Risk Factors for Thrombotic Events in Patients with PNH: A Nested Case-Control Study in the International PNH Registry

INTRODUCTION Although thrombotic events (TEs) are the leading cause of paroxysmal nocturnal hemoglobinuria (PNH)-related mortality, the risk factors predictive of TEs are not well established. Several small or previous studies reported that the proportion of PNH cells, elevated lactate dehydrogenase (LDH), age, thrombosis at diagnosis, and treatment may impact TE risk.1-5 The International PNH Registry (NCT01374360) is an observational cohort study containing the largest database of safety, quality-of-life, and outcome data from patients with PNH. Here, we analyzed patient data from the Registry to identify risk factors for TEs. METHODS Data from Registry patients who were untreated at enrollment, had an incident TE after enrollment, non-zero follow-up time, and with documented birthdate, sex, enrollment date, treatment status, and country, were included in this analysis. The first TEs experienced by eligible patients after enrollment were identified as TE cases; the date of the index TE event was defined as the Index Date. Up to five controls were selected from the risk set for each TE case matched on age (±5 years at Index Date), gender, country, and history of bone marrow disease (BMD). Cases that could not be matched with at least one control were excluded from the study. For covariates included in the analysis, conflicting or absent values were marked as "missing." Univariate conditional logistic regression was used to estimate odds ratios (ORs) with 95% Wald confidence intervals (CIs) of TE associated with candidate risk factors: glycophosphatidylinositol (GPI)-deficient granulocytes, GPI-deficient erythrocytes, LDH ratio, recent high-disease activity (HDA; defined as within six months prior to the Index Date, LDH ratio ≥1.5xULN, and hemoglobin <10 g/dL or at least one of the following symptoms: abdominal pain, dyspnea, dysphagia, fatigue, hemoglobinuria, and/or male erectile dysfunction), LDH ratio and number of HDA symptoms, history of TE, history of major adverse vascular event (MAVE), and recent prophylactic anticoagulant (PA) use. RESULTS Due to the strict eligibility criteria, 57 TE cases and 189 non-TE controls met the conditions and were matched for the case-control study. The mean age at Index Date was 46.8 years for TE cases and 47.1 years for non-TE control (Table A). Cases were more likely to have a clone size of ≥ 50% GPI-deficient granulocytes, an LDH ratio ≥ 1.5xULN, recent HDA, and a history of TE or MAVE, compared with controls. From univariate analyses, the following factors were found to be associated with statistically significantly increased risk of TE: recent HDA (OR, 2.65; 95% CI, 1.10-6.61), LDH ≥1.5xULN and 2-3 HDA symptoms (OR, 8.61; 95% CI, 1.46-96.96), LDH ≥1.5xULN and ≥4 HDA symptoms (OR, 14.50; 95% CI, 1.70-209.25), and a history of TE (OR, 3.60; 95% CI, 1.41-9.24) or MAVE (OR, 2.17; 95% CI, 0.96-4.80), and recent PA use (OR, 4.35; 95% CI, 1.57-13.13) (Figure A). The strengths of this analysis include a robust study design for evaluation of a rare outcome and multiple risk factors, increased generalizability with an international patient population, and the ability to evaluate both medical history and recent clinical characteristics relevant to PNH and TE; however, not all patients had available data for each parameter assessed and the number of TE cases identified were relatively small. Despite these limitations, factors that were statistically significantly associated with increased TE risk were identified from the analysis. CONCLUSIONS Based on this observational PNH Registry analysis, we identified several clinical features of PNH that were associated with an elevated risk of TE, including ≥50% GPI-deficient granulocyte clone size, LDH ratios ≥1.5xULN, recent HDA, LDH ≥1.5xULN plus HDA symptoms, a history of TE or MAVE, and recent PA use compared with non-TE controls; for recent PA use, these patients were most likely at increased risk of TE, which may explain why they received treatment. Our data add to the findings of previously published studies1,4 by expanding the results to a broader patient population. These results highlight the importance and urgency of identifying and monitoring risk factors for TE in patients with PNH to inform treatment decisions. Disclosures Hoechsmann: Roche: Consultancy, Honoraria; Apellis: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Alexion: Consultancy, Honoraria, Research Funding. Peffault De Latour:Apellis: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Alexion Pharmaceuticals Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Hill:Alexion Pharmaceuticals, Inc.: Current Employment. Röth:Roche: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria; Apellis: Consultancy, Honoraria; Alexion Pharmaceuticals Inc.: Consultancy, Honoraria, Research Funding; Biocryst: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Devos:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Patriquin:Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Apellis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Alexion Pharmaceuticals, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Jain:Alexion Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Zu:Alexion Pharmaceuticals, Inc.: Ended employment in the past 24 months; Merck & Co.: Current Employment. Lee:Alexion Pharmaceuticals Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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BCX9930, a Potent, Selective, Oral Factor D Inhibitor, Demonstrates Proof-of-Concept As Monotherapy in Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH)

Blood ◽

10.1182/blood-2020-138838 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 14-15

Author(s):

Austin Kulasekararaj ◽

Jacques Le Roux Malherbe ◽

Andrew McDonald ◽

Melanie Cornpropst ◽

Phil Collis ◽

...

Keyword(s):

South Africa ◽

Board Of Directors ◽

Research Funding ◽

Total Bilirubin ◽

Proof Of Concept ◽

Advisory Committees ◽

Clone Size ◽

The Past ◽

History Of ◽

Pre Treatment

INTRODUCTION: PNH, a rare, chronic, life-threatening disease, is characterized by hemolytic anemia due to uncontrolled activity of the complement alternative pathway (AP), bone marrow failure, and thrombosis. Inhibition of C5 by intravenously administered eculizumab and ravulizumab reduces intravascular hemolysis, but PNH red blood cells (RBCs) become opsonized and susceptible to extravascular hemolysis (Risitano et al, Blood 2009). Only approximately half of PNH patients become transfusion independent with eculizumab treatment (Hillmen et al, NEJM 2006). BCX9930 is a potent, selective, orally administered inhibitor of complement factor D. Inhibition of factor D may prevent both intravascular and extravascular hemolysis in PNH. In healthy subjects, BCX9930 showed linear pharmacokinetics and dose-related AP suppression, and was safe and generally well-tolerated over a wide dose range. Here we describe safety and laboratory data establishing proof-of-concept for BCX9930 monotherapy in PNH patients in Study BCX9930-101 (NCT04330534). METHODS: Ongoing Study BCX9930-101 includes an open-label, dose-ranging evaluation of BCX9930 in PNH subjects who may either be naïve to C5 inhibitors (and receive BCX9930 as monotherapy) or have an incomplete treatment response to eculizumab or ravulizumab (with BCX9930 added to existing treatment). Up to 4 sequential cohorts each use a forced titration design for the first 28 days (Figure 1). Subjects enrolled in South Africa can participate in an individualized 48-week extension if they derive benefit at Day 28. Clinical benefit from BCX9930 is evaluated using laboratory monitoring and symptom assessment. Safety and tolerability are evaluated via clinical and laboratory monitoring, causality of adverse events is assessed by investigators, and the study is overseen by an independent Data Monitoring Committee. Data from Cohort 1 through 28 days is reported; data from the extension and subsequent cohorts will be subsequently summarized as available. RESULTS: To date, four C5 inhibitor naïve PNH subjects in South Africa have enrolled in Cohort 1. These subjects had PNH for a median of 4.5 years; 2 subjects had a history of transfusions in the past year; 1 subject each had a history of aplastic anemia or major thrombosis. Pre-treatment lactate dehydrogenase (LDH), total bilirubin, hemoglobin (Hb), reticulocyte count, and RBC PNH Type III clone size ranged from 3.7-11.1 × ULN, 0.61-3.3 mg/dL, 6.1-11.6 g/dL, 0.13-0.29 × 106/µL, and 41.4%-88.6% respectively. Treatment over 28 days with 50 mg twice daily (BID; Days 1-14) and 100 mg BID (Days 15-28) of BCX9930 produced dose-dependent, clinically meaningful improvements across hemolysis biomarkers (Figure 2). Decreases were observed in LDH (4/4), reticulocytes (4/4), and total bilirubin (2/2 subjects with elevated pre-treatment values). Increases were observed in Hb (3/4) and PNH RBC clone size (4/4). One subject showed an initial response to BCX9930 50 mg BID, followed by worsening indicators of hemolysis temporally associated with an upper respiratory tract infection (URTI; onset on Day 7). With an increase in dose to 100 mg BID and resolution of the URTI, LDH and reticulocytes fell and Hb rose. All four subjects reported one or more PNH-associated symptoms, including hemoglobinuria, jaundice, fatigue, erectile dysfunction, headache and abdominal pain, prior to enrollment. With the exception of one subject with persistent hemoglobinuria, all symptoms resolved by Day 28 on BCX9930. Three subjects experienced moderate headache that resolved in < 3 days after initiating BCX9930. One subject developed a rash during treatment with amoxicillin for an URTI; the rash resolved while continuing BCX9930 dosing. One subject on concomitant chronic corticosteroids and azathioprine had an unrelated fatal serious adverse event of disseminated varicella during the study extension. Based on review of safety data, Cohort 2 opened at doses of 200 mg BID and 400 mg BID and, in the 3 subjects who continued into the extension, the dose was titrated to ≥ 200 mg BID. CONCLUSIONS: Oral BCX9930 elicited rapid changes in laboratory parameters indicative of reduced hemolysis and clinical benefit and was safe and generally well-tolerated over a 28-day dosing interval. These interim results establish proof of concept for monotherapy with BCX9930 in the treatment of C5-inhibitor naïve PNH patients and support evaluation of higher doses. Disclosures Kulasekararaj: Alexion:Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grants, Speakers Bureau;Ra Pharma:Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grants, Speakers Bureau;BioCryst Pharmaceuticals, Inc.:Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees;Apellis:Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grants, Speakers Bureau;Roche:Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Novartis:Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grants, Speakers Bureau;Celgene:Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grants, Speakers Bureau.Malherbe:Key Oncologics:Honoraria, Other: Conference sponsor;Novartis:Other: Conference sponsor;Astellas:Honoraria, Other: Conference sponsor;Takeda:Consultancy;Acino:Honoraria;Shire:Other: Conference sponsor;BioCryst Pharmaceuticals, Inc.:Consultancy;Janssen:Consultancy, Honoraria, Other: Conference sponsor;Roche:Honoraria, Other: Conference sponsor.McDonald:venetoclax advisory board in South Africa (in CLL context):Consultancy;Alberts Cellular Therapy:Current Employment.Cornpropst:BioCryst Pharmaceuticals, Inc.:Current Employment.Collis:BioCryst Pharmaceuticals, Inc.:Current Employment.Davidson:BioCryst Pharmaceuticals, Inc.:Current Employment.Chen:BioCryst Pharmaceuticals, Inc.:Current Employment.Tower:BioCryst Pharmaceuticals, Inc.:Current Employment.Gesty-Palmer:BioCryst Pharmaceuticals, Inc.:Current equity holder in publicly-traded company, Ended employment in the past 24 months.Sheridan:BioCryst Pharmaceuticals, Inc.:Current Employment.Risitano:Alexion:Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau;Alnylam:Research Funding;Novartis:Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau;Pfizer:Speakers Bureau;Achillion: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;Biocryst:Membership on an entity's Board of Directors or advisory committees;RA pharma:Research Funding;Amyndas:Consultancy;Samsung:Membership on an entity's Board of Directors or advisory committees;Roche:Membership on an entity's Board of Directors or advisory committees;Jazz:Speakers Bureau.

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Lenalidomide Plus Dexamethasone Versus Lenalidomide Plus Melphalan and Prednisone: A Case-Control Study in Newly Diagnosed Elderly Myeloma Patients.

Blood ◽

10.1182/blood.v114.22.2877.2877 ◽

2009 ◽

Vol 114 (22) ◽

pp. 2877-2877

Author(s):

Francesca Gay ◽

S. Vincent Rajkumar ◽

Patrizia Falco ◽

Shaji Kumar ◽

Angela Dispenzieri ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Low Dose ◽

Case Control Study ◽

Case Control ◽

High Dose ◽

Primary Therapy ◽

Newly Diagnosed ◽

Advisory Committees ◽

Control Study

Abstract Abstract 2877 Poster Board II-853 Background and Objective: In newly diagnosed multiple myeloma (MM) patients, treatment with lenalidomide plus high-dose dexamethasone (RD) was superior to high-dose dexamethasone in terms of both response rates and 1-year progression-free survival (PFS) (Zonder JA et al, Blood 2007;110:77). Preliminary results suggest that the combination lenalidomide plus low-dose dexamethasone (Rd) compared to the RD regimen yields significantly better 2-year overall survival (OS) (Rajkumar SV et al, J Clin Oncol 2008;26:8504). The combination of melphalan, prednisone, and lenalidomide (MPR) has been investigated in a phase I/II study showing promising results (Palumbo A et al, J Clin Oncol 2007; 25:4459-4465). The goal of this case –control study was to compare the efficacy and the toxicity of the lenalidomide/dexamethasone (len/dex) combination vs MPR as primary therapy for newly diagnosed elderly MM patients, to determine the additive value of melphalan compared to a regimen of lenalidomide plus corticosteroid. Patients and methods: Data from 51 newly diagnosed MM patients enrolled in Italy in a phase I/II dose-escalating trial, from January to October 2005, with MPR, were analyzed. For comparison of their outcome, 37 patients were identified among newly diagnosed patients seen at the Mayo Clinic from March 2005 to December 2008 who received len/dex as primary therapy and were enrolled in phase II or III trials. Patients treated with MPR received 9 monthly cycles of oral melphalan (doses ranging from 0.18 to 0.25 mg/kg on days 1-4), prednisone (2 mg/kg on days 1-4) and lenalidomide (doses ranging from 5 to 10 mg/day on days 1-21). After 9 cycles, patients started maintenance with lenalidomide alone (10 mg, days 1-21) until relapse or progression. Patients treated with len/dex received oral lenalidomide (25 mg/day, days 1-21) plus dexamethasone, either at low-dose (n=17) (40 mg orally days 1, 8, 15, 22) or at high-dose (n=21) (40 mg orally on days 1-4, 9-12, and 17-20). Treatment was continued until progression, relapse or unacceptable toxicity, or could be stopped at the physician's discretion. Patients (n=13) were allowed to receive transplant if they wished and were deemed eligible. Outcome was analyzed on an intention-to-treat basis. The Chi-square or the rank sum tests were used to compare variables. Time-to-event analysis was performed using the Kaplan-Meier method and comparisons were determined by the log-rank test and the Cox proportional hazards model. Results: On intention-to-treat analysis, 15.7% versus 23.7% patients, respectively in the MPR and in the len/dex group, (p=0.342) achieved a complete response, and 43.2% vs 47.4%, (p=0.691) achieved at least a very good partial response. Time-to-progression (TTP) (median: 24.7 vs 27.5 in MPR and len/dex groups, respectively; HR 1.04; 95% CI 0.55-1.98; p=0.903), PFS (median: 24.7 vs 27.5 in MPR and len/dex groups, respectively; HR 1.03; 95% CI 0.55-1.92; p=0.926) and OS (2-year OS: 86.2% in MPR group vs 89.1% in len/dex, HR 0.86; 95% CI 0.38-1.98; p=0.730) were not significantly different between the 2 groups. No significant differences in TTP, PFS and OS were reported when MPR patients were compared with the subgroup of patients treated with low-dose dexamethasone plus lenalidomide. Similar results were found when the analysis was restricted to MPR patients and len/dex pair mates receiving lenalidomide plus low/dose dexamethasone, matched according to age and sex, and who did not received transplant. The toxicity profile was different in the two groups. Hematologic grade 3-4 toxicities were more common with MPR compared with len/dex, in particular neutropenia (66.7% vs 21.1%, p < 0.001) and thrombocytopenia (31.4% vs 2.6%, p < 0.001), respectively. Grade 3-4 gastrointestinal events (13.2% vs 2.0%, p= 0.080), thrombotic events (13.2 vs 5.9, p= 0.279) and fatigue (10.5% vs 3.9%, p= 0.395) were more common with len/dex compared with MPR. Conclusion: Results of this case-control study show that both MPR and Rd are efficacious regimens for elderly MM patients. Data need however to be carefully evaluated and randomized control trials are needed to confirm these results. Disclosures: Off Label Use: research drug in combination to standard of care. Kumar:celgene: Research Funding; millenium: Research Funding; bayer: Research Funding; novartis: Research Funding; genzyme: Research Funding. Dispenzieri:celgene: Research Funding. Gertz:celgene: Honoraria; genzyme: Honoraria; millenium: Honoraria; amgen: Honoraria. Lacy:celgene: Research Funding. Musto:celgene: Honoraria. Fonseca:medtronic: Consultancy; genzyme: Consultancy; celgene: Consultancy; amgen: Consultancy; BMS: Consultancy; otsuka: Consultancy. Petrucci:celgene: Honoraria; Janssen Cilag: Honoraria. Greipp:celgene: Research Funding. Boccadoro:jansen Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; pharmion: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Palumbo:Janssen-Cilag: Honoraria; Celgene: Honoraria.

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Crizanlizumab 5.0 Mg/Kg Exhibits a Favorable Safety Profile in Patients with Sickle Cell Disease: Pooled Data from Two Phase II Studies

Blood ◽

10.1182/blood-2019-123965 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 991-991 ◽

Cited By ~ 2

Author(s):

Julie Kanter ◽

Darla K Liles ◽

Kim Smith-Whitley ◽

Clark Brown ◽

Abdullah Kutlar ◽

...

Keyword(s):

Clinical Trial ◽

Board Of Directors ◽

Sickle Cell ◽

Research Funding ◽

Pooled Analysis ◽

Advisory Committees ◽

Phase Ii Studies ◽

Increased Risk ◽

History Of ◽

Favorable Safety

Background: Crizanlizumab, a humanized monoclonal antibody that binds P-selectin and blocks interaction with its ligands (including leukocyte PSGL-1), is under investigation for preventing vaso-occlusive crises (VOCs) in individuals with sickle cell disease (SCD). Crizanlizumab 5.0 mg/kg was shown to significantly reduce the median annual rate of VOCs by 45.3% versus placebo (Hodges-Lehmann median absolute difference of -1.01 vs placebo, 95% CI [-2.00, 0.00]; P=0.01) (Ataga et al. N Engl J Med 2017). Aims: This pooled analysis evaluated key safety endpoints in patients treated with the recommended dose of crizanlizumab (5.0 mg/kg monthly, following 2 loading doses in the first month). Methods: Data were pooled from 2 Phase II studies of SCD patients (any genotype) with a history of VOCs leading to a healthcare visit. SUSTAIN (NCT01895361) was a randomized, placebo-controlled study in patients aged 16-65 years who had experienced 2-10 VOCs in the previous 12 months. SOLACE-adults (A2202) is an ongoing, open-label PK/PD study (NCT03264989) in patients aged 16-70 years who had experienced at least 1 VOC in the previous 12 months; data cut-off for this analysis was 1 March 2019. Adverse events (AEs) were evaluated based on MedDRA v21.1. AE severity in SOLACE was assessed based on CTCAE v5; in SUSTAIN, severity was collected as mild/moderate/severe but then recategorized for this analysis to a 5-point scale similar to CTCAE grading. AEs of special interest (ie known class effects; AEs identified preclinically or in previous studies; or potentially relevant based on the mechanism of action of crizanlizumab) were also evaluated and included infections, infusion-related reactions (IRRs) and hemostatic effects. As monoclonal antibodies can induce an immune response, anti-drug antibodies (ADAs) were also measured. Results: In total, 111 patients (SUSTAIN, n=66; SOLACE, n=45) received crizanlizumab 5.0 mg/kg: 59 females (53.2%) and 52 males (46.8%). Median age was 29 years (range 16-65). The most common SCD genotypes were HbSS (n=73; 65.8%) and HbSC (n=19; 17.1%), and 75 patients (67.6%) were receiving hydroxyurea (HU). Most patients (n=67; 60.4%) had 1-4 VOCs in the previous 12 months. Median duration of exposure to crizanlizumab was 46 weeks (range 4-58). At least 1 AE was reported in 94 patients (84.7%), the most common (≥15%) being headache (n=22; 19.8%), nausea (n=18; 16.2%) and back pain (n=17; 15.3%). AEs were mild/moderate (grade 1 or 2) and resolved spontaneously in most patients; 23 patients (20.7%) had a grade 3 AE and 1 (0.9%) had a grade 4 AE (neoplasm). At least 1 serious AE was reported in 24 patients (21.6%); serious AEs with a suspected relationship to crizanlizumab were reported in 6 patients (5.4%). Twenty-eight patients (25.2%) discontinued treatment prematurely (n=23 in SUSTAIN, n=5 to date in SOLACE): discontinuations due to AEs (bradycardia and breast cancer) occurred in 2 patients (1.8%); neither was considered related to crizanlizumab. There were 2 on-treatment deaths in SUSTAIN, but neither were considered related to crizanlizumab. Infection events were reported in 51 patients (45.9%), the most common (≥5%) being upper respiratory tract infection (n=13, 11.7%) and urinary tract infection (n=11, 9.9%). There were no grade 4 infections and none led to discontinuation. Data suggest no increased risk or severity of infection in studies with crizanlizumab. Two patients (1.8%) experienced IRRs; the events were not serious and did not lead to discontinuation. Bleeding events were rare, with most observed hemostatic AEs being abnormal laboratory parameters occurring only once. Treatment-induced ADAs were transiently detected in 1 patient (0.9%) and spontaneously resolved. There were no clinically relevant laboratory (hematology, biochemistry, liver) or ECG abnormalities, or vital sign changes, and no notable differences in the AE incidence rates by gender, ethnicity or HU use. Conclusions: This pooled analysis shows that crizanlizumab 5.0 mg/kg was well tolerated, with a favorable safety profile, in patients with SCD and a history of VOCs. Most AEs were mild/moderate, and discontinuations due to AEs were infrequent. The immunogenic potential of crizanlizumab appears low and there is currently no evidence for an increased risk of infection or bleeding. SOLACE-adults and SOLACE-kids (6 months to <18 years) are ongoing, and the randomized Phase III STAND trial is recruiting. Disclosures Kanter: bluebird bio, Inc.: Consultancy; SCDAA: Membership on an entity's Board of Directors or advisory committees; NHLBI: Membership on an entity's Board of Directors or advisory committees; Rockpointe: Honoraria; Peerview: Honoraria; Jeffries: Consultancy; Medscape: Honoraria; GLG: Consultancy; Cowen: Consultancy; Guidepoint Global: Consultancy; Sangamo: Consultancy, Honoraria; Modus: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Imara: Consultancy. Liles:Novartis: Other: PI on clinical trial Sickle cell ; Shire: Other: PI on clinical trial Sickle cell ; Imara: Other: PI on Clinical trial- Sickle cell . Brown:Novartis, Inc: Research Funding. Kutlar:Bluebird Bio: Other: DSMB Member; Micelle Biopharma: Other: DSMB Chair; Novartis: Consultancy; Global Blood Therapeutics, Inc. (GBT): Research Funding; Novo Nordisk: Research Funding. Elliott:Novartis: Employment, Equity Ownership. Shah:Novartis Pharmaceuticals: Employment, Other: Shareholder. Lincy:NOVARTIS PHARMA AG: Employment. Poggio:Novartis: Employment. Ataga:Advisory Board: Global Blood Therapeutics, Novartis: Membership on an entity's Board of Directors or advisory committees, Other: VINDICO WILL FORWARD DISCLOSURES ONCE RECEIVED AND SIGNED NOT RECEIVED TO DATE; VINDICO WILL FORWARD DISCLOSURES ONCE RECEIVED AND SIGNED NOT RECEIVED TO DATE: Other: VINDICO WILL FORWARD DISCLOSURES ONCE RECEIVED AND SIGNED NOT RECEIVED TO DATE; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Global Blood Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Emmaus Life Sciences: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bioverativ: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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TP53 Status As Well As Cytogenetic Complexity Significantly Impact on Prognosis in Myelodysplastic Syndromes with Complex (≥3 anomalies) Aberrant Karyotypes

Blood ◽

10.1182/blood-2019-126671 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3007-3007

Author(s):

Christina Ganster ◽

Roxana Schaab ◽

Katayoon Shirneshan ◽

Lea Naomi Eder ◽

Anna Mies ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Genetic Profile ◽

Fish Analysis ◽

Advisory Committees ◽

Clone Size ◽

Increased Risk ◽

Travel Grant ◽

The Impact ◽

Tp53 Status

Introduction: Complex aberrant karyotypes (CK, ≥3 cytogenetic aberrations, CA) are associated with an unfavorable prognosis and an increased AML transformation rate in MDS. However, even MDS with CK (CK-MDS) are heterogeneous in terms of genetic profile and prognosis. Recently, we demonstrated that a high number of CA as well as mutations in TP53 (TP53mut) are associated with increased risk in CK-MDS (Haase et al, 2019). However, as there is a strong association between CK-MDS and TP53mut, it is still a matter of debate whether the karyotype and TP53mut are prognostically independent genetic markers. Furthermore, loss of heterozygosity (LOH) of 17p13 (TP53LOH), due to loss of genetic material or to copy number neutral LOH (CN-LOH), is also associated with a poor prognosis. We here aimed to characterize TP53mut andTP53LOH in CK-MDS and to elucidate the impact of cytogenetics, TP53mut and TP53LOH on the outcome of CK-MDS. Methods: We included 178 pts with MDS (N=138), CMML (N=5) and secondary AML after MDS (AML with myelodysplasia-related changes, N=35), all with CK. The median precentage of bone marrow (bm) blasts was 11% (range: 0-90%). The median age was 72 yrs (range: 30-95 yrs). The male:female ratio was 1.23:1. The number of CA was determined by banding analysis in all cases. The karyotype was confirmed by multicolor FISH in 134 cases. TP53LOH was verified by FISH analysis of the TP53 locus in 17p13 (146 analyses) and/or molecular karyotyping (MK, 41 analyses). In 144 cases further FISH probes in addition to TP53 were used. TP53mut was identified by NGS (54 cases) or Sanger sequencing (124 cases). Follow-up data for survival analyses were available for 127 pts with MDS and oligoblastic AML with less than 30% bm blasts. Results: The median number of CA was 7 (range: 3-46), 98/178 pts (55%) showed a TP53mut (median VAF: 34%, range: 8-93%) and 64/178 (36%) a TP53LOH (median FISH clone size: 65%, range: 6-99%), including 9 pts with a CN-LOH in 17p13. The CN-LOH was either identified by MK (5/41 pts (12%) where MK was available showed a CN-LOH, 4/5 with TP53mut) or by NGS (4/54 pts (7%) where NGS was available showed a VAF >70% and normal TP53-FISH). In total, a TP53mut and/or a TP53LOH was identified in 116/178 pts (65%). Overall survival (OS) did not significantly differ between CK-MDS with TP53mut only, TP53LOH only, and TP53mut+TP53LOH (Fig.1). Therefore, we merged TP53mut and TP53LOH to TP53altered in all further analyses. Regarding the cytogenetic characterization of pts with TP53altered, the number of CA was significantly higher in pts with TP53altered than in pts with normal TP53 (median 9 CA (range: 3-46) vs 5 CA (range: 3-24), P<0.001). Also notable was that the founder clone of pts with TP53altered included significantly more cases with del(5q) (determined by FISH, 69/92 cases, 75%) compared to pts with normal TP53 (22/52 cases, 42%, P<0.001). The number of CA as well as the TP53 status contributed significantly to OS (Fig.2). The presence of anemia (Hb <10 g/dl) at first diagnosis of the CK had the greatest impact on OS (HR: 3.95) in the multivariate model (Cox regression), followed by an altered TP53 gene (TP53mut and/or TP53LOH; HR: 3.53) and the presence of ≥5 CA (HR: 2.33). Based on these three parameters with the greatest impact on OS, we created a simple provisional prognostic system. One scoring point each was assigned to anemia (Hb <10 g/dl), TP53altered, and ≥5 CA. Regarding OS, the resulting four risk groups separated very well (Fig.4). Conclusions: The presence of ≥5 CA is associated with reduced OS in CK-MDS. A TP53mut as well as a TP53LOH both further segregate outcome. The impact of the clone size of TP53mut and TP53LOH on survival is currently being evaluated. Our data imply that the TP53 status (TP53mut and/or TP53LOH) and the complexity of the karyotype are independent prognostic markers. Based on the presence of anemia, the TP53 status (TP53mut and/or TP53LOH), and the number of CA, the individual risk of CK-MDS can be estimated more accurately. This will allow to better tailor treatment decisions for individual pts with CA. Funding (FS): 2017 SGR 288-GRC Disclosures Germing: Jazz Pharmaceuticals: Honoraria; Novartis: Honoraria, Research Funding; Amgen: Honoraria; Celgene: Honoraria, Research Funding. Kaivers:Jazz Pharmaceuticals: Other: Travel Support. Kröger:Celgene: Honoraria, Research Funding; DKMS: Research Funding; JAZZ: Honoraria; Medac: Honoraria; Neovii: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Riemser: Research Funding; Sanofi-Aventis: Research Funding. Hertenstein:RS Media: Research Funding. Döhner:Daiichi: Honoraria; Jazz: Honoraria; Novartis: Honoraria; Celgene: Honoraria; Janssen: Honoraria; CTI Biopharma: Consultancy, Honoraria. Bug:Hexal: Membership on an entity's Board of Directors or advisory committees; Celgene Neovii: Other: travel grant; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead Sciences: Membership on an entity's Board of Directors or advisory committees, Other: Travel grants; Sanofi: Other: travel grants; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grants; Jazz Pharmaceuticals: Honoraria; Pfizer: Membership on an entity's Board of Directors or advisory committees. Nickelsen:Roche Pharma AG: Membership on an entity's Board of Directors or advisory committees, Other: Travel Grants; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant; Janssen: Membership on an entity's Board of Directors or advisory committees. Platzbecker:Celgene: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Novartis: Consultancy, Honoraria.

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Thyroid disorders and breast cancer risk in Asian population: a nationwide population-based case–control study in Taiwan

BMJ Open ◽

10.1136/bmjopen-2017-020194 ◽

2018 ◽

Vol 8 (3) ◽

pp. e020194 ◽

Cited By ~ 8

Author(s):

Chien-Hsiang Weng ◽

Yi-Huei Chen ◽

Ching-Heng Lin ◽

Xun Luo ◽

Tseng-Hsi Lin

Keyword(s):

Breast Cancer ◽

Index Date ◽

Case Control Study ◽

Asian Population ◽

Population Based ◽

Case Control ◽

Thyroid Disorders ◽

Increased Risk ◽

History Of ◽

Control Study

ObjectiveTo evaluate whether hyperthyroidism or hypothyroidism increases the risk of subsequent breast cancer in an Asian population.DesignNationwide population-based case–control study.SettingAll healthcare facilities in Taiwan.ParticipantsA total of 103 466 women (mean age 53.3 years) were enrolled.Methods51 733 adult women with newly diagnosed primary breast cancer without a previous cancer history between 2006 and 2011 were identified and included in our study. 51 733 women with no cancer diagnosis prior to the index date were age matched as controls. Diagnosis of hyperthyroidism or hypothyroidism prior to the diagnosis of breast cancer or the same index date was identified, age, histories of thyroid disease treatment, oestrogen use and radioactive iodine treatment were adjusted.Main outcome measuresTo identify risk differences in developing breast cancer among patients with a medical history of hyperthyroidism or hypothyroidism.ResultsThere was a significantly increased risk of breast cancer in women with hyperthyroidism under the age of 55 years (age <45: OR 1.16, P=0.049; age 45–55: OR 1.15, P=0.019). Patients with hypothyroidism also showed an increased risk of breast cancer (OR 1.19, P=0.029) without statistical significance after stratification by age group (age <45, 45–55, >55 years). Treatment for thyroid disorders did not alter the association in subgroup analyses (P=0.857; 0.262, respectively).ConclusionsAsian women under 55 years of age with history of hyperthyroidism have a significantly increased risk of breast cancer regardless of treatment. Women with history of hypothyroidism may also have an increased risk.

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Baseline Laboratory Parameters Potentially Associated with Thrombophilia in Patients with Chronic ITP.

Blood ◽

10.1182/blood.v120.21.2191.2191 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2191-2191

Author(s):

Raymond S.M. Wong ◽

Kalpana Bakshi ◽

Andres Brainsky

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Protein S ◽

Coagulation Cascade ◽

Published Data ◽

Employment Equity ◽

Advisory Committees ◽

Increased Risk ◽

History Of ◽

Equity Ownership

Abstract Abstract 2191 Background: The concept that chronic immune thrombocytopenia (cITP) may be pro-thrombotic has progressively gained acceptance as reports show an increased risk of thromboembolism (TEE) among cITP patients. A report from the Danish National Patient Registry showed an incidence of venous TEE of 5.32/1000 patient years (PYs) among cITP patients and 2.04/1000 PYs in a reference cohort (Severinsen 2010). Similar results were found in a US claims database study (Bennett 2008). ITP experts have gradually acknowledged this higher risk, but the reason for it is not understood. Many hematologic markers have been shown to be indicators of thrombophilia or activation of the clotting cascade (Jenkins 2012; De Stefano 2002; Tsai 2002); to our knowledge they have not been systematically and prospectively studied in cITP patients. Aim: Describe the frequency of potential laboratory predictors of thrombophilia in cITP. Methods: Adults with cITP were enrolled in an ongoing study to evaluate effects of eltrombopag on the bone marrow. A “thrombophilia panel” of suspected/known indicators of a thrombophilic state or activation of the coagulation cascade was collected at baseline. Patients could not have been treated with thrombopoietin receptor (TPO-R) agonists 6 months prior to enrollment. Patients with history of TEE and ≥2 risk factors for thrombosis were not eligible for enrollment. Results: Baseline thrombophilia panels were available for all 167 patients. Median age was 41 years; 108 (65%) patients were female. Approximately half of the patients were Caucasians (48.5%), while 31.1% and 19.2% had Central South and East Asian heritage. Median time since ITP diagnosis was 3.9 years (range, 0.2–45.7). Thirteen (8%) patients reported prior exposure to TPO-R agonists. Most patients (95%) had no family history of TEE and no patient had a history of TEE. Most patients (81%; Table 1) had abnormal levels of at least one well-known or suspected predictor of thrombosis or marker of activation of the coagulation cascade, and 93 (56%) had >1 abnormality. The most frequent abnormalities were elevated Factor VIII (48%), elevated d-dimer (32%), lupus anticoagulant (26%), and deficient protein S (22%; Table 2). Discussion: To our knowledge this is the only published prospective study of a thrombophilia profile in a cohort of cITP patients. Recently published data suggest that patients with cITP have a higher risk of TEE but no adequate explanation for this has been furnished. The fact that a high proportion of patients in this study had markers of thrombophilia or activation of clotting provides a working hypothesis that may at least partially elucidate this trait. Summary/conclusions: The multiple baseline abnormalities in possible predictors of thrombophilia may support the theory that ITP is pro-thrombotic, but they need to be assessed in and compared to the general population to allow proper understanding of their implications. The potential correlation of these abnormalities with TEE in this cohort will be reported upon study conclusion. Disclosures: Wong: GlaxoSmithKline: Research Funding; Pfizer: Research Funding; Biogen-Idec: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bayer: Consultancy, Research Funding; Johnson & Johnson: Research Funding; MSD: Research Funding; Roche: Research Funding; Bristol-Myers Squibb: Research Funding. Bakshi:GlaxoSmithKline: Employment, Equity Ownership. Brainsky:GlaxoSmithKline: Employment, Equity Ownership, Patents & Royalties.

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Blastomycosis in Missouri: epidemiology and risk factors for endemic disease

Epidemiology and Infection ◽

10.1017/s0950268803008987 ◽

2003 ◽

Vol 131 (2) ◽

pp. 907-914 ◽

Cited By ~ 44

Author(s):

M. V. CANO ◽

G. F. PONCE-DE-LEON ◽

S. TIPPEN ◽

M. D. LINDSLEY ◽

M. WARWICK ◽

...

Keyword(s):

Risk Factors ◽

Genetic Factors ◽

Case Control Study ◽

Case Control ◽

Prior History ◽

Black Race ◽

Increased Risk ◽

History Of ◽

Independent Risk Factors ◽

Control Study

Between 1992 and 1999, 93 cases of blastomycosis, including 25 laboratory confirmed cases, were identified in Missouri (annual incidence, 0·2/100000 population). Mississippi County in southeastern Missouri had the highest incidence (12/100000) with a much higher rate among blacks than whites in this county (43·2/100000). The mortality rate, 44% was also higher among blacks. To determine risk factors for endemic blastomycosis, a case-control study was conducted among southeastern Missouri residents. Independent risk factors for blastomycosis were black race and a prior history of pneumonia. No environmental exposures or socioeconomic factors were significantly associated with increased risk. The increased risk among blacks may possibly be related to genetic factors, but further studies are needed to clarify this. However, heightened awareness of the disease and a better understanding of the risk factors are important and may lead to earlier diagnosis and start of treatment, possibly improving outcome.

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Clonal Hematopoiesis in Older Women with Extremely Skewed, Non-Random X-Inactivation Is Associated with Previous Cardiovascular and Cerebrovascular Events

Blood ◽

10.1182/blood-2018-99-120323 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2574-2574

Author(s):

Emily Marre ◽

Julia Erin Wiedmeier ◽

Zhenzhen Zhang ◽

Hyunjung Lee ◽

Dana Parker ◽

...

Keyword(s):

Risk Factors ◽

Board Of Directors ◽

Research Funding ◽

X Inactivation ◽

High Cholesterol ◽

Advisory Committees ◽

Clonal Hematopoiesis ◽

History Of ◽

Equity Ownership ◽

Humara Assay

Abstract Age-related clonal hematopoiesis (CH) is a common condition that is associated with an increased risk of hematologic malignancies (HM) and cardiovascular disease (CVD). The majority of candidate driver mutations occur in epigenetic regulatory genes such as ASXL1, DNMT3A, and TET2 genes. However, a significant proportion of older people harbor clonal hematopoiesis without candidate driver mutations. In older women, clonal hematopoiesis can also be detected by the human androgen receptor A gene (HUMARA) assay regardless of the presence or absence of candidate driver mutation(s). The HUMARA assay evaluates non-random X-inactivation (NRX-I) as a marker for clonal hematopoiesis. The purpose of this study is to evaluate the association between NRX-I and cardiovascular risk factors and other health correlates. We screened for NRX-I in 904 women ages 65 and older participating in an ongoing, prospective cohort study in Oregon (Women Engaged in Advancing Health Research [WEAR] study). This approach was used to enhance the investigation of changes in CH that occur over time that may prove to be impactful for health outcomes. We examined the HUMARA results and any association with previous health history using a cross-sectional study design. Analysis of variance and logistic regression analyses were used to examine the relationship between HUMARA assay results and baseline CVD risk, controlling for age and race. HUMARA assay results were quantified and 3 groups were established: random X-inactivation, NRX-I, and extremely skewed NRX-I. No significant differences were detected between groups with respect to age, race, education, reproductive health indices or body mass index. With respect to cardiovascular risk factors, women with extreme NRX-I were more likely to be lifetime non-smokers compared to women without NRX-I and those with NRX-I with less skewing (P: 0.049), though no difference was seen in the proportion of current smokers (P: 0.213) and the total pack years smoked by those with a smoking history (P: 0.846).The proportion of subjects reporting statin or other cholesterol lowering medication did significantly differ between groups, with 24.3% women without NRX-I reporting statin use, versus 30.4% in women with NRX-I, and 36.7% in women with NRX-I extreme skewing (P: 0.005). Post-hoc pairwise tests showed significant differences between women with no NRX-I and women with NRX-I extreme skewing (P: 0.004). Cardiovascular event history differed significantly between the three groups of interest. 5.6% of women without NRX-I reported a history of transient ischemic attack (TIA), cerebral vascular accident (CVA), or myocardial infarction (MI) versus 7.0% in the NRX-I group and 11.0% in the NRX-I with extreme skewing group (P: 0.05). Post-hoc pairwise tests showed significant differences between women with no NRX-I and women with NRX-I extreme skewing (P: 0.043). The adjusted odds of TIA, CVA, or MI more than doubled (OR: 2.15, 95%CI: 1.14-3.42) among women with extremely skewed HUMARA results compared to women with NRX-I, controlling for age, high cholesterol, smoking history, hypertension, and type II diabetes. Cholesterol was also found to be independently associated with TIA, CVA, and MI. Women with hypercholesterolemia were 1.84 times as likely to report a history of TIA, CVA, or MI compared to women without hypercholesterolemia (95% CI: 1.06, 3.20). In summary, prediction of major adverse cardiac events is based on the presence of traditional risk factors including high blood pressure, high cholesterol, uncontrolled diabetes, smoking, and family history. Yet there is significant residual risk; many will still die from CVD without these risk factors. NRX-I, in addition to enriching for mutations known to confer CVD and HM risk; may be a marker for additional and unique health risks. An association between NRX-I, high cholesterol, and history of TIA, CVA, and MI, supports the current biological hypothesis that clonal hematopoiesis, perhaps irrespective of the cause or underlying driver mutation, is a driver for CVD. Disclosures Druker: Celgene: Consultancy; Fred Hutchinson Cancer Research Center: Research Funding; Third Coast Therapeutics: Membership on an entity's Board of Directors or advisory committees; Leukemia & Lymphoma Society: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead Sciences: Consultancy, Membership on an entity's Board of Directors or advisory committees; Blueprint Medicines: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Beta Cat: Membership on an entity's Board of Directors or advisory committees; Aptose Therapeutics: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Oregon Health & Science University: Patents & Royalties; McGraw Hill: Patents & Royalties; Vivid Biosciences: Membership on an entity's Board of Directors or advisory committees; Patient True Talk: Consultancy; GRAIL: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals: Research Funding; Monojul: Consultancy; Cepheid: Consultancy, Membership on an entity's Board of Directors or advisory committees; ALLCRON: Consultancy, Membership on an entity's Board of Directors or advisory committees; Aileron Therapeutics: Consultancy; Amgen: Membership on an entity's Board of Directors or advisory committees; Bristol-Meyers Squibb: Research Funding; Henry Stewart Talks: Patents & Royalties; Millipore: Patents & Royalties; MolecularMD: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; ARIAD: Research Funding. Dao:Incyte: Consultancy.

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Use of Blood Transfusions In Paroxysmal Nocturnal Hemoglobinuria Patients with and without Aplastic Anemia Enrolled In the Global PNH Registry

Blood ◽

10.1182/blood.v116.21.2241.2241 ◽

2010 ◽

Vol 116 (21) ◽

pp. 2241-2241

Author(s):

Hubert Schrezenmeier ◽

Robert A Brodsky ◽

Petra Muus ◽

Monica Bessler ◽

Jeffrey Szer ◽

...

Keyword(s):

Bone Marrow ◽

Board Of Directors ◽

Research Funding ◽

Paroxysmal Nocturnal Hemoglobinuria ◽

Employment Equity ◽

Advisory Committees ◽

Clone Size ◽

History Of ◽

Equity Ownership ◽

To Receive

Abstract Abstract 2241 Background: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare clonal hematopoietic stem cell disease characterized by complement-mediated hemolysis which can lead to life-threatening complications including thrombosis, kidney disease, pulmonary hypertension, pain, anemia, and severe fatigue. PNH clones occur in a number of patients with concomitant aplastic anemia (AA) and other bone marrow disorders (BMD). Some patients with PNH and/or BMD may require red blood cell (RBC) transfusions to treat anemia due to hemolysis or bone marrow hypoplasia. Aims: To characterize the use of RBC transfusions among PNH patients with and without underlying AA. Methods: Enrollment data from 117 clinical sites participating in the observational PNH Registry in 16 countries on 5 continents was analyzed. Patients are included in the Registry regardless of the proportion of cells with deficiency of glycosylphosphatidyl-inositol anchored proteins (GPI-AP), bone marrow pathology, symptoms, or treatments. Sites collect clinical history at enrollment and additional data every 6 months. Demographic data, use of transfusions and other treatments, lab results, and symptoms are summarized for PNH patients with and without AA. Results: As of June 30, 2010 there were 655 enrolled patients in the Registry (53% female, median age 43). At enrollment, 28% of patients had history of AA and 45% had no history of BMD. Patients with underlying AA had lower median GPI-AP deficient granulocytes than those without BMD (median = 53% vs. 86%, respectively, p<.01) and patients in both groups had similar evidence of hemolytic activity when stratified by clone size (median LDH fold above normal upper limit was 0.90 vs. 0.94, p=.39 for patients with and without AA and clone size <10%; median = 3.41 vs. 4.84, p=.08 for AA vs. no BMD and clone size ≥50%). Not all PNH patients required transfusions: 56% of all patients required transfusions in the year prior to enrollment. Although patients with and without AA were equally likely to be treated with blood transfusions in the year prior to study enrollment overall, some differences emerged when stratified by clone size. For patients with clone size <50%, AA patients were almost twice as likely to receive transfusion in the previous year as patients without BMD (39% vs. 20%, p=.08). However, regardless of underlying AA, the proportion of patients receiving transfusions, in the prior year increased as clone size increased (29%, 31%, and 69% for clone sizes <10%, 10–49%, and ≥50%, respectively, p<.01). When patients were stratified by percent reticulocytes at enrollment (below vs. above the median value of 4.16%), 45% vs. 75% received transfusion in the prior year (p<.01). Among patients receiving a transfusion in the year prior to enrollment, the mean number of RBC units transfused was 9.6 for patients with underlying AA and 7.9 for patients with no BMD (p=.10). However, approximately twice as many patients with AA received 20+ RBC units in that year compared to patients without BMD (20% vs. 11%, p=.09). Number of transfused units in that year was similar by clone size (mean 9.5 vs. 8.6 for clone size <50% vs. ≥50%, p=.57). Concomitant treatment with anticoagulants or immunosuppressants was similar among patients who had received a transfusion in the past year compared to patients with no transfusions (39% vs. 33%, p=.13 and 26% vs. 22%, p=.25 respectively). Patients with AA had more bruising and bleeding while patients without BMD had more hemoglobinuria, dysphagia, and abdominal pain. Transfused patients with AA had more fatigue than non-transfused patients with AA (68% vs. 48%, p=.02). Conclusions: A substantial proportion (56%) of patients with PNH, but not all, required at least one transfusion in the year prior to enrolling in the registry, independent of underlying AA. The proportion of patients who had at least one transfusion increased with clone size. Among patients who had at least one transfusion, there was a trend for patients with underlying AA to receive more RBC units than patients without BMD. PNH patients with AA have fewer GPI-AP deficient granulocytes but demonstrate elevated hemolysis similar to patients without history of BMD when patients with similar clone sizes were compared. This Global PNH Registry, which remains open to accrual ([email protected]), should help to redefine prospectively the long-term natural history of PNH, its treatments, and the outcomes of treatment. Disclosures: Schrezenmeier: Alexion Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees. Brodsky: Alexion Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees. Muus: Celgene: Membership on an entity's Board of Directors or advisory committees; Alexion: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Bessler: Alexion Pharmaceutical Inc: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees; Taligen: Consultancy. Szer: Alexion Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees. Maciejewski: Celgene: Research Funding; Eisai: Research Funding; Alexion: Consultancy. Socié: Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees. Urbano-Ispizua: Alexion: Membership on an entity's Board of Directors or advisory committees. Kanakura: Alexion: Membership on an entity's Board of Directors or advisory committees. Hoechsmann: Alexion: Speakers Bureau. Rosse: Alexion: Consultancy, Membership on an entity's Board of Directors or advisory committees. Khursigara: Alexion Pharmaceuticals, Inc.: Employment, Equity Ownership. Karnell: Alexion Pharma International: Employment, Equity Ownership. Bedrosian: Alexion Pharmaceuticals, Inc.: Employment, Equity Ownership. Hillmen: Alexion Pharmaceuticals, Inc: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Risk Factors for Venous Ulcer Following ACUTE Venous Thromboembolism: Results from the Riete Registry

Blood ◽

10.1182/blood.v126.23.3548.3548 ◽

2015 ◽

Vol 126 (23) ◽

pp. 3548-3548

Author(s):

Jean-Philippe Galanaud ◽

Laurent Bertoletti ◽

Paolo Prandoni ◽

Pedro Gallego ◽

Daniela Mastroiacovo ◽

...

Keyword(s):

Risk Factors ◽

Board Of Directors ◽

Venous Ulcer ◽

Advisory Committees ◽

Venous Ulcers ◽

Increased Risk ◽

History Of ◽

Male Sex ◽

One Year

Abstract Background: Venous ulcer, the most serious consequence of chronic venous insufficiency (CVI), is associated with a high morbidity, impaired quality of life and high costs. To date, risk factors for venous ulcer after acute VTE have not been characterized. Objective: To identify independent predictors of venous ulcer development one year after an acute VTE event. Methods: Using data from the RIETE international registry, we analysed risk factors for venous ulcers in patients with an objectively confirmed symptomatic acute VTE (DVT and/or pulmonary embolism (PE)) and followed up for at least one year. During follow-up, signs and symptoms of CVI, occurrence of a venous ulcer in the leg ipsilateral to DVT or, in the absence of reported DVT, in any leg were reported by local investigators. Independent predictors of venous ulcers were assessed using a stepwise multivariable model. Results: Of the 34,144 patients included in the RIETE registry, 4,305 were recruited in centres participating in long-term (1 to 3 years) follow-up. Of these, 54% (n=2,337) underwent an assessment for CVI. After a mean (SD) follow-up of 383 (+/-575) days, 55% (n=1297) had signs or symptoms of CVI and 2.5% (n=59) had developed a venous ulcer. History of previous VTE (OR=4.4 [2.6 - 7.7], signs of venous insufficiency (i.e. leg varicosities) at time of VTE event (OR=2.3 [1.3 - 4.0]), diabetes (OR=2.0 [1.0 - 3.8]), obesity (OR=1.8 [1.1 - 3.2]) and male sex (OR=2.7 [1.5 - 4.9]) were independent predictors of an increased risk of venous ulcer. Conversely, older age, presence of an objectively confirmed DVT at study enrolment, anticoagulant duration (<1 vs. >1 year), anticoagulant type (extended low molecular weight heparin vs. vitamin K antagonist), or presence of vena cava filter had no significant impact on risk of venous ulcer. When restricting our analysis to the 1790 patients with objectively confirmed DVT only, results remained similar in magnitude. Proximal character of DVT was associated with a 30% non-significant increased risk of - unquestionable - post-thrombotic ulcer but the proportion of distal DVT was low in our population (11%). Conclusions: After an acute VTE event, history of VTE, pre-existing signs of CVI, male sex, diabetes and obesity independently influenced the risk of venous ulcer. VTE therapeutic management (neither duration nor drugs) did not appear to modify this risk. Our results suggest that clinicians should consider strategies aimed to prevent ulcers in high risk patients, such as preventing VTE recurrence, use of compression stockings in those with CVI and encouraging weight loss in obese patients. Disclosures Galanaud: bayer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Daichi: Membership on an entity's Board of Directors or advisory committees, Research Funding. Bertoletti:Daichi: Honoraria; bayer: Honoraria; BMS-Pfizer: Consultancy, Honoraria. Monreal:Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; boehringer: Consultancy, Membership on an entity's Board of Directors or advisory committees; daichii: Consultancy, Membership on an entity's Board of Directors or advisory committees.

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