bluuebunny/crossref_metadata_2025_split huggingface dataset:
TSP-A74, a Novel Therapeutic Monoclonal Antibody Against TfR1 for Treatment of Hematologic Malignancies
Authors: Zhang Lilin , Nomura Fumiko , Aikawa Youichi , Sudo Yukio , Morishita Kazuhiro , Kurosawa Yoshikazu 
Published: October 2019

Abstract
Transferrin receptor 1(TfR1) is a type II transmembrane glycoprotein regulating the intracellular uptake of iron and is involved in cell growth, proliferation and survival. TfR1 is highly expressed on malignant cells, including those of hematologic malignancies. Therefore, TfR1 may be an attractive target for therapeutic monoclonal antibodies.
We generated a panel of fully-human, anti-TfR1 monoclonal antibodies and evaluated the anti-tumor effects of these antibodies both in vitro and in vivo. The results led to the selection of TSP-A74, an antibody with potent in vitro and in vivo anti-tumor activity, for further evaluation in several hematologic malignancy models. First, the efficacy of TSP-A74 was evaluated in acute myeloid leukemia (AML) models. Two AML cell lines, Kasumi-1 and HL-60, were subcutaneously inoculated in severe combined immunodeficiency (SCID) mice. After the tumors were grown to a size of 150 mm3, TSP-A74 was administrated intravenously (IV) once weekly for 4 weeks at doses of 0.4, 2 and 10 mg/kg and 1, 3 and 10 mg/kg for the Kasumi and HL60 xenograft models, respectively. TSP-A74 demonstrated complete tumor regression in these two xenograft models at 10 mg/kg and complete tumor growth suppression in the Kasumi model at 2 mg/kg. Even at the low dose of 1 mg/kg, TSP-A74 demonstrated tumor growth inhibition (TGI) of 60% in the HL60 model. Next, the anti-tumor efficacy of TSP-A74 was assessed in an acute lymphoblastic leukemia (ALL) model. The ALL cell line, CCRF-CEM, was engrafted into SCID mice intravenously. After 3 days, TSP-A74 was administrated IV at a dose of 10 mg/kg once weekly for 4 weeks. The control mice (n=10) rapidly developed leukemia and none survived at 42 days after leukemia cell engraftment. However, 7 of 10 (70%) mice treated with TSP-A74 survived to 179 days after engraftment when the study was terminated. Finally, the efficacy of TSP-A74 was evaluated in non-Hodgkin's lymphoma subcutaneous xenograft models. TSP-A74 produced complete regression of established tumors in the SU-DHL-2 (diffuse large B-cell lymphoma) xenograft model at a dose of 3 mg/kg and tumor growth inhibition of 100 % in the HH (cutaneous T cell lymphoma) xenograft model at a dose of 10 mg/kg. These results indicate that the human anti-TfR1 monoclonal antibody, TSP-A74, could be a new therapeutic candidate for hematologic malignancies.

Disclosures
Zhang: Perseus Proteomics Inc.: Employment. Nomura:Perseus Proteomics Inc.: Employment. Aikawa:Perseus Proteomics Inc.: Employment. Sudo:Perseus Proteomics Inc.: Employment. Morishita:Perseus Proteomics Inc.: Research Funding.
Prognostic Stratification of Acute Myeloid Leukemia and Mylodysplastic Syndrome Patients on the Basis of Genetic Variations
Authors: ALI Muhammad , Basit Sulman , Masood Muhammad tariq , Yousafzai Yasar Mehmood , Naseer Asif , Rahman Sadeeq ur , Jelani Musharraf , Khan Imran , Khan Yousaf , Jameel Abid , Ahmed Jawad , Taj Abid Sohail 
Published: October 2019

Abstract
Acute Myeloid Leukemia (AML) is a heterogeneous disorder characterized by the accumulation of acquired genetic alterations in hematopoietic progenitor cells that alter normal mechanisms of self-renewal, and differentiation. Once a rapidly and life fatal disease, the prognosis of AML has improved in the past decades. Recurrent cytogenetic and molecular genetic abnormalities are proven to be of diagnostic and therapeutic value. All cases of AML cannot be explained by the low resolution cytogenetic techniques or biased molecular genetic approaches. Recent advancements in high resolution genomic techniques has allowed detection of additional submicroscopic abnormalities in the AML genome. This study set out to determine the copy number alterations (CNAs) in bone marrow and oral epithelial samples from 08 AML cases by whole genome Single Nucleotide Polymorphism (SNP) genotyping using Illumina OmniExpress-12 v1-1 Bead Chips containing 700,000 SNPs. Additionally, using a targeted approach with TaqMan real-time quantitative polymerase reaction (RT-qPCR), we tested for previously reported SNP (rs11554137) in a group of 47 AML patients.
The group of patients comprised of AML-M1 (n=1), M2 (n=5), M4 (n=1) and M5 (n=1), SNP genotyping data analysis identified 13 acquired CNAs in 05 out 08 AML patients. Deletions were more common than amplifications. These CNAs were distributed across all FAB subtypes except AML-M3.AML-M4 subtypes were found to have more CNAs compared to other subtypes. Notably, in three AML-M2 cases4q24 microdeletion was identified. This region spans TET2 gene which is has been shown to cause microdeletions and copy-neutral loss of heterozygosity (LOH) in a patient with diverse myeloid malignancies. Oral epithelial cells from the same patients were negative for the CNAs. Moreover, the 47 patients tested for known SNPs, 4 patients (8.5%) were found positive for rs11554137. SNP (rs11554137) has been reported to be of prognostic importance for overall survival (OS).
The results from this study shows CNAs in regions implicated in myeloid malignancies. The use of high-resolution genomic array identified significant number of CNAs and SNPs which were not previously documented in AML patients in Pakistani population. Further studies dissecting out their role in AML pathogenesis are required.

Disclosures
No relevant conflicts of interest to declare.
The Isoform II of SRSF1: A Potential Biomarker in the Progression of Pediatric Acute Lymphoblastic Leukemia
Authors: Xu Liting , Zheng Huyong 
Published: October 2019

Abstract
Background: Acute lymphoblastic leukemia (ALL) is the most frequently occurring malignant neoplasm in children. Despite advances in treatment and outcomes for ALL patients, the pathogenesis of the disease remains unclear. Alternative splicing modulates the expression of many oncogene and tumor-suppressor isoforms. SRSF1, a prototypical SR protein has been recognized as an oncoprotein. SRSF1 has been reported to be auto-regulated into multiple isoforms that differ in function in various physiological or pathological conditions.
Methods: Matched, newly diagnosed (ND), complete remission (CR) and relapse (RE) bone marrow samples from 50 patients were collected in order to evaluate the expression patterns of SRSF1 spliced isoforms. The function of isoforms of SRSF1 in leukemogenesis was investigated in leukemia cell lines.
Results: Both in mRNA and protein level, we identified significant up-regulation of the three main spliced isoforms of SRSF1 and the isoform II is the main variant in the ND samples. Importantly, the expression of three isoforms of SRSF1 returned to normal levels after CR. But the protein isoforms rebound in the RE samples, and the isoform II is high expressed a short-term state prior to morphological or immunological change in the RE cases. We also observed the isoform II can promote significantly to the formation of cell clones.
Conclusion: Our results indicate that the alternative splicing of SRSF1 may plays a critical role in leukemogenesis in pediatric ALL, and the isoform II may be a sensitive predictor of relapse and a potential target for the anti-leukemic therapy.

Disclosures
No relevant conflicts of interest to declare.
Health-Related Quality of Life (HRQoL) Measurements in Multiple Myeloma Patients Obtained By EORTC QLQ-C30; A Critical Review of Interpreting HRQoL Data in Longitudinal Studies
Authors: Nielsen Lene Kongsgaard , Jarden Mary , Andersen Christen Lykkegaard , Frederiksen Henrik , Abildgaard Niels 
Published: October 2019

Abstract
Introduction: Multiple myeloma (MM) patients report more symptoms and more severe symptoms than patients with other hematological malignancies, resulting in reduced health-related quality of life (HRQoL). Because survival is improving in MM patients there is an increased need for focus on HRQoL. The aim of this review was to interpret published longitudinal studies in MM patients according to a difference in HRQoL score, which is perceived as beneficial to the patient. Such criteria for minimal important differences (MID) in HRQoL score has been explored by Kvam et al (Eur J Haematol 2010, 84:345-53) and has been defined by a concensus expert panel (Cocks et al, Eur J Cancer 2012, 48:1713-21).
Methods: A literature search was performed May 2016 in PubMed, Embase, PsycINFO and CINAHL. Publications with longitudinal follow-up using the EORTC QLQ-C30 instrument for HRQoL measurement of physical functioning, global quality of life, fatigue or pain were included, and evaluation of mean change from baseline was carried out according to MID as defined by Kvam, and according to minimal, medium and large changes as defined by Cocks.
Results: 11 first-line, 3 consolidation, 2 maintenance, 7 relapse studies, and one population-based study were included. In general, large and medium improvements were reported during first-line treatments. During consolidation with autologous hematopoietic stem cell transplantation, temporary large deteriorations were reported, but equalization occurred with even large improvements compared to baseline reportings. Deterioration or no beneficial change in global quality of life or fatigue are reported by the MM patients during relapse treatment. HRQoL data during maintenance therapy are sparse. For summary of results, see Figure 1.
Conclusions: Guidelines for interpreting HRQoL changes with definitions of MID have been developed, but consensus is missing. Improvements in HRQoL are far more likely during first-line compared to relapse treatment regimens. The background of these findings should be in focus in future studies and HRQoL measurements should be part of maintenance studies in the future.

Disclosures
No relevant conflicts of interest to declare.
Treatment of High Risk Aggressive B Cell Lymphomas with DA EPOCH R- a Retrospective Analysis
Authors: Panny Michael , Troppan Katharina , Neumeister Peter , Nösslinger Thomas , Keil Felix 
Published: October 2019

Abstract
Background: Promising results in patients suffering from high risk DLBCL, Burkitt`s lymphoma (BL), gray-zone lymphoma (GZL) and primary mediastinal B cell lymphoma (PMBCL) treated with DA-EPOCH R have been reported.
In our centres high risk DLBCL - defined as double-hit/double hit score 2 or high/ high-intermediate risk NCCN IPI -, BL, MGZL and PMCL are treated with DA EPOCH R.
Methods: Retrospective analysis of toxicity and efficacy in DA EPOCH R treated patients.
Results: So far 39 previously untreated patients with a median age of 54a (28a - 76a) have been treated with a total of 190 cycles of DA EPOCH R: 16 DLBCL, 9 GZL, 8 PMBCL, 6 BL. 37 Patients have finished treatment, 2 are stilll on treatment.
Targeted ANC < 500/l occurred in 46%, thrombocytopenia < 25.000/l in 20% and anemia <8g/dl in 12,5% of all cycles. Dose escalation was possible in 27 (73%) patients - but only in 5 (38%) of 13 patients > 65a. 15 (63%) of 24 patients aged < 65a received at least dose level 3. Due to peripheral sensory neuropathy, Vincristine had to be dose reduced in 52% of all cycles. Other CTCAE grade III/IV non-hematopoietic toxicities were infrequent and manageable.
After a median follow up of 10 months (range: 1-25) overall survival (OS) rate is 74%. 2 patients in PR were (1 PMBCL, 1 GZL) bridged to allogenic stem cell transplantation , 1 patient in CR had to be switched to a less toxic regimen due to repeated febrile neutropenia after 3 cycles of treatment. In 16 high risk DLBCL patients (8 DHS2/DHL, 8 high/high intermediate NCCN IPI) OS is 80% after a median follow up of 12 month. As predescribed in literature, prognosis of relapsed or refractory patients is poor: 7 out of 8 (4GZL, 2 DLBCL, 1 BL, 1 PMBCL) relapsed/ refractory died. Causes of death were: 2 infectious complications (1 DLBCL HIV associated, 1 GZL) and 5 progressive disease.
Conclusion: Although still preliminary, limited data, DA EPOCH R seems to be a feasible treatment with acceptable toxicity and a promising response rate. Dose escalation is age dependent. Especially in patients with high risk DLBCL DA EPOCH R is an alternative to (insufficient) induction therapy with R CHOP and is challenging more toxic regimens like R ACVBP or R Hyper CVAD.

Disclosures
No relevant conflicts of interest to declare.
Correlation of Morphological Dysplasia and Immunophenotypic Features in Myelodysplastic Syndromes
Authors: Velloso Elvira D Rodrigues Pereira , Cosentino Rosana M , Suganuma Liliana Mitie , Barroso Rodrigo de Souza , Bacal Nydia Strachman , Colombini Marjorie P , Silveira Paulo 
Published: October 2019

Abstract
The Myelodysplastic Syndromes (MDS) are a group of clonal hematopoietic stem cell diseases characterized by cytopenias, dysplasia in one or more myeloid cell lines, ineffective hematopoiesis and increased risk for development of acute myeloid leukemia (AML).The pathological hallmark of myelodysplastic syndromes (MDS) is marrow dysplasia, which represents the basis of the World Health Organization (WHO) classification of these disorders. However, morphological diagnosis of MDS may have difficulties, with poor inter-observer agreement.Recently, Della Porta and col.(on behalf of Rete Ematologica Lombarda (REL) Network), described a new morphological score system to define dysplasia, that showed high sensitivity and specificity (>90%) andbetter inter-operator agreement (Leukemia 2015;29:66-75). In addition, new toolsfor diagnostic and prognostic purposes were developed.Flow cytometry (FCM) was addedin standard European Leukemia Net guidelinesasrecommended tool for diagnosis and prognosis in MDS, and a simple MDS-FCM scoring system based on four parameters (mainly CD34 and granulocytic cells) by Ogata and col. showed a good specificity (Haematologica 2009;94:1066-1074).
The aim of this study is to correlate morphological and immunophenotypic features in suspicion of MDS.
The study comprised two steps: the first used for morphological validation, included 33 bone marrow (BM) smears from patients with suspected MDS with or without therapy, reviewed by four experts hematologists blinded to clinical data. Dysplasia was evaluated using WHO 2008 criteria and Della Porta's score: 100 erythroblasts, 100 granulocytic cells and 30 megakaryocytes for dysplasia and 500 nucleated cells for blast cells percentage. The second step included 69 BM samples from patients with suspected MDS (27 with final diagnosis of MDS) and was used to correlate cytology and immunophenotypic findings. The morphological aspects were reviewed by one of the expert hematologists, using the same previous criteria and blinded to clinical data. Inter-operator reproducibility of morphological analyses was assessed by Intraclass Correlation Coefficient (ICC). Acceptable reproducibility was defined as ICC > 0.4. The correlation of minimal morphological criteria with immunophenotypic criteria of Ogata and col. was assessed by Discordance rate and Spearman correlation.
The results are shown in table.
In conclusion our study shows good inter observer reproducitibility, in both used criteria. The use of new criteria of Della Porta to the erythroid series was slightly better, suggesting that can be useful in diagnosing myelodisplasias. Immunophenotypic data had a good agreement with morphologic data in confirmed cases of MDS.
Table 1 Table 1.

Disclosures
No relevant conflicts of interest to declare.
Comparison of the IPSS and IPSS-R in Predicting Survival and Response of Myelodysplastic Syndrome Patients to 5-Azacitidine
Authors: Shapiro Roman M , Lazo-Langner Alejandro 
Published: October 2019

Background
The international prognostic risk score (IPSS) is a validated tool in the prognosis of myelodysplastic syndromes (MDS). Patients who fall into the Int-2 and High categories of the IPSS qualify for treatment with 5-azacitidine, a hypomethylating agent that has been shown to provide a survival advantage with these prognostic risk scores. The IPSS was recently updated, with the newer revised IPSS (IPSS-R) risk score taking into account more cytogenetic data than the IPSS. It has not yet been determined whether the IPSS-R provides an advantage over the IPSS in predicting outcome with 5-azacitidine. The objective of this study was to reclassify a cohort of MDS patients at a single academic center using the IPSS-R, and to determine its ability to predict survival and response to 5-azacitidine.
Methods
This study was approved by the institutional board review. A total of 97 patients with a diagnosis of MDS were treated with 5-azacitidine at the London Health Science Center up until 2015. Both the IPSS and IPSS-R could be calculated for 77 patients. Kaplan-Meier survival curves were constructed for the patients categorized based on the IPSS and IPSS-R. The scores were also compared based on objective response rates (ORR = complete response + partial response + hematologic improvement) as defined by the IWG 2006 criteria that were determined for all patients.
Results
All 77 patients included in the study had qualified for 5-azacitidine treatment according to provincial criteria, and had an IPSS score int-2 or high. Upon reclassification using the IPSS-R, 2/77 patients were scored as low, 14/77 patients were scored as intermediate, 24/77 patients were scored as high, and 37/77 patients were scored as very high risk. Kaplan-Meier survival analysis (Figure 1) indicated there was no statistically significant difference between the IPSS-R intermediate, high, and very high survival curves (log-rank p = 0.774). The objective response rate for all 77 patients treated with 5-azacitidine was 23%, with ORR of 21% for IPSS-R intermediate, 17% for IPSS-R high, and 38% for IPSS-R very high.
Conclusions
The IPSS-R is an alternative prognostic risk scoring system that takes into account additional cytogenetic data compared to the IPSS. In our center the IPSS-R has not resulted in prognostic risk categories that are an improvement over the IPSS in predicting survival in response to 5-azacitidine. The IPSS-R very high risk patients had double the objective response rate to 5-azacitidine compared to the intermediate and high risk groups.

Disclosures
Lazo-Langner: Bayer: Honoraria; Pfizer: Honoraria; Daiichi Sankyo: Research Funding.
Impact of Novel Agents on Frequency of Second Salvage Autologous Transplantation in Patients with Multiple Myeloma
Authors: Pathak Prajwol , Unnikrishnan Athira , Zou Fei , Leather Helen , Cogle Christopher R. , Hsu Jack W , Brown Randy A. , Wingard John R. , Norkin Maxim 
Published: October 2019

Abstract
Introduction:
High dose melphalan followed by autologous hematopoietic stem cell transplant (ASCT) is the standard of care in eligible multiple myeloma (MM) patients (pts). It is common practice to collect sufficient stem cells for two transplants, for the first ASCT immediately after induction, and for salvage ASCT following disease progression. We investigated the frequency of salvage second ASCT in the era of novel agents to determine if there has been a change in practice.
Methods:
We retrospectively reviewed medical records of MM pts who had stem cells collected for two ASCTs from 03/1996 to 12/2014. We then compared pts who received their first ASCT prior to January 2007 to those after this time. We excluded pts who received their second transplant as part of a clinical protocol, who received subsequent allogenic transplants, and pts who received 2 ASCT transplants as part of initial therapy. Fisher's exact test was used to assess significance of categorical independent variables and t-test was used to assess significance of continuous variables.
Results:
Forty of 506 pts (7.9%) received salvage second ASCT (Fig 1). Among 195 MM pts who received their first ASCT before 2007, 19 pts (9.7%) received salvage ASCT. After 2007, 21 of 311 MM pts (6.7%) received salvage ASCT (P= 0.24). When comparing salvage ASCT in the two time periods, no significant differences were noted, with the
exception of a slightly lower KPS status (80% vs 70%, P=0.001), and the use of novel agents before the salvage therapy (0/19 (0%) vs 17/21 (81%), p <0.001). Otherwise the clinical characteristics, prior response and response duration, and initial stage were similar. Prior to 2007, 6 of 44 (14%) pts older than 65 years received salvage ASCT, whereas after 2007 only 3 of 110 (3%) patients received salvage ASCT (p = 0.017).
Conclusions:
Outside of clinical trials, the use of salvage second ASCT for relapsed MM is not frequent, and was noted to be decreasing further after 2007. We speculate that this 30% relative reduction in the frequency of salvage ASCT after 2007 is likely explained by the introduction of novel agents such as bortezomib and lenalidomde into the clinical practice, the use of maintenance therapy post-ASCT, and more non-ASCT options for salvage treatment after relapse. Further studies are needed to investigate the optimal timing for salvage ASCT and the patients who will best benefit from such treatment.
Figure 1 Figure 1.

Disclosures
Wingard: Astellas: Consultancy; Gilead: Consultancy; Ansun: Consultancy; Fate Therapeutics: Consultancy; Merck: Consultancy.
Survival Improvement of Patients with Chronic Lymphocytic Leukemia (CLL) in Routine Care. a Retrospective Analysis of All Patients with CLL Who Were Treated in an Oncology Group Practice in Germany Between 1995-2015
Authors: Weide Rudolf , Feiten Stefan , Chakupurakal Geothy , Friesenhahn Vera , Kleboth Kristina , Lutschkin Julia , Thomalla Jörg , van Roye Christoph , Heymanns Jochen , Köppler Hubert 
Published: October 2019

Abstract
Introduction:Progress has been made in the diagnosis and treatment of patients with CLL who receive their treatment within prospective clinical trials. Clinical trials only include patients who fulfill the selection criteria and hence do not reflect outcomes in routine practice. Data with regards to the diagnosis, treatment and survival of patients in routine care reflecting the improvements in survival following implementation of newer therapy strategies and agents are not available.
Methods: A retrospective analysis of all patients with CLL who were treated in an oncology group practice in Germany between 1995-2015. Relevant clinical data concerning diagnosis, treatment and survival were transferred from clinical files into a database and analysed statistically using SPSS.
Results:676 CLL patients with a median age of 67 (35-92) were identified. At initial diagnosis 521 patients (77.1%) were in Binet stage A, 83 (12.3%) Binet stage B and 36 (5.3%) Binet stage C. Due to external diagnosis of 36 patients (5.3%) the stage at initial diagnosis couldn't be retrieved. 361 patients (53.4%) never received any treatment. 315 patients (46.6%) needed therapy with a median of 2 therapy lines (1-13). Regimens most frequently applied were: Bendamustine-containing (68.9%), Rituximab-containing (65.4%), Chlorambucil-containing (55.9%), Bendamustine+Rituximab combinations (48.3%) and Fludarabine-containing (39.4%). Regimens containing recently approved drugs could be found as well. 5.1% received Ibrutinib, 2.9% Obinutuzumab and 2.2% Idelalisib. 17.8% of patients were treated within a clinical trial. 5 and 10 year overall survival was 84.5% and 60.4%. Median overall survival according to Binet stage was 13 years for Binet A, 9 years for Binet B and 9 years for Binet C. Patients who needed therapy had a median overall survival of 11 years (0-42) compared to 17 years (0-27) of patients who never needed any therapy.
Conclusions: 53.4% of CLL-patients never needed any therapy. Patients who needed therapy had a much lower life expectancy compared to patients who never needed therapy. Treatment consisted mainly of Bendamustine, Rituximab, Chlorambucil, Bendamustine+Rituximab combinations and Fludarabine leading to a marked prolongation of survival compared to historical controls and registry data.

Disclosures
No relevant conflicts of interest to declare.