bluuebunny/crossref_metadata_2025 huggingface dataset:
CXCR4 Is a Regulator Of Disease Involvement Of Extramedullary Myeloma Confirmed By a Novel Mouse Model For Extramedullary Disease
Authors: Mishima Yuji , Moschetta Michele , Reagan Michaela R , Zhang Yong , Sahin Ilyas , Maulkhan Niraj , Roccaro Aldo M , Ghobrial Irene M.
Published: October 2019

Background

Extramedullary disease (EMD) in patients with multiple myeloma occurs mostly in advanced disease or relapse. EMD seems to have a different pathogenesis from medullary myeloma and is often characterized by a more aggressive clinical course. To date molecular mechanisms of development of EMD have not been fully understood. Methods: Human MM cell lines, IM-9 and MM1S were serially selected in immune-deficient mice. IM-9 and MM1S cells were inoculated intravenously and harvested from the tumors developed in the bone marrow (BM) and liver (site of extramedullary disease), aiming to establish BM-prone and liver-prone clones. Tumor progression was periodically checked by bioluminescence (BLI) and in vivo live confocal imaging. After three rounds of in vivo selections, the cells of both BM- and liver-prone were characterized by gene and protein expression and cellular functional assays. Results: We obtained three liver-prone sub-clones in both IM-9 and MM1S after serial in vivo selections. These cells had equal proliferation rates in vitro compared to the original or BM-prone cells, but exhibited more aggressive phenotype in vivo. Liver-prone clones had significantly higher migration ability than BM-prone clones (11.6% vs 6.1% migration, respectively p=0.018). Gene and protein expression analysis revealed that each liver-prone clone had a higher expression of sets of chemokine receptors specifically CXCR4. Using thein vivo metastatic model CXCR4-over expressing myeloma cells exhibited higher metastatic property to the extramedullary organs whereas CXCR4-knockdown cells has less tumor metastasis to the liver. Discussion: We established EMD-prone human multiple myeloma cell lines that reproducibly developed liverinvolvement consistent with human extramedullary disease. These cells exhibited higher migratory ability and increased expression of several chemokine receptors, specifically CXCR4. We validated the effect of CXCR4 on developing extramedullary myeloma using our established in vivo mode. Further studies to determine the role of CXCR4 for therapeutic targeting of extramedullary disease in MM are ongoing.

Disclosures:

Ghobrial: Sanofi: Research Funding; Noxxon: Research Funding; BMS: Advisory board, Advisory board Other, Research Funding; Onyx: Advisoryboard Other.
Baicalein Synergy Lenalidomide To Induce Apoptosis Of Myeloma Cell
Authors: Zhang Ruibo , Ma Zi , Liu Shangqin , He Li , Xu Chaoping , Hu Guiying , Huang Jianying , Zhang Yicheng
Published: October 2019

Objective

To understand the apoptotic effects and cereblon (CRBN) gene and protein expression induced by baicalein in MM cells.

Methods

Apoptotic MM cells induced baicalein，lenalidomide or combination of BAI and lenalidomide were stained by using Annexin-V and analyzed by flow cytometry. RT-PCR was used to detect CRBN gene expression in MM cells. CRBN protein expression was detected by western blot in MM cell lines.

Results

At the concentration of 40 μmol/L, baicalein can induce apoptosis of U266 cells in a time-dependent manner. At the different BAI treated time points (24h, 48h, 72h), the apoptotic cell percentages were 6.11%, 11.9%, 16.7%; After treated RPMI 8226 cells for 72 hours, combined application of baicalein and lenalidomide (both concentrations are 40 μmol/L) could induce more cell apoptosis than baicalein or lenalidomide alone. The apoptotic cell percentages induced by baicalein, lenalidomide or combined application of baicalein and lenalidomide were 15.9%, 4.27%, and 57.5%. CRBN gene expression detected by RT-PCR could be induced by baicalein in U266 cells in a dose-and time-dependent manner. Treated U266 cells for 24h at concentrations of 10 μmol/L, 20 μmol/L and 40 μmol/L, baicalein upregulated CRBN gene expression times were 2.246 ± 0.068, 2.399 ± 0.178 and 3.591 ± 0.061,respectively，compared to the control group. Statistically, the P values were 0.003, 0.009 and 0.001; Treated U266 cells at concentrations of 40 μmol/L at different time points (6h, 12h and 24h), baicalein upregulated CRBN gene expression times were 2.372 ± 0.079, 2.494 ± 0.189 and 3.228 ± 0.151, its P values were 0.002, 0.008 and 0.002.CRBN protein expression detected by using western blot could be induced by baicalein in both U266 and RPMI8226 cell lines.

Conclusions

Baicalein at suitable concentrations induced MM cells apoptosis in a time-dependent manner. Comparison with the single component used alone,combined application of baicalein and lenalidomide exhibited stronger inhibition effect on proliferation of RPMI 8226. Considering CRBN is the cellular target for lenalidomide, baicalein can up-regulate the CRBN gene and protein expression in MM cells and may enhance MM cell sensitivity to apoptotic stimuli. Therefore, baicalein up-regulated CRBN gene and protein expression and sensitized MM cells to apoptosis stimuli induced by lenalidomide. It provides us a possibility for baicalein clinical application to overcome the resistance to lenalidomide for MM patients in the future

Disclosures:

No relevant conflicts of interest to declare.
Circulating microRNA 483-5p in multiple myeloma as a novel biomarker for diagnosis and predicting survival
Authors: Xiaoyan Qu , Zhao Min , Wu Shuang , Wenjun Yu , Jiaren Xu , Xu Ji , Li Jianyong , Lijuan Chen
Published: October 2019

Background

MicroRNAs (miRNAs) are a class of small non-coding single stranded RNAs whose dysregulation of expression plays an important role in cancer development. Circulating miRNAs are novel biomarkers in several cancers including acute myeloblastic leukemia and diffuse large B cell lymphoma. Thus, we explored whether the miRNAs in plasma could be a useful clinical biomarker for multiple myeloma (MM) patients.

Methods

MiRNA microarray was conducted to determine deregulated miRNAs in plasma of MM patients. TaqMan real-time PCR was used to validate the results. Receiver operating characteristic (ROC) analysis was performed to reveal the diagnostic accuracy of the significantly deregulated miRNAs as potential biomarkers. The Kaplan-Meier and log-rank tests were used to assess the correlation of miRNAs with progression-free survival (PFS).

Results

The expression levels of five miRNAs in plasma were up-regulated while eight miRNAs were down-regulated in MM patients compared to normal controls according to microarray. Validation of the five miRNAs detected as promising biomarkers was carried out. MiR-483-5p was found to have potential as diagnostic biomarkers in myeloma. ROC analysis revealed that miR-483-5p had considerable diagnostic accuracy, yielding an ROC-AUC (the areas under the ROC curve) of 0.722 (sensitivity 61%, specificity 75%). The expression levels of miR-483-5p are associated with Durie-Salmon (DS) staging system and ISS staging system (p < 0.01). After a median follow up of 10 months (range: 2-60 months) from diagnosis, the median PFS of patients highly expressing miR-483-5p and of low expression patients was 11 and 21 months, respectively (p=0.04).

Conclusions

These data demonstrate that miR-483-5p highly expresses in the plasma of MM patients. MiR-483-5p may serve as a diagnostic and prognostic biomarker in MM.

Disclosures:

No relevant conflicts of interest to declare.
Jewish Immigrants Of Middle Eastern Origin Have a Lower Incidence Of Multiple Myeloma Compared To Both North African and European Jews In a Cohort Of 746,200 Israeli Men Followed From Late Adolescence
Authors: Leiba Merav , Afek Arnon , Derazne Estela , Leiba Adi , Keinan-Boker Lital , Shamiss Ari , Nagler Arnon , Kark Jeremy D.
Published: October 2019

Differences in the prevalence of Multiple Myeloma across races have been observed, with a two to three fold greater prevalence of Multiple Myeloma in African Americans compared with Caucasians. Little is known about the incidence or prevalence of Multiple Myeloma in other populations.

The association between father's country of origin and the incidence of Multiple Myeloma was examined in a nationwide population-based cohort.

Health-related data on 746,200 16-19 year old Jewish males examined for fitness for military service between 1967 and 1998 were linked to the Israel National Cancer Registry to derive Multiple Myeloma incidence up to 2006.

During 17,352,349 person-years of follow-up, 109 examinees developed plasma cell dyscrasias. West Asian origin (predominantly Middle Eastern) was protective compared to European (predominantly Ashkenazi) origin (HR 0.40; 95% CI 0.23-0.70; p=0.001). The association persisted when adjusted for year of birth (HR 0.39; 95% CI 0.22-0.68; p=0.001), and also when restricted to Israeli-born males (HR 0.44; 95% CI 0.24-0.82; p=0.01).

In conclusion, adolescents of Middle Eastern origin are at persistently lower risk of developing Multiple Myeloma compared to European origin, suggesting a genetic background in the pathogenesis of Multiple Myeloma.

Disclosures:

No relevant conflicts of interest to declare.
Multiple Myeloma In Patients Under 40 Years Old Is Associated With High-Risk Features and Worse Outcomes
Authors: Costello Caitlin L.
Published: October 2019

Background

The median age of patients diagnosed with multiple myeloma (MM) is approximately 70 years old. It is an uncommon malignancy in persons younger than 40 years, representing only 2% of all patients diagnosed with MM. It has been suggested that young patients may present with more aggressive and less common disease features, frequently delaying the initial diagnosis and thereby affecting outcomes. With this background, we explored the outcome of young MM patients presenting to our institution over the past thirteen years.

Methods

We performed a retrospective review of a cohort of 236 patients with MM who received treatment for active MM at the University of California, San Diego Moores Cancer Center between January 2000 and July 2013.  The demographics and disease features of patients up to 40 years of age at diagnosis were analyzed using descriptive statistics. The survival outcomes of these young patients were compared with the remainder of the cohort using the Kaplan-Meier method.

Results

Nineteen (6.5%) out of the 236 patients with MM were ²40 years of age at diagnosis, with a median age of 35.5 years old. The median follow-up of this group of young patients was 42 months (range 5-92). The patient and disease characteristics are outlined in Table 1. Seven young patients (37%) had MM with no heavy chain component, including light chain only secreting or non-secretory disease.  Seven patients (37%) had a non-IgG paraprotein. Nine (56%) patients presented with extramedullary plasmacytomas. Two (10%) patients had plasma cell leukemia. All patients received at least one treatment regimen that included a novel agent. Fifteen patients (79%) had received high-dose therapy, and four patients (21%) underwent allogeneic stem cell transplantation (SCT) after at least one prior autologous SCT. The 5-year and 7-year overall survival (OS) from diagnosis was 51.7% and 28%, respectively, and the median OS was 60.7 months. In contrast, the median OS of patients ≥41 years old at diagnosis was 78.6 months (p=0.15, figure 1).

Conclusion

In this single center study with long follow up, we demonstrate that patients diagnosed with MM ²40 years of age exhibit several high-risk features and frequently present with advanced stage disease. Despite the use of novel agents in this population, there is a statistical trend towards a worse outcome with an 18-month difference in median overall survival when compared to older patients with MM. More aggressive treatment strategies are needed to improve survival in this young patient population.

Disclosures:

No relevant conflicts of interest to declare.
Multiple Solitary Plasmacytoma: Characteristics, Response To Therapy, Survival In Nine Patients From a Single Institute
Authors: Zhang Yanru , Qi Junyuan , Qiu Lugui
Published: October 2019

Objective

  The International Myeloma Working Group in 2003 recognized a separate classification of plasmacytomas that occur as multiple sites of disease in soft tissue, bone, or both  as multiple solitaryplasmacytoma (MSP). There are only few cases of MSP described in literatures. As a rare mylema, relatively little is known about its features, treatment response, and survival.

Method

  we have retrospectively analyzed nine patients with MSP in our hospital from 2009 to 2013.

Result 

The median age was 49 (26-49) years old. There were six males and three females. All but one had M-protein in serum and/ or urine. There was a predominance of lambda light chain (6/8). Most cases had multiple bone lesions (8/9).Only one had multiple solitary extramedullary plasmacytoma localized on CNS tissue and right lumber. Most (6/9) were stage III of DS for and seven cases were stage I of ISS. Six patients were treated with regimen containing bortezomib as induction therapy. And one of them underwent high-dose of chemotherapy with autologous stem cell transplantation (HDT/ASCT) at CR as part of their front-line therapy. Another three patients were treated with conventional alkylating agent combined with glucocorticoid based chemotherapy. After initial chemotherapy, seven patients reached CR, one PR. In first line combinational chemotherapy that containing bortezomib (Btz) (n=6), 100% patients achieved CR ,compared with that of 33.3% in patients treated with conventional chemotherapy (P =0.083). Date cut-off was July 20, 2013, a median follow-up of 28.5 (range2-38) months. The median OS time was 29, median progression -free survival (PFS) was 8 months. However, none of them progressed to MM. In addition, compared with the patients whose regimes included Btz (n=6), the patients who got conventional chemotherapy (n=3) had a trend towards poorer median OS (not reach versus 28 months, P = 0.116) and shorter median PFS (6 months versus 38 months, P = 0.356).

Conclusion

  MSP was at early stage at diagnosed. Most cases were male and λ light chain type. Although there was a good treatment response, these patients easily progressed. ISS may not suitable for evaluation of prognosis with MSP.Bortezomib based therapy could further deepen degree of remission , prolong the survival.

Disclosures:

No relevant conflicts of interest to declare.
Tryptophan Metabolites Analogue, N-(3,4-dimethoxycinnamonyl) Anthranilic Acid, Ameliorates Acute Graft-Versus-Host Disease Through Inhibiting Th1 Responses
Authors: Xu Jinhuan , Zhang Yicheng
Published: October 2019

Local catabolism of tryptophan (Trp) by indoleamine 2,3-dioxygenase (IDO) is considered an important mechanism of regulating T cell immunity. N-(3,4-dimethoxycinnamonyl) anthranilic acid (3,4-DAA) is an active synthetic anthranilic acid derivative which was proved to be effective to treat type±helper T lymphocytes (Th1) mediated autoimmune diseases such as multiple sclerosis. In this report, we investigated the effects of 3,4-DAA on the acute graft versus host disease (aGVHD) following allogeneic bone marrow transplantation (allo-BMT) and its potential mechanism of action. we established a murine aGVHD model, 3,4-DAA was injected intraperitoneally at 200 mg/kg/day per mouse immediately after allo-BMT or at the onset of aGVHD for 14 consecutive days; the signs of aGVHD and the survival were recorded periodically; the histological changes of target organs were evaluated with hematoxylin-eosin staining; the IDO activity and cytokine levels in plasma were measured by reverse-phase high-performance liquid chromatography (HPLC) and enzyme linked immunosorbent assay (ELISA), respectively. We revealed that administration of 3,4-DAA after allo-BMT significantly reduced the severity and the histological score of aGVHD; The survival for mice receiving 3,4-DAA prophylaxis and treatment were prolonged in comparison to the vehicle control mice. The plasma levels of IFN-γ, TNF-α, IL-12 and IL-2 in 3,4-DAA treatment group were found to be decreased, while the IDO activity, the IL-10, IL-5 and IL-4 levels elevated in these mice. In consistent with the in vivo results, 3,4-DAA also inhibited IFN-γ and IL-2 production of spleen T lymphocytes in vitro. Our findings suggest that 3,4-DAA can diminish the murine experimental aGVHD through inhibition of Th1 response; this property makes it a potential alternative agent for prevention and treatment of GVHD in the clinic.

Disclosures:

No relevant conflicts of interest to declare.
Chemotherapy With Infusion Related HLA-Mismatched Hematopoietic Stem Cells For Hematologic Malignancies: A Novel Therapeutic Strategy
Authors: Fu Li , Wang Zhao
Published: October 2019

Objective

To investigate the therapeutic outcomes of chemotherapy with infusion related HLA-mismatched hematopoietic stem cells for hematologic malignancies.

Method

Therapy responses and hematopoietic recovery as well as complications of 9 patients were analyzed.

Result

In the 9 patients aged 29-67 years, four were acute myeloid leukemia, one was acute B lymphocytic leukemia, two were multiple myeloma, one was Hodgkin’s disease, one was diffuse large B cell lymphoma. The average MNC was (3.12±1.29)×108/kg, CD34+ cells was (1.71± 1.00)×106/kg, CD3+ cells was (2.13±0.99)×108/kg. There was complete remission in four patients, partial remission in one, disease progression in four. Following up 2 to 14 months, four patients was in survival. No donor chimerism was detected and no graft-versus-host disease was observed in any patient.

Conclusion

Chemotherapy with infusion related HLA-mismatched hematopoietic stem cells for hematologic malignancies may provide a promising treatment method as a novel therapeutic strategy.

Disclosures:

No relevant conflicts of interest to declare.
Oral Cryotherapy For The Prevention Of Mucositis Following Myeloablative Conditioning and Hematopoietic Stem Cell Transplantation
Authors: Lu Yin , Zhu Xiaming , Depei Wu
Published: October 2019

Purpose

To investigate the effect of oral cryotherapy for the prevention of oral mucositis in recipients of Hematopoietic Stem Cell Transplantation(HSCT) after myeloablative conditioning and to specify its best timing and duration.

Methods

This study was a prospective randomized controlled clinical study, involving 37 patients from the bone marrow transplantation unit of the First Affiliated Hospital of Soochow University. In addition to the basic oral care given to all patients, study participants were divided into two experimental groups given oral cryotherapy and one control group. Optimal timing of the oral cryotherapy intervention was explored, based on pharmacokinetics of drug elimination. During the period of conditioning, experimental group 1(Exp.1) received oral cryotherapy from the beginning of drug infusion continuously until the end of drug infusion; experimental group 2 (Exp.2) received oral cryotherapy starting half way through the infusion of the drug. The rate and severity of mucositis was evaluated according to the National Cancer Institute-Common Toxicity Criteria. Data were then analyzed using SPSS15.0.

Results

Oral mucositis occurred on cheeks (43.9%), tongue (27.57%) and lips (15.7%). There was no difference regarding the incidence of severe mucositis ≥ Grade 3 (33% in Exp.1 group, 15% in Exp.2 group, and 25% in the control group, p = ns) and its duration (8 days in Exp.1 group, 2.5 days in Exp.2 group, and 7 days in the control group, p = ns). However, the frequency of vomiting episodes was significantly reduced in Exp.2 with 10 episodes (2-28) versus 21 (2-60) in the control group (p=0.01) and 12.5 (2-39) in exp 1. [Conclusions] A short duration of oral cryotherapy beginning at midpoint of infusing the chemotherapy schedule significantly reduced vomiting associated with myeloablative conditioning. These preliminary results in view of the low statistical power of the study justify further trials.

Disclosures:

No relevant conflicts of interest to declare.
Successful Hematopoietic Stem Cell Transplantation In a Child With Paroxysmal Nocturnal Hemoglobinuria
Authors: Karasu Gulsun , Ay Yilmaz , Akbayram Sinan , Kilic Suar Caki , Pekün Fügen , Yesilipek M. Akif
Published: October 2019

Introduction

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal hematopoietic stem cell disorder characterized by complement-mediated hemolysis, thrombosis, and bone marrow failure. The clinical manifestations of PNH are usually seen in adulthood and are very rarely reported in children. The experience with transplantation in the management of children with PNH is also very limited. Here in this paper, we report a child with PNHpresenting with an episode of hemolytic anemia who was treated successfully with hematopoietic stem cell transplantation (HSCT).

Case Presentation

An eleven-year-old patient presented with a history of fatigue. On physical examination, there was no lymphadenopathy, and liver and spleen were not palpable. Laboratory analysis revealed a hemoglobin of 5.7 g/dL, platelets of 124.000/mL, and white blood cells were 1420/ml. She had increased lactate dehydrogenase and reticulocyte count and decreased haptoglobulin level. Bone marrow biopsy showed erythroid hyperplasia and relative hypocellularity in myeloid cell lines. Chromosomal karyotyping of bone marrow cells was normal. To look for PNH, immunophenotyping was performed. Flow cytometric analysis showed a PNH clone within the RBCs, granulocytes and monocytes. These findings were consistent with a diagnosis of PNH and she was started on anti-complement therapy with eculizumab. Since matched sibling donor was available, she was referred to our center for transplantation. The conditioning regimen of HSCT consisted of fludarabine (40 mg/m2day -9 to -6) and busulphan (4 mg/kg, day -5 to -2) combined with anti-thymocyte globulin (ATG) (Fresenius, Munich, Germany) (5 mg/kg, day -2 to 0). GVHD prophylaxis consisted of metotrexate plus cyclosporin. The infusion of bone marrow stem cells contained 11.8x106 CD34+ cells/kg and 7.9 x108total nucleated cells/kg. The patient had no significant complications in the post-transplant period. Neutrophil and platelet engraftment occurred on posttransplant day 11 and day 18, respectively. She is alive and is doing well over 14 months following BMT. Recovery is complete with full donor chimerism and the eradication of PNH clone.

Conclusion

PNH can occur in children but is often misdiagnosed and mismanaged. Although with the advent of anti-complement therapy, pure hemolytic anemia is no longer a clear indication for HSCT in adult patient, it is not licensed for use in pediatrics. HSCT is the only curative option for patients with PNH and if suitable matched sibling donor is available, transplant should be considered. However, the experience with tranplantation is also very limited. This case is worth mentioning as it shows that busulphan, fludarabine and ATG can be safely and effectively used for conditioning in PNH in children.

Disclosures:

No relevant conflicts of interest to declare.
Post-Transplantation Cyclophosphamide and Mesenchymal Stem Cells Infusion For Graft-Versus-Host Prophylaxis For Patients With Advanced Disease After Allogenic Bone Marrow Transplantation
Authors: Drokov Mikhail , Parovichnikova Elena , Kuzmina Larisa , Vasilyeva Vera , Karyakina Alexandra , Galstian Gennadyi , Savchenko Valeri G.
Published: October 2019

Introduction

Allogenic bone marrow transplantation (allo-BMT) with high-dose, post-transplantation cyclophosphamide (CY) to promote graft-host tolerance has become an alternative for standard immunosuppression. This post-BMT CY-based immunosuppression regimen has comparable efficacy with other immunosuppressive regimens including cyclosporine A and mycophenolate mofetil. Previously we reported a significant reduction of acute GVHD rate by using MSC infusion for GVHD prophylaxis (n=19, p=0.009) [Abstract 1256, 52nd ASH Annual Meeting abstract]. So we studied high-dose, post-transplantation cyclophosphamide and mesenchymal stem cells (MSC) infusion for graft-versus-host (GVHD) prophylaxis for patients with advanced disease after FLAMSA (where amsacrin was substituted for idarubicin) and FluBuATG conditioning regimen.

Patients and methods

7 patients with a median age 38 years (24-59 years; 5 males, 2 females; 4 donors/recipient pairs was sex matched, 3 was sex mismatched). All patients with advanced disease (relapsed or refractory AML n=4, ALL n=2, MM n=1) with a median blast cells 17.4%, underwent allo-BMT (n=5 from HLA-identical related donor, and n=2 from unrelated donor). Conditioning regimen was composed of fludarabine, busulfan, and horse anti-thymocyte immunoglobuline for 2 patients, in 4 patients FLAMSA was applied, and 1 patient has no conditioning regimen at all (he was in profound prolonged aplasia after previous course of chemotherapy). For GVHD prophylaxis CY at dose 50 mg/kg daily at day +3 (n=2) and at day +3,+4 (n=5) was used. All patients also received MSC for acute GVHD prophylaxis at day of recovery (WBC>1*109/l) at dose 1*106/kg. No other immunosuppression was used.

Results

Neutrophil engraftment was achieved at a median day +20 (range from 17 to 44 days). Acute GVHD occurred in 3 patients (43%) at a median day +45; all cases were Grade 2-3 (with only skin n=2; and with skin and liver involvement n=1); there was only 1 patient with late refractory GVHD in this study treated with prednisone at a dose 2 mg/kg; all other patients responded to initial treatment with cyclosporine A at 3 mg/kg. Overall mortality rate was 42.6%. 1 patient died in CR at day +60 due veno-occlusive disease (TRM - 14%). Relapses occurred in 2 patients (28.6%) at a 3,8 and 2.4 months. The overall survival is 51.4% with a median of follow-up 3,9 month.

Conclusion

Despite the fact that we study small group use of cyclophosphamide with MSC for GVHD prophylaxis is a very attractive approach for patients with advanced disease, and needs further investigation.

Disclosures:

No relevant conflicts of interest to declare.
The Comparison of Immune Components in Three Grafts for Stem Cell Transplantation
Authors: Fan Qian , Liu Hui , Liu Can , Ling Yiwen , Dai Min , Zhang Yu , Fan Zhiping , Xuan Li , Sun Jing , Liu Qifa
Published: October 2019

Background

Recently, a few data showed that Granulocyte-colony-stimulating factor (G-CSF) modified bone marrow (G-BM) grafts leaded a lower morbidity and mortality of graft-versus-host disease(GVHD), compared with G-CSF mobilized peripheral blood stem cells (G-PBSCs) and steady state bone marrow (SS-BM) grafts. However, the mechanism of this difference is not fully understood. In this study, we compared the immune components in the three grafts.

Methods

Twenty patients undergoing HLA-matched sibling donor stem cell transplantation(SCT) were enrolled in this study. Patients were randomized to receive G-BM (n=10) or G-PBSCs (n=10) transplantation. Immune components, including Human leucocyte antigen-G (HLA-G), Myeloid-derived suppressor cells (MDSCs) and T cell subsets, were detected in bone marrow (BM) and peripheral blood (PB) of donors before and at day 5 after G-CSF mobilization.

Results

Among 20 patients, 2 patients developed acute GVHD (aGVHD) and 5 developed chronic GVHD (cGVHD) in G-PBSCs group, and no patients developed aGVHD and only 1 developed limited cGVHD in G-BM group. For the grafts, the proportion of MDSCs in PB and BM was 1.47% ± 0.12% and 2.26% ± 0.35% (P=0.001), respectively, before mobilization. After 5 days of G-CSF mobilization, the proportion of MDSCs in PB and BM increased to be 2.73% ± 0.68% and 2.56% ± 0.12%, respectively. The increase is significant both in PB and BM (P=0.000,P=0.002, respectively), while no significant difference was found between the proportion of MDSCs in G-PB and G-BM graftes (P=0.115). The levels of HLA-G (both soluble and membrane bound) in PB and BM all increased significantly after G-CSF mobilization (all P<0.05). And the levels of HLA-G (both soluble and membrane bound) in BM were all higher than that in PB, including before and after G-CSF mobilization (all P<0.05). The total numbers of CD3+ cells were similar in BM before and after mobilization, both significantly lower than that in PB (both P<0.001). However, the lowered CD4+ cells and increased CD8+ cells in G-BM leaded to a significantly lower CD4:CD8 ratio than that in SS-BM and G-PB (both P<0.001).

Conclusions

The differences of immune components in the grafts might play a part in the different morbidity and mortality of GVHD. The higher expression of HLA-G in the grafts might be the main reason for the lower morbidity and mortality of GVHD in G-CSF-primed bone marrow transplantation.

Disclosures:

Liu: It was supported by 863 Program (No. 2011AA020105), National Public Health Grand Research Foundation (Grant No. 201202017).: Research Funding; It was supported by National Natural Science Foundation of China (Grant No.81000231, No.81270647) and Science and Technology Program of Guangzhou of China (11A72121174).: Research Funding.
Intraoral GS-Nitroxide (JP4-039) Reduces Local Mucositis and Distant Marrow Suppression Toxicities In Head and Neck Irradiated Fancd2-/- (FVB/N) Mice
Authors: Berhane Hebist , Xu Karen , Goff Julie P. , Kalash Ronny , Epperly Michael W. , Dixon Tracy M. , Shields Donna , Franicola Darcy , Li Song , Gao Xiang , Wipf Peter , Greenberger Joel S.
Published: October 2019

The DNA repair defect in Fanconi Anemia patients limits effective radiotherapy. We quantitated oral cavity tissue damage in Head and Neck irradiated FancD2-/-, Fancd2+/- and FancD2+/+ mice, parameters of femoral bone marrow hematopoiesis and the effect of intraoral administration of mitochondrial targeted JP4-039 delivered in novel F15 liposomes.  Adult 10-12 week mice were irradiated to the head and neck to 24, 26 or 28 Gy, shielding all tissue below the cervical spine.  JP4-039/F15 was administered to a subgroup intraorally 10 min before irradiation.  On day 2 or 5 post irradiation, mice were sacrificed, tongue and femur marrow harvested for histopathology, and marrow was assayed for hematopoietic colony formation.  At 5 days post 26 Gy, FancD2 +/- and Fancd2 -/- mice had significantly greater tongue ulceration (52.8 ± 6.5%, p=0.0014 and 59.4 ± 3.4%, p=0.0001, respectively) compared to FancD2 +/+ mice (21.7±4.7%).  JP4-039/F15 significantly reduced local tongue ulceration in all genotypes: FancD2 +/+ reduced to 12.2 ± 1.0 (p = 0.0049), FancD2 +/- reduced to 10.6 ± 3.5 (p < 0.0001) and FancD2 -/- reduced to 11.0 ± 2.5 (p < 0.0001).  FancD2 -/- and FancD2 +/- mice showed “bystander-effect” reduction in femur marrow CFU-GM at 2 days after 26 Gy compared to nonirradiated controls (p=0.007).  FancD2 -/- mice showed decreased BFU-E at day 2 after 24 Gy (p=0.009), CFU-GEMM after 26 Gy (p=0.048), BFU-E after 26 Gy and significantly less CFU-GM after 26 Gy or 28 Gy (p=0.017 and p=0.028, respectively). Intraoral JP4-039 prevented the marrow cytoreductive effects of head and neck irradiation. No reduction in femur marrow CFU-GM, BFU-E or CFU-GEMM was detected in FancD2+/+ mice.  Biallelic or monoallelic loss of the Fancd2 gene renders mice sensitive to head and neck irradiation and is accompanied by distant femur marrow suppression.  Both local and distant irradiation toxicities are ameliorated by intraoral administration of JP4-039.  FancD2-/- mice are an excellent model for testing new agents to control local and distant “bystander effect” toxicities of ionizing irradiation.

Disclosures:

No relevant conflicts of interest to declare.
Impact Of a Federal Program On response Rate & Survival, In a Cohort Of Patients With Diffuse Large B- Cell Lymphoma. Analysis In a Single National Reference Institution In Mexico
Authors: Candelaria Myrna , Labardini Juan , Ramirez Ana Florencia , Aviles Alejandro , Estrada-Lobato Enrique , Meneses-Garcia, Md Abelardo , Mohar Alejandro
Published: October 2019

The actual standard of care of Diffuse Large B-Cell Lymphoma (DLBCL) includes rituximab in combination with chemotherapy, with overall response rates  up to 76 %.  However, this treatment may not be accessible to many patients because of limited economical resources, particularly in  developing countries, where most of the treatment must be paid from the pocket of patients or their families.   In Mexico, since 2011 a Federal program has fully covered   the treatment of patients with DLBCL. At the Instituto Nacional de Cancerología (INCan) in Mexico city 214  patients with ths disease have been treated without cots with the standard of care.   The   mean age at diagnosis was 56.7 +15.9 (22-91). This series of cases was compared with a retrospective analysis of cases with DLBCL seen at the INCan between 2006-2008  None A total of 264 cases were retrospectively analyzed.  No differences were found in demographic and clinical characteristics at the time of diagnosis. However, a clear  positive impact was found in the group that received full treatment thanks to this new social coverage by this new social security program. The follow-up and completion of treatment was 99%.,   In contrast: from 264 in the retrospective group, 209 (79 %)  were treated, but only 29 (10.9 %) were able to receive an optimal treatment, including rituximab.  These differences in treatments had a clearly impact   on the response rate, as shown in the following table:A: Retrospective cases.N (%) B: Cohort.N (%) p Patients. 264 214 -- Treatment:CHOP-R (standard of   care)CHOP0-2 cycles** 2918055** 20410*-- 0.001 Response (all   patients) :CompletePartialStable diseaseProgressiveNot evaluable, lost   of follow up 103  (39)31 (11.7)11 (4.1 )24  (9)95 (36) 124 (58)19 (8.8)0 --29 (13.5)-- 0.001 Relapse rate (%) 93 (35 %) 43 (20%) 0.0001 *7 patients did not received rituximab because of HBV & 3 HIV positive had < 100 absolute CD4 counts.**Patients who abandoned treatment because of reduced economical resources.

These results demonstrate the importance of social programs that may accessible   standard treatment options in countries with limited resources.

Disclosures:

No relevant conflicts of interest to declare.
Fatal and Serious Anaphylaxis Following Peginesatide Administration
Authors: Bennett Charles L. , Jacob Sony , Macdougall Iain C , Moore Tom , Georgantopoulos Peter , Nichols Judy , Yarnold Paul , Sartor Oliver , Raisch Dennis W. , Mikhail Ashraf , Norris LeAnn , Kessler Samuel , Magwood Jametta , Goldsmith David
Published: October 2019

Background

In March 2012, the Food and Drug Administration (FDA) approved peginesatide as anemia therapy for chronic kidney disease patients. In December, the manufacturer warned that a large dialysis organization identified eight patients with peginesatide-associated anaphylaxis. In February 2013, the organization again reported five anaphylaxis events, including three deaths, and discontinued administering peginesatide. After a manufacturer’s review identified five peginesatide-associated anaphylaxis deaths, the manufacturer discontinued marketing the drug.

Methods

We reviewed peginesatide-associated anaphylaxis in FDA’s Adverse Event Reporting System (FAERS). Clinical findings and product lot numbers were analyzed. Inclusion criteria included peginesatide administration and toxicity within thirty minutes of administration.

Results

Between July 2012 and February 2013, 38 CKD patients developed anaphylaxis within a median of five minutes following peginesatide administration (range, zero to 20 minutes). Findings included dyspnea (25 patients), chest pain (10), hypotension (18), diaphoresis (9), pruritis (11), rash (3), angioedema (5), and vomiting (9). Five deaths from cardio-respiratory arrests occurred. Exposure-adjusted incidence was 1.5 cases of anaphylaxis per 1,000 peginesatide-treated patients. Of five FAERS reports for anaphylaxis occurring in February 2013, three included the product lot number C18881 while two did not have lot numbers.  Of 33 FAERS anaphylaxis events reported prior to December 4, 2012; 18 included the lot number C18685, two reports included the lot number C18696, one included the lot number C18881, and lot numbers were not identified for the remaining 12 reports.

Conclusion

Anaphylaxis can occur within minutes of initiating peginesatide therapy. Production or supply chain management problems may be the underlying etiology.

Disclosures:

Macdougall: Affymax and Takeda: Consultancy, Research Funding. Mikhail: Affymax and Takeda: Consultancy, Research Funding. Goldsmith: Affymax and Takeda: Consultancy, Research Funding.
Expansion, Differentiation and Transplantation of Human Endothelial Progenitor Cells Derived from Umbilical Cord Blood CD34+ Cells
Authors: Qin Meng , Zhang Qing-Yu , Ma Yupo , Dai Wei , Jiang Yongping
Published: October 2019

Transplantation of endothelial progenitor cells (EPCs)/endothelial cells (ECs) has been developed as a cell therapy for ischemic diseases and hemophilia A, due to the capacities of these cells to repair vascular damage and produce factor VIII. The strategies and the mechanisms of this type of cell therapy have been extensively investigated in the past decades. However, given the problems associated with host immune responses to grafts in allotransplantation, the difficulties in obtaining adequate numbers of suitable cells for transplantation represent additional obstacles for a successful cell therapy. In the present study, human umbilical cord blood CD34+ mesenchymal cells (MCs), which generate low immune response, have been adopted as the source of endothelial progenitors. Our major goal is to establish a highly efficient approach to stimulate the expansion and subsequent differentiation of human endothelial progenitor cells (EPCs), in order to obtain sufficient quantities of healthy cells for therapeutic use. The CD34+ cells isolated from human umbilical cord blood were cultured for 6 days in a customized basal medium supplemented with a modified cytokine cocktail, including SCF, Flt-3L, TPO, IL-3, and GM-CSF. At the end of proliferation stage, cell number was calculated with Flow Cytometry, and cell morphology was characterized as well. The numbers of CD34+ cells and CD34+/CD133+/VEGFR-2+ early EPCs cells were found to be increased by approximately 108-fold and 41.9-fold, respectively, on day 6. In the differentiation stage, the attached cells were transferred to EGM-2 basal medium supplemented with FBS and additional nutrients, including VEGF, IGF, EGF, and FGF, for another 15 days. Following this two-step culture, the generated adherent cells were found to have proliferated more than 1200 folds over the initial EPCs, and they were identified as mature endothelial cells expressing CD31, vWF and FVIII. Furthermore, we developed a nonobese diabetic, severe combined immunodeficient (NOD/SCID) mouse model with portal sinusoidal endothelium injury. The NOD/SCID mice were treated with the produced EPCs/ECs through hepatic portal vein injection at the dose of 6x10^6 cells. Tissue examination demonstrated that GFP-labeled transplanted cells migrated and integrated into liver structure, where they expressed specific endothelial cell markers. Therefore, through our unique approach, we can provide an excellent source of healthy endothelial progenitors for cell therapy.

Disclosures

Qin: Biopharmagen corp: Employment. Jiang:Biopharmagen.corp: Employment.
Low ADAMTS13 Activity Is a Strong Risk Factor for Ischemic Stroke: A Prospective Cohort Study - the Rotterdam Study
Authors: Sonneveld Michelle Alida Helena , Maat Moniek de , Portegies Marileen L.P. , Hofman Albert , Turecek Peter L , Rottensteiner Hanspeter , Scheiflinger Friedrich , Koudstaal Peter J. , Ikram Mohammed A. , Leebeek Frank
Published: October 2019

Introduction.ADAMTS13 has antithrombotic properties because it cleaves Von Willebrand factor (VWF) in smaller, less active multimers. Low ADAMTS13 activity may therefore increase the risk of arterial thrombosis, including ischemic stroke. We prospectively studied the association between ADAMTS13 activity, VWF antigen (VWF:Ag) levels and ischemic stroke in the Rotterdam Study, a population-based cohort study among subjects ≥ 55 years.

Methods.We included 5941 individuals without a history of stroke or TIA. Blood was drawn at baseline and ADAMTS13 activity (expressed as % of normal plasma) was measured using the FRETS-VWF73 assay and VWF:Ag levels by ELISA. All individuals were followed for development of stroke or TIA. The association between ADAMTS13 activity, VWF:Ag levels and ischemic stroke were assessed by Cox proportional hazard regression analysis.

Results.Over an average follow-up time of 9.5 years, 461 participants suffered from a stroke, 306 of which definitely classified as ischemic. After adjustment for cardiovascular risk factors, individuals with ADAMTS13 activity in the lowest quartile had a higher risk of ischemic stroke (HR 1.65, 95% CI 1.16 – 2.32) than those in the reference highest quartile. In individuals with low ADAMTS13 activity and high VWF:Ag levels the risk of ischemic stroke risk was 3.5 fold increased (HR 3.51, 95% CI 1.60 – 7.70).

Conclusions.In this large prospective population study, low ADAMTS13 activity predicts the risk of ischemic stroke, independently of age, sex, and established cardiovascular risk factors. This risk was even higher in individuals with both low ADAMTS13 activity and high VWF antigen levels.

Figure 1 Figure 1.

Disclosures

Turecek: Baxter Innovations GmbH, Vienna, Austria: Employment. Rottensteiner:Baxter Innovations GmbH: Employment. Scheiflinger:Baxter Innovations GmbH: Employment. Leebeek:CSL Behring and Baxter: Membership on an entity's Board of Directors or advisory committees.
Survival Difference in Multiple Myeloma By Place of Birth
Authors: Khanal Bindu Raj , Nepal Barsha , Ghimire Krishna B
Published: October 2019

Introduction:

Multiple Myeloma (MM) survival has improved in last decade with better understanding of disease process and use of novel agents. There is limited data if there is survival difference in MM by place of birth. We choose United States and South Asian Association for Regional Cooperation (SAARC) countries to see if there any difference in survival among these two geographical regions. SAARC consists of 8 south Asian countries: Afghanistan, Bangladesh, Bhutan, India, Sri Lanka, Nepal, Maldives and Pakistan.

Methods:

We analyzed Surveillance Epidemiology and End Results (SEER), SEER 18 registry to compare relative survival (RS) of US born and SAARC countries born MM patients, who were diagnosed with MM during (1973-2011). We analyzed RS during three eras: pre transplant era (1973-1995), transplant era (1996-2002) and era of novel agents (2003-2011) by age (≤65 and >65 years) and sex. We used SEER*Stat software to calculate Z value.

Results:

There were 228 SAARC born and 42,629 US born MM patients diagnosed during (1973-2011). Median age of diagnosis for SAARC countries born MM patients was 64 years (range: 27-88) and 82 of them were female. Median age of diagnosis for US born MM patients was 68 years (range: 18-99) and 19,385 of them were female.

There was no significant difference in RS between SAARC born and US born MM patients during pre-transplant and transplant eras. In the era of novel agents, RS of SAARC born MM patients was significantly higher compared to US born MM patients (64±5.1% vs 47.6±0.5%, Z value 3.4) at 3 years and (47.6±6.2% vs 32.2±0.5%; Z value 3.3) at 5 years.

Analysis by sex showed, both male and female SAARC born MM patients had higher RS compared to US born MM patients at 3 and 5 years during era of novel agents.

Similarly, younger (≤65 years) SAARC born MM patients had significantly better survival than US born MM patients at 3 and 5 years. Older (>65 years) SAARC born MM patients also had significantly better survival at 3 years but there was no significant difference at 5 years.

Conclusions:

Our study showed that there is survival difference Multiple Myeloma patients by place of birth. MM patients born is SAARC countries have better survival than patients born in US. It could possibly be related to difference in disease biology, socioeconomic status and access to health care. We need more studies in future to confirm these findings and individualise treatment plan.

Disclosures

No relevant conflicts of interest to declare.
Incidence and Outcomes of Pediatric Myelodysplastic Syndrome in the US
Authors: Xavier Ana , Kutny Matthew A. , Costa Luciano J
Published: October 2019

Background

There is lack of epidemiological data on pediatric myelodysplastic syndrome (p-MDS) in the literature. MDS became reportable to the Surveillance, Epidemiology and End Results (SEER) Program in 2001, providing an opportunity to estimate the incidence and survival of pediatric patients with MDS in the United States.

Methods

We utilized data from the National Cancer Institute SEER-18 to determine the incidence and long term overall survival (OS) of pediatric patients (ages 0 to 20 years) diagnosed with de novo MDS or therapy-related MDS. Inclusion criteria was diagnosis of MDS (International Classification of Diseases-Oncology, Third Edition, ICD-O-4 codes 9980/3, 9991/3, 9992/3, 9982/3, 9985/3, 9983/3, 9986/3, 9986/3, 9989/3, 9985/3, 9975/3, and 9987/3) between 2001 and 2011. Follow up was updated through the end of 2011 (November 2013 submission). Overall survival was estimated using the method of Kaplan-Meier. A Cox proportional hazard model was used to compare the effects of age, race, gender, histological subtype, and etiology (de novovs. therapy-related) on survival.

Results

The incidence of p-MDS was 1.16 cases/1 million population*year. A greater incidence occurred in children younger than 1 year of age possibly reflecting congenital bone marrow failure syndromes (Figure 1). A total of 314 p-MDS cases were included in the analysis with median follow up of 31 months (range 0-131). Median age of patients was 9 years; 167 (53.3%) had MDS unclassifiable (NOS), 40 (12.7%) had therapy-related MDS (t-MDS), 44 (14%) had refractory anemia with excess blasts (RAEB), 32 (10.3%) had refractory anemia (RA), 17 (5.4%) had refractory cytopenia with multilineage dysplasia (RCMD), 6 (1.9%) had refractory anemia with ring sideroblasts (RARS), 5 (1.6%) had refractory anemia with excess blasts in transformation (RAEBT), and 3 (0.9%) had MDS associated with isolated del(5q). Male patients comprised 154 (49%) of cases. Racial groups included white (218, 69.4%), 52 (15.7%) black, 37 (11.8%) of other races, and 7 (2.3%) the race was unknown.

The 5 year-OS for the entire cohort was 68% (95% C.I.=62.3-73.7). Patients with t-MDS had significantly worse 5 year-OS (41.2%; 95%C.I.=23.8-58.6) compared to those with de novo MDS (71.3%; 95%C.I.=65.3-77.2; P=0.004, Figure 2). In multivariate analysis of age, race, gender, histological subtype, and etiology (de novovs. therapy-related) utilizing Cox regression model, only t-MDS was associated with higher risk of death (HR=2.07, 95% C.I.=1.25-3.42, P=0.005).

Conclusions

Pediatric MDS is a rare disorder, with higher incidence among children younger than 1 year of age. Over two thirds of p-MDS patients will become long-term survivors, although significantly inferior outcome is seen in t-MDS.

Figure 1 Figure 1.

Figure 2 Figure 2.

Disclosures

No relevant conflicts of interest to declare.