Inherited Thrombophilia and the Risk of Arterial Ischemic Stroke: A Systematic Review and Meta-Analysis

Abstract Introduction:The inherited thrombophilias Factor V Leiden (FVL), the Prothrombin G20210A mutation (PTM), Protein C deficiency (PCD), Protein S deficiency (PSD), and Antithrombin deficiency (ATD) are well-established predisposing factors for venous thromboembolism, but their role in arterial thrombosis such as arterial ischemic stroke remains uncertain. The 2018 American Heart Association/American Stroke Association clinical practice guideline recommends against thrombophilia testing in patients with ischemic stroke, though such testing remains common in clinical practice. We conducted a systematic review and meta-analysis to evaluate the association of inherited thrombophilias and risk of arterial ischemic stroke in adults. Methods:A systematic literature search was performed using MEDLINE, EMBASE, and Cochrane Library Databases from inception to December 31, 2017 without language restrictions. Manual reviews of conference abstracts and bibliographies of included studies were performed to identify additional eligible studies. We included case-control studies of adults age ≥15 years that reported the prevalence of at least one of the inherited thrombophilias of interest (FVL, PTM, PCD, PSD, ATD) in both subjects with a history of arterial ischemic stroke (cases) and subjects without arterial ischemic stroke (controls). Studies were required to have ≥10 subjects in each group. Studies that enrolled patients with transient ischemic attack, hemorrhagic stroke, cerebral venous sinus thrombosis, and other arterial thromboses were excluded. Two reviewers (T.C. and E.D.) independently searched the literature and extracted data from eligible studies. Disagreements were resolved by consensus or a third reviewer (A.C.) when necessary. Methodological quality of included studies was appraised using the NIH Quality Assessment of Case-Control Studies assessment tool. Data analysis was performed using R version 3.4.4. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using a random-effects model. Inter-study heterogeneity was evaluated using Cochran's Q test and I2statistics. Prespecified subgroup analyses were performed in young patients (<65 years), patients with a patent foramen ovale (PFO), and patients with cryptogenic stroke. Funnel plots and Egger's test were used to assess for the presence of publication bias. The study protocol is available on PROSPERO (CRD42018090020). Results:A total of 1,730 records were retrieved from the literature search. After screening by title and abstract, 1527 records were excluded. The remaining 203 references underwent full text review, 71 of which met eligibility criteria and were included in the analysis. These 71 studies collectively enrolled 13,347 stroke patients and 31,676 controls. The number of studies that reported on FVL, PTM, PCD, PSD, and ATD were 59, 47, 14, 15, and 11, respectively. Heterogeneity among studies was low. Compared with controls, inherited thrombophilia was significantly more common in patients with arterial ischemic stroke for the following defects: homozygous FVL (OR 2.24; 95%CI, 1.24-4.07; I2=0%), heterozygous FVL (OR 1.32; 95%CI, 1.11-1.57; I2=33%), homozygous PTM (OR 7.19; 95%CI 2.47-20.95; I2=0%), heterozygous PTM (OR 1.53; 95%CI, 1.27-1.84; I2=2%), PCD (OR 2.70; 95%CI, 1.44-5.04; I2=0%), and PSD (OR 2.75; 95%CI, 1.56-4.85; I2=34%) (Figure 1). Statistical significance was not reached for ATD (OR 1.84; 95%CI, 0.92-3.71; I2=11%). Subgroup analyses showed a higher magnitude of stroke risk in young patients across all thrombophilias. The associations were non-significant for patients with PFO and cryptogenic stroke (Table 1). Funnel plots were symmetrical and Egger's test was non-significant (p>0.05), suggesting absence of publication bias, for all thrombophilias except heterozygous FVL (p=0.003). Conclusions: Our results suggest that inherited thrombophilias including FVL, PTM, PCD, and PSD are associated with an increased risk of arterial ischemic stroke, particularly in young patients. The association with FVL and PTM is stronger in the homozygous than in the heterozygous state, suggesting a potential dose-response relationship and causal role for inherited thrombophilias. The implications of these findings with respect to the evaluation and management of patients with ischemic stroke require further investigation. Disclosures Crowther: Alnylam: Equity Ownership; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Shinogi: Consultancy; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Leo Pharma: Research Funding; Octapharma: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; Bayer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Alexion: Speakers Bureau. Garcia:Bristol Meyers Squibb: Consultancy; Daiichi Sankyo: Research Funding; Janssen: Consultancy, Research Funding; Pfizer: Consultancy; Portola: Research Funding; Incyte: Research Funding; Retham Technologies LLC: Consultancy; Shingoi: Consultancy; Boehringer Ingelheim: Consultancy. Cuker:Kedrion: Membership on an entity's Board of Directors or advisory committees; Spark Therapeutics: Research Funding; Synergy: Consultancy; Genzyme: Consultancy.

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Warfarin Resumption after Intracranial Hemorrhage: A Systematic Review and Meta-Analysis

Blood ◽

10.1182/blood.v128.22.3821.3821 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3821-3821

Author(s):

Chatree Chai-Adisaksopha ◽

Christopher M Hillis ◽

Daniel M. Witt ◽

Sam Schulman ◽

Mark Crowther ◽

...

Keyword(s):

Systematic Review ◽

Ischemic Stroke ◽

Board Of Directors ◽

Intracranial Hemorrhage ◽

Research Funding ◽

Meta Analysis ◽

Forest Plot ◽

Thromboembolic Events ◽

Advisory Committees ◽

All Cause Mortality

Abstract Objective: To assess the effect of warfarin resumption in patients who experienced warfarin-associated intracranial hemorrhage. Study design: Systematic review and meta-analysis Data sources:We searched MEDLINE (1966 to July 2016), EMBASE (1980 to July 2016) and Cochrane Library electronic database (up to July 2016). Inclusion criteria:Studies were eligible for inclusion if (1) they were randomized controlled trials, prospective cohort or retrospective cohort studies, (2) studies that included adult patients (≥18 years), (3) studies that investigated the patients who experienced warfarin-associated intracranial bleeding, (4) studies that evaluated incidence of recurrent intracranial hemorrhage, thromboembolic events, and all-cause mortality, and (5) studies that reported on patients with warfarin resumption compared to controls (those who did not resume warfarin). Main outcome and measures: Primary outcome was all-cause mortality. Secondary outcomes were ischemic stroke, thromboembolic events, recurrent intracranial hemorrhage and any bleeding. Pooled relative risks (RRs) were calculated using random-effects model. Results: Seven studies were included in the meta-analysis, involving 623 patients who resumed warfarin and 1851 patients who did not resume warfarin after warfarin-associated intracranial hemorrhage. Majority of patients were anticoagulated due to atrial fibrillation, prosthetic heart valve and venous thrombosis. Median time to resume warfarin ranged form 11 days to 39.2 days. Warfarin resumption significantly reduced risk of all-cause mortality (17.06% vs 35.71%), RR 0.50, 95% confidence interval [CI];0.33-0.77, I-square=58.7%, Figure 1. Lower ischemic stroke was observed in patients who resumed warfarin (4.89% vs 7.64%), RR 0.67, 95%CI; 0.45-0.99, I-square=0%, Figure 2. Composite outcome of thromboembolic event was lower but not significant in patients who resumed warfarin (7.35% vs 11.48%), RR 0.61, 95%CI; 0.39-1.07, I-square=50.7%. Recurrent intracranial hemorrhage was not significantly different between patients who resumed and those who did not resume warfarin (7.33% vs 7.39%), RR 1.14, 95%CI; 0.57-2.27, I-square=51.0%, Figure 3. Any bleeding was not significantly different between 2 groups (8.23% vs 8.31%), RR 1.03, 95%CI; 0.73-1.43, I-square=50.4%. Conclusions: Major limitation of this meta-analysis included potential selection bias of the original studies, specifically, patients with better prognosis tended be selected to restart warfarin. In summary, , warfarin resumption after warfarin-associated intracranial hemorrhage was associated with lower risk of all-cause mortality and ischemic stroke without a significant increase in recurrent intracranial hemorrhage. Figure 1 Forest plot of all-cause mortality comparing patients who do and do not resume warfarin. Figure 1. Forest plot of all-cause mortality comparing patients who do and do not resume warfarin. Figure 2 Forest plot of ischemic stroke comparing between patients who do and do not resume warfarin. Figure 2. Forest plot of ischemic stroke comparing between patients who do and do not resume warfarin. Figure 3 Forest plot of recurrent intracranial hemorrhage comparing between patients who resume warfarin versus those who did not resume. Figure 3. Forest plot of recurrent intracranial hemorrhage comparing between patients who resume warfarin versus those who did not resume. Disclosures Hillis: Celgene: Consultancy; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Honoraria. Crowther:AKP America: Membership on an entity's Board of Directors or advisory committees; Alexion: Consultancy, Speakers Bureau; Bayer AG: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Boehringer-Ingelheim: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb - Pfizer alliance: Honoraria; Celgene: Honoraria; CSL Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Daichii: Honoraria; Leo Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Octapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Ortho Clinical Diagnostics: Honoraria; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees.

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Lipoprotein (a) Levels in Childhood Arterial Ischemic Stroke

Clinical and Applied Thrombosis/Hemostasis ◽

10.1177/1076029609334124 ◽

2009 ◽

Vol 16 (2) ◽

pp. 214-217 ◽

Cited By ~ 13

Author(s):

Serap Teber ◽

Gülhis Deda ◽

Nejat Akar ◽

Kazım Soylu

Keyword(s):

Risk Factor ◽

Ischemic Stroke ◽

Young Patients ◽

Control Group ◽

Healthy Children ◽

Case Control Studies ◽

Arterial Ischemic Stroke ◽

Lipoprotein A ◽

Screening Programs ◽

Stroke In Young Adults

Lipoprotein (a) is a cholesterol-rich plasma lipoprotein with a lipid composition similar to that of low-density lipoproteins (LDL). Many prospective and case-control studies identified elevated levels of lipoprotein (a) as a risk factor for premature myocardial infarction and stroke. Elevated lipoprotein (a) has been identified as a genetically determined risk factor for stroke in young adults, but only preliminary data are available on its role as a risk factor for ischemic stroke in infants and children. Fifty two children with arterial ischemic stroke and 78 age- and sex-matched healthy children were studied. Data of this study indicate that 26.9% of children with arterial ischemic stroke had high lipoprotein (a) levels in comparison with the age matched healthy control group. Measurement of lipoprotein (a) should be included in screening programs performed in young patients suffering not only from venous thromboembolism but also arterial ischemic stroke, in addition to other thrombophilic factors.

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Inherited Thrombophilia and the Risk of Arterial Ischemic Stroke: A Systematic Review and Meta‐Analysis

Journal of the American Heart Association ◽

10.1161/jaha.119.012877 ◽

2019 ◽

Vol 8 (19) ◽

Cited By ~ 2

Author(s):

Thita Chiasakul ◽

Elizabeth De Jesus ◽

Jiayi Tong ◽

Yong Chen ◽

Mark Crowther ◽

...

Keyword(s):

Systematic Review ◽

Ischemic Stroke ◽

Meta Analysis ◽

Arterial Ischemic Stroke ◽

Inherited Thrombophilia

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Low Molecular Weight Heparin for Prevention of Placenta-Mediated Pregnancy Complications: An Individual Patient Data Meta-Analysis

Blood ◽

10.1182/blood.v126.23.890.890 ◽

2015 ◽

Vol 126 (23) ◽

pp. 890-890

Author(s):

Marc Rodger ◽

Johanna IP de Vries ◽

Evelyne Rey ◽

Jean-Christophe JCG Gris ◽

Ida Martinelli ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Low Molecular Weight Heparin ◽

Individual Patient Data ◽

Meta Analysis ◽

Risk Difference ◽

Patient Data ◽

Low Molecular Weight ◽

Single Center ◽

Advisory Committees

Abstract Introduction Placenta-mediated pregnancy complications (PMPC) include pre-eclampsia, late pregnancy loss, placental abruption, and the small-for-gestational age (SGA) newborn. They are leading causes of maternal, fetal, and neonatal morbidity and mortality. Affected women are at an elevated risk of recurrence in subsequent pregnancies. We completed a pooled summary-based (i.e. study level) meta-analysis that strongly suggests that low-molecular-weight heparin (LMWH) reduces the risk of recurrent PMPCs. However, our study-level meta-analysis was limited by high clinical and statistical heterogeneity likely due to the inclusion of women with heterogeneous prior PMPCs and trial designs (e.g. single vs multi-center trials). To address these limitations, the trialists agreed to conduct an individual patient data meta-analysis to identify sources of heterogeneity including exploring which patients benefit from LMWH and which outcomes are prevented. Methods We conducted a systematic review to identify randomised controlled trials that were eligible to contribute individual patient data to a meta-analysis to evaluate the effectiveness of LMWH for reducing the risk of PMPC in women with prior PMPCs. The primary outcome was a composite of early-onset or severe pre-eclampsia, birth of an SGA newborn < 5th percentile, late pregnancy loss (> 20 weeks), or placental abruption leading to delivery. Individual patient data from eligible women were re-coded in a prescribed format and combined in a common dataset for analysis. All studies were assessed for risk of bias. Results Data from 1049 women in nine trials were analysed; Participants were mostly Caucasian (88%) with a mean age of 31.518 had thrombophilia. 525 women were randomised to LMWH and 524 to no LMWH. In our primary outcome analysis, LMWH did not significantly reduce the risk of recurrent PMPCs (LMWH 60/459 (13.1%) vs. no LMWH 92/449 (20.5%) p=0.1). Significant heterogeneity was noted between single center and multi-center trials. In multi-center trials, LMWH reduced HELLP (p=0.03) but none of the other secondary outcomes, whereas in single center trials LMWH reduced all of the secondary outcomes. In sub-group analysis, in multi-center trials LMWH reduced the primary outcome in women with prior abruption (p<0.01) but none of the other sub-groups, whereas in single center trials LMWH was beneficial in all the sub-groups (prior pre-eclampsia, prior severe pre-eclampsia, prior early onset pre-eclampsia, prior SGA <10th, prior SGA < 5th and prior abruption). Conclusions In this individual patient data meta-analysis, LMWH does not appear to reduce the risk of recurrent PMPC in women with prior PMPC. Promising results suggest that women with prior abruption may benefit from LMWH but this should be replicated in future multi-center trials. PROSPERO registration:CRD42013006249 Table. Primary Analysis All Studies Multi-Center Studies Single Center Studies Composite outcome Risk difference (95% CI) N=908 -0.07 (-0.16, 0.01)p = 0.10 N=524 -0.01 (-0.11, 0.09) p = 0.89 N=384 -0.17 (-0.21, -0.13) p < .0001 Secondary Outcome Analyses Severe or Early Preeclampsia Risk difference (95% CI) N=946 -0.04 (-0.10, 0.02) p = 0.20 N=562 0.01 (-0.06, 0.07) p = 0.81 N=384 -0.11 (-0.16, -0.07) p <.0001 HELLP Risk difference (95% CI) N=813 -0.02 (-0.04, -0.004) p = 0.01 N=429 -0.01 (-0.02, -0.001) p = 0.03 N=384 -0.04 (-0.07, -0.01) p = 0.02 SGA <10 Risk difference (95% CI) N=913 -0.08 (-0.14, -0.02) p = 0.01 N=529 -0.03 (-0.10, 0.03) p = 0.32 N=384 -0.14 (-0.18, -0.10) p <0.0001 Abruption leading to delivery Risk difference (95% CI) N=945 -0.01 (-0.02, 0.003) p = 0.14 N=561 -0.01 (-0.03, 0.01) p = 0.53 N=384 -0.016 (-0.027, -0.005) p = 0.005 Subgroup Analyses Prior preeclampsia Risk difference (95% CI) N=583 -0.12 (-0.19, -0.04) p = 0.002 N=288 -0.06 (-0.19, 0.06) p = 0.34 N=295 -0.17 (-0.24, -0.11) p <.0001 Prior severe or early onset Preeclampsia Risk difference (95% CI) N=487 -0.10 (-0.19, -0.02) p = 0.02 N=236 -0.04 (-0.19, 0.12) p = 0.65 N=251 -0.17 (-0.23, -0.11) p <.0001 Any prior late loss (2 >12 weeks or 1 >16 weeks) Risk difference (95% CI) N=245 0.001 (-0.11, 0.12) p = 0.98 N=0 Prior SGA < 10 Risk difference (95% CI) N=305 -0.12 (-0.25, 0.01) p = 0.08 N=203 -0.03 (-0.17, 0.10) p = 0.64 N=102 -0.29 (-0.38, -0.20) p <.0001 Prior abruption Risk difference (95% CI) N=281 -0.16 (-0.22, -0.11) p <.0001 N=95 -0.13 (-0.22, -0.04) p = 0.01 N=186 -0.18 (-0.22, -0.14) p <.0001 Disclosures Rodger: Biomerieux: Honoraria, Research Funding. Off Label Use: Low Molecular Weight Heparin to prevent pregnancy complications. de Vries:Pfizer: Research Funding. Rey:Leo Pharma: Other: Travel Grant. Gris:Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Stago: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Leo Pharma: Consultancy, Speakers Bureau; LFB: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Baxter: Research Funding; BI: Speakers Bureau; Bayer: Speakers Bureau; BMS: Speakers Bureau. Schleussner:Bayer: Speakers Bureau; Pfizer: Research Funding, Speakers Bureau; Merck: Research Funding, Speakers Bureau. Middeldorp:GSK/Aspen: Research Funding; Bayer: Consultancy, Speakers Bureau; BI: Consultancy, Speakers Bureau; BMS: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy, Research Funding, Speakers Bureau; Daiichi-Sankyo: Consultancy, Speakers Bureau. Bates:Eli Lilly Canada: Other: I hold the Eli Lilly Canada/May Cohen Chair in Women's Health. Eli Lilly Canada provides unrestricted funding for partial salary support through this Chair. Eli Lilly Canada does not manufacture/distribute drugs relevant to the topic to be discussed..

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Outcomes with Interferon in Essential Thrombocythemia: A Systematic Review and Meta-Analysis

Blood ◽

10.1182/blood-2021-145675 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3147-3147

Author(s):

Moazzam Shahzad ◽

Mamoon Ahmed ◽

Sakina Abbas ◽

Muhammad Arslan ◽

Tooba Kashif ◽

...

Keyword(s):

Systematic Review ◽

Board Of Directors ◽

Interferon Alpha ◽

Essential Thrombocythemia ◽

Research Funding ◽

Meta Analysis ◽

Molecular Response ◽

Publicly Traded ◽

Advisory Committees ◽

Hematological Response

Abstract Introduction Essential thrombocythemia (ET) is a BCR-ABL negative myeloproliferative disorder characterized by high burden of symptoms, thrombocytosis, increased risk of thrombosis and bleeding, and risk of progression to Myelofibrosis. Interferon alpha (IFN-α) is a potent immunomodulation agent proposed to be capable of inducing complete hematological remission in patients with myeloproliferative disorders. Many INF- α have been studied for treatment of patients with ET. We present a systematic review and meta-analysis assessing the efficacy of IFN-α therapy in patients with ET. Methods Following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines, a comprehensive literature search was conducted on PubMed, Cochrane, and Clinical trials.gov using MeSH terms and keywords for " Thrombocythemia, Essential " AND " Interferons " in April 2021. We did not place any time constraints. Our search produced a total of 825 records and duplicates were removed. After screening and removing irrelevant and review articles, we included 21 original articles reporting IFN-α as the only treatment for ET in adult patients. The data were collected for baseline characteristics of the participants and efficacy and safety of the intervention. Quality evaluation was done using the NIH quality assessment tool. The inter-study variance was calculated using the Der Simonian-Laird Estimator. Proportions along with 95% Confidence Interval (CI) were extracted to compute pooled analysis using the 'meta' package by Schwarzer et al. in the R programming language (version 4.16-2). Results A total of 388 patients from 21 articles were evaluated. The median age of participants was 54 (35-62) years and 31% (n=64/205) were males. The type of IFN used were Interferon-alpha in 4 studies, pegylated (PEG)IFN-α-2a in 2 studies, IFN-α-2b in 6 studies, recombinant IFN-α-2C in 3 studies, recombinant IFN-y in 1 study, PEG-IFN-2b in 1 study, recombinant IFN-2b in 2 studies, and PEG-IFN in 1 study. The pooled overall hematological response (OHR) was 86.4% (95% Cl 0.67-0.98, I 2= 65%, p=0.02, n=73) with complete hematological response (CHR) of 70.6% (95% Cl 0.54-0.84, I 2=34%, p=0.21, n=65) and partial hematological response (PHR) of 13% (95% Cl 0.02-0.27, I 2=42%, p=0.16, n=65). The pooled overall molecular response (OMR) was 84% (95% Cl 0.72-0.93, I 2=13%, p=<0.01, n=81) with complete molecular response (CMR) of 64.2% (95% Cl 0.41-0.84, I 2=68%, p=<0.01, n=81) and partial molecular response (PMR) of 35% (95% Cl 0.16-0.56, I 2=33%, p=0.01, n=43). Side effects reported were nausea, allergic reactions, liver dysfunction, dose dependent mild myalgia, fever, malaise, itching, persistent fever, headache, and flu like symptoms. Conclusion Interferon alpha, in different formulations shows consistent and high activity in patients with essential thrombocythemia. It resulted in clinical responses, as well as molecular responses. Side effect profiles were consistent among different reports and were reasonable tolerated. There is a large body of evidence supporting actively and safety of this approach in a diverse ET patient population. Figure 1 Figure 1. Disclosures McGuirk: Gamida Cell: Research Funding; Juno Therapeutics: Consultancy, Honoraria, Research Funding; Magenta Therapeutics: Consultancy, Honoraria, Research Funding; Kite/ Gilead: Consultancy, Honoraria, Other: travel accommodations, expense, Kite a Gilead company, Research Funding, Speakers Bureau; Astelllas Pharma: Research Funding; Novartis: Research Funding; Allovir: Consultancy, Honoraria, Research Funding; Bellicum Pharmaceuticals: Research Funding; Fresenius Biotech: Research Funding; Novartis: Research Funding; EcoR1 Capital: Consultancy; Pluristem Therapeutics: Research Funding. Yacoub: Dynavex: Current equity holder in publicly-traded company; Cara: Current equity holder in publicly-traded company; Ardelyx: Current equity holder in publicly-traded company; Agios: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ACCELERON PHARMA: Membership on an entity's Board of Directors or advisory committees; CTI Biopharma: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Consultancy, Honoraria, Speakers Bureau; Seattle Genetics: Honoraria, Speakers Bureau; Hylapharm: Current equity holder in publicly-traded company.

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Ipsilateral internal carotid artery web and acute ischemic stroke: A cohort study, systematic review and meta-analysis

PLoS ONE ◽

10.1371/journal.pone.0257697 ◽

2021 ◽

Vol 16 (9) ◽

pp. e0257697

Author(s):

Brian Mac Grory ◽

Erez Nossek ◽

Michael E. Reznik ◽

Matthew Schrag ◽

Mahesh Jayaraman ◽

...

Keyword(s):

Systematic Review ◽

Cohort Study ◽

Ischemic Stroke ◽

Carotid Artery ◽

Acute Ischemic Stroke ◽

Meta Analysis ◽

Cryptogenic Stroke ◽

Young Patients ◽

Carotid Bifurcation ◽

Stroke Patients

Introduction The carotid web is a compelling potential mechanism of embolic ischemic stroke. In this study, we aim to determine the prevalence of ipsilateral carotid web in a cohort of ischemic stroke patients and to perform a systematic review and meta-analysis of similar cohorts. Patients & methods We performed a retrospective, observational, cohort study of acute ischemic stroke patients admitted to a comprehensive stroke center from June 2012 to September 2017. Carotid web was defined on computed tomography angiography (CTA) as a thin shelf of non-calcified tissue immediately distal to the carotid bifurcation. We described the prevalence of carotid artery webs in our cohort, then performed a systematic review and meta-analysis of similar cohorts in the published literature. Results We identified 1,435 potentially eligible patients of whom 879 met criteria for inclusion in our analysis. An ipsilateral carotid web was detected in 4 out of 879 (0.45%) patients, of which 4/4 (1.6%) were in 244 patients with cryptogenic stroke and 3/4 were in 66 (4.5%) patients <60 years old with cryptogenic stroke. Our systematic review yielded 3,192 patients. On meta-analysis, the pooled prevalence of ipsilateral carotid web in cryptogenic stroke patients <60 was 13% (95% CI: 7%-22%; I2 = 66.1%). The relative risk (RR) of ipsilateral versus contralateral carotid web in all patients was 2.5 (95% CI 1.5–4.2, p = 0.0009) whereas in patients less than 60 with cryptogenic stroke it was 3.0 (95% CI 1.6–5.8, p = 0.0011). Discussion Carotid webs are more common in young patients with cryptogenic stroke than in other stroke subtypes. Future studies concerning the diagnosis and secondary prevention of stroke associated with carotid web should focus on this population.

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Cladribine Combined with Idarubicin and High-Dose AraC (CLIA2) As a Frontline and Salvage Treatment for Young Patients (≤65 yrs) with Acute Myeloid Leukemia

Blood ◽

10.1182/blood-2018-99-119271 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4039-4039 ◽

Cited By ~ 1

Author(s):

Mansour Alfayez ◽

Hagop M. Kantarjian ◽

Farhad Ravandi ◽

Guillermo Garcia-Manero ◽

Marina Y. Konopleva ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Young Patients ◽

Multiparameter Flow Cytometry ◽

Intrathecal Therapy ◽

High Dose ◽

Advisory Committees ◽

Genetics Research ◽

Equity Ownership

Abstract Background Nucleoside analogues such as cladribine can increase the efficacy of cytarabine (araC) by modulating deoxycytidine kinase. The addition of cladribine to standard 7+3 chemotherapy has been shown to improve survival in pts with AML (Holowiecki JCO 2012). Results of our part-1 phase-2 clinical trial (cladribine combined with intermediate dose araC and idarubicin (CLIA1)) reported promising results that exceeded pretreatment expectations for response and tolerability (Jain, et. al. ASH 2016). Based on that, and the benefit of higher doses of cytarabine in younger patients (UK-MRC AML, Willemze JCO 2014), we investigated a higher dose of araC in combination with cladribine and idarubicin (CLIA2). Methods Non-APL, non-core binding factor AML pts 18-65 yrs of age with adequate organ function were enrolled in 1 of 3 cohorts: de novo AML, secondary AML (s-AML), or relapsed/refractory AML (R/R). Induction was cladribine 5 mg/m2 IV over 30 minutes on days 1-5, followed by araC 2g/m2 IV on days 1-5, and idarubicin 10 mg/m2 IV days 1-3. Consolidation consisted of up to 5 more cycles of CLIA2 for 3 days instead of 5. Dose-adjustments were allowed for age and PS. Sorafenib or midostaurin was added for pts with FLT3 mutations which occurred in 35% of pts on this study. Prophylactic intrathecal therapy was offered to higher risk pts at count nadir during cycle 1. Mutation profiling was performed using next generation sequencing prior to starting therapy. Results 65 patients were enrolled, with a median age of 47 yrs (range, 24-65): 37 pts (57%) in the frontline, 12 (19%) pts in the s-AML, and 16 (25%) in the R/R cohorts. Pt characteristics and outcomes by cohort are outlined in Table 1. The most commonly detected mutations at baseline were TET2 (45%), DNMT3a (37%), FLT3 (35%), ASXL1 (28%), and NPM1 (28%). Of 35 evaluable pts in the frontline cohort, 31 responded (ORR=89%) with 27 CR (77%) and 4 CRi (11%). Among the responders, 61% were negative for minimal residual disease (MRD [-]) by multiparameter flow cytometry. In the s-AML cohort, 10 pts were evaluable with an ORR of 60% (6/10) with 5 CR (50%) and 1 CRp (10%); 4 (67%) were MRD [-]. In the R/R cohort, 14 pts, previously treated with a median of 1 (1-4) prior therapy were evaluable for response. There were 7 CR (50%), 1 CRi (7%), for ORR of 57%; and 63% were MRD [-]. The median OS was not reached in the frontline and s-AML cohorts with median follow up of 5.2 and 11.5, months, respectively. In the R/R cohort, the median follow up was 4.7 months and median OS was 6.7 months [Figure.1]. Relapse-free survival was not reached in frontline and salvage cohort, and was 9.1 months in s-AML with median follow up of 5.2, 3.9, and 3.5 months in frontline, s-AML, and salvage cohorts, respectively [Figure.2]. The regimen was well tolerated. The most common ≥ grade 3 possibly-related non-hematologic adverse events were fever/infection (38), bleeding (2), and abnormal liver function test (3). Conclusion The 3-drug combination with a higher dose of araC, CLIA2, is safe and effective in younger pts with AML. Compared to our prior experience in pts with s-AML, using higher dose of cytarabine in CLIA2 for this cohort seems to have the highest impact. This trend however was also seen in the salvage and frontline cohorts when compared to the results from CLIA1. Response rates for pts in the newly-diagnosed AML, s-AML, and in the salvage settings are promising and should be explored further in larger studies and compared to current standard regimens. Disclosures Ravandi: Jazz: Honoraria; Amgen: Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Sunesis: Honoraria; Sunesis: Honoraria; Macrogenix: Honoraria, Research Funding; Orsenix: Honoraria; Jazz: Honoraria; Xencor: Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Xencor: Research Funding; Macrogenix: Honoraria, Research Funding; Seattle Genetics: Research Funding; Abbvie: Research Funding; Bristol-Myers Squibb: Research Funding; Orsenix: Honoraria; Amgen: Honoraria, Research Funding, Speakers Bureau; Seattle Genetics: Research Funding; Abbvie: Research Funding. Konopleva:Stemline Therapeutics: Research Funding. Daver:Otsuka: Consultancy; Novartis: Consultancy; Incyte: Research Funding; Kiromic: Research Funding; Daiichi-Sankyo: Research Funding; Incyte: Consultancy; Novartis: Research Funding; ImmunoGen: Consultancy; Alexion: Consultancy; Sunesis: Consultancy; Pfizer: Research Funding; Pfizer: Consultancy; Karyopharm: Consultancy; Sunesis: Research Funding; BMS: Research Funding; ARIAD: Research Funding; Karyopharm: Research Funding. DiNardo:Bayer: Honoraria; Karyopharm: Honoraria; Abbvie: Honoraria; Celgene: Honoraria; Medimmune: Honoraria; Agios: Consultancy. Bose:Constellation Pharmaceuticals: Research Funding; Incyte Corporation: Honoraria, Research Funding; Astellas Pharmaceuticals: Research Funding; Blueprint Medicines Corporation: Research Funding; Celgene Corporation: Honoraria, Research Funding; CTI BioPharma: Research Funding; Pfizer, Inc.: Research Funding. Andreeff:SentiBio: Equity Ownership; Jazz Pharma: Consultancy; Oncoceutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Eutropics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Research Funding; Astra Zeneca: Research Funding; Oncolyze: Equity Ownership; Celgene: Consultancy; Aptose: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Reata: Equity Ownership; Daiichi-Sankyo: Consultancy, Patents & Royalties: MDM2 inhibitor activity patent, Research Funding; United Therapeutics: Patents & Royalties: GD2 inhibition in breast cancer . Pemmaraju:abbvie: Research Funding; cellectis: Research Funding; samus: Research Funding; SagerStrong Foundation: Research Funding; stemline: Consultancy, Honoraria, Research Funding; novartis: Research Funding; plexxikon: Research Funding; daiichi sankyo: Research Funding; Affymetrix: Research Funding; celgene: Consultancy, Honoraria. Jabbour:novartis: Research Funding. Cortes:novartis: Research Funding. Kadia:Abbvie: Consultancy; BMS: Research Funding; Novartis: Consultancy; Celgene: Research Funding; Celgene: Research Funding; Takeda: Consultancy; Pfizer: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Jazz: Consultancy, Research Funding; Takeda: Consultancy; Abbvie: Consultancy; BMS: Research Funding; Jazz: Consultancy, Research Funding; Novartis: Consultancy; Amgen: Consultancy, Research Funding.

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Meta-Analysis of Long-Term Risk of Recurrent Venous Thromboembolism after Stopping Anticoagulation in Men and Women with First Unprovoked Venous Thromboembolism

Blood ◽

10.1182/blood-2018-99-113589 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2527-2527 ◽

Cited By ~ 1

Author(s):

Faizan Khan ◽

Alvi Rahman ◽

Marc Carrier ◽

Clive Kearon ◽

Jeffrey I. Weitz ◽

...

Keyword(s):

Board Of Directors ◽

Anticoagulant Therapy ◽

Research Funding ◽

Meta Analysis ◽

First Year ◽

Advisory Committees ◽

Men And Women ◽

Second Year ◽

Recurrent Vte

Abstract Background: The optimal duration of anticoagulation after a first unprovoked venous thromboembolism (VTE) is uncertain. Anticoagulant therapy is highly effective at reducing the risk of recurrent VTE, but this clinical benefit is not maintained once anticoagulation is stopped. Current guidelines suggest considering indefinite anticoagulation in all patients with unprovoked who have a non-high bleeding risk. However, this is a weak recommendation based on limited evidence. Deciding whether patients with a first unprovoked VTE should be considered for indefinite anticoagulant therapy requires estimation of the long-term risk of recurrent VTE after stopping anticoagulation. This risk however, is poorly established, hindering decision making. Methods: We performed a systematic review and meta-analysis of randomized clinical trials and prospective observational studies to determine the rate of recurrent VTE in the first year, in the second year, between years 2 and 5, and years 5 and 10; and the cumulative incidence for recurrent VTE at 2, 5 and 10 years after stopping anticoagulation in men and women with first unprovoked VTE, who had completed at least 3 months of initial treatment. Studies were identified through a comprehensive literature search using MEDLINE, EMBASE and the Cochrane CENTRAL databases. Data clarifications were requested from authors of eligible studies. Rates of recurrent VTE were calculated for each study from the total number of recurrent VTE events divided by the person-years of follow-up, and then pooled using random-effects meta-analysis. Results: Fourteen studies involving 6, 446 patients were included in the analysis. Among men with a first unprovoked VTE, the pooled rate of recurrent VTE per 100 person-years after stopping anticoagulation was 11.2 events (95% CI, 9.0-13.6) in the first year; 7.4 events (95% CI, 5.5-9.5) in the second year; 4.4 events/year (95% CI, 3.2-5.7) between years 2 and 5, and 3.8 events/year (95% CI, 1.6-6.9) between years 5 and 10 [Table 1]. Among women with a first unprovoked VTE, the pooled rate of recurrent VTE per 100 person-years after stopping anticoagulation was 8.6 events (95% CI, 6.5-11.0) within the first year; 5.2 events (95% CI, 3.5-7.2) in the second year; 3.0 events/year (95% CI, 1.6-4.7) between years 2 and 5, and 2.0 events/year (95% CI, 1.3-2.9) between years 5 and 10 [Table 1]. In men and women respectively, the cumulative incidence for recurrent VTE was 17.8% (95% CI, 14.0%-21.9%) and 13.4% (95% CI, 9.8%-17.4%) at 2 years, 28.2% (95% CI, 22.0%-34.4%) and 20.9% (95% CI, 14.0%-28.5%) at 5 years, and 40.8% (95% CI, 28.0%-53.9%) and 28.5% (95% CI, 19.5%-38.3%) at 10 years after stopping anticoagulant therapy [Table 2]. Conclusions: Among patients with a first unprovoked VTE who have completed at least 3 months of initial treatment, men have a higher long-term risk of recurrent VTE after stopping anticoagulation, and may be given greater consideration for indefinite anticoagulant therapy. Our findings affirm the importance of considering patient's sex in deciding the optimal duration of anticoagulation, and as such, emphasize the need for individualized, patient-centered approach for the long-term management of unprovoked VTE. Disclosures Carrier: BMS: Honoraria, Research Funding; Leo Pharma: Research Funding; Pfizer: Honoraria; Bayer: Honoraria. Weitz:Bristol-Myers Squibb: Honoraria; Daiichi-Sankyo: Honoraria; Ionis: Consultancy, Honoraria; Janssen: Honoraria; Servier: Honoraria; Novartis: Honoraria; Bayer: Honoraria; Boehringer Ingelheim: Honoraria, Research Funding. Schulman:Boehringer-Ingelheim: Honoraria, Research Funding; Daiichi-Sankyo: Honoraria; Sanofi: Honoraria; Bayer: Honoraria. Couturaud:Pfizer: Research Funding; Bayer: Honoraria, Other: Travel Support; AstraZeneca: Honoraria; Actelion: Other: Travel Support; Intermune: Other: Travel Support; Leo Pharma: Other: Travel Support; Daiichi Sankyo: Other: Travel Support. Becattini:Bayer HealthCare: Other: Lecture Fees; Boehringer Ingelheim: Other: Lecture Fees; Bristol Meyer Squibb: Other: Lecture Fees. Agnelli:Daiichi Sankyo: Other: Personal Fees; Boehringer Ingelheim: Other: Personal Fees; Bayer Healthcare: Other: Personal Fees; Pfizer: Other: Personal Fees; Bristol-Myers-Squibb: Other: Personal Fees. Brighton:Glaxo Smith Klein: Other: Personal Fees; Novo Nordisk: Other: Personal Fees; Bayer: Other: Personal Fees. Lensing:Bayer: Employment. Prins:Pfizer: Consultancy; Daiichi Sankyo: Consultancy. Hutton:Cornerstone Research Group: Honoraria. Palareti:Roche: Membership on an entity's Board of Directors or advisory committees; Werfen: Speakers Bureau; Alfa-Wassermann: Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees. Prandoni:Pfizer: Consultancy; Daiichi-Sankyo: Consultancy; Sanofi: Consultancy; Bayer: Consultancy. Büller:Pfizer: Consultancy, Research Funding; Daiichi-Sankyo: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Sanofi-Aventis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Bayer: Consultancy, Research Funding; Boehringer Ingelheim: Consultancy, Research Funding; Thrombogenics: Consultancy, Research Funding; Isis: Consultancy, Research Funding; GlaxoSmithKline: Consultancy, Research Funding. Rodger:Biomerieux: Research Funding.

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Survival Trends in Young Patients with Waldenstrom Macroglobulinemia: Over 5 Decades of Experience

Blood ◽

10.1182/blood.v128.22.1810.1810 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1810-1810

Author(s):

Jonas Paludo ◽

Nishanth Vallumsetla ◽

Stephen Ansell ◽

Abhisek Swaika ◽

Tania Jain ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Young Patients ◽

Age At Diagnosis ◽

Control Population ◽

Control Group ◽

Advisory Committees ◽

Younger Patients ◽

The Past ◽

Frontline Therapy

Abstract Background Waldenstrom macroglobulinemia (WM) is an IgM-associated lymphoplasmacytic lymphoma, first described over seven decades ago. Although WM is typically a disease of the elderly, with a median age at diagnosis of ~ 67 years, approximately 10% of patients are ≤50 years (y) of age at diagnosis. Data for young patients are sparse and the few available studies demonstrate inconsistent findings, with potential overestimation of survival owing to inclusion of patients with smoldering WM. In this case-control study, we evaluate outcomes, prognostic features and impact of changing therapies in a large cohort of young symptomatic WM patients compared to matched older patients seen over the course of the past five decades. Methods The medical records of all WM patients seen consecutively at Mayo Clinic from 01/1960 to 10/2013 were reviewed. Of 1181 patients, 140 (11.8%) were ≤ 50 y of age at diagnosis. A cohort of patients 65 y or older at diagnosis, matched 1:1 by the time of diagnosis, served as the control population. The patients were divided into 3 groups based on the timing of initiation of therapy: Group 1 (1960-1977), Group 2 (1978-1995) and Group 3 (1996-2013). The baseline characteristics were compared. Initiation of frontline therapy was used for all time-to-event analysis using the Kaplan Meier method. Results Younger patients were more likely to present with adenopathy and splenomegaly, have higher IgM levels and hyperviscosity symptoms (Table 1). The median follow-up from the frontline therapy was similar (10.7 y vs. 10 y for the control population). At the time of analysis, 91% of the deaths for the younger cases were WM-related compared to 58% in the control arm (p=0.0001). Younger patients had a better OS with a median disease-specific survival (DSS) of 15.6 y (95% CI: 13-21; 10-y OS of 77%) vs. 11 y (95% CI: 7.8-12; 10-y OS of 51%) for the older patient (p=0.0003). Among the young patients, there was no difference in the median DSS across the 3 groups (p=0.42). However, the median DSS for the control group incrementally improved (p=0.02) over the 3 time periods (Table 1). In the younger patients, no improvement in DSS was noted with the use of either frontline rituximab-based therapy compared to non-rituximab based regimens [median NR (95% CI: 7.6-NR) vs. 15.8 y (95% CI: 13-22) with other regimens, p=0.30], or frontline chlorambucil-based compared to non-chlorambucil based regimens [median 16 y (95% CI: 12-22) vs 15.6 y (95% CI: 12-NR) with other regimens, p=0.73]. In the control group, however, there was significant difference in DSS among patients who received frontline rituximab-based compared to non-rituximab based regimens [median NR (95% CI: 8.3-NR) vs 9.1 y (95% CI: 5.6-12) with other regimens, p=0.04], or frontline chlorambucil-based vs non-chlorambucil based regimens [8 y (95% CI: 5-12) vs 12.3 y (95% CI: 11-NR) in other regimens; p=0.001]. Conclusion Striking differences in presentation are evident in young WM patients compared to their older counterparts. The incorporation of rituximab to the previously existing anti-WM regimens and the transition to non-chlorambucil based regimens has resulted in substantial survival gains in the older WM population over the past five decades. However, such improvement in outcome has not yet been observed in the young patients. The majority of younger patients, despite a protracted disease course, succumb to their disease. Disclosures Ansell: BMS, Seattle Genetics, Merck, Celldex and Affimed: Research Funding. Ailawadhi:Pharmacyclics: Consultancy; Novartis: Consultancy; Amgen Inc: Consultancy; Takeda Oncology: Consultancy. Reeder:Novartis: Research Funding; Celgene: Research Funding; BMS: Research Funding; Millennium: Research Funding. Kumar:Kesios: Consultancy; Janssen: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; AbbVie: Research Funding; BMS: Consultancy; Onyx: Consultancy, Research Funding; Glycomimetics: Consultancy; Millennium: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Noxxon Pharma: Consultancy, Research Funding; Array BioPharma: Consultancy, Research Funding; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees. Dispenzieri:Alnylam: Research Funding; Celgene: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; pfizer: Research Funding; Jannsen: Research Funding. Kapoor:Celgene: Research Funding; Takeda: Research Funding; Amgen: Research Funding.

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Upfront Alternative Donor Transplant Versus Immunosuppressive Therapy in Patients with Severe Aplastic Anemia Who Lack Fully HLA Matched Related Donor: Systematic Review and Meta-Analysis of Retrospective Studies. on Behalf of the Severe Aplastic Anemia Working Party of European Group for Blood and Marrow Transplantation (SAAWP of EBMT)

Blood ◽

10.1182/blood-2020-140846 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 6-7

Author(s):

Hind Alotaibi ◽

Mahmoud Aljurf ◽

Regis Peffault De Latour ◽

Shahid Iqbal ◽

Andrea Bacigalupo ◽

...

Keyword(s):

Aplastic Anemia ◽

Board Of Directors ◽

Older Patients ◽

Research Funding ◽

Retrospective Studies ◽

Meta Analysis ◽

Severe Aplastic Anemia ◽

Advisory Committees ◽

Hematopoietic Stem ◽

Meta Analyses

Introduction: WIdiopathic aplastic anemia is a rare and life threatening disorder characterized by immune mediated hematopoietic stem cells dysfunction. The standard treatment strategy of severe aplastic anemia (SAA) has been hematopoietic stem cell transplant (HSCT) for children and adults younger than the age of 40 if an HLA matched sibling donor (MSD) is available. Immunosuppressive therapy (IST) is the mainstay of treatment for older patients or when MSD is not available. The response rate to IST with the use of horse anti-thymocyte globulin (ATG) is around 70%. Despite that, many patients suffer from relapse or clonal evolution. The use of alternative donor transplant (ADT) from matched unrelated donor (MUD) or HLA haploidentical donor (HID) is not commonly used in frontline setting. We herein, conducted a systematic review and meta-analysis of retrospective studies to compare the outcome of IST versus ADT as upfront therapy for SAA. Methods: WWe conducted a comprehensive search in PUBMED/MEDLINE and EMBASE (1998-2019) for retrospective studies that compared the outcome of ADT with IST as upfront therapy in patients with SAA. The study was conducting in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. We included the studies with 10 patients or more in each arm. Studies that included patients with inherited aplastic anemia or PNH are excluded. The primary outcome is the 5-year overall survival. Two authors independently screened the studies, extracted the data, and evaluated the quality of included studies and discrepancies were resolved by a third author. Study quality was evaluated by description of study characteristics, patients' characteristics, treatment details, and outcome. The odd ratio (OR) for 5-year survival was measured by Mantel-Haenszel test using random effect model. We also conducted another search and meta-analysis to compare upfront with salvage ADT. The meta-analyses were performed using Review Manager software version 5.3. Result: WWe screened a total of 697 articles (506 EMBASE, 191 PUBMED/MEDLINE). Five studies met our inclusion criteria included a total of 343 patients (176 in ADT group and 167 in IST group) for upfront ADT versus IST comparison and 6 studies with a total of 298 patients (198 in upfront ADT group and 100 in salvage ADT group) for upfront versus salvage ADT comparison. Included patients were of pediatric age group in 4 out of 5 studies. Xu ZL et al, included adult patients with median age 28 (18-49) years in upfront ADT arm and 32 (18-62) years in IST arm. Of those, only 10 patients in ADT group and 12 patients in IST group were above age of 40. In ADT versus IST comparison, the type of transplant was HID in three studies (total of 124 patients) and MUD/MMUD in two studies (total of 52 patients). The rabbit ATG was used in three studies, horse ATG in one study, and both types were used in one study (total of 68 patients received horse ATG and 99 patients received rabbit ATG). In term of disease severity, all included patients were SAA and very SAA (VSAA). Five studies were included in meta-analysis for 5-year overall survival. The pooled OR is statistically significant at 0.44 [95% CI 0.23-0.85] in favor of upfront ADT (Fig 1-A). The survival outcome was compared between upfront versus salvage ADT in 6 studies. The pooled OR is statistically significant at 0.31 [95% CI 0.15-0.64] in favor of upfront ADT (Fig 1-B). Conclusion: WThe pooled analysis of this study showed a potential survival advantage of upfront ADT over IST in patients with SAA who lack an HLA identical sibling donor. The use of ADT earlier in the disease course rather than as a salvage in young patients with severe disease, may improve survival. Data in older patients are limited, and at present, we cannot recommend ADT upfront in older patients. Given the limitations of our study including various types of IST, heterogeneity of patient population, health care systems, and retrospective nature of included studies; further studies are needed to confirm our findings. Disclosures Peffault De Latour: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Research Funding; Apellis: Membership on an entity's Board of Directors or advisory committees; Alexion Pharmaceuticals Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Schrezenmeier:Alexion Pharmaceuticals Inc.: Honoraria, Research Funding. Hoechsmann:Apellis: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Alexion: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria. Risitano:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Alnylam: Research Funding; Alexion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Jazz: Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees; Samsung: Membership on an entity's Board of Directors or advisory committees; Amyndas: Consultancy; RA pharma: Research Funding; Biocryst: Membership on an entity's Board of Directors or advisory committees; Apellis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Achillion: Membership on an entity's Board of Directors or advisory committees; Pfizer: Speakers Bureau. DiPersio:Magenta Therapeutics: Membership on an entity's Board of Directors or advisory committees.

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