Frequency of Venous Thromboembolism in 6513 Patients with COVID-19: A Retrospective Study
Background: Patients infected with coronavirus 2 (SARS-CoV-2) appear to be at increased risk for venous thromboembolism (VTE), especially if they become critically ill with coronavirus disease 2019 (COVID-19). Some centers have reported very high rates of thrombosis despite anticoagulant prophylaxis. Methods: The electronic health record (EHR) of a New Orleans-based health system was searched for all patients with PCR-confirmed SARS-CoV-2 infection who were either admitted to hospital or treated and discharged from an emergency department between March 1 and May 1, 2020. From this cohort, patients with confirmed VTE (either during or after their hospital encounter) were identified by administrative query of the EHR. Results: Between March 1, 2020 and May 1, 2020, 6,153 patients with COVID-19 were identified; 2,748 of these patients were admitted, while 3,405 received care exclusively through the emergency department. Data on patient outcomes were determined up until and including May 21, 2020. In total, 637 patients required mechanical ventilation and 206 required renal replacement therapy. Within the hospitalized cohort, the overall mortality rate was 24.5% and VTE occurred in 86 patients (3.1%). In the 637 patients who required mechanical ventilation at some point during their hospital stay, 45 developed VTE (7.2%). After a median follow-up of 14.6 days, VTE had been diagnosed in 3 of the 2,075 admitted who were discharged alive (0.14%). Conclusions: Among 6,153 patients with COVID-19 who were hospitalized or treated in emergency departments, we did not find evidence of unusually high VTE risk. Pending further evidence from prospective, controlled trials, our findings support a traditional approach to primary VTE prevention in patients with COVID-19. Disclosures Crowther: Precision Biologicals: Membership on an entity's Board of Directors or advisory committees; Hemostais Reference Laboratories: Honoraria; Pfizer: Speakers Bureau; CSL Behring: Speakers Bureau; Alnylam: Divested equity in a private or publicly-traded company in the past 24 months; Servier Canada: Membership on an entity's Board of Directors or advisory committees; Diagnostica Stago: Speakers Bureau; Asahi Kasei: Membership on an entity's Board of Directors or advisory committees.
Abstract Patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) appear to be at increased risk for venous thromboembolism (VTE), especially if they become critically ill with COVID-19. Some centers have reported very high rates of thrombosis despite anticoagulant prophylaxis. The electronic health record (EHR) of a New Orleans–based health system was searched for all patients with polymerase chain reaction–confirmed SARS-CoV-2 infection who were either admitted to hospital or treated and discharged from an emergency department between 1 March 2020 and 1 May 2020. From this cohort, patients with confirmed VTE (either during or after their hospital encounter) were identified by administrative query of the EHR.: Between 1 March 2020 and 1 May 2020, 6153 patients with COVID-19 were identified; 2748 of these patients were admitted, while 3405 received care exclusively through the emergency department. In total, 637 patients required mechanical ventilation and 206 required renal replacement therapy. Within the hospitalized cohort, the overall mortality rate was 24.5% and VTE occurred in 86 patients (3.1%). In the 637 patients who required mechanical ventilation at some point during their hospital stay, 45 developed VTE (7.2%). After a median follow-up of 14.6 days, VTE had been diagnosed in 3 of the 2075 admitted who were discharged alive (0.14%). Among 6153 patients with COVID-19 who were hospitalized or treated in emergency departments, we did not find evidence of unusually high VTE risk. Pending further evidence from prospective, controlled trials, our findings support a traditional approach to primary VTE prevention in patients with COVID-19.
Introduction: The majority of newly diagnosed multiple myeloma (NDMM) patients are currently treated with lenalidomide-based regimens as their first line of therapy. This trend is likely to continue in the coming years. Typically, lenalidomide is administered until disease progression and has significantly contributed to better outcomes in these patients. However, most patients relapse, and prognosis worsens with each relapse. The choice of optimal treatment for patients who relapse while receiving lenalidomide as first line of therapy is unclear. Moreau et al (Blood Cancer J. 9, 38 [2019]) concluded that there is limited data on approved combinations for treating these patients and are restricted by the low number of lenalidomide-refractory patients enrolled in the pivotal trials. Results from the ongoing clinical trials of the combination of carfilzomib and anti-CD38 antibodies were not available at the time of the Moreau et al publication. The aim of this targeted literature review was to include this new data and to summarize currently available evidence on progression-free survival (PFS) for the treatment of RRMM patients who progressed on lenalidomide-based regimens. Methods: A targeted literature review was conducted to identify registrational clinical trials in patients with RRMM reporting PFS outcomes. PubMed, congress proceedings, and product labels were searched between Jan 2014 to July 2020. In addition to PFS, demographic, disease characteristics and treatment history were extracted for the trial populations to contextualize potential variations in study outcomes. The regimens studied in these trials were classified as lenalidomide-based, proteasome inhibitor (PI)-based and pomalidomide-based. Number of prior lines of therapy, prior exposure and refractoriness to lenalidomide and bortezomib were reported. Results: Twelve registrational trials were identified based on the search criteria (Table 1). Most pivotal trials assessing lenalidomide-based regimens (POLLUX, ELOQUENT-II, TOURMALINE-MM1) except the ASPIRE trial excluded patients who were refractory to lenalidomide. Trials evaluating PI-based regimens (e.g., CANDOR) or pomalidomide-based regimens (e.g., OPTIMISMM) included these patients, with more recent studies enrolling a larger proportion. Percentage of lenalidomide-exposed (and lenalidomide refractory) ranged from 40% (32%) in CANDOR to 98% (90%) in ELOQUENT III. These studies also enrolled a larger proportion of patients who were bortezomib-exposed, although most of these patients were at first relapse, with the exception of ELOQUENT III and ICARIA where most patients were at third relapse. Among lenalidomide-refractory patients, the median-PFS (mPFS) observed for the pomalidomide-based regimens ranged from 9.5 to 10.1 months and that observed for PI-based regimens ranged from 4.9 to 25.7 months. PFS in the lenalidomide-refractory subgroup was considerably shorter than in the ITT population. The mPFS for patients receiving carfilzomib/daratumumab/dexamethasone (KDd; CANDOR) and isatuximab/carfilzomib/dexamethasone (IsaKd; IKEMA) was not reached at median follow-up of 16.9 and 20.7 months respectively. While the mPFS for (KDd) for lenalidomide-refractory patients in CANDOR trial was not yet reached at median follow up of 16.9 months; the mPFS of 25.7 months for KDd in the MMY-1001 trial appears to be the longest among the assessed regimens. Conclusion: Patients refractory to lenalidomide have shorter PFS and represent a population with high unmet need. This targeted literature review suggests that the PI-based KDd regimen provides longer PFS compared to other lenalidomide-sparing regimens in lenalidomide-refractory populations. Heterogeneity across trial populations may limit the comparability of these treatments. Disclosures Mateos: Regeneron: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Consultancy, Honoraria; Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie/Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; PharmaMar-Zeltia: Consultancy; GlaxoSmithKline: Consultancy. Medhekar:Amgen Inc.: Current Employment, Current equity holder in publicly-traded company. Majer:Amgen (Europe) GmbH: Current Employment, Current equity holder in publicly-traded company.
BACKGROUND: Venous thromboembolism (VTE) is the second leading cause of death in cancer patients. The treatment of cancer-associated VTE carries a significantly greater risk of major bleeding (MB) and recurrent VTE compared to that in non-cancer patients. CHEST Guidelines suggest the use of low molecular weight heparin (LMWH) over a vitamin K antagonist (VKA) in patients diagnosed with VTE and cancer. The last decade has seen an emergence of non-VKA anticoagulants (NOACs) for the treatment of VTE. Despite completed and ongoing clinical trials, there is a lack of real-world evidence comparing the effectiveness and safety of LWMH with VKAs and NOACs among VTE patients with active cancer. Therefore, this study evaluates the risk of MB, clinically relevant non-MB (CRNMB), and recurrent VTE (fatal or non-fatal) among VTE patients with active cancer prescribed apixaban, LMWH, or warfarin in routine clinical practice. METHODS: Four US commercial insurance claims databases were used to identify VTE patients with active cancer (defined as cancer diagnosis or cancer treatment [chemotherapy, radiation and cancer-related surgery] within 6 months before or 30 days after VTE diagnosis) who initiated apixaban, LMWH, or warfarin within 30-days following the first VTE event (01SEP2014-31MAR2018). Patients who used LMWH as bridging therapy for warfarin (≤14 days before or after warfarin initiation) were classified as warfarin users. Patients were followed to the earliest of: health plan disenrollment, death, index therapy discontinuation, switch to another anticoagulant, study end, or a maximum of 6 months. Additional analysis using all available follow-up was also conducted. Stabilized inverse probability treatment weighting (IPTW) was used to balance treatment cohorts. Cox proportional hazard models were used to evaluate the risk of MB, CRNMB, and recurrent VTE. RESULTS: After applying all eligibility criteria, 3,393 apixaban, 6,108 LMWH, and 4,585 warfarin patients were identified with mean ages of 65, 64, and 64 years, respectively. After IPTW, all patient characteristics were balanced. The mean follow-up was 105, 88, and 113 days for apixaban, LMWH, and warfarin, respectively. Among the weighted VTE cancer population, 51% of the patients had metastatic cancer and 77% of patients received cancer treatment. Further, 15% of patients had very high-risk cancer (brain, stomach, or pancreas), and 40% patients had high-risk cancer (lung, lymphoma, gynecologic, bladder, testicular, renal cell carcinoma). Apixaban patients had a lower risk of MB, CRNM bleeding, and recurrent VTE compared to LMWH. Apixaban patients also had a lower risk of recurrent VTE and a similar risk of MB and CRNM bleeding compared to warfarin. Warfarin patients had a similar risk of MB, CRNM bleeding, and recurrent VTE compared to LMWH (Figure). When the entire available follow-up period (mean follow-up was 137, 106, and 166 days for apixaban, LMWH, and warfarin, respectively) was used, the trends were similar to the 6-month analysis for apixaban vs. LMWH and warfarin vs. LMWH. However, apixaban patients were associated with a lower risk of both MB and recurrent VTE compared to warfarin patients. CONCLUSION: VTE patients with active cancer initiating apixaban had significantly lower risk of MB, CRNM bleeding, and recurrent VTE compared to LMWH patients. Apixaban patients also had a lower risk of recurrent VTE compared to warfarin patients. These results may be helpful for clinicians in evaluating different anticoagulation treatments for VTE patients with active cancer. Further studies are needed to evaluate these outcomes between different anticoagulation treatment options. Figure Disclosures Cohen: Lifeblood: Other: advisor to Lifeblood: the thrombosis charity and is the founder of the European educational charity the Coalition to Prevent Venous Thromboembolism; ONO: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; TRN: Consultancy; UK Government Health Select Committee: Other: advised the UK Government Health Select Committee, the all-party working group on thrombosis, the Department of Health, and the NHS, on the prevention of VTE; Temasek Capital: Consultancy; ACI Clinical: Consultancy; Navigant: Consultancy; McKinsey: Consultancy; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AbbVie: Consultancy; Aspen: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Boston Scientific: Consultancy; Boehringer-Ingelheim: Consultancy, Speakers Bureau; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CSL Behring: Consultancy; GlaxoSmithKline: Consultancy, Speakers Bureau; GLG: Consultancy; Guidepoint Global: Consultancy; Johnson and Johnson: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Leo Pharma: Consultancy; Medscape: Consultancy, Speakers Bureau. Keshishian:STATinMED Research: Other: I am a paid employee of STATinMED Research which is a paid consultant to Bristol-Myers Squibb Company and Pfizer Inc.. Lee:Pfizer Inc.: Employment, Equity Ownership. Wygant:Bristol-Myers Squibb Company: Employment. Rosenblatt:Bristol-Myers Squibb: Other: Stock Owner ; Bristol-Myers Squibb Company: Employment. Hlavacek:Pfizer Inc.: Employment. Mardekian:Pfizer Inc.: Employment. Wiederkehr:Pfizer Inc.: Employment. Sah:STATinMED Research: Other: I am a paid employee of STATinMED Research which is a paid consultant to Bristol-Myers Squibb Company and Pfizer Inc.. Luo:Pfizer Inc.: Employment.
Introduction Immunomodulatory agents (IMiD's) are associated with an increased risk of venous thromboembolism (VTE), particularly when combined with high dose steroids. Studies evaluating the use of lenalidomide-bortezomib-dexamethasone (RVD) and carfilzomib-lenalidomide-dexamethasone (KRD) in the frontline setting for multiple myeloma (MM) have reported a 6% and 24% incidence of thrombosis, respectively, despite primary thrombotic prophylaxis with aspirin (ASA) (Richardson, et al. Blood. 2010; Korde, et al. JAMA Oncol 2015). Recent data, including the Hokusai VTE Cancer Trial, have suggested that safety and efficacy of direct oral anticoagulants (DOACs) are preserved in the setting of treatment of solid malignancy-associated thrombosis (Raskob, et al. N Engl J Med. 2018; Mantha, et al. J Thromb Thrombolysis. 2017). Despite this data, there is limited experience and use of DOACs in prevention of thromboses in the setting of hematologic malignancies, specifically MM. After careful review of literature, since early 2018, we changed our clinical practice and routinely placed newly diagnosed MM (NDMM) patients receiving KRD at Memorial Sloan Kettering Cancer Center (MSKCC) on concomitant rivaroxaban 10 mg once daily, regardless of VTE risk stratification. In the following abstract, we present VTE rates and safety data for newly diagnosed MM patients receiving RVD with ASA vs. KRD with ASA vs. KRD with rivaroxaban prophylaxis. Methods This was an IRB-approved, single-center, retrospective chart review study. All untreated patients with newly diagnosed MM, receiving at least one cycle of RVD or KRD between January 2015 and October 2018 were included. The period of observation included the time between the first day of therapy until 90 days after completion of induction therapy. Patients were identified by querying the pharmacy database for carfilzomib or bortezomib administration and outpatient medication review of thromboprophylaxis with rivaroxaban or ASA. VTE diagnoses were confirmed by ICD-10 codes and appropriate imaging studies (computed tomography and ultrasound). Descriptive statistics were performed. Results During the observation period, 241 patients were identified to have received RVD or KRD in the frontline (99 RVD with ASA; 97 KRD with ASA; 45 KRD with rivaroxaban). Baseline characteristics were well distributed among the three arms, with a median age of 60 (30-94) in the RVD ASA arm, 62 (33-77) in the KRD ASA arm, and 60 (24-79) in the KRD rivaroxaban arm. Patients had International Staging System (ISS) stage 3 disease in 13% (N=13), 9.3% (N=9), and 11% (N=5) of the RVD ASA, KRD ASA, and KRD rivaroxaban arms, respectively. Median weekly doses of dexamethasone were higher in both KRD arms, 40 mg (20-40) vs. 20 mg (10-40) in the RVD ASA arm. The average initial doses of lenalidomide were 22 mg in the RVD ASA arm compared to 25 mg in both the KRD ASA and KRD rivaroxaban arms. After querying the pharmacy database, no patients were identified to have a history or concomitant use of erythropoietin stimulating agent (ESA) use. Treatment-related VTE's occurred in 4 patients (4.0%) in the RVD ASA arm, 16 patients (16.5%) in the KRD ASA arm, and in 1 patient (2.2%) in the KRD rivaroxaban arm. Average time to VTE was 6.15 months (Range 5.42, 9.73) after treatment initiation in the RVD ASA group, while it was 2.61 months (Range 0.43, 5.06) in the KRD ASA group and 1.35 months in the KRD rivaroxaban group. Minor, grade 1 bleeding events per the Common Terminology Criteria for Adverse Events (CTCAE) were identified in 1 (1.1%) patient in the RVD ASA arm, 5 (5.2%) patients in the KRD ASA arm, and 1 (2.2%) patient in the KRD rivaroxaban arm. Conclusion More efficacious MM combination therapies have been found to increase the risk of VTE when using ASA prophylaxis, indicating better thromboprophylaxis is needed. We found patients receiving ASA prophylaxis with KRD were more likely to experience a VTE and these events occurred earlier compared to patients receiving ASA prophylaxis with RVD. Importantly, the rate of VTE was reduced to the same level as ASA prophylaxis with RVD when low-dose rivaroxaban 10 mg daily was used with KRD, and without necessarily increasing bleeding risk. Our retrospective data support the development of prospective clinical trials further investigating DOAC use in thromboprophylaxis for NDMM patients receiving carfilzomib-based treatments. Figure Disclosures Hassoun: Novartis: Consultancy; Janssen: Research Funding; Celgene: Research Funding. Lesokhin:BMS: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Janssen: Research Funding; GenMab: Consultancy, Honoraria; Serametrix Inc.: Patents & Royalties; Genentech: Research Funding; Juno: Consultancy, Honoraria. Mailankody:Juno: Research Funding; Celgene: Research Funding; Janssen: Research Funding; Takeda Oncology: Research Funding; CME activity by Physician Education Resource: Honoraria. Smith:Celgene: Consultancy, Patents & Royalties, Research Funding; Fate Therapeutics and Precision Biosciences: Consultancy. Landgren:Theradex: Other: IDMC; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Other: IDMC; Sanofi: Membership on an entity's Board of Directors or advisory committees; Adaptive: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. OffLabel Disclosure: Off-label use of rivaroxaban for outpatient prophylaxis of venous thromboembolism (VTE) will be explicitly disclosed to the audience.
BACKGROUND After a standard anticoagulation period (3-6 months), the risk of venous thromboembolism recurrence (RVTER) needs to be considered. Such risk is higher in unprovoked events and patients with persistent risk factor. The increase of D-dimer (DD) levels during the therapy seems to be strongly associated to RVTER. The use of rivaroxaban 10 mg/day and apixaban 2.5mg/12h as an extended therapy (ET) after the standard anticoagulation period has been proven to be an effective strategy to prevent recurrence without increasing bleeding events. AIM To assess the effectiveness and safety of reduced doses of rivaroxaban and apixaban as ET in patients with RVTER and to compare their DD levels with those of a control group on anticoagulant therapy at a standard dose. METHODS From April 2016 to June 2020, we included patients with venous thromboembolism (VTE) who received ET with rivaroxaban and apixaban with/at reduced doses. Dose reduction was performed following the clinical algorithm of our unit (Fig. 1). The DD values were determined using HemosIl D-Dimer HS-500 and the cut-off value was established at 500 µg/L DD levels were compared with a control group of 235 patients with VTE who received ET with standard doses of anticoagulation. DD levels were measured at the time of diagnosis (D1), initiation of treatment (D2) and 3 months after treatment (D3). RESULTS From a total of 116 patients (65.5% women), 77.6% (n=90) received rivaroxaban 10 mg/24h and 22.4% received apixaban 2.5 mg/12h as an ET. The mean duration of the initial anticoagulant therapy was 12 +/- 8.8 months. The mean DD value prior to the ET was 388 µg/L. In this group, 63.8% (n=74) was an unprovoked VTE and 17.2% (20) had hereditary thrombophilia. The mean of follow-up time was 6.9 +/- 8.3 months. No recurrences of VTE were observed during the follow-up and only one major bleeding event was reported in a high-bleeding risk patient. We observed a progressive decrease of DD levels from the VTE diagnosis to the last visit, with D1, D2, and D3 values of 987 µg/L ± 324, 388 µg/L ± 134, and 288 µg/L ± 98, respectively. There were no differences in d-dimer concentrations between patients with reduce doses of rivaroxaban or apixaban and the control group with standard doses (D1: 85.6% vs 81%, p =0.22; D2: 10.2% vs 8.0%, p =0.14; and D3: 9.1% vs 9.5%, p =0.18). CONCLUSIONS Our data indicated that an ET strategy with reduced doses of rivaroxaban or apixaban is effective and safe. We did not observe significant differences in DD levels at follow-up compared to the control group receiving a standard dose of anticoagulation. Further studies are needed in order to select and standardize dose reduction criteria in secondary prevention. Figure 1 Disclosures Campoy: boehringer ingelheim: Consultancy; Daiichi Sankyo: Speakers Bureau. Sierra:Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharmaceuticals: Research Funding; Astellas: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead-Kite: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Daiichi Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Olivera:Daiichi Sankyo: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Boehringer Ingelheim: Consultancy, Speakers Bureau; BAYER: Consultancy.
Abstract INTRODUCTION Thrombophilia is associated with an increased risk of venous thromboembolism (VTE). Despite this link, determining the presence or absence of such conditions has no role in VTE management including determining the choice or duration of anticoagulant therapy. Testing can be potentially harmful when results are misinterpreted or impact patient anxiety and insurance eligibility. METHODS We performed a retrospective chart review of adult patients presenting to the emergency department (ED) or were admitted to the University of Alberta Hospital (UAH), Royal Alexandra Hospital (RAH) and Grey Nuns Hospital (GNH) and underwent any number of thrombophilia tests (including factor V Leiden [FVL], prothrombin gene mutation [PT20210], protein C [PC], protein S [PS], antithrombin [AT] and antiphospholipid antibody testing). To assess for appropriateness of testing, categories of data were collected including presence of other strong risk factors obviating the need to look for other causes, indicators for higher yield (age of patient, presence of family history of VTE, idiopathic nature of VTE), presence of factors that confound testing (such as therapeutic anticoagulation) and relevant follow up (appropriate repeat testing when necessary). We also collected basic patient demographics, VTE details and ordering physician/service details to evaluate under what circumstances testing may be ordered more frequently. RESULTS 134 charts of patients tested for thrombophilia were reviewed between 2007-2013 at UAH and RAH Hospitals. A total of 965 thrombophilia tests were done (see analysis table). 13.4% of the testing was ordered by hematologists, 23.1% by neurologists, 52.2% by other internists. Overall, all patients had tests performed inappropriately, lacked appropriate follow up or had uninterpretable results and none had documented counseling prior to thrombophilia testing. CONCLUSIONS Thrombophilia testing is frequently ordered inappropriately and not adequately followed up. Strategies to educate physicians on indications and limitations of testing are warranted. These strategies can help decrease over/under/misinterpretation of thrombophilia testing as well as result in significant savings to the health care system if testing can be reduced. Table 1. Demographics Sample Size Males Females Total 74 (55.22%) 60 (44.78%) 134 (100%) Age at time of testing (Yrs) Range 19-88 Average 48.7 Patients' Test Results Test Times Performed Abnormal Results APCR 134 (100%) 32 (23.8%) FVL genetic test 58 (43%) 21 (39%) PT20210 105 (77%) 4 (3.8%) Protein C 100 (74.1%) 8 (8%) Protein S 99 (73.3%) 16 (16.2%) AT levels 99 (73.3%) 19 (19.2%) Anticardiolipin Ab 117 (86.7%) 4 (3.4%) Lupus Anticoagulant 109 (81.3%) 10 (10.2%) Provoking Factors Patients with One or More Provoking Factors Major 10 7.4% Moderate 74 56% Minor 29 21.8% No Provoking Factors 49 36.8% Family History of VTE 12 8.9% Protein C and Protein S Testing Done During Acute VTE 64 64% Patient was on Warfarin 25 25% Number of Abnormal Test Results 24 16% Number of Repeated Abnormal Tests 0 0% AT Testing Total Tests Performed 99 73.3% Done During Acute VTE 62 63% Patient was on Therap. Heparin or LMWH 62 62.6% Number of Abnormal Test Results 19 19.2% Abnormal Tests Repeated? 7 37% Repeat Tests Showing Normal Results 3 57% APA Testing Tests were Repeated After 12 Weeks for Confirmation 11% Disclosures Wu: Leo Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.
Abstract Background: Splenectomy is a therapy for many conditions the most common of which are trauma, Hodgkin lymphoma, thalassemia and hereditary or autoimmune hemolytic anemia, and immune thrombocytopenia (ITP). By 1960 splenectomy had been known to create a risk of over-whelming post splenectomy sepsis (OPSS) with a high mortality rate. More recently population-based studies from Denmark have suggested that there is also an increased risk of thromboembolic (TEE) complications. Thromboembolic events generally include venous thrombosis (deep vein thrombosis (DVT) and pulmonary embolism (PE)) and arterial thrombosis (stroke and myocardial infarction [MI]). ITP and hemolytic anemias have been shown to independently have increased risks of arterial and venous TEE which has complicated assessment of additive effects of splenectomy. While splenectomized patients appear to be at increased risk of arterial and venous thromboses, the incidence and which TEEs predominate remains unclear as does the timing of occurrence of the TEEs. Method: The Nurses' Health Study (NHS) was established in 1976 and enrolled 121,700 female nurses between 30-55 years old. The nurses completed baseline questionnaires and biennial follow up questionnaires. In 2004, NHS participants were asked whether they had undergone splenectomy. The primary outcomes of this study included DVT,PE, and MI, which were identified through self-report on biennial questionnaires. MIs were confirmed through medical record review. End of follow-up for this study went through 2016, date of death, or diagnosis of outcome, whichever came first. Loss to follow up was very low and causes of deaths were carefully tracked. Descriptive statistics compared the splenectomy vs non-splenectomy participants with respect to basic demographic factors and variables that may be related to the outcomes. Cox proportional hazards models were run to evaluate incidence rates for primary and secondary outcomes. We conducted age-adjusted, as well as multivariable adjusted models. Multivariate models were adjusted for age, body mass index, smoking history, diabetes mellitus, high blood pressure, and high cholesterol, thus taking into account known predictors of the specific TEEs. Multivariate models were updated every two years to account for time varying confounders. Results： In 2004, 323 participants reported having had a splenectomy, out of 96,000 completing the questionnaire. There was a strong, significant association between splenectomy and subsequent DVT (n=613) and PE (n=840). The multivariate adjusted HR was 3.73 (95%CI: 1.77-7.86) and 3.80 (95%CI: 2.04-7.10) respectively. When considered together as a composite outcome, the splenectomized participants had a 3.52-fold higher risk (95%CI: 2.12-5.85) of PE/DVT compared with non-splenectomy. There was no association between splenectomy and MI (n=1011; HR = 0.97, 95% CI: 0.31-3.01). Given the very limited number of stroke cases in the splenectomized population, we were underpowered/unable to evaluate the association of splenectomy and subsequent risk of stroke. Conclusion: This study found that splenectomized patients are at a 4-fold increased risk of PE and DVT as compared to not-splenectomized individuals. These findings were not dependent on any of the potentially confounding variable analyzed. We found no association between splenectomy and MI. There are limitations to these results. No information was available on family history and perioperative thrombo-prophylaxis. Also we do not know exactly when or why splenectomy was performed; there were at least 34 women who had splenectomy for ITP but in most cases the underlying disease was unknown. Since the nurses in 1976 were already between 30-55 years old, it is no longer possible to retrospectively obtain sufficient information. Therefore, the splenectomy question has been added to the current survey for NHS#2. We will pursue the relevant information in a follow up letter to respondents who reported having undergone splenectomy while seeing if the findings of NHS#2 confirm those of NHS#1. Figure 1 Figure 1. Disclosures Bussel: Principia/Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; UCB: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: DSMB; Momenta/Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Argenx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Dova/Sobi: Consultancy, Membership on an entity's Board of Directors or advisory committees; CSL: Other: DSMB; RallyBio: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Rigel: Consultancy, Membership on an entity's Board of Directors or advisory committees; UptoDate: Honoraria.
Abstract Introduction Immune thrombocytopenia (ITP), defined as an isolated low platelet count (<100 × 10 9/L), occurs in approximately 1 in 1000 to 10,000 pregnancies in the United States and is the most common cause of severe thrombocytopenia (platelet count <50 × 10 9/L) detected in the first and second trimesters. Treatment for ITP during pregnancy is limited by the lack of safety evidence for the fetus/infant. The Pregnancy Surveillance Program (PSP) was conducted to collect safety information on pregnancy and fetal outcomes of women exposed to the thrombopoietin receptor agonist romiplostim before conception, during pregnancy, or immediately postpartum. Here, we report pregnancy and birth outcomes as well as adverse events (AEs) for mother and fetus/infant. Methods Pregnancy outcomes data from women of 25 different countries were collected from August 1, 2017-March 15, 2020. Authorization to obtain pregnancy and infant health information as well as follow up with healthcare professionals was obtained from the mothers. One follow-up attempt was made if the mother was unresponsive, and two follow-up attempts were made 6-8 weeks after the mother's estimated date of delivery. Additional follow-ups were conducted when the infant was 6 and 12 months of age. Romiplostim pregnancy exposure cases reported during the data-collection period were entered into the PSP database and reported to global health authorities per local rules and regulations. Abnormal pregnancies were defined as those with at least one serious AE. Birth outcomes included live birth, premature birth, spontaneous abortion, elective termination, and stillbirth. Results Overall, 200 pregnancies were reported, including 11 pregnancies from clinical study sources, and 189 pregnancies from non-trial sources; 188 women were exposed to romiplostim. Two pregnancies were ongoing at the time of data cutoff (March 15, 2020). The median (Q1, Q3) overall duration of romiplostim exposure was 156 (44, 522) days (data available for 56 women), and 28 (7, 60) days during pregnancy (data available for 53 women). Median (Q1, Q3) age for the pregnant women was 30 (27, 33) years. Concomitant medications for ITP were used by 61 (32%) women and included corticosteroids (n=37), immunoglobulins (n=29), and rituximab (n=8). Overall, 43 (23%) women received treatment with romiplostim in the third trimester with median (Q1, Q3) exposure of 21 (7, 63) days. Of the 86 known pregnancy outcomes by trimester exposure (Figure 1), 40 (46.5%) were normal pregnancies with 15% abnormal birth outcomes, and 46 (53.5%) were abnormal pregnancies with 65.2% abnormal birth outcomes; 26 (56.5%) of the abnormal pregnancies were low platelet counts. Three cases of ectopic pregnancy were reported among women receiving romiplostim for ITP prior to conception. In all three women, romiplostim was continued up to, during, and after the ectopic pregnancy. One molar pregnancy was reported in a woman who received romiplostim for chronic ITP for approximately one year before conception. Of the 96 known birth outcomes, 57.3% were normal term, 11.5% were spontaneous abortion, 9.4% were term with complication (inguinal hernia, congenital cytomegalovirus infection, trisomy 8, and single umbilical artery), 9.4% were elective termination, and 12.4% were other outcomes (including 11 premature births, and one stillbirth). Twelve infants (including one case of twins) had thrombocytopenia at birth, of whom nine received immunoglobulins, and three received platelet transfusions. Out of the 12 infants, eight had resolution of thrombocytopenia within a week, and four (including the twins) had no available information about outcomes. No infant had defective immune system development, neoplasm, or bone marrow reticulin formation. One infant was diagnosed with fetal and neonatal alloimmune thrombocytopenia that resolved two months after birth. Among the 12 thrombocytopenic infants, six had good and six had unknown current/discharge health status. Conclusions The available data from the PSP suggested that the risk of adverse birth outcomes was low regardless of the timing of exposure. Additionally, no substantial safety concerns were identified for the mothers, fetuses, and infants due to romiplostim use during pregnancy. The results are complicated, however, by the abnormal pregnancies in women with severe ITP who comprised the majority of cases where romiplostim was used. Figure 1 Figure 1. Disclosures Bussel: UCB: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: DSMB; Dova/Sobi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Rigel: Consultancy, Membership on an entity's Board of Directors or advisory committees; CSL: Other: DSMB; Principia/Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Momenta/Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; UptoDate: Honoraria; Argenx: Consultancy, Membership on an entity's Board of Directors or advisory committees; RallyBio: Consultancy, Membership on an entity's Board of Directors or advisory committees. Cooper: Principia and Sanofi: Consultancy; Sanofi and Principia: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel, accommodations expenses. Lawrence: Amgen Inc: Current Employment, Current equity holder in publicly-traded company. Michel: Amgen: Consultancy; Rigel: Honoraria; Novartis: Consultancy; Argenx: Honoraria; UCB: Honoraria; Alexion: Honoraria. Wang: Amgen Inc: Current Employment, Current equity holder in publicly-traded company. Saad: Amgen: Current Employment, Current equity holder in publicly-traded company.
Abstract Wiskott Aldrich syndrome (WAS) is a rare X-linked primary immunodeficiency associated with thrombocytopenia, eczema, infectious, autoimmune complications, and lymphomas. Patients lacking an HLA-matched donor may benefit from an alternative therapeutic approach based on the infusion of autologous gene corrected CD34+ cells. We previously reported a non-randomised, open-label, phase 1/2 clinical study applying a lentiviral vector based gene therapy (GT) protocol in 7 paediatric patients with severe WAS (score ≥ 3/5) (S. Hacein-Bey Abina et al, JAMA 2015). One patient died 7 months after GT because of pre-existing severe opportunistic infections, as reported. Two additional patients have been treated since that initial report, with a follow-up of at least 4 years. We here present a comprehensive long-term study on 8 patients with a follow-up from 4 to 9 years (median 7.6). The safety and efficacy of the approach is thoroughly investigated, with a particular focus on the correction of thrombocytopenia and auto-immunity. A stable engraftment of genetically and functionally corrected lymphoid and myeloid cells was reached in all patients, with no serious treatment-associated adverse events or concerning clonal expansion. Corrected lymphoid cells displayed a selective advantage over time with increasing vector copy number (VCN) level. In turn, this led to (i) sustained expression of WAS protein (WASp) in the patients' cells and (ii) clinical resolution of severe eczema and susceptibility to recurrent infections. In line with these results, T-cell function was restored after GT, as shown by the recovery of immune synapse assembly and the normalization of naïve T cell numbers. The T-cell compartment was also reconstituted in the patient treated at the age of 30 years, suggesting that GT for WAS is a treatment option in adult patients. In parallel with the robustness of T-cell reconstitution a normalized B-cell compartment was observed after GT, as shown in particular by increasing levels of WASp + switched memory B cells over time and the age-matched levels of KRECs. Five patients out of 8 were able to discontinue Ig replacement therapy while achieving normal post-vaccination antibody titers. Autoimmune disorders and bleeding episodes were significantly less frequent, despite only partial correction of the platelet compartment. After GT, a few autoimmune manifestations were observed: the persistence of lower extremity vasculitis (P2, very severe prior to GT), the new occurrence of nephrotic syndrome (P9), and the presence of anti-platelet antibodies (P2, P4, P7). The levels of circulating autoantibodies detected before GT (including ANA and vasculitis-related autoantibodies) normalized after treatment. Following GT, platelets were found to express sub-normal levels of WASp and to only partially augment their size. Platelet function studies indicated a partial correction of the platelet compartment achieved by GT, which may be sufficient to prevent occurrence of the hemorrhagic symptoms typical of WAS. Our results suggest that lentiviral GT provides sustained clinical benefits for patients with WAS. Overall clinical remission was observed in our patients despite very severe disease scores before GT. More efficacious and more reliable transduction protocols and conditioning regimen are likely to further improve outcomes, particularly with regard to platelet recovery, where the advantages of intrinsic correction are less apparent. Disclosures Booth: Orchard Therapeutics: Consultancy, Honoraria; SOBI: Consultancy, Honoraria; Takeda: Honoraria; GSK: Honoraria; Rocket Pharmaceuticals, Inc.: Consultancy. Thrasher: Orchard Therapeutics: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Generation bio: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; 4Bio Capital: Consultancy, Membership on an entity's Board of Directors or advisory committees; Rocket Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. Cavazzana: Smart Immune: Other: co-founder.
Introduction: The open-label, expanded access study (RIALTO) demonstrated that blinatumomab is efficacious with a manageable safety profile in children with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (R/R BCP-ALL). Blinatumomab is a BiTE® (bispecific T-cell engager) immuno-oncology therapy that activates cytotoxic T cells to kill target B cells. Here, findings from the final analysis of RIALTO are presented (NCT02187354). Methods: Enrolled in the study were children >28 days and <18 years of age with R/R CD19+ BCP-ALL (defined as ≥2 relapses, relapse after allogeneic hematopoietic stem cell transplant [alloHSCT], or refractory to prior treatments) and ≥5% blasts or <5% blasts but with minimal residual disease (MRD) level ≥10−3. Blinatumomab was given as continuous infusion in a 6-week cycle (4 weeks on and 2 weeks off) for up to 5 cycles and safety follow-up visit 30 days post-treatment. Patients with <25% blasts were dosed at 15 µg/m2/day, whereas those with ≥25% blasts were dosed at 5 µg/m2/day (days 1-7 of cycle 1) followed by dose increase to 15 µg/m2/day. Primary endpoint was incidence of treatment-emergent (TE) and treatment-related (TR) adverse events (AEs). Secondary endpoints included complete response (CR; <5% blasts) and MRD response (<10−4 blasts by PCR or flow-cytometry) in the first 2 cycles, relapse-free survival (RFS), overall survival (OS), and alloHSCT rate after blinatumomab treatment. Results: As of the data cutoff date (January 10, 2020) for the final analysis, demographics and baseline characteristics of 110 patients enrolled (median age, 8.5 years [95% CI 0.4-17.0]), 61% had <50% blasts at baseline, and 11% had <5% blasts (n=12; with MRD ≥10−3) remain unchanged compared with the primary analysis (Table 1). For best treatment response within the first 2 cycles, results are comparable to that of the primary analysis. Among 110 patients, overall CR rate was 62.7% (n= 69). Of 98 patients with ≥5% blasts at baseline, 59% (n=58) achieved CR; of them, 79% (n=46) achieved an MRD response and 62% (n=39) proceeded to HSCT. The 2 patients with t(17;19) achieved CR with an MRD response. Of the 4 patients with germline trisomy 21 (Down syndrome), 3 achieved CR with an MRD response Among the 12 patients with <5% blasts but with MRD ≥10−3 at baseline, 92% (n=11) achieved CR and MRD response; 75% (n=9) proceeded to HSCT (Table 2). Of the 5 patients who had received prior blinatumomab , 4 achieved CR. Of 110 patients treated with blinatumomab, median OS (95% CI) was 14.6 (11-24.5) months with median follow-up time of 18.2 months, which increased by 1.5 months compared with that reported in the primary analysis, with 29.9% of patients still surviving at month 24. Median RFS (95% CI) remains unchanged at 8.5 months (4.7-14.0), with a median follow-up time of 11.5 months in patients who achieved CR; 38% of patients relapsed and 9% died. RFS was more favorable for patients who received HSCT post blinatumomab (70%) than for those who did not (30%) at month 12, respectively, which is consistent with the results from primary analysis. Among patients who had HSCT prior to blinatumomab (n= 45), median OS (95%) was 16.6 (7.1-NE) months vs 14.6 (10.9-24.5) months in patients without HSCT prior to blinatumomab (n= 65). Compared with the primary analysis, 5 additional patients received HSCT after achieving CR in the final analysis. Median OS among patients in CR after HSCT by MRD responders vs MRD non-responders was NE at 15-month analysis (Figure). Safety results in the final analysis were consistent with those reported in the primary analysis. Of 110 patients, 99% experienced TEAEs, with 65% being grade ≥3 (see Table 3 for details). TRAEs were reported in 74% of patients; 26% were grade ≥3 and 19% were deemed serious. Details on grade ≥3 TRAEs are shown in Table 3. The 9 fatal AEs, unrelated to blinatumomab, occurred due to relapse and progressive nature of the disease (Table 3). Conclusions: Overall, the safety and efficacy results from the final analysis are consistent with those reported in the primary analysis as no new safety signals were observed. These findings strengthen the observation that blinatumomab demonstrates durable efficacy and is a suitable treatment option in children with R/R BCP-ALL. Table 1. Disclosures Locatelli: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Medac: Speakers Bureau; Miltenyi: Speakers Bureau; Bellicum Pharmaceutical: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceeutical: Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Zugmaier:Amgen: Current Employment, Other: Personal Fees ; 20190300609: Patents & Royalties: Licensed patient . Mergen:Amgen: Current Employment, Current equity holder in publicly-traded company. Bader:Medac: Patents & Royalties, Research Funding; Amgen: Consultancy, Speakers Bureau; Neovii: Research Funding; Celgene: Consultancy; Novartis: Consultancy, Speakers Bureau; Riemser: Research Funding. Schlegel:bluebird bio: Honoraria. Bourquin:Servier: Other: Travel Support. Handgretinger:Amgen: Honoraria. Brethon:Amgen: Other: invitation to meetings, remunerations for oral presentations, advices for the record of Blinatumomab in pediatrics in France. Rössig:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria; Pfizer: Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees; EUSA Pharma: Membership on an entity's Board of Directors or advisory committees; Genetech: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Kormany:Amgen: Current Employment, Current equity holder in publicly-traded company. Viswagnachar:IQVIA: Current Employment.
