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  • American Society of Hematology  (4)
  • 2010-2014  (4)
  • 1
    Online Resource
    Online Resource
    Continued Transmission of Parvovirus B19 in Plasma-Derived Factor Concentrates After the Implementation of B19 Nucleic Acid Plasma Minipool Screening,
    American Society of Hematology ; 2011
    In:  Blood Vol. 118, No. 21 ( 2011-11-18), p. 3378-3378
    Details
    In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 3378-3378
    Abstract: Abstract 3378 Background: Parvovirus B19 (B19) is a small, non-enveloped virus that causes a typically benign flu-like illness most commonly in childhood. However, B19 has been associated with arthritis and poses a hazard to the fetus of a pregnant woman. Because infection is common and viremia can occur before symptoms develop, about 1% of blood donations can be contaminated with B19 virus. The virus is resistant to current viral inactivation steps used in the manufacture of plasma-derived (P-D) anti-hemophilic factor concentrates and B19 transmission through these products has been documented. Since 2000, manufacturers have used a B19 nucleic acid test (NAT) to screen plasma pools and withhold from fractionation those with B19 DNA exceeding an established threshold. No study of populations using these products has been conducted to assess the impact of the screening on B19 transmission. Methods: Blood specimens obtained from participants of the CDC-sponsored Universal Data Collection (UDC) surveillance system of persons with bleeding disorders conducted by specialized US bleeding disorders clinics were used in a B19 seroprevalence study. Since B19 NAT screening began in 2000, only participants born after January 1, 2001 were eligible for study. Data collected on treatment products used by participants both prior to and after enrolment in UDC were used to categorize lifetime exposure as 1) no products, 2) recombinant (recomb) products only, 3) P-D products only, or 4) both recomb and P-D products. The proportions of participants with B19 IgG antibodies were compared across age and product exposure categories to determine whether users of products were at higher risk of past infection with B19 compared to those exposed to B19 only by the usual respiratory route. Results: A total of 1,643 specimens from 1,043 participants aged 2 – 7 years were tested. Demographic and clinical characteristics of study participants are shown in Table 1. Compared to subjects with no exposure to products, subjects in nearly every age group exposed to either P-D products alone or to both P-D and recomb products had a higher B19 prevalence (Table 2). In a logistic regression analysis that controlled for differences in the distribution of age, sex, bleeding disorder, treatment type, number of bleeds in previous 6 months, hemophilia inhibitor status, and year specimen obtained, participants exposed to P-D products alone were 1.7 times more likely to have B19 antibodies than those unexposed to blood or factor products (p = 0.002). In addition, there was a significant overall trend of increasing B19 prevalence over time. Discussion/Conclusion: P-D factor products are important therapies for people with VWD, hemophilia inhibitors and rarer factor deficiencies. Although we had no data on clinical illness, these serologic data provide evidence for continued transmission of B19 through these products after implementation of B19 NAT screening. Lowering the B19 threshold for plasma pool rejection should be considered. More importantly, effective viral inactivation processes are needed to protect users of these products not only from infection with B19 but from other as yet unidentified or emerging viruses that would not be detected by B19 NAT. Disclosures: Kessler: Novo Nordisk Inc.: Consultancy.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V118.21.3378.3378
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2011
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 2
    Online Resource
    Online Resource
    Identification of Patients At High Risk for Recurrent Venous Thromboembolism by Whole Blood Gene Expression Analysis
    American Society of Hematology ; 2011
    In:  Blood Vol. 118, No. 21 ( 2011-11-18), p. 2305-2305
    Details
    In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 2305-2305
    Abstract: Abstract 2305 Background. Recurrent venous thromboembolism (VTE) occurs in ∼30% of patients with spontaneous VTE after completion of a standard course of anticoagulant therapy. D-dimer levels and selected clinical parameters have been used to identify patients at low risk for recurrent VTE, who may safely discontinue antithrombotic therapy. We have used gene expression profiles to distinguish patients with a single VTE from patients with recurrent VTE. The purpose of this study was to extend this initial report and identify unique gene expression patterns from whole blood that correlate with different risk profiles for VTE recurrence. Methods. Patients with ≥1 prior VTE, with the first event occurring at age 18 years or older and 〉 3 months from the most recent event were recruited for this study. Patients were allocated into 4 groups: (1) ‘low-risk’ patients had sustained ≥1 provoked VTE; (2) ‘moderate-risk’ patients had sustained 1 unprovoked VTE (with or without provoked VTE); (3) ‘high-risk’ patients had sustained ≥2 unprovoked VTE and had no evidence for antiphospholipid antibodies; and (4) antiphospholipid syndrome (APS) patients met established consensus criteria for APS. A similar number of individuals with no prior history of VTE were enrolled as a control population. Citrated plasma, serum and PAXgene RNA tubes were collected, processed and stored at −80°C until shipped to the CDC for analysis. Antiphospholipid testing was performed on all participants to confirm correct group distribution. Total RNA was isolated from whole blood drawn into PAXgene tubes. Following sample labeling and normalization, cRNA samples were hybridized to Illumina HT-12 Beadchips to assay whole genome gene expression with over 47,000 probes against human transcripts. Two hundred and twenty six unique samples passed initial quality control measures. Quality assessment of raw data was done using GenomeStudio. The raw data files were converted to a text file using the IlluminaExpression FileCreator in GenePattern and then log transformed, normalized and median-centered using Cluster. Both unsupervised (hierarchical clustering using Cluster) and supervised analyses (SAM) were used to identify genes that were differentially expressed between the groups. GATHER was used to help understand the biological processes and gene ontology of the gene lists generated by Cluster and SAM. Results. A total of 226 participants were enrolled into the study. Characteristics of the patient groups are summarized in the Table. Demographically, the groups were similar except that patients in the high-risk group tended to be older and were more likely male. The number of events per patient, and the proportion on anticoagulant therapy, increased with the risk group. Antiphospholipid antibodies were detected in several patients in each of the 3 non-APS VTE patient groups, but in most cases this was a single test positive; antiphospholipid antibodies were present in the majority of patients with APS, typically with more than one test positive (37 of 45 with complete testing, 82%). Preliminary analysis of the gene expression profiles using an unsupervised clustering by gene on the high-risk and low-risk groups identified multiple genes that distinguished the two groups, including 18 immune response genes identified by GATHER. These two patient groups were also distinguished by SAM analysis, and multiple genes in the MAPK signaling pathway that separated the two groups were identified by the KEGG pathways in GATHER. Additional analyses are being performed on all of the groups. Conclusions. Whole blood gene expression profiling can be used to develop profiles that distinguish patients with VTE who differ based on their risk of recurrent events. Individual genes identified in these profiles may provide biological insights into the molecular basis for recurrent VTE. Disclosures: Heit: Daiichi Sankyo: Honoraria; Ortho-McNeil Janssen: Honoraria; Covidien: Honoraria. Manco-Johnson:Octapharma AG: Consultancy; Bayer: Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V118.21.2305.2305
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2011
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 3
    Online Resource
    Online Resource
    A Phase II Clinical Trial of Rituximab, Cyclophosphamide, Bortezomib, and Dexamethasone (R-CyBor-D) in Relapsed Low Grade and Mantle Cell Lymphoma
    American Society of Hematology ; 2014
    In:  Blood Vol. 124, No. 21 ( 2014-12-06), p. 4410-4410
    Details
    In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 4410-4410
    Abstract: Introduction Non-Hodgkin lymphoma responds to single agents such as cyclophosphamide, combination therapy such as CVP and immunotherapy with monoclonal antibodies such as rituximab. There is no consensus on the optimal treatment for relapsed low grade or mantle cell lymphoma. Based on the success and tolerability of combining alkylating agents with proteasome inhibitors in multiple myeloma, a phase II clinical trial of rituximab, cyclophosphamide, bortezomib, and dexamethasone (R-CyBor-D) was designed to explore the efficacy and safety of this combination in relapsed low grade and mantle cell lymphoma (MCL). Methods This trial enrolled relapsed patients at Mayo Clinic from October 2008 to March 2014. Eligibility required age≥18; biopsy proven follicular grades 1 or 2 lymphoma (FL), MCL, small lymphocytic lymphoma/chronic lymphocytic leukemia, marginal zone B-cell lymphoma, or Waldenström’s macroglobulinemia (WM); life expectancy 〉 3 months; ECOG PS 0, 1 or 2; measurable disease; Hb ≥8g/dl, ANC ≥1200/uL, platelet ≥75,000/uL, creatinine ≤1.5xULN, total bilirubin ≤1.5xULN, alkaline phosphatase ≤3xULN, AST ≤3xULN; and willingness to sign informed consent. Women of child bearing potential had pregnancy testing and all patients followed recommendations for contraception. Treatment included rituximab 375 mg/m2 IV on day 1 and oral cyclophosphamide 300 mg/m2, IV bortezomib 1.3 mg/m2, and oral dexamethasone 40 mg on days 1, 8, 15, and 22 in a 28-day cycle. Treatment was continued two cycles beyond best response or a maximum of 12 cycles. Allopurinol 300 mg on days 0-14 for the first cycle was strongly recommended. Results 21 patients were enrolled prior to study closure due to slow accrual. Bortezomib was initially given on days 1, 4, 8, and 11 in the first 16 patients, but was subsequently modified to days 1, 8, 15, and 22 due to significant peripheral neuropathy (PN). Median age was 69 years (range 51-80) and 13 (62%) were male. 62% had stage IV disease and 17 (81%) had 2 or more prior treatments with 3 (14%) having prior autologous stem cell transplantation. Histologies included FL-I (n=6), FL-II (n=2), MCL (n=8), and WM (n=5). Patients completed a median of 4 cycles of treatment (range 1-12), discontinuing due to 9 (43%) completion per protocol, 4 (19%) progression, 5 (24%) adverse events, 1 (5%) patient refusal, and 2 (10%) other reasons. Median follow-up is 32.8 months (0.9-54.8). CR or PR as best response was observed in 13 (62%, 95% CI 38-82%; 4 CR [19%], 9 PR [43%] ) patients. By histology, CR or PR was observed in 7 (88%) FL patients (4 CR, 3 PR); 2 (25%) MCL patients (both PR), and 4 (80%) WM patients (all PR). CR or PR was observed in 10/16 (62%; 4 CR, 6 PR) before and 3/5 (60%; all PR) after the change in bortezomib schedule. Among 13 patients with CR or PR, median duration of response was 25.9 months (95% CI 8.0-not reached). Median PFS and OS were 11.6 months (95% CI 3.8-not reached) and 54.8 months (95% CI 24.6-54.8), respectively. At least one Gr≥3 adverse event at least possible related was observed in 14 (67%) patients, the most common being leucopenia (7, 33%), neutropenia (7, 33%), thrombocytopenia (6, 29%), anemia (5, 24%), PN (5, 24%), and fatigue (3, 14%). Peripheral sensory neuropathy at least possibly related was Gr1, Gr2, and Gr3 in 5 (24%) patients each, with a lower rate observed for patients after the change in bortezomib schedule (before 13/16 [81%] Gr≥1, after 2/5 [40%] Gr≥1). Among 14 patients who completed a baseline and at least one post-baseline FACT/GOG-NTX additional concerns questionnaire, 10 (71%) reported clinically meaningful (≥3-point) worsening in patient-reported neurotoxicity (8/11 [73%] before and 2/3 [67%] after the change in bortezomib schedule). Conclusions Our results suggest R-CyBor-D is a safe and effective combination in patients with relapsed low grade and mantle cell lymphomas. High response rates were seen in FL and WM. The majority of significant AE’s were hematologic. However, sensory neuropathy was common with twice weekly dosing of bortezomib and lessened with weekly dosing. Determination of optimal treatment regimens in this population remains an unmet need. Additional clinical trials including larger patient numbers are necessary to confirm these observations. This trial was sponsored by Millennium Disclosures Off Label Use: bortezomib was used in combination therapy to treat relapsed low grade lymphomas and Waldenstrom's macroglobulinemia. Bergsagel:Novartis: Research Funding; Constellation Pharmaceutical: Research Funding; OncoEthix: Research Funding; MundiPharma: Research Funding. Tiedemann:Janssen: Honoraria. Reeder:Millennium, Celgene, Novartis: Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V124.21.4410.4410
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2014
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 4
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    Online Resource
    Whole-Exome Sequencing Identifies Novel Risk Variant for Thrombotic Storm
    American Society of Hematology ; 2011
    In:  Blood Vol. 118, No. 21 ( 2011-11-18), p. 1229-1229
    Details
    In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 1229-1229
    Abstract: Abstract 1229 Background: Thrombotic storm (TS) is an extremely severe clinical phenotype that occurs in a very small subset of patients with venous thromboembolic disease. It is characterized by patients who exhibit two or more of the following in a short period of time; 1) 〉 2 acute arterial/venous thromboemboli, and/or thrombotic microangiopathy, 2) unusual location, 3) progressive/recent unexplained recurrence, and/or 4) refractory to and/or atypical response to therapy (Kitchens et al., Am J Med, 2011). We hypothesize these patients possess an underlying prothrombotic risk factor that results in an accelerated form of thrombosis following an initial event that provokes the attack in the relevant clinical context. Methods: To identify potential genetic risk variants we performed whole-exome sequencing on a TS participant and his unaffected parents and sibling. The proband was a 14 year old male who presented with thrombosis of the sagittal, right transverse and sigmoid sinuses following a sports-related knee injury. There was no personal or family history of venous thromboembolism, and a hypercoagulable workup, including testing for antiphospholipid antibodies, was negative. His course was complicated by the development of disseminated intravascular coagulation, delaying early initiation of anticoagulant therapy. Despite aggressive supportive care, which included anticoagulation therapy, the proband did not improve and expired after severe cerebral edema with herniation was diagnosed by clinical exam and CT imaging. At autopsy, bilateral pulmonary emboli and extensive pelvic vein thrombosis were also identified. DNA was extracted from whole blood and the relevant regions were captured using the Agilent Sure Select 50mb kit. Sequencing was performed on the Illumina HiSeq2000 under the manufacturer's recommended protocol. Alignment of reads to the reference was performed using BWA, and genotype calls were made with GATK. Variants were initially filtered based on quality (depth ≥ 8, phred-like quality ≥ 30), function (nonsense, missense, splicing), and novelty. Additional filters include inheritance mode (autosomal recessive or de novo heterozygote), conservation (phastcons score 〉 0.5, GERP score 〉 2), and damage prediction (SIFT or Polyphen). Potential variants were validated using Sanger sequencing. Results: Whole-exome sequencing identified over 127,000 variants in the nuclear family with at least one member having a high quality variant at the position. Filtering these variants based on function, novelty, and high quality in parents and affected proband reduced the list to 2,735 variants. Of these, 7 variants fit an autosomal recessive model (homozygous in the proband, heterozygous in both parents, not homozygous in the unaffected sibling); of these 7, two were at conserved sites, predicted to be damaging, and also called using SAMTOOLS. The first of the recessive variants is a nonsense variation in the EGFL8 gene (tyrosine to stop codon, at the 74th amino acid; tyr74stop), and the second is in HLA-E (gln276pro). Of the initial list of 2,735 variants there were 138 that fit a de novo heterozygous model (present in the affected proband, but not parents); of these 138, two were at a conserved site, predicted to be damaging, and were also called with SAMTOOLS. The first de novo heterozygote is in SLC26A2 (arg178stop), and the second variant is in PRMT7 (arg531trp). These four variants were resequenced using Sanger sequencing within the family. Three of the variants (EGFL8, SLC26A2, and PRMT7) were confirmed using Sanger; the fourth (HLA-E) is still being resequenced. Discussion: These variants represent excellent candidate loci for thrombotic storm risk. In particular, the EGFL8 variant is a homozygous change to a stop codon less than one quarter of the way through the open reading frame – a change that likely severely damages protein function. Additionally, EGFL8 (epidermal growth factor-like domain-containing protein 8) has two EGF domains, a common motif identified in hemostatic and fibrinolytic proteins, and is therefore potentially involved in coagulation. These variants will be further analyzed for frequency in controls and tested in animal models for functional significance. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V118.21.1229.1229
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2011
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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