bluuebunny/crossref_metadata_2025_split huggingface dataset:
Improving Outcomes in Patients with Renal Failure Secondary to Multiple Myeloma: Results From ChAR2M2.
Authors: Hutchison Colin , Airia Parisa , Cook Mark , Grima Daniel 
Published: October 2019

Abstract
Abstract 1875
Poster Board I-900

Study purpose:
To explore how free light chain (FLC) removal by high cut-off haemodialysis (HCO-HD) has been adopted into clinical practice for the management of renal failure secondary to multiple myeloma. Describing treatment patterns and the laboratory and clinical outcomes associated with its use.

Methods:
A chart audit of patients treated with FLC removal by HCO-HD, using the Gambro HCO 1100 dialyser, was performed in 16 dialysis centers across 9 countries. Patient demographics, treatment patterns and dialysis side-effects were recorded. In addition, the following outcomes were measured: dialysis independence and reductions in serum FLCs concentrations at 12 and 21 days.

Results:
Data for 66 patients was entered. Patients had an average age of 65.1 (SD×10.1); 42 of them (63.64%) were male and 24 (36.36%) were female. Sixteen (24%) presented with relapsing myeloma and 50 (76%) had de novo disease. On average, each patient received 13 HCO-HD sessions (SD×8). Forty-one patients became dialysis independent (62.12%), after an average of 12 sessions. Dialysis related side-effects were reported in 6% of all patients. Forty patients (60.61%) were reported to have a sustained reduction in serum FLC concentrations by day 12. By day 21 this had increased to forty-one (62.12%). Among the patients who achieved a sustained reduction in serum FLC concentrations, 28 (70%) had a decline in FLC levels of more than 50% by day 12 and 34 (82.93%) by day 21. Among patients who achieved sustained reduction of more than 50% in serum FLC concentrations by day 12, 75% became dialysis independent. In comparison only 53% of those with a reduction of less than 50% became dialysis independent (p×0.007). Furthermore, among patients who achieved sustained FLC reduction of greater than 75%, 81% became dialysis independent. The rate of dialysis independence was also significantly higher in patients with de novo disease compared with those with relapsing myeloma (64% versus 56%, p×0.04).

Conclusion:
Free light chain removal by HCO-HD was well tolerated and associated with a very high rate of dialysis independence in patients with renal failure secondary to multiple myeloma. Rates of renal recovery were greater in patients with de novo myeloma and those who achieved an early reduction in serum FLC concentrations.

Disclosures:
No relevant conflicts of interest to declare.
Pharmacodynamic (PD) Biomarker Assay Validation for SB1518, a Novel Oral JAK2 Inhibitor in Phase 1 Clinical Trials for Advanced Leukemias, Myeloproliferative Diseases and Lymphoma.
Authors: Hart Stefan , Goh Kee Chuan , Tan Yong Cheng , Chithra Amalini , Wood Jeanette 
Published: October 2019

Abstract
Abstract 1888
Poster Board I-911

Introduction:
Abnormalities in JAK2 and FLT3 kinases are reported in various hematological malignancies and may underlie the pathogenesis of these diseases. An activating mutation of JAK2, namely JAK2V617F is the most common mutation in bcr-abl-negative chronic myeloproliferative disorders (MPDs). Activation of wild type JAK2 has been reported in Hodgkin lymphoma (HL) and primary mediastinal large cell Non-Hodgkin lymphomas (NHL) due to loss of Suppressor of Cytokine Signaling (SOCS)-1 gene. Abnormalities in FLT3 are present in ∼30% of acute myelogenous leukemias (AML). SB1518 is a potent inhibitor of both JAK2 (IC50 = 22 nM) and its JAK2V617F mutant (IC50 = 19 nM) as well as FLT3 (IC50 = 22 nM) and it mutant D835Y (IC50 = 6 nM). As a consequence, SB1518 inhibits the proliferation of human leukemia and lymphoma cell lines dependent on either JAK2 or FLT3 activation (IC50 =35–240 nM), and has antitumor activity in nude mouse models of FLT3- (MV4-11) or JAK2-dependent (BaF3-JAK2V617F) leukemia. SB1518 is currently being evaluated in Phase 1 clinical trials for advanced leukemias, MPDs and lymphoma. We describe here the development and assessment of biochemical biomarkers to assess the pharmacodynamic (PD) efficacy of SB1518 in the phase I clinical trials.

Methods and Results:
Sensitive flow cytometric and quantitative Western-blot assays were developed for measuring downstream JAK2 and FLT-3 signaling; namely STAT5/3 phosphorylation in tumor tissue, fixed cells from whole blood or lysed PBMCs. These assays were validated by demonstrating target inhibition after ex vivo treatment of PBMCs from healthy human donors and in blood cells and tumor tissue after oral dosing of normal and tumor bearing nude mice with SB1518. Initial data obtained from analysis of whole blood and PBMCs from patients treated with SB1518 in the ongoing Phase 1 clinical trials demonstrate target inhibition even at the lowest dose level of 100 mg/day on the first day of oral dosing.

Conclusion:
In summary, we have developed and quantitative biomarker assays and applied them to demonstrate PD target efficacy of SB1518 in animal tumor models as well as patients in ongoing phase 1 clinical trials.

Disclosures:
Hart: S*BIO PTE LTD: Employment, Equity Ownership. Goh:S*BIO PTE LTD: Employment. Tan:S*BIO PTE LTD: Employment. Chithra:S*BIO PTE LTD: Employment. Wood:S*BIO PTE LTD: Employment.
Trends in the Incidence of HIV-Related Hematologic Malignancies in the Era of Combination Antiretroviral Therapy and Predictors of HIV-Related Non-Hodgkin's Lymphoma Development and Survival.
Authors: Taggart Linda R , Isogai Pierre K , Risebrough Nancy , Mittmann Nicole , Rachlis Anita R , Imrie Kevin R , Cheung Matthew C 
Published: October 2019

Abstract
Abstract 1916
Poster Board I-939

Introduction:
Since the introduction of combination antiretroviral therapy (cART), the incidence rates of non-Hodgkin's lymphoma (NHL) and primary central nervous system lymphoma (PCNSL) have declined; however, less is known about the rates of other hematologic malignancies such as Hodgkin lymphoma (HL) and multiple myeloma (MM). We aimed to study changes in the incidence and outcomes of hematologic malignancies (HMs) in the pre- and post-cART eras.

Methods:
A retrospective analysis of The Ontario HIV Treatment Network Cohort Study (OCS) was performed. The OCS is an ongoing prospective study of HIV-infected adults from 11 sites throughout Ontario, Canada. Incidence rates of HMs were calculated for the pre- (<1997) and post-cART (≥ 1997) eras and compared using Poisson regression analysis. Median survival for each HM was calculated using Kaplan Meier techniques and compared using the logrank test. Predictors of NHL and death from NHL including age, sex, CD4 count, viral load, previous AIDS-defining illness, cART era and duration of HIV infection were evaluated using Cox proportional hazard models. All variables except sex were considered time dependent variables.

Results:
The OCS database included 4118 individuals with 41978 person-years of follow up over 28 years (1980-2008). There was no significant difference in the incidence of HM in the pre- and post-cART eras (3.6 versus 4.1 cases per 1000 person-years, p-value=0.49) although incidence of PCNSL trended downward (0.8 versus 0.4 cases per 1000 person-years, p-value=0.13) and incidence of HL trended upward (0.1 versus 0.4 cases per 1000 person-years, p-value=0.08). Those with HL had the longest median survival, followed by NHL and PCNSL (63, 39 and 4 months respectively). Predictors of NHL development included low CD4 count, high viral load and pre-cART era. Predictors of death following NHL diagnosis were low CD4 count, previous AIDS-defining illness and longer duration of HIV infection.

Conclusion:
Since the introduction of cART, the overall incidence of HM has not significantly changed in this cohort. However, as fewer individuals in the cART era develop low CD4 counts, high viral loads and AIDS-defining illnesses, reduced incidence of NHL in this cohort and improved survival following NHL may become apparent.

Disclosures:
No relevant conflicts of interest to declare.
TNFRSF14 Is Mutated in a Subset of Follicular Lymphoma and Correlated with Inferior Prognosis.
Authors: Cheung K-John , Johnson Nathalie , Affleck Joslynn , Severson Tesa , Steidl Christian , Ben-Neriah Susanna , Schein Jacqueline , Morin Ryan , Moore Richard , Shah Sohrab P , Qian Hong , Paul Jessica , Telenius Adele , Lai Betty , Relander Thomas , Lam Wan L , Savage Kerry J. , Connors Joseph M , Brown Carolyn , Marra Marco , Gascoyne Randy D. , Horsman Douglas E. 
Published: October 2019

Abstract
Abstract 1919
Poster Board I-942
The secondary genetic events associated with follicular lymphoma (FL) development are obscure as to the identification of critical driver genes. Clinical correlative studies have implicated chromosome band 1p36 deletions and linked them to a propensity for transformation and poor outcome. This region also showed a high frequency of copy-neutral loss of heterozygosity as demonstrated by SNP array analysis. In this study, we applied BAC array comparative genomic hybridization (array CGH) to 141 FL specimens and detected deletion of 1p36 in 20% of the cases with a minimum region of deletion (MRD) of ∼100 kb within the band 1p36.32. The majority of cases displayed heterozygous deletion, while two cases showed homozygous deletion. The MRD encompassed five genes: HES5, LOC115110, TNFRSF14, C1orf93 and MMEL1. Methylation status of CpG in the promoter region of genes in the MRD revealed no difference among samples differing in 1p36 status. However, exonic sequencing of the MRD genes identified somatic base mutations only in the TNFRSF14 gene in four of five selected cases with 1p36 deletion. Lower expression of TNFRSF14 was also found in 1p36 deleted cases. Validation of TNFRSF14 mutations was undertaken in an expanded cohort of 251 FL patients which showed that 45 cases (18%) displayed a total of 50 mutations and that inferior prognosis was significantly associated with TNFRSF14 mutation status. We propose that TNFRSF14, a gene previously implicated in growth inhibition and Fas-induced apoptosis, is a candidate tumor suppressor gene in FL.

Disclosures:
No relevant conflicts of interest to declare.
Activation of PI3K/Akt/mTOR Pathway in Diffuse Large B-Cell Lymphomas: Clinical Significance and Inhibitory Effect by Rituximab.
Authors: Li Jun-min , Xu Zi-zhen , Wang Ai-hua , Hu Jiong 
Published: October 2019

Abstract
Abstract 1934
Poster Board I-957
A better understanding of the biology of diffuse large B cell lymphoma(DLBCL) is needed in the developement of potential therapeutic agents that target specific intracellular pathway. In this study, expression of the important members of PI3K/Akt/mTOR signaling pathway and their clinical significance were investigated in 73 cases of DLBCL. Immunohistochemical analyses showed that activation of Akt and its downstream targets such as p-p70S6K, p-4E-BP1, YB-1 and Mcl-1 were present in DLBCL cases. Activation of PI3K/Akt/mTOR pathway was related to poor disease outcome in DLBCL patients treated by CHOP but not in those treated by R-CHOP. Rituximab combined with chemotherapy could down-regulate PI3K/Akt/mTOR activation and reverse its negative effect on chemotherapy-treated patients. The effect of Rituximab alone or combined with the mTOR inhibitor Rapamycin was further evaluated in DLBCL cell line SUDHL-4. Rituximab combined with Rapamycin possessed synergic effect in down-regulating PI3K/Akt/mTOR signaling pathway, inhibited proliferation and caused G1 arrest in DLBCL cell line. The results showed that PI3K/Akt/mTOR signaling pathway activation presented in DLBCL may be considered as a prognostic biomarker and a promising target for therapeutic intervention.

Disclosures:
No relevant conflicts of interest to declare.
A Comparison of Gene Expression Pattern in Major Histocompatibility Class II-Low Diffuse Large B-Cell Lymphoma with Plasmablastic Lymphoma.
Authors: Wilkinson Sarah T. , Bob Roshanak , Stein Harald , Schwartz Mark , Braziel Rita M. , Gascoyne Randy D. , Rimsza Lisa M. 
Published: October 2019

Abstract
Abstract 1941
Poster Board I-964
Multiple studies have repeatedly shown that loss of MHC II expression correlates with poor patient prognosis in diffuse large B-cell lymphoma (DLBCL). Major histocompatibility complex class II (MHCII) molecules present peptides for antigen recognition and are important for the adaptive immune response. Loss of MHCII expression is also one of the changes seen during normal B-cell differentiation into plasma cells. Plasmablastic lymphoma (PBL) is another B-cell lymphoma characterized by a proliferation of large B-cells with a plasma cell immunophenotype and very poor prognosis. In this study, we questioned whether DLBCL cases that have low MHCII expression have a similar gene expression pattern to PBL. Unstained cuts from formalin-fixed, paraffin-embedded tissue blocks of 101 DLBCL and 76 PBL cases were analyzed for gene expression using a quantitative nuclease protection assay (qNPA, ArrayPlateR). The 42 genes on the array were previously identified as B-cell lineage-related or prognostically important in DLBCL. DLBCL cases were divided into low [MHCII(-)] and high [MHCII(+)] MHC II expression using a 20% cutoff for expression of HLA-DRB by qNPA, as previously described (L Rimsza et al, Blood 2008). Genes that differed significantly between lymphoma types were determined using the Partek Genomics SuiteR software, using ANOVA tests with a false discovery rate of 0.05. Thirty of the 42 genes on the array (71%) were differentially expressed between DLBCL as a whole and PBL. As expected from the literature, the PBL cases had less expression of B-cell antigen, MHCII, and germinal center-related genes as compared to DLBCL. Of these 30 genes, 29 were also different between MHCII(+) and PBL. In contrast, only 21 genes of the 42 on the array (50%) were differentially expressed between MHCII(-) and PBL, indicating a less dissimilar expression pattern between these two sets of cases. Of the 21 genes, two were uniquely different between MHCII(-) and PBL. Both of these, FN1 and CTGF, are found in the extracellular matrix and were low in the MHCII(-) cases. This finding, that the MHCII(-) cases are similar, but not identical to PBL, agrees with our previous immunohistochemistry studies suggesting MHCII(-) cases may be invoking selected mechanisms of differentiation (S Wilkinson et al, AACR Annual Meeting 2009, #2712). Our findings confirm the hypothesis that MHCII(-) DLBCL have a more plasma cell-like expression pattern than MHCII(+) DLBCL. These findings may have implications for pathogenesis and treatment.

Disclosures:
Schwartz: High Throughput Genomics: Employment. Gascoyne:Roche Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Rimsza:High Throughput Genomics: Memorandum of understanding with HTG to run qNPA assay at no cost..
CD80 (B7.1) Is Expressed On Both Malignant B Cells and Tumor Infiltrating T Cells in Non-Hodgkin's Lymphomas.
Authors: Tangri Shabnam , Dakappagari Naveen , Estrellado Annalee , Weng Andrew P. , Holmes Elizabeth , Saville M. Wayne , Hariharan Kandasamy , Ho Steffan 
Published: October 2019

Abstract
Abstract 1953
Poster Board I-976
CD80 is a member of the B7/CD28 family of regulatory proteins. B7/CD28 proteins are expressed on the surface of cells of the adaptive and innate immune system (i.e. lymphocytes, monocyte/macrophages, dendritic cells, myeloid-derived suppressor cells). These proteins function to establish a biologically optimal and dynamic balance between immune activation and inhibition or self-tolerance. Interactions between CD80 and its receptors, which include CD28, CTLA4 and PD-L1, contribute to both stimulatory as well as inhibitory or homeostatic regulation. Galiximab, an antibody directed against CD80, is currently under investigation for the treatment of follicular NHL. Initial clinical trials demonstrated that galiximab is well tolerated and suggest that combining galiximab with rituximab may provide clinical benefit. While expression of CD80 by malignant B cells in non-Hodgkin's lymphoma (NHL) has been reported, these studies utilized poorly quantitative immunohistochemical methods. To gain further understanding of the potential role of CD80 as a therapeutic target in NHL, CD80 expression was evaluated by six-color flow cytometric analysis of primary lymphoma cell suspensions generated from diagnostic biopsies of patients presenting with lymphadenopathy. Results obtained to date confirm that CD80 is uniformly expressed by malignant cells in a large majority of cases of follicular lymphoma (N=63), diffuse large B cell lymphoma (N=38), mantle cell lymphoma (n=7), marginal zone lymphoma (n=12) and small lymphocytic lymphoma (n=9). Furthermore, CD80 expression was also observed on tumor-infiltrating, non-malignant T cells.
These results confirm the nearly ubiquitous expression of CD80 by malignant B cells in follicular, diffuse and other low grade NHL. Furthermore, these data demonstrate expression of CD80 by non-malignant cells (e.g. T cells) that define the tumor microenvironment. Further work to expand this dataset and to evaluate the expression of CD80 in non-T, non-B cells is ongoing. The expression of CD80 by malignant cells as well as non-malignant cells in NHL provides an opportunity to not only employ therapeutic antibodies to direct anti-tumor effector function such as antibody-dependent cellular cytotoxicity, but to also potentially interfere with interactions involving CD80 that might be involved in establishing an immune suppressive microenvironment supportive of tumor growth.

Disclosures:
No relevant conflicts of interest to declare.
Cooperation of MLL/AF10(OM-LZ) with K-Ras Mutation Induced Myeloid Sarcoma in a Mouse Bone Marrow Transplantation Model.
Authors: Fu Jen-Fen , Shih Lee-Yung 
Published: October 2019

Abstract
Abstract 1964
Poster Board I-987
We analyzed genetic mutations in a large cohort of AML patients and found that two of the five patients with MLL/AF10 and N-/K-RAS mutations had cutaneous tumors (myeloid sarcomas). To study the cooperative role of MLL/AF10 and N-/K-RAS in the formation of myeloid sarcoma, we established two cell lines by retroviral transduction of MLL/AF10(OM-LZ) and K-RASG12C into GFP-B6 mouse bone marrow cells. Flow cytometric analysis revealed that the cells with MLL/AF10(OM-LZ) and K-RASG12C showed a decreased Mac-1 and CD115 expression when compared with the cells with a single MLL/AF10(OM-LZ) mutation. Microarray and RT-PCR analyses revealed an increased gene expression in Hoxa10 and Meis1, but not Hoxa9. In addition, the phagocytosis related genes, Cybb and Lyz were decreased in the cells harboring MLL/AF10(OM-LZ) and K-RASG12C. These results suggested that cooperation of MLL/AF10(OM-LZ) and K-RASG12C mutations blocked the cells in a more primitive hematopoietic stage. When the two cell lines were intra-peritoneally injected into B6 mice, the mice developed myeloproliferative disease-like myeloid leukemia as that of the mice transplanted with cells carrying a single MLL/AF10(OM-LZ) fusion gene. The median survival time were 33±4.2 and 31.6±5.1 days, respectively, which were shorter than that of the mice transplanted with cells carrying a single MLL/AF10(OM-LZ) fusion gene (49.8±5.0 days). We found that the majority (84%) of mice transplanted with cells harboring both MLL/AF10(OM-LZ) and K-RASG12C mutations formed multiple tumor masses involving gastrointestinal tract, kidney, peritoneum, paraspinal soft tissue, and/or skin. Cytological examination from the imprint smears of tumor masses showed massive infiltrates of leukemia blastic cells. Immunohistochemical stains of the paraffin-fixed histological sections of tumor masses were positive for GFP, confirmed that the tumor cells were generated from the transplanted cell lines. We have established a mouse model which can be used for further study of the myeloid sarcoma formation.

Disclosures:
No relevant conflicts of interest to declare.
Loss of L3MBTL1, a Candidate 20q12 Tumor Suppressor Gene, Leads to DNA Damage.
Authors: Gurvich Nadia , Voza Francesca , Menendez Silvia , Nimer Stephen 
Published: October 2019

Abstract
Abstract 1974
Poster Board I-997
The L3MBTL1 gene is located on the long arm of chromosome 20 (q12), a region commonly lost in several myeloid malignancies, including myeloproliferative diseases (MPD), myeloprodysplastic disorders (MDS), and acute myeloid leukemias (AML). MDS and AML frequently have complex cytogenetic profiles, and are thought to arise due to accumulation of several cooperating mutations. We have previously reported that L3MBTL1 is highly expressed in human hematopoietic progenitor cells. L3MBTL1 is a homolog of Drosophila polycomb L3MBTL tumor suppressor protein. Thus, L3MBTL1 is a candidate gene in 20q12 myeloid disorders. We have depleted L3MBTL1 by RNAi in several human cell lines, and find that loss of L3MBTL1 leads to a decrease of cells in the S phase of the cell cycle and accumulation in G2/M phase. Cells with depleted L3MBTL1 have an increase of spontaneous DNA breaks, as evidenced by accumulation of γH2A.X foci and comet assay. The presence of DNA breaks leads to activation of DNA damage response, as the L3MBTL1 knockdown cells have increased levels of phosphoChk1 (Ser317 and Ser345), phosphoChk2 (Thr68), phosphoATM (Ser1981), p21 and p53. The DNA damage in the L3MBTL1-depleted cells activates DNA repair machinery, as shown by the increase in Rad51 levels. We propose that the spontaneous DNA damage caused by depletion of L3MBTL1 could contribute to the development of 20q12 myeloid malignancies.

Disclosures:
No relevant conflicts of interest to declare.