bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ibandronate and Renal Function In Myeloma Patients
Authors: Bergner Raoul , Breuer Jochen , Sandermann Andreas , Uppenkamp Michael J. , Hoffmann Martin 
Published: October 2019

Abstract
Abstract 5047

Introduction:
Treatment of myeloma bone disease with bisphosphonates (BP) is standard of care. However, renal toxicity due to BP treatment tends to be a major problem in myeloma patients, especially. At highest risk are patients with reduced renal function and patients who had switched the BP. Toxicity appears typically after few month of BP treatment.
We evaluated the renal safety of ibandronate (IBD) in myeloma patients, who were treated with IBD for myeloma bone disease. The patients were stratified according to pretreatment and kidney function.

Methods:
In a prospective noninterventional study about safety and efficacy of IBD in breast cancer patients it turned out that myeloma patients were also included unintentionally. Out of 3540 documented patients 105 myeloma patients were identified. The data from these myeloma patients were evaluated separately.
The patients were subdivided in 4 groups according to their glomerular filtration rate [GFR]: GFR>90 (1), 60–90 (2), 30–59 (3) and <30 (4) ml/min. Since pretreatment with other BP could be of influence, patients were analysed according to former pretreatment: no BP (I), IBD (II), and other BP (III). The renal function was calculated every month over a period of six month by the MDRD-formula.

Results:
105 patients were available for evaluation. In 99 patients RF was documented over a minimum of 5 months. The initial RF was (1) n=14, (2) n=36, (3) n=38 and (4) n=17, respectively. At baseline there were no differences in renal function according to their pretreatment. A total number of 692 infusions were documented. The IBD dosage was 6 mg in 90% of all infusions, 4 mg in 3,6%, 3 mg in 2% and 2 mg in 4.4%, respectively. The GFR (mean GFR+/−SD) was stable over time in the groups 1–3 and increased significantly in group 4;
The mean changes were similar in all groups irrespectively of the pretreatment. In 9 patients the treatment was terminated prematurely, due to disease progression (n=3), death due to myeloma during study period (n=3). Two patients were lost by follow up and one patient declined further treatment.

Discussion:
The data of this noninterventional study demonstrate, that there is no evidence for renal toxicity of IBD in myeloma patients in all stages of renal function. Quite in contrary to previous observations with other BP patients with worse kidney function (stage 4) had a significant improvement of GFR over the study period. The reason for this observation remains unclear, because parameters like hypercalcemia or burden of light chains are not recorded in this study.

Disclosures:
Off Label Use: Ibandronate is not approved for myeloma bone diease.
Thalidomide Based Regimens for Treatment of Unfit Patients with Relapsed and Refractory Multiple Myeloma: a Monocentric Experience
Authors: Moscetti Alessandro , Saltarelli Francesca , Bianchi Maria Paola , Monarca Bruno , La Verde Giacinto 
Published: October 2019

Abstract
Abstract 5048
Thalidomide, an immunomodulating drug with antiangiogenic activity, is an efficacious therapeutic option for unfit patients with multiple myeloma. Its efficacy may be increased by the addiction of steroids or other cytotoxic drugs such melphalan or cyclophosphamide. In this study we assessed the efficacy and toxicity of thalidomide based regimens as savage therapy in a series of elderly patients with relapsed/refractory multiple myeloma. Previous treatments included at least one therapy (range 1–4), such as high dose dexamethasone, alkylating agents, anthracyclines, IFN-α and autologous graft. Thalidomide 50–200 mg/die was administered orally in a total of 16 patients (median age 73.8 years, range 59–84) with relapsed/refractory multiple myeloma observed in our Hematology Department between May 2004 and January 2010. Oral dexamethasone or prednisone was added to the treatment. All patients continued therapy until relapse or progression and were prospectively followed-up including accurate monitoring of side effects. Response to thalidomide was assessed according to the European Group for Blood and Marrow Transplantation criteria. The median follow-up time was 25.6 months (range 8 – 68). Overall response rate was 81.2% (13/16 patients) with a median duration of response of 26.7 months (range 7 – 67): 3 patients showed a very good partial remission, 10 partial response, 1 stable disease and 2 progression of disease. During follow-up, 6 patients died (3 due to progression, 2 due to other neoplasm, 1 due to heart failure), 10 patients are still alive (2 VGPR and 7 PR in continuous therapy, 1 PD in third line therapy). No response was observed in 3/16 patients (18.7%). Despite the following side effects, mild to moderate bradycardia (25%, 1 needed PMK positioning and 1 dose reduction), peripheral sensitive polyneuropathy (18.7%) and constipation (6%), no patient discontinued therapy. This study shows that thalidomide based regimens are an effective therapy with a high response rate and manageable side effects when used in patient with multiple myeloma with relapsed/refractory disease.

Disclosures:
No relevant conflicts of interest to declare.
JAK2 V617F Mutation In Atypical Chronic Myeloid Leukemia
Authors: Nam Myung-Hyun , Kim Ju-Yeon , Yoon Soo-Young , Lim Chae Seung , Lee Chang Kyu , Cho Yunjung , Kim Young-Kee , Lee Kap No 
Published: October 2019

Abstract
Abstract 5069
Atypical chronic myeloid leukemia (aCML) is a rare leukemic disorder which shows myelodysplastic and myeloproliferative features simultaneously. Some cases of JAK2 V617F mutation in aCML were reported before WHO criteria introduced (Jelinek J et al. Blood 2005; Jones AV et al. Blood 2005; Levine RL et al. Blood 2005). However, Fend F et al observed no JAK2 V617F mutation in aCML as defined by WHO classification (Fend F et al. Leuk Res 2008), which result was refuted by a case report (Campiotti L et al. Leuk Res 2009). Here we analyzed JAK2 V617F mutation with amplification refractory mutation system (ARMS) and direct sequencing in three cases of aCML and found a case with JAK2 V617F mutation. All three cases were diagnosed as aCML according to WHO classification and showed significant myelodysplastic/myeloproliferative features in peripheral blood and bone marrow aspirates. Absence of BCR/ABL1 gene rearrangement was confirmed by FISH analysis, and conventional cytogenetic analysis revealed trisomy 8 in a case with no JAK2 V617F mutation. The patient with JAK2 V617F mutation poorly responds with hydroxyurea therapy and is showing prolonged leukocytosis.

Disclosures:
No relevant conflicts of interest to declare.
Posttransplant Lymphoproliferative Disorders (PTLD) After Renal Transplantation: Focus on HLA Antigens
Authors: Strandhave Charlotte , Jørgensen Kaj Anker , Bendix Knud , Jespersen Bente , Pedersen Robert Schou , Søndergaard Esben , Mortensen Leif Spange , d'Amore Francesco 
Published: October 2019

Abstract
Abstract 5074

Background:
PTLD is a lymphoid proliferation that develops as a consequence of immunosuppression. It represents monoclonal B-cell, or rarely T-cell, proliferations, occurring in a setting of decreased T-cell immune surveillance. It has been shown that HLA-B mismatching is associated with increased risk of skin cancer in recipients of renal transplants. An association between skin cancer related to human papillomavirus and HLA-A11 has also been established in this group of patients. Bakker et al has shown that HLA-B mismatching is a risk marker of PTLD. More specifically, Subklewe et al found that HLA-B18 and HLA-B21 were associated with increased risk of PTLD, whereas mismatch at HLA-A03 and HLA-DR7 level reduced the risk of PTLD. We therefore hypothesized that mismatch of certain HLA alleles may be risk predictors of PTLD after renal transplantation.

Methods:
According to the national renal transplantation database of the Danish Society of Nephrology, 872 renal transplantations in 793 patients were performed at Aarhus University Hospital between 1990 and 2005. A total of 11 cases of PTLD were retrospectively identified through the National Danish Pathology database and individually reviewed by an experienced hematopathologist (KB). PTLD patients were investigated according to transplantation procedure, clinicopathological patient characteristics, type of lymphoma, outcome and HLA haplotype of both donor and recipient.

Results:
Univariate Cox regression analysis showed no positive correlation between risk of PTLD and number of HLA-B mismatches, or with HLA-A or HLA-DR mismatches. Conversely, we found a decreased risk with one/two HLA-B mismatches compared to no mismatches (p<0.01). With regard to specific alleles, HLA-B37 showed a trend towards an association with PTLD (OR = 8.62; 95% CI 1.70–43.6; P<0.04), whereas the same association was significantly stronger for HLA-DR6 (OR= 30.7; 95% CI 4.97–189.8; p<0.005). Unlike earlier reports, no association with HLA-B18 and HLA-B21 mismatches was observed.

Conclusions:
Our data suggest not only that the risk of developing PTLD is unaffected by an increasing number of HLA-B mismatches, but that a low number of such mismatches may even protect against PTLD developement. In our analysis, we found a moderate correlation between PTLD and HLA-B37, and a stronger one with HLA-DR6. The latter observation has never been previously reported. Further analyses with larger cohorts of renal transplant patients are needed to clarify the role of HLA antigens as risk markers for PTLD in order to establish whether a pre-emptive PTLD monitoring of renal transplant patients expressing certain haplotypes/haplotype mismatches is justified.

Disclosures:
No relevant conflicts of interest to declare.
Demylinating Peripheral Neuropathy and Lymphoplasmacytic Lymphoma
Authors: Huff Carol Ann , Chaudhry Vinay , Sumner Charlotte , Cornblath David 
Published: October 2019

Abstract
Abstract 5090
Lymphoplasmacytic lymphoma (LPL) is a neoplasm of small B lymphocytes, plasmacytoid lymphocytes, and plasma cells, which does not fulfill criteria for any of the other small B-cell lymphoid neoplasms (WHO 2008). Neuropathy has been described in association with Waldenstrom's macroglobulinemia, but less so with LPL. We present 7 cases of neuropathy and LPL to highlight the variable presentations. 1) A 56 year old man developed sensory ataxia with an IgM kappa non-MAG paraprotein. CSF protein was 97. Stabilized on MMF, he slowly worsened. Plasma exchange (PE) was given with improvement. Bone marrow (BM) 4 years into his course revealed LPL. Rituximab was given, and his PE reduced. 2) A 49 year old woman developed progressive weakness with rapid decline in January 2010. NCS showed demyelinating polyneuropathy, and CSF protein was 179. An IgM kappa non-MAG paraprotein was found. BM was normal. PE was given with improvement but later prednisone, IVIg and rituximab twice did not help. Repeat BM revealed 2% clonal CD20+ CD5negCD10neg B cells by flow cytometry. PE was given with modest improvement. Cyclophosphamide 1 gm/m2 monthly was given with improvement. 3) A 53 year old man noted imbalance and distal weakness. NCS showed absent SAPs and prolonged distal and F wave latencies. An anti-MAG positive, IgM kappa paraprotein was found. In 2002 BM was normal. He received rituximab weekly × 4 doses. 7 years later, he developed anemia and worsening neuropathy. Repeat BM showed 0.5% CD20+CD5negCD10neg kappa-restricted B cells by flow cytometry and weekly rituximab was reinitiated. 4) A 62 year old man developed weakness and areflexia. NCS showed asymmetric demyelinating polyneuropathy. Biclonal gammopathy of IgM kappa and IgG kappa was found. BM showed LPL by histopathology. Prednisone was given with improvement. Later two courses of weekly rituximab were given. 5) A 55 year old woman developed asymmetric weakness. NCS showed asymmetric demyelinating polyneuropathy. MRI showed enlargement, abnormal signal intensity, and abnormal enhancement of bilateral radial, median, and ulnar nerves. She was found to have an IgG kappa paraprotein and LPL on BM biopsy. She was treated with rituximab, cyclophosphamide, fludarabine, and PE. In each case, the primary feature driving the need for therapy was the neuropathy and not the underlying hematologic process. Further, worsening neuropathy in 3 cases led to repeat bone marrow biopsies revealing a clonal B cell process and a diagnosis of lymphoplasmacytic lymphoma. Thus, in the presence of an IgM monoclonal gammopathy and peripheral neuropathy, we suggest bone marrow examination for LPL and then consideration of therapy directed toward the abnormal B cell clone.

Disclosures:
No relevant conflicts of interest to declare.
REFRACTORY Blastic Extramedullary Plasmacytoma
Authors: Trainor Sebastian , O'Briain D. S , Gillham Charles , O'Mahony Deirdre 
Published: October 2019

Abstract
Abstract 5102
Tumour classification defines clinically distinctive, non-overlapping disease entities that serve the basis for future investigation and therapeutic management. The World Health Organization committee for classification of haematological malignancies is truly one of the first worldwide group to provide a consensus approach encompassing morphology, immunophenotyping, genetic and clinical features. However, there are limitations. Not all diseases fit into specific categories. Attention to unique clinical presentations facilitates our continued education. We report a blastic variant of an extramedullary plasmacytoma.
A fit 61 year old Caucasian man presented with a progressive neck and right upper limb (RUL) pain. No other relevant past medical or family history. Examination revealed a sensory neuropathy involving the 7th cervical dermatome. MRI cervical spine revealed a 5cm right paravertebral mass extending from C5-T1, surrounding the right vertebral artery and the roots and trunks of the right brachial plexus. It extended into the right neural foramina at the C5-C6, C6-C7 and C7-T1 levels with more minimal invasion at the C4-C5 level. Over a two week period he complained of increasing RUL pain, a right Horner's syndrome and weakness of the small muscles of his hand. An excision biopsy of the mass was performed and staging investigations were completed including CT body, lumbar puncture, bone marrow aspirate/biopsy, serum and urine protein electrophoresis. A PET/CT showed the right sided paraspinal nodal mass with low to moderate metabolic activity.
A diffuse, monotonous population of medium size cells with average nuclear: cytoplasm ratios, blastic chromatin, round nuclei and smooth contours surrounding a relatively unremarkable reactive lymph node. Mitoses are readily apparent, along with 'starry sky' appearance imparted by numerous tangible-body macrophages within the infiltrate. An extensive immunohistochemical panel were performed. The cells of interest express CD45, Cd38, vs38, CD138, MUM1, CD4, CD15, p53, weak CD19 and lambda light chain. The proliferation rate by Ki-67 is high approximately 60%. The overall phenotype was consistent with plasma cell differentiation but the mitotic rate and morphological rate does not fit well.
An initial response to definitive radiotherapy (40Gy/20fr) was swiftly followed 6 weeks later with a profound C5 radiculopathy. MRI imaging confirmed an extra-axial lesion, lying partially within the radiation port. The patient is now receiving salvage chemotherapy.
The behaviour of this lesion both under the microscope at the bench and the bedside is at odds with that predicated for a plasmacytoma, highlighting the critical importance of interplay between different medical disciplines. While blastic variants have been described for many haematological malignancies, it has not been previously reported in this situation.

Disclosures:
No relevant conflicts of interest to declare.
Sideroblastic Anemias Associated with Marked Thrombocytosis, the Role of JAK2 (V616F) Mutation (exon 6 and 12)
Authors: Corinaldesi Giorgio 
Published: October 2019

Abstract
Abstract 5135
The refractory anemia with ringed sideroblasts (RARS) and multilineage dysplasia is often associated with marked thrombocytosis; the research of JAK2 (V617F) mutant alleles was positive, JAK2 mutation is present in patients with polycythaemia vera (70%-95%), essential throbocythemia (32%-58%), CIMF (36%-50%), resulting in a valine to phenylalanine substitution at position 617; the mutation increases the kinase activity of JAK2 and the auto-phosphorylation and hyperactivation of EPOR and TPOR these two causing eritroid cells hyperplasia, the increase of dysgranulocytopoiesis with small hypolobulated dysplastic form and megakaryocytopoiesis with cluster of giant cells and enhanced risk for thrombosis greater than 30% or recurrent thrombosis greater than 20%. Dysgranulocytopoiesis features includes hypogranulation of myeloid cells, pseudo Pelger form, ringed sideroblastosis, thrombocytosis (>600.000/nL) with refractory cytopenia, and signficantly higher levels of PF4.
We have studied 8 patients with RARS–T, and we have found that JAK2 mutation is present in 5 out of 8 patients; these patients had a significantly higher white cells count, an increase of the tyrosin-kinase 2, and an enhanced activation of downstream transcription factors such as STAT-3 and STAT-5 A/B signalling cytokines that induce FOXP3 up regulation in activated CD4+, CD25+ regulatory T cells. Several defects of aggregation are present and deficiency of ATIII, PC, PS, splenomegaly were associated with a mild bleeding tendency.

Disclosures:
No relevant conflicts of interest to declare.
Safe and Efficient Chelation by Deferasirox In Thalassemia Major Patients with Low Liver and Cardiac Iron Concentrations
Authors: Grosse Regine , Janka Gritta , Jarisch Andrea , Nielsen Peter , Yamamura Jin , Fischer Roland 
Published: October 2019

Abstract
Abstract 5168
Chelation treatment of iron overload from chronic blood (RBC) transfusion is still a challenge to both, patients and medical caretakers. Different treatment regimes have been recommended so far, especially for chronically transfused patients with low or even normal liver iron concentration. We report the results from 16 regularly transfused patients with thalassemia major (TM) who were on iron chelation treatment under normal to mild liver iron concentration (LIC). All patients received deferoxamine (DFO) treatment before they changed to deferasirox (DSX) treatment.
16 TM patients (mean age 13.6 y) were treated with DSX (median dose 18 mg/kg/d, range: 7 – 33 mg/kg/d) for 6 to 71 months. Liver iron measurements by biomagnetic susceptometry (BLS) and/or MRI-R2 as well as cardiac MRI-R2* were performed in intervals of 6 to 12 months. The median LIC was 782 μ g/g-liver wet weight (range: 460 μ g – 1122 μ g). Median RBC transfusion rate was 8500 ml/y, equivalent to about 2 erythrocyte concentrates per 3 weeks or a daily iron influx of 16.2 mg/d. For each measurement interval, the ratio of daily iron influx and DSX dose rate was calculated. This represents the equilibrium molar efficacy for iron balance.
In all 16 TM patients no severe side effects were observed and creatinine was in the normal range of < 0.9 mg/d throughout the treatment with DSX. From baseline DFO treatment interval to the endpoint of DSX treatment, liver iron decreased by 124 – 4689 μ g/g-liver (conversion factor of 6 for mg/g-dry-wgt), while serum ferritin decreased by -596 to 8283 μ g/l. For all measurement intervals, molar chelation efficacies between 18 % and 56 % were calculated at equilibrium with a median efficacy of 31 % (interquartile range = 16 %). This agrees with molar efficacies of DSX reported earlier, but for relatively higher LIC and chelation doses (Blood 2005; 106(11):#2690 and Blood 2007; 110(11):#2776). The cardiac R2* (median R2* = 38 s-1) was either below the normal threshold of 50 s-1 (T2* > 20 ms) or decreased by about 24 %/y under DSX treatment. In these few patients at low LIC, this was even higher than recently reported.

Conclusion:
Even in patients with normal to mild LIC iron chelation treatment with DSX is safe, does not result in increased creatinine levels or severe side effects and is as efficient as in patients with higher LIC.

Disclosures:
No relevant conflicts of interest to declare.
Upregulation of Von Willebrand Factor, Von Wilelbrand Factor Propeptide, and ADMATS-13 In End-Stage Renal Disease
Authors: Fareed Jawed , Litinas Evangelos , Hoppensteadt Debra , Thethi Indermohan , Bansal Vinod 
Published: October 2019

Abstract
Abstract 5189
End-Stage Renal Disease (ESRD) is a complex syndrome in which systemic vascular pathophysiologic changes contribute to adverse cardiovascular and cerebrovascular manifestations. Cardiovascular disease alone is present in over 60% of patients with ESRD and contributes heavily to mortality among this population. Von Willebrand Factor (vWF) plays a well known role in platelet aggregation and has been shown to be upregulated in many thromboembolic conditions. However in many conditions, the role of von Willebrand Factor Propeptide (vWFpp), a peptide cleaved prior to assembly of active vWF multimers, and ADAMTS-13, the enzyme responsible for disassembly and deactivation of vWF multimers, have not been examined. The purpose of this study is to better characterize the relationship among vWF, vWFpp, and ADAMTS-13 as it relates to ESRD. Plasma samples from 51 patients with ESRD were collected prior to maintenance hemodialysis. A group of 50 normal individuals, both male and female, was included as control. Concentrations of vWF and vWFpp were quantified using the GTI® vWF & Propeptide Assay. A separate assay was used to measure ADAMTS-13 in these samples (GTI®). This data as well as the ratio of vWF:vWFpp were analyzed using the Mann-Whitney U test (two-tailed with Gaussian approximation). Compared to the controls, there was an upregulation of all three analytes in patients with ESRD. Levels of vWF were increased 1.3 fold, (mean 128 ± 69 U/dL, range 9.2 to 308) compared to control (mean 101 ± 60, range 22 to 332). Similarly, there was a 1.6 fold increase in both vWFpp (mean 148 ± 92, range 8.0 to 361) compared to (mean 92 ± 23, range 60 to 163) and ADAMTS-13 (mean 131 ± 27, range 67 to 150) compared to (mean 84 ± 22, range 36 to 128). However, the ratio of vWFpp:vWF (mean 1.2 ± 0.6, range 0.4 to 3.3) was unchanged compared to control (mean 1.2 ± 0.7, range 0.4 to 3.6). This study shows a previously uncharacterized increase in vWFpp and further validates the upregulation of vWF in ESRD. The normal vWFpp:vWF ratio implies an increased production in vWF in response to endothelial damage without any apparent alteration in vWF degradation or clearance. The proportional increase in ADAMTS-13 activity suggests that the increased vWF is being cleaved into inactive monomers. However, further studies are required to assess the proportion of vWF in each mulitmeric form and better understand the exact interaction among these components in ESRD.

Disclosures:
No relevant conflicts of interest to declare.