bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Efficacy and Safety of CLAG±Ida/Mito+Ven As Salvage Therapy of Relapsed/Refractory Acute Myeloid Leukemia
Authors: Yu Guopan , Yin Zhao , Zhang Yu , Jiang Xuejie , Nie Xiaqi , Yao Zurong , Xu Dan , Shi Pengcheng 
Published: December 2023

Purpose: As known CLAG±Ida/Mito regimen is recommended by different guidelines as a chioce for salvage therapy of relapsed/refractory acute myeloid leukemia (RR-AML). Recent study showed venetoclax (Ven) added to CLAG+Ida as frontline treatment of AML acquired a good response and well toleration. Yet, how CLAG±Ida/Mito+Ven works in the salvage therapy of RR-AML remains unclear. Aim of this study was to analyze the efficacy and safety of CLAG±Ida/Mito+Ven as salvage therapy of RR-AML.
Methods: A single center, retrospective study was performed. Patients with RR-AML, who were salvagedly treated with CLAG±Ida/Mito+Ven during July 2021 to June 2023, were included. CLAG±Ida/Mito+Ven: cladribine 5mg/m 2 day 1-5, cytarabine 1-1.5g/m 2 day 1-5, PEG-G-CSF 6mg day 0, idarubicin 6mg/m 2 day 1-3 or mitoxantrone 6mg/m 2 day 1-3 (lipo-Mito 20mg/m 2 day 1), Ven 400mg day 2-8.
Results: 33 patients were included, with a median age of 42(15-72) years old, male to female 17/16, de novo/sAML 31/2, refractory/relapsed 17/16, ELN-low /intermediate/high risk 7/10/16. They previously received median 2(1-12) cycles of chemotherapy, including 2 relapsed after allogeneic hematopoietic stem cell transplantation (allo-HSCT), 14 with prior hypomethylating agents (HMA). Among the 33 patients with CLAG+Ven, 3 were combined with Mito, 1 with Ida, 15 with FLT3 inhibitors. After one cycle of salvage therapy, 24(72.7%) acquired response, including 22(66.7%) with CR/CRi, 15(45.5%) with MRD-negative (accounting for 68.2% of the patients with CR/CRi). Multivariate analysis showed that prior HMA, FLT3 mutation and ELN-high risk were the independently poor factors for CR/CRi. With a median follow-up of 3(1-23) months, 15(45.5%) patients were bridged to allo-HSCT, 3(12.5%) relapsed, 5(15.2%) died, including 3 died of leukemia progression and 2 with transplant-related motality. Patients obtaining CR/CRi had significantly longer overall survival (mOS, 19.8(15.8-23.8) months) than those without (mOS, 5.1(2.7-7.5) months, P=0.013). Patients being bridged to allo-HSCT also had significantly better OS than those without. During the salvage therapy, the median duration of agranulocytosis was 19(11-40) days. 25(75.6%) patients underwent manageable infection. The motality of the 30 and 60 day were 0.
Conclusion: CLAG±Ida/Mito+Ven might be a chioce for salvage therapy of RR-AML, with the CR/CRi rate of 66.7%, MRD-negative rate of 68.2% and well toleration.
Key words: CLAG, venetoclax, salvage therapy, relapsed/refractory, acute myeloid leukemia
CSF1R Inhibition Promotes Neuroinflammation and Behavioural Deficits during Graft-Versus-Host Disease in Mice
Authors: Adams Rachael C , Carter-Cusack Dylan , Llanes Genesis T , Hunter Christopher R , Vinnakota Janaki Manoja , Ruitenberg Marc , Vukovic Jana , Bertolino Patrick , Chand Kirat K. , Wixey Julie A. , Nayler Samuel P , Hill Geoffrey R , Furlan Scott N , Zeiser Robert , MacDonald Kelli PA 
Published: December 2023

Chronic graft-versus-host disease (cGVHD) remains a significant complication of allogeneic hematopoietic stem cell transplantation. Central nervous system (CNS) involvement is becoming increasingly recognised, where brain-infiltrating donor MHC class II + bone marrow-derived macrophages (BMDM) are implicated mediators of pathology. Colony-stimulating factor 1 receptor (CSF1R)-dependent BMDM are established mediators of cutaneous and pulmonary cGVHD, and clinical trials assessing the efficacy of CSF1R antibody blockade to deplete macrophages are promising. We hypothesized that CSF1R antibody blockade may also be a useful strategy to prevent/treat CNS cGVHD.
We leveraged studies in acute GVHD (aGVHD) to determine the feasibility of an antibody-based approach for depleting brain microglia and macrophages. Moreover, we queried whether CSF1R blockade may be a viable therapy for CNS aGVHD, which has been shown to be mediated by host microglia. Increased blood-brain barrier permeability during aGVHD facilitated CNS antibody access. However, CSF1R blockade early post-transplant induced region-specific microglia depletion and was associated with unexpected exacerbation of aGVHD neuroinflammation, including increased T cell and inflammatory monocyte infiltration, and whole brain cytokine levels. In established cGVHD, vascular changes and anti-CSF1R efficacy was more limited. Anti-CSF1R-treated mice retained donor BMDM, activated microglia, CD8 + and CD4 + T cells, and local cytokine expression in the brain. These findings were recapitulated in GVHD recipients where CSF1R was conditionally depleted in donor CX3CR1 + BMDM. Notably, inhibition of CSF1R signalling post-transplant failed to reverse either acute or chronic GVHD-induced behavioral changes. Taken together, these data suggest that ongoing clinical trials of CSF1R inhibition should assess neurological adverse events in patients.
In contrast to the lack of efficacy with CSF1R inhibition, transfer of Ifngr-/- grafts reduced MHC class II + BMDM infiltration, resulting in improved behaviour. Furthermore, single nuclei RNA sequencing of brains from mice receiving wild-type or Ifngr-/- allografts revealed a disease-associated interferon-inducible mature oligodendrocyte population in the cGVHD brain. This was markedly reduced in recipients of Ifngr-/- grafts, indicating that targeting this axis can promote brain repair beyond the myeloid compartment during cGVHD. In summary, our findings reveal unexpected neurological immune toxicity during CSF1R blockade and highlight the IFNGR pathway as an alternative target for the treatment of cGVHD within the CNS.
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 &lt; 0.001). The median day of ANC recovery was 16 and 28 days, respectively (p &lt; 0.001). The median day of platelet recovery was 16 and 20 days, respectively (p &lt; 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&lt;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&lt;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&lt;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&lt;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&lt;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&lt;0.001). Within this subgroup, CIR and TRM were 44.9% vs. 75.1% (P&lt;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&lt;0.001), and EFS5y were 18.8±5.8% vs. 43.1±5.9% (P&lt;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&lt;0.001), and EFS5y were 37.2±6.7% vs. 53.9±6.7% (P&lt;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).