bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dose of Deferasirox Correlates with Effects but Is Different in Low-Risk Myelodysplastic Syndrome and Aplastic Anemia
Authors: Zhang Ruoxi , Wang Zhao , Han Bing 
Published: November 2021

Abstract

Backgrou n d : Patients with low-risk myelodysplastic syndrome (MDS) and aplastic anemia (AA) often need transfusions, which may accelerate the iron overload. The aim of this study was to evaluate the efficacy, safety and dose-effect relation of deferasirox (DFX) for patients with low-risk MDS and AA who were refractory to regular treatment in the real-world setting.
M ethods: This was a retrospective study. Patients with low-risk MDS or AA who failed to standard treatments and were transfusion-dependent were enrolled. DFX was given as the only treatment apart from transfusion. Patients were recorded for their medical history, laboratory tests, nuclear magnetic resonance (MRI), echocardiography and calculated for their overall survival (OS). Dose-effect relations of DFX were evaluated after the first 6 months. Total annual exposure of DFX was calculated after 12 months, expressed as accumulated exposure time at dose of 20mg/kg/d.
R esults: Of the 112 patients finally enrolled, 61 (54.5%) were low-risk MDS and 51 (45.5%) were AA. The median age was 56 (10, 89) years and 52.7% patients were males. The minimum dose of DFX for significant SF decrease was 20 mg/kg/d at 6 months; and the minimum accumulation of DFX had to reach 9 months at 20 mg/kg/d to maintain the efficacy at the time of 12 months for patients with low-risk MDS (p＜0.050). Different from MDS, the minimum dose for significant SF decrease was 10 mg/kg/d at 6 months; and the minimum accumulation had to reach 3 months at 20 mg/kg/d to maintain the efficacy at the time of 12 months for patients with AA (p＜0.050). Meanwhile, with same dose of exposure, significant improvements in hematological parameters were also observed in AA, but no dose-effect relations were found in MDS. 62.3% MDS and 51.0% AA patients stopped transfusion in the next 6 months. Erythroid responders had lower SF than non-responders after 12 months of DFX, both for MDS and AA (p＜0.05). Lower alanine aminotransferase (ALT) and aspartate aminotransferase (AST) compared with baseline after 12 months of DFX were observed and longer exposure time correlated with lower ALT (p＜0.050). No significant changes in cardiac function, however. Similar side effects were found in MDS and AA, with gastrointestinal disorders and elevated serum creatinine the most common. Higher dose and longer exposure time of DFX correlated with longer overall survival, both for patients with MDS and AA (p＜0.050).
Conclusion: Although dose of DFX varies greatly in different individuals, a significant decrease in SF and an improvement of hematologic parameters, organ functions, or even overall survival can be achieved if the accumulate dose reaches a certain level. In that case, patients with low-risk MDS need higher dose than those with AA.
Figure 1 Figure 1.

Disclosures
No relevant conflicts of interest to declare.
PKM2 Inhibition Enhances the Sensitivity of Doxorubicin in ABC Diffuse Large B-Cell Lymphoma Cells
Authors: Zhan Minglang , Wei Xiaolei , Huang Weimin , Wei Yongqiang , Feng Ru 
Published: November 2021

Abstract
Background: Pyruvate kinase muscle isoenzyme 2 (PKM2) is a key enzyme in aerobic glycolysis and thought to contribute to cancer cell metabolic reprogramming and regulating the reactive oxygen species (ROS). Doxorubicin has been showed to induced activated-B cell types diffuse large B-cell lymphoma (ABC-DLBCL) cells death by ROS accumulation. Our purpose was to evaluate whether PKM2 inhibition could enhance the sensitivity of doxorubicin in ABC-DLBCL.
Methods: MTT assay was used to evaluate the proliferation of 2 ABC-DLBCL cell lines by treated with PKM2 inhibitor, PKM2 shRNA and doxorubicin. Apoptosis were detected by FCM after staining with Annexin V/SYTOX Green. Western Blot was used to evaluated the expression of PARP, Mcl1, Bcl2, Bax, Bim, p38 and JNK in ABC-DLBCL cells treated with PKM2 inhibition, PKM2 shRNA and doxorubicin.
Results: PKM2 expression was found in both U2932 and SuDHL2 cell lines. Both PKM2 inhibitor and doxorubicin could inhibit the proliferation and induce apoptosis in ABC-DLBCL cell lines. PKM2 inhibitor could enhance the doxorubicin-induced apoptosis. ShRNA was used to knock down the PKM2 expression in ABC-DLBCL cell lines and PKM2 KD cell lines were more sensitive to doxorubicin. PKM2 inhibition could increase the expression of cleaved PARP, Bax, Bim, p38 and JNK as well as decrease Mcl1 and Bcl2 expression
Conclusions: PKM2 inhibition could sensitize ABC-DLBCL cell lines to the cytotoxic effects of doxorubicin.
Key words: PKM2, Doxorubicin, Diffuse large B cell lymphoma

Disclosures
No relevant conflicts of interest to declare.
Triple Post-Transplant Cyclophosphamide (PTCY) Based Gvhd Prophylaxis for HLA Matched or HLA Haploidentical Transplants
Authors: Galli Eugenio , Metafuni Elisabetta , Giammarco Sabrina , Limongiello Maria Assunta , Innocenti Idanna , Autore Francesco , Laurenti Luca , Chiusolo Patrizia , Sorà Federica , Bacigalupo Andrea , Sica Simona 
Published: November 2021

Abstract
We report a retrospective analysis of 198 consecutive allogeneic stem cell transplant (HSCT) recipients, who received post transplant cyclophosphamide (PTCY), cyclosporine and mycophenolate mofetile as g raft-versus-host-disease (GVHD) prophylaxis. The donor was either HLA matched (n=78) (siblings -32- or unrelated -46) , or a haploidentical relative (HAPLO) (n=120). End points of the study were acute and chronic GVHD, transplant related mortality (TRM), relapse, disease free survival (DFS) and graft versus host and relapse free survival (GRFS). The two groups were comparable except for an older age (49 vs 56 years) in the haplo-HLA group. The diagnosis was mainly acute leukemia (57%), myelofibrosis (21%) or lymphoma (12%). Conditioning was myeloablative in 77% and 73% respectively (p=0.57).
Acute GVHD grade II-IV developed in 10% of the HLA matched transplants vs 27% in the HAPLO group (p=0.005). The latter also had more moderate-to-severe cGVHD (4% vs 23%, p&lt;0.001). The cumulative incidence of transplant related mortality (TRM) at 1 year for the HLA matched vs HAPLO patients, was 10% vs 21% (p=0.04) (Fig.1) , with age over 60 years being the major negative predictor in multivariate analysis.
Relapse at 1 year was 24% for HLA matched vs 10% for HAPLO transplants (p=0.051) (Fig.1).
Disease free survival (DFS) at 1 year was 65% and 68% in matched and HAPLO patients, respectively (p=0.85) (Fig.1) and GRFS 55% vs 49% (p=0.18). In multivariate analysis, age over 60 years was the strongest predictor of DFS and GRFS (HR 1.73, p=0.03 and HR 1,65, p= 0.02).
In conclusion: when using the same triple PTCY based GVHD prophylaxis, HLA matched grafts are associated with significantly less acute and chronic GvHD, if compared with HAPLO grafts. There is a trend for reduced TRM at 1 year, especially in chronic myelo-lymphoproliferative disorders, and a trend for increased relapse, resulting in identical disease free survival.
Figure 1 Figure 1.

Disclosures
Laurenti: Gilead: Honoraria; Roche: Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; BeiGene: Honoraria. Sica: Pfizer: Honoraria.
CD43 Expression Is an Adverse Prognostic Factor in Newly Diagnosed Multiple Myeloma
Authors: Ning Xueqin , Wei Yongqiang , Wei Xiaolei , Feng Ru , Chen Bingyuan , Yi Zhengshan , Zheng Zhongxin 
Published: November 2021

Abstract
CD43 expression is an adverse prognostic factor in newly diagnosed multiple myeloma
Introduction
CD43 is an abundant, heavily-glycosylated, cell surface protein expressed on bone marrow hematopoietic stem cells and most white blood cells. Previous studies have found that CD43 also expressed in some types of lymphoma cells and associated with adverse outcomes. However, the prognosis value of CD43 expression in multiple myeloma (MM) remain unknown.
Patients and Methods
A total of 109 MM patients, newly diagnosed in Nanfang Hospital of Southern Medical University from January 2017 to December 2019, were included in the study. CD43 was detected by flow cytometre as follows: 2 ml of heparin anticoagulated bone marrow was collected from the patients at the time of diagnosis，1×10 6 cells were detected, and a gate was set for identifying abnormal plasma cells characterized by CD138 expression and CD38. CD43 positive was defined as more than 20% of the plasma cells expressed CD43.
Results
A total of 109 patients with newly diagnosed MM were enrolled in the study, including 77 patients (70.6%) for CD43 positive and 32 patients (29.4%) for CD43 negative . The median age was 58 years, and the male-female ratio was 1.7:1. Patients in the CD43 positive group were more likely to have international staging system (ISS) stage III (67.5% VS 46.9%, P= 0.044), hemoglobin &lt; 85g/L (64.9% VS 37.5%, P= 0.008), 13q deletion (31.4% VS 10.4%), and higher percentage of bone marrow monoclonal plasma cells detected by flow cytometry (5.5% VS 1.4%, P=0.003).
Most patients enrolled in the study received bortezomib-based treatment. The very good partial response (VGPR) or better rate after 4 induction cycles was significantly lower in the CD43 positive group than CD43 negative group (35.1% VS 56.3%, P=0.041), and the overall response rate (ORR) in the CD43 positive group was lower than that in CD43 negative group (75.3% VS 84.4%, P=0.299), but no significantly difference.
The median follow-up time was 22 months. Patients with CD43 positive had significantly lower PFS (median PFS 24 months VS not reached, P =0.012), and OS (median OS not reached, P = 0.023) than those with CD43 negative. Multivariate analysis indicated that CD43 positive expression was an independent poor risk factor for PFS (HR 2.517 95%CI 1.178-5.376, P = 0.017) and OS (HR 3.664 95%CI 1.100-12.075, P = 0.034).
Conclusion
Our study showed that CD43 expression was an adverse prognosis for multiple myeloma.

Disclosures
No relevant conflicts of interest to declare.
A Transgenic Mouse Model of Cardiac AL Amyloidosis
Authors: Martinez-Rivas Gemma , Ayala Maria , Bender Sebastien , Roussel Murielle , Jaccard Arnaud , Bridoux Frank , Sirac Christophe 
Published: November 2021

Abstract
Background: AL amyloidosis is the most frequent type of amyloidosis caused by the deposition in tissues of fibrillar aggregates composed of an abnormal immunoglobulin (Ig) light chain (LC) and leading to organ dysfunction. The most frequent and severe forms involve kidney and heart. Research on this disease suffers from the lack of reliable animal models, that could allow a better understanding of the disease and the design of new therapeutic strategies. In the present study, we aimed at reproducing AL amyloidosis in a mouse model.
Methods: We developed an original transgenic approach using an insertion of a human pathogenic LC gene in the endogenous mouse kappa locus, such as the LC is produced by the naturally Ig producing B and plasma cells. Then, to avoid the association of human LCs with endogenous murine HCs, we backcrossed this strain with the DH-LMP2A mice, characterized by a high number of plasma cells devoid of endogenous HC. This strategy leads to a production of the human free LC similar or higher than in patients and proved efficient to reproduce in mice several monoclonal gammopathies of clinical significance (MGCS) (Fig.1A).
Results: Despite strong LC production (Fig.1B), mice did not naturally develop AL amyloidosis. In vitro, the full length LC was resistant to amyloid formation at physiological conditions but the variable domain (IGLV6) showed high propensity to form fibrils. A single injection of amyloid fibrils and/or seeds, obtained from the variable domain (VL) of the human LC gene, led to amyloid deposits starting at 1 month post-injection, especially in the heart, spleen, liver and, to a lesser extent, in the kidney (Fig.1C). We confirmed that the deposits contain the full-length human LCs, which elongate VL fibrils in vivo (Fig.1D).
Conclusions: This is, to our knowledge, the first transgenic mouse model of AL amyloidosis closely reproducing human lesions, especially in heart. Further studies are needed to better understand the early biochemical events leading to AL amyloidosis in vivo, but this model already shows that a partial degradation of the LC is likely required to initiate amyloid fibrils and that once seeded, the full length LC can elongate these fibrils. This mouse model opens new perspectives to better understand the toxicity of amyloid LC, their involvements in different biological processes and organ dysfunction and of course, to test new therapeutic approaches.
Figure 1 Figure 1.

Disclosures
Roussel: Takeda: Consultancy; Janssen: Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria; BMS: Honoraria; Amgen: Consultancy. Jaccard: Janssen: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; Abbvie: Honoraria. Bridoux: Janssen: Consultancy; AstraZeneca: Consultancy, Speakers Bureau. Sirac: Attralus, Inc: Patents & Royalties, Research Funding.
Dynamic Assessment of Measurable Residual Disease in Favorable-Risk Acute Myeloid Leukemia in First Remission, Treatment, and Outcomes
Authors: Yu Sijian , Liu Qifa 
Published: November 2021

Abstract
Purpose:We aimed to investigate outcomes of different post-remission treatment (PRT) choices based on dynamic measurable residual disease (MRD) in favorable-risk AML (FR-AML).
Methods: Four hundred and three younger patients with FR-AML in first complete remission (CR1) were enrolled in this registry-based cohort study, including 173 who received chemotherapy (CMT), 92 autologous stem cell transplantation (auto-SCT), and 138 allogeneic SCT (allo-SCT). Subgroup analyses were performed based on dynamic MRD after the first, second, and third courses of chemotherapy. The primary endpoint was the 5-year overall survival (OS).
Results: For patients with negative MRD after 1 course of chemotherapy, comparable OS was observed among the CMT, auto-SCT and allo-SCT groups (p=.284). But CMT had better graft-versus-host-disease-free, relapse-free survival (GRFS) than allo-SCT (p=.027). For patients with negative MRD after 2 courses of chemotherapy, comparable OS was also observed among the three groups (p=.967). However, CMT and auto-SCT had better GRFS than allo-SCT (p=.045; p=.020, respectively). For patients with negative MRD after 3 courses of chemotherapy, allo-SCT had better disease-free-survival than CMT (p=.011). However, OS was comparable among the three groups (p=.177). For patients with persistently positive MRD after 3 courses of chemotherapy or recurrent MRD, allo-SCT had better OS than CMT and auto-SCT (p=.012; p=.046, respectively).
Conclusions: Dynamic MRD might improve therapy stratification and optimize PRT selection for FR-AML in CR1. CMT might be preferable for patients with negative MRD within 3 cycles of chemotherapy while allo-SCT for patients with persistently positive MRD after 3 cycles of chemotherapy and recurrent MRD.

Disclosures
No relevant conflicts of interest to declare.
Thromboembolic Complications in a Pediatric Patient Population: Treatment with Direct Oral Anticoagulants. Monitoring of Treatment Efficiency with D-Dimer Levels and Safety Profile By Thromboelastogram
Authors: Ameri Afshin , Anderson Courtney M , Smith Joetta H , Patel Julisa 
Published: November 2021

Abstract
Direct oral anticoagulants (DOAC) such as the thrombin inhibitor Dabigatran and the coagulation factor Xa inhibitors Apixaban and Rivaroxaban have been in clinical use for the past 5-6 years. Familiarity with their use in the general pediatric population with thrombosis secondary to inflammatory disorders and rheumatologic disease is currently not as prevalent due to the widespread more conventional anticoagulation practice with the fractionated heparins in particular Lovenox. In this report we would like to summarize our experience in a pediatric patient population ranging from 3- 17 years with thrombotic disease. Of 55 patients with various thrombotic events 16 patients were treated with DOAC. There were 5 patients who had underlying inflammatory disease including COVID. Thrombotic complications included arterial as well as venous thrombotic events. All patients had elevated D-Dimer levels ranging from 360-4000 mcg/ml on diagnosis and normalized with successful anticoagulation. All patients had resolution of thrombosis. Thrombelastogram (TEG) were obtained on isolated patients during therapy and were useful to balance anticoagulation to prevent hemorrhagic complications.
In conclusion, DOAC are a safe and effective alternative to LMW Heparin in pediatric patients with arterial or venous thrombosis. Monitoring should include determination of D-Dimer levels for efficacy of treatment and TEG in cases with arterial disease where bleeding may be a secondary complication of therapy.

Disclosures
No relevant conflicts of interest to declare.
Hemogen/BRG1 Cooperativity Is Required for Erythrocyte Maturation and Hemoglobin Production during Mammalian Erythropoiesis
Authors: Guo Xiang 
Published: November 2021

Abstract
Hemogen, also known as EDAG, is a hematopoietic tissue-specific gene that regulates the proliferation and differentiation of hematopoietic cells. However, the mechanism underlying hemogen function in erythropoiesis is unclear. We found that depletion of hemogen in human CD34 + erythroid progenitor cells and HUDEP2 cells significantly reduced the expression of genes associated with heme and hemoglobin synthesis, supporting a positive role of hemogen in erythroid maturation. In human K562 cells, hemogen antagonized the occupancy of co-repressors NuRD complex and facilitated LDB1 complex-mediated chromatin looping. Hemogen recruited SWI/SNF complex ATPase BRG1 as a co-activator to regulate nucleosome accessibility and H3K27ac enrichment for promoter and enhancer activity. To ask if hemogen/BRG1 cooperativity is conserved in mammalian systems, we generated hemogen KO/KI mice and investigated hemogen/BRG1 function in murine erythropoiesis. Loss of hemogen in E12.5-E16.5 impeded erythroid differentiation through reducing the production of mature erythroblasts. ChIP-seq in WT and hemogen KO animal revealed BRG1 is largely dependent on hemogen to occupy chromatin at erythroid gene promoters and enhancers. In summary, hemogen/BRG1 interaction in mammals is essential for erythroid maturation and hemoglobin production through its active role in promoter and enhancer activity and chromatin organization.

Disclosures
No relevant conflicts of interest to declare.
Definitive Hematopoietic Stem Cells Minimally Contribute to Embryonic Hematopoiesis
Authors: Ulloa Bianca A , Habbsa Samima S , Potts Kathryn S , Lewis Alana , McKinstry Mia , Payne Sara , Flores Julio , Nizhnik Anastasia , Feliz Norberto Maria , Mosimann Christian , Bowman Teresa V. 
Published: November 2021

Abstract
Definitive hematopoietic stem cells (HSCs) emerge in the embryo and sustain major adult hematopoietic lineages. Although their functional potential is detected by transplant, nascent HSC contribution during development is both unknown and difficult to address due to the overlapping emergence of HSC-independent progenitors-cells that lack the multipotency and/or longevity of HSCs but express many of the same markers. Using sorted hematopoietic stem and progenitor cells from zebrafish embryos, we performed single cell RNA sequencing to decipher HSC and HSC-independent progenitor heterogeneity during the time frame of their emergence and initial maturation. After batch correction and dimensional reduction, we identified seven distinct populations that are inferred from RNA velocity analysis to originate from pre-hemogenic endothelium and develop into three main differentiation trajectories. We also determined that HSCs can be distinguished from HSC-independent progenitors based on the temporal regulation and differential activity of the draculin (drl) promoter that was previously shown to mark adult-contributing HSCs. From these studies, we found that the drl promoter is active in HSCs and HSC-independent progenitors at 1-day post-fertilization (dpf) but becomes highly expressed primarily in HSCs by 2 dpf. We applied a drl:cre-ER T2 tamoxifen-inducible Cre-loxP lineage-tracing approach to selectively lineage trace HSCs starting at 2 dpf and track their myeloid and lymphoid contribution during larval development and adulthood. We determined that HSC-independent progenitors primarily contribute to developmental lymphomyelopoiesis with minimal HSC contribution until after 7 dpf. Consistent with this result, we demonstrated that although HSCs robustly regenerated after hematopoietic injury using a novel inducible larval HSC injury model, their depletion had almost no impact on lymphoid and myeloid cell numbers up to 7 dpf. These findings suggest that HSCs are not entirely dormant during development and that there exists an uncoupling of HSC self-renewal and differentiation in development. In conclusion, we determine that it is the HSC-independent progenitors, and not HSCs, that sustain embryonic and early larval lymphomyelopoiesis. Acquiring a greater understanding regarding developmental differences in progenitor and HSC specification and maturation will inform and improve the generation of functional HSCs from renewable pluripotent stem cells.

Disclosures
No relevant conflicts of interest to declare.
Chimerism of Blood T-Cells and Leukemia Lineage Cells Following Myeloablative Hematopoietic Cell Transplantation Is a Risk Factor for Relapse and Chronic Graft-Versus-Host Disease
Authors: Khanolkar Rutvij A. , Dharmani-Khan Poonam , Khan Faisal M , Storek Jan 
Published: November 2021

Abstract
Background: Mixed chimerism of blood leukemia lineage cells has been reported to be highly predictive of relapse (Mattsson J et al. Leukemia 2001), but the utility of T-cell chimerism is controversial.
Methods: Chimerism of T-cells (CD3 +) and leukemic lineage cells (CD13 +/CD33 + for myeloid malignancies and CD19 + for B-lymphoid malignancies) was measured in the peripheral blood for 600 hematopoietic cell transplant (HCT) recipients at 3-months post-transplant. Conditioning was myeloablative (fludarabine+busulfan+4GyTBI) and GVHD prophylaxis was with ATG+CsA+MTX.
Results: Mixed (&lt;95% donor) chimerism was present in 6% of patients in the leukemic lineage and 16% of patients in T-cells. Compared to patients with complete chimerism (≥95%), mixed chimerism predicted a significantly greater incidence of relapse (52% vs. 27%, P=0.044), and surprisingly, also a greater incidence of cGVHD (43% vs. 23%, P=0.028). Patients with mixed leukemic lineage chimerism also had poorer cGRFS (7% vs. 39%, P&lt;0.001) and OS (29% vs. 55%, P&lt;0.001). Mixed T-cell chimerism predicted a significantly greater incidence of relapse (46% vs. 24%, P&lt;0.001) and lower cGVHD incidence (9% vs. 31%), with no difference in cGRFS or OS. The sensitivity/specificity/positive predictive value (PPV)/negative predictive value (NPV) of mixed leukemic lineage and T-cell chimerism for relapse were 65%/55%/35%/81% and 66%/57%/60%/79%, respectively. Sensitivity/specificity/PPV/NPV was similarly poor for cGVHD. In patients with complete leukemic lineage chimerism at 3-months, a ≥5% drop in donor chimerism at any future timepoint had sensitivity/specificity/PPV/NPV of 82%/79%/79%/82% for subsequent relapse.
Conclusion: In the setting of myeloablative conditioning and ATG-based GVHD prophylaxis, mixed chimerism at 3-months post-transplant is a risk factor for subsequent relapse. However, the utility of these measurements in guiding medical interventions may be limited by insufficient predictive values. Nevertheless, patients with mixed chimerism may be candidates for more intensive surveillance.

Disclosures
Storek: Atara Biotherapeutics: Other: Site PI, Research Funding.