Evaluation of Paroxysmal Nocturnal Hemoglobinuria Disease Burden: The Patient's Perspective. A Report From the International PNH Registry.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1525-1525 ◽  
Author(s):  
Petra Muus ◽  
Jeffrey Szer ◽  
Hubert Schrezenmeier ◽  
Robert A Brodsky ◽  
Monica Bessler ◽  
...  
Keyword(s):  
Abdominal Pain ◽  
Chest Pain ◽  
Board Of Directors ◽  
Disease Burden ◽  
Advisory Committees ◽  
Clone Size ◽  
The Past ◽  
Patient Reported ◽  
History Of ◽  
Equity Ownership

Abstract Abstract 1525 Background: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare clonal hematopoietic stem cell disease characterized by complement-mediated hemolysis, a variable degree of bone marrow failure and thrombophilia, which may lead to reduced quality of life (QOL). There have been few reports of the disease burden of PNH from the patient's perspective. Aims: To describe patient-reported QOL, hospitalization, and missed work at time of PNH registry enrollment and to evaluate the association of these patient-reported outcomes (PROs) with demographics; patient reported symptoms (abdominal pain, chest pain and hemoglobinuria); and clinical characteristics (years since diagnosis, granulocyte clone size, underlying bone marrow disorder [BMD] and prior thrombotic event [TE]). Methods: Enrollment data from 117 clinical sites participating in the observational PNH Registry in 16 countries on 5 continents was analyzed. Patients are included in the Registry if they have a PNH clone regardless of clone size, other BMD, symptoms, or treatments. As part of the study, patients are asked to complete questionnaires at enrollment including the six subscales of the EORTC QLQ-C30 (range=0-100, higher scores better) and the FACIT-Fatigue scale (range=0-52, higher scores better). Patients are also asked “in the past 6 months have you been admitted to a hospital for your PNH” and “in the past 6 months did you miss work as a result of PNH” (questions about work were added later in the study). Statistical analysis used ANOVA and Chi-square tests as appropriate. Results: As of August 2010 there were 657 patients enrolled in the Registry. Of these, 377 (57%) patients completed a baseline questionnaire (BQ) and are included in this analysis. Patients with and without a completed BQ were comparable on most study variables, although patients with a higher clone size were less likely to complete a BQ. Patients had a mean age of 45.8±17.6 years; 54% were female. Median PNH (granulocyte) clone size was 75% (nearly two-thirds had a clone size ≥50%), 45% had BMD (mostly aplastic anemia) and 12% had history of TE. Abdominal pain in the last 6 months was reported by 45% of patients, chest pain by 28%, and hemoglobinuria by 64%. Mean EORTC scores (general population reference in parenthesis) were: global health=64.4 (71.2), physical functioning=79.7 (89.8), role functioning=73.9 (84.7), emotional functioning=76.0 (76.3), cognitive functioning=81.1 (86.1), and social functioning=77.2 (87.5). Thus, scores for PNH patients were decreased by about 10% in 4 of the 6 subscales. PNH patients had a mean FACIT-Fatigue score of 36.6, while a general population reference is 43.6 (or a 16% reduction). PROs were independent of time since diagnosis, PNH clone size, or underlying BMD. Males reported better physical, emotional, and social functioning and less fatigue than females (all p<.05). As expected, age strongly affected physical functioning (p<.01). Patients with prior TE reported worse global health, physical, role, cognitive functioning, and more fatigue than patients without prior TE (all p<.05). Patients reporting abdominal pain, chest pain, or hemoglobinuria had significantly worse EORTC and FACIT-fatigue scores on every scale (all p<.05). Overall, 26% of patients had a PNH-related hospitalization in the past 6 months. Patients who reported TE, abdominal pain, chest pain, or hemoglobinuria were more likely to be admitted to the hospital (all p<.05). There were 109 patients out of 244 (45%) who worked at a paid job. Of these,30% missed work in the past 6 months due to PNH. Patients were more likely to miss work if they had abdominal pain (47% vs 19%, p<.01 or hemoglobinuria (42% vs. 7%, p<.01). Conclusion: The disease burden to PNH patients is evident. Mean QOL is reduced in patients with PNH by 10 to 16% on most scales compared to the general population. One of four patients was hospitalized and 30% of patients with a paid job missed work due to PNH over a 6-month period. History of thrombosis and presence of PNH-related symptoms strongly affected QOL and hospitalization, while missed work was mostly impacted by symptoms. This global PNH Registry, which remains open to accrual ([email protected]), should help to redefine prospectively the long-term natural history of PNH, its treatments, and the outcomes of treatment, including outcomes measured from the patient's perspective. Disclosures: Muus: Celgene: Membership on an entity's Board of Directors or advisory committees; Alexion: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Szer:Alexion Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees. Schrezenmeier:Alexion Pharmaceuticals, Inc: Honoraria, Membership on an entity's Board of Directors or advisory committees. Brodsky:Alexion Pharmaceuticals, Inc: Membership on an entity's Board of Directors or advisory committees. Bessler:Alexion Pharmaceutical Inc: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees; Taligen: Consultancy. Socié:Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees. Urbano-Ispizua:Alexion: Membership on an entity's Board of Directors or advisory committees. Maciejewski:Celgene: Research Funding; Eisai: Research Funding; Alexion: Consultancy. Rosse:Alexion: Consultancy, Membership on an entity's Board of Directors or advisory committees. Kanakura:Alexion: Membership on an entity's Board of Directors or advisory committees. Khursigara:Alexion Pharmaceuticals, Inc.: Employment, Equity Ownership. Karnell:Alexion Pharma International: Employment, Equity Ownership. Bedrosian:Alexion Pharmaceuticals, Inc.: Employment, Equity Ownership. Hillmen:Alexion Pharmaceuticals, Inc: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 14-15
Author(s):  
Austin Kulasekararaj ◽  
Jacques Le Roux Malherbe ◽  
Andrew McDonald ◽  
Melanie Cornpropst ◽  
Phil Collis ◽  
...  
Keyword(s):  
South Africa ◽  
Board Of Directors ◽  
Research Funding ◽  
Total Bilirubin ◽  
Proof Of Concept ◽  
Advisory Committees ◽  
Clone Size ◽  
The Past ◽  
History Of ◽  
Pre Treatment

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

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

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2241-2241
Author(s):  
Hubert Schrezenmeier ◽  
Robert A Brodsky ◽  
Petra Muus ◽  
Monica Bessler ◽  
Jeffrey Szer ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Board Of Directors ◽  
Research Funding ◽  
Paroxysmal Nocturnal Hemoglobinuria ◽  
Employment Equity ◽  
Advisory Committees ◽  
Clone Size ◽  
History Of ◽  
Equity Ownership ◽  
To Receive

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

Clinical Signs and Symptoms In Non-Transfused Patients With Paroxysmal Nocturnal Hemoglobinuria From a Korean Prospective PNH Registry

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3720-3720
Author(s):  
Jong Wook Lee ◽  
Jun Ho Jang ◽  
Jin Seok Kim ◽  
Je-Hwan Lee ◽  
Deog-Yeon Jo ◽  
...  
Keyword(s):  
Risk Factors ◽  
Abdominal Pain ◽  
Board Of Directors ◽  
Paroxysmal Nocturnal Hemoglobinuria ◽  
Clinical Symptoms ◽  
Transfusion Requirement ◽  
Shortness Of Breath ◽  
Advisory Committees ◽  
Clone Size ◽  
History Of

Abstract Introduction Paroxysmal nocturnal hemoglobinuria (PNH) is a rare and progressive disease driven by chronic complement mediated hemolysis leading to thromboembolism (TE), renal impairment, and death. Transfusion requirement has been one complication that has suggested a more severe case of PNH. Here, we report the prevalence of clinical symptoms, hemolysis, and TE in non-transfused (no transfusions in the past 12 months) PNH patients from the Korean prospective PNH registry. Methods Korean patients with a diagnosis of PNH are eligible for inclusion in the prospective registry study designed to identify key symptoms in close proximity of the event and support the associations of hemolysis and other risk factors. The study included medical history data from the time of diagnosis and to enrollment. Patient data included in this study were captured using an electronic case report form that collected patient demographics; medical history; PNH-specific information including RBC and granulocyte clone size; and laboratory values. PNH was confirmed at each individual site using a consistent flow cytometry or FLAER protocol based on the expression of CD55, CD59, or CD24. The PNH granulocyte and RBC clone sizes were also evaluated. Chronic kidney disease (CKD) was measured by eGFR and proteinuria. Results Data are presented for 106 PNH patients; all of these patients have been actively participating in the study since the first patient enrollment at Dec, 2011. At enrollment patients had a median age of 47 years (range 20 to 84) and 57 (54%) were female. The majority of patients (87.2%) were reported to have ≥10% granulocyte clone size and 74% of patients had LDH levels ≥1.5 x ULN. The most frequently reported clinical symptoms were fatigue (62%), hemoglobinuria (58%), CKD or renal failure (45%), pain (including abdominal pain and backache, 43%), and thrombosis was reported in 16 patients (15%). About half of the patients (43%) had never been transfused for at least 12 months prior to enrollment (non-transfused). Non-transfused patients continue to experience LDH ≥1.5 x ULN and was not different when compared to patients requiring transfusions (P=0.654). Prevalence of abdominal pain, shortness of breath and chest pain, symptoms associated with risk of TE, as well as fatigue and hemoglobinuria were similar between both groups (table). We also note that history of TE prior to entering the registry was similar between both groups (P=0.507). Prevalence of thrombocytopenia and neutropenia was similar between the groups; however, prevalence of anemia (hemoglobin<8g/dL) was lower in non-transfused patients (P=0.002). Conclusions Our analyses demonstrate that non-transfused PNH patients can continue to experience hemolysis, a risk factor for thrombosis and organ damage. Indeed, non-transfused patients continue to experience abdominal pain, chest pain and shortness of breath at a similar rate as transfused patients in our patient cohort. We further note that non-transfused patients also experienced a similar history of TE at enrollment. Some PNH patients may compensate for the loss of RBC due to hemolysis as demonstrated by fewer patients with anemia (hemoglobin<8g/dL) in the non-transfused group. However, thrombocytopenia and neutropenia in the non-transfused were similar suggesting marrow function alone maybe not explain why some patients do not need transfusions. Overall these data suggest that transfusion requirement alone is not a measure of risk for poor outcomes. A full clinical work up including history of TE should be followed in newly diagnosed PNH patients and treatment management should be based on presenting risk factors regardless of transfusion requirement. Further investigation on the risk of clinical symptoms, hemolysis, and TE in PNH patients who do not receive blood transfusion is warranted. Disclosures: Lee: Alexion Pharmaceutical Company: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Jang:Alexion Pharmaceutical Company: Honoraria, Membership on an entity’s Board of Directors or advisory committees.

Disease and Clinical Characteristics of Patients with Polycythemia Vera: An Early View of the Reveal Study

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2813-2813
Author(s):  
Brady Stein ◽  
Alison Moliterno ◽  
Ralph V. Boccia ◽  
Ahmad B. Naim ◽  
Joseph A. Cordaro ◽  
...  
Keyword(s):  
Research Funding ◽  
Clinical Characteristics ◽  
Thromboembolic Event ◽  
Employment Equity ◽  
Advisory Committees ◽  
Reveal Study ◽  
Patient Reported ◽  
The Us ◽  
History Of ◽  
Equity Ownership

Abstract Background: Patients with polycythemia vera (PV) have an increased symptom burden (eg, fatigue, pruritus, and splenomegaly-related symptoms) and an increased risk of mortality compared with the general population, often resulting from thrombotic events, disease transformation to myelofibrosis, or secondary malignancies. There are limited data regarding PV burden and treatment patterns in a contemporary, real-world US setting. REVEAL is an ongoing observational study being conducted to describe contemporary demographics, burden of disease, clinical management, patient-reported outcomes, and healthcare resource utilization among patients with PV in the US. The objective of this assessment is to describe the clinical characteristics at enrollment among patients currently enrolled in REVEAL (enrollment from July 22, 2014 to June 9, 2015). Methods: REVEAL is a multicenter, noninterventional, nonrandomized, prospective, observational study. Eligible patients are ≥18 years of age with a PV diagnosis and currently under active management by a physician in the US. Data regarding disease and clinical characteristics, patient-reported outcomes, and health resource utilization are being collected at usual-care visits over a planned 36-month observation period. Analyses of these preliminary data were descriptive. Results: At data cutoff, 865 patients were enrolled (total planned enrollment, n=2000) from 174 sites (academic, n=27; community, n=147). Median (range) age at enrollment was 67 (22-95) years, 55.5% were male, 89.5% were white, and 45.4% had a history of smoking. Most patients (99.4%) had health insurance, including Medicare (56.0%), PPO (24.3%), or HMO (11.6%). Fifty-two percent were retired, 29.6% were employed, and 4.5% were unable to work or disabled. A total of 40.2% of patients completed a college/graduate degree, 19.9% had some college, and 32.5% completed high school or the equivalent. Documented major World Health Organization diagnostic criteria included JAK2V617F mutation in 50.9% of patients, elevated hemoglobin in 52.3%, and red cell mass in 5.5%. A bone marrow biopsy was conducted in 24.0% of patients, approximately half of whom (52.4% of the 24.0%) had trilineage myeloproliferation. Erythropoietin levels were abnormal in 19.7% of patients. Approximately half (46.6%) of patients had physician-reported PV-related symptoms at diagnosis, most frequently fatigue (25.2%) and pruritus (14.0%). At enrollment, median disease duration was 52.6 months; 42.3% of patients were diagnosed ≥5 years before enrollment. The most common comorbidities were hypertension (51.3%), obesity (14.2%), dyspnea (13.4%), myalgia (11.2%), and diabetes mellitus (11.1%). Mean hematocrit was 44.9%, hemoglobin was 14.5 g/dL, white blood cell count was 11.4×109/L, platelet count was 363.7×109/L, and absolute neutrophil count was 363.7×109/L. Twenty-one percent of patients had a history of thrombotic events, with 13.1% and 8.6% of patients experiencing ≥1 venous or arterial thromboembolic event, respectively. Of the 261 reported thrombotic events, 43.7% occurred after diagnosis of PV. The most common PV symptoms recorded at enrollment (using the Myeloproliferative Neoplasm Symptom Assessment Form) were fatigue (37.1%), pruritus (24.0%), headache (18.6%), insomnia (17.0%), dizziness (13.2%), bone pain (10.5%), and blurred vision (7.9%); 19.7% of 518 evaluable patients had palpable splenomegaly. Fewer than half of patients were receiving aspirin at enrollment (47.7%). The most common PV treatments ± aspirin were phlebotomy (PBT; 63.5%), hydroxyurea (HU; 42.2%), watchful waiting (5.3%), and ruxolitinib (3.1%); 23.0% of patients received PBT + HU. Conclusion: The REVEAL study is unique in that it captures data from both academic and community centers, and therefore includes a broader segment of the PV population typically not described in the literature. REVEAL can provide novel insights into questions related to the contemporary demographics of PV, practice patterns regarding diagnosis and therapy, and the real-world burden of PV and its impact on patients' quality of life and work productivity. Preliminary descriptive data from this early subset of patients suggest that a high proportion of patients report having PV-related symptoms at diagnosis, fewer patients are treated with aspirin than expected, and that thromboembolic event rates remain high after diagnosis. Disclosures Stein: Incyte Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees. Moliterno:Incyte Corporation: Membership on an entity's Board of Directors or advisory committees. Boccia:Incyte Corporation: Honoraria. Naim:Incyte Corporation: Employment, Equity Ownership. Cordaro:Incyte Corporation: Employment, Equity Ownership. Peng:Incyte Corporation: Employment, Equity Ownership. Sun:Incyte Corporation: Employment, Equity Ownership. Parasuraman:Incyte Corporation: Employment, Equity Ownership. Mesa:Promedior: Research Funding; Novartis Pharmaceuticals Corporation: Consultancy; NS Pharma: Research Funding; CTI Biopharma: Research Funding; Gilead: Research Funding; Pfizer: Research Funding; Incyte Corporation: Research Funding; Genentech: Research Funding.

scholarly journals Evaluation of Disease Burden and Response to Treatment in Adults with Type 1 Gaucher Disase Using a Validated DS3 Severity Score Index

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4957-4957
Author(s):  
Neal J. Weinreb ◽  
Eleanor Feingold ◽  
Suma Shankar ◽  
Barry E. Rosenbloom ◽  
David Finegold
Keyword(s):  
Board Of Directors ◽  
Disease Burden ◽  
Fellowship Training ◽  
Age At Diagnosis ◽  
Advisory Committees ◽  
Important Improvement ◽  
Lytic Lesions ◽  
History Of ◽  
Pre Treatment

Abstract BACKGROUND: DS3 scoring is a method of expressing an integrated assessment of disease burden in a given patient based on bone, hematologic and visceral domains. A DS3 severity score index for adult patients with type 1 Gaucher disease (GD1) was developed and tested for validity, reliability and feasibility (Weinreb NJ et al. Genet Med 2009; 12:1-8). However, the DS3 score has not yet been applied to large numbers of patients across different clinics. We developed a consortium of five geographically separated North American GD treatment centers to further investigate the DS3 score as a tool for initial assessment, long term follow up and evaluation of treatment responses. METHODS: 133 adult patients with a history of IV enzyme treatment (ERT) for GD1 were recruited under informed consent. All patients agreed to allow International Collaborative Gaucher Registry (ICGG, supported by Genzyme) data with additional clinical phenotyping to be used to calculate DS3 and annotate longitudinal changes. An ICGG independent data center collated the information. Baseline DS3 scores were calculated around the date of initial treatment. Follow up scores were calculated annually with a ±3 month window. Because the calculation of DS3 scores is sensitive to missing data, some values were imputed. RESULTS: Patient characteristics: 68 patients (51%) identified all grandparents as Ashkenazi Jews. 48 of 52 N370S/N370S patients had complete or partial Ashkenazi Jewish ethnicity. N370S/L444P was the most common genotype among non-Jewish patients. 118 patients had at least one N370S allele. Median age at the time of GD1 diagnosis was 28 (0-85) y. 38 patients (26.6%) had a history of splenectomy. Treatment commenced at a median age of 45 (6-87) y with a median follow up on treatment of 14 (1-23) y. Baseline DS3 scores: In 58 patients, pre-treatment scores 6.0-14.9 (median 7.84) signified marked disease severity. 31 patients (53%) had a history of pre-treatment splenectomy. Median age at diagnosis was 18 (0-68) y. Median age at first treatment was 44 (7-69) y. Only 11 patients (19%) were N370S homozygous. 44 patients (76%) had major bone pathology (avascular necrosis, fractures, lytic lesions) pre-treatment. Fifty-three patients had moderate disease severity (DS3 3.00-5.93; median 4.33). Splenectomy prevalence was 15.1%. Median age at diagnosis was 32 (4-85) y; median age at first treatment was 50 (6-87) y. 26 patients (49%) were N370S/N370S. 9 patients (17%) had major pre-treatment bone disease. Twenty-two patients had mild severity disease (DS3 0.40-2.93; median 2.40). Median age at diagnosis was 40 (1-71) y; median age at first treatment was 44 (9-73) y. None had splenectomy or major pre-treatment bone disease. 15 patients (68%) were N370s/N370S. Response to treatment: Health-state transitions occurred primarily during the first 5 treatment years. Of 58 patients with marked pre-treatment disease, 33% remained so after Y1. At Y5, 14% were “marked,” 50% “moderate,” 19% “mild,“ 17% not evaluable (NE). Of 53 “moderate” patients, 38% continued so after Y1. At Y5, 30% were “moderate,” 49% “mild,” 21% NE. No patient worsened in severity category. Of 22 “mild” patients, all remained so at Y1, At Y5, 2 patients had transitioned to “moderate” (DS3 scores 3.07 and 3.17); 64% remained “mild” and 27% were NE. Among evaluable marked severity patients, 76% had clinically important improvement (defined as a -3.1 ΔDS3 from baseline) at Y5. In “moderate” patients with initial DS3 scores 4.58-5.93, 41% had clinically important improvement at Y5. No patients with baseline DS3 scores <4.50 had a clinically important response. CONCLUSIONS: DS3 is an effective tool for assessing pre-treatment disease burden in GD1 and for monitoring response to therapy. It is consistent with indirect indicators of GD1severity such as genotype and early age of diagnosis and symptom onset. ERT is associated with clinically important improvement in DS3 scores in patients with high severity scores. Nevertheless, even with sustained improvement in DS3 scores, GD1 patients on ERT, especially those with risk factors such as splenectomy and pre-treatment bone pathology are at continual risk for emerging major bone complications (Fig 1,2). SUPPORT: Independent Investigator Grant from Genzyme. DS3 score Figure 1. “Marked” severity patients: change in mean (+/-) SD DS3 scores with ERT Figure 1. “Marked” severity patients: change in mean (+/-) SD DS3 scores with ERT Years Figure 2. Major (AVN, fractures, lytic lesions) bone event-free survival Figure 2. Major (AVN, fractures, lytic lesions) bone event-free survival Disclosures Weinreb: Genzyme, a Sanofi Company: Consultancy, Honoraria, Research Funding, Speakers Bureau; Shire HGT: Honoraria, Speakers Bureau; Pfizer Corporation: Consultancy, Honoraria, Speakers Bureau. Shankar:Genzyme, a Sanofi Company: Consultancy, Honoraria, Travel reimbursement, received funds for fellowship training, for educational and patient meetings Other; Shire: Consultancy, Honoraria, Travel reimbursement, received funds for fellowship training, for educational and patient meetings, Travel reimbursement, received funds for fellowship training, for educational and patient meetings Other; Protalix-Pfizer: Consultancy, Honoraria, Travel reimbursement, received funds for fellowship training, for educational and patient meetings, Travel reimbursement, received funds for fellowship training, for educational and patient meetings Other; Biomarin: Consultancy, received funds for fellowship training, for educational and patient meetings, received funds for fellowship training, for educational and patient meetings Other; Actelion: Consultancy, received funds for fellowship training, for educational and patient meetings Other. Rosenbloom:Genzyme, a Sanofi Company: Consultancy, Honoraria, Travel reimbursement Other. Finegold:Genzyme, a Sanofi Company: Honoraria, Membership on an entity's Board of Directors or advisory committees; Shire HGT: Honoraria, Membership on an entity's Board of Directors or advisory committees; Protalix Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees.

scholarly journals Real-World Observations and Practical Considerations of Subcutaneous Daratumumab Administration in Multiple Myeloma

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 5018-5018
Author(s):  
E. Bridget Kim ◽  
Elizabeth O'Donnell ◽  
Andrew R. Branagan ◽  
Jill N. Burke ◽  
Cynthia C. Harrington ◽  
...  
Keyword(s):  
High Risk ◽  
Board Of Directors ◽  
Comparable Efficacy ◽  
Prior History ◽  
Rapid Infusion ◽  
Advisory Committees ◽  
Optimal Monitoring ◽  
Systemic Reactions ◽  
Patient Reported ◽  
History Of

Abstract Background: Subcutaneous daratumumab (dara-SC) has several advantages over intravenous daratumumab (dara-IV). It has significantly shorter administration time, lower rates of systemic reactions, and smaller administration volume, while maintaining comparable efficacy and safety. Its fixed dosing allows for easier preparation. At our institution, standard approach is to monitor for 4h following the initial dara-SC dose for those at high risk for systemic reactions, defined as no prior dara use, treatment break ≥90d, or any prior history of reactions. We also administer montelukast and fexofenadine for the first 2 doses of dara-SC in addition to the usual standard pre-medications. Herein, we share our experience with dara-SC use in both dara-naïve and dara-exposed patients in order to gain practical insight, such as optimal monitoring duration, considerations for transitioning between dara-IV and dara-SC, and the place of therapy for dara-IV based on adverse events (AEs). Methods: Between June 2020 and June 2021, patients who received at least one dose of dara-SC were identified and their record was reviewed for any systemic reactions, hypersensitivity medication use, and patient reported AEs. Results: Since June 2020, our dara-SC drug use increased from 38% to 91% of all doses. There were 208 patients who received at least 1 dose of dara-SC. Of 208 patients, 99 (47.6%) were dara-naïve and 109 (52.4%) had prior dara exposure - either transitioning from dara-IV on schedule or had dara-IV as a past line of therapy. We identified 124 patients who met the criteria for 4h post dara-SC injection monitoring: dara-naïve (79.8%), treatment break ≥90d (18.5%), or prior history of reactions (1.6%). Only 5 experienced systemic reactions, representing 4% among those at high risk. All reactions were mild requiring minimal intervention and occurred following the first dara-SC dose. Onset of reactions and type of intervention during the 4h monitoring window were: hypotension (2h; fluid), nausea/vomiting (2.5h; hypersensitivity medications), and sinus tachycardia (4h), while 2 patients had transient chest pressure/tightness at home (1 within 24h, 1 between 1-6d following the dose). Eleven patients (5%) receiving dara-SC converted back to dara-IV, with AEs being the most common reason. Diarrhea, fatigue, and injection site reactions were among the most frequent patient-reported AEs. When transitioning back to dara-IV, a 90min rapid infusion rate was used if &gt;4 prior dara doses were given. No infusion-related reactions were observed. Conclusion: The introduction of dara-SC has significantly improved patient experience. We observed a lower rate of systemic reactions compared to previous reports of 10% with first dose of dara-SC. This may be partly due to our strengthened pre-medication strategy. Opportunities exist to further improve and apply practical considerations when administering dara-SC. Based on our results, shortening on-site monitoring time may be feasible. Disclosures O'Donnell: Onocopeptide: Consultancy; Karyopharm: Consultancy; Janssen: Consultancy; Bristol Myer Squibb: Consultancy; Adaptive: Consultancy; Takeda: Consultancy. Branagan: Adaptive: Consultancy; Sanofi-Genzyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees; CSL Behring: Consultancy. Raje: Celgene, Amgen, Bluebird Bio, Janssen, Caribou, and BMS: Other. Yee: GSK: Consultancy; Janssen: Consultancy; Amgen: Consultancy; Bristol Myers Squibb: Consultancy; Adaptive: Consultancy; Oncopeptides: Consultancy; Sanofi: Consultancy; Takeda: Consultancy; Karyopharm: Consultancy.

scholarly journals Disease and Clinical Characteristics of Patients with Essential Thrombocythemia Enrolled in the MOST Study

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4306-4306
Author(s):  
Abdulraheem Yacoub ◽  
Roger M. Lyons ◽  
Srdan Verstovsek ◽  
Ryan Shao ◽  
David Tin Chu ◽  
...  
Keyword(s):  
United States ◽  
Observational Study ◽  
Board Of Directors ◽  
Essential Thrombocythemia ◽  
Research Funding ◽  
Clinical Characteristics ◽  
The United States ◽  
Advisory Committees ◽  
History Of ◽  
Equity Ownership

Abstract Introduction: Essential thrombocythemia (ET) is a chronic myeloproliferative neoplasm characterized by clonal platelet production and an increased risk for thrombotic and hemorrhagic events. Limited real-world data exist regarding the clinical characteristics and treatment patterns of ET in the United States; most prior data have been generated outside the United States. The Myelofibrosis and Essential Thrombocythemia Observational STudy (MOST) is an ongoing observational study being conducted to describe contemporary demographics, burden of disease, clinical management, and patient-reported outcomes in patients with specific risk categories of myelofibrosis (MF) or ET in the United States. This analysis describes the clinical characteristics of patients with ET currently enrolled in MOST. Methods: MOST is a multicenter, noninterventional, prospective, observational study in patients with a clinical diagnosis of specific risk categories of MF or ET (NCT02953704). Eligible patients with ET included high-risk patients (≥ 60 years of age and/or a history of thromboembolic events [TEs]), or low-risk patients currently receiving ET-directed therapy. Key exclusion criteria included participation in blinded investigational drug studies, life expectancy ≤ 6 months, or diagnosis of other malignancy. Data regarding disease and clinical characteristics are collected at usual-care visits over a planned 36-month observation period. Patient demographics and clinical characteristics at enrollment were described with descriptive statistics. Results: At data cutoff (May 18, 2018), 793 eligible patients were enrolled from 85 sites since November 29, 2016. The median age at enrollment was 70 (range, 24-95) years, 66.5% were female, and 89.8% were Caucasian. The median time from ET diagnosis to enrollment was 4.2 (range, 0.0-42.1) years with a proportion of patients diagnosed within 1 year (19.5%), 1 to < 5 years (35.0%), 5 to < 10 years (21.7%), or ≥ 10 years (23.8%) of enrollment. Approximately 40% of patients were retired and 42.7% were working full- or part-time at enrollment. A total of 212 patients (26.7%) had a history of TE at the time of enrollment. The type of TE was available for 148 patients, the most common was arterial events (53.4%); 33.1% had venous, and 13.5% of patients had both arterial and venous events. Six hundred and eighty-eight patients (86.8%) were classified as high-risk. Assessments at the time of ET diagnosis, among evaluable patients, included bone marrow biopsy (51.4%; 393/765) and mutational testing (77.2%; 590/764). Three hundred and forty-nine patients had mutation test results reported at the time of diagnosis; of patients with JAK2 V617F test results reported at the time of diagnosis (n = 313), 78.6% were positive for JAK2 V617F (Table 1). Laboratory values and peripheral blood counts were reported for patients with available data (Table 2). The majority of patients (87.9%) had received at least 1 ET-directed therapy prior to enrollment, which in some cases was the same medication the patient was receiving at the time of enrollment. At the time of enrollment, 740 patients (93.3%) were receiving at least 1 current ET-directed therapy, including HU (71.6%; 530/740), anagrelide (13.1%; 97/740), ruxolitinib (4.7%; 35/740), interferon (3.0%; 22/740), and busulfan (0.3%; 2/740). Of 793 patients, the most frequently occurring relevant comorbid conditions were hypertension (52.7%), history of smoking (44.7%), and hyperlipidemia (24.1%). Among 761 patients with ET-related symptoms assessed at diagnosis, the most common symptoms documented by healthcare providers included constitutional (22.9%), vasomotor (16.0%), and spleen-associated symptoms (3.9%), and pruritus (2.6%). Conclusions: Prior real-world data in ET has predominately been generated outside of the United States or has been reported from single institutional experiences. The MOST study will provide a more complete picture of the patient characteristics and outcomes of patients receiving ET-directed therapy in the United States. Ultimately, these data will be important for determining ET treatment gaps and areas of unmet need. Disclosures Yacoub: Cara Therapeutics: Equity Ownership; Inycte: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Ardelyx, INC.: Equity Ownership; Seattle Genetics: Honoraria, Speakers Bureau; Dynavax: Equity Ownership. Verstovsek:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Italfarmaco: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy. Shao:ASH: Membership on an entity's Board of Directors or advisory committees; ASCO: Membership on an entity's Board of Directors or advisory committees. Agrawal:Incyte: Speakers Bureau. Sivaraman:Incyte: Employment. Colucci:Incyte: Employment, Equity Ownership. Yao:Incyte: Employment. Mascarenhas:Celgene: Membership on an entity's Board of Directors or advisory committees; Promedior: Research Funding; CTI Biopharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Merck: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Research Funding; Janssen: Research Funding.

Lintuzumab and Low-Dose Cytarabine Compared to Placebo and Low-Dose Cytarabine in Patients with Untreated Acute Myeloid Leukemia (AML) 60 Years and Older: Results of a Randomized, Double-Blinded Phase 2b Study,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3613-3613 ◽  
Author(s):  
Jeffrey E. Lancet ◽  
Mikkael A. Sekeres ◽  
Brent L. Wood ◽  
Laurie E. Grove ◽  
Larissa Sandalic ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Low Dose ◽  
P Value ◽  
Advisory Committees ◽  
History Of ◽  
Equity Ownership ◽  
Double Blinded ◽  
Low Dose Cytarabine

Abstract Abstract 3613 Background: Older adults with AML who decline intensive induction chemotherapy lack effective therapeutic options, as evidenced by a median overall survival (OS) of ∼5 months with low-dose cytarabine treatment (Burnett 2007). Leukemic blast cells express CD33 in most patients with AML. While antitumor activity has been previously demonstrated by CD33-directed agents, none of these are currently available. Lintuzumab (SGN-33) is a humanized antibody directed to CD33 that was studied in patients with myeloid malignancies and demonstrated tolerability with modest monotherapy activity. To determine if the addition of lintuzumab to low-dose cytarabine could prolong survival in older patients with untreated AML, a randomized, placebo-controlled, double-blinded phase 2b study was conducted (ClinicalTrials.gov #NCT00528333). Methods: The study was conducted at 72 international sites between November 2007 and August 2010. Patients were >60 years of age with centrally confirmed, previously untreated AML; the minimum blast percentage required was 20% with ≥50% CD33 expression. Maximum allowed WBC at baseline was 30,000/μL. All patients declined treatment with intensive induction chemotherapy. Cytarabine 20 mg was administered SC twice daily on Days 1–10 of each 28-day cycle (12 cycles maximum). Patients were randomized to additionally receive either lintuzumab 600 mg or placebo IV: in Cycle 1 on Days 1, 8, 15, and 22, and on Days 1 and 15 of subsequent cycles. Patients were stratified according to age, ECOG performance status (PS), and history of antecedent hematologic disorder (AHD). Cytogenetic risk was determined at baseline according to Fröling 2006. The primary endpoint of the study was OS, determined using an unstratified log rank test. Secondary endpoints included peripheral blood count recovery, transfusion requirements, infection rates, and quality of life. As patients choosing less-intensive therapy often incorporate quality of life into their treatment decision, follow-up bone marrow biopsies were not required in the study. Results: 211 patients were randomized in the study (107 lintuzumab arm, 104 placebo arm). The study arms appeared balanced; overall, the median patient age was 70 years (range 60–90), 53% were female, and baseline ECOG PS was 0/1 (55%) or 2 (45%). Baseline blast percentages were ≥30% in 74% of patients and 23% had a history of AHD. A median of 95% CD33 expression was documented at baseline in either bone marrow or peripheral blood. Median number of treatment cycles was 4 in the lintuzumab arm and 3 in the placebo arm. At the time of the analysis, 24 patients were alive and the maximum follow-up was 32 months. The estimated median OS for the lintuzumab + low-dose cytarabine arm was 4.7 months compared with 5.1 months for the placebo + low-dose cytarabine arm with a hazard ratio (lintuzumab to placebo) of 0.96, indicating that lintuzumab was not associated with a treatment effect (P value 0.76, 95% CI [0.72, 1.28]). Rates of infections or fevers of unknown origin requiring hospitalization or IV antibiotics did not differ between the study arms. Overall, 28% of patients were observed to have no peripheral blasts, ANC >1.0 x109/L, platelets >100 × 109/L, and no transfusions for at least 1 week. The median OS among all patients was 5.0 months, which was significantly impacted by cytogenetic risk (8.7 months for standard-risk compared with 4.5 months for high-risk; P value 0.0024). The incidence of adverse events (AEs) was comparable between the treatment groups, with the exception of infusion-related reactions which occurred more frequently in the lintuzumab arm. The most common ≥ Grade 3 non-hematologic AEs in the study were pneumonia (12%) and sepsis (8%). Conclusions: In this randomized, placebo-controlled, double-blinded phase 2b trial, the combination of lintuzumab and low-dose cytarabine did not improve OS compared with placebo and low-dose cytarabine. While lintuzumab was not effective, CD33 remains a compelling target for AML because it is widely expressed by malignant cells and appears to be absent from pluripotent hematopoietic stem cells. This was the largest study to date of patients treated with low-dose cytarabine; the median OS across both treatment arms was 5 months. A similar outcome was observed in the subgroup of patients with high-risk cytogenetics, confirming that low-dose cytarabine remains a valid comparator in trials of older patients with AML. Disclosures: Lancet: Seattle Genetics, Inc.: Research Funding. Off Label Use: Lintuzumab is an investigational monoclonal antibody directed against CD33. Sekeres:Celgene Corp.: Membership on an entity's Board of Directors or advisory committees; Celgene Corp.: Honoraria; Seattle Genetics, Inc.: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees. Wood:Seattle Genetics, Inc.: Research Funding. Grove:Seattle Genetics, Inc.: Equity Ownership; Seattle Genetics, Inc.: Employment. Sandalic:Seattle Genetics, Inc.: Equity Ownership; Seattle Genetics, Inc.: Employment. Sievers:Seattle Genetics: Employment, Equity Ownership. Jurcic:Seattle Genetics, Inc.: Consultancy; Seattle Genetics, Inc.: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics, Inc.: Research Funding.

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.

Iron Deficiency Anemia in Infants and Toddlers – Role of Milk and Constipation

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 5171-5171
Author(s):  
Madhavi Lakkaraja ◽  
Lesley Small ◽  
Maura Frank ◽  
Aliza Solomon ◽  
Nicole Kucine ◽  
...  
Keyword(s):  
Iron Deficiency ◽  
Board Of Directors ◽  
Research Funding ◽  
Deficiency Anemia ◽  
Infants And Toddlers ◽  
Iron Intake ◽  
Advisory Committees ◽  
Phone Calls ◽  
History Of ◽  
Equity Ownership

Abstract Abstract 5171 Introduction: One of the most common nutritional deficiencies in the world is iron-deficiency anemia and young children are at high risk of developing it. In spite of fortification of foods in the United States, there is a high prevalence of anemia in infants and toddlers increasing their risk of neuro-developmental effects. Constipation is defined as delay or difficulty in defecation ≥ 2 weeks. Around one year of age, various changes are commonly implemented in a child's diet including introduction of whole milk and solids. Children may then present with sub-clinical colitis, constipation and anemia secondary to blood loss in stool or develop anemia due to increased consumption of milk. The American Academy of Pediatrics (AAP) recommends screening for anemia at 1 year and 2 year visits. The only clue to intolerance to milk may be symptomatic constipation and treating the anemia and switching the type of milk often helps to resolve this problem. This study explores the relation between iron deficiency, constipation and milk. Methods: This is an ongoing prospective study, which has been extended from Cornell to different centers. Data presented here is only from the Cornell principal site. Children between 6 months and 30 months visiting the resident's pediatric clinic and having routine blood work drawn as a part of their visit were included in the study. The National Health Sciences (NHS) Constipation questionnaire was administered to the parents of these children; ≥ 2 was considered Constipation. In addition, a detailed diet history of the child, and history of medicines and illness was taken and questions were asked about family history of anemia, constipation and allergies. If the mother was breast feeding, questions were asked about her dairy intake. Comparisons were made between children with and without constipation/iron deficiency. If the child had Hemoglobin (Hgb) <11, the child was started on Iron as per clinic policy, and phone calls were made to check for compliance with Iron. In addition letters including a printed calendar and a note on Iron rich foods were mailed out to the parents. Results: Two hundred five children, 92 females and 113 males between 8 and 30 months mean age 16. 7 months, are enrolled in the study. Seventy-two children (35 %) were constipated (score ≥2). Forty-two children (20. 5%) had Hgb <11. Children who had Hgb < 11 were not more constipated (45%) than those who had Hgb ≥11 (35%). In the Hgb <11 group, there was no significant difference in Hgb between children with and without constipation (p = 0. 19), however there was a difference in Hgb between infants with a Constipation score 0 and score 1 (p = 0. 03). Of the 42 children who had Hgb <11, 3 were later found to have sickle trait or alpha thalassemia trait, which were identified when iron intake did not improve the Hgb level. Compliance with Iron: Of the 39 children who were on Iron, 9 parents could not be reached via phone. Only 6 parents gave no Iron at all but another 12 did not give Iron properly resulting in 18/30 or 60% of infants/toddlers not receiving an adequate trial of replacement Iron. Among the side effects of Iron, one parent felt Iron caused rash on back and wanted multivitamin with Iron after finishing a month's course, one child had discoloration of teeth, so the parent gave it with juice. Two parents with infants with apparent true milk protein allergy colitis said constipation improved with diet change and iron. Conclusions: The prevalence of mild anemia is high in infants and toddlers. There was no clear association of constipation and anemia. Compliance is one of the key factors for Iron replacement therapy and in view of how erratic compliance was, it is imperative to give proper instructions to the parent while prescribing Iron. Material to better indicate which foods were rich in iron and follow-up phone calls were included in the management to optimize iron intake of anemic children. We will include more patients, more closely monitor the change in the diet of the child, and monitor responses to Iron therapy in children with low Hgb. In addition, different practices at other involved centers e. g. Brooklyn hospital Center may allow comparison of the time of screening (9 months v/s 1 year) and testing with Hemoglobin/Hematocrit versus a full Complete Blood Count with indices. Disclosures: Bussel: Amgen: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cangene: Research Funding; GlaxoSmithKline: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genzyme: Research Funding; IgG of America: Research Funding; Immunomedics: Research Funding; Ligand: Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai, Inc: Membership on an entity's Board of Directors or advisory committees, Research Funding; Shinogi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Symphogen: Membership on an entity's Board of Directors or advisory committees; Sysmex: Research Funding; Portola: Consultancy.

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