bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multicenter Retrospective Study on the Development of Peripheral Lymphocytosis During Second-Line Dasatinib Therapy for Chronic Myeloid Leukemia
Authors: Lee Ha Yeon , Lee Su Jin , Ha Boram , Yi Jun Ho , Jung Chul Won , Kim Dae-Young , Lee Je-Hwan , Lee Kyoo Hyung , Sohn Sang Kyun , Kim Sung Hyun , Lee Won-Sik , Park Joon Seong , Yhim Ho-Young , Kwak Jae-Yong , Kim Hyeoung Joon , Kim Yeo-Kyeoung , Kim Inho , Park Seonyang , Kim Dong Hwan (Dennis) 
Published: October 2019

Abstract
Abstract 2275

Background:
Dasatinib is known to induce large granular lymphocyte (LGL) expansion, which correlates with better clinical efficacy. The current retrospective study attempted to investigate the incidence of lymphocytosis following second-line dasatinib therapy in chronic myeloid leukemia (CML) and to analyze the clinical factors predictive of the development of lymphocytosis, as well as association with treatment outcomes.

Method:
Fifty CML patients who failed imatinib treatment and received dasatinib for 3 months or more, were enrolled from 9 centers in the Republic of Korea. The cumulative incidence of lymphocytosis was assessed, and cytogenetic and molecular response, treatment failure, loss of response, progression to advanced disease, and survival were evaluated and analyzed according to the development of lymphocytosis.

Results:
After a median of 17 months of dasatinib therapy, complete cytogenetic (CCR) and major molecular response (MMR) was noted in 23 and 16 patients, respectively. Twenty three patients (46%) developed lymphocytosis following dasatinib therapy (median onset 4 months). No clinical predictive factor for the development of lymphocytosis was found. The cytogenetic response was significantly better in the group that developed lymphocytosis (LC+), as compared to the group without lymphocytosis (LC-); the LC+ group showed a higher complete cytogenetic response (CCyR; 78.3% vs. 29.6%, p=0.001) and major molecular response (MMR; 52.2% vs. 14.8%, p=0.005), in comparison to the LC- group. The development of lymphocytosis after dasatinib was identified as a favorable independent marker for predicting a CCyR (p=0.002) or MMR following dasatinib therapy (p=0.003).

Conclusion:
The present study suggested that 1) lymphocytosis following dasatinib therapy is not rare phenomenon with incidence of 46%; 2) it might be associated with higher response following dasatinib therapy. Further study is necessary to identify which subset of lymphocytes was expanded and to reveal the exact mechanism by which dasatinib induces lymphocyte expansion.

Disclosures:
No relevant conflicts of interest to declare.
Mast Cells Reduce Gvhd Severity In Allogeneic Transplantation by Reducing the Proliferation of Conventional T Cells
Authors: Leveson-Gower Dennis B , Sega Emanuela I , Kalesnikoff Janet , Florek Mareike , Galli Stephen J , Negrin Robert 
Published: October 2019

Abstract
Abstract 243
Mast cells are important effector cells in many innate and adaptive immune responses, and can influence the function of several immune cells including granulocytes, monocytes/macrophages, dendritic cells, T cells, B cells, NK cells, and NKT cells. In contrast to their well-know pro-inflammatory roles, in certain models, mast cells have been shown to decrease inflammation and tissue injury. We explored the biological activity of mast cells in a well-established model of mouse graft-versus-host disease (GVHD) by comparing C57BL/6-KitW-sh/W-sh mice (which lack mast cells) to wild-type (WT) C57BL/6 (H-2b) recipients in a major-MHC mismatched model of allogeneic transplantation. After myeloablative irradiation, recipients received 5×106 T-cell depleted bone marrow cells from FVB/N donors (H-2q) on day 0 followed by transfer of 2×106 FVB/N CD4 and CD8 conventional T cells (Tcon) at a 2:1 ratio on day 4. A dramatic decrease in survival was observed in the animals lacking mast cells where 100% of KitW-sh/W-sh recipients died by day 15 following transplantation while over 50% of WT recipients were alive at day 60 (p < 0.0001). The exacerbated GVHD in KitW-sh/W-sh mice correlated with an increase in Tcon proliferation as indicated by bioluminescence imaging (BLI), particularly in lymph node, liver, and gastrointestinal tract tissue sites (p < 0.001). The percentage of Foxp3 positive Treg cells was similar before and after transplantation in KitW-sh/W-sh and WT recipients, and CD4+CD25hi Treg from KitW-sh/W-sh mice were capable of suppressing T cell proliferation in a mixed leukocyte reaction. When KitW-sh/W-sh mice were given 5×106 bone marrow-derived cultured mast cells (BMCMCs) i.p., mast cell re-population of the gut and peritoneal cavity was indicated by both BLI and traditional staining methods. Preliminary experiments with KitW-sh/W-sh recipients engrafted with BMCMCs i.p. 6 weeks before allogenic transplantation demonstrated improved survival in the above GVHD model, but not if the BMCMCs were derived from IL-10-/- C57BL/6 mice. Together, these results support the hypothesis that mast cells can decrease Tcon proliferation and reduce GVHD severity by a mechanism that involves production of IL-10 by mast cells but which is independent of CD4+CD25+ Treg.

Disclosures:
No relevant conflicts of interest to declare.
Profiling of Aberrant DNA Methylation In AML Reveals Subclasses of CpG Islands with Epigenetic or Genetic Association
Authors: Gebhard Claudia , Sadeh Mohammed , Glatz Dagmar , Schwarzfischer Lucia , Spang Rainer , Ehninger Gerhard , Thiede Christian , Andreesen Reinhard , Rehli Michael 
Published: October 2019

Abstract
Abstract 2498
CpG islands show frequent and often disease-specific epigenetic alterations during malignant transformation, however, the underlying mechanisms are poorly understood. We used methyl-CpG immunoprecipitation (MCIp) to generate comparative DNA methylation profiles of 30 patients with acute myeloid leukemia for human CpG islands across the genome. DNA methylation profiles across 23.000 CpG islands revealed highly heterogeneous methylation patterns in AML with over 6000 CpG islands showing aberrant de novo methylation in AML. Based on these profiles we selected a subset of 380 CpG islands (covering 15.000 individual CpGs) for detailed fine-mapping analyses of aberrant DNA methylation in 185 patients with AML (50% normal karyotype). We found that a proportion of patients (5/185) displayed a concerted hypermethylation at almost all studied loci, representing the rare CpG island methylator phenotype (CIMP) in AML. Meta analysis of methylation profiling and published ChIP sequencing data separated CpG islands in two groups. A highly correlated subgroup of CpG island regions was strongly associated with histone H3 lysine 27 trimethylation in human hematopoietic progenitor cells, suggesting that disease-related de novo DNA methylation at these CpG islands is linked with polycomb group protein (PcG)-mediated repression. The group of mainly non-PcG target CpG islands showed heterogeneous methylation patterns across patients and unsupervised hierarchical clustering revealed a correlation of methylation profiles with genetic disease markers, including oncofusion proteins as well as CEBPA- and NPM1-mutations. Our study suggests that both epigenetic as well as genetic aberrations may underlay AML-related changes in CpG island DNA methylation states.

Disclosures:
No relevant conflicts of interest to declare.
Amelioration of Murine Immune Thrombocytopenia by CD44 Antibodies: a Potential Therapy for ITP?
Authors: Crow Andrew R. , Song Seng , Suppa Sara J , Lazarus Alan H 
Published: October 2019

Abstract
Abstract 2528
Intravenous immunoglobulin (IVIg) is used to treat autoimmune diseases such as ITP. IVIg is a limited resource and its dosage and cost are both high. Although considered safe, it will always carry a theoretical risk of transferring infectious disease. Thus it would thus be highly desirable to improve the efficacy of IVIg or develop monoclonal antibodies, capable of mimicking the clinical effects of IVIg. Work by others has successfully improved the efficaciousness of IVIg in murine models of autoimmunity: It has been shown that enriched sialylated IVIg has a therapeutic effect at a 1 log fold lower dosage than IVIg; and a sialylated recombinant Fc fragment of IgG functions successfully at a 2 log fold lower dosage than IVIg.
CD44 is a widely expressed cell surface polymorphic glycoprotein. It is involved in many processes including tumour metastasis and inflammation. CD44 antibodies have been successfully used to treat several murine autoimmune disease models, including inflammatory arthritis and experimental autoimmune encephalomyelitis, although their mechanism of action remains unclear. To explore the potential for monoclonal antibodies as a treatment for ITP as well as further explore their mechanisms of action, we tested 8 monoclonal CD44 antibodies in murine ITP, and found 4 antibodies which could successfully ameliorate ITP; 2 of these antibodies function at a full 3 log fold lower dosage as compared to IVIg. Further characterization of the 2 most successful antibodies (5035-41.1D and KM114) demonstrated that, similar to IVIg, i) the expression of the inhibitory IgG receptor FcγRIIB was required for their ameliorative function and ii) complement-depleted mice also responded to anti-CD44 treatment. Dissimilar to IVIg, the Fc portion of the CD44 antibody was not required: an F(ab')2 fragment of antibody KM114 also significantly ameliorated thrombocytopenia at an equivalent molar concentration as intact KM114. Thus while KM114 functions by an FcγRIIB sensitive mechanism, FcγRIIB is unlikely a direct target of the Fc region of this antibody and likely plays a downstream role in the amelioration of immune thrombocytopenia, similar to IVIg. These data demonstrate that CD44 antibodies can function therapeutically in murine ITP and we speculate that they could potentially provide a very low dose recombinant therapy for the treatment of ITP.

Disclosures:
No relevant conflicts of interest to declare.
Serious Adverse Drug Reactions (sADRS) Associated with Hematopoietic Growth Factors: A Systematic Review From the Southern Network on Adverse Reactions (SONAR) Program
Authors: Norris LeAnn , Qureshi Zaina , Barnato Sara , Lai Stephen , Bennett Charles 
Published: October 2019

Abstract
Abstract 2555
Erythrpoiesis stimulating agents (ESAs) and the granulocyte hematopoietic growth factors granulocyte colony stimulating factor (G-CSF) and pegylated G-CSF revolutionized supportive care approaches to anemia and neutropenia, respectively. Thrombopoietin-receptor agonists improve antibody-mediated thrombocytopenia management. For these drugs, as with all agents, a comprehensive understanding of sADRs is important, however, often difficult to do. We reviewed sADRS described in meta-analyses and web-site materials maintained by regulatory agencies and manufacturers reports (1989 to July 2010; n=2,094). Overall, 28 systematic reviews, six package inserts, three medication guides, four FDA Risk Evaluation and Mitigation Systems (REMS) materials, 16 Summaries of Product Characteristics/Product Assessment Reports were included. For ESAs, common sADRs associated with increased relative risks (RRs) included: mortality among cancer patients with chemotherapy-associated anemia or cancer patients not receiving active treatment (RRs: 1.1–1.2); cerebrovascular and cardiovascular events among chronic kidney disease patients ((RRs: 1.3, 1.9), and venous thromboembolism in the cancer setting (RRs;16-1.7). For G-CSF/pegylated-GCSF, rare instances of myelodysplasia/acute myeloid leukemia (MDS/AML) associated with statistically increased RRs were reported among breast cancer patients receiving chemotherapy in trials reported from one NCI-sponsored clinical trials group, one meta-analysis, and one review of Medicare/SEER databases (RR: 1.9–2.1), although the absolute risks were very small (< 2 per 100,000 treated patients). Other rarely reported sADRs (total N < 20) included splenic rupture following G-CSF stimulation of healthy peripheral blood stem donors. Bone marrow fibrosis and collagen deposition were reported with thrombopoietin receptor agonists, although the implications of this finding is uncertain. Also, instances of VTEs were reported among persons who developed high platelet counts following administration of these thrombopoeitin receptor agonists. SADRs are commonly associated with ESA administration in a range of settings, are uncommon occurrences with G-CSF/pegylated G-CSF, and are not well characterized for thrombopoieitin receptor agonists. Formal pharmacovigilance initiatives are ongoing, including FDA mandated REMS with restricted distribution requirement for ESAs in the cancer setting (APPRISE) and the NEXUS and the PROMACTA CARES programs for thrombopoeitin receptor agonists.
ESAs (Cancer) ESAs (CKD) G-CSF/Pegylated G-CSF VTE Mortality Cerebrovascular and CVD AML/MDS RR 1.57 and 1.67 1.10 to 1.17 1.34 and 1.92 2.14 and 1.92 95% CI 1.31–1.87 and 1.35–2.06 1.02–1.20 and 1.06–1.30 1.03–1.74 and 1.38–2.26 1.12–4.08 and 1.19–3.07 Baseline Risk Absolute Risk Common Common Common Rare (2/100,000)

Disclosures:
Bennett: Pfizer: Consultancy.
Ethnicity Significantly Influences Incidence Patterns and Predicts Mortality: Adult Hodgkin Lymphoma (HL) In the United States (US)
Authors: Evens Andrew M , Shiuan Eileen , Kwon Soyang , Gordon Leo I , Chiu Brian 
Published: October 2019

Abstract
Abstract 2683

Background:
Pediatric HL studies have suggested survival differences based on ethnicity. However, little data is available regarding the impact, if any, of ethnicity on incidence patterns, disease histology, and/or survival among adult HL.

Methods:
We examined data for 13 US SEER areas, several of which contain large Hispanic and Black populations. Case information was obtained from the 11/2009 SEER data submission released April 2010. We analyzed incidence, HL histology, and mortality rates according to ethnicity, age, and gender. We also examined incidence patterns across the past four decades. All analyses used SEER*Stat.

Results:
A total of 16,783 HL cases were diagnosed among residents in the 13 SEER registry areas during 1992–2007, with non-Hispanic Whites contributing the largest number (n=11,890), followed by Hispanics (n=2,190), and Blacks (n=1,724). Consistent with SEER 9 results (1973 data), Whites show a continued bimodal age-incidence curve (6.0/100,000 ages 25–29, 2.5/100,000 ages 50–54, and 4.5/100,000 age 75–79). However, Blacks have a much less apparent bimodal pattern (4.5/100,000 ages 25–29, 2.6/100,000 ages 50–54, and 3.0/100,000 ages 75–79), while Hispanics are distinctly not bimodal with a small increase at 20–24 (2.4/100,000) followed by an exponential-like increase with peak HL incidence at ages 80–84 (7.0/100,000). Moreover, among persons >65 years, HL is currently significantly more common in Hispanics than Whites (4.7-7.0/100,000 vs 3.9–4.5/100,000, respectively, p<0.05). With gender, HL is more common in males than females, regardless of ethnicity. Interestingly, the male excess, however, does not occur until ages 30–34 (all ethnicities). Furthermore, from 1975–2007, HL incidence increased in Black females (annual percent change (APC) = 2.5; p<0.05) and White females (APC = 0.4; p<0.05). According to histology, both nodular sclerosis and mixed cellularity are more common in Whites followed by Blacks and Hispanics, while in persons age 60–84, both histologies are significantly more common in Hispanics compared with Whites and Blacks. Over the past 20 years, mortality has declined within each race by 10.3%–13.7% (p<0.05). However, age-specific ethnic survival disparities are apparent (Figure 1). For ages 65–84, Hispanics have a significantly increased mortality rate compared with Whites/Blacks (p<0.05). Conversely, among ages 20–44, Hispanics have a lower mortality rate versus Whites and Blacks.

Conclusions:
Multiple important epidemiologic and mortality differences are evident across and within ethnicities in adult HL.
*Both sexes (1992-2007). Rates are per 100,000. Mortality source: US Mortality Files, National Center for Health Statistics, CDC. Accessed August 12th, 2010.

Disclosures:
No relevant conflicts of interest to declare.
The Novel Organic Arsenical, Darinaparsin (ZIO-101), Induces Apoptosis through AKT and MEK/ERK Pathways In Hodgkin Lymphoma (HL) and T-Cell Lymphoma (TCL) Cell Lines
Authors: Bhalla Savita , Prachand Sheila , Gordon Leo I , Evens Andrew M 
Published: October 2019

Abstract
Abstract 2840

Background:
The inorganic arsenic, arsenic trioxide (ATO), has a narrow therapeutic index, which has limited its clinical use in most malignancies. Darinaparsin (ZIO-101, S-dimethylarsino-glutathione), synthesized by conjugating dimethylarsenic to glutathione, is a novel organic arsenical that is under investigation as a novel agent for the treatment of cancer. Furthermore, early-phase clinical trials with darinaparsin have demonstrated low toxicity and encouraging clinical efficacy in relapsed/refractory hematologic malignancies.

Methods:
We treated several TCL cell lines (Jurkat, C10MJ, Hut-78, and MT2) and the resistant HL cell line, L428, with increasing concentrations of darinaparsin (0.5-5μM) +/− the MEK inhibitor, U0126, or ERK siRNA (Qiagen HiPerFect transfection). Cell survival and apoptosis were measured by MTT and Annexin-V/propidium iodide staining, respectively. Further, tumor intracellular darinaparsin and ATO concentrations were assessed with mass spectrometry, while transcription pathway intermediates were analyzed by Western blotting.

Results:
Darinaparsin inhibited cell growth and induced apoptosis in all cell lines at 1–3μM. At 2μm (48 hours), darinaparsin induced approximately 80% apoptosis in each of the four TCL lines, while 3μM resulted in 65% apoptosis in L428 cells. By comparison, >10μM of ATO (48 hours) was required to induce 40% apoptosis in TCL and 25% apoptosis in L428. At 1–3μM, darinaparsin induced significant increases in caspase 3 and PARP activation in TCL, while interestingly, minimal caspase or PARP was observed in L428. Notably, in L428 cells at 1 hour, mass spectrometry showed that intracellular accumulation of darinaparsin was >10-fold higher as compared with equivalent ATO concentrations (p<0.01). We also treated L428 cells with U0126 (5μM) or ERK2 siRNA, both combined with darinaparsin. Pre-incubation with U0126 or siRNA knock down of ERK2, followed by treatment with darinaparsin, significantly enhanced darinaparsin-induced apoptosis (p<0.05). To further investigate darinaparsin-induced signaling pathways, we analyzed phospho-AKT (p-AKT), and phospho-ERK (p-ERK) in Jurkat and L428. We found down-regulation of p-AKT in Jurkat as well as L428 cells, while total AKT remained unchanged. Additionally, an increase in p-ERK was observed in L428 cells with 2–3μM darinaparsin, while p-ERK was down-regulated in Jurkat cells.

Conclusions:
Darninaparsin induces significant cell death in HL and TCL cell lines that is mediated through AKT and MEK/ERK-based pathways. Additionally, markedly higher intracellular darinaparsin levels are achieved in lymphoma cells compared with equivalent concentrations of ATO. Continued pre-clinical and clinical trial investigation of darinaparsin in HL and TCL is warranted.

Disclosures:
No relevant conflicts of interest to declare.
Targeting the PI3K/AKT/Survivin Pathway with Ritonavir In Therapy-Resistant Mantle Cell Lymphoma
Authors: Nordgren, Tara M , Hegde Ganapati , Munger Corey , Vose Julie M. , Joshi Shantaram 
Published: October 2019

Abstract
Abstract 2855
Mantle cell lymphoma (MCL) is an aggressive B cell lymphoma accounting for about 6% of non-Hodgkin's lymphoma cases in the US. While multiple therapy regimens are available to treat MCL, patients ultimately relapse within 3–4 years from therapy-resistant MCL, making MCL carry the worst prognosis of all non-Hodgkin's B cell lymphomas. To improve therapies for patients with MCL, we must understand the biological causes for relapse and therapy-resistance in MCL and develop mechanisms to target the unique properties in relapsing MCL. Recently, we have isolated and produced therapy-resistant MCL cell lines by inoculating NOD-SCID mice with a human MCL cell line, Granta-519 (GP), and subsequently treating with CHOP chemotherapy regimen plus bortezomib. When mice relapsed following therapy, tumor cells were isolated from the kidneys and livers, and cultured to produce stable cell lines, named GRK and GRL, respectively. GRK and GRL cells exhibited increased proliferative and therapy-resistant properties in vitro, and GRL showed increased aggressiveness in vivo also, as compared with GP. Using quantitative PCR (qRT-PCR) to assess the activation of pathways relating to lymphoma progression, the PI3K/Akt/survivin pathway was found to be differentially activated in GRL and GRK compared to GP, including a 6.5 fold increase in survivin in GRL. Therefore, we inhibited survivin in GRL using the FDA-approved protease inhibitor ritonavir (Abbott Laboratories), as recent studies suggest this compound is able to downregulate survivin in lymphoblastoid B cells (Dewan, et al. Int J Cancer 2009; 124[3]: 622–629). When GRL cells were incubated with ritonavir plus vincristine or doxorubicin, MTT assays showed significant inhibition of cell proliferation/survival (p < 0.05) compared to the effects of ritonavir alone. Also, flow cytometric analysis of Annexin V demonstrated dose-dependent induction of apoptosis upon ritonavir treatment in GRL. In addition, qRT-PCR analysis demonstrated a decrease in mRNA expression of the pro-survival genes cyclin D2, Rel A, survivin, and BCL2 in GP and GRL cells after ritonavir treatment. Together, these studies demonstrate the potentials of utilizing ritonavir in a combined treatment regimen designed to target therapy-resistant MCL. As ritonavir is already an FDA-approved drug, these studies hold promise for expediting future in vivo and clinical studies that may eliminate therapy-resistant cells responsible for relapse in MCL patients.(This research was supported by the Lymphoma Research Foundation, New York, NY).

Disclosures:
No relevant conflicts of interest to declare.