancer Therapeutics Response Portal project, to screen for drugs effective in DS-ALL. We screened top candidate drugs in DS-ALL and non-DS ALL patient samples in vitro, and tested FK866 and cucurbitacin I in vivo in mice xenografted with a DS-ALL patient sample.

Results: Kras G12D.Pax5 +/- mice developed B-ALL with complete penetrance, with significantly shorter median survival in the Dp16 versus WT background (Figure 1A; 80 versus 114 days, p<0.0001). GSEA demonstrated upregulation of DNA repair signaling pathways in Dp16 B-ALL, recapitulating a signature observed in human DS-ALL. Growth of Dp16 and WT B-ALL cell lines, and DS-ALL and non-DS ALL patient samples, was inhibited at low nanomolar concentrations by novel therapies targeting NAMPT, DNA damage responses, autophagy, and JAK and PI3K/mTOR signaling. In mice xenografted with a DS-ALL patient sample, the NAMPT inhibitor FK866 significantly reduced the leukemic burden compared to vehicle (Figure 1B; 14.6% vs 22.4% after 4 weeks of treatment, p<0.005). The effect of FK866 was also significant after weeks 2 and 3 of treatment.

Conclusions: We have generated the first de novo mouse model and cell lines recapitulating DS-ALL, which we have employed in drug screens to identify novel therapeutic approaches. These studies suggest promising candidates for further study in DS-ALL and other high-risk ALL subtypes to reduce toxicity and improve outcomes.
A Systematic Review of Venetoclax and Azacitidine: Effectiveness and Safety for Newly Diagnosed and Relapsed Acute Myeloid Leukemia Patients
Authors: Ibrahim Ahmed , Yousaf Muhammad Abdullah , Anwar Zain , Anum . , Batool Maha , Rehman Mohammad , A Safdar Omar , Khattak Zeeshan Ahmed , Faraz Fatima , Khalid Huma
Published: December 2023

Introduction: Acute Myeloid Leukemia (AML) remains the most prevalent acute leukemia in adults, often associated with a bleak prognosis. Current treatment recommendations for elderly AML patients incorporate a combination of venetoclax (Ven) and azacitidine (AZA) following trials that underscored Ven's efficacy. This review seeks to analyze and summarize the literature concerning the effectiveness and safety of the Ven + AZA regimen for adult patients with newly diagnosed (ND) and relapsed/refractory (R/R) AML, and those unsuitable for intensive chemotherapy.

Materials and Methods: Following PRISMA guidelines, a comprehensive electronic literature search was conducted across PubMed, Embase, Clinicaltrials.gov, Cochrane Library, and Web of Science from inception to 2023. MeSH terms and relevant keywords for (Leukemia, Myeloid, Acute) AND (Venetoclax) AND (Azacitidine) were used. From 327 initially identified articles, 12 studies were selected for inclusion, and citation searching further added 2 studies, summing up to 14. We analyzed data from a combined patient pool of 1256.

Results: The review encompassed 13 non-randomized and 1 randomized clinical trials. The median patient age was 75.2 years. Primary outcomes comprised complete remission (CR) and complete remission with incomplete count recovery (CRi), yielding a pooled CR/CRi of 57.8%. Secondary outcomes included an overall response rate (ORR) of 61.1%, and a median overall survival (mOS) of 8.94 months with a median follow-up duration of 13.25 months (Table 1). Notably, high-grade adverse effects were predominantly hematological (anemia, neutropenia, thrombocytopenia, febrile neutropenia) while low-grade effects primarily involved gastrointestinal symptoms (nausea, vomiting, diarrhea, constipation, decreased appetite, etc).

Conclusion: The current data suggest that the Ven + AZA regimen is both efficacious and well-tolerated for treating newly diagnosed and relapsed/refractory AML. Cytopenias across all three cell lines emerged as the most reported adverse effects of Ven + AZA therapy. Ongoing Phase III clinical trials are expected to enhance our understanding of this regimen's efficacy and safety profile, solidifying its role in standard AML therapy.
Prognostic Impact of Minimal Disseminated Disease (MDD) and Minimal Residual Disease (MRD) in Chinese Pediatric Patients with ALK-Positive Anaplastic Large Cell Lymphoma (ALCL)
Authors: Yang Keyan , Yang Jing , Li Yang , Li Fu , Yang Xiaomei , Liu Ying , Zhu Qing , Sun Lirong , Jiang Jian , Dai Yunpeng , Guan Guotao , Liu Ansheng , Zheng Mincui , Wu Pan , Wang Jian , Qu Lijun , Zhang Leping , Jia Yueping , Liu Wei , Zhou Jianwen , Zhang Baoxi , Wang ZhuJun , Wang XiGe , Gao Hui , Zheng Qinlong , Zhang Yonghong
Published: December 2023

# Keyan Yang and Jing Yang contribute equally to this article.

* Corresponding to both Qinlong Zheng (zhengql@gobroadhealthcare.com) and Yonghong Zhang (zhangyongh@gobroadhealthcare.com)

Backgrounds:

Anaplastic lymphoma kinase positive anaplastic large cell lymphoma (ALK+ALCL) is characterized by the occurrence of the ALK fusion and subsequently ALK fusion kinase protein expression. It has been reported that minimal disseminated disease (MDD) and minimal residual disease (MRD) detected by RQ-PCR are independent prognostic factors.

Purpose & Methods:

To explored the prognostic roles of MDD and MRD in Chinese pediatric patients with ALCL, we conduct a retrospective study in a cohort of 204 Chinese children and adolescent ALK+ALCL patients treated at multiple centers of the China Network of Childhood Lymphoma (CNCL). The median follow-up time was 39 months (95%CI: 34-44.7). MDD level as ALK fusion copy number was measured by quantitative RT-PCR at the initial diagnosis. Based on the Overall Survival (OS) data, cut-off values of 1.63 in peripheral blood (PB) and 1.43 in bone marrow (BM) were determined by using the maximally selected rank statistics, with the c-index values of 0.904 in PB and 0.895 in BM.

Results:

The prevalence of MDD in PB and/or BM of Chinese pediatric patients with ALK+ALCL was 24.8%, while the MDD level were significantly correlated between PB and BM (R=0.8, p<2.2e-16). In addition, the 3-year OS (PB, 87.8% vs. 100%; BM, 87.9% vs. 100%) and EFS (PB, 73.2% vs. 94.8%; BM, 80.0% vs. 93.2%) were revealed with significant difference, when analyzed by MDD level. The combined analyses of both MDD level (with the same cut-off value) and MRD results (positive vs. negative), either after 1 st course of treatment (MRD1) or 2 nd course of treatment (MRD2), indicated the further poor prognosis, both in 3-year OS (PB, MRD1, 64.8% vs. 100%, MRD2, 72.9% vs. 100%; BM, MRD1, 64.8% vs. 100%, MRD2, 68.8% vs. 100%) and EFS (PB, MRD1, 40.0% vs. 95.3%, MRD2, 45.0% vs. 95.1%; BM, MRD1, 40.0% vs. 94.7%, MRD2, 35.7% vs. 94.4%).

Conclusion:

Summary, in this work, MDD level detected by quantitative RT-PCR was revealed as a strong factor in prognostic evaluation of Chinese children and adolescent patients with ALK+ALCL, which showed its important role in clinical detection at initial diagnostic. In future, the further validation work could be carried out in different cohort of ALK+ALCL patients, even with larger enrolled population size and longer follow-up time.
The Pediatric-Inspired Regimen Improved Quality and Quantity of Life for Patients with Acute Lymphoblastic Leukemia，Beyond Age, Risk Stratification, and Hematopoietic Stem Cell Transplantation
Authors: Chen Junjie , Wang Zhixiang , Liu Qifa , Zhou Hongsheng
Published: December 2023

Abstract

Purpose

Patients in the Nanfang hospital with acute lymphoblastic leukemia (ALL) have had continuous survival improvement since the 2000s. To examine the main factors affecting prognosis, we conducted a retrospective analysis at a single center.

Patients and Methods

1023 evaluable patients were in this analysis (median age, 26, with a range of 14 to 73 years). The pediatric-inspired regimen, PDT-ALL-2016 regimen, was introduced in 2016, since then all patients received this treatment (N=414). While all patients between 2000 and 2015 received adult regimens (N=612). The median follow-up time for the PDT-ALL-2016 cohort was 44.7 months, and that for the adult regimen cohort was 92.9 months.

Results

For the whole series, the 5-year overall survival (OS5y) was 57.8±5.3% in PDT-ALL-2016 cohort and 31.3±5.4%in the adult regimen cohort (P<0.001). There was no significant difference in treatment-related mortality (TRM) between the two cohorts, with rates of 11.9% and 10.6%, respectively (P=0.652). The PDT-ALL-2016 cohort showed a lower cumulative incidence of relapse (CIR) at 5-year (38.1%) compared to the adult regimen (61.1%, P<0.001). Subgroup analysis revealed that all age groups, except for patients aged 41-50 years (HR=0.77, 95% CI, 0.48-1.21, P=0.251), can benefited from the PDT-ALL-2016 regimen. Notably, the older patients subgroup (50-73 years old) showed a significant improved outcome within the PDT-ALL-2016 cohort, compared with adult regimen cohort (HR=0.3, 95% CI, 0.17-0.54, P<0.001). Within this subgroup, CIR and TRM were 44.9% vs. 75.1% (P<0.001) and 4.3% vs. 12.1% (P=0.196), in PDT-ALL-2016 cohort and adult regimen cohort, respectively. Furthermore, subgroup analysis indicated that both high-risk and standard-risk patients had better outcome in the pediatric-inspired regimen cohort. For the HR group, OS5y were 25.1±6.3% vs. 55.5±6.1% (P<0.001), and EFS5y were 18.8±5.8% vs. 43.1±5.9% (P<0.001) in two cohorts. Patients who underwent allo-HSCT could also benefit from PDT-ALL-2016 regimen. For this subgroup, OS5y were 47.7±7.1% vs. 67.7±6.1% (P<0.001), and EFS5y were 37.2±6.7% vs. 53.9±6.7% (P<0.001) in adult regimen cohort and PDT-ALL-2016 cohort, respectively.

Conclusion

For adult ALL patients, compared with adult regimen, pediatric-inspired regimen resulted in significant improved outcome in all age and risk groups, as well as in patients who underwent allo-HSCT.

This research was supported by the National Natural Science Foundation of China(NFSC82170163, 81970147), Clinical Study of Nanfang Hospital(LC2016ZD009/2019CR012).
A Phase 2, Open-Label Study to Assess the Pharmacokinetics, Pharmacodynamics and Safety of Orally Administered Epeleuton in Patients with Sickle Cell Disease
Authors: Andemariam Biree , Sheehan Vivien A. , Hamza Moayed , Kelly Kirsty , Climax John
Published: December 2023

Background.

Sickle cell disease (SCD) is a rare hereditary multi-system disorder that is caused by a single mutation in the beta allele of the hemoglobin gene, leading to the production of sickle hemoglobin (HbS). HbS polymerizes when deoxygenated, resulting in red blood cell (RBC) sickling and membrane damage, ultimately leading to a cascade of events which include hemolysis, chronic anemia, inflammation, and vaso-occlusion. Despite recent progress, there is a need for additional disease-modifying therapeutic options.

Epeleuton is 15-hydroxy eicosapentaenoic acid (15(S)-HEPE) ethyl ester, a novel synthetic second generation w-3 fatty acid which targets key drivers of hemolysis and multicellular adhesion. In preclinical studies in Townes humanized SCD mice and SCD patient RBCs, epeleuton acts as a disease-modifying agent by simultaneously decreasing (a) systemic and local inflammatory activation, (b) endothelial adhesion, (c) organ damage and (d) intravascular hemolysis and sickling. Epeleuton has been administered to 343 subjects in clinical trials, with a favorable safety and tolerability profile.

Objective

To evaluate the pharmacokinetics, pharmacodynamics and safety of orally administered epeleuton in patients with SCD.

Study Design and Methods.

This open-label, phase 2, multicenter study (NCT05861453) will enroll approximately 30 adult patients with a confirmed diagnosis of SCD (HbSS and HbSß0-thalassemia). Participants must have hemoglobin levels of 5.0-9.5g/dL at screening, 2-10 vaso-occlusive crises (VOCs) in the past 12 months, and a high adhesion index at screening defined as RBC laminin adhesion > 400 cells. Concomitant treatment with a stable dose of hydroxyurea is permitted during the study. Key exclusion criteria include receiving an RBC transfusion within three months of enrolment, receiving voxelotor, crizanlizumab or l-glutamine within six weeks of enrolment and, prior hematopoietic stem cell transplant.

The trial has a 28-day screening period, followed by a 16-week treatment phase and a 30-day post-treatment follow-up period. Study participants will attend the clinic on 6 occasions at screening, baseline, weeks 4, 8 and 16 (end-of-treatment) and the week 20 post-treatment follow-up visit. Enrolled patients will receive epeleuton 2g BID (4g daily) for 16 weeks. Study endpoints include change from baseline in hemoglobin levels, hemolytic markers, assessments of RBC health, soluble adhesion molecules, RBC adhesion, whole blood adhesion and rates of VOC.

Conclusion:

Treatments that can simultaneously target hemolysis and cellular adhesion may have an important disease-modifying utility for patients with SCD. The results of this study are anticipated to confirm the potential of epeleuton to address multiple aspects of SCD and to guide the design and conduct of future studies in patients with SCD.
Mega-Dose Decitabine Intensified Regimen Is More Effective at Eliminating Pre-HSCT Measurable Residual Disease Compared to the Bu/Cy Regimen: A Multicenter Prospective Phase II Study
Authors: Zheng Hao , Lv Meng , Yan Chenhua , Liu Jing , Zhang Yuanyuan , Mo Xiao-Dong , Sun Yuqian , Wang Yu , Zhang Xiaohui , Xu Lanping , Huang Xiao-Jun
Published: December 2023

Background:

Acute myeloid leukemia (AML) patients with high-risk pre-HSCT measurable residual disease (MRD, KMT2A-r, etc.) have a high relapse rate (>50%) even after allogeneic hematopoietic stem cell transplantation(allo-HSCT). In 2018, we developed two multi-institutional, single-arm, prospective phase II trials, to investigate the efficacy and safety of a novel intensified conditioning with “Mega-Dose 400mg/m 2” decitabine following allo-HSCT for high-risk MRD AML (NCT03793517).

Method：

Inclusion: 1) Detectable pre-HSCT MRD detected by recurrent genetic abnormalities (KMT2A-r, DEK, etc.) in ELN adverse-risk AML; or high-level pre-HSCT MRD in all risk groups, defined as the reduction of recurrent genetic abnormalities ≤1 log compared to initial diagnosis (RUNX1:RUNX1T1, etc.); 2) Age≥18; no HSCT history, available donor; ECOG 0-2, HCT-CI 0-3. Uniform conditioning regimen: intravenous decitabine (200mg/m 2/day) on days-12, -11, intravenous cytarabine+ busulfan+ cyclophosphamide (Bu/Cy) on days -10 to -2 (Blood. 2015;125(25):3956-62). The primary endpoint was cumulative incidence of relapse (CIR). Competing risk analysis and time-dependent Cox model were constructed in R software 4.21. Contemporary MRD+ AML patients with the same recurrent genetic abnormalities following Bu/Cy regimen or relapsed/refractory AML patients following 400mg/m 2 decitabine regimen (NCT03799224) were enrolled as nest-control to compare the post-HSCT kinetics of recurrent genetic abnormalities.

Results: Between Dec 2018-Feb 2023, twenty-one patients received allo-HSCT from HLA-matched siblings (n=2), and haploidentical donors (n=19), including 13 patients with KMT2A-r genes. Median follow-up was 19 (4.6-58) months after HSCT. The cumulative 30-day neutrophil (median 13 days) was 100.0% and 100-day platelet engraftment and 95.2% (median 21 days); all patients reached negative MRD by flow cytometry after HSCT. This conditioning regimen was well tolerated without irreversible grade III-IV toxicity peri-engraftment.

Primary endpoint: 2-year CIR was 5.6% (95%CI: 0.3-23.3). Secondary endpoint: 2-year NRM was 4.8% (0.3-20.2); 2-year LFS was 89.6% (77-100); 2-year OS was 89.3% (76.2-100). The median fold reductions (log10) of leukemia burden with recurrent genetic abnormalities were 3.6 (range 1.3-5.1) one month after HSCT (Figure).

Conclusion: Compared to Bu/Cy regimen, “Mega-Dose” decitabine (400mg/m2) is a novel conditioning regimen with improved efficacy to eradicate pre-HSCT MRD and reduce post-HSCT relapse.
Statin Use and Its Effects on Survival Outcomes and Rates of Gvhd in Allogeneic Stem Cell Transplant Patients: Results from Real-World Cohorts
Authors: Fuqua Jacob , Abonofal Abdulrahman , Safi Danish , Khan Maimoona , Khan Hiba , Yingling Spencer , Safi Salah Ud Din
Published: December 2023

Introduction:

The effect of statin use in allogeneic stem cell transplant remains unclear. There have been conflicting results in studies examining the impact of statins on engraftment, graft-versus-host-disease, survival, and long-term outcomes in stem cell transplant recipients.

Methods:

Retrospective data was extracted using the TriNetX database. The primary endpoint was overall survival at 5 years, risk of death, and graft-versus-host-disease in the two cohorts.

Results:

5045 patients were identified in cohort-1 (statin cohort) and 10,181 patients were identified in cohort-2 (non-statin cohort). Table-1 shows patient characteristics at baseline. Propensity-score-matching was used to balance the two cohorts. Patient count in each group after matching was 3702 (Table-2). Overall survival was 59.32% in cohort-1 versus 48.55 % in cohort-2, with HR of 0.685 (95% CI 0.634, 0.740) in favor of cohort 1 (Figure-1). Median OS for cohort-1 was not reached versus 1593 days for cohort-2. Risk of death in cohort-1 and 2 was 0.311 and 0.4 respectively (Figure-2), with a risk difference for the death of -0.089 (95% CI, -0.110, -0.067, p-value <0.001), in favor of cohort-1. Risk of graft-versus-host-disease was 0.648 and 0.674 in cohort-1 and 2 respectively (Figure-3), with a risk difference of -0.026 (95% CI -0.054, 0.002, p-value 0.065), and risk ratio of 0.961 (95% CI 0.921, 1.003). Survival-probability was higher at 5 years in cohort-1 regardless of presence or absence of GVHD.

Conclusions:

Our retrospective analysis of a large patient cohort showed improved OS and decreased risk of death with statin use in allogeneic stem cell transplant patients, regardless of presence or absence of GVHD, even though the average total and LDL cholesterol levels were higher in statin-group. The difference in graft-versus-host-disease was not statistically significant in both cohorts, however, there was a trend towards decrease GVHD in statin-cohort. To the best of our knowledge, this is the first large database based study evaluating the effect of statin use on outcomes in patients undergoing allogeneic stem cell transplant. Phase 3 clinical trials are needed to further answer this question.
Revumenib Maintenance Therapy Following Revumenib-Induced Remission and Transplant
Authors: Zucenka Andrius , Issa Ghayas C. , Arellano Martha , Khazal Sajad , Khera Nandita , Stock Wendy , Cuglievan Branko , Gu Yu , Nguyen Huy Van , Smith Angela R. , Stein Eytan M.
Published: December 2023

Background: The potent and selective oral menin-histone-lysine N-methyltransferase 2A (KMT2A) inhibitor revumenib (SNDX-5613) induced complete remissions with clearance of residual disease in acute leukemias refractory to multiple previous lines of therapy ( Nature. 2023;615:920-924). Here we report outcomes following the resumption of revumenib after hematopoietic stem cell transplant (HSCT).

Methods: Patients aged ≥30 days with relapsed or refractory (R/R) acute leukemias with genetic alterations associated with HOXA overexpression, including KMT2A-rearranged ( KMT2Ar) or nucleophosmin 1 ( NPM1)-mutated leukemias, were enrolled in the AUGMENT-101 phase 1/2, multicenter, open-label, dose-escalation study (NCT04065399). Patients received revumenib every 12 hours (q12h) in 28-day continuous cycles. Patients who achieved a complete response (composite definition [CRc]), morphological leukemia-free state, or partial response could undergo HSCT without leaving the study. Revumenib was stopped before the HSCT conditioning regimen but, per a protocol amendment, could be resumed after HSCT if the patient was in CRc. Measurable residual disease (MRD) was assessed using multiparameter flow cytometry and/or polymerase chain reaction.

Results: Between November 5, 2019, and June 28, 2023, a total of 131 phase 1 patients were enrolled and treated in the AUGMENT-101 study. Nine patients with acute myeloid leukemia (AML) from the AUGMENT-101 study resumed revumenib (8 after transplant and 1 after a stem cell boost [Table 1]). Seven patients had KMT2Ar and 1 patient each had nucleoporin 98 rearranged (NUP98r) and mutated NPM1. Revumenib was resumed 59 to 180 days after HSCT (Table 2). Dose was reduced for 4 of 9 patients to mitigate adverse events of thrombocytopenia (n=3) and leg pain (n=1), and revumenib was discontinued in 4 of 9 patients because of progressive disease (n=2), cytopenias (n=1), and not reported (n=1). Revumenib duration of treatment (DOT) in the maintenance setting at the time of this analysis ranged from 23 to 588 days, with treatment ongoing for 5 of the 9 patients. CRc was maintained in 6 of 9 patients after HSCT and maintenance revumenib. One patient with reported MRD after HSCT converted to MRD-negative status following initiation of revumenib maintenance therapy. Overall, MRD-negative remissions were maintained in 5 patients as of the data cut off.

Conclusions: With 3 patients on revumenib maintenance therapy for more than a year, long-term responses, including conversion to MRD-negative status, were seen in these heavily pretreated patients with AML. Resuming revumenib post HSCT had a tolerable safety profile consistent with that previously reported for the AUGMENT-101 study.
Outcomes of Treosulfan Vs. Busulfan Based Conditioning Regimens in Adult Patients Undergoing Allogeneic HSCT: Real Life Data from a Single Center
Authors: Uzay Ant , Gündogdu Yasemin , Kartı Süleyman Sami , Koşan Barış , Yetiş Tuğba
Published: December 2023

Introduction

The type of conditioning regimen has a great impact on the outcome of patients who undergo allogeneic HSCT since graft versus host disease (GVHD), infections, regimen related organ and tissue toxicities are among the most important causes of post-transplant mortality. Despite the regimen related toxicity profile of busulfan, supported by information from the results of clinical trials and real-world data, it is still commonly used worldwide. Treosulfan has advantages in terms of dose of administration, lower incidence of sinusoidal obstruction syndrome and lower neurotoxicity. We aimed to retrospectively investigate outcomes and compare results of patients who underwent matched and haploidentical allogeneic HSCT with treosulfan based or busulfan based reduced intensity conditioning, non-myeloablative conditioning and myeloablative conditioning regimens in our institution.

Methods

From September 2016 to November 2022, treosulfan was administered to 94 patients while 85 patients received busulfan. We analyzed outcomes as regimen related-toxicity, chronic and acute GVHD, overall survival, non-relapse mortality, relapse related mortality and fungal infection. The myeloablative dose of busulfan was 12.8 mg/kg while it was 9.6 mg/kg for the non myeloablative regimen which was combined with fludarabine. The myeloablative dose of treosulfan was 42 mg/m2 while a dose range of 30-36 mg/m2 was administered for the reduced intensity conditioning.

Results

The median follow up was 14 months for the treosulfan group while it was 11 months for the busulfan group (p = 0.16). Regimen related toxicity, which was monitored during the hospital stay and 3 months after discharge were 11.7% and 7.1% for treosulfan and busulfan respectively and were similar between two groups. Extensive chronic GVHD was encountered in 15.7% of the patients in the treosulfan group compared to 32.1% in the busulfan group (p < 0.001). Similarly, chronic skin GVHD was observed in 3.6% of the patients who received treosulfan while it was seen in 22.6% of the busulfan group (p < 0.001). Acute GVHD (grade 3 or higher) was encountered in 32.2% of the patients within the treosulfan group while it was encountered in 31.6% of the patients in the busulfan group. Overall survival was 47.5% and 36.5 % in the treosulfan group and busulfan groups respectively. The relapse-related mortality was 17 % in the treosulfan group while it was 34% in the busulfan group. Fungal infection was observed in 23.4% and 36.5% of the patients in treosulfan and busulfan groups respectively.

Conclusion

Treosulfan, with a lower chronic GVHD incidence and similar regimen related toxicity profile appears to be a safe alternative to busulfan and prospective randomized controlled trials are needed to confirm the results in our study.

Keywords: Busulfan; treosulfan; conditioning regimen; stem cell transplantation
Palmitoleic Acid Extracted from Fish Oil Inhibit aGVHD By Immune Regulation
Authors: Xu Jingjing , Zhu Haojie , Chen Dabing , Kong Hui , Chen Shaozhen , Ye Chenjing , Hu Jianda , Yang Ting
Published: December 2023

Objective: This study aims to explore the immunosuppressive effect of palmitoleic acid (POA), derived from fish oil extract, on lymphocytes in vitro and its potential impact on the clinical outcome and survival prognosis of rodents with acute graft-versus-host disease (aGVHD).

Methods: In vitro experiments involved using CCK8 to determine the influence of various concentrations of POA on the growth and proliferation of lymphocytes. Flow cytometry was employed to assess POA's inhibitory effect on T lymphocyte activation triggered by fluorobol ester (PMA) and ionomycin (IM). For evaluating the therapeutic effect of POA on aGVHD, C57bl/c mice were used as donors and BALB/C mice as recipients. The aGVHD mouse model was established to observe the impact of POA on aGVHD treatment, survival, and prognosis.

Results: In vitro experiments demonstrated that POA concentrations ranging from 250uM to 500uM inhibited the proliferation of PMA and IM-activated T lymphocytes and reduced the proportion of CD4+CD25+ cells without causing significant cytotoxicity. The aGVHD mouse model exhibited clinical symptoms like bristling, depilation, anal redness and swelling, and loose stools, along with characteristic pathological changes in the liver and small intestine. Treatment with POA significantly extended the survival period and reduced the clinical score of aGVHD in the model mice.

Conclusion: Palmitoleic acid derived from fish oil shows promise as a potential treatment for acute graft-versus-host disease following allogeneic hematopoietic stem cell transplantation, warranting further research on its immunosuppressive properties.

Keywords: Fish oil extract, palmitoleic acid, acute graft-versus-host disease, allogeneic hematopoietic stem cell transplantation, immunosuppression.
Malaria in Children with Sickle Cell Anaemia in Areas with Low, Moderate and High Transmission in Uganda
Authors: Namazzi Ruth , Idro Richard , Kalibala Dennis , Ssenkusu John , Akun Pamela , Mboizi Vincent , Gondwe Thandile Nkosi , Munube Deogratias , Kasirye Philip , Nabaggala Catherine , John Chandy C. , Green Nancy S. , Robberstat Bjarne , Hensbroek Boele van , Kuile Feiko ter , Phiri Kamija S. , Opoka Robert
Published: December 2023

Background. Few large prospective studies have evaluated burden and outcomes of malaria in children with sickle cell anaemia (SCA) in malaria endemic countries. We evaluated the incidence, complications and outcome of malaria in three cohorts of Ugandan children with SCA in three areas with differing malaria transmission.

Methods. Cohort 1 were SCA aged 3-9 years, enrolled in the hydroxyurea therapy for neurological and cognitive protection in Uganda (BRAINSAFE II) trial at Mulago Hospital, a low transmission area, while cohort 2 and 3 aged 6 months to 15 years, were enrolled in the dihydroartemisinin-piperaquine (DP) or sulphadoxine-pyrimethamine (SP) for the chemoprevention of malaria in SCA (CHEMCHA) trial at Jinja Hospital (moderate transmission) and Kitgum Hospital (high transmission). In cohort 1, all received SP for malaria chemoprophylaxis and hydroxyurea at 20-30mg/kg/day, while cohorts 2 and 3, received either DP or SP for malaria chemoprevention, and a proportion (10%) received hydroxyurea in the study.

Results. A total of 706 participants were enrolled: 267, 249 and 190 at Mulago, Jinja and Kitgum respectively. The mean age was 6.5 (SD 3.4) years; 5.1 (1.7), 7.9 (4.3) and 6.8 (3.5) years for Mulago, Jinja, and Kitgum respectively. Incidence of malaria was 13 (95% CI 6, 20) per 100 child years in low, 38 (95% CI 26, 51) in moderate and 104 (95% CI 64, 144) in the high transmission area, p<0.001. Adjusting for hydroxyurea treatment, incidence of malaria was 33 (95%CI 14, 52) per 100 child year on hydroxyurea and 51 (95%CI 40, 62) per 100 child years without hydroxyurea, p=0.001. The most common SCA-related complications were anaemia (39.6%, 133/336), and pain (27.7%, 93/336) among children with malaria. Over a period of 1042.8 person years, there were 115 admissions for malaria, with an overall incidence of 11 per 100 child year (95% CI 9, 13), and this differed across sites, p<0.001. Overall, 1.5% (11/706) children died, and 18.2% (2/11) deaths were directly related to malaria infection.

Conclusion. Malaria incidence remains high among Ugandan children with SCA, and differs by transmission patterns. Prevention strategies should be strengthened, especially in high transmission areas.
Cytomegalovirus Reactivation Concurrent with Bloodstream Infection Early after Allogeneic Hematopoietic Stem Cell Transplantation: Association with Poor Prognosis
Authors: Ren Jinhua , Chen Shaozhen , Yang Ting , Hu Jianda
Published: December 2023

In patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT), infections are a leading cause of death, particularly cytomegalovirus reactivation (CMVr) and bloodstream infection (BSI). This retrospective study aimed at evaluating the incidence of CMVr and BSI, identify the risk factors, assess their impact on survival, and examine the association between CMVr and BSI in allo-HSCT recipients during the first 100 days post-transplantation. The study population consisted of 500 allo-HSCT recipients who were CMV-DNA-negative before allo-HSCT. Of these, 400 developed CMVr, and 75 experienced BSI during the 100 days after allo-HSCT. Multivariate regression analysis indicated that graft failure and acute-GVHD were significant risk factors for poor prognosis, while CMVr and BSI were not. Among the 500 patients, 56 (14%) developed both CMVr and BSI. CMVr did not increase the incidence of BSI, but the combination of CMVr and BSI significantly reduced the 6-month overall survival (P=0.003) and long-term survival (P=0.002). Our study provides real-world data on the impact of post-transplant CMVr and BSI on survival, particularly in regions such as our China province, where CMV IgG prevalence is high.
Neurocognitive Performance Changes with Chimeric Antigen Receptor T-Cell Therapy in Patients with Hematologic Malignancies
Authors: Giri Smith , Giri Smith , Ubersax Clare , Tucker Abigail , Bal Susan , Godby Kelly , Costa Luciano , Bhatia Smita , Williams Grant , Ravi Gayathri , Narkhede Mayur , Murdaugh Donna
Published: December 2023

Introduction:

Chimeric antigen receptor (CAR) T cell therapy is a transformative therapy that has revolutionized the care of patients with hematologic malignancies. However, CAR-T cell therapy is associated with several short-term toxicities such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). The impact of CAR-T cell therapy on neurocognitive outcomes is unknown. Here, we report on our prospective study examining the changes in neurocognitive performance before and after CAR T cell therapy.

Methods:

This single-center prospective cohort study recruited consecutive recipients of CAR-T cell therapy enrolled in a prospective study NCT05556928 and a phase II clinical trial NCT04975555. Patients underwent neurocognitive assessment using the NIH Toolbox Cognition Battery (NIHTB-CB). Baseline assessment was done within 3 weeks before receiving CAR-T cell therapy. Follow up assessment was conducted at 90 days of receiving CAR T therapy. Domain specific T-scores adjusted for age, sex, race/ethnicity, and education were calculated. Change in T-scores between pre and post assessments were evaluated, with significant cognitive change defined as +/- 0.5 standard deviations from the mean.

Results:

Twenty-six eligible patients were identified, of which 9 completed both pre and post assessments. The median age was 66 years (range 45-79) at the time of CAR T cell therapy with 76.9% males and 38.5% being Non-Hispanic Black. Cancer types included diffuse large B-cell lymphoma (46.2%), multiple myeloma (38.5%), and follicular lymphoma (11.5%). Our baseline cognitive assessment showed that our eligible patient cohort had a median total composite T-score of 42 (range 30-64); twelve (46%) patients were one or more standard deviations below the mean. Of the 9 patients that completed a follow up assessment, a decline in one or more cognitive domains was seen in 89% of patients. Largest declines were seen in the cognitive domain of processing speed (66.7%, Figure 1).

Conclusion:

CAR T cell therapy recipients experienced a short-term cognitive decline in multiple domains. These findings can be used to educate future patients on potential toxicities of CAR T-cell therapy. We continue to enroll participants into our study and updated data will be presented at the meeting.
EP102: Pharmacological Inhibition of METTL3 Elicits Tumor Growth Inhibition In Vivo and Demonstrates Synergy with Venetoclax in Various AML Models
Authors: Fraser Graeme , Sorlet Catherine , Parmentier Nicolas , Hartiel Anne-France , Hospied Sandrine , Mompied Clement , Absil Genevieve , Oukoloff Killian , Dutheuil Guillaume
Published: December 2023

METTL3 is the RNA methyltransferase predominantly responsible for the addition of N-6-methyladenosine (m6A), the most abundant modification to mRNA. The prevalence of m6A and the activity and expression of METTL3 have been linked to the appearance and progression of acute myeloid leukemia (AML) 1. EPICS has discovered and optimized a small molecule inhibitor of METTL3 (“M3i”). M3i was shown to inhibit the enzymatic activity of METTL3 (IC 50 = 1.8 nM, SPA assay). The anti-proliferative effects of M3i was demonstrated in various AML cell lines (Kasumi, IC 50 = 63 nM; MV-411, IC 50 = 506 nM; KG1a, IC 50 = 99 nM). Biomarkers were evaluated following M3i treatment of Kasumi and MV-411 cells with consistent results demonstrating depletion of oncoproteins relevant to apoptotic (BCL-2, MCL1) and proliferative (MYC, BRD4, SP1) pathways. In addition, combined treatment with M3i and venetoclax showed clear synergistic effects 2 to inhibit proliferation on both cell lines consistent with the depletion of BCL-2 and MCL1, known targets for venetoclax activity and resistance mechanisms. M3i has been optimized for oral dosing with oral exposure confirmed in mouse, rat and minipig (oral bioavailability >80%, rat; >30%, minipig). In vivo efficacy was evaluated in a disseminated xenograft model using established systemic MV-411-Luc-mCh-Puro 3 in female NSG mice where M3i (10, 30 mg/kg, oral, QDx31 days) demonstrated dose-dependent tumor growth inhibition (p<0.01, relative to vehicle control) of cancer progression as measured by in-life imaging and confirmed by flow cytometry demonstrating significant, dose-dependent pharmacological knockdown of hCD45+ cells in bone marrow, blood and spleen (p<0.01, in all cases). These results confirm that the pharmacological inhibition of METTL3 arrests proliferation of AML and further provide a mechanistic basis for the synergistic activity of M3i in combination with venetoclax as is a viable strategy for the treatment of disease.

1Yankova E et al. (2021), Nature 593:597-601; 2Ianevski A et al. (2022), Nucl Acids Res 50:W739-W743; 3Trachet E (2016), LabCorp Drug Development website: model spotlight MV (4;11)
Comparison of Live Cell Enrichment Methods for Single-Cell Rnaseq
Authors: Meskauskaite Urben Brigita , Krause Tobias , Takizawa Meril , Snopkowski Catherine , Masilionis Ignas , Remsik Jan , Parisotto Yollanda , Brown Chrysothemis , Boire Adrienne , Pe'er Dana , Sharma Roshan , Chaligne Ronan
Published: December 2023

Single-cell RNA sequencing (scRNA-seq) has emerged as a powerful tool for investigating cellular diversity and gene expression profiles at the individual cell level. However, to ensure accurate analysis of scRNA-seq data, it is crucial to generate high-quality single-cell suspensions by effectively removing dead cells, debris, and ambient RNA. This study aims to assess and compare the performance of five commercially available methods for dead cell removal: Fluorescence activated cell sorting (FACS), Akadeum Microbubble kit, StemCell EasySep kit, Miltenyi Biotec Dead Cell Removal Kit, and LevitasBio Levicell Live Cell Enrichment.

Among the 5 methods we evaluated, FACS is considered the gold standard technique due to its remarkable efficiency and versatility. However, the high-pressure nature of FACS can exert mechanical stress on cells during the sorting process, potentially affecting cellular viability and gene expression profiles. On the other hand, the remaining four methods, while less versatile, utilize milder conditions, which may better preserve fragile cell populations.

To evaluate those 5 methods, we used two tissues requiring only no to mild dissociation process: lymph node and cerebrospinal fluid (CSF). Viability of cells from each tissue was assessed using trypan blue staining after dissociation. The cell suspensions were then subjected to the five dead cell removal methods following the manufacturer's instructions. For each cell suspension, 10,000 cells were targeted using the 10x Genomics 3' v3.1 kit. The evaluation criteria encompassed hands-on time, required equipment, cost, improvement in live cell percentage, cell type recovery, gene expression profile, and cellular stress response.

We hope these findings will provide valuable guidance for researchers in selecting the most suitable dead cell removal method based on their experimental requirements, thereby facilitating efficient, cost-effective, and high-quality scRNA-seq analysis.