bluuebunny/crossref_metadata_2025 huggingface dataset:
Indirect Comparisons of the New Oral Anticoagulants in Patients with Non-Valvular Atrial Fibrillation
Authors: Zolfaghari Shabnam , Harenberg Job , Marx Svetlana , Wehling Martin
Published: October 2019

Abstract 4363

The efficacy and safety of new oral anticoagulants has been demonstrated for prevention of ischemic stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF) by dabigatran in the RE-LY trial (150mg and 110mg bid), rivaroxaban in the ROCKET AF trial (20mg od), and apixaban in the ARISTOTLE trial (5mg bid) versus INR-adjusted warfarin. Direct comparisons of the NOACs in this indication are unlikely to be performed.

A total of 4 indirect comparisons of these trials on the efficacy and safety of NOACs in patients with NVAF have now been published within only 3 months (Lip et al 2012, Harenberg et al 2012, Mantha et al 2012, Wells et al 2012). Here, we compare the results of these 4 network meta-analysis (NMA).

In all 4 NMAs of the 3 new oral anticoagulants dabigatran (150mg bid) showed superior efficacy in preventing ischemic stroke plus systemic embolism to dabigatran (110mg bid, p<0.04) and rivaroxaban (p<0.04). Apixaban had equivalent efficacy with rivaroxaban and dabigatran (either dose). Apixaban was safer (less major bleeding) than dabigatran (150mg bid, p<0.04) or rivaroxaban (p<0.005). Intracerebral haemorrhage occurred with equal frequency for all agents and regimens except for rivaroxaban (higher risk than dabigatran 110mg bid, p<0.005). Myocardial infarction occurred less frequently with rivaroxaban and apixaban compared to either dose of dabigatran (all p<0.05). All-cause mortality was not different for any agent or regimen. Some minor differences between the NMAs may result from the approved doses of dabigatran by the FDA (150mg bid and 75mg bid) and EMA (150mg bid and 110mg bid), as the inclusion of the 110 mg bid dose of dabigatran into the NMA may not be seen relevant in the US.

Based on this comparison, doctors and patients have to decide which suggestions of the 4 groups of authors seem more convincing: to change to or to start with one of the NOACs depending on the individual thrombotic or bleeding risk or to wait for the results from a large (and expensive) head-to-head randomised controlled trial which may take years to perform.

Disclosures:

No relevant conflicts of interest to declare.
Bleeding Intensity Following Tooth Extraction Is Moderated by Anxiety Independently of Treatment with anticoagulants– Development of an Internet Based Questionnaire Across Countries
Authors: Zolfaghari Shabnam , Marx Svetlana , Fischer Jeelka , Hassani Parastoo , Damian Marinella , Frölich Lutz , Harenberg Job
Published: October 2019

Abstract 4364

Anticoagulation with dose adjusted vitamin-K antagonists (VKA, therapeutic range of the international normalized ratio (INR) of 2 to 3) and low dose aspirin (65 to 330 mg daily) enhance bleeding following tooth extraction. However, intensity of bleeding varies substantially between patients. Guidelines disagree regarding interruption or continuation of anticoagulation for tooth extraction. We hypothesized that personality traits may moderate bleeding intensity under anticoagulation.

A total of 180 patients (77 female, 103 male, 49.9+15.3 years (mean, standard deviation)) underwent tooth extraction without interruption of anticoagulation. Sixty three patients did not take any anticoagulant (group 1), 60 patients were on aspirin (group 2), and 57 patients on VKA (INR 2–3, group 3). Patients completed a validated state-trait anxiety inventory (STAI), a personality inventory with 12 dimensions (Freiburg personality inventory (FPI)), and a self-developed questionnaire on general attitudes regarding general feeling and anxiety before tooth extraction. Dentists (JF, PH) rated bleeding intensity ranging from 0 to 9 according a standardized protocol.

Intensity of bleeding after tooth extraction was higher in group 3 (score <5 in 40%, score >5 in 60% of patients) compared to groups 1 (40% and 60%) and 2 (53% and 47%) and higher in group 2 compared to group 1 (p<0.005, chi-square test) as expected. Higher anxiety values in STAI questionnaire correlated positively with higher bleeding scores (p<0.0001). High values of some of the FPI dimensions correlated positively with self-consciousness (p<0.0001), physical complaints (p<0.001), and emotionality (p<0.0001) life, and negatively with satisfaction (p<0.02) and extraversion (p<0.003) without differences between groups 1 to 3. Anxiety symptoms of the self questionnaire were identified as moderating factor on bleeding intensity following tooth extraction independently of anticoagulation (p<0.0001) according multinominal regression analysis. Other items of the self questionnaire such as physiological stress symptoms, regular performance of visits, bad experience with dentists, and pains during tooth extraction did not influence bleeding intensity.

A short questionnaire is developed to identify the anxiety score of patients as a tool for a non pharmaceutical medical intervention to reduce bleeding complications following tooth extraction. Because differences of the moderating effect of bleeding by personality traits may exist between cultures, the questionnaire will be made available across countries www.blutverduennung.uni-hd.de

Disclosures:

No relevant conflicts of interest to declare.
Use of recombinant factor VIIa in treatment of bleeding episodes for patients with refractoriness to platelet transfusion therapy
Authors: Sandilya Vijay , Gupta Namita
Published: October 2019

Abstract 4382

Recombinant factor VIIa (rVIIa) is currently used for treatment and prevention of bleeding episodes in hemophilia with inhibitors, congenital factor VII deficiency, and acquired hemophilia. We report a series of 3 cases of immune mediated refractoriness to platelet transfusion therapy that were successfully treated with rVIIa, an off-label use. Data was obtained retrospectively over a 6 month period. All patients were known to be platelet refractory with presence of significant titers of plasma HLA antibodies. Two patients had undergone matched unrelated donor HSCT and the third patient suffered from Myelodysplastic syndrome (MDS). Two of the patients presented with GI bleeding and the third with intracranial bleeding. Due to limited availability of HLA matched platelets and negligible increment in platelet count from ABO matched platelets, use of factor VIIa was considered. Transfusion with PRBCs to maintain a Hemoglobin (Hb) > 8.0g/dl and close monitoring of coagulation parameters were performed. Patients received boluses of rFVIIa at 90mcg/kg, every 3–12 hrs. The dose of rFVIIa ranged from 10800–28,000 mcg/day. All three episodes of bleeding achieved clinical or radiologic improvement. No toxicities or arteriothrombotic events were observed with rFVIIa use. Our experience indicates that rFVIIa might be an effective treatment option for patients with refractoriness to platelet transfusion therapy. The optimal dosing schedule in this clinical situation needs to be studied.

Patient demographics and outcomes Patient Diagnosis Pre-intervention Hb/platelet rFVIIa used (microgms) PRBC/Platelet transfused (units) Clinical outcome SV – GI bleed ALL-MUD, BMT, day +102. 7.9/4000 28000/d × 4 days 6/3 Bleeding stopped and Hemoglobin stabilized on day 4 CS- GI bleed AML-MUD,BMT, day + 78 7.8/3000 25200/d × 2 days 2/2 Bleeding stopped and Hemoglobin stabilized on day 2 MW-Intracranial hemorrhage MDS – IPSS risk group Intemediate-2 7.6/6000 10800/d × 2 days 2/2 Improvement in Neurological exam and stabilization on CT scan seen by day 3

Disclosures:

Off Label Use: Recombinant factor VIIa for refractoriness to platelet transfusion therapy.
The W–x–x–W Motif in the TSR1 of ADAMTS13 Is Important for Its Secretion
Authors: Ling Jing , Su Jian , Ma Zhenni , Ruan Changgeng
Published: October 2019

Abstract 4389

Introduction:

The W-x-x-W motif is commonly found in the thrombospondin type 1 repeat (TSR) of various extra cellular proteins called TSR super family proteins, including thrombospondins, ADAMTSs, F-spondin and properdin. The W–x–x–W motif is known to bind with heparin, heparan sulfate proteoglycans, collagen and transforming growth factor-β, suggesting functional significance in cell–cell interaction and/or cellular signaling. However, the function of W-x-x-W in ADAMTS13 is unclear. In this study, we investigated the role of the W-x-x-W motif of ADAMTS13.

Materials and Methods:

We generated a W-x-x-W mutant (W387A) construct of ADAMTS13, and expressed the mutant and the wild-type constructs in HELA cells. Percentage of the protein secretion was defined as the concentration in the culture medium divided by the concentrations in the culture medium and cell lysates, multiplied by 100%. The binding affinity of the mutant or wild-type ADAMTS13 was investigated by enzyme-linked immunosorbent assay. Measurement of ADAMTS13 proteolytic activity toward von Willebrand factor (VWF) multimers was based on the generation of a dimeric 176-kDa fragment resulting from cleavage of VWF at the Y1605-M1606 bond, under denaturing condition and high shear stress condition, analyzed by Western blots.

Results:

SDS-PAGE gel analysis showed that the W387A mutant was secreted less efficiently relative to the wild-type construct. As for the binding affinity for the VWF multimer, there was no difference between the wild-type and mutant ADAMTS13. The W387A mutant was less active under denaturing condition; the same result was reproduced when FRETS-VWF73 was used as the substrate. However, under high shear stress condition, the mutant was as efficient as the wild-type ADAMTS13.

Conclusions:

The W–x–x–W motif is necessary for efficient secretion of ADATMS13. Further studies are needed to determine the contribution of the motif to the VWF cleave activity of ADAMTS13.

Disclosures:

No relevant conflicts of interest to declare.
Comparison of the Use of TFPI Inhibition and Plasma Dilution to Increase the Sensitivity of Thrombin Generation Assay to Measure the Procoagulant Activity of Microvesicles
Authors: Gheldof Damien DG , Mullier François , Chatelain Bernard , Dogne jean-Michel , Chatelain Christian
Published: October 2019

Abstract 4392

Introduction:

Patients with cancer have a 7- to 10- fold increased risk of developing venous thromboembolism. Circulating microvesicles (MVs) could be a predictive biomarker for venous thromboembolism in cancer. Thrombin generation assay is a useful technique to detect procoagulant activity of MVs. However, thrombin generation assay suffers from a lack of sensitivity due to the presence of Tissue Factor Pathway Inhibitor (TFPI) in plasma.

Aims:

To improve the sensitivity of thrombin generation assay to tissue factor (TF) by limiting the interference of TFPI.

Methods:

Serial dilutions of MDA-MB231 cells were incubated for 45 min at 37°C to generate MVs. Samples were then centrifuged and supernatants which contain MVs were used for thrombin generation assay. Normal pooled plasma was incubated with inhibitor of TFPI or was diluted twice to decrease plasma level of TFPI. Lagtime was used as a surrogate marker of thrombin generation assay to detect procoagulant activity of MVs.

Results:

i) Inhibition of TFPI decreased twice the cell concentration needed for a significant reduction of lagtime and decreased 2.4-fold the intra-assay variability. ii) Plasma dilution had no impact on the thrombin generation assay sensitivity when thrombin generation assay was triggered by MVs derived from MDA-MB-231.

Conclusions:

Thrombin generation is a very sensitive method to study the procoagulant activity of TF-MVs. The sensitivity can be increased by inhibition of TFPI with specific monoclonal antibody against its Kunitz Domain I. A twice plasma dilution is an interesting alternative to study the procoagulant activity of MVs by thrombin generation assay with a good sensitivity, especially when low plasma quantities are available.

Disclosures:

No relevant conflicts of interest to declare.
Identification of Novel Fusion Genes with 28S Ribosomal DNA in Hematologic Malignancies
Authors: Kobayashi Satoru , Taki Tomohiko , Nagoshi Hisao , Chinen Yoshiaki , Yokokawa Yuichi , Kanegane Hirokazu , Matsumoto Yosuke , Kuroda Junya , Horiike Shigeo , Nishida Kazuhiro , Taniwaki Masafumi
Published: October 2019

Abstract 4418

Chromosomal translocations play a crucial role in tumorigenesis, often resulting in the formation of chimeric genes or in gene deregulation through position effects. Hematologic malignancies are associated with a large number of such rearrangements. In this study, we have identified 28S ribosomal DNA (RN28S1) gene as a novel fusion partner of the B-cell leukemia/lymphoma 11B (BCL11B), immunoglobulin kappa variable 3–20(IGKV3–20), and component of oligomeric golgi complex 1 (COG1) locus in T-cell acute lymphoblastic leukemia (T-ALL), Burkitt lymphoma (BL) and multiple myeloma (MM), respectively.

RN28S1-BCL11B fusion gene was identified in T-ALL with t(6;14)(q25;q32) by cDNA bubble PCR using BCL11B primers, whereas the breakpoint of 14q32 was near, but out of, the BCL11B. BLAST search revealed that the RN28S1 was fused to BCL11B within exon3 (coding region). During the expression analysis of RN28S1-BCL11B, We identified the same type of RN28S1-BCL11B fusion transcripts in a BL and 2 MM cell lines, and unexpectedly identified other RN28S1-fusion transcripts in hematologic malignancy cell lines. Fusion of RN28S1 and IGKV3–20 exon2 (coding region) was detected in 2 BL and a MM cell lines, and that of RN28S1 and COG1 within exon 13 (coding region) in a MM cell line. Furthermore, RN28S1 breakpoint was concentrated in between 1.4∼1.8kb.

RN28S1 is located in the p12 region of chromosomes 13, 14, 15, 21 and 22. The ribosomal RNA (rDNA) gene repeats are essential housekeeping genes found in all organisms. A gene amplification system maintains large clusters of tandemly repeated copies in the chromosome, and as the product, ribosomal RNA accounts for ∼70% of total RNA in the cell.

rDNA exists in high copy number in most eukaryotic cells. Repeatitive genes tend to lose copies through homologous recombination among the repeats. The rDNA has a gene amplification system, thought to be present in most eukaryotes, that function to keep high copy numbers. In the tumor cells, rDNA is transcribed higher than normal cells for cell proliferation. Thus, that may be associated with chromosome instability.

RN28S1 degradation was reported to be associated with apoptosis of hematologic malignancies, and previously, another group was detected RN28S1-BCL6 fusion genes in gastric lymphoma. This case was no expression of BCL6 protein. In conclusion, these results suggest that RN28S1 fusions are concerned with the play something role of tumorigenesis. Because of RN28S1 fused to BCL11B, IGKV3–20 and COG1 whose breakpoints were involved in the coding region, we speculate that these fusion genes are not produce normal structure.

Disclosures:

No relevant conflicts of interest to declare.
Micro-RNA Profile of Childhood Acute Lymphoblastic Leukemia
Authors: Karagun Barbaros Sahin , Antmen Bulent , Sasmaz Ilgen , Tanriverdi Kahraman , Ucar Gulsum , Kilinc Yurdanur
Published: October 2019

Abstract 4824

Micro-RNAs are functional, non-protein coding RNA molecules and their transcriptions provided by intron or exon regions of the genome and non-protein coding regions of RNA genes. The role of micro-RNAs in acute leukemia has become the subject of research increasingly. In this study we aimed to identify micro-RNA profiles in the childhood acute leukemia that one of hematologic malignancies.

Fourty nine patients who were diagnosed with acute leukemia and admitted to Cukurova University Faculty of Medicine Department of Pediatric Hematology between December 2010 and September 2011. Blood samples were taken twice in patient groups at diagnosis and during remission and plasma samples were stored. Blood samples were taken once in the healthy group and plasma were separated. The plasma samples were investigated by PCR analysis of micro-RNA. Acute leukemia was diagnosed by cytomorphological, immuno histochemical and flow cytometric studies. Thirtyone patients who were diagnosed with ALL and fortyseven healthy children as a control group were included to study.

miR20a, miR25, miR92a, miR30c, miR106b, miR203, miR150, miR192, miR302c, miR184, miR218, miR320, miR342-3p, miR223, miR328, miR483-5p, miR376a, miR381, miR451, miR576-3p, miR548a levels were increased in newly diagnosed ALL patients when compared to healthy controls (p <0.05). The miR20b, miR342-3p and miR548a levels were found higher in healthy controls than the newly diagnosed ALL patients group (p <0.05) Healthy control groups when compared with pediatric ALL patients whose in remission; miR769-3p, miR20a, miR92a, miR16, miR27b, miR192, miR320, miR223, miR484, miR451 levels were found higher in healthy control groups than the patients. Newly diagnosed pediatric ALL patients compared with patients whose in remission; miR30c, miR106b, miR25, miR184, miR218, miR302c, miR483-5p levels were increased in newly diagnosed pediatric ALL patients than ALL patients whose in remission (p<0.05).

miRNAs are thought to be identified at a different level of expression in normal and pathological tissues can be determined between the miRNAs that are effective diagnosis and treatment of human cancers. We showed the microRNA profils that may play new roles treatment of acute leukemia in the futures.

Disclosures:

Kilinc: ApoPharma Inc.: Research Funding.
Normal Blood and Bone Marrow Wt1 Expression Level in Extramedullary Relapse in AML Patient
Authors: Girshova Larisa , Romanova Ekaterina , Gorunova Elena , Kholopova Irina , Nikulina Tatiana , Mirolubova Julia , Ivanov Vladimir , Zaritskey Andrey
Published: October 2019

Abstract 4825

Wilms' tumor gene 1 (WT1) that encodes a transcription factor has elevated expression in 90% of AML. High level of WT1 gene expression in bone marrow and peripheral blood of patients with AML indicates the presence of leukemia tumor burden. Thus, quantifying assessment of the level of WT1 could predict relapse. It is important to monitor a universal marker in the absence of target molecular genetic abnormalities in the disease onset. There are few data related to extramedullary relapses. Here we describe the patient with extramedullary relapse without concomitant elevation of WT1 expression.

The patient is 22 year old male with the first early bone marrow and CNS relapse of AML. Cytogenetics- (45XY, t (3, 5) (q29; q15), −7, der (7), add (11) (p15)). Blast cells immunophenotype was CD45 + CD34 + CD38 + CD117 +. There was high blast count with high expression of WT1 level (Tabl 1). And there was no expression of other molecular genetic prognostic markers. Therapy with high dose of cytarabine with intrathecal administration of cytotoxic drugs was conducted. The complete hematological and cytogenetic remission was achieved after the first induction. Also there was no any blast cell in the CSF, WT1 expression decreased by 1,87 log (WT1 level became normal). Consolidation of remission with three similar courses with high doses of cytarabine was conducted. Extramedullary relapse during bone marrow and CNS remission with unilateral lesion of the lacrimal gland and the periorbital area( 2.8 × 3.4×4.6 cm )was diagnosed in 6 month. Relapse was confirmed by histological and immunochemical study of the left lacrimal gland biopsy, blasts phenotype was similar to the phenotype of bone marrow blasts at AML onset. WT1 level in bone marrow and peripheral blood remained within normal limits: 15.5 WT1/104 ABL copies and 13.4 WT1/104 ABL copies respectively. Therapy with high dose cytarabine and mitoxantrone was used as an induction. After this therapy a local remission was diagnosed according to MRI. Consolidation courses were followed by a course of radiotherapy to the area of the left orbit. Bone marrow remission and low-level expression of WT1 remained to be normal. Thereafter the patient has undergone unrelated allogeneic bone marrow transplantation.

Conclusion.

We have described isolated AML relapse without elevation of WT1. A possible reason for normal level of expression of WT1 in patients with extramedullary relapse may be a small amount of the extramedullary formation, its location and features of blood supply of the body area.

Disclosures:

No relevant conflicts of interest to declare.
Outcome of Nodular Lymphocyte Predominant Hodgkin Lymphoma Patients Treated with or without Rituximab
Authors: Mocikova Heidi , Michalka Jozef , Koren Jan , Stepankova Pavla , Wild Alexander , Raida Ludek , Markova Jana , Kral Zdenek , Trneny Marek , Indrak Karel , Mayer Jiri , Kozak Tomas
Published: October 2019

Abstract 4878

Background.

Strong CD20 expression in nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) suggests the feasibility of rituximab in the treatment of this disease.

Methods.

We analysed the outcome of 102 patients with NLPHL treated with or without rituximab in combination with conventional treatment: chemotherapy and/or radiotherapy. Histologies were reviewed for the purpose of this study. Rituximab was administered in 26 of 102 NLPHL patients (13 in the first line treatment and in 13 of 20 relapsed patients). Additionally, rituximab with chemotherapy was administered in 11 patients with histologic transformation to diffuse large-B cell lymphoma. Median follow-up was 7.1 years. Median patient age was 34.2 years.

Results.

The 10-year overall survival (OS) rate and progression - free survival (PFS) of the whole group was 88% and 65%, respectively. There was no difference in OS and PFS in patients with clinical stage IA without risk factors treated without or with rituximab (30 vs 3 patients) and conventional treatment, however the follow-up in the rituximab group was short. The addition of rituximab to conventional treatment did not affect the OS in the group of patients with more advanced disease: 58 patients without vs 10 with rituximab (94% [95% CI: 88 – 100%] vs 100% [-], P=0.566). PFS in both groups did not differ significantly in the first line treatment (69% [95% CI: 57 – 82%] vs 100% [-], P=0.165), however when all lines of treatment were analysed, PFS was significantly better in patients treated without rituximab (92% [95% CI: 84 – 100%] vs 38% [95% CI: 22 – 65%], P< 0.001). Histologic transformation to diffuse large B - cell lymphoma was diagnosed in 11 rituximab naive patients, but this was not statistically significant when compared to 0 patients after rituximab treatment (14,5% vs 0%, P=0.061). Histologic transformation was the only poor prognostic factor that influenced OS (HR 7.936, P=0.004).

Conclusions.

Rituximab does not prevent relapses in NLPHL. This study confirms favorable OS of NLPHL patients regardless whether rituximab was used or not. The absence of histologic transformation in NLPHL patients treated with rituximab deserves further investigation.

Disclosures:

No relevant conflicts of interest to declare.
High Incidence of tMDS in Elderly Lymphoma Patients Subjected to Radioimmunotherapy
Authors: Zimowska-Curylo Dagmara , Jurczak Wojciech , Giza Agnieszka , Jakobczyk Malgorzata , Krawczyk Katarzyna , Skotnicki Aleksander B
Published: October 2019

Abstract 4882

Background:

Conventional therapies with cytotoxic agents for disseminated NHL are associated with a high risk of therapy related myeloid neoplasm (tMN). The latency period between exposure to this agents and development of tMN ranges from one to 10 years.

Radioimmunotherapy (RIT) uses monoclonal antibodies, specifically binding to antigens of tumor cells, as a carrier for the radioisotope. The radiation is delivered not only to the antibody –bound tumor cell, but also neighboring cells.

Methods:

In the years 2005–2011 radioimmunotherapy with ibritumomab tiuxetan was used in 102 patients with FL (during consolidation therapy), MCL (as consolidation of the first-line treatment and after achieving PR in the first- or second-line therapy), DLBCL and MCL (in the HDT supported by auto-SCT). 5 patients (4,9%) ( 4 with MCL/ 1 with FL) subjected to RIT developed tMDS. All patients with MCL in previous treatment were exposed to alkylating agents, antymetabolites and inhibitors of II topoisomerase. All patients had hypoplastic bone marrow year after RIT.

Results:

Median time to diagnosis of tMDS after treatment with RIT was 2,3 years. 4/5 during 6 month transformed into tAML. In peripheral blood of all patients anemia, thrombocytopenia or pancytopenia was observed. All patient in histophatology had dysplastic changes in 3 hematopoetic lines with 5% blast cells, without elevated percentage of ring sideroblasts. Each patient had typical for tMDS complex abnormalities with monosomy of chromosome 5 or 7, or abnormalities of this chromosome [table 1]. Three of this patients was treated with azacitidine, one of this patients was prepared to RIC allo BMT but developed tAML and died during induction therapy. All patients received supportive care.

Conclusion:

The development of secondary hematological malignancies (tMDS and tAML) after RIT is very closely related to the drugs applied in the induction treatment especially purine analogues. Higher incidence of tMDS in patients with MCL confirm the relationship of occurrence of secondary MDS and AML after radioimmunotherapy with the earlier use of purine analogs (fludarabine) and cumulative damage to bone marrow cells rather than exclusively associated with administration of RIT.

Disclosures:

No relevant conflicts of interest to declare.
Activity of Rituximab-Bendamustine (RB) Combination in Nodular Lymphocyte Predominant Hodgkins Lymphoma (NLPHL)
Authors: Devarakonda Srinivas S , Haddad Philip A
Published: October 2019

Abstract 4894

Nodular Lymphocyte Predominant Hodgkin's Lymphoma (NLPHL) is an uncommon subtype of Hodgkin's lymphoma. NLPHL represents a more indolent disease than classical Hodgkin's lymphoma. It has unique clinicopathological features that resemble indolent Non Hodgkin's Lymphomas and hence, the tendency to manage it as such.

We reviewed the activity of Rituximab-Bendamustine (RB) combination in 2 cases of relapsed NLPHL. The first patient is a 53 year old African American man who was diagnosed with Ann-Arbor Stage IIA NLPHL in 2005. He was initially treated with 3 cycles of ABVD after which he was lost to follow up. He sought medical attention in 2008 and a repeat PET/CT showed persistent cervical lymphadenopathy consistent with his known disease but the patient refused therapy at that time. Three years later, he presented with weight loss and enlarging cervical lymph nodes. A repeat biopsy of these nodes confirmed his initial diagnosis of NLPHL. He was reluctant to undergo any chemotherapy similar to the initial treatment because of the side effects. He was then treated with 4 cycles of RB followed by involved field radiation therapy, which he tolerated well. Post therapy PET/CT scan revealed a complete remission. The second patient is a 62 year old white man who was initially diagnosed with IE DLBCL of the proximal jejunum in 2004 which was successfully treated with R-CHOP. After five years he was found to have diffuse lymphadenopathy. Excisional biopsy revealed NLPHL. The patient refused to take adriamycin containing regimen or combination therapy since he poorly tolerated it before and agreed to try RB instead. He was treated with 6 cycles of RB. Re-staging PET/CT scans revealed near complete resolution. The patient was referred for autologous stem cell consolidation. He underwent adequate stem cell collection and successfully engrafted. Both patients continue to be disease free as of their last clinic visit.

Rituximab –Bendamustine combination seems to have significant activity in NLPHL, reminiscent of its activity in indolent non-Hodgkin's lymphomas. Incorporation of the regimen into front line treatment of patients with this disease needs further study and evaluation.

Disclosures:

Off Label Use: Rituximab and Bendamustine are not FDA approved for NLPHL. Haddad:Cephalon: Honoraria, Speakers Bureau.
B Cell Receptor (BCR) Signal Pathways Confer Microenvironment-Mediated Drug Resistance and Are Promising Therapeutic Targets for B Cell Lymphomas
Authors: Tao Jiangchuan , Lwin Tint , Zhao Xiaohong , Zhang Ling , Moscinski Lynn , Sotomayor Eduardo M. , Dalton William S. , Tao Jianguo
Published: October 2019

Abstract 4918

Despite intensive efforts in developing new therapies, B-cell lymphoma remains essentially incurable with standard therapeutic approaches. Dynamic interactions between the lymphoma cell and its microenvironment play a critical role in lymphoma development and response to therapy. There is accumulating evidence pointing to an essential role of BCR signaling in B-cell lymphomas. Recently, inhibitors of BCR signaling have become an area of substantial clinical interest. We therefore studied the role of BCR signal pathways in stroma-mediated lymphoma cell survival. We demonstrated that adhesion of the various B-cell lymphoma cell lines to lymph node stromal cells enhanced activation of BCR signaling pathways: activation of phosphatidylinositol 3-kinase (PI3K), Bruton's tyrosine kinase (Btk) and extracellular signal-regulated kinase (ERK) pathways. Inhibition of Btk by PCI 32765 or PI3K by CAL101 significantly blocked BCR signal pathways, triggered lymphoma cell apoptosis and overcame stroma-mediated drug resistance. Furthermore, targeting BCR signal pathway disrupted microenvironmental stroma-lymphoma interaction through regulation of CXCR4 expression. Collectively, these data support that BCR activation not only controls intrinsic survival pathway related to B lymphoma cell but also regulates stroma-mediated extrinsic lymphoma cell survival as well as lymphoma cell homing and interplay with its microenvironment. As a result, this study suggests that targeting BCR signal pathway molecules is a promising therapeutic strategy to lymphoma therapy.

Disclosures:

No relevant conflicts of interest to declare.
The Impact of Comorbidity in Myelodysplastic Syndromes
Authors: Huang Yu-Chung , Chen Kuo-Wei , Hong Ying-Chung , Liu Chia-Jen , Yu Yuan-Bin , Tzeng Cheng-Hwai
Published: October 2019

Abstract 4940

Introduction

Myelodysplastic syndrome (MDS) is a heterogeneous clonal hematopoietic cell disorder. The prognostic implication of comorbidities at diagnosis of MDS is emerging.

Objective

We aimed to investigate the impact of comorbidity on the patients with MDS.

Method

Totally 263 MDS patients during a 15-year period in single institute were collected.

The clinical characteristics and the extra-hematological systemic diseases at diagnosis were all registered in this database. Well established prognostic models, including original International Prognostic Scoring System (IPSS), WHO classification-based Prognostic Scoring System (WPSS), and total MDACC scores were evaluated in our cohort.

Results

Comorbidity was present in 76. 4% of patients. In univariate and multivariate analysis, HCT-CI ≥ 3 was significantly associated with poor outcome. IPSS, WPSS and MDACC were informative to discriminate between risk groups of patients with MDS. By comparing AIC values in the Cox proportional hazards analysis, MDACC had superior prognostic value followed by IPSS and WPSS. A modified score incorporating HCT-CI and MDACC divided patients into four risk groups. The 3 year-survival rate was 72%, 40%, 31%, 4%, respectively.

Conclusion

Building new models incorporating comorbidities to current prognostic score help to predict survival in patients with MDS.

Disclosures:

No relevant conflicts of interest to declare.
Extreme Thrombocytosis Under Azacitidine in Patients with Myelodysplastic Syndrome
Authors: Kelaidi Charikleia , Kokkinidis Dimitrios , Protopappa Maria , Papaioannou Georgios , Batsis Ioannis , Apostolou Chrysa , Stamatopoulos Kostas , Athanasiadou Anastasia , Anagnostopoulos Achilles , Vadikoliou Chrysanthi
Published: October 2019

Abstract 4961

Background:

Platelet increase under azacitidine in patients with myelodysplastic syndrome (MDS) has been acknowledged as an early predictive factor of response to treatment. However, extreme thrombocytosis under azacitidine has not been reported.

Methods:

We studied consecutive patients with MDS or MDS/myeloproliferative neoplasm (MDS/MPN) who had platelet counts near or over 1, 000 G/L under azacitidine.

Results:

Four patients, sex ratio 1:1, with median age of 65 years, had extreme thrombocytosis under azacitidine. Baseline characteristics were: WHO classification RAEB-2/CMML-1/CMML-2 in 2/1/1 patients, median platelet count 248 G/L (<400 G/L in all), normal karyotype/+8, −9/−7 in 2/1/1 patients, IPSS low/int-2/high in 1/2/1 patients. None had reticulinic fibrosis or ring sideroblasts>15% at baseline. A median number of 8 cycles of azacitidine was administered. Individual platelet counts reached 2, 960 G/L, 800 G/L, 1, 188 G/L and 2, 740 G/L. Thrombocytosis occured early after treatment onset or resumption (Figure 1). Histologic findings under treatment were: Increased cellularity (N=4), micromegakaryocytes and other signs of megakaryocytic dysplasia (N=4), reticulinic fibrosis grade I and II in 1 and 2 patients, respectively. JAK2 V617F mutation was detected in 1 patient (with maximum platelet count of 2, 900 G/L) and was undetectable in the remaining patients. None had a thrombotic or hemorrhagic event. Two patients had a concomitant increase of WBC count. Response to azacitidine was CR, PR and stable disease in 1/1/2 patients. Three patients received hydroxyurea (HU) in addition to azacitidine and one patient underwent hematopoietic stem cell transplantation (HCT). AML transformation occurred in 1 patient 25 months after azacitidine onset. Median overall survival after azacitidine onset was 25 months.

Conclusion:

Extreme thrombocytosis of the range of essential thrombocytosis, with megakaryocytic dysplasia and hyperplasia, was noted under azacitidine in 4 patients with MDS-MDS/MPN and normal baseline platelet count. Hypothetically, azacitidine may induce the expression of critical genes of megakaryopoiesis or platelet release in patients with rare mutations. Notably, JAK2 mutation was detected in only one patient. Alternatively, demethylation could unmask an underlying unclassified MDS/MPN similar to RARS-T.

Disclosures:

No relevant conflicts of interest to declare.
Multiple Myeloma, Detection of Four Unfavorable Genetic Pronostic Factor by Interphase Two-Color Fluorescence in Situ Hybridization Analyses: A Study of 33 Patients At Diagnosis or Relapse
Authors: Barragan Carlo Sergio , Hansson Silvia B. , Cicchini Silvina A , Hidalgo Federico J , Ochoa Claudia E , Nunez Gabriela , Flores María Gabriela , Salvador Teresa , Saba Silvia
Published: October 2019

Abstract 5004

Background:

Interphase Fluorescence in situ hybridization (FISH) has improved the detection of early bad prognostic genomic aberrations in Myeloma (MM) is a fast and reliable method. We used this assay in myeloma patients at diagnosis, after relapse or treatment failure.

Methods:

Interphase Mononuclear cells from Bone Marrow of 36 Caucasian patients, 13 men and 23 women, age ranged from 40 to 84 years (median, 64) with MM. were analyzed by LEXEL Live FISH probes, for deletions in chromosome band 13q14. 3, 17p13. 1; IGH/CCND1 translocation dual fusion and cMYC breakapart 8 Chromosome.

Results:

Chromosomal aberrations were detected in 16 of 33 evaluable patient samples of a total 36 patients population. The most frequent aberrations were 7/16 in 13p14. 3 band deletion (43. 75%) 7/33 (21%); 5/16 (31, 25%)patients with deletion had 17p13. 15/33 (15, 15%); 3 cMYC breakapart 3/16 (18. 75%) 3/33 (9%); IGH/CCND1 translocation in 3 patients 3/16 (18. 75%) 3/33 (9%), two of them associated one with cMYC and the other with 13p14. 3. We found other association: A)13p14. 3; 17p13. 1 and cMYC in (1/33). B) 13p14. 3 and cMYC (1/33) C) 17p13. 1; cMYC (1/33). Two patients had 8 chromosome trisomy 2/33 (6%). We foun that 13p14. 3, 17p13. 1 and cMYC association was correlated with a worst and fast evolution. Who had 13p14. 3 band deletion had a worst evolution in our patients. cMyc was associated with a poor prognosis.

Conclusions:

Genomic aberrations are independent prognosis factors of disease progression, chemotherapy respond and survival in Myeloma. Novel DNA molecular target and bone marrow micro environment modification drugs such as bortezomib and thalidomide or lenalidomide must be use in first line associated perhaps with standar chemotherapy drugs for improving result and consolidate this patients with autologous bone marrow transplantation avoiding the dilate of this strategic in patient with poor prognosis. Future trials must be performed to include a more complete panel of probes in Myeloma.

Disclosures:

No relevant conflicts of interest to declare.
Multiple Myeloma Associated GI Polyposis
Authors: Nabbout Nassim , Hawari Mohamad El , Schulz Thomas K.
Published: October 2019

Abstract 5009

Multiple myeloma is a neoplastic proliferation of monoclonal plasma cells that can result in osteolytic bone lesions, hypercalcemia, renal impairment, bone marrow failure, and the production of monoclonal gammopathy. The gastrointestinal tract is rarely involved in myeloma. GI polyposis is a rare manifestation of extra-medullary disease in multiple myeloma. Such cases usually present as gastrointestinal hemorrhage or intestinal obstruction.

A 53-year-old African American male recently diagnosed with multiple myeloma presented with three-day history of rectal bleed and fatigue. EGD showed multiple raised, polypoid, rounded lesions with a superficial central ulceration in the stomach. Colonoscopy showed similar lesions in the ascending and transverse areas of the colon that ranged in size from 5 to 16 mm in diameter. Biopsies showed that these polyps were made of plasma cells. A bone marrow biopsy showed diffuse involvement (greater than 90%) of bone marrow with multiple myeloma with anaplastic features. The patient was started on bortezomib at diagnosis, however, he passed away a few weeks later.

This type of metastatic disease has been described in isolated case reports in the literature, while solitary GI plasmacytoma has been reported more frequently. In rare cases, multiple myeloma can involve the GI tract which may lead to bleed or obstruction. This involvement is likely a marker of aggressivity. This example of extra-medullary disease in myeloma is an uncommon variant with features of poor prognosis and dedifferentiation.

Disclosures:

No relevant conflicts of interest to declare.
Baicalein Inhibites Multiple Myeloma Cells Proliferation and Migration by Interfering Wnt Signaling Pathway
Authors: Xu Chaoping , Liu Shangqin , Huang Jianying , Zhang Yicheng , He Li , Cai Huili , Zhang Ruibo , Ji Jinna , Zhou Dingxin , Ma Zi
Published: October 2019

Abstract 5019

Background:

The Wnt/β-catenin signaling pathway has been implicated in a variety of tumor cell survival and proliferation, including myeloma cells. It can facilitate myeloma cell proliferation by upregulating the expression of many related genes, such as c-myc, cyclin D1, MMP and so on. We have previously demonstrated that Baicalein, a important component of Scutellaria radix from Huang-Lian-Jie-Du-Tang(HLJDT), can inhibit cell proliferation and induce cell death in myeloma cell through suppressing NF-κB activation (Ma Z, et al., Blood, 2005, 105(8): 3312–3318). In clinic, we found that HLJDT had a very good effective in multiple myeloma(MM) patients treatment (data not show). But, the precise molecular mechanism of HLJDT exerts its anti-tumor effects remains poorly understood. Here we further evaluated alternative mechanisms which is responsible for inhibition myeloma cell proliferation and migration by baicalein.

Methods:

Myeloma cell lines, RPMI8226 and U266 cells, were used for the analysis. MTT assay was used to assess cell viability in RPMI8226 and U266 cells which were exposed to baicalein with different concentrations and time period. Immunofluorescence assay and western blot analysis were used to assess β-catenin protein expression in MM cell lines. Transwell chamber migration assay was used to assess migration ability of myeloma cells treated with different concentrations of baicalein. RT-PCR analysis was used to assess β-catenin, c-myc, cyclin D1 and integrin β7 mRNA expression.

Results:

Baicalein can inhibit the MM cell lines proliferation in a dose- and time-dependent manner as measured by MTT assay. Immunofluorescence images and western bloting revealed that treatment of baicalein decreased the β-catenin protein expression level in myeloma cells. The mRNA expression level of β-catenin, c-myc and cyclin D1 was also decreased by baicalein treatment. In addition, we found that baicalein has an ability to inhibit the migration of MM cell llines, RPMI8226 and U266 cell, by decreasing the integrin β7 mRNA expression in a dose-dependent manner.

Conclusion:

Baicalein can inhibit myeloma cell proliferation is related to downregulation of β-catenin, c-myc and cyclin D1 genes expression, and the inhibition of myeloma ia associated with suppression of integrin β7 gene expression. Thus, HLJDT may have a potential of clinical applications in MM patient treatment.

Disclosures:

No relevant conflicts of interest to declare.
A Prospective, Randomized, Chemoprevention Trial of Celecoxib for High Risk Monoclonal Gammopathy of Undetermined Significance and Asymptomatic Multiple Myeloma
Authors: Horwitz Leonard J. , Faiman Beth , Elson Paul , Baz Rachid , Hussein Mohamad , Lust John A , Mehta Paulette , Reu Frederic J. , Habecker Becky , Reed Janice , Karam Mary Ann , Dean Robert M , Sobecks Ronald , Hsi Eric D. , Kaushal Varsha , Kalaycio Matt
Published: October 2019

Abstract 5045

Observation remains the standard approach to patients with monoclonal gammopathy of undetermined significance (MGUS) and asymptomatic multiple myeloma (AMM) who lack end-organ impairment characteristic of symptomatic MM. Institution of early MM therapy has not been shown to improve survival or alter the natural progression of the disease. Cyclooxygenase-2 (COX2) inhibitors inhibit proliferation and induce apoptosis in drug resistant MM cell lines. 23 asymptomatic adult patients with a serum monoclonal protein >1g/dL, from Cleveland Clinic, Mayo Clinic, or University of Arkansas Medical Center between August 2005 and April 2008 were randomized to either celecoxib or placebo in a double-blind, 1:1 fashion. The primary end point was change in the monoclonal protein concentration after 6 months. Correlative biomarkers, including IL6 and IL-6R, CD4/CD8+ T-cell ratios, and beta-2 microglobulin, were examined before and after treatment. Celecoxib had no significant effect on the median monoclonal protein concentration, which went from a median of 1. 44 to 1. 65 g/dL with placebo and 2. 42 to 2. 24 g/dL with Celecoxib (p=0. 36), or on any of the analyzed correlative markers (all p-values >0. 34). One patient's monoclonal protein concentration increased on placebo, but he did not require treatment for symptomatic MM. There were no adverse events of Grade 2 or higher. Celecoxib was well tolerated in contrast to previous reports when given in higher doses and in combination with thalidomide. Although accrual was limited we conclude that celecoxib has no clinical or immunologic effect on high risk asymptomatic plasma cell disorders. This study does not support using celecoxib for preventing progression to symptomatic MM. Future studies on progression of MGUS to symptomatic MM would require more patients and a longer follow-up period.

Disclosures:

Off Label Use: Celecoxib for chemoprophylaxis. Hussein:Celgene: Employment. Reu:Celgene: Research Funding.
Combination Therapy Based on Bortezomib for Newly Diagnosed Multiple Myeloma Patients
Authors: He Jingsong , Yang Li , Jin Dian , Lin Xuanru , Yang Qianqian , Han Xiaoyan , Zheng Gaofeng , Zheng Weiyan , Wei Guoqing , Wu Wenjun , Ye Xiujin , Shi Jimin , Xie Wanzhuo , Zhang Jie , Lin Maofang , Huang He , Cai Zhen
Published: October 2019

Abstract 5048

Introduction:

Novel drugs, such as bortezomib, have significantly improved the response rates in multiple myeloma (MM), but little has been reported on bortezomib-based therapies in Chinese patients.

Methods:

In the initial eight 28-day cycles, newly diagnosed ymptomatic patients were treated with combination therapy including bortezomib plus dexamethasone (PD) and the triplet combinations of PD with adriamycin (PAD), cyclophosphamide (PCD), thalidomide (PDT) between February 1, 2006 and May 31, 2012. Among the above regimens, bortezomib (1. 3 mg/m2) was given intravenously on days 1, 4, 8, 11, while dexamethasone (20 mg/m2/day) was given intravenously on days 1–2, 4–5, 8–9, 11–12, adriamycin (10 mg/m2) was given intravenously on days 1–4, cyclophosphamide (200 mg/m2) was given intravenously on days 1–4 and thalidomide (100 mg) was administered orally each day.

Results:

The overall response rate (¡Ý partial response, PR) of all the 151 eligible patients was 88. 7% (including 29. 8% very good partial response (VGPR) and 25. 8% complete response/near complete response (CR/nCR). The responses per IMWG criteria for patients are shown in Table 2. The median PFS was 20. 3 months (95% CI: 14. 8–25. 8 months) in the patients who received PDT, 24. 8 months (95% CI: 20. 0–30. 0 months) in the patients who received PCD, 22. 9 months (95% CI: 17. 6–28. 2 months) in patients who received PAD and 21. 8 months (95% CI: 15. 3–28. 3 months) in the patients who received PD with no significant differences between the groups. The median OS for PD arm was 42. 0(95% CI: 20. 1–63. 9 months) months while other arms were not reached, but the median OS for PDT, PCD and PAD was significant longer than PD (P=0. 042, 0. 039, 0. 010). PFS and OS for patients with favorable cytogenetics were significantly longer than those with unfavorable cytogenetics by FISH. The frequently observed hematologic toxicities (Grade 3/4) were: thrombocytopenia (17. 00%), neutropenia (15. 00%) and anemia (8. 61%). The most common non-hematologic toxicities included (all Grades) peripheral neuropathy(57. 61%), fatigue(27. 15%), infection(23. 84%), constipation(22. 52%), herpes zoster(17. 22%) and diarrhea(15. 23%).

Conclusions:

Our experience indicated that bortezomib-based regimens were active and well-tolerated for MM patients, and triplet combinations were superior to PD. Serious Adverse events were rare in the Chinese patients with MM who received bortezomib-based chemotherapy.

Disclosures:

No relevant conflicts of interest to declare.