bluuebunny/crossref_metadata_2025 huggingface dataset:
Retrospective Analysis of Patients with Refractory Cytopenia with Unilineage Dysplasia.
Authors: Wang Yuchun , Du Xin , Geng Suxia
Published: October 2019

Abstract 4847

Background

Myelodysplastic syndromes (MDS) are a group of clonal heterogeneous bone marrow stem cell disorders characterized by dysplastic hypercellular marrows with peripheral cytopenias. Accurate diagnosis and classification are essential for subgroup identification and prognostic assessment of patients with MDS. Classification systems such as the World Health Organization (WHO) classification are widely used but do not always provide sufficient prognostic information. So WHO improved the classification systems last year(2008). The major change was that refractory anemia (RA) was substituted by refractory cytopenia with unilineage dysplasia (RCUD). The aim of this study was to apply the new WHO classification to re-evaluate MDS with RA.

Methods

MDS patients with RA diagnosed between 2000 and 2008 were retrospectively reclassified with WHO criteria (2008).

Results

According to the new WHO classification, RCUD is intended to encompass those myelodysplastic syndromes (MDS) which present with a refractory cytopenia with unilineage dysplasia and includes refractory anemia (RA), refractory neutropenia (RN) and refractory thrombocytopenia (RT), so in 34 cases diagnosed as RA, 12 cases (12/34,35%) still pertained to RA, 19 cases (56% ) to RN and 3 (9%) cases to RT. IPSS showed 94% of RCUD cases categorized as low or intermediate-I risk. The median survival of patients with RCUD was 84 months.

Conclusions

RA is the main subtypes of RCUD. Understanding the clinical features of RCUD accurately is helpful to determine the right subtype of RCUD. The new WHO classification system was improved to provide better diagnostic criteria.

Disclosures

No relevant conflicts of interest to declare.
Blood Product Use in Recently Diagnosed Persons with Myelodysplastic Syndrome: A Population Study.
Authors: Ramsey Scott D , McDermott Cara L , Beck Sara J , Lopez Jose A. , Dinwiddie Stephen C , McCune Jeannine S
Published: October 2019

Abstract 4849

Many patients with myelodysplastic syndrome (MDS) experience cytopenias that require blood product support. The extent to which MDS patients utilize blood products following diagnosis is unknown. The objective of this study was to characterize the use of blood products among recently diagnosed MDS patients in western Washington State. Records from the NCI's Surveillance, Epidemiology, and End

Results

(SEER) cancer registry for western Washington State were searched for patients diagnosed with MDS between 2001 and 2007. These records were linked to Puget Sound Blood Center (PSBC) database records. The PBSC is the major supplier of blood products for the Washington SEER region. SEER identified a total of 781 newly diagnosed patients during 2001-2007. The average age was 72.84, 76% were over age 65 and 55% were over age 75. Fifty-eight percent were male and 88% were white race. The most common MDS subtypes included refractory anemia (24%) and refractory anemia with excess blasts (21%); 33% had no specified subtype. Three hundred seventy-six patients (48%) received at least one blood product within 12 months of diagnosis; packed red blood cells (RBCs) (n=361 persons) and platelets (n=222 persons) were most commonly transfused. Among those receiving at least one transfusion of RBCs or one transfusion of platelets respectively, patients received an average of 15.40 units of RBCs and 15.37 units of platelets over 12 months from diagnosis; of these patients, the highest quartile used an average of 39.84 RBCs and 33.81 platelets per person. The proportion of MDS patients receiving any RBCs within 12 months of diagnosis increased from 24% in 2001 to 54% in 2007. Platelet use within 12 months of diagnosis increased from 12% of patients in 2001 to 39% in 2007. Among those receiving at least one platelet transfusion or at least one red blood cell transfusion within 12 months of diagnosis the number of products transfused increased over time, from an average of 8.00 platelet units (SD 5.77) and 8.85 units of RBCs (SD 11.21) in 2001 to 14.12 platelet units (SD 20.31) and 15.98 units RBCs (SD 19.35) in 2007 (p<0.0001, p<0.0001, respectively). Approximately half of newly diagnosed MDS patients receive at least one blood product in the first 12 months following diagnosis. Blood product use has increased substantially from 2001 to 2007, in terms of both the proportion of patients receiving them and the number of transfusions per person. Further study is needed to determine the factors leading to more aggressive use of blood products in these patients.

Disclosures

No relevant conflicts of interest to declare.
Using Multiparametric Flow Cytometry to Analysis the Immunophenotypic Abnormalities of Bone Marrow Cells in Patients with MDS-RAEB.
Authors: Huang Jing , Du Xin , Geng Suxia , Zhou Maohua , Weng Jianyu , Wu Suijing , Guo Rong , Lu Zesheng , She Miaorong
Published: October 2019

Abstract 4856

Objective

The multiparametric flow cytometry is becoming a very useful tool of the diagnosis and prognostication for patients with Myelodysplastic Syndrome(MDS). This study was aimed at using multiparametric flow cytometry to explore the immunophenotypic abnormalities of bone marrow cells from patients with RAEB.

Methods

We collected BM samples from 12 MDS-RAEB patients (6 male, 6 female, Median Age 67.5) and 20 non-MDS patients (11 male, 9 female, median age 32.5, 7 AA, 5 PNH, 3 IDA, 1 ALL, 2 CML, 2 MM). The multiparametric flow cytometric analysis was performed using an extensive panel of monoclonal antibodies. We used the conventional and secondary gating strategies to analysis the BM cells compartments such as the percents of blast cells and the expression of lineage and maturation-associated antigens of BM hemopoietic cells quantified.

Results

Compared with the non-MDS group, the proportion of blast cells increased significantly in the MDS-RAEB group (P=0.001), but the percentages of nucleated erythrocyte, lymphocyte, monocyte and granulocyte were no significant difference (P=0.954, P=0.893, P=0.730 and P=0.182). As the percentage of blasts cells increasing, the survival time became shorter (13 ± 6 vs 35 ± 15 months; P=0.02). The expressions of haemopoietic stem/progenitor cell surface marker CD34+ and T lymphocyte surface marker CD7+ on blast cells were much higher by secondary gating method than non-MDS group (P=0.009, P=0.002, respectively), while no significant difference of the expression of CD56 (P=0.375). The expressions of CD7+ and CD56+ on lymphocyte were no significant difference between the two groups (P=0.195, P=0.369, respectively), however the expression of CD19+ may be different (P=0.039). The expressions of CD33+ and CD13+ on granulocyte were no significant difference between the two groups (P=0.289, P=0.744, respectively). However, the expression levels of CD15+CD11b+, CD15+CD11b-, CD10+, HLA-DR, CD56+ in the MDS-RAEB group were significantly higher than those in the non-MDS group, specially, the levels of CD10+, HLA-DR and CD56+ were much higher (P=0.016, P=0.011, P=0.005, P=0.005 and P=0.005, respectively) and these patients showed a shorter median overall survival (15 ± 5 vs 36 ± 10 months; p = 0.03).

Conclusions

The percentage of blast cells increased in MDS-RAEB patients and the expressions of CD34+, CD7+ on blast cells and the expressions of CD10+, HLA-DR and CD56+ on granulocyte is higher than non-MDS group. It will be necessary to increase the number of cases (MDS-RAEB) to confirm our findings. Using multiparametric flow cytometry can find the immunophenotypic abnormalities more sensitively, accurately and objectively, and this new approach could provide much more useful information in the diagnosis and prognosis of MDS-RAEB patients.

Disclosures

No relevant conflicts of interest to declare.
The Epitope Targeted by Apoptosis-Inducing ICAM-1 Antibody B11 Is Highly Expressed in Multiple Myeloma.
Authors: Hansson Markus , Veitonmäki Niina , Lindblom Anders , Frendéus Björn
Published: October 2019

Abstract 4897

Complex adhesive and non-cognate interactions participate in multiple myeloma disease progression, resistance to apoptosis, and development of drug resistance. In spite of significant recent attempts to develop new drug classes targeting both myeloma and its microenvironment, multiple myeloma remains an incurable disease warranting development of more effective therapies. Applying novel combined target and drug discovery methodology we isolated a human tumor cell apoptosis-inducing antibody (IgG B11) targeting ICAM-1, as previously described. ICAM-1 is a cell adhesion molecule strongly implicated in myeloma pathophysiology, both regarding bone marrow stromal cell mediated disease progression and cell adhesion mediated drug resistance. We here characterize B11 epitope expression by multicolor FACS analysis in 25 patients investigated for multiple myeloma referred to Department of Hematology, Lund University Hospital, Lund, Sweden and 5 healthy controls. The B11 epitope was highly expressed in plasma cells in 5 of 5 patients with myeloma and in 1 of 1 patient with AL (light chain) amyloidosis. A comprehensive preclinical program assessing IgG B11 anti-myeloma activity and evaluating IgG B11 safety has been conducted. Based on these studies, and having received an investigational new drug (IND) approval from the U.S. Food and Drug Administration (FDA), clinical phase I trials with IgG B11 will soon commence.

Disclosures

Veitonmäki: BioInvent International: Employment. Lindblom:BioInvent International: Employment, Equity Ownership. Frendéus:BioInvent International AB: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties.
Fluorescent in Situ Hybridization Analysis at Bone Marrow Biopsy Section in Multiple Myeloma.
Authors: Hae Cho Eun , Lee Sang-Mi , Eom Hyeon-Seok , Kim In-Suk , Lee Gyeong-Won , Kong Sun-Young
Published: October 2019

Abstract 4898

Introduction

The technique of fluorescence immunophenotyping and interphase cytogenetics as a tool for the investigation of neoplasms has recently been introduced to detect molecular cytogenetic abnormalities in plasma cell myeloma of bone marrow (BM) aspirate. However, in case of sub-optimal BM aspirate or the focal distribution of myeloma in the BM, the plasma cells are significantly lower in the BM aspirate than those of biopsy section. Therefore, we have developed a sensitive fluorescence in situ hybridization (FISH) technique which is combined with immunochemistry and is applicable to BM biopsy section for molecular cytogenetic study of plasma cell neoplasms.

Patients and Methods

Conventional cytogenetic analysis and FISH results of BM samples of 35 multiple myeloma (MM) patients at the time of diagnosis have been evaluated. The probe for IgH rearrangement has been used for hybridization with myeloma cells coupled with CD138 immunostain at BM biopsy section.

Results

Nineteen patients (54.3%) had abnormal FISH IgH results in biopsy section, whereas seven (20%) cases had abnormal findings in BM aspirate. FISH IgH analysis at biopsy section revealed various signal patterns and proportions (range 6-87%) of cells with atypical signals out of CD138 positive cells. Among five cases with <10% of plasma cells at BM aspirate, four (80%) had abnormal FISH results at biopsy section, whereas one (20%) had abnormal signals at aspirate. There is no correlation between the proportions of cells with atypical signal corrected by the plasma cell count at BM aspirate and the proportions of cells with atypical signal at biopsy section.

Conclusions

FISH analysis combined with immunostain which is applied at biopsy section is a highly sensitive and convenient technique to detect and quantify monoclonal plasma cells. It could be used for molecular cytogenetic study in plasma cell neoplasms even though there are less than 10% of plasma cells at BM aspirate and the monitoring of residual disease.

Disclosures

Kong: National cancer center, Korea: Research Funding.
The Prognostic Impact of Fluorescent-in Situ Hybridization (FISH) and Conventional Karyotying in Korean Multiple Myeloma Patients: A Retrospective Multicenter Study.
Authors: Kim Min Jae , Oh Suk Joong , Min Chang Ki , Park Chong Won , Yoon Hwi-Joong , Do Young Rok , Kim Byung Soo , Kim Yang Soo , Eom Hyeon Seok , Ryoo Hun-Mo , Kim Sung Hyun , Shin Ho Jin , Bang Soo-Mee , Kim Seok Jin , Yoon Sung-Soo , Lee Dong Soon , Suh Cheolwon , Kim Jin Seok , Won Jong Ho , Park Seongkyu , Kim Min Kyoung , Shim Hyeok , Kang Hye Jin , Kim Chul Soo , Lee Je-Jung , Kwak Jae-Yong , Jo Deog Yeon , Lee Jae Hoon ,   Korean Multiple Myeloma Working Party
Published: October 2019

Abstract 4902

Introduction

Cytogenetics and fluorescent-in situ hybridization (FISH) are important outcome predictors in multiple myeloma (MM). There were only few small studies that investigated prognostic implication of FISH and/or conventional karyotyping in Korean MM patients. We investigated the incidences and prognostic significances of chromosomal abnormalities detected by FISH and/or conventional karyotyping among Korean MM patients.

Patients and Methods

We collected data of patients from Korean Myeloma Registry and performed retrospective analysis. We compared the survival of patients with chromosomal abnormalities and other clinical findings.

Results

From 2000 to 2009, total of 801 newly diagnosed myeloma patients were enrolled in this study. Median age of patients was 62 years. Median overall survival was 82 months, and median follow up of time was 92 months. Among the patients who had conventional karyotype analysis, 17.1% were complex karyotype, followed by del13q (7.4%), hyperdiploidy (7.6%), hypodiploidy (3.0%), and t(11;14) (3.9%). Among the patients who had FISH analysis, 22.8% were del 13q, followed by t(11;14) (18.2%), t(4;14) (13.7%), del17p (11.8%) and t(14;16) (5.9%). Univariate analyses revealed that complex karyotype (p<0.01), hypodiploidy (p=0.01), del13q (p<0.01) by conventional karyotyping, and t(4;14) (p=0.04) by FISH negatively impacted the overall survival. Other genomic aberrations did not affect the overall survival. Clinical parameters that impact on overall survival were percentage of plasma cells in bone marrow, serum beta2-microglobulin, creatinine, low hemoglobin, and low albumin levels. On multivariate analysis, percentage of plasma cells in bone marrow (p<0.01) and low serum albumin level (p<0.01) were independent risk factors for overall survival.

Conclusions

Our results showed that complex karyotype, hypodiploidy, t(4;14), and del13q by FISH and/or conventional karyotyping were negative prognostic factors for overall survival in univariate analyses. On multivariate analysis, low serum albumin level and percentage of plasma cells in bone marrow were independent risk factors for overall survival. In future, prospective trial with laboratory standardization is warranted for more reliable results from FISH and/or conventional karyotyping in MM patients.

Disclosures

Suh: Janssen Korea: Research Funding.
The Presence of Multinuceated Plasma Cells in Bone Marrow Aspirates Has No Clinical Significance.
Authors: Shumate Mark , Whitehead Cecille
Published: October 2019

Abstract 4904

There is no published literature on the clinical significance of multinucleated plasma cells in bone marrow aspirates. The few references in the literature that mention multinucleated plasma cells imply that their presence is pathologic. We decided to investigate the clinical significance of these cells. All bone marrow aspirates done at the Atlanta VAMC from 1/1/99 until 8/1/99 were examined by a skilled hematopathology technician for 2 minutes. The presence of multinucleated plasma cells were recorded if they were identified. We then determined clinical characteristics of the patients and compared the characteristics of those with multinucleated plasma cells and those without. RESULTS. There were a total of 61 aspirates for review. 34 of these had identified multinucleated plasma cells MNPCs. The average age of the group with MNPC was 58.7 years (SD 15.4) and the group without MNPC was 61.6 (SD 12.4). 11 of the 27 patients without MNPC were alive at 10 years (41%) while 14 of the 34 patients with MNPC were alive at 10 years (also 41%). Among the group with MNPC who were still alive at 10 years the average change in serum creatinine over the 10 year period was .23 mg/dl. Among the group without MNPCs the average change in serum creatinine over the 10 year period was .26 mg/dl. Finally, 12 of the 34 patients (35%)with MNPCs were found to have a clonal lymphoid disorder sometime over the 10 year period after their aspirate, while 10 of the 27 patients (37%, a nonsignificant difference)without MNPCs were found to have a clonal lymphoid disorder.

CONCLUSION

MNPC have no impact on survival or changes in renal function over a 10 year period. Furthermore, their incidence is not impacted by age. Finally, they do not predict the occurrence of clonal lymphoid disorders. We conclude that MNPC are likely a normal variant of plasma cells

Disclosures

No relevant conflicts of interest to declare.
Inhibition of Constitutively Activated JAK/STAT3 Pathway in Multiple Myeloma Cells Leads to Induction of Protective Autophagy.
Authors: Ma Huihui , Lu Caisheng , Ziegler Judith , Feng Rentian , Lentzsch Suzanne , Mapara Markus Y.
Published: October 2019

Abstract 4914

Constitutive activation of Janus Kinase-2 (JAK-2)/signal transducer and activator of transcription-3 (STAT3) has been implicated to play a crucial role in the pathogenesis of Multiple Myeloma (MM). Therefore, targeted inhibition of STAT3 is an attractive therapy for MM patients. JSI-124 is a natural product isolated from various plant families and has been recently described as a specific inhibitor of JAK2/STAT3. It has been shown to exert strong apoptosis-inducing effects against STAT3+ tumor cell lines in vitro and in vivo. However, there is little information available about the anti-tumor effects of JSI-124 on myeloma cells. We therefore tested the role of JSI-124 as a potential novel anti-MM compound and were able to determine that JSI-124 has potent anti-myeloma properties against human MM cell lines. Our results revealed that JSI-124 could inhibit both constitutively expressed and IL-6 induced phosphorylation of Tyr705 STAT3 as well as other important cell signal pathways that regulate cell proliferation in MM cell lines. However, the anti-myeloma effects were not restricted to STAT3+ MM cells. In STAT3+ cells JSI-124 induced cell death, which was predominantly caspase dependent. In contrast, JSI-124 induced both caspase-dependent and caspase-independent cell death in STAT3-MM cells. Furthermore, JSI-124 induced DNA damage only in STAT3- MM cells. Surprisingly, STAT3- cell lines were more sensitive to JSI-124-induced growth inhibition and induction of cell death than STAT3+ MM cell lines. Further analysis revealed that JSI-124 led to induction of autophagy only in STAT3+ MM cells as determined by upregulation of LC3B. A dramatic increase of JSI-124-dependent apoptosis was observed when the autophagy pathway was blocked by Chloroquine suggesting that STAT3-inhibition in STAT3+ MM cells leads to protective autophagy, which can be overcome by Chlorquine treatment. Interestingly, inhibition of autophagy by Chloroquine or 3-mA in STAT3+ cell lines U266 or ARH 77 resulted in AIF release and well as caspase-independent cell death. The results in this study suggest that JSI-124 could be an effective anti-myeloma agent regardless of STAT3 activation status and that combination with Chloroquine may enhance its anti-MM effect.

Disclosures

Lentzsch: celgene: Consultancy, Honoraria, Research Funding; cephalon: Consultancy, Research Funding. Mapara:Resolvyx: Consultancy, Honoraria, Research Funding; Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees; GENTIUM: STOCK OWNERSHIP.
CC102528: A Novel Histone Deacetylase Inhibitor in the Hydroxamate Family Demonstrates Potent Anti-Myeloma Activity.
Authors: Li Zhi-Wei , Leung Crystal , Hu Mengyin , Xiang Jinbao , Jiang Chao , Steinberg Jeffrey A , Shen Jing , Li Mingjie , Wang Cathy S , Sanchez Eric , Bonavida Benjamin , Chen Haiming , Bai Xu , Berenson James R.
Published: October 2019

Abstract 4927

Despite advances in the treatment of multiple myeloma (MM), the disease remains incurable. Thus, there is a need for the development of new drugs to improve the outcome for patients with this common B-cell malignancy. Histone acetylation, which is controlled by the balanced activities between histone acetyltransferase (HAT) and histone deacetylase (HDAC), is a major epigenetic modification that may contribute to tumorigenesis. Through inhibition of HDAC activity, HDAC inhibitors (HDACis) increase acetylation level of histones as well as other tumor suppressor gene products; and, therefore, are potential anti-cancer agents. Based on the structures, currently available HDAC inhibitors can be divided into four groups, including hydroxamates, cyclic peptides, aliphatic acids, and benzamides. We have screened a library of combined compounds and identified two potential novel HDACis (CC102528 and CC102598) that demonstrate potent anti-MM effects in vitro. Both compounds are hydroxamate derivatives with IC50 below 5 μM in the MM cell line RPMI8226 as determined with the MTS assay. These compounds induce apoptotic cell death and inhibit HDAC activity in MM cells as determined with Annexin V staining followed by flow cytometric analysis and acetylation status of histones, respectively. Interestingly, only CC102528, but not CC102598, caused death of nearly all MM cells when used at 10 μM or 20 μM. These results suggest that CC102528 blocks HDACs more efficiently than CC102598, or CC102528 targets additional intracellular molecules that are also responsible for its greater anti-MM activity. These results suggest that CC102528 could be a potential novel agent for the treatment of MM. We are currently evaluating the anti-MM effects of this compound in combination with other currently available agents for the treatment of MM including bortezomib, melphalan, dexamethasone, and doxorubicin. We are also determining the effects of this drug alone and in these combinations on normal peripheral blood and bone marrow mononuclear cells. In addition, modifications of CC102528 are being made, and we will determine if these newer analogs improve upon the anti-MM effects of the parent compound. Updated data from these additional studies will be reported at the meeting.

Disclosures

No relevant conflicts of interest to declare.
Thalidomide-Dexamethasone as Induction Therapy Prior to Autologous Stem-Cell Transplantation in Patients with Newly Diagnosed Multiple Myeloma and Renal Failure.
Authors: Tosi Patrizia , Zamagni Elena , Tacchetti Paola , Ceccolini Michela , Perrone Giulia , Brioli Annamaria , Pantani Lucia , Petrucci Alessandro , Baccarani Michele , Cavo Michele
Published: October 2019

Abstract 4934

Multiple myeloma (MM) patients presenting with renal feature at disease onset should not be excluded from high-dose therapy programs; seeking novel effective and non-nephrotoxic induction regimens is thus mandatory in order to maximize the reduction of tumor burden prior to transplant.

From May 2002 to February 2008, 31 newly diagnosed MM patients (18 male, 13 female, median age 60 years) with symptomatic MM and renal failure, defined as creatinine clearance '50ml/min, were enrolled in a clinical trial aimed at evaluating the efficacy and the feasibility of a thalidomide-based regimen as induction therapy in preparation to autologous stem cell transplantation. Sixteen patients had a more severe renal impairment (creatinine clearance '30ml/min) and 7 of them were in chronic hemodyalisis. After informed consent, patients received four months of combined oral thalidomide (thal) (100mg/day for two weeks and 200mg/day thereafter) and dexamethasone (dex) (40mg/day on day 1-4, 9-11, 17-20/28 days on odd cycles and on day 1-4 on even cycles); peripheral blood stem cell collection was thus to be performed after priming with high-dose cyclophosphamide + G-CSF or G-CSF alone; a single or double autologous stem cell transplantation was then to follow, upon preparation with high-dose melphalan. After induction, a PR or better was obtained in 23 patients (74%), with 8 patients (26%) achieving a VGPR or better. No difference in response rate was observed in patients with a baseline creatinine clearance ≥30ml/min (86%) or < 30ml/min (62%). An improvement in renal function was more frequently observed in patients achieving ≥ PR (82% vs. 37% in patients obtaining < PR, p =0.04). Twenty-six patients underwent peripheral blood stem cell mobilization; in 17 of them (65%) the procedure was successful resulting in the collection of > 4 × 106 CD34+ cells/kg. Fifteen patients received a double autologous stem cell transplantation while a single transplant was performed in four patients. Overall, median event-free survival was 30 months, and median survival has not been reached, upon 32 months median follow-up. Toxicity profile of thal-dex was comparable to that observed in patients with a normal renal function. In conclusion, our data show that thal-dex can be safely administered in patients with newly diagnosed MM and renal failure. given the relationship between recovery of renal function and response to induction treatment, more intensive thal + bortezomib-including regimens could be potentially useful in order to rescue a higher number of patients.

Disclosures

Off Label Use: Thalidomide plus dexamethasone in newly diagnosed multiple myeloma.
Successful Bortezomib-Based Therapy in POEMS Syndrome.
Authors: Tang Xiaowen , Shi Xiaolan , Sun Aining , Qiu Huiying , Gu Bin , Zhou Huifen , Xue Shengli , Liu Yuejun , Ruan Changgeng , Depei Wu
Published: October 2019

Abstract 4966

POEMS syndrome is a rare multisystem disease characterized by polyneuropathy (P), organomegaly (O), endocrinopathy (E), serum M-protein (M), and skin changes (S). Owing to the fairly little refined mechanisms underlying the pathogenesis of POEMS syndrome, standard and general-accepted regimens have not been established to date. Recently, we successfully treated a POEMS syndrome patient who was unresponsive to conventional therapies by using bortezomib-based regimen. This 37-year-old patient represented a number of typical manifestations including: 1) paresthesia, 2) increased level of IgA » type of M protein, 3) elevated concentration of serum VEGF (vascular endothelial growth factor), 4) splenomegaly, gynaecomastia, limbs edema, hydropericardium, hydrothorax, and plethora. According to the latest Mayo Clinic criteria, the diagnosis of POEMS syndrome could thus be comfirmed. After several courses of classical regimens [VAD (Vincristine, doxorubicin, dexamethasone), CMP (cyclophosphamide, melphalan and prednisone) and AD (doxorubicin and dexamethasone)], the patient poorly responded with only slight improvement and failed to achieve remission. Following the patient's informed consent and Ethics Committee approval, a tentative VDD regimen was carried out. The details were as follows: Bortezomib, at a dose of 1.3-1.6 mg/m2 (initial cycle: 1.3 mg/m2 in the first week, 1.6 mg/m2/w in following three weeks; next three cycles: 1.6 mg/m2/w×4 weeks in each cycle); 40 mg of Liposomal doxorubicin on the fourth day of the first week; and 10 mg of dexamethasone during the initial 4 days of first cycle. Each course was at 21 days interval. Following four cycles of VDD, the patient acquired remarkable improvement (concerning neurological disease, skin changes, clonal plasmacytosis, and organomegaly) and finally achieved complete remission. To our knowledge, It should be the first time in the world that the bortezomib-based new strategy could be applied effectively against the POEMS syndrome. Further, we could speculate that the VDD regimen would be a potent candidate in the treatment of POEMS syndrome, at least in the conventional therapy-resistant condition.

Disclosures

No relevant conflicts of interest to declare.
Skin Malignancies Associated with HYDROXYUREA Use in MYELOPROLIFERATIVE DISORDERs and Sickle Cell Patients: Incidence and Significance.
Authors: Chiha Maguy , Younes Mohamad , Arnaout Karim , Hanbali Amr
Published: October 2019

Abstract 4969

BACKGROUND

Hydroxyurea (HU) is one of the mainstay agents used to treat myeloproliferative disorders as well as sickle cell anemia. There has been lately increasing reports of secondary skin malignancies in patients receiving Hydroxyurea therapy but the literature consists essentially of case reports. Current incidence of melanoma skin cancer in the general population in the United States is 15 per 100 000 person, and of non melanoma skin cancer is 230 per 100 000 lightly pigmented individuals and 3.4 per 100 000 darkly pigmented individuals.

METHODS

We reviewed 292 charts of patients treated with HU in our institution. 237 patients carried a diagnosis of myeloproliferative disorder, 14 patients were treated for sickle cell anemia and 41 patients were being treated with HU for HIV as part of a regimen to decrease viral load. Charts were reviewed looking for development of skin malignancies.

RESULTS

Among the patients with sickle cell anemia, the incidence of skin cancer was nil. Among the patients with HIV there were 2 cases of non melanoma skin cancer. Among patients with myeloproliferative disorders, there were 16 cases of skin cancer. The pathology was non-melanoma skin cancer. Subgroup analysis based on skin phenotype revealed that the incidence was higher than the general population in both dark and light-skinned individuals: the rate was 0.9434 per 100 among the dark skinned individuals, statistically significant when compared to the established rate of 0.0034 per 100 dark-skinned individual in the general population. Similarly among light-skinned individuals, the calculated rate was 12.0968 per 100-person, which is statistically significant compared to the rates in light-skinned individuals in the general population of 0.2300 per 100 person with a p-value of 0.001.

CONCLUSION

Our study showed a significantly higher incidence of non-melanoma skin cancer among patients treated with HU. While HU is well known to have cutaneous side effects in terms of hyperpigmentation, skin ulcers, scaling or skin atrophy, its implication in skin cancers had only been in the form of case reports. Our study thus highlights a true risk of skin malignancies with HU. It is worth noting though that there were only non-melanoma skin cancers, which are non-aggressive, localized and treatable. Thus this heightened incidence of skin cancer does not appear to bear a mortality or morbidity burden on patients treated with HU.

Disclosures

No relevant conflicts of interest to declare.
In Vitro Testing of Suppresion of T Regulatory Cells ( Treg) by Lenalidomide Is Correlated to Treatment Response of Lenalidomide in Patients with Primary Myelofibrosis ( PMF).
Authors: Wang Jen-Chin , Chen Chi , Rathnasabapathy Chentyl , Kafeel Muhammad I. , Singh Amrit , Sun Yiwu
Published: October 2019

Abstract 4987

Except allogenic bone marrow transplatation with either myeloblative or reduced intensity conditioning, there is no effective treatment for PMF. Age-related morbility and mortality factors limit this application. Anti-Jak2 treatment relieves splenomegaly but does not improve cytopenia. IMiDs on the other hand can improve anemia in up-to 20% of transfusion dependent anemic patients with PMF. In order to asses the underlying mechanism and to predict treatment responsiveness, in vitro suppression of Treg cells by lenalidomide correlated to clinical treatment response was performed. Six patients with transfusion dependent and ESD ( erythropoietin stimulating drugs) resistant PMF were studied. Mononuclear cells from blood in patients with PMF were cultured in the culture medium with FCS and Il-2 ( 100 IU/ml) in the presence of lenalidomide or DMSO for 6 days, the cells were then stained for Treg cells ( CD4+, CD 25 +,and FoxP3+,) and analyzed by flow cytometry using Treg Detection Kit from Miltenyi Biotec Inc (Auburn, CA). Treg cells were enumerated as percentage of selected CD4 + cells. The results showed that in the 4 patients who responded to lenalidomide treatment, Treg cells were suppressed by the in vitro testing by lenalidomide, while in the two patients who were clinically refractory to lenalidomide treatment, their Treg cells were not suppressed by in vitro lenalidomide treatment. These results suggest that in transfusion dependent PMF, Treg cells may play a role in the pathogenesis of anemia and that effectiveness of lenalidomide treatment may be partly related to its suppression of Treg cells. Further studies to recruit more patients and to explore the role of Treg cells in modulating erythroipoiesis in PMF using the erythroid methylcellulose culture systems are currently in progress

Disclosures

No relevant conflicts of interest to declare.
It is Different the Survival of Primary Extranodal Non Hodgkin Lymphoma?.
Authors: Giraldo Pilar , Franco-Garcia Esther , Alvarez Ramiro , Garcia-Carpintero Gloria , Martos Carmen
Published: October 2019

Abstract 5028

Introduction

There are few studies that evaluate the difference in incidence and survival of primary extranodal lymphomas (PEL) as compared to nodal lymphomas. In the Population Based Cancer Registry of Zaragoza (PCRZ) working since 1960, all incident cases of hematologic and non hematologic cancer are including. PCRZ is a data source for epidemiological studies.

Objectives

1. Review and reclassify cases of NHL diagnosed during the period 1992-2004. 2. Define the incidence of PEL in PCRZ during this period. 3. Analyze the survival of the PEL and compare it with that of nodal NHL.

Materials and methods

Based on the data PCRZ, we have reviewed and reclassified the patients with NHL according to REAL classification and the new WHO classification (2008), diagnosed during the period 1992-2004, to determine location and histology. The follow-up period of cases was completed by December 31, 2007 Data sources: medical records, histological reports and discharged hospital reports. Population at risk: 9,255,818 person-years. We have calculated crude incidence rates (IR) and standardized by age (SIR), using the European population as standard. For the calculation of survival and confidence intervals (95%) had used the Kaplan-Meier method and the log-rank test was used to compare survival curves.

Results

During the period of study a total of 4,570 primary hematological disorders were included in the PCRZ; 1,987 (43.4%) were NHL (IR: 19×105 person-years), 331 (16.6%) of them were classified as PEL, which represented a 2.7 SIR x105 person-years (male: 183 cases (55.2%), mean age 59.2 years, SIR: 3.1 ×105 person-years and women 148 cases (44.7%), mean age 66.8 years, SIR: 2,4 ×105 person-years. Only 10% of cases will be reclassified related to histology or location. The most common site was gastrointestinal tract (50.4%), skin (19.8%), glands (10.0%), oral cavity and pharynx (7.9%), lung (2.9%), CNS (2.4%), orbit (2.1%) and other locations (4.5%). Histological types: MALT 60.2%, BDLCNHL: 18.3%, FNHL: 4.7%, MCNHL: 3.2%, MZNHL: 6.5%, T-NHL: 7.1%. Median survival for PEL was 6.61 years (95% CI: 3.7-9.5) and 5.01 years for nodal lymphomas (95% CI: 4.1-5.9). The survival at 5 years was 53.5% and 50% respectively. There were no statistically significant differences between PEL group and the nodal NHL, according to the location or by gender. The differences in survival were associated with histological subtype of lymphoma. These results were similar to those in the data EUROCARE.

Conclusions

No differences in incidence in PEL and nodal NHL were observed according to gender and age. There were no statistically significant differences between the survival of the PEL and nodal NHL, survival is more influenced by histology than by location.

This work partially funded by the project HAEMACARE

Disclosures

No relevant conflicts of interest to declare.
The Value of D-Dimer in Patients with Increased C-Reactive Protein Suspected of Pulmonary Embolism.
Authors: Siemes Claire , Berendes Paul , van der Straaten Frans , Cleophas Ton , Levin Mark-David
Published: October 2019

Abstract 5056

OBJECTIVE

To investigate the relation between elevated levels of C-reactive protein (CRP) and D-dimer, and to study whether D-dimer levels can be interpreted in relation to elevated levels of CRP in the prediction of a pulmonary embolism in order to increase its specificity without decline in sensitivity.

METHODS

Between august 2004 and april 2007 (33 months) serum levels of C-reactive protein (mmol/L) and D-dimer (mmol/L) were cross-sectionally collected and pulmonary embolisms on CT-angiograms were scored within 48 hours. The study was devided into three parts. First, characteristics of excluded persons were studied. Second, the correlation between CRP and D-dimer level was considered in those with a defined (i.e. values with < and > symbols excluded) biomarker level. Finally, the effect of CRP level on the sensitivity of D-dimer for pulmonary embolisms was examined.

RESULTS

CRP and D-dimer levels were positively correlated ( r = 0.37; p < 0.001), and both were increased in persons with a pulmonary embolism (CRP: p = 0.02; D-dimer: p < 0.001). 14 % of variability in D-dimer level was explained by CRP level. Median D-dimer levels were increased in the pulmonary embolism (PE) group, however, the increase in D-dimer level by CRP quartile as was found in the non-PE was not seen in de PE-group. Adding the interaction term of CRP and D-dimer to the statistical model showed some influence on the area under the curve (AUC). Nevertheless, this was not significantly different from the model with only D-dimer levels. However, when stratified for CRP quartile, ROC-curves of the predictive effect of D-dimer on pulmonary embolisms showed a decrease in AUC by increment of CRP quartile.

CONCLUSION

CRP and D-dimer are positively correlated, and both predictive of PE. The predictive value of D-dimer for PE declines by increment of CRP, although this seems to be safely for a broader range of accompanied CRP levels.

Disclosures

No relevant conflicts of interest to declare.
RhoA Effector mDia1 Is Required for PI 3-Kinase-Dependent Actin Remodeling and Spreading by Thrombin in Platelets.
Authors: Chen Xiequn , Gao Guangxun , Wang Jishi
Published: October 2019

Abstract 5077

The RhoA effector mDia1 is involved in controlling the balance between filamentous and monomeric actin, but its role in modulating thrombin-induced actin remodeling and platelet spreading on fibrinogen matrices remains unclear. In this study, mDia1 was shown to translocate to the platelet cytoskeleton following thrombin stimulation, in a phosphoinositide 3-kinase (PI 3-kinase)-dependent manner. AntimDia1 loading or pretreatment with PI 3-kinase inhibitors essentially abrogated thrombin-elicited actin stress fiber formation, with a corresponding decrease in the proportion of platelets exhibiting a fully spread morphology. We also investigated the mechanisms underlying the effects of mDia1 on thrombin-induced actin remodeling and platelet spreading, and found that these involved PI 3-kinase-mediated induction of mDia1 interaction with RhoA. Collectively, these results suggest that the PI 3-kinase/RhoA/mDia1 axis is a critical pathway for coupling thrombin signaling to actin cytoskeletal remodeling during platelet spreading.

Disclosures

No relevant conflicts of interest to declare.
Phenobarbital for Long-Term Management of Marked Hyperbilirubinemia.
Authors: Shojania A. Majid
Published: October 2019

Abstract 5089

Gilbert's syndrome (GS) is associated with a mild chronic unconjugated hyperbilirubinemia, due to partial deficiency of bilirubin uridine diphosphate glucuronyl transferase (UDPGT). Phenobarbital is a known inducer of hepatic UDPGT and has been used in hyperbilirubinemia of newborns. It has also been used as a test for support of the diagnosis of GS. However, because hyperbilirubinemia of GS is mild and harmless, phenobarbital is not used for treatment of hyperbilirubinemia in adults. I report a case of a 46-year-old woman who, because of having chronic hereditary hemolytic anemia and GS, had marked hyperbilirubinemia with psychosocial problems, as the result of her hyperbilirubinemia and her skin color, which responded well to chronic phenobarbital treatment. Case report- CH was diagnosed to have hereditary high phosphatidylcholine hemolytic anemia (HHPCHA) at the age of 23. She was seen again at the age of 30 because of very high serum ferritin and iron saturation which seemed disproportionally high for the degree of her mild hemolytic anemia (51Cr RBC survival T½ of 16.5 days). Further investigation revealed that she had hereditary hemochromatosis due to homozygosity for H63D HFE gene. She was started on phlebotomies initially weekly and later on every 2-3 months to control her iron overload. During the follow-up it was noted that her serum unconjugated bilirubin (SUB) was persistently much higher than is expected from her mild hemolytic anemia (up to 288 μmol/L). Since she had no abnormality of liver function tests, I suspected that she also has Gilbert's syndrome. In September 2008 her blood was sent for genetic testing which showed that she has an additional TA repeat [(TA)7/(TA)7], confirming the diagnosis of GS. On January 21, 2009 when her SUB was 149 μmol/L, she expressed concern that her friends and coworkers keep making fun of her, because of the orange color of her face and sclera. She was started on phenobarbital 30 mg daily for a month and then 60 mg daily. This therapy rapidly brought her bilirubin down and changed the color of her face to normal, making her very happy. Her SUB on February 20, March 20 and June 30, 2009 were 103, 63 and 37 μmol/L, respectively.

Conclusion

Gilbert's syndrome is a common hereditary disorder that can aggravate hyperbilirubinemia of chronic hemolytic anemia. However, this association is often unrecognized, because many physicians attribute the hyperbilirubinemia to hemolysis and do not look for associated GS. In chronic hemolytic anemias, if hyperbilirubinemia is more than expected, the possibility of an associated GS should be considered. If such association exists, small daily doses of phenobarbital can markedly reduce this hyperbilirubinemia and improve the psychosocial effects of hyperbilirubinemia. Furthermore, marked reduction of bilirubin, following the therapeutic trial of Phenobarbital, will confirm the association of GS with hemolytic anemia.

Disclosures

No relevant conflicts of interest to declare.
Molecular Characterization in Two Families Bearing Glucose-6-Phosphate Dehydrogenase Deficiency (G6PD) IN Rosario, Argentina.
Authors: del Luján Irma , Pérez Susana Mabel SMP , Botta Sabrina SB , Rescia Virginia VR , Davoli Mauro MD , Milani Angela Cristina ACM
Published: October 2019

Abstract 5093

Introduction:

G6PD deficiency is a frequent worldwide enzymopathy, with sex-linked inheritance, the gene that codifies the enzyme localizes at the X chromosome. Males are hemizygous (Hem) for disease, while women are heterozygous (Het), i.e. carriers, and very rarely homozygous, or double heterozygous and consequently, develop disease. There are over 120 deficient molecular variants observed in Afro-Americans and in the malaria endemic region of the Mediterranean Basin. In previous studies in Argentina we have reported a low prevalence, 0,2-0,3 %, although the predominant molecular variants are unknown. Most of deficiencies are clinically detected when the patient is submitted to oxidative stress produced by infections, therapeutic drugs, or Vicia fava ingestion, develops an acute hemolytic anemia (AHA) of variable severity.

Materials and Methods:

Two male patients and their families were studied. 1) A1: 45y aged male, with AHA after bean ingestion, as well as the following relatives: mother (M1); sister (S1); three nephews (N1, N2, N3) and a niece (N4) without positive AHA history. 2) A2: 55y aged male, with two AHA episodes in childhood and adolescence, one of them associated with an infection, and the mother (M2). The evaluation clinical and hematological of the patients were normal Laboratory assays: Hemogram, Hemoglobin (Hb) (Coulter AcT10); Reticulocytes (Ret); Brewer test (B.T.); Heinz bodies (HB); Cytochemical method modified (Gurbuz, N; et al): NV: 86,8 % positive cells (CYT); Enzymatic activity (EA) Kinetic Method (Beutler-OMS): NV: 8.0±1.6 G6PD/gHb IU and Polymerase Chain Reaction with Enzyme Restriction (PCR-ER) for characterization of different variants: G6PDMed(563G□T), G6PD A376(A□G), G6PD A376(A□G) 202(G□A); G6PD A 376(A□G) 680 (G□T) y G6PD A 376(A□G) 968 (T□C).

Results:

Conclusions:

The EA confirmed the deficit of probands and nephews N1 and N3 without previous AHA history. The heterozygous character of females was not defined by this method but PCR-ER and CYT mod. supported the obliged carriers heterozygosis and the potential ones, demonstrating that CYT is more sensitive for carrier detection than other screening techniques or EA. The deficient phenotype was correlated with the detected variants, since the Mediterranean G6PD: G6PD Med(563G□T) (Type II, OMS) and G6PD A376(A□G) 202(G□A) (Type III, OMS) are associated with AHA induced by infections or Vicia Fava ingestion. The finding in Argentina of these two variants, that are frequent in the Mediterranean region, it is in accordance with the fact that our population has mainly Italian, Spanish (family 1) and Jewish (family 2) ancestors. The detection of deficient without hemolysis, as well as carriers is of the utmost importance in genetic counseling.

Disclosures:

No relevant conflicts of interest to declare.
Is There a Difference in the Preclinical Safety Parameters of Different Intravenous Iron Compounds?.
Authors: Toblli Jorge , Cao Gabriel , Oliveri Leda , Angerosa Margarita
Published: October 2019

Abstract 5097

Background

Intravenous (i.v.) iron has been effectively used to manage anemia in hemodialysis, chemotherapy-induced anemia and cardiac failure patients. However, i.v. iron preparations may cause different degree of oxidative stress and tissue inflammation. In the current study the effects of five i.v. iron preparations on haemodynamic, oxidative stress and inflammatory response were examined.

Methods

Sixty rats (n=10/group) received high molecular weight (HMW) iron dextran (Dexferrum®, American Regent, Inc., USA), low molecular weight (LMW) iron dextran (INFeD®, Watson Pharmaceuticals, USA/CosmoFer®, Vitaline Pharma, UK), ferric gluconate (Ferrlecit®, Watson Pharmaceuticals, USA), ferric carboxymaltose (Ferinject®, Vifor Pharma, Switzerland), iron sucrose (Venofer®, Vifor Pharma, Switzerland) or isotonic saline solution (control) in a blinded controlled study. Five i.v. doses of iron (40 mg iron/kg) or saline were administered over 4 weeks.

Results

Systolic blood pressure was significantly reduced in the LMW dextran group, whereas serum iron and percentage transferrin saturation were significantly elevated in all treatment groups. Creatinine clearance was reduced and proteinuria increased in the ferric gluconate group only (p<0.01) (day 1 to 29). Liver enzyme levels in the blood were significantly increased in the ferric gluconate and two dextran groups on days 1, 8 and 29 compared with the ferric carboxymaltose and iron sucrose groups. Analysis of liver, heart and kidney homogenates on day 29 showed a significant increase in catalase and malondialdehyde levels in the ferric gluconate group, and an increase in CuZn-superoxide dismutase and glutathione peroxidase activity accompanied with a decrease in the reduced-to-oxidized glutathione ratio in the ferric gluconate and two dextran groups (p<0.01). TNF-α and IL6 levels were significantly elevated in liver, heart and kidney samples from the ferric gluconate and two dextran groups but not the ferric carboxymaltose, iron sucrose or control groups on day 29.

Discussion

In this study, there was a difference in the hemodynamic and functional response to the different i.v. iron preparations. These findings indicate that HMW/LMW iron dextran and ferric gluconate have less favourable safety profiles in rats than ferric carboxymaltose and iron sucrose.

Disclosures

Toblli: Vifor Pharma: Research Funding.