ALBERT

Description: Background: Von Willebrand disease (vWD) is the most common inherited bleeding disorder with a reported prevalence of 1% in epidemiological studies and symptomatic prevalence of 1 in 10,000. Pregnancy in vWD is associated with increased bleeding risk particularly postpartum hemorrhage. Treatment options include desmopressin acetate (DDAVP), plasma derived factor concentrates and antifibrinolytic agents. Human Recombinant von Willebrand factor (vWF) (Vonvendi®) has been approved in the United States for on demand treatment and perioperative management of adults with vWD. It has been shown to maintain sustained levels of VWF activity but requires co-administration with FVIII to achieve adequate FVIII levels. Recombinant VWF is an option for patients who refuse blood for religious reasons. Case: Here we describe a 39 year old patient in her third pregnancy who is a Jehovah's Witness. Consent was obtained from the patient for this report. She was initially diagnosed with von Willebrand`s disease at the age of six, when she had hematuria. At the age of 11, with menarche, she had significant menorrhagia resulting in symptomatic anemia, a reduction in her hemoglobin concentration to 44 g/L, requiring uterine artery embolization. She was placed on an oral contraceptive pill for menorrhagia. She used DDAVP for trauma induced injury. Her first pregnancy resulted in spontaneous abortion. She required a D&C and DDAVP was used. Prior to delivery of the second pregnancy DDAVP was used but she had postpartum hemorrhage, requiring additional dosing of DDAVP and uterine artery embolization. In the current pregnancy, aPTT was 36.4 seconds with normal PT and platelet count and blood group O. At 15 weeks' gestational age, VWF antigen (ACL TOP 700 -IL HemosIL) was 0.11 units/ml (normal range for blood group O 0.45-1.5 unit/ml), ristocetin cofactor (ACL TOP 700 -IL HemosIL), 0.09 units/ml (normal range 0.48-2.0 units/ml for blood group O), and FVIII level (Sysmex CS5100 -Dade Actin FS) 0.09 units/ml (normal range 0.58-1.9 units/ml). Factor levels at 23 weeks' gestation 1 hour following DDAVP were FVIII 1.05 units/ml, VWF antigen 0.5 units/ mL, and ristocetin cofactor 0.52 units/ml. She was willing to accept recombinant factor concentrates only. Results: She had an elective admission for induction of labor at 37 weeks but proceeded to Cesarean Section due to non-progression of labor. Her PTT on admission was 40 seconds with VWF antigen of 0.11 units/ml, VWF activity 〈 0.07 units/ml and FVIII 0.13 units/ml. The Table describes her levels following the administration of recombinant vWF. She was administered Vonvendi® on a planned dose of 40 IU/kg Xynta® and rFVIII 30 IU/kg to increase factor levels to more than 50%; 60-min following infusions vWF : RCo was 0.64 U/ml with FVIII 0.79 U/ml. The Cesarean section was performed under spinal anesthesia without complications. Tranexamic acid was used intravenously before the delivery of the neonate and continued for first two days and then changed to oral dose. Target levels were achieved over the 5 days after delivery with the current regimen. She experienced a transient hypersensitivity reaction with urticaria and dyspepsia after the third dose of Vonvendi®. She did not have significant bleeding. Her hemoglobin concentration remained stable at 120 g/L throughout her inpatient stay. The neonate did not have bleeding with delivery but was found to have VWF antigen of 0.11 U /ml, VWF activity of 0.07 U/ml and FVIII of 0.16 U/ml. Genetic analysis of the mutation associated with her vWD is in progress. Conclusion: The use of rvWF and rVIII resulted in adequate hemostasis peripartum. Further prospective data are required to reaffirm the safety and dosing of rvWF for peripartum management of patients with vWD who require intervention. Disclosures Kazi: Shire: Other: Vonvendi was provided by Shire.

Description: Introduction Essential thrombocythemia (ET), polycythemia vera (PV) and myelofibrosis (MF) are a group of hematopoietic stem cell-derived clonal disorders collectively known as the classical, Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs). Although MPN diagnoses are typically made in the sixth or seventh decade of life, approximately 20% of ET patients and 15% of PV patients are under the age of 40 years. Pregnancy with an MPN is associated with maternal thrombosis, hemorrhage and placental dysfunction leading to fetal growth restriction or loss. The aims of this systematic review were to determine the risk of maternal and fetal complications in pregnancy complicated by MPN and to quantify the benefit of commonly used interventions. Methods A systematic search was conducted using MEDLINE (1946 to July 2018), EMBASE (1947 to July 2018), Cochrane Database of Systematic Reviews (2005 to July 2018), CCRCT (inception to June 2018), and Epub Ahead of Print & Other Non-Indexed Citations (inception to July 2018). Bibliographic references were reviewed for additional studies. There were no date or language restrictions and the review was registered with PROSPERO (CRD42018090680). Studies were included if they reported on maternal or fetal outcomes of pregnancy in patients with an MPN. Case reports and series including fewer than 10 patients were excluded. Duplicate reports were excluded, with only the most recent or most informative included. Data were extracted independently by two investigators (D.M. and S.K.). The primary outcome was live birth. Secondary outcomes included fetal complications (e.g. intrauterine growth restriction) and maternal complications (e.g. pre-eclampsia, thrombosis, hemorrhage). Study quality was assessed using the Newcastle-Ottawa Scale. Analyses were performed using Open Meta-Analyst version 10.12 and Review Manager version 5.3. Results The search strategy resulted in 4191 records of which 22 met the inclusion criteria (Figure 1). The studies included a total of 779 women and 1226 pregnancies. Fifteen of the studies included patients with ET, 3 included patients with PV, and 4 included patients with any classical MPN. There were no studies of MF patients that met our inclusion criteria. Most of the studies were retrospective cohort studies (19) and 3 were prospective cohort studies. Among 1226 pregnancies, the live birth rate was 70%. Of 821 pregnancies with ET and 171 with PV, the live birth rate was 71% and 51%, respectively. The live birth rate was higher in patients with ET who received low dose aspirin during pregnancy than those managed with observation alone (OR 5.0; 95% CI 2.2 - 11.3; I226%; Figure 2). There was no further improvement with the addition of low molecular weight heparin (LMWH) to aspirin (OR 2.8; 95% CI 0.67 - 11.7; I20%). Interferon alpha (INF) during pregnancy was also associated with a higher live birth rate (OR 3.9; 95% CI 1.5 - 10.4; I22.5%; Figure 3). The presence of the JAK2 mutation resulted in a lower live birth rate (OR 0.58; 95% CI 0.4 - 0.9; I26%; Figure 4). Maternal events were unaffected by the addition of aspirin (OR 0.48; 95% CI 0.16 - 1.4; I20%) or INF (OR 0.1; 95% CI 0.01 - 1.5; I20%). Risk of bias assessment was performed using the Newcastle-Ottawa scale. Most studies included a representative cohort and follow up was generally adequate to at least 6 weeks postpartum. Only 3 studies included a control group. Conclusions The preliminary results of our systematic review determined that the live birth rate is lower in pregnant patients with MPN as compared to the general population. The chance of a successful pregnancy was higher in patients with ET than PV and the presence of the JAK2 mutation increased the risk of fetal loss. Patients who received low-dose aspirin during pregnancy had a 5-fold higher odds of a successful pregnancy than those managed with usual care and observation alone. Cytoreduction with INF improved the odds of live birth by nearly 4-fold. Maternal events were uncommon overall and no intervention was found to be beneficial. Our review is limited by generally small sample sizes and the retrospective nature of most studies. Additionally, given that the studies span up to 4 decades, our results may be affected by changing standards of care. Pregnancy in patients with MPN is uncommon and this is the only systematic review to determine the chance of successful pregnancy and quantify the benefit of commonly used interventions. Disclosures Maze: Novartis: Consultancy, Honoraria. Kazi:Shire: Other: Vonvendi was provided by Shire. Gupta:Novartis: Consultancy, Honoraria, Research Funding; Incyte: Research Funding.

Description: Epstein-Barr virus associated lymphoproliferative disease is a serious complication of immunosuppression, particularly after transplantation. Initial treatments usually comprise reduction of immunosuppression, rituximab and/or chemotherapy. However, some patients fail to respond or are unsuitable for chemotherapy and so are candidates for adoptive cellular therapy. Here we report outcomes from the use of a bank of 25 third party derived Epstein-Barr virus specific lymphocyte cell lines cryopreserved for immediate use, issued on a best-HLA match basis. Cells have been issued to 70 patients. The infusions were well tolerated, although in two patients, evidence of mild, transient, cutaneous GVHD was observed, both treated with topical agents. In one patient, there was a temporary worsening of neurological symptoms, thought to represent a tumour flare in a patient who responded. 59 patients have received cells with a follow up of 〉6 months, 34 (58%) male and 25 (42%) female. The median age was 31 years (range 1 - 82). 48 patients had received transplants, 28 HSCT and 20 solid organs. All HSCT patients had received transplants from unrelated donors. SOT types were as follows: kidney, 10; liver, 3; heart, 2; bowel, 1; liver, small bowel and pancreas, 1; combined liver and kidney, 1; combined kidney and pancreas, 1; heart and kidney, 1. Eleven patients were immune suppressed due to causes other than transplantation: five with congenital immunodeficiencies, two on maintenance for acute lymphoblastic leukemia and two on immunosuppressive drugs (1 Crohn disease and 1 Systemic Lupus Erythematosus). One patient had EBV positive natural killer/T cell lymphoma and one diffuse large B cell lymphoma of the elderly. Responses were observed in 35/59 (59%) patients, with rates being highest (75%) post-solid organ transplantation, intermediate (64%) in non-transplant cases and lowest (46%) after hematopoietic stem cell transplantation (p=0.13, Fisher exact). Although most patients were treated after more conventional therapies had failed or were deemed inappropriate, 39% were alive at time of census. Overall survivals were only somewhat less than response rates after solid organ transplantation (60%) and in non-transplant (54%) patients, but worse (18%) after hematopoietic stem cell transplantation (p=0.007, logrank). The mean survival was 2.3 years (95% CI 1.6 - 3.0) and median survival 0.7 years (95%CI 0.0 - 1.8y). Survivals were higher in patients who had not had a transplant or after undergoing SOT versus HSCT, and this difference was statistically significant (p=0.007; log rank). Outcomes were notably good for solitary central nervous system lesions with 12/13 responses (p=0.012, Fisher exact). At census, 132 HLA matching requests have been processed and 61 allocation reviews completed. The median number of class I matches was 3 (range 0-6) and class II matches 2 (range 0-4). The median number of class I+II matches was 4.5 (range 0-9). For CTLs issued the median number of class I matches was 3 (range 1-6) and class II matches 2 (range 0-4). The median number of class I+II matches was 5 (range 2-9). Response rates were moderately higher using better HLA-matched lymphocytes, although this only reached statistical significance (p=0.043) if a one tailed linear-by-linear association test was used. Despite the license covering all European Union countries, locations of recipients were biased towards the United Kingdom (58/64). These data support the use of third party derived cytotoxic lymphocytes in this difficult to treat group of patients, although their current use after hematopoietic stem cell transplantation remains to be optimized. Figure. Figure. Disclosures Kazi: Shire: Other: Vonvendi was provided by Shire. Vickers:GSK: Equity Ownership; University of Aberdeen: Patents & Royalties.

Description: Introduction With advancement in medical knowledge and comprehensive care more women with hematological disorders are proceeding with pregnancy. These women have unique needs during the perinatal period, where the intersection of the Hematological disease and pregnancy can mutually impact each other, resulting in significant morbidity and even mortality. Hematologists, Internal Medicine (IM) physicians and Obstetricians are increasingly faced with the complex care of these women. The aim of this study is to assess the learning needs of these stakeholders in the care of pregnant women with hematological conditions to direct the development of educational activities. Methods We conducted a cross-sectional study using a self-administered electronic questionnaire sent to Hematologists, Obstetricians, Maternal-Fetal Medicine (MFM) Specialists and IM Specialists across Canada. The study was approved by the Research Ethics Board of Sinai Health System in Toronto, Ontario. The questionnaire assessed physician characteristics, physicians' previous educational experiences in Maternal Hematology, self-assessment of knowledge and confidence in managing pregnancy in these women, and preferences for further learning activities in Maternal Hematology. The questionnaire was pilot tested by two hematology resident physicians and two MFM fellow physicians at the University of Toronto and modifications were made to the survey based on this feedback. The survey was administered electronically in English in collaboration with the Canadian Hematology Society and Canadian MFM program directors, using an online survey-distributing website, Survey Monkey™. Participation was voluntary and anonymous. Data were exported into Excel (Microsoft, Redmond, Washington, USA) for statistical analysis. Following overall descriptive analyses (frequencies and proportions), responses were further tabulated by participant specialty. Results The survey was administered from December 2019 to March 2020. 97 participants responded to the survey, and 82 (84.5%) completed it. The 15 (15.5%) incomplete surveys (completion of less than 25% of the questionnaire), were excluded from analysis. Respondents included 17 (20.7 %) MFM specialists, 21 (25.6%) Obstetricians, 34 (41.5%) hematologists and five (6.1 %) IM physicians. Half of respondents had 〈 5 years of practice (52.6%%) and there was a similar distribution of respondents with 5-10 years (12.8%) and 11-15 years (12.8%) in practice. Most respondents were female (69.6%). Overall, 38% of respondents described the quality of their prior educational experiences as 'very useful' or 'extremely useful'. Approximately half of the respondents rated their knowledge of Maternal Hematology as intermediate, 25% as beginner and 25% as advanced. The majority of Hematologists and IM specialists (64%) considered their knowledge in Maternal Hematology as 'intermediate'; specialists in Obstetrics and MFM were divided with 30.8% considering their knowledge at the 'beginner' level and 38.5% at the 'intermediate' level. Only 3.7% of respondents described their knowledge level as 'expert'. Most respondents in Obstetrics and MFM (84.2%) considered knowledge of how to diagnose venous thromboembolism during pregnancy as 'extremely important followed by knowledge of thromboprophylaxis (63.2%) and therapeutic anticoagulation during pregnancy (63.2%) (Figure 1). Amongst Hematology and IM physicians, thrombotic microangiopathy was rated by the greatest proportion of respondents (59%) as being "extremely important". For the format of educational activity, three quarters of the respondents preferred a blended learning program, which would include a combination of face-to-face teaching and technology-enhanced learning activities. Respondents predominantly (76.2%) agreed that learning collaboratively with other specialties in a combined Maternal Hematology program would be helpful. Conclusion These results suggest that an interdisciplinary learning program involving collaboration across relevant subspecialties would be preferred by participants for the teaching and learning of Maternal Hematology. A program involving blended (in-person and technology-enhanced) learning modalities was viewed favorably by participants, and should aim to incorporate various topics, which may be prioritized differently amongst specific subspecialties. Disclosures Malinowski: Alexion: Other: Advisory board; Alexion: Honoraria. Shehata:Ferring: Honoraria.