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

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 991-991 ◽  
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.

scholarly journals Predictors of Maternal Morbidity Among Participants Enrolled in the Sickle Cell Disease Implementation Consortium Registry

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 3-3
Author(s):  
Rita V Masese ◽  
Dominique Bulgin ◽  
Liliana Preiss ◽  
Mitchell Knisely ◽  
Eleanor Stevenson ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Sickle Cell ◽  
Research Funding ◽  
Transfusion Requirement ◽  
The United States ◽  
Acute Chest Syndrome ◽  
Maternal Outcomes ◽  
Maternal Complications ◽  
Advisory Committees ◽  
Increased Risk

Introduction Pregnancy in sickle cell disease (SCD) is associated with an exacerbation of SCD-related complications and an increased risk of maternal complications. The increased risk is partly due to physiologic adaptations in pregnancy, which include increased metabolic demands and a hypercoagulable state. The maternal death rate for SCD is 629 per 100,000 deliveries, compared to 12 per 100,000 deliveries in black women and 6 per 100,000 deliveries in the general population (Raider et al., 2016). Studies on maternal and perinatal outcomes of patients with SCD present inconsistent and conflicting results. Some studies have reported an increase in maternal complications such as pre-eclampsia, acute chest syndrome and thromboembolic events, while other studies have reported no significant risk in adverse maternal outcomes. The inconsistent findings reported in prior studies may be attributed to small sample sizes and single-centered sites. Our study aims to determine the prevalence and predictors of maternal morbidity among participants enrolled in the SCD Implementation Consortium (SCDIC) registry, which is the largest, most geographically diverse SCD participant sample in the United States. Methods This cross-sectional study included women enrolled in the SCDIC registry who had at least one pregnancy event. The SCDIC is composed of eight academic SCD centers across the United States and one data-coordinating center. Participants were enrolled in the SCDIC registry if they were 18 to 45 years of age and had a confirmed diagnosis of SCD. Enrolled participants completed a series of surveys that collected sociodemographic information, SCD and pregnancy history and data abstractions of participants' medical records was completed. Medical complications queried during pregnancy included: vaso-occlusive episodes, acute chest syndrome, blood transfusion requirement, preeclampsia, maternal diabetes and deep venous thrombosis. Descriptive analysis of sociodemographic, clinical and maternal characteristics was conducted. Bivariate analysis was performed using Chi-Square test, Mann-Whitney U test, t-test, and logistic regressions, as appropriate. A p-value of ≤ 0.05 was considered statistically significant for all analysis. Results The study sample included 743 women who had at least one pregnancy event, and a total of 1066 live births. Almost all women (96.3%) were African American, with a median age of 21 years (inter-quartile range of 19 to 23 years) at first birth. The majority had Hb SS SCD genotype (69.5%; 513 of the 738 with SCD genotype data). Of all reported pregnancies, participants did not use hydroxyurea during conception (78%), and pregnancy (84.5%). Only 2.7 % of the women reported using fertility drugs or assisted reproductive procedures. Seventy five percent of the pregnancies that ended in live births had maternal complications. The leading complications were vaso-occlusive episodes (61.2%), pregnancy requiring blood transfusion(s) (33.2%), preeclampsia (15.4%), deep venous thrombosis (5.6%) and acute chest syndrome (7.7%). When the pregnancies were stratified by SCD genotype, women with Hb SS had a higher occurrence of acute chest syndrome (63.4% vs. 26.7%), transfusion requirement (70.8% vs. 21%) and preeclampsia (66.7% vs 22.4%). In the univariate logistic regressions, multiparous women, with a history of adverse maternal outcomes in a previous pregnancy, had higher odds of vaso-occlusive episodes (OR: 3.42; 95% CI: 2.42-4.94) acute chest syndrome (OR:4.99; 95% CI:2.56- 9.48), transfusion requirement (OR:3.86; 95% CI:2.64- 5.69), and pre-eclampsia (OR:3.36; 95% CI:2.05-5.45). Conclusion In this large multicenter registry, we found pregnant women with SCD have significant maternal complications. Early antenatal care by healthcare providers knowledgeable about risk factors for adverse maternal outcomes in SCD is essential improve maternal and fetal outcomes and reduce the maternal death rate for SCD. Disclosures Hankins: Novartis: Research Funding; Global Blood Therapeutics: Consultancy, Research Funding; MJH Life Sciences: Consultancy, Patents & Royalties; UptoDate: Consultancy; National Heart, Lung, and Blood Institute: Honoraria, Research Funding; LINKS Incorporate Foundation: Research Funding; American Society of Pediatric Hematology/Oncology: Honoraria. Treadwell:Global Blood Therapeutics: Consultancy; UpToDate: Honoraria. King:Amphivena Therapeutics: Research Funding; Bioline: Consultancy; Celgene: Consultancy; Cell Works: Consultancy; Incyte: Consultancy; Magenta Therapeutics: Membership on an entity's Board of Directors or advisory committees; Novimmune: Research Funding; RiverVest: Consultancy; Tioma Therapuetics: Consultancy; WUGEN: Current equity holder in private company. Gordeuk:CSL Behring: Consultancy, Research Funding; Global Blood Therapeutics: Consultancy, Research Funding; Imara: Research Funding; Ironwood: Research Funding; Novartis: Consultancy. Kanter:SCDAA Medical and Research Advisory Board: Membership on an entity's Board of Directors or advisory committees; AGIOS: Membership on an entity's Board of Directors or advisory committees; BEAM: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; GLG: Honoraria; Jeffries: Honoraria; Cowen: Honoraria; Wells Fargo: Honoraria; NHLBI Sickle Cell Advisory Board: Membership on an entity's Board of Directors or advisory committees; Medscape: Honoraria; Guidepoint Global: Honoraria; bluebird bio, inc: Consultancy, Honoraria; Sanofi: Consultancy. Glassberg:Pfizer: Research Funding; Global Blood Therapeutics: Consultancy; Eli Lilly and Company: Research Funding. Shah:Novartis: Consultancy, Research Funding, Speakers Bureau; Alexion: Speakers Bureau; CSL Behring: Consultancy; Bluebird Bio: Consultancy; Global Blood Therapeutics: Consultancy, Research Funding, Speakers Bureau.

scholarly journals Sickle-Cell Disease in Greece: Patient Reported Outcomes Related to Clinical Complications, Treatment Choices and Attitudes, Beliefs and Trends Affecting Potential Participation in Clinical Trials - a Greek National Multicentric Study

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4838-4838
Author(s):  
Sophia Delicou ◽  
Michael D. Diamantidis ◽  
Konstantinos Manganas ◽  
Eftychios Eftychiadis ◽  
Despoina Pantelidou ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Board Of Directors ◽  
Sickle Cell ◽  
Research Funding ◽  
Educational Status ◽  
Current Treatment ◽  
Advisory Committees ◽  
Chi Square ◽  
Clinical Complications

Background: Sickle cell disease (SCD) is an autosomal recessive disorder caused by a point mutation in the β-globin chain of hemoglobin that forms hemoglobin S. It is clinically characterized by complicated episodes of veno-occlusive crises (VOC), emergency room (ER) visits and uncomplicated inpatient admissions. Aim: We investigated the clinical complications and treatment choices of a large cohort of Greek SCD patients, representative of the whole country. Most importantly, this study aimed to assess patients' attitudes and beliefs regarding their enrollment in clinical trials testing new drugs. We examined the factors influencing such a participation. Patients and Methods: A total of 254 patients from 10 Thalassemia and Sickle Cell Departments across Greece (110 men/144 women), aged 18 - over 65, 210 (82.7%) with β-thalassemia/sickle cell trait and 44 (17.3%) with homozygous SCD participated in the study. The participants had variable educational and socioeconomic background. They all answered an anonymous self-report questionnaire during their medical evaluations between November 2018 and May 2019, including their demographic and clinical characteristics, their current treatment and their opinion regarding a possible participation in a clinical trial for SCD. Descriptive statistical analysis using calculated scale variables and Chi-square test were performed. Results: All participants completed the survey. During the previous year, 64 patients (25.3%) had no admissions for VOC, 128 (50.6%) had 1-5, whereas 21 (8.3%) had 5-10 and 40 (15.8%) more than 10. Except for acute pain crises, the most frequent complications were chronic pain (59%), liver/spleen dysfunction (32.4%), infectious episodes (29.5%), iron overload (23.8%) and pulmonary hypertension (20.1%). In addition to hematological care, patients seeked medical attention from expert physicians for disease complications; 77.6% of the patients reported that they yearly visited a cardiologist, 42.4% an ophthalmologist, 31.9% an orthopedic, 28.4% a pneumonologist, 28.9% a hepatologist, 12.6% an urologist, 14% a nephrologist, 11.9% an infectious disease doctor, 10.1% a pain management specialist and 8.1% a neurologist. The therapeutic approaches included daily folic acid supplementation (86.1%), vaccines (68.3%), hydroxyurea (66.3%), antibiotics (57.1%), simple pain moderators (52.4%), opioids (48.8%) and iron chelators (30.2%). Previous experience in clinical trials was reported by only 17 patients (6.9%). Regarding the patients' attitudes towards a probable clinical trial, 41.3% were positive to try new therapies, 28.3% negative and 30.4% neutral. 67.2% were satisfied with their current treatment, without excluding a potential participation in clinical trials; such treatment satisfaction correlated significantly with older age, lower income and secondary hemochromatosis under chelation treatment (p<0.05). 40% reported that they had been waiting for years for a new treatment, but 43.2% strongly denied becoming an experimental mouse model, whereas 47.3% mentioned that they would trust their doctors' advice correlating positively with male gender and higher income (p<0.05). Lower educational status, prior intake of hydroxyurea and residence/origin in the capital in contrast to the countryside (chi-square, p<0.05) significantly correlated with a potential clinical trial participation. Internet and television information motivated patients to seek more details from their doctor. Concerning the factors rated as the most important for a potential participation in a clinical trial, 7 out of 10 patients of our cohort considered of utmost equal importance the effectiveness of a probable treatment and the relative toxicity. Conclusions: Most SCD patients have chronic complications and visit specialized physicians. Since the participation of larger number of patients in clinical trials is essential for the application of novel drugs, the most important factors of our cohort are the effectiveness of a probable treatment and the relative toxicity, along with the trust to the doctor. These factors are crucial, influencing patients' decision. Even though a proportion of our patients remain skeptical towards clinical trials, an increasing number is willing to participate, which correlates positively with residence in the capital, lower educational status and prior intake of hydroxyurea. Disclosures Kattamis: Apopharma: Honoraria; Vertex: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees; Ionis: Membership on an entity's Board of Directors or advisory committees; ViFOR: Membership on an entity's Board of Directors or advisory committees; Novartis Oncology: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Symeonidis:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; MSD: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Tekeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding.

scholarly journals Risk of Hospitalization for Vaso-Occlusive Episode in Patients with Sickle Cell Disease after out-Patient Exposure to Systemic Corticosteroids

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2048-2048
Author(s):  
Ondine Walter ◽  
Pierre Cougoul ◽  
Julien Maquet ◽  
Pablo Bartolucci ◽  
Maryse Lapeyre-Mestre ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Board Of Directors ◽  
Sickle Cell ◽  
Research Funding ◽  
Cell Disease ◽  
National Health Insurance System ◽  
Advisory Committees ◽  
Systemic Corticosteroids ◽  
Increased Risk ◽  
Case Period

Abstract Introduction : Sickle cell disease (SCD) is an inherited disorder which affects 300,000 newborns per year. Vaso-occlusive episodes (VOEs) cause an important morbi-mortality and a decreased quality of life in patients with SCD. Some risk factors of VOE are well known, like infection, cold exposure, stress, pulmonary diseases and dehydration. Exposure to systemic corticosteroids has been suspected to increase the occurrence of VOEs in few case reports or series. However, no comparative study has been conducted to demonstrate this risk which is still debated, resulting in discrepancies among guidelines on SCD management. This study aimed to assess the risk of hospitalization for VOE associated with out-hospital exposure to systemic corticosteroids in patients with SCD in France. Methods : Data source was the French national health insurance system database, named SNDS (Système National des Données de Santé) between 2010 and 2018. The SNDS links sociodemographic, out- and in-hospital data for the entire French population (&gt;66 million inhabitants). The study population consisted in all patients with SCD with at least one hospitalization for VOE during the study period, identified with a primary discharge diagnosis of VOE (D57.0 code of the international classification of disease, 10 th version; positive predictive value: 98.6%). All genotypes (homozygous SS-SCD and double-heterozygous SCD) were included. Because we assessed out-hospital exposure to corticosteroids, patients hospitalized during the three months before the first VOE were excluded. We performed a case-case-time-control study (Figure 1). This self-controlled design results in self-adjustment for time-independent confounders, including genotype. The outcome was the first hospitalization for VOE. The exposure to oral and injectable corticosteroids, identified using out-hospital reimbursement data, was assessed during a case period (28 days before the outcome) compared to the exposure during a control period (28 days, starting 84 days before the outcome). The same comparison was made among future cases (matched patients hospitalized for VOE the year after the given case), in order to adjust for the trend of exposure to corticosteroids (calendar variations of corticosteroid exposure). Results : Overall, 5,151 cases of VOEs were included in the main analysis. Median age at first VOE was 16.9 years; 317 (6.2%) patients were exposed to corticosteroids during the case period. In the main analysis, corticosteroid exposure was significantly associated with the occurrence of hospitalizations for VOEs: adjusted Odds Ratio (aOR): 3.81, 95% confidence interval (95% CI): 2.44 to 5.61. In patients exposed to hydroxyurea, the aOR was 2.61, 95% CI: 1.07 to 6.39, compared with an aOR of 4.00, 95% CI: 2.53 to 6.30 in unexposed patients. In the subgroup analysis by age, the aOR was 2.81, 95% CI: 1.49 to 5.30 in children, and 4.45, 95% CI: 2.37 to 8.37 in adults. The results were consistent in all sensitivity analyses. Conclusion : This study showed an association between outpatient exposure to systemic corticosteroids with an increased risk of hospitalization for VOE, in both adults and children. Hydroxyurea may reduce this risk in adults. Figure 1 Figure 1. Disclosures Bartolucci: GBT: Consultancy; Emmaus: Consultancy; Fabre Foundation: Research Funding; AGIOS: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Lecture fees, Steering committee, Research Funding; Jazz Pharma: Other: Lecture fees; INNOVHEM: Other: Co-founder; Bluebird: Consultancy, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy; Hemanext: Consultancy; Addmedica: Consultancy, Other: Lecture fees, Research Funding. Moulis: Argenx: Membership on an entity's Board of Directors or advisory committees; Sobi: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Grifols: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Real World Evidence of Prescription Patterns and Effect of Oxbryta (voxelotor) for Patients with Sickle Cell Disease

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 31-32
Author(s):  
Nirmish Shah ◽  
Ahmar Urooj Zaidi ◽  
Michael U. Callaghan ◽  
Darla Liles ◽  
Clarissa E. Johnson ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Board Of Directors ◽  
Sickle Cell ◽  
Real World ◽  
Research Funding ◽  
Cell Disease ◽  
Advisory Committees ◽  
Real World Evidence ◽  
Disease Modifying

Background: Sickle cell disease (SCD) is a chronic illness characterized by anemia, recurrent severe pain and recurrent organ damage, affecting approximately 100,000 persons in the United States. Prior to November 2019, FDA approved SCD disease-modifying treatments included only hydroxyurea (HU) and L-glutamine. However, voxelotor (Oxbryta®) was recently approved under an accelerated approval based on the HOPE study for the treatment of adult and pediatric patients with SCD 12 years of age and older. We aimed to provide real world evidence of the types of patients prescribed voxelotor and preliminary evidence of potential treatment effects. Methods: Patient records were reviewed from five medical centers with comprehensive sickle cell care. All patients prescribed voxelotor from Nov 25, 2019 to July 31, 2020 were included in our analysis. Data reviewed included: patient demographics, hydroxyurea use, as well as pre- and post- voxelotor changes on red cell transfusion number, vaso-occlusive crisis (VOC) and hemoglobin (Hb) values. In addition, voxelotor dosage changes, side effects, and patients perception on impact on their health were recorded. Descriptive and summary statistics were used to provide results. Results: We reviewed data from 60 patients (18 pediatric and 42 adult), across the five centers, who were prescribed voxelotor. Mean age was 33 (SD 13.8) years old with 63% female patients. All patients were African-American/Black and 96% were HbSS (2% Hb SC and 2% HbSOArab). Eighty (80)% were on hydroxyurea, 20% were on chronic transfusions, and 10% were on erythropoietin stimulating agents when prescribed voxelotor. Mean baseline hemoglobin during the 3 months prior to initiation was 7.38 g/dL (SD 1.46) with all patients started at the recommended dose of 1500mg. Annualized VOC events for the year prior to starting voxelotor was 0.62 (SD) or 7.44 VOCs per year. Across all sites, 31 patients were prescribed voxelotor but had either not initiated drug, not returned for follow up labs at time of analysis, or refused to take drug once approved (n=1). Nine patients had only 1 month of follow labs to review and an additional 18 patients with 3 months of follow up labs. These 27 patients were followed for an average of 6.0 months (SD 7.7) on treatment with 4 patients (15%) requiring dose adjustment to 1000mg. Dose adjustments were for side effects including abdominal pain, diarrhea, loose stools and nausea/vomiting. One patient had dosing changed from daily to three times a day. Average hemoglobin during steady state after 1 and 3 months of treatment were 8.6 g/dL (SD 1.8) and 8.0 g/dL (SD 1.8), respectively. In addition, 52% increased by 1g/dL at 1 month (n=21) and 44% increased by 1g/dL at 3 months (n=18). The mean maximum hemoglobin obtained during the 3-month period following initiation of voxelotor was 8.9 (SD 2.1) g/dL. During follow up visits, several patients reported 'more energy' and improvement in 'morning achiness' and 'quality of life', while a few patients noted no change in stamina or well-being. Three patients (5%) had drug discontinued due to becoming pregnant, unexplained elevation of liver enzymes, and due to excessive abdominal pain and nausea. Annualized VOC rates after voxelotor initiation were numerically decreased, although limited by short follow up. Conclusion: We present real world evidence of prescribing patterns and initial outcomes from the use of newly approved voxelotor. We found the majority of patients prescribed voxelotor were the HbSS genotype, on hydroxyurea, and with a mean baseline Hb &lt;7.5 g/dL, indicating an initial focus on more anemic patients. Interestingly, one-fifth of the prescribed patients where on chronic transfusions. Consistent with the HOPE trial, the average Hb levels was found to have increased at 1 month and 3-month follow up. Our preliminary results support an overall increase in hemoglobin in patients treated with voxelotor and we aim to continue following patients over a longer follow up period. This provides important real-world evidence for this newly approved disease-modifying therapy for SCD. Disclosures Shah: Alexion: Speakers Bureau; CSL Behring: Consultancy; Novartis: Consultancy, Research Funding, Speakers Bureau; Global Blood Therapeutics: Consultancy, Research Funding, Speakers Bureau; Bluebird Bio: Consultancy. Zaidi:Global Blood Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Emmaus Life Sciences: Consultancy, Honoraria; Imara: Consultancy, Honoraria; bluebird bio: Consultancy, Honoraria; Cyclerion: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Callaghan:Grifols: Honoraria, Membership on an entity's Board of Directors or advisory committees; Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Site Investigator/sub-I Clinical Trial, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Site Investigator/sub-I Clinical Trial, Research Funding; Sancillio: Other; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; NovoNordisk: Other, Speakers Bureau; Biomarin: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Site Investigator/sub-I Clinical Trial, Speakers Bureau; Global Blood Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Speakers Bureau; Alnylum: Current equity holder in publicly-traded company; Bioverativ: Membership on an entity's Board of Directors or advisory committees; Spark: Honoraria, Membership on an entity's Board of Directors or advisory committees; Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Hema Biologics: Honoraria, Membership on an entity's Board of Directors or advisory committees. De Castro:Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees; FORMA Therapeutics: Membership on an entity's Board of Directors or advisory committees; GlycoMimetics: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Clinical Outcomes and Healthcare Utilization in Patients with Sickle Cell Disease: A Nationwide Cohort Study of Medicaid Beneficiaries

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3459-3459
Author(s):  
Rishi J Desai ◽  
Mufaddal Mahesri ◽  
Raisa Levin ◽  
Denise Globe ◽  
Krista McKerracher ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Board Of Directors ◽  
Sickle Cell ◽  
Research Funding ◽  
Cell Disease ◽  
Advisory Committees ◽  
Risk Of Mortality ◽  
Increased Risk ◽  
Ed Visits ◽  
Event Rates

Introduction: There is limited contemporary evidence on clinical outcomes and healthcare use in sickle-cell disease (SCD) patients enrolled in US Medicaid. We aimed to provide contemporary estimates for rates of vaso-occlusive crises (VOC), mortality, and healthcare resource utilization (HRU) in SCD patients enrolled in US Medicaid. Methods: We conducted a cohort study using nationwide Medicaid insurance claims data (2000-2013). Patients were included based on ≥1 inpatient or ≥2 outpatient HbSS SCD diagnosis claims after 365 days continuous enrollment in Medicaid (or continuous eligibility since birth if age at diagnosis is &lt;1 year). Patients were followed until Medicaid disenrollment, death, bone marrow transplant, or end of data availability (December 31, 2013). Outcomes included frequency of VOCs, event rates of HRU including emergency department (ED) visits, hospitalizations, outpatient visits, and blood transfusions, and all-cause mortality during the follow-up period. All outcomes were reported as annualized event rates (with 95% confidence intervals). VOCs were stratified by age-group (&lt;1, 2-6, 7-12, 13-18, 19-35, 35+ years), VOCs at baseline (&lt;2, 2-4, &gt;=5), race (African American or not), and sex. The impact of VOCs on the risk of mortality was analyzed using an extended multivariable Cox model with VOCs modeled as time-varying and updated annually. Results: A total of 44,033 SCD patients were included in the analysis; 47% were female, 82% were African American, and a mean (SD) age of 15.7 (13.6). The average VOC rate was 3.71 (95% CI: 3.70-3.72) VOCs per person-year over an average follow-up period of 4.3 years. The rate of VOCs was substantially higher among patients aged 19-35 years and those with a higher VOC frequency at baseline (Table 1). Overall, the event rates (95%CI) per person year for other HRU outcomes were: 2.97 (2.97-2.98) ED visits, 2.39 (2.38-2.40) hospitalizations, 5.80 (5.79-5.81) outpatient visits, and 0.91 (95%CI: 0.90-0.91) blood transfusions. The mortality rate was 1.13 (95%CI: 1.08-1.17) events per 100 person-years overall, with the highest rate being 4.91 (95%CI: 4.58-5.25) events per 100 person-years among patients ≥ 35 years of age. Higher VOC burden in the preceding year was associated with an increased risk mortality: 2-4 VOC vs. 0 or 1 VOC: Hazard Ratio (HR)=1.36 (95%CI: 1.21-1.52); ≥ 5 VOC: HR= 1.56 (95%CI: 1.39-1.75). Conclusion: The burden of SCD in US Medicaid enrollees is substantial, especially during early adulthood, with markedly high rates of VOCs, mortality, and healthcare utilization. A higher VOC rate in the preceding year was associated with an increased risk of mortality suggesting a need for careful management of SCD patients with higher VOC burden. Table 1. Annualized rates of vaso-occlusive crises (VOC) among sickle cell disease patients enrolled in Medicaid. VOC, vaso-occlusive crises; CI, confidence interval. Table 1 Disclosures Desai: Merck: Research Funding; Bayer: Research Funding. Globe:Vertex Pharmaceuticals Incorporated: Employment. McKerracher:CRISPR Therapeutics: Employment. Mutebi:Vertex Pharmaceuticals Incorporated: Employment. Bohn:Bohn Epidemiology: Equity Ownership; Vertex Pharmaceuticals Inc: Consultancy. Achebe:Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees; Pharmacosmos: Membership on an entity's Board of Directors or advisory committees; Fulcrum Therapeutics: Membership on an entity's Board of Directors or advisory committees; Bluebird Bio: Membership on an entity's Board of Directors or advisory committees. Schneeweiss:Genentech: Research Funding; Boehringer Ingelheim: Research Funding; Aetion, Inc.: Consultancy, Equity Ownership; Whiscon LLC: Consultancy.

scholarly journals Implementation of Escort-HU Extension: European Sickle Cell Disease Cohort - Hydroxyurea - Extension Study : Interests and Methodology

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3098-3098
Author(s):  
Mariane de Montalembert ◽  
Ersi Voskaridou ◽  
Lena Oevermann ◽  
Giovanna Cannas ◽  
Anoosha Habibi ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Board Of Directors ◽  
Sickle Cell ◽  
Research Funding ◽  
Steering Committee ◽  
Leg Ulcers ◽  
Cell Disease ◽  
Advisory Committees ◽  
History Of

Abstract The efficacy and long-term effectiveness of hydroxycarbamide/hydroxyurea (HU) in the prevention of painful crises and in the decrease of mortality and morbidity in sickle cell disease (SCD) patients have been established (Charache et al. 1992; Steinberg et al 2010, Voskaridou et al 2010). From January 2009 to March 2019, the non-interventional prospective cohort study ESCORT-HU was conducted to evaluate the use of HU in real-life conditions and to collect information on the long-term safety of HU when used in current practice for the prevention or treatment of symptomatic complications in patients with sickle cell disease (SCD) (Montalembert et al 2021). A total of 1906 patients, 55% of adults, were enrolled in this study in 62 centres (Germany, Greece, Italy and France). The mean exposure to HU in this cohort was 30 months, for a cumulative exposure of 7310 patient-per year. The main objectives of ESCORT-HU have been fulfilled as regards the collection of data on the most common concerns associated with the use of HU in SCD patients: myelosuppression, child growth, concomitant administration of live vaccines, safety in population with renal and hepatic impairment and frequency of SCD events (painful crises, acute chest syndrome, stroke, acute splenic sequestration, infections, blood transfusions and hospitalizations) (Montalembert et al 2021). In order to better identify potential long-term risks and specific concerns of HU therapy, ESCORT-HU extension is being implemented in Europe with the goal of 2500 patients enrolled. Main risks targeted by the study are leg ulcers, one of the most limiting factors to continue a treatment with HU. Patients will be recruited over a 5-year period. In addition to patients already involved in the first ESCORT-HU study, new at-risk patients might be added such as patients with a history of HU exposure of at least 5 years, to allow a follow-up of patients treated with long-term HU to fully estimate the incidence of potential risk of malignancies prepubescent children aged more than 10 years for girls and more than 13 years for boys in order to document impact or not of HU on puberty and realisation of cryopreservation,patients with a history of leg ulcers, to search for discriminating criteria between leg ulcer caused by the disease and HU-induced leg ulcer,pregnant women without interruption of HU 3 months before the beginning of the pregnancy and males treated with HU whose partner is pregnant and without discontinuation of HU 3 months before the beginning of the pregnancy. To date, there is a limited number of pregnancies exposed to HU with documented outcome. Despite no adverse effects on pregnancy or on the health of the foetus/new-born have been registered, an increase of the number of pregnancies with documented outcomes will allow for meaningful assessment of foetal outcome following exposure to HU during pregnancy, 10 months after the beginning of ESCORT-HU extension, 818 patients have been enrolled in 70 investigational sites in 4 countries (Greece, Italy, Germany and France) (see Graph below). A first steering committee was hold in June 2021. Its conclusions were that distribution of patients (genotype, sex, age) was consistent with the first study and the number of events reported until now was coherent with what was expected per year, with no occurrence of major concern. This extension study involves most of competence centres which manage SCD patients. SC patients have become increasingly well cared for in recent decades and have seen their life expectancy increase. HU treatment is now a chronic treatment possibly for life in many patients with SCD, better its knowledge of its efficiency and tolerance, better patient adherence to treatment will be. Figure 1 Figure 1. Disclosures de Montalembert: Addmedica: 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; Bluebird Bio: Consultancy, Membership on an entity's Board of Directors or advisory committees; Vertex: Consultancy. Voskaridou: ADDMEDICA: Consultancy, Research Funding; BMS: Consultancy, Research Funding; GENESIS: Consultancy, Research Funding; NOVARTIS: Research Funding; PROTAGONIST: Research Funding; IMARA: Research Funding. Oevermann: NOVARTIS: Consultancy; GBT: Consultancy. Joseph: bluebird bio: Consultancy. Colombatti: BlueBirdBio: Membership on an entity's Board of Directors or advisory committees, Research Funding; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees. Bartolucci: INNOVHEM: Other: Co-founder; Jazz Pharma: Other: Lecture fees; AGIOS: Consultancy; Addmedica: Consultancy, Other: Lecture fees, Research Funding; Fabre Foundation: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Lecture fees, Steering committee, Research Funding; Bluebird: Consultancy, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy; GBT: Consultancy; Emmaus: Consultancy; Hemanext: Consultancy. Brousse: BLUEBIRDBIO: Consultancy; ADDMEDICA: Consultancy. Galactéros: Addmedica: Membership on an entity's Board of Directors or advisory committees.

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

Blood ◽  
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.

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

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 6-8
Author(s):  
Britta Hoechsmann ◽  
Regis Peffault De Latour ◽  
Anita Hill ◽  
Alexander Röth ◽  
Timothy Devos ◽  
...  
Keyword(s):  
Risk Factors ◽  
Board Of Directors ◽  
Research Funding ◽  
Index Date ◽  
Case Control Study ◽  
Advisory Committees ◽  
Clone Size ◽  
Increased Risk ◽  
History Of ◽  
Control Study

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 &lt;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.

Long Term Efficacy and Tolerance of Pegylated Interferon Alpha Therapy for Patients with High Risk Essential Thrombocythemia: An Observational Study of the French Intergroup of Myeloproliferative Disorders (FIM)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1845-1845
Author(s):  
Lydia Roy ◽  
Jean Christophe Ianotto ◽  
Joelle Guilhot ◽  
Christian Récher ◽  
Laurence Legros ◽  
...  
Keyword(s):  
Clinical Trial ◽  
High Risk ◽  
Observational Study ◽  
Board Of Directors ◽  
Research Funding ◽  
Myeloproliferative Disorders ◽  
Advisory Committees ◽  
Hematologic Response ◽  
History Of

Abstract Background: Therapeutic guidelines in essential thrombocytemia (ET) are based on established criteria, ie. age more than 60 years, history of thrombosis, platelets more than 1000-1500 ×109/L and to lesser degree cardio-vascular risk factors. Hydroxyurea and anagrelide are the most commonly used cytoreductive therapy for high risk ET. Despite a proven activity in Ph negative myeloproliferative disorders, generalized use and efficacy of Interferon-alpha (IFN-α) have been hampered by frequent side effects. Nonetheless it is a non leukemogenic therapeutic option for younger patients (pts) and during pregnancy. Two phase II trials using Pegylated (Peg) forms of IFN-α in pts with polycythemia vera (PV) or high risk ET have provided interesting results: i) an improved toxicity profile generally associated with a rapid hematolologic response, ii) a molecular response described in a subset of JAK2V617F positive PV or ET pts treated with PegIFN-α. Aim: To estimate the rationale of PegIFN-α therapy selection in high risk ET patients, efficacy and tolerance. Methods:Cases of high risk ET patients, who started PegIFN-α therapy between 2006 and 2011, were reported by centres of the French Intergroup of Myeloproliferative disorders and included in an observational study. We collected information regarding history of MPN, treatment, hematologic response at different timepoints, toxicities related to PegIFN-α, thrombo-hemorrhagic events and hematologic progression. The current analysis was performed on 103 consecutive pts. Results: Median follow-up from ET diagnosis was 9 years (3-27). 74% of pts were female, median age was 37 years (range 16-67). Previous vascular event was observed in 36% of cases and JAK2V617F mutation was detected in 52% of pts. . Median time from diagnosis to PegIFN-α was 40 months (1-255). PegIFN-α was administered after hydroxyurea and anagrelide in second or third line (56% and 27% respectively). No prior therapy has been used for 16% of pts. Reasons for starting PegIFN-α were lack of hematologic response (21%), toxicity to prior therapies (17%), pregnancy (15%), or medical decision for younger pts (47%). Pts received either PegIFNα-2a (n=91) or PegIFNα-2b (n=12), based on physician decision. According to the 2009 European LeukemiaNet criteria and with a median exposure to PegIFN-α of 29 months (1-92), 81% of pts achieved a complete hematologic response (CHR). Cumulative incidence of CHR were 58 % (95% CI: 49-68), 73% (95% CI: 65-81) and 80% (95% CI: 71-87) at 6, 12 and 24 months respectively. By analysing the response according to JAK2 status, cumulative incidence of CHR was better for the JAK2V617F positive subgroup (p=0.0183, overall). At 36 months estimated CHR rates were 89% (95% CI: 79-95) and 70% (95% CI: 57-82) for JAK2VF positive vs negative subgroup respectively. Median exposure to PegIFN-α was 29 months in both groups. At last follow-up, with a median of 42 months since PegIFN-α initiation, 53% of the pts were still treated with PegIFN-α. Among them, 76% have maintained a CHR. Reasons for discontinuation of PegIFN-α (47% of pts) were consecutive to PegIFN-α toxicity (59%), -mainly chronic moderate non hematologic toxicity-, or hematologic responses were considered insufficient in16%. In addition, PegIFN-α has been stopped in a subset of pts who achieved a durable stable CHR. In Conclusion, This study provides results of PegIFN-α therapy in a cohort of high risk ET pts not included in clinical trials. In this selected population of young pts, a durable efficacy of therapy was observed in half of patients. Characteristics of hematologic response according to molecular status will be presented. These results support the PegIFN-α as an alternative therapy to hydroxyurea and anagrelide in high risk ET, and warrant its investigation in further prospective randomized studies. Disclosures Roy: Merck: Peg-Interferon provided for academic clinical trial in CML Other. Off Label Use: Peg-Interferon in essential thrombocythemia. Gyan:Roche: Research Funding. Nicolini:BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Ariad: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Kiladjian:Roche: Peg-Interferon provided for academic clinical trial in PV Other.

scholarly journals Association between the Risk of Low/High-Count Monoclonal B-Cell Lymphocytosis (MBL) and the Chronic Lymphocytic Leukemia (CLL) Polygenic Risk Score (PRS)

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5538-5538
Author(s):  
Geffen Kleinstern ◽  
Sara J. Achenbach ◽  
Dennis P. Robinson ◽  
Aaron D. Norman ◽  
Kari G. Chaffee ◽  
...  
Keyword(s):  
Family History ◽  
Board Of Directors ◽  
Research Funding ◽  
Polygenic Risk Score ◽  
Advisory Committees ◽  
High Count ◽  
Polygenic Risk ◽  
Increased Risk ◽  
History Of ◽  
Age And Sex

Abstract Background MBL is a precursor state to CLL, with a prevalence of ~5-8% in the general population and 15-18% in CLL families. To date, 41 single nucleotide polymorphisms (SNPs) have been found to be associated with CLL. We previously showed that a PRS of the weighted average of the number of risk alleles of these SNPs is associated with CLL risk using cases and controls from the International Lymphoma Epidemiology (InterLymph) Consortium. We validated this score in an independent sample of CLL cases and controls from the Genetic Epidemiology of CLL (GEC) Consortium, a cohort of families with ≥2 members with CLL. In the CLL families we also reported an association between the PRS and MBL risk, where 93% of MBLs were low-count MBL. Here we evaluate the PRS in an independent sample ascertained from the Mayo Clinic Biobank. Methods The Mayo Clinic Biobank is a large-scale bio-repository of adult patients assembled to provide a wide array of health-related research studies. Biobank participants (N=2530) were screened for MBL using a highly-sensitive, 8-color (CD38, CD45, Kappa, Lambda, CD19, CD23, CD5 and CD20) flow-cytometry assay on stored cryopreserved peripheral blood mononucleotide cells. Low-count and high-count MBL were defined as those individuals who had <85% and ≥85 clonal B-cells out of total B-cells, respectively. Individuals without MBL ("controls") were frequency matched to MBLs based on age and sex, after excluding non-Caucasian and non-interpretable flow results. Participants were genotyped using the Illumina OmniExpress array. Standard genotyping quality-control metrics were applied. We computed the PRS as previously published and categorized it by quintiles based on values previously used with InterLymph controls. The middle quintile served as the reference category. We used logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CI), adjusting for age at consent, sex, and socioeconomic status. In addition, we compared the median PRS by low-count MBL and high count MBL using the Mann-Whitney U test. Results We identified 276 MBLs overall and 2109 controls; 97% (N=267) of MBLs had low-count MBL and only 3% (N=9) had high-count MBL. We then selected 844 controls frequency matched to the MBL cases on age and sex. Family history of leukemia/lymphoma was 11.3% among MBLs overall and 8.8% among controls. The median PRS was 7.88 and 7.46 (Figure) among MBLs overall and controls, respectively. The continuous PRS had a 1.75-fold increased risk for MBL overall (CI:1.5-2.1, P=2.65x10-12). Compared to the middle quintile, the highest quintile had 2.2-fold increased risk for MBL overall (CI:1.5-3.3, P=1.46x10-4) and the lowest quintile had 0.6-fold decreased risk (CI:0.4-0.96, P=0.03). The median PRS for low-count and high count MBL were 7.86 and 8.04, respectively. The continuous PRS had a 1.75-fold increased risk for low-count MBL (CI:1.5-2.1, P=4.81x10-12) and a 1.89-fold increased risk for high-count MBL (CI:0.8-4.2, P=0.13), however, the effect is not statistically significant between high-count and low-count MBL (P=0.89). Conclusion In this independent sample, we validated our previous findings that the CLL PRS is associated with MBL risk. Although the sample size of high-count MBL was limited (N=9), there is evidence of a weak trend towards a higher PRS compared to low-count MBL and controls Larger sample size of high-count MBL is warranted in order to stratify MBL risk by low-count and high-count MBL. These results may help identify individuals at higher risk of MBL including low-count and high-count MBL, beyond the risk associated with age and family history of CLL. Figure: Polygenic risk score distribution by control and MBL status Figure. Figure. Disclosures Parikh: Janssen: Research Funding; Pharmacyclics: Honoraria, Research Funding; Gilead: Honoraria; Abbvie: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; MorphoSys: Research Funding. Cerhan:Nanostring: Research Funding; Celgene: Research Funding; Jannsen: Other: Scientific Advisory Board. Kay:Janssen: Membership on an entity's Board of Directors or advisory committees; Acerta: Research Funding; Infinity Pharm: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Agios Pharm: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Cytomx Therapeutics: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Tolero Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Morpho-sys: Membership on an entity's Board of Directors or advisory committees. Shanafelt:Genentech: Research Funding; Pharmacyclics: Research Funding; GlaxoSmithKline: Research Funding; Jansen: Research Funding.

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