bluuebunny/crossref_metadata_2025_split huggingface dataset:
FcRL5 as a Target of Antibody-Drug Conjugates for the Treatment of Multiple Myeloma.
Authors: Polson Andrew G. , Zheng Bing , Elkins Kristi , Lau Jeffery , Go Mary Ann T. , Scales Suzie J. , Yu Shang-Fan , Chesi Marta , Bergsagel P. Leif , Ebens Allen J. 
Published: October 2019

Abstract
Abstract 3836
Poster Board III-772
Antibody-drug conjugates (ADCs), potent cytotoxic drugs linked to antibodies via specialized chemical linkers, provide a means to increase the effectiveness of chemotherapy by targeting the drug to neoplastic cells while reducing side effects. Target selection is a key component to the success of an ADC. In addition to expression on the tumor, the target should have limited expression on normal tissues. The most prevalent and best-studied surface antigens on multiple myeloma (MM) cells, CD138, CD38, CD72, and CD56, all have relatively broad expression patterns that may lead to target-dependent toxicities with ADCs. We have previously shown that FcRL5/FcRH5/IRTA2 is expressed only on B-cells and plasma cells. Here we show that FcRL5 is expressed on the surface of MM cells from 85% of patients and thus could be a target for antibody and ADC treatments of MM. As experience in humans with anti-CD20 antibodies suggests that depletion of B-cells does not present a major safety issue, FcRL5 appears to have an excellent expression pattern as an ADC target for MM. Internalization of target antigens is known to increase the efficacy of ADCs and we found that FcRL5 is internalized upon antibody binding, an ideal trait. We made two different ADCs consisting of anti-FcRL5 antibodies 1) conjugated through cysteines to monomethylauristatin E (MMAE) by a maleimidocaproyl-valine-citrulline-p-aminobenzyloxycarbonyl (MC-vcPAB) linker that is designed to be cleaved by cathepsins (Anti-FcRL5-MC-vcPAB-MMAE); and 2) conjugated via lysines to the maytansinoid DM4 through a disulified linker designed to be cleaved by reducing conditions (anti-FcRL5-SPDB-DM4). These ADCs were tested for cell killing in vitro and in xenograft studies using OPM2 cells stably expressing FcRL5. While unconjugated anti-FcRH5 and control ADCs were not effective, anti-FcRL5-MC-vcPAB-MMAE and anti-FcRL5-SPDB-DM4 were effective at killing this MM cell line both in vitro and in vivo. Furthermore, the anti-FcRL5-SPDB-DM4 conjugate was effective in a SCID-rabbit bone model of MM using the LD cell line. These data suggest that FcRL5 ADCs could be an effective treatment for MM.

Disclosures:
Polson: Genentech, Inc.: Employment, Equity Ownership. Zheng:Genentech, Inc.: Employment, Equity Ownership. Elkins:Genentech, Inc.: Employment, Equity Ownership. Lau:Genentech, Inc.: Employment, Equity Ownership. Go:Genentech, Inc.: Employment, Equity Ownership. Scales:Genentech, Inc.: Employment, Equity Ownership. Yu:Genentech, Inc.: Employment, Equity Ownership. Chesi:Genentech, Inc.: Consultancy; Amgen: Consultancy; Celgene: Consultancy; Merck: Research Funding. Bergsagel:Genentech, Inc.: Consultancy; Amgen: Consultancy; Celgene: Consultancy; Merck: Research Funding. Ebens:Genentech, Inc.: Employment, Equity Ownership, Patents & Royalties.
Retrospective Database Analysis of the Effect of Zoledronic Acid (ZOL) On Skeletal-Related Events (SREs) in Patients (Patients) with Multiple Myeloma (MM).
Authors: Henk Henry J , Kaura Satyin , Perez Jose Ricardo , Becker Laura 
Published: October 2019

Abstract
Abstract 3881
Poster Board III-817

Background
For MM patients with malignant bone lesions (BM), SREs including pathologic fracture, spinal cord compression, hypercalcemia of malignancy, and radiotherapy and/or surgery to bone are associated with significant morbidity and mortality and reduced quality of life. ZOL is an IV bisphosphonate (BP) proven to reduce and delay incidence of SREs in several tumor types. This study was designed to assess the benefit of long-term ZOL use in a real-life setting.

Methods
Claims-based analysis of commercial and Medicare data from a large US managed care plan and a 45 health-plan database was used to evaluate SRE rates, time from BM to 1st SRE, and mortality in patients treated with ZOL or no IV BP therapy. Patients older than 18 years with MM and BM diagnosed between Jan 2001 and Dec 2006 were included. Treatment Persistency was defined as the absence of a >45 day gap between ZOL administrations. Continuous enrollment in the health plan for 6 months before and no prior evidence of BM or IV BP use were required. When assessing mortality, patients with a date of death less than 30 days following index date were excluded. Patients were followed until they disenrolled from the plan or to the end of the study's follow-up period. In this study, SREs were defined as evidence of pathologic fracture, spinal cord compression, and radiotherapy and/or surgery to bone.

Results
The study sample included 1,655 Patients with a mean age of 61.7 ± 11.9 years; approx. 64% were treated with ZOL and 36% with no IV BP. Incidences of SREs and mortality rates were both greater in the no IV BP group (incidence rate ratio [IRR] = 1.58; p-value<0.001 and mortality rate = 1.71; p-value=0.0234) vs. the ZOL groups. Longer persistency with ZOL was associated with a lower risks of first SRE compared with no IV BP (trend test p-value=0.0025) [TABLE 1].

Conclusions
This study showed that in MM Patients with BM, ZOL use was associated with a lower risk of SREs, including fractures, and lower mortality rates. In addition, longer persistence was found to be associated with lower risk of SRE.

Disclosures:
Kaura: Novartis: Employment, Equity Ownership. Perez:Novartis: Employment, Equity Ownership.
Thromboembolic Events (TEE) with Lenalidomide-Based Therapies for Multiple Myeloma (MM): Emory Experience.
Authors: Nooka Ajay K , Kaufman Jonathan L. , Heffner Leonard T , Gleason Charise L. , Lonial Sagar 
Published: October 2019

Abstract
Abstract 3888
Poster Board III-824

Introduction
Lenalidomide is a derivative of thalidomide with an additional amino group at position 4 and removal of a carbonyl group that has enhanced efficacy and reduced toxicity relative to its parent compound. However, studies have reported the incidence of TEE from 3-23.8%. We proceeded to evaluate incidence and risk factors of TEE associated with lenalidomide-based therapies in patients with multiple myeloma at our institution.

Methods
We reviewed 152 records of patients that were prescribed lenalidomide from prescribing information obtained from Celgene pharmaceuticals as well as reviewing patient information from all clinical trials from 2004 until October 2008. IRB approval was obtained. 146 patients (pts) were included in study after excluding 6 pts in whom lenalidomide was used for non-myeloma indications. Lenalidomide was indicated for induction in 22 (15%) pts and for maintenance/salvage in 124 (85%) pts.

Results
81 (55.5%) pts were male and 65 (44.5%) were female. White pts (65%) contributed to majority of our pt population. Median age (range) is 62 months (23-87); stage III disease is seen in 23 pts (22%); median (range) β-2 microglobulin is 2.68 (0.8-43.51) and median (range) creatinine is 1.05 (0.6-21). Pts received a median (range) of 7 (1-58) cycles. Overall ten (6.8%) TEEs were observed including nine venous TEEs (6.12%) and one arterial TEE (0.68%). Nine pts developed TEE despite being on ASA prophylaxis. Median (range) time to event was 17 weeks (4-158). Median (range) cycles of lenalidomide before the event were 3.5 (1-38). 60% of events took place in the first 4 months of initiation of therapy. On univariate analysis, erythropoietin use vs. none (21.4% vs. 5.3% p=0.023); median number of cycles ≥7 vs. <7 (11.1% vs. 2.7% p=0.044) and previous history of DVT vs. none (20% vs. 4.1%; p=0.014) were identified as significant risk factors. Steroid doses, BMI were not identified as risk factors. On multivariate analysis, age <60 (HR 0.11 95%CI 0.00-0.50; p = 0.021) had a significant protective impact on developing TEE. Median survival (range) in pts with TEE is 102 months (100.4-103.6) and pts without TEE is 99 months (79.38-118.62); log rank 0.125.

Conclusion
Neither high dose steroids nor the BMI were identified as risk factors for TEE. All pts with venous TEE had high risk factors validating the risk model of IMWG. No impact on overall survival was seen between pts with TEE and pts without TEE.

Disclosures:
Kaufman: Celgene: Consultancy, Research Funding; Millenium: Consultancy; Genzyme: Consultancy; Merck: Research Funding. Heffner:Millenium: Honoraria. Gleason:Millenium: Consultancy. Lonial:Celgene: Consultancy; Millennium: Consultancy, Research Funding; BMS: Consultancy; Novartis: Consultancy; Gloucester: Research Funding.
Charlson Comorbidity Index Is An Independent Prognostic Factor Among Elderly Patients with Diffuse Large B-Cell Lymphoma (DLBCL).
Authors: Takeuchi Jin , Hojo Atsuko 
Published: October 2019

Abstract 3923
Poster Board III-859

Introduction
Wide use of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) has improved the clinical outcome for elderly patients with DLBCL; however, a higher prevalence of coexisting disorders remains a problem. Correlation between their comorbidities and prognosis has not yet been well investigated.

Patients and methods
We retrospectively analyzed all patients over 65 years old who had been newly diagnosed with DLBCL at our institution from 2001 to 2008. To assess their comorbid medical status, we calculated the Charlson Comorbidity Index (CCI) for patient excluding primary disease. Prognostic factors were identified by Cox proportional hazards regression model. We classified patients into a low CCI group (CCI 0-1) and a high CCI group (CCI 2 or higher). Kaplan-Meyer curves for each group were evaluated by logrank test.

Results
A total of 80 patients were enrolled in this analysis. The median age was 73 (range 66-90) and the median observation period was 28 months (range 4-90 months). 62 patients (77.5%) were treated with R-CHOP, 15 (18.6%) underwent some other regimen, and 3 (3.8%) were given best supportive care only. According to revised International Prognostic Index (r-IPI), 43 patients were in the good risk group and the others were in the poor risk group. The estimated 3 year over all survival (OS) rate for these groups were 90% and 45% (p<0.0001). As for CCI, 14 patients (17.5%) were assigned to the high CCI group. Multivariate analysis revealed high CCI was associated with worse OS, while independent of r-IPI [Hazard Ratio (HR) 3.20, 95% Confidence interval (CI) 1.28-7.41, p=0.0145]. Among r-IPI poor risk patients, the high CCI group was inferior to the low CCI group for the 3 year OS rate (14% vs 56% p=0.0358), whereas this was not significant among r-IPI good risk patients (69% vs 94% p=0.0617).

Conclusions
Among elderly patients with DLBCL, high CCI is independently associated with poor survival. Patients having both poor r-IPI and high CCI may need discrete strategies.

Disclosures:
No relevant conflicts of interest to declare.
Metalloproteinase Inhibitors Inhibit the Release of Soluble CD27 by Waldenström's Macroglobulinemia Cells.
Authors: Zhou Yangsheng , Liu Xia , Gong Ping , Xu Lian , Ciccarelli Bryan , Yang Guang , Patterson Christopher J , Treon Steven 
Published: October 2019

Abstract
Abstract 3942
Poster Board III-878
Waldenström's macroglobulinemia (WM) is characterized by bone marrow infiltration with lymphoplasmacytic cells (LPCs), and increased presence of mast cells. CD27 is a marker of memory B-cells, and is heterogeneously expressed on the cell surface of WM cells. In recent studies, we showed that the soluble CD27 (sCD27) is produced by WM LPC and is a faithful marker of disease burden in WM patients. Importantly, sCD27 triggers via CD70 the expression of CD40L on neighboring Mast Cells, which in turn supports the growth and survival of WM LPC. sCD27 therefore represents a promising target for the treatment of WM. The mechanism for sCD27 release in WM remains to be elucidated, but is likely cleaved from cell surface CD27. We therefore examined the effects of various matrix metalloproteinase (MMP) inhibitors on the production of sCD27. sCD27 levels were measured by ELISA from supernatants of cultured BCWM.1 and BL2126 B-cells transfected with a vector expressing either FLAG-tagged CD27 (pCD27-FLAG) or a control vector. PMA treatment of pCD27-FLAG transfected BCWM.1 WM and BL2126 cells led to sustained sCD27 release in cultured supernatants; in contrast, PMA treatment of control vector transfected cells showed minimal sCD27 release. Importantly, treatment of pCD27-FLAG transfected BCWM.1 WM and BL2126 cells with MMP 8 and MMP 3 inhibitors (Calbiochem) led to four-fold and two-fold decrease in sCD27 levels, respectively (Figure 1). In contrast, no significant change in sCD27 release was observed following treatment with MMP 2/9 or non-specific MMP inhibitors. These studies demonstrate that matrix metalloproteinases play an important role in sCD27 release, and provide the framework for efforts examining MMP 8 and 3 specific inhibitors in the treatment of WM.

Disclosures:
No relevant conflicts of interest to declare.
Transformation of Indolent Small B-Cell Lymphoma to Histiocytic Sarcoma: Report of Two Cases with Molecular/Genetic Evidence of Clonal Relationship Between Two Morphologically and Immunophenotypically Distinctive Neoplasms.
Authors: Wang Endi , Hutchinson Charles Blake , Huang Qin , Sebastian Siby , Rehder Catherine 
Published: October 2019

Abstract
Abstract 3960
Poster Board III-896

Introduction
Rare cases of histiocytic sarcoma (HS) have been reported in association with indolent small B-cell neoplasms, either concurring with or following a small B-cell lymphoma. The biologic relationship between these two morphologically and immunophenotypically distinct neoplasms in same patients remains unclear, though recent data suggest a possible “transdifferentiation” from follicular lymphoma (FL) to HS.

Patients and Methods
We investigate the clonal relationship in two cases of B-cell lymphoma with subsequent HS, using immunohistochemical stains, PCR-based immunoglobulin heavy chain (IGH) gene rearrangement/sequencing analysis and interphase FISH study on formalin fixed, paraffin-imbedded tissue sections.

Results
Case 1 is a 62-year-old female with splenic marginal zone lymphoma (SMZL) who developed HS in a groin lymph node one year after the diagnosis of SMZL. PCR/sequence analysis of IGH gene showed a monoclonal rearrangement carrying identical DNA sequences of PCR products from the spleen with SMZL and the lymph node with HS. Case 2 is a 61-year-old female with a remote history of FL who developed supraclavicular lymphadenopathy and multiple other infiltrating foci. A supraclavicular lymph node biopsy demonstrated HS. PCR analysis detected a monoclonal rearrangement of the IGH gene and interphase FISH analysis revealed IGH/BCL-2 fusion, a genetic hallmark for FL. Although negative for other B-cell associated antigen markers, HSs show partial retention of primary neoplasms B-cell lymphomas' immunoprofiles, including expression of Oct-2 in both cases, and expression of bcl-6 and enhanced expression of bcl-2 in case 2.

Conclusion
The data provide a genotypic evidence of common clonal origin between mature B-cell lymphoma and subsequent HS in the same patients, suggesting “transdifferentiation” to HS could occur in other small B-cell lymphoma, in addition to FL. The transformed HSs might have incompletely inherited primary neoplasms' expression signatures by retaining B-cell lymphomas' characteristic immunoprofile to certain extent. The exact mechanism governing the conversion of mature B-cell lymphoma to HS is largely a mystery and remains to be elucidated by more scientific studies, though a few pathways have been proposed for the process, including transdifferentiation, dedifferentiation and common progenitor models.

Disclosures:
No relevant conflicts of interest to declare.
Pten Inactivating Mutations Promote Loss of MYC “Oncogene Addiction” in a Conditional Zebrafish Model of T-ALL.
Authors: Gutierrez Alejandro , Feng Hui , Faucherre Adele , Hertog Jeroen Den , Prochownik Edward V. , Testa Joseph R. , Kanki John , Look A. Thomas 
Published: October 2019

Abstract
Abstract 3977
Poster Board III-913
The MYC oncogene is overexpressed in most human cases of T-cell acute lymphoblastic leukemia (T-ALL), and our laboratory previously developed a zebrafish model of MYC-induced T-ALL that closely recapitulates the most common subtype of human T-ALL, which demonstrates overexpression of TAL1 and LMO2. We have now developed a conditional zebrafish model of MYC-induced T-ALL, based on the rag2-driven expression of a MYC-estrogen receptor (MYC-ER) fusion transgene, in which T-ALL is induced by 4-hydroxytamoxifen treatment. Most cases of T-ALL in this model exhibit 'oncogene addiction' to MYC, as evidenced by the regression of established tumors when 4HT treatment is discontinued. However, the genetic determinants of 'addiction' to the MYC oncogene are unknown. Deletion of the PTEN tumor suppressor has been found to be a recurrent abnormality in human T-ALL, and we have now identified abnormalities in PTEN, PI3K or AKT in 48% of human T-ALL. Due to a partial genome duplication that occurred during evolution, zebrafish have two pten genes, pten-A and pten-B, which are both ubiquitously expressed and are largely redundant. In order to examine the consequences of pten inactivation in MYC-induced T-ALL, we mated zebrafish loss-of-function mutations in pten-A and pten-B into our rag2-MYC-ER line that also carries the rag2-GFP transgene, allowing the in vivo monitoring of tumor onset and regression. Zebrafish were raised in 4-hydroxytamoxifen beginning at 5 days post-fertilization, and tumor onset was monitored via fluorescence microscopy. At the time of tumor onset, zebrafish were removed from 4-hydroxytamoxifen, and tumor regression was monitored weekly. Although pten loss-of-function mutations did not accelerate the onset of MYC-induced T-ALL, these did affect tumor regression. We found that T-ALL underwent regression in 68% (21/31) of zebrafish whose germline pten status was wild-type, while regression occurred in only 21% (7/32) of zebrafish harboring loss of any of their germline pten alleles (p=0.0003). The effect of pten inactivation on tumor regression was phenocopied by the expression of a constitutively active murine Akt2 transgene in the MYC-ER line, indicating that the effect of pten inactivation is mediated through the activation of AKT. Our studies provide new evidence that the PTEN-PI3K-AKT pathway is an important modulator of MYC ‘oncogene addiction’ in zebrafish T-ALL.

Disclosures:
No relevant conflicts of interest to declare.
A Randomized, Controlled Two-Center Pilot Trial of a 6-Month Exercise Training Program to Treat the Post-Thrombotic Syndrome: The EXPO Pilot Trial.
Authors: Kahn Susan , Shrier Ian , Shapiro Stan , Houweling Adrielle H , Hirsch Andrew , Reid Robert , Kearon Clive , Rodger Marc , Kovacs Michael J. , Anderson David , Wells Philip S 
Published: October 2019

Abstract
Abstract 3984
Poster Board III-920

Background
Exercise training is an effective treatment for lower limb arterial claudication and may also have the potential to improve the post-thrombotic syndrome (PTS).

Objectives
We conducted a randomized, allocation concealed, controlled, assessor-blinded multicenter pilot trial to provide preliminary data on the effectiveness of a 6-month exercise training program in improving the PTS.

Methods
Patients aged 18-75 years with unilateral DVT diagnosed >6 months previously and ipsilateral PTS (Villalta criteria) were screened for participation in the trial at 2 centres in Canada (Montreal & Ottawa). Eligible, consenting patients were randomized to Active Training (AT), a 26-week trainer-supervised program consisting of leg strengthening, leg stretching and aerobic exercise, or Attention Control (AC), a 1-hour presentation on PTS + monthly phone follow-ups. Participants had study visits at Baseline (T0), 3 mths (T3) and 6 mths (T6) to measure generic (SF-36) and venous disease-specific (VEINES-QOL) quality of life (QOL), PTS severity (Villalta scale), leg strength (number of heel lifts) and leg flexibility (stretch angle, in degrees, for quadriceps, hamstring, gastrocnemius and soleus muscles). Within-subject changes from T0 to T6 were compared in AT vs. AC using repeated measures two-way ANOVA.

Results
From 2007-2008, 43 patients were recruited (21 randomized to AT, 22 to AC). Mean age was 47 years, 44% were male, and 49% had moderate or severe PTS. At 3 and 6 mths, PTS severity category improved in 65% of AT vs. 26% of AC (p=0.02) and 61% of AT vs. 46% of AC (p=ns), respectively. Other results are shown in Table (for all outcomes except Villalta score, + change signifies improvement from T0 to T6).

Conclusion
In our pilot trial, exercise training improved PTS severity, QOL, leg strength and leg flexibility in patients with PTS. Exercise training appears to be a promising modality to treat PTS, and a large, adequately powered trial is warranted. Funded by Canadian Institutes of Health Research

Disclosures:
No relevant conflicts of interest to declare.
Plasma Cholinesterase Activity in ITP Patients with/without Thrombosis.
Authors: Bidot Carlos J , Ahn Yeon-Soong , Esquenosi Jacob , Bidot Carlos , Ortega Camile , Horstman Larry Lawrence , Dudkiewicz Pamela B , Jy Wenche 
Published: October 2019

Abstract
Abstract 3997
Poster Board III-933

Introduction
In the process of immune mediated destruction, platelets may become activated and release procoagulant microparticles in ITP (Immune Thrombocytopenic Purpura). Although bleeding is common manifestation, some patients with ITP may suffer thrombotic complications, often presenting with TIA like syndromes. Brain MRI revealed findings consistent with ischemic small vessel disease in this subgroup (J Lab Clin Med 119: 334, 1992, Thromb Res 107:337, 2002). Recently acetylcoholinesterase (AChE) of RBC and/or non-specific plasma cholinesterase (ChE) was reported to be associated with the inflammation of blood vessels and may be a marker of some inflammatory states. In the present study we investigated plasma ChE activity in patients with ITP with or without thrombotic complication.

Methods
(i) Patients. We measured ChE activity in 49 patients with ITP. They were sub-grouped as having thrombosis (TBS), F/M (11/7), and non-thrombosis (Non-TBS), F/M (23/8). The TBS group included 9 with TIA like syndrome, 6 with CAD and 3 with venous thrombosis. (ii) Assay of ChE was essentially by Ellman's method. In our system, milli-absorbance units/min (mA/min) x 0.065 = umols substrate cleaved/min. Values reported here are in units of mA/min per mL plasma. Normal controls (NC, n=14) had a cutoff of 3000 mA/min per mL plasma (=mean +2SD). (iii) Sample handling. Platelet-poor plasma (PPP) was prepared by centrifuging 10 min at 1800 xg, then frozen in aliquots. For assay, it was diluted 1:20 with saline, then 5 uL and 10 uL were used in 96-well microtiter plate.

Results
(i) We observed higher level of ChE in the TBS group compared to Non-TBS in ITP. The TBS group (+/- SD) had mean value 2859 ±866, while the Non-TBS group had 2267 ±777 (units as above). This difference was significant, p<0.02. (ii) In TBS groups, we compared TIA subgroup with other TBS subgroup and observed that the n=9 patients with TIA had higher activity compared to the other TBS: 3250 vs 2466 mA/min per mL plasma. However, this difference did not reach significance in this small patient population. Further, 5/9 TIA patients (66%) had ChE activities >3000 (normal cutoff values) compared to only 2/9 (22%) of those with other TBS >3000.

Conclusion
(i) The ChE activity of ITP patients with TBS is significantly increased compared to Non-TBS in ITP patients. It has been suggested that Blood ChE/AChE may reflect some inflammatory, prothrombotic states. (ii) ITP patients with TIA exhibited higher ChE activity among TBS subgroups in ITP, suggesting that ChE activity may serve as a useful biomarker in TIA like syndrome associated with ITP. However, further study in a larger number of patients is needed to confirm these preliminary findings.

Disclosures:
No relevant conflicts of interest to declare.