scholarly journals Off-Label Prescription of Hydroxycarbamide (Hydroxyurea, HU) for Severe Anemia: Preliminary Results from European Non-Interventional, Multicentric, Prospective Escort-HU Study

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. 758-758
Author(s):  
Mariane De Montalembert ◽  
Gylna Loko ◽  
Jerome Clouzeau ◽  
Valentine Brousse ◽  
Frederic Galacteros ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Expert Panel ◽  
Safety Data ◽  
Incidence Rates ◽  
Cell Disease ◽  
Advisory Committees ◽  
Off Label ◽  
Preliminary Results ◽  
The Mean

Abstract HU is licensed in Europe in the prevention of recurrent painful vaso-occlusive crises (VOC) including acute chest syndromes in adults, adolescents and children older than 2 years with sickle-cell disease (SCD). However, based on US and European expert panel recommendations (Yawn 2014, Habibi 2015) and results from placebo-controlled clinical trials, HU could be useful in SCD patients with severe anemia without VOC since it has been demonstrated to increase total Hb level (Wang 2011) and to decrease the need for blood transfusion. We hereby present preliminary results on effectiveness and safety data related to the prescription of HU for anemia from ESCORT-HU (European Sickle Cell Disease COhoRT - HydroxyUrea), a multicentric, prospective, non-interventional European study designed to collect long-term safety data on HU in SCD population. Between January 2009 and June 2017, 1841 patients were enrolled from 63 centers in France, Germany, Greece and Italy, amongst which 126 patients (6.8%) were started on HU for anemia from 34 centers. Of these 126, 96 were HU-naive. These HU-naive patients treated for anemia ('anemic' subpopulation) were selected for analysis to evaluate effectiveness and safety of HU in this indication and compared with data in HU-naive patients treated for other SCD indications. Demographic data and Hb genotypes are displayed in Table 1. The mean age, distribution of gender, Hb genotype and the mean HU dose at initiation were comparable in the 'anemic' subpopulation and the 'non-anemic' HU-naive cohort. Not surprisingly, mean Hb level at initiation was markedly lower in the 'anemic' subpopulation (7.07 ± 0.88 g/dl) than in the 'non-anemic' HU-naive cohort (8.71 ± 1.51 g/dl), with a lower proportion of patients with history of VOC and SCD-related hospitalization prior to HU initiation. The mean HU dose after 6 months was comparable in both groups (15.6 ± 3.83 mg/kg/day and 15.4 ± 4.11 mg/kg/day, respectively). Variation of blood parameters are displayed in Table 2. Similarly to what has been observed previously, a dramatic rise in Hb concentration (> 2 g/dl) was observed. This increase was comparable in absolute value to the increase observed in non-anemic patients. An increase in HbF was observed in the "anemic" subpopulation, with a near 2-fold increase in %HbF, markedly in children. Changes in reticulocyte counts were inconclusive due to small number of patients in the dataset. Safety of HU in the population of patients treated for anemia was evaluated by comparing incidence rates of non-SCD related adverse events (AEs) in HU-naive patients treated for anemia with the 'non-anemic' HU-naive ESCORT-HU subpopulation (Table 3). With mean follow-up periods of 18.3 months in 'anemic' subpopulation and 34.2 months in 'non-anemic' HU-naive cohort, preliminary results showed no striking difference in the incidence rate of reported AEs (total and serious) between the two populations (112.5% vs 139.8%, respectively for incidence rate of total AEs), and in the distribution of AEs by System Organ Class (SOC), at least in SOC where the number of adverse events was large enough to allow for comparison between the groups. Similarly, when focusing on AE causally related to HU (as judged by the investigators), the most frequently reported toxicity in the 'anemic' population was myelosuppression (anemia, neutropenia thrombocytopenia, pancytopenia reported in 4 children, one event each), as in the 'non-anemic' HU-naive cohort, with comparable incidence rates. In conclusion, even though HU is not licensed in Europe in severe chronic anemia, European and US expert panel guidelines recommend treatment with HU in this indication. Data from ESCORT-HU observational study on a subset of SCD patients treated off label in this indication confirmed total Hb level increase while the safety profile of HU in this subpopulation did not differ significantly from the 'non-anemic' HU-naive population. Disclosures De Montalembert: Novartis: Consultancy, Honoraria, Research Funding; Addmedica: Consultancy, Honoraria, Research Funding. Brousse: Add Medica: Membership on an entity's Board of Directors or advisory committees. Galacteros: Addmedica: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Is There a Clinical Benefit to Switch Hydroxyurea (HU) Drug in Sickle Cell Disease (SCD)?

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 4-5
Author(s):  
Frédéric Galactéros ◽  
Ersi Voskaridou ◽  
Anoosha Habibi ◽  
Giovanna Cannas ◽  
Laure Joseph ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Board Of Directors ◽  
Sickle Cell ◽  
Clinical Benefit ◽  
Research Funding ◽  
Fine Tuning ◽  
Cell Disease ◽  
Advisory Committees ◽  
Previously Treated ◽  
The Mean

The European Sickle Cell Disease Cohort - Hydroxyurea (ESCORT-HU) study was initiated when HU got an approval in SCD in Europe. This non-interventional prospective cohort study conducted in patients treated with HU according to current clinical practice with SCD was terminated in 2019 after enrolment of 1906 patients in 4 European countries. The main objective was to refine the safety profile of hydroxycarbamide, as well as to identify unexpected toxicities, especially after long-term treatment. However clinical effectiveness evaluated by recording painful crises lasting more than 48 hours, episodes of ACS, number of hospitalisations related to SCD, and biological parameters were also regularly recorded according to the frequency of the hospital visits. At inclusion, 926 (48.7%) patients had been previously treated off the label with HU (as HU was only approved for myeloproliferative disorders at the time), with mean duration of HU treatment of 5.74 ± 4.98 years. The mean age of this subgroup was 27.60 ± 14.81 years compared to 19.75 ± 15.79 years of the patients never been treated with HU before enrolment Of the 926 patients, 299 (32%) were younger than 18 years. As showed in the table 1, hemoglobin level remains unchanged during the first two years but the HbF% increased in the HU-pretreated subgroup. In the "HU-naïve group", despite lower baseline Hb level et HbF% at baseline , similar outcome were obtained after 12 or 24 months. In terms of clinical outcomes, after 1 year of treatment the number of vaso-occlusive crises (VOC), acute chest syndrome (ACS) or hospitalizations decreased dramatically (table 2) in both group. The median duration of follow-up in the cohort was 45 months (0-128). 123.7 ± 62.7 months was the mean total exposure to HU in the HU-pretreated subgroup. In term of safety, neutropenia, thrombocytopenia and dry skin were the most frequent HU- related adverse events reported but with comparable cumulated incidence between the HU-pretreated subgroup and HU-naïve subgroup (Table 3). Conclusion: In real life setting, a significant improvement of the vasoocclusive symptoms was observed. Improvement of the compliance thanks to a treatment dedicated to the disease is probably one reason for better effectiveness; as suggested bythe lower red blood cell MCV was lower than expected at baseline in patients previously treated with HU. It is also possible that the increase in HbF% observed during the treatment could be another reason for clinical benefit. Paule and al (2011) demonstrated that daily regimen of HU were superior to weekly regimen. The fine tuning of the daily dose possible with HU tablets might be another reason of clinical optimization. Disclosures Galactéros: Addmedica:Membership on an entity's Board of Directors or advisory committees.Voskaridou:BMS:Consultancy, Research Funding;ADDMEDICA Company:Consultancy, Research Funding;NOVARTIS Company:Research Funding;GENESIS Company:Consultancy, Research Funding;PROTAGONIST Company:Research Funding;ACCELERON Company:Consultancy, Research Funding.Habibi:Pfizer:Consultancy;Bluebird:Consultancy;Novartis:Consultancy;Addmedica:Consultancy.De Montalembert:bluebird bio:Honoraria, Membership on an entity's Board of Directors or advisory committees;Vertex:Honoraria, Membership on an entity's Board of Directors or advisory committees;Addmedica:Honoraria, Membership on an entity's Board of Directors or advisory committees;Novartis:Honoraria, Membership on an entity's Board of Directors or advisory committees.

scholarly journals Outcomes of Pregnancies in Patients with Sickle-Cell Disease : Update from European Non-Interventional, Multicentric, Prospective Escort-HU Study

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 891-891
Author(s):  
Frédéric Galactéros ◽  
Giovanna Cannas ◽  
Pablo Bartolucci ◽  
Ersi Voskaridou ◽  
Laure Joseph ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Board Of Directors ◽  
Sickle Cell ◽  
Live Birth ◽  
Research Funding ◽  
Current Practice ◽  
Cell Disease ◽  
Advisory Committees ◽  
Live Births ◽  
The Mean

Hydroxyurea (HU) is approved in EU and USA for the prevention of vaso-occlusive crises (VOC) including acute chest syndromes (ACS) in patients over 2 years with sickle-cell disease (SCD). Patients on HU wishing to conceive should stop treatment 3 to 6 months before pregnancy if possible. Pregnancy in SCD female patients are considered at risk for the mother and the fetus. This condition is associated with increased pain, infections, thromboembolic events,[1] and vaso-occlusion in placenta can lead to adverse fetal outcomes.[2] A few cases of HU exposure during pregnancy in SCD patients previously published[3],[4] suggested that the risk of deleterious teratogenic effect of HU shown in animal species[5] may have been overestimated in humans.[6] Therefore, a much larger dataset of pregnancies with HU exposure was needed. ESCORT-HU study (European Sickle Cell Disease COhoRT - HydroxyUrea) is a multicentric, prospective, non-interventional European study initiated to collect information about long-term safety of HU when used in current practice. This is the first study in which all pregnancy courses were collected irrespectively of action taken with HU before or during pregnancy. Overall 1906 patients were enrolled from 63 centers in France, Germany, Greece and Italy, 854 men (45%) and 1052 women (55%) among them around 2/3 aged from 15 to 49 years during the follow-up. During the study, 125 pregnancies in 101 women and 12 pregnancies in 10 partners of male patients were collected in the study, regardless HU exposure. In pregnancies with HU paternal exposure, 10 live births and 2 miscarriages were reported. Durations of HU exposure and outcomes of pregnancies in females treated with HU are provided in Table 1. The mean age at the pregnancy was 30 years. The mean HU duration before pregnancy was nearly 5 years. In only 16 pregnancies with maternal exposure (15%) HU was stopped at least 15 days before conception. In 43 pregnancies (34%), transfusions were reported. Live births were reported in 73% of pregnancies with maternal HU exposure excluding voluntary abortions. There was no statistical difference (Chi-squared test) in the proportions of live birth in exposed and non-exposed females (p=0.577). VOC or ACS have been reported in 3 women after the stop of HU. Although women are advised to stop HU before pregnancy, in current practice continuation of HU may be required and HU remains the only alternative to protect the mother and the fetus from deleterious effects of VOC. In conclusion, the data on pregnancy outcome following HU exposure are reassuring when compared to those in general SCD population. Overall in ESCORT-HU, 61% of pregnancies resulted in live birth, which is more than the 42% of pregnancies in the MSH study participants.4 It is notable, without considering voluntary abortions, that the percentage of live birth in ESCORT-HU reached 71%. The rate of preterm delivery (13%) was similar to the one (16%) in HbSS patients from a French cohort.[7] The fertility in women treated with HU seems to be even better and no particular problem in newborns has been reported to date. Disclosures Galactéros: Addmedica: Membership on an entity's Board of Directors or advisory committees. Cannas:Addmedica: Membership on an entity's Board of Directors or advisory committees. Bartolucci:AddMedica: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; HEMANEXT: Membership on an entity's Board of Directors or advisory committees. Voskaridou:Addmedica: Membership on an entity's Board of Directors or advisory committees; Acceleron: Consultancy, Research Funding; Genesis: Consultancy, Research Funding; Protagonist: Research Funding; Celgene Corporation: Consultancy, Research Funding.

scholarly journals Clinical and Biomarker Predictors for Avascular Necrosis in Sickle Cell Disease

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3091-3091
Author(s):  
Michael Rabaza ◽  
Maria Armila Ruiz ◽  
Liana Posch ◽  
Faiz Ahmed Hussain ◽  
Franklin Njoku ◽  
...  
Keyword(s):  
Risk Factors ◽  
Sickle Cell Disease ◽  
Board Of Directors ◽  
Avascular Necrosis ◽  
Sickle Cell ◽  
Research Funding ◽  
Medical Attention ◽  
Cell Disease ◽  
Advisory Committees ◽  
Early Management

Abstract Introduction Sickle cell disease (SCD) affects 1 in 365 African Americans and approximately 25 million people world-wide. A common skeletal system complication is avascular necrosis (AVN), which can cause substantial pain and a reduced quality of life. While early management of AVN is focused on increasing range of motion with physical therapy and pain relief, there are no clear predictors for who is more likely to develop AVN and earlier institution of these preventive measure could help decrease disease progression. Vascular endothelial growth factor (VEGF) is a biomarker of endothelial injury and may indicate reduced vascular supply to the femoral or humeral head. Here we describe potential risk factors and biologic pathways for AVN in SCD, as understanding these may lead to improvements in future monitoring, early detection, and early intervention practices. Methods We investigated clinical and laboratory risk factors associated with AVN in a cohort of 435 SCD patients from our center. Blood samples, clinical, and laboratory data were collected at the time of enrollment during a clinic visit. Genotyping for alpha thalassemia was performed by PCR and the serum concentration of VEGF was measured by ELISA. AVN status was confirmed by review of the medical record and available imaging. We conducted a cross-sectional analysis comparing categorical and linear variables by AVN status using the chi-square and Kruskal-Wallis test, respectively. The independent association of the clinical and laboratory variables with AVN status was determined by logistic regression analysis. The initial model included variables with a P-value < 0.1 on univariate analysis and the final model was ascertained by stepwise forward and backward selection. Median values and interquartile range (IQR) are provided. Results The median age of the cohort was 32 (IQR, 24 - 43) years, 57% (250/435) were female, and 46% (198/435) were on hydroxyurea. AVN was observed in 34% (149/435) of SCD patients. SCD patients with AVN were older, had more frequent vaso-occlusive crises requiring medical attention, and had a higher body mass index (Table I) (P ≤ 0.002). We measured VEGF in 241 of the SCD patients with serum samples available at the time of enrolment. Serum VEGF concentrations trended higher in SCD patients with versus without AVN (420 vs. 359 pg/mL, respectively; P = 0.078). In the multivariate analysis model, AVN was independently associated with increased number of vaso-occlusive crises (OR 1.1, 95% CI: 1.0 - 1.14; P = 0.02), AST concentration (natural log OR 0.5, 95% CI: 0.2 - 0.9; P = 0.03), VEGF concentration (natural log OR 1.4, 95% CI: 1.0 - 1.9; P = 0.047), and tobacco use (OR 1.9, 95% CI: 0.9 - 3.7; P = 0.078). Discussion In conclusion, we demonstrate a high prevalence of AVN in an adult cohort of SCD patients. The presence of AVN was independently associated with a greater frequency of vaso-occlusive pain episodes, which may demonstrate a shared pathophysiology between AVN and vaso-occlusion that merits further investigation. We demonstrate that serum VEGF concentrations are higher in SCD patients with AVN and may be a clinical tool to identify those at high-risk and for earlier intervention for this complication. Figure 1 Figure 1. Disclosures Gordeuk: Modus Therapeutics: Consultancy; Novartis: Research Funding; Incyte: Research Funding; Emmaus: Consultancy, Research Funding; Global Blood Therapeutics: Consultancy, Research Funding; CSL Behring: Consultancy. Saraf: Pfizer: 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, Research Funding.

scholarly journals Clingen Coagulation Factor Deficiency Variant Curation Expert Panel: Meeting the Need for Recommendations to Curate Variants in the Coagulation Factor Genes

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5794-5794
Author(s):  
Shruthi Mohan ◽  
Kristy Lee ◽  
Manuel Carcao ◽  
Bhavya S Doshi ◽  
Kate Downes ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Blood Coagulation ◽  
Research Funding ◽  
Expert Panel ◽  
Coagulation Factor ◽  
Variant Classification ◽  
Variant Interpretation ◽  
Advisory Committees ◽  
Factor Deficiency ◽  
Coagulation Factor Deficiency

The genetics of blood coagulation has been an ongoing area of research; and with the advent of next generation sequencing panels, there is a significant increase in the number of variants identified in coagulation factor genes. Several published reports and online databases document the variants observed in patients with bleeding disorders; however, the clinical interpretation of these variants is not always straight-forward. To enable gene-specific variant interpretation in coagulation factor deficiency disorders, the National Institutes of Health (NIH)-funded effort, Clinical Genome Resource (ClinGen), has developed the Coagulation Factor Deficiency Variant Curation Expert Panel (CFD-VCEP). The CFD-VCEP is comprised of expert clinicians, genetic counselors, clinical laboratory diagnosticians and researchers working toward the goal of developing and implementing standardized protocols for sequence variant interpretation for coagulation factor genes. The CFD-VCEP adapts the 2015 American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines for precise and consistent variant classification to genes involved in blood coagulation deficiencies. These guidelines recommend the use of 28 criteria codes based on the evidence category and the strength of the evidence (see Figure below). The first two genes under the purview of CFD-VCEP are F8 (OMIM: 300841) and F9 (OMIM: 300746). Pathogenic variants in the F8 and F9 genes resulting in the loss of protein function cause Hemophilia A and B, respectively. Owing to the similarity between these two genes with respect to their role in the coagulation cascade as well as the resulting phenotype, specification of variant curation guidelines for both genes has been undertaken simultaneously. With the completion of guideline specification for F8 and F9, the CFD-VCEP will subsequently continue this effort for other coagulation factor genes, while also curating F8 and F9 variants reported in ClinVar and other variant databases. Modifying the ACMG/AMP guidelines involves gene- and disease-informed specifications of the recommended criteria codes. This includes identifying which codes are applicable and which are not, defining gene- and disease-specific cut-offs such as for population frequency, and making code strength adjustments when appropriate. The specified guidelines are further refined based on their performance on a set of pilot variants (n = 30) for each gene compared to existing assertions of variant classification in ClinVar and by diagnostic laboratories represented in the CFD-VCEP. F8 and F9 variants classified by the CFD-VCEP will be submitted to ClinVar at the 3-star review status, with the tag of "FDA-recognized database", and the CFD-VCEP plans to begin this process by the second quarter of 2020. The considerations by the CFD-VCEP in the guideline-specification process and results from the pilot analysis will be discussed. This effort will lead to the standardized use of evidence criteria for the evaluation of variants in F8 and F9, which will reduce the number of variants of uncertain significance and those of conflicting interpretations, making genetic testing results more informative for providers and patients. The CFD-VCEP also encourages sharing de-identified data on variants among laboratories, which enables accurate and consistent curations. Figure Disclosures Lee: UNC Hemophilia Treatment Center: Employment. Carcao:Biotest: Honoraria, Membership on an entity's Board of Directors or advisory committees; Grifols: Honoraria, Membership on an entity's Board of Directors or advisory committees; Shire/Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk Inc: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Agios: Research Funding; LFB: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bioverativ/Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kemball-Cook:European Association for Haemophilia and Allied Disorders: Other: Freelance . Leebeek:CSL Behring: Research Funding; uniQure BV: Consultancy, Research Funding; Baxalta/Shire: Research Funding. Miller:Division of Blood Disorders, National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention: Consultancy.

Improvement in Right Ventricular Function Following 1 Year of Deferasirox Therapy in Patients with β-Thalassemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 5106-5106
Author(s):  
Gillian Smith ◽  
Dudley J. Pennell ◽  
John B. Porter ◽  
M. Domenica Cappellini ◽  
Lee Lee Chan ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Chelation Therapy ◽  
Iron Chelation ◽  
Left Ventricular ◽  
Myocardial Iron ◽  
Advisory Committees ◽  
Off Label ◽  
Cardiac Siderosis ◽  
Rv Function

Abstract Abstract 5106 Background Heart failure secondary to myocardial siderosis remains the main cause of death in regularly transfused patients with β-thalassemia. Once-daily oral iron chelation therapy with deferasirox (Exjade®) has been shown to reduce body iron burden in patients with transfusion-dependent anemias, and the removal of myocardial iron has been demonstrated in several clinical studies including the prospective, multicenter EPIC study. Here we report for the first time an evaluation of right ventricular (RV) function assessed using magnetic resonance (MR) techniques in β-thalassemia patients with myocardial siderosis treated with deferasirox in the EPIC study. Methods The cardiac sub-study of EPIC enrolled patients with β-thalassemia aged ≥10 yrs who had MR myocardial T2* >5–<20 ms (indicating cardiac siderosis), left ventricular ejection fraction ≥56%, serum ferritin (SF) levels of >2500 ng/mL, MR (R2) liver iron concentration (LIC) of >10 mg Fe/g dry weight (dw), and a lifetime minimum of 50 transfused blood units. Deferasirox was initiated at 30 mg/kg/day and subsequent dose adjustments of 5–10 mg/kg/day were based on changes in SF, month-6 cardiac T2* and safety parameters. The following RV parameters were assessed using MR; ejection fraction (RVEF), volumes (end-systolic [RVESV] and end-diastolic [RVEDV]) and mass (RVM). All parameters were assessed at the CMR core laboratory in London, UK after 6 and 12 months of deferasirox treatment. Results 114 patients were enrolled in the cardiac sub-study (54 male, 60 female; mean age 20.9 ± 7.3 years). Baseline myocardial T2* was <10 ms in 47 (41%), and 10–20 ms in 67 (59%) patients. Mean baseline LIC was 28.2 ± 10.0 mg Fe/g dw, median serum ferritin was 5235 ng/mL, and the mean amount of transfused blood in the previous year was 185 mL/kg. 68% of patients had received prior deferoxamine (DFO) and 32% DFO/deferiprone combination chelation therapy. Mean actual deferasirox dose over 12 months was 32.6 mg/kg/day. RVEF increased significantly from a mean ± SD baseline of 65.8 ± 6.2% to 67.6 ± 6.4% at 6 months (P=0.013) and 68.7 ± 5.7% at 12 months (P<0.0001; Figure). RVESV significantly decreased from 35.0 ± 14.5 mL at baseline, to 33.4 ± 12.8 mL (P=0.034; Figure) by 12 months and RVEDV significantly increased from 101.0 ± 31.8 mL at baseline to 105.7 ± 33.4 mL (P=0.04; Figure) by 12 months. There were no significant correlations between any of the RV function parameters assessed and T2*. There was a borderline significant reduction in RVM from 46.8 ± 14.6 g at baseline to 44.9 ± 12.4 g at 12 months (P=0.088). Reference RVEF, RVESV, RVEDV and RVM have been defined in healthy subjects as 66 ± 6 %, 50 ± 14 mL, 144 ± 23 mL and 48 ± 12 g, respectively (A M Maceira et al. Eur Heart J 2006;27:2879–88), although values were shown to vary significantly by gender, body surface area and age. Conclusions To our knowledge, this is the first study to show a change in RV volumes and improvement in RV function associated with iron chelation. The RVEF improved with increased RVEDV and decreased RVESV, which is suggestive of improved RV and left ventricular compliance respectively resulting from removal of myocardial iron. However, improvements in pulmonary vascular resistance may also play a role. Disclosures Smith: Novartis Pharma AG: Consultancy, Employment at Royal Brompton Hospital funded by Novartis Pharma AG. Pennell:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Apopharma: Consultancy, Honoraria; Cardiovascular Imaging Solutions: Equity Ownership; Siemens: Research Funding. Off Label Use: THE SPECIFIC USE OF CHELATION FOR CARDIAC SIDEROSIS IS OFF-LABEL. Porter:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Vifor International: Membership on an entity's Board of Directors or advisory committees. Cappellini:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genzyme: Membership on an entity's Board of Directors or advisory committees. Chan:Novartis: Honoraria, Research Funding. Aydinok:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Ibrahim:Novartis: Research Funding. Lee:Novartis: Consultancy, Speakers Bureau. Viprakasit:Thai Government: Employment; Novartis: Honoraria, Research Funding; GPO-L-ONE clinical study sponsor by Government Pharmaceutical Organization of Thailand: Honoraria, Research Funding. Kattamis:Novartis: Consultancy, Honoraria, Speakers Bureau. Habr:Novartis Pharmaceuticals: Employment. Domokos:Novartis Pharma AG: Employment. Hmissi:Novartis Pharma AG: Employment. Taher:Novartis: Honoraria, Research Funding.

A Randomized Phase 2 Trial of Bortezomib–Dexamethasone Versus Bortezomib–Dexamethasone with Added Cyclophosphamide or Lenalidomide in Multiple Myeloma Patients Achieving Stable Disease After Four Cycles of Bortezomib–Dexamethasone Administered as Second-Line Treatment.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4937-4937
Author(s):  
Meletios A. Dimopoulos ◽  
Huw Roddie ◽  
Meral Beksac ◽  
Lotfi Benboubker ◽  
Romualdas Jurgutis ◽  
...  
Keyword(s):  
Renal Function ◽  
Board Of Directors ◽  
Research Funding ◽  
Safety Data ◽  
Phase 2 ◽  
Advisory Committees ◽  
Ortho Biotech ◽  
Function Group ◽  
Grade 3 ◽  
Renal Function Group

Abstract Abstract 4937 Bortezomib (Velcade®) plus dexamethasone (Vel/Dex) is known to be effective and well tolerated in patients with multiple myeloma (MM). As demonstrated in the frontline setting, the addition to Vel/Dex of cyclophosphamide (VCD) or lenalidomide (Revlimid®; VRD) may lead to improved efficacy, but may be associated with increased toxicities; however, few studies have prospectively assessed Vel/Dex as second-line therapy. This randomized, open-label, parallel-group, phase 2 study in patients who have relapsed after or are refractory to primary MM therapy is designed to evaluate the safety and efficacy of an additional 4 cycles of Vel/Dex, VCD, or VDR in patients achieving stable disease (SD) after 4 cycles of Vel/Dex. Bortezomib-naïve patients aged ≥18 years, with measurable MM, KPS ≥60, life expectancy ≥6 months, adequate hematologic and hepatic function, and without grade ≥2 peripheral neuropathy (PN) received 4 3-week cycles of Vel/Dex (Vel 1.3 mg/m2 IV on days 1, 4, 8, and 11, and Dex 20 mg PO on days 1, 2, 4, 5, 8, 9, 11, and 12). Patients then received a further 4 cycles of therapy as follows: patients achieving at least a partial response (PR) received Vel/Dex; patients with SD underwent central randomization to receive Vel/Dex, VCD, or VRD; patients with progressive disease (PD) discontinued treatment. Here we report efficacy and renal function improvement in patients who had the opportunity to complete the initial 4 cycles of Vel/Dex as of April 2009, and safety data for patients who received at least 1 dose of study drug. Response was assessed by IMWG uniform response criteria based on measurement of serum and urine M-protein prior to treatment on day 1 of each cycle, at end of treatment, and monthly thereafter. Renal function as defined by calculated glomerular filtration rate (GFR; Cockcroft–Gault formula) was assessed prior to treatment on day 1 of cycles 1–5. Adverse events (AEs) were graded using NCI CTCAE v3.0. A total of 122 patients have been enrolled; by data cut-off (July 21 2009), 24 (20%) had not completed a single treatment cycle and are excluded from the safety population (N=98). Eighteen had received <4 cycles at data cut-off. Of the remaining 80 who were eligible for response, 63 had completed 4 cycles, 6 discontinued prior to completing 4 cycles (due to PD in 3 patients, death in 1, drug-related AEs in 2), 9 were not under treatment at data cut-off, and 2 had died. Their median age was 62 years (range 34–86), 55% were male, 21.3% had KPS ≤70; median time from prior therapy was 18.6 months. Response rate in the efficacy population was 41/80 (51%) after 4 cycles, including 8% CR. Median times to first and best response were 37 and 57 days, respectively. Patient renal function (by GFR) at baseline, median improvement in GFR, and responses achieved by the 10 patients in whom GFR improved by at least one renal function group are shown in the Table. Among the 98 patients who received at least one treatment dose, mean cumulative doses of bortezomib and dexamethasone were 14.6 mg/m2 (4.9, 4.5, 4.4, and 4.3 mg/m2 in cycles 1–4) and 478 mg (151.8, 145.6, 145.4, and 144.0 mg for cycles 1–4), respectively. Most patients (90%) reported AEs, including 39% with grade 3/4 AEs and 23% with serious AEs, within the first 4 cycles. The most common grade 3/4 AEs included thrombocytopenia (13%), anemia (7%), and pneumonia (6%). AEs resulting in dose reductions/treatment stop were seen in 21%/10% of patients. Incidence of sensory PN and PN was 29% (3% grade 3/4); most PN events were reversible, with 68% resolving within a median 53 days. Updated efficacy and safety data for the first 4 cycles of Vel/Dex for all patients enrolled by July 31 will be presented. Table: Improvement in renal function (as measured by GFR)* Renal function group at baseline, n† <15 mL/min 3 15–<30 mL/min 6 30–<60 mL/min 33 ≥60 mL/min 36 Median GFR (median improvement from previous cycle), mL/min At baseline 58.3 After cycle 1 64.4 (4.8) After cycle 2 68.9 (2.9) After cycle 3 68.6 (9.9) After cycle 4 73.5 (9.4) Renal improvement by at least 1 grade, n (response achieved) 10 <15 to 15–<30 mL/min 1 (1 CR) 15–<30 to 30–<60 mL/min 1 (1 PR) 30–<60 to ≥60 mL/min 8 (2 CR, 1 VGPR, 3 PR, 2 SD) * 1 patient only had a baseline GFR measurement and was not included in the renal analysis † 1 patient had no baseline GFR measurement Disclosures Dimopoulos: Ortho Biotech: Consultancy, Honoraria; Millennium Pharmaceuticals, Inc.: Honoraria. Beksac:Celgene: Honoraria, Research Funding, Speakers Bureau; Janssen-Cilag: Honoraria, Research Funding, Speakers Bureau. Langer:Celgene: Consultancy; Ortho Biotech: Consultancy. Facon:Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees; Johnson and Johnson: Membership on an entity's Board of Directors or advisory committees.

Randomized Phase II Study Evaluating the Efficacy and Safety of Deferasirox in Non-Transfusion-Dependent Thalassemia Patients with Iron Overload.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 5111-5111 ◽  
Author(s):  
Ali Taher ◽  
John B. Porter ◽  
Antonis Kattamis ◽  
Vip Viprakasit ◽  
Tomasz Lawniczek ◽  
...  
Keyword(s):  
Iron Overload ◽  
Board Of Directors ◽  
Phase Ii ◽  
Research Funding ◽  
Iron Concentration ◽  
Transferrin Saturation ◽  
Safety Data ◽  
Efficacy And Safety ◽  
Thalassemia Intermedia ◽  
Advisory Committees

Abstract Abstract 5111 Background Clinically mild forms of thalassemia exist that, unlike β-thalassemia major, require no or only infrequent transfusions (eg. β-thalassemia intermedia, HbH disease). However, due to increased gastrointestinal iron absorption secondary to ineffective erythropoiesis these patients may still develop iron overload. For example, thalassemia intermedia patients (n=74) within a cross-sectional study had a mean serum ferritin (SF) of 1023 ng/mL (range 15–4140) and a mean liver iron concentration (LIC) of 9 mg Fe/g dw (range 0.5–32.1) at baseline despite most being transfusion-naïve (n=20) or rarely transfused (n=45), and only nine receiving regular transfusions (2–4 times/yr) (Taher et al. ITIFPaP: 13th International TIF Conference for Thalassaemia Patients & Parents, October 8–11 2008, Singapore, poster number MON04). Non-transfusional iron overload leads to the same serious clinical sequelae as transfusional iron overload, including liver, cardiac and endocrine dysfunctions. As patients with non-transfusional iron overload are not candidates for phlebotomy due to their underlying anemia, chelation therapy is the only available option for decreasing their iron burden. However, there is currently limited data available on the use of chelation in this population. The once-daily oral iron chelator deferasirox (Exjade®) is currently approved for the treatment of iron overload in patients with transfusion-dependent anemia. This prospective, randomized, double-blind, placebo-controlled Phase II ‘THALASSA’ study will evaluate the efficacy and safety of deferasirox in patients with non-transfusion-dependent thalassemia. Methods Non-transfusion-dependent thalassemia patients aged ≥10 yrs will be randomized 2:1:2:1 to starting doses of deferasirox/placebo 5 mg/kg/day/ deferasirox/placebo 10 mg/kg/day over a planned 12-month treatment period. Doses can be doubled after 6 months should patients require a higher dose, which will be determined after 6 months of treatment. All patients are required to have a baseline LIC of ≥5 mg Fe/g dw, as measured by R2 magnetic resonance imaging, and SF levels of >300 ng/mL. Patients will be excluded if they have: anticipated regular transfusions during the study (sporadic transfusions, such as in cases of infection, are allowed); any transfusion within 6 months prior to study start, chelation within 1 month prior to study start; HbS variants of thalassemia; impaired renal and liver function. Primary efficacy endpoint is absolute change from baseline in LIC at 12 months; secondary efficacy endpoints include change from baseline in LIC after 6 months and in SF after 6 and 12 months, as well as change in hematological and iron metabolism parameters (eg hemoglobin, transferrin saturation). Safety assessments include adverse event and laboratory parameter monitoring. 156 patients are planned for inclusion. Results As of 3 August 2009, 18 sites had been activated. Sites currently activated are in Thailand (n=5), Turkey (n=4), Italy (n=3), Malaysia (n=2), UK (n=2) Lebanon (n=1). Fifty-seven patients have been randomized to either deferasirox or placebo and their demographic data are shown in Table 1. Conclusions Similar to transfusion-dependent thalassemia patients, non- transfusion-dependent thalassemia patients also develop iron overload. This ongoing study will generate prospective efficacy and safety data for the use of deferasirox in non-transfusion-dependent thalassemia patients with iron overload. To prevent long term complications due to iron overload, it is important to assess iron chelation in this patient population as they are not candidates for phlebotomy due to the underlying anemia. Disclosures Taher: Novartis: Honoraria, Research Funding. Porter:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Vifor International: Membership on an entity's Board of Directors or advisory committees. Kattamis:Novartis: Consultancy, Honoraria, Speakers Bureau. Viprakasit:Thai Government: Employment; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Government Pharmaceutical Organization of Thailand: Honoraria, Research Funding. Lawniczek:Novartis Pharma AG: Employment. Pereno:Novartis Pharma AG: Employment. Schoenborn-Kellenberger:Novartis Pharma AG: Employment. Cappellini:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genzyme: Membership on an entity's Board of Directors or advisory committees.

Effect of the Cytochrome P450 3A4 Inducers, Rifampicin and Dexamethasone, on the Pharmacokinetic, Pharmacodynamic and Safety Profile of Bortezomib In Patients with Multiple Myeloma (MM) and Non-Hodgkin's Lymphoma (NHL)

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3983-3983
Author(s):  
Andrzej Hellmann ◽  
Simon A. Rule ◽  
Jan Walewski ◽  
Ofer Shpilberg ◽  
Huaibao Feng ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Proteasome Inhibition ◽  
Employment Equity ◽  
Advisory Committees ◽  
Time Curve ◽  
Once Daily ◽  
Cyp3a4 Inducer ◽  
Equity Ownership ◽  
The Mean

Abstract Abstract 3983 Background: Bortezomib is primarily metabolized by cytochrome P450 (CYP) 3A4 and 2C19 enzymes. Effects of co-administration of rifampicin (a potent CYP3A4 inducer) and dexamethasone (weak CYP3A4 inducer) on the pharmacokinetic (PK), pharmacodynamic (PD) and safety profiles of bortezomib were evaluated. Methods: Patients with relapsed or refractory multiple myeloma (MM) or non-Hodgkin's lymphoma (NHL) were enrolled in this open-label, 2-stage, parallel-group study. In stage 1, patients were randomized (1:1) to receive 3 cycles of bortezomib (1.3 mg/m2) on d 1, 4, 8, and 11 q3wk either alone or in combination with rifampicin 600 mg once-daily on d 4 to 10 of cycle 3 only. Stage 2 patients received bortezomib at same dose and schedule in combination with dexamethasone 40 mg once-daily on d 1 to 4 and d 9 to 12 of cycle 3 only. Patients could continue with bortezomib monotherapy for up to 10 cycles in case of clinical benefit. For PK/PD, blood samples were collected before and through 72 hours following bortezomib administration on d 11 of cycles 2 and 3. PK was the primary endpoint, secondary endpoints included PD (proteasome inhibition) and safety. Results: 61 patients were enrolled (39 MM, 22 NHL) in the study. 13 were treated with bortezomib + rifampicin, 18 with bortezomib + dexamethasone, and 30 with bortezomib only. Co-administration of rifampicin reduced the mean bortezomib maximum plasma concentration (Cmax) by approximately 23% (118 vs 93 ng/mL) and the mean area under plasma concentration-time curve from 0 to 72 hours (AUC72) by approximately 45% (223 vs 123 ng.h/mL). Co-administration of dexamethasone had no effect on mean AUC72 (179 vs 170 ng.h/mL). The mean bortezomib Cmax was 20% lower after co-administration of dexamethasone (140 vs 119 ng/mL); however this difference in Cmax was within the observed variability in Cmax during cycle 2 (CV=38%) and cycle 3 (CV=45%). Mean (SD) maximum percent proteasome inhibition (Emax) and area under percent proteasome inhibition-time curve from 0 to 72 hours (AUE72h) were comparable for bortezomib alone and in combination with rifampicin (Emax: 61.9 [4.56] vs. 62.3 [3.81] and AUE72h: 836 [323] vs. 777 [358]). Co-administration of dexamethasone did not affect the Emax (66.7 [4.27] vs. 61.8 [6.69]) or AUE72h (1329 [638] vs. 1157 [381]). Safety profiles were consistent with prior bortezomib experience in this population. Drug-related serious adverse events and treatment discontinuations were reported in 7/30 (23%) and 8/30 (27%) in bortezomib-only, in 3/13 (23%) and 3/13 (23%) in bortezomib + rifampicin, and 3/18 (17%) and 5/18 (28%) in bortezomib + dexamethasone subgroups. Investigator-assessed responses (CR+PR) were observed in 13/17 MM and 6/13 NHL patients in bortezomib-only, in 6/9 MM and 3/4 NHL patients in bortezomib + rifampicin, and in 10/13 MM and 2/5 NHL patients in bortezomib + dexamethasone subgroups. Conclusions: Co-administration of dexamethasone did not affect the PK or PD profiles of bortezomib. Co-administration of rifampicin reduced bortezomib exposure (AUC) by approximately 45%. Patients receiving bortezomib concomitantly with strong CYP3A4 inducers, such as rifampicin, should be monitored for reduction in clinical effect, while concomitant administration of weak CYP3A4 inducers, such as dexamethasone, is not expected to affect the bortezomib pharmacologic profile. Disclosures: Off Label Use: Discussion of Velcade in NHL subtypes other than mantle cell lymphoma is included. Rule:Johnson & Johson: Consultancy, Speakers Bureau; Roche: Consultancy. Walewski:Johnson & Johnson: Honoraria, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen-Cilag: Investigators fee. Shpilberg:Johnson & Johnson: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Feng:Johnson & Johnson: Employment. van de Velde:Johnson & Johnson: Employment, Equity Ownership. Patel:Johnson & Johnson: Employment, Equity Ownership. Skee:Johnson & Johnson: Employment. Girgis:Johnson & Johnson: Employment. Louw:Janssen-Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Key Oncologics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers-Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

Hemophilia Experiences, Results and Opportunities (HERO) Study: US Respondent Demographics and Impact of Diagnosis On Career and Lifestyle Decisions and Quality of Life

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4244-4244
Author(s):  
Diane J Nugent ◽  
Chris Guelcher ◽  
Angela Forsyth ◽  
Neil Frick ◽  
Michelle Rice ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Daily Life ◽  
Psychosocial Assessment ◽  
Psychosocial Issues ◽  
Full Time ◽  
Advisory Committees ◽  
Constant Pain ◽  
The Mean ◽  
Extreme Pain

Abstract Abstract 4244 Objectives: The HERO initiative was developed to increase understanding of the psychosocial issues impacting people with moderate-severe hemophilia (PWH). Methods: Following ethics review and informed consent, 675 adult PWH (≥ 18) and 561 parents of children with hemophilia (CWH) in 10 countries completed ∼45 min psychosocial assessment including EQ-5D, a health-related visual analog scale (0–100, coded as an eleven-point categorical response), and a 7 point scale assessing pessimistic (1) to optimistic (7) outlook on the next 5 years. US participants were recruited through National Hemophilia Foundation's eNote distribution and Facebook. Results: The 189 US PWH had a median (range) age of 35(18–74). The 190 US parents of CWH had a median (range) age of 37(23–59) years; mean age of oldest son <18 was 8.6. Most PWH/parents reported hemophilia A (111/126, 59%/66%) with 45/18 (24%/9%) reporting inhibitors. Most parent respondents were female (79%) and responsible for their son's care (75%). PWH reported bone/arthritis (48%), pain (39%), HCV 34%, HIV 16%, and psychological (35%) comorbidities related to hemophilia; 40% reported cardiovascular conditions. PWH/parents completed full time education (84%/88%) or were in school (12%/6%). Most PWH/parents were employed full- or part-time (72%/72%). Of PWH, 13% reported long-term disability and 24% disability-related benefits. Many PWH/parents (44%/30%) reported their selection of a job took into account caring for their/their son's hemophilia; few reported no impact on choice of job (25%/22%) or working life (17%/33%). Most PWH/parents reported office-based jobs (57%/47%) or light-to-moderate manual labor (23%/44%). Many felt current treatment allowed them to work in most situations (36%/43%). Negative impacts included voluntarily leaving a job (30%/19%), not being hired (21%/7%), not being promoted (17%/12%) or losing a job (16%/11%). Adult PWH tended to have a lower risk profile for current activities/sports than CWH (low/medium/high risk: PWH 81%/49%/17% vs. CWH 67%/66%/40%). Common activities for PWH/CWH included: swimming (28%/46%), fishing (38%/34%), walking (33%/24%), golf (29%/19%), cycling (22%/29%), gym (23%/11%), and Frisbee (17%/22%). The mean (SD) EQ-5D index of PWH was 0.763 (0.195), median 0.800. While fewer older patients were surveyed, they had lower EQ-5D indexes: Overall, 42% rated their health 80–100 (see figure). The percent rating 80–100 was lower for older PWH (<30, 53%; 31–40, 45%; 41+, 24%), those with inhibitors (24% vs. 48%), spontaneous bleeds in the past 12 months (39% vs. 61%), musculoskeletal comorbidities (36% vs. 78%) and those unemployed (20% vs. 47%). On the EQ-5D components, 71% reported moderate or extreme pain or discomfort. Within the prior 4 weeks, 92% reported pain interfered with their daily life (54% moderate-extreme pain). Moderate-extreme interference was more common in PWH aged 41+ (76% vs. 46%), and with inhibitors (62% vs. 51%) or musculoskeletal complications (65% vs. 7%). Of the 92% reporting pain interfering with functioning, 43% reported only bleed-related pain, 17% continuous pain, and 36% continuous pain worsened by bleeds. The mean/median outlook on the next five years was optimistic for PWH (5.32/6) and parents (5.82/6) and didn't vary by age group. Mean ratings were lower for PWH with inhibitors (4.73 vs. 5.51) and not working (4.81 vs. 5.49). PWH/parents with inhibitors (56%/56%) more than those without inhibitors (46%/35%) agreed, “My whole life revolves around [my/my son's] hemophilia”. Conclusions: HERO provides a unique database with demographic and medical/treatment data collected to facilitate in-depth study of psychosocial issues. Despite physical disability and challenges of caring, adult PWH and parents of CWH respectively overcome significant barriers to maintain employment. Adult PWH actively participate in low-medium risk activities, while CWH participate more fully. Using generic tools to allow comparability, impairment of QoL was consistent with other hemophilia studies, lower than in the general population and similar to normative data in elderly populations with chronic/disabling conditions. This was reflected in often constant pain impacting daily life. Adult PWH and parents of CWH were none-the-less generally optimistic about the future. Disclosures: Nugent: Novo Nordisk: Membership on an entity's Board of Directors or advisory committees. Guelcher:Novo Nordisk: Membership on an entity's Board of Directors or advisory committees. Forsyth:Novo Nordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees. Frick:National Hemophilia Foundation: Employment. Rice:National Hemophilia Foundation: Employment. Iorio:Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; NovoNordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Baxter: Membership on an entity's Board of Directors or advisory committees; Bayer: Research Funding; BioGen Idec: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Wisniewski:Novo Nordisk Inc.: Employment. Cooper:Novo Nordisk Inc.: Employment.

Preliminary Safety Results from the Phase IIIb GREEN Study of Obinutuzumab (GA101) Alone or in Combination with Chemotherapy for Previously Untreated or Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3345-3345 ◽  
Author(s):  
Francesc Bosch ◽  
Thomas Illmer ◽  
Mehmet Turgut ◽  
Agostino Cortelezzi ◽  
Susan F. Lasserre ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Board Of Directors ◽  
Safety Profile ◽  
Research Funding ◽  
Safety Data ◽  
Lymphocytic Leukemia ◽  
Advisory Committees ◽  
Phase Iiib ◽  
Unfit Patients ◽  
Grade 3

Abstract Background: The novel, glycoengineered type II anti-CD20 monoclonal antibody, obinutuzumab (GA101) has demonstrated superior efficacy to chlorambucil (Clb) monotherapy and to Clb in combination with rituximab (R-Clb) with an acceptable safety profile in CLL. However, an increased rate of infusion-related reactions (IRRs) has been observed with the obinutuzumab(G)-Clb combination compared with R-Clb during the first cycle of treatment. The GREEN study (NCT01905943) is an ongoing phase IIIb, multicenter, open-label trial investigating the safety and efficacy of obinutuzumab alone or in combination with chemotherapy in patients with previously untreated or relapsed/refractory CLL. We report safety data from cohort 1, which aimed to reduce IRRs on the first day of obinutuzumab administration in previously untreated patients using a lower dose and slower infusion rate than in previous studies. Methods: Subjects aged ≥18 years withdocumented CLL, an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2 and adequate hematologic function are enrolled. Treatment includes obinutuzumab (1000mg) administered intravenously on days (D) 1 (25mg) and 2 (975mg), D8, and D15 of cycle (C) 1, and on D1 of C2–6, alone (any patient: n=18) or in combination with 28-day cycles of chemotherapy: fludarabine plus cyclophosphamide (FC; n=46) for fit patients (cumulative illness rating scale [CIRS] ≤6 and creatinine clearance [CrCl] ≥70mL/min), Clb (n=8) for unfit patients (CIRS >6 and/or CrCl <70mL/min) or bendamustine (B; n=86) for fit/unfit patients. The primary outcome is safety, including the frequency, type and severity of adverse events (AEs). The present analysis focuses on IRRs, defined as treatment-related AEs occurring during or within 24 hours of infusion. Results were assessed to determine if a low obinutuzumab dose (25mg) and slow infusion rate (12.5mg/hour) on D1 (the current recommended C1D1 regimen is 100mg at 25mg/hour) could reduce IRRs. Analysis was based on a data cut-off of 28 April 2014, planned for when the first 150 previously untreated patients had completed cohort 1. Results: Of 158 subjects eligible for the IRR analysis (Table), median age was 65.0 (34.0–83.0) years and the majority were males (65.2%) with Binet stage B (52.5%) or C (31.0%) CLL. Median observation time was 2.09 (0.2–6.0) months and median exposure time was 1.0 (0.0–4.8) month. IRRs occurring in ≥10% of patients were chills (14.6%) and pyrexia (15.2%). Serious IRRs in ≥1% of patients were tumor lysis syndrome (TLS; 3.8%) and pyrexia (1.3%). Grade ≥3 IRRs experienced by ≥1% of patients were TLS (5.7%), hypertension (1.3%) and hypotension (1.3%). IRRs were most frequent in C1D1 (Fig). In the overall safety population (n=172; previously untreated patients) the most frequently reported serious AEs of special interest included IRR (8.1%) and neutropenia (11.0%). AEs of particular interest, thrombocytopenia, cardiac, and hemorrhagic events, were experienced by 16.3%, 3.5% and 3.5% of patients, respectively. Table. Table. Conclusions: Preliminary safety data from the GREEN study, assessing the use of obinutuzumab alone or in combination with chemotherapy (B, FC or Clb) in subjects with untreated CLL, are in line with the known safety profile of obinutuzumab in similar populations. Although there is limited exposure time available for subjects in GREEN, IRRs seemed to be more manageable and a lower proportion of subjects with IRRs grade ≥3 was observed compared with previous studies. No new safety signals were reported. However, since the number of discontinuations during C1 was comparable with previous obinutuzumab studies, the decision was taken to further improve IRR rates by assessing additional dexamethasone premedication in cohort 2. Final safety data from the study will be presented at a later timepoint. Figure 1 Figure 1. Disclosures Bosch: Roche: Consultancy, Research Funding, Speakers Bureau. Off Label Use: GAZYVA (obinutuzumab) is a CD20-directed cytolytic antibody and is indicated, in combination with chlorambucil, for the treatment of patients with previously untreated chronic lymphocytic leukemia (CLL). This abstract reports on obinutuzumab alone or in combination with chemotherapy for previously untreated or relapsed/refractory CLL.. Lasserre:F. Hoffmann–La Roche: Employment. Truppel-Hartmann:F. Hoffmann–La Roche: Employment. Leblond:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Foà:Roche-Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Stilgenbauer:Roche: Consultancy, Honoraria, Research Funding.

Sign in / Sign up

Export Citation Format

Share Document