Clinical Characteristics of Classic Paroxysmal Nocturnal Hemoglobinuria (PNH) in Pediatric Patients: A Comparison with Classic PNH in Adults. An International PNH Registry Study

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2102-2102 ◽  
Author(s):  
Alvaro Urbano-Ispizua ◽  
Hubert Schrezenmeier ◽  
Petra Muus ◽  
Jaroslaw P Maciejewski ◽  
Gérard Socié ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Board Of Directors ◽  
Research Funding ◽  
Pediatric Patients ◽  
Event Rate ◽  
Adult Patients ◽  
Employment Equity ◽  
Advisory Committees ◽  
Clone Size ◽  
Equity Ownership

Abstract Abstract 2102 Background: Paroxysmal nocturnal hemoglobinuria (PNH) is a chronic, life-threatening hematopoietic stem cell disorder characterized by deficiency of the GPI-anchored complement inhibitory proteins CD55 and CD59. Uncontrolled complement activation is responsible for chronic hemolysis that leads to the serious clinical morbidities including thromboembolism (TE) and chronic kidney disease, which increase risk of mortality. PNH is infrequent in children and as such, there is a paucity of data in the literature examining their burden of disease. This is the largest series of pediatric patients with PNH, and the first comparison with adult PNH patients. AIM: To assess the clinical differences between pediatric and adult PNH patients with classic/hemolytic PNH. Methods: Data from 1143 PNH patients from 204 clinical sites in 21 countries on 5 continents (as of 6/30/11) were analyzed to evaluate clinical characteristics of PNH. Patients registered as having classic/hemolytic PNH were initially included (n=559). Of these, 62 additional patients were excluded due to either a <30% granulocyte clone size, or missing data on enrollment date, date of birth, sex, date of disease start and history of TE. The final population for this study was 497 patients, classified into two groups, those first diagnosed at age <18 years (pediatric patients N=49) and at age ≥18 years (adult patients N=448). Baseline demographics, laboratory values, PNH-related medical history, and physician-reported PNH symptoms were compared for pediatric and adult patients. Patients/guardians gave informed consent prior to enrollment. Results: The median age at disease start for pediatric patients was 15 years (5–17), and for adults was 33 years (18–87). Hemoglobin, leucocytes, neutrophils, reticulocytes, LDH, and number of transfusions were similar between both pediatric and adult patients. There were no differences in GPI-deficient granulocyte or RBC clone sizes between pediatric and adult patients. Follow-up was longer for children (mean + SD, in years: 14.5 + 13.6 vs 9.6 + 9.1, P<0.001, respectively). The number of pediatric and adult patients receiving concomitant medications such as anticoagulants (peds 49% vs adults 54.9%; P=0.43) and eculizumab (peds 40.8% vs adults 45.5%; P=0.53) prior to enrollment were similar. No differences between pediatric and adult patients were observed in bone marrow disorders, renal impairment, hemoglobinuria, abdominal pain, dysphagia, headache and shortness of breath. In contrast, pediatric patients reported less fatigue (57.1% vs. 76.8%; P=0.001). TE incidence was 12.2% for pediatric and 23.9% for adults, which was statistically significant when the length of the time of exposure to this complication was taken into account; TE event rate was significantly lower in pediatric patients compared to adults (1.0/100 pt-yrs vs 4.4/100 pt-yrs; P<0.001 by Poisson regression). Patients with TE had a mean granulocyte clone size of 85.7% vs 81.0% for patients without TE (P=0.026). Both in children and adults the risk of TE was much higher than expected for the general population (general pediatric population: TE incidence is 0.07 per 10,000 or 0.0007%, vs 12.2% in this study). TE events at venous sites (hepatic/portal, mesenteric/visceral, renal, and cerebral veins) and arterial sites were less frequent in pediatric patients compared to adults. The most striking difference in TE type was thrombophlebitis/deep vein thrombosis, which occurred significantly less frequently in pediatric than adult patients (2.0% vs 11.8%; p=0.037). In multivariate analysis, age >18 years at disease onset and kidney disease were predictors of TE (odds ratio [OR] 3.01, 95% CI 1.15–7.72; P=0.02, and OR 1.87, 95% CI 1.03–3.4; P=0.04, respectively), while clone size was not a significant predictor of TE (OR 1.010, 95% CI 0.995–1.025; P=0.18). Conclusions: Pediatric PNH patients experience a significant burden of disease similar to adult PNH patients. There were no differences in LDH levels, GPI-deficient clone size, or in the incidence of bone marrow disorders, renal impairment, hemoglobinuria, abdominal pain, shortness of breath and dysphagia between pediatric and adult patients. TE event rate was lower in pediatric PNH patients when compared to adults, especially for those with concomitant kidney disease However, TE still remains an issue in this population and pediatric PNH patients are at significant risk for TE. Disclosures: Urbano-Ispizua: Alexion: Membership on an entity's Board of Directors or advisory committees. Schrezenmeier: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; Novarts: 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. Szer:Alexion Pharmaceuticals, Inc.: 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 Pharmaceuticals, Inc.: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees; Taligen: Consultancy. Rosse:Alexion: Consultancy, Membership on an entity's Board of Directors or advisory committees. Kanakura:Alexion: Consultancy, Membership on an entity's Board of Directors or advisory committees. Khursigara:Alexion: 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 Northstar-2: Updated Safety and Efficacy Analysis of Lentiglobin Gene Therapy in Patients with Transfusion-Dependent β-Thalassemia and Non-β0/β0 Genotypes

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3543-3543 ◽  
Author(s):  
Alexis A. Thompson ◽  
Mark C. Walters ◽  
Janet L. Kwiatkowski ◽  
Suradej Hongeng ◽  
John B. Porter ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Clinical Trials ◽  
Board Of Directors ◽  
Research Funding ◽  
Advisory Board ◽  
Adult Patients ◽  
Employment Equity ◽  
Advisory Committees ◽  
Transfusion Independence ◽  
Equity Ownership

Background Transfusion-dependent β-thalassemia (TDT) is treated with regular, lifelong red blood cell (RBC) transfusions and despite iron-chelating therapy, carries a risk of serious organ damage from iron overload and other complications. Transplantation with autologous CD34+ cells encoding a βA-T87Q-globin gene (LentiGlobin for β-thalassemia) is being evaluated in patients with TDT. Interim results are presented here from the ongoing, international, single-arm, phase 3 Northstar-2 study (HGB-207; NCT02906202) of LentiGlobin gene therapy in pediatric, adolescent, and adult patients with TDT (defined by receiving ≥100 mL/kg/yr of RBCs or ≥8 RBC transfusions/yr) and non-β0/β0 genotypes. Methods Patients undergo hematopoietic stem cell (HSC) mobilization with G-CSF and plerixafor. Following apheresis, CD34+ cells are transduced with BB305 lentiviral vector and infused into patients after pharmacokinetic-adjusted, single-agent busulfan myeloablation. The primary efficacy endpoint is transfusion independence (TI; weighted average hemoglobin [Hb] ≥9 g/dL without RBC transfusions for ≥12 months). HSC engraftment, βA-T87Q-globin expression, Hb levels, detection of replication competent lentivirus (RCL), and adverse events (AE) are also assessed. Patients are followed for 2 years and offered participation in a long-term follow-up study. Summary statistics are presented as median (min - max). Results Twenty patients were treated in Northstar-2 as of 13 December 2018 and have been followed for a median of 8.1 (0.5 - 22.2) months. At enrollment, median age was 16 (8 - 34) years; 5 patients were &lt;12 years of age. Median drug product cell dose was 8.0 (5.0 - 19.9) x106 cells/kg and vector copy number was 3.2 (1.9 - 5.6) copies/diploid genome. Time to neutrophil and platelet engraftment in the 18/20 and 15/20 evaluable patients was 22.5 (13 - 32) and 45 (20 - 84) days, respectively. Non-hematologic grade ≥3 AEs in ≥3 patients after LentiGlobin infusion included stomatitis (n=12), febrile neutropenia (n=6), pyrexia (n=4), epistaxis (n=3), and veno-occlusive liver disease (n=3). One serious AE of grade 3 thrombocytopenia was considered possibly related to LentiGlobin. No patient died, had graft failure, or had detection of RCL. No insertional oncogenesis has been observed. Gene therapy-derived HbAT87Q stabilized approximately 6 months after infusion. In adolescent and adult patients treated with LentiGlobin, median HbAT87Q at Months 6, 12 and 18 was 9.5 (n=11), 9.2 (n=8), and 9.5 (n=3) g/dL, respectively. The median total Hb without transfusions at Months 6, 12, and 18 were 11.9 (n=11), 12.4 (n=8), 12.3 (n=2) g/dL, respectively. At Month 6, 91% (10/11) of patients had total Hb of &gt;11 g/dL without transfusions. Five adolescent and adult patients were evaluable for the primary endpoint of transfusion independence, 4 (80%) of whom achieved TI. The median weighted average Hb during TI was 12.4 (11.5 - 12.6) g/dL which compared favorably to pre-transfusion nadir Hb levels before enrollment (median 9.1 g/dL [7.5 - 10.0 g/dL]). At time of analysis, the median duration of TI was 13.6 (12.0 - 18.2) months. One patient who did not achieve TI stopped transfusions for 11.4 months but resumed transfusions due to recurrent anemia. This patient had a 71.4% reduction in RBC transfusion volume from Month 6 to Month 18 compared to baseline. Marrow cellularity and myeloid:erythroid (M:E) ratios were evaluated in 8 adolescent and adult patients with ≥12 months follow-up to assess the effect of LentiGlobin treatment on dyserythropoiesis. Seven of 8 patients had improved marrow M:E ratios at Month 12 (0.63 - 1.90) compared with baseline (0.14 - 0.48). In patients who stopped transfusions, soluble transferrin receptor levels were reduced by a median of 72% (58% - 78%) at Month 12 (n=6). Updated outcomes in adolescents and adults and outcomes in pediatric patients will be reported. Summary In this update of the Northstar-2 study of LentiGlobin gene therapy in patients with TDT and non-β0/β0 genotypes, transfusion independence was observed in 4/5 evaluable adolescent and adults and 10/11 treated patients had total Hb of &gt;11 g/dL without transfusion support 6 months after LentiGlobin infusion. HbAT87Q stabilized approximately 6 months after treatment and patients who stopped RBC transfusions had improved erythropoiesis. A safety profile consistent with busulfan conditioning was observed after LentiGlobin gene therapy. Disclosures Thompson: bluebird bio, Inc.: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Baxalta: Research Funding. Walters:TruCode: Consultancy; AllCells, Inc: Consultancy; Editas Medicine: Consultancy. Kwiatkowski:bluebird bio, Inc.: Consultancy, Research Funding; Terumo: Research Funding; Celgene: Consultancy; Agios: Consultancy; Imara: Consultancy; Apopharma: Research Funding; Novartis: Research Funding. Porter:Protagonism: Honoraria; Celgene: Consultancy, Honoraria; Bluebird bio: Consultancy, Honoraria; Agios: Consultancy, Honoraria; La Jolla: Honoraria; Vifor: Honoraria; Silence therapeutics: Honoraria. Thrasher:Rocket Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Orchard Therapeutics: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Generation Bio: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; 4BIOCapital: Membership on an entity's Board of Directors or advisory committees. Thuret:BlueBird bio: Other: investigators for clinical trials, participation on scientific/medical advisory board; Celgene: Other: investigators for clinical trials, participation on scientific/medical advisory board; Novartis: Other: investigators for clinical trials, participation on scientific/medical advisory board; Apopharma: Consultancy. Elliot:bluebird bio, Inc.: Employment, Equity Ownership. Tao:bluebird bio, Inc.: Employment, Equity Ownership. Colvin:bluebird bio, Inc.: Employment, Equity Ownership. Locatelli:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bellicum: Consultancy, Membership on an entity's Board of Directors or advisory committees; bluebird bio: Consultancy; Miltenyi: Honoraria.

A First-In-Human Phase 1 Study Of The Antibody-Drug Conjugate SGN-CD19A In Relapsed Or Refractory B-Lineage Acute Leukemia and Highly Aggressive Lymphoma

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1437-1437 ◽  
Author(s):  
Uma Borate ◽  
Amir T. Fathi ◽  
Bijal D. Shah ◽  
Daniel J. DeAngelo ◽  
Lewis B. Silverman ◽  
...  
Keyword(s):  
B Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Pediatric Patients ◽  
Antibody Drug Conjugate ◽  
Employment Equity ◽  
Advisory Committees ◽  
Drug Conjugate ◽  
Equity Ownership ◽  
Antibody Drug

Abstract Background CD19, a member of the immunoglobulin superfamily, is a B-cell specific marker that is found on B cells as early as the pro-B cell stage. CD19 is maintained upon malignant transformation and is expressed in the majority of patients with B-lineage leukemia and non-Hodgkin lymphoma (NHL). SGN-CD19A is a novel antibody-drug conjugate composed of a humanized anti-CD19 monoclonal antibody conjugated to the microtubule-disrupting agent monomethyl auristatin F (MMAF) via a maleimidocaproyl (mc) linker. Upon binding to CD19, SGN-CD19A internalizes and releases cys-mcMMAF, which binds to tubulin and induces G2/M arrest and apoptosis in the targeted cells. Methods A first-in-human, phase 1, open-label, dose-escalation study has been initiated to investigate the safety, tolerability, pharmacokinetics (PK), and antitumor activity of SGN-CD19A in adult and pediatric patients with relapsed or refractory (R/R) B-cell leukemia or highly aggressive B-cell lymphoma (CT.gov NCT01786096). Eligible patients must have a pathologically confirmed diagnosis of B-cell acute leukemia (B-ALL), Burkitt leukemia or lymphoma, or B-cell lymphoblastic lymphoma (B-LBL), and be R/R to at least 1 (adults) or 2 (pediatric) prior systemic regimens. A modified continual reassessment method is being used for dose allocation and maximum tolerated dose (MTD) estimation. SGN-CD19A is administered IV on Days 1 and 8 of 21-day cycles at up to 7 cohort-specific doses (0.3–2.3 mg/kg). Results Thirteen patients (11 adults, 2 pediatric) with R/R leukemia (9 B-ALL) or lymphoma (3 B-LBL, 1 Burkitt lymphoma) have been treated in this ongoing study. Adults (73% female) have a median age of 60 years (range, 26–74) and have received a median of 2 prior systemic therapies (range, 1–6). Four of the 11 adults (36%) have also received an allogeneic stem cell transplant (SCT). The pediatric patients, 2 females 13-and 14-years-old, have each received 3 prior systemic therapies; one of the pediatric patients has also received 2 allogeneic SCTs. To date, patients have been treated at 0.3 mg/kg (2 patients), 0.6 mg/kg (3 patients), 1.0 mg/kg (3 patients), and 1.3 mg/kg (5 patients). The maximum number of cycles received by a patient is 7. Four patients remain on treatment and 9 patients have discontinued treatment (7 due to progressive disease, 1 because of investigator decision, and 1 due to death). One patient with B-ALL treated at 1.0 mg/kg developed cardiac arrest in the setting of pre-existing electrolyte abnormalities and died 7 days after the first dose of SGN-CD19A; although this event was considered unrelated to study drug by the investigator, a possible relationship could not be excluded due to temporal association. Treatment-emergent adverse events reported for ≥10% of adult patients were nausea (64%); fatigue and pyrexia (55% each); chills (36%); headache (27%); and dyspnea, hypertension, oral pain, thrombocytopenia, tumor lysis syndrome, and vomiting (18% each). Drug-related AEs in adult patients were pyrexia (55%); nausea (45%); chills (36%); fatigue (27%); and headache, oral pain, and blurred vision (9% each). Drug-related AEs reported for the pediatric patients were abdominal pain, cough, diarrhea, dyspepsia, hyperuricemia, nausea, peripheral neuropathy, pruritus, pyrexia, tachycardia, and urticaria (all Grade 1 or 2, each in one patient). Preliminary data demonstrate rapid clearance of antibody-drug conjugate at low doses in patients with leukemia, suggesting target-mediated drug disposition. To date, best responses for patients with lymphoma are stable disease (2 patients) and progressive disease (2 patients). Best responses for the 8 leukemia patients with available response assessments are complete remission (1 adult at 1.3 mg/kg); resistant disease with clinical benefit, i.e., improvement in leukemia-related symptoms (4 patients); and progressive disease (3 patients). Conclusions MTDs have not yet been identified for adult or pediatric patients and dose-escalation continues in both populations. Antitumor activity has been observed, including 1 complete remission in a heavily pretreated B-ALL patient. Nonlinear clearance of the antibody-drug conjugate in leukemia patients suggests target-mediated disposition. Updated safety, PK, and response data will be presented at the meeting. A second trial is evaluating SGN-CD19A every 3 weeks in aggressive B-cell NHL (CT.gov NCT01786135). Disclosures: Borate: Seattle Genetics, Inc.: Research Funding; Genoptix: Consultancy. Fathi:Millennium: Research Funding; Seattle Genetics, Inc.: Advisory/Scientific board membership Other, Research Funding; Agios: Membership on an entity’s Board of Directors or advisory committees; Teva: Membership on an entity’s Board of Directors or advisory committees. Shah:Seattle Genetics, Inc.: Research Funding; NCCN: Membership on an entity’s Board of Directors or advisory committees; SWOG: Membership on an entity’s Board of Directors or advisory committees; Celgene: Speakers Bureau; Janssen/Pharmacyclics: Speakers Bureau. DeAngelo:Seattle Genetics, inc.: Research Funding. Silverman:Seattle Genetics, Inc.: Advisory/scientific board membership Other. Cooper:Seattle Genetics, Inc.: Research Funding. Albertson:Seattle Genetics, Inc.: Employment, Equity Ownership. O'Meara:Seattle Genetics, Inc.: Employment, Equity Ownership. Sandalic:Seattle Genetics, Inc.: Employment, Equity Ownership. Stevison:Seattle Genetics, Inc.: Employment, Equity Ownership. Chen:Seattle Genetics, Inc.: Consultancy, Research Funding, Speakers Bureau, Travel expenses Other.

scholarly journals The Global aHUS Registry: Characteristics of 826 Patients with Atypical Hemolytic Uremic Syndrome

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4640-4640
Author(s):  
Christoph Licht ◽  
Gianluigi Ardissino ◽  
Gema Ariceta ◽  
David J. Cohen ◽  
Christoph Gasteyger ◽  
...  
Keyword(s):  
Hemolytic Uremic Syndrome ◽  
Board Of Directors ◽  
Research Funding ◽  
Atypical Hemolytic Uremic Syndrome ◽  
Age Groups ◽  
Adult Patients ◽  
Employment Equity ◽  
Advisory Committees ◽  
Uremic Syndrome ◽  
Equity Ownership

Abstract Background: Atypical hemolytic uremic syndrome (aHUS) is a rare, genetic, life-threatening disease predominantly caused by chronic, uncontrolled complement activation that leads to thrombotic microangiopathy and renal and other end-organ damage. The aHUS Registry, established in April 2012, is an observational, noninterventional, multicenter, global initiative to collect information on patient outcomes regardless of treatment approach. It facilitates availability of follow-up data for eculizumab. Methods: Patients with clinical diagnoses of aHUS (irrespective of identified complement abnormality or treatment) are eligible. Demographic, medical/disease history, and treatment outcomes data are collected at enrollment and prospectively thereafter. Results: By June 30, 2015, 826 patients enrolled (Table). Overall, 54.7% of patients, including 45.1% of pediatric and 62.7% of adult patients, were female. Patients were most commonly enrolled after their first TMA event. Thrombosis occurred more frequently in adult than pediatric patients. Nonrenal conditions, including gastrointestinal, cardiovascular, central nervous system, and pulmonary, were common in both age groups and occurred in 11.0%‒20.3% overall. Eculizumab was administered to 57.3% of patients, of whom 87.3% were treated prior to enrollment. Conclusions: Registry baseline characteristics demonstrate differences between pediatric and adult patients with aHUS, notably frequencies of thrombosis. Nonrenal conditions are frequent in both age groups. Ongoing and future analyses will further enhance understanding of aHUS history and progression. Additional clinical sites are encouraged to enroll patients to facilitate knowledge acquisition and optimization of patient care and quality of life. Disclosures Licht: Alexion Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Achillon: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Ardissino:Alexion Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees. Ariceta:Alexion Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. Cohen:Astellas: Consultancy; Alexion Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; Merck: Consultancy; Genentech: Research Funding. Gasteyger:Alexion Pharma International SàRL: Employment, Equity Ownership. Greenbaum:Alexion Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Ogawa:Alexion Pharmaceuticals: Employment, Equity Ownership. Kupelian:Alexion Pharmaceuticals: Employment, Equity Ownership. Schaefer:Alexion Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees. Vande Walle:Alexion Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Frémeaux-Bacchi:Alexion Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

scholarly journals Chronic Kidney Disease Is Under-Screened in SCD and Mild Albuminuria Is Associated with a Drop in Hemoglobin: A Report from the Grndad Sickle Cell Registry

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2284-2284
Author(s):  
Elizabeth Williams ◽  
Elizabeth Brown ◽  
Deepa Manwani ◽  
Payal Desai ◽  
Joshua J. Field ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Sickle Cell Disease ◽  
Kidney Disease ◽  
Board Of Directors ◽  
Sickle Cell ◽  
Research Funding ◽  
Cell Disease ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership

The Globin Research Network for Data and Discovery (GRNDaD) is a combined effort, from 6 US clinical sites (Baltimore, Cleveland, Columbus OH, Milwaukee, Oakland, and The Bronx) that care for people with sickle cell disease (SCD), to improve care through shared data collection and review and quality improvement. Using a single IRB-Reliant protocol, we have assembled harmonized baseline and annual data on 758 adults with sickle cell disease (41.7% male and 58.3% female, mean age 35.5), collected on a REDCap server housed at Johns Hopkins. For this study, we reviewed adherence to the 2014 NHLBI Guidelines on the management of SCD -- which recommends annual screening for chronic kidney disease (CKD) by testing for albuminuria or proteinuria in anyone over the age of 10 with sickle cell disease. To evaluate whether subjects had an annual visit in any given year we used the recording of a well visit hemoglobin. Of the 758 adults in the study 411 had at least one year of follow up data marked as completed. Among these 411 adults there were 826 distinct observations. Of these 826 observations, 137 observations among 85 subjects did not have any hemoglobin lab drawn, suggesting that they did not have a well outpatient visit during that year. Amongst the observation years, where a well hemoglobin was performed, yearly screening for albuminuria occurred in 37.4% (258/689) of annual observations. There was an association between having screening for CKD and site of care (p<.0001), with some sites having adhered to guidelines in 34.2% of observation years and others having adhered 75.9% of years. There was no association between adherence and genotype or sex. Albuminuria was associated with a clinical phenotype. A multi-variable linear mixed effects model controlling for age and gender with a randomly varying intercept based on the subject, excluding chronically transfused subjects, and stratified by sickle cell anemia (HbSS or HbSB0, SCA) or variant genotypes was used. There was a significant association in those with SCA between the presence of albuminuria between 30 and 300, level (A2) and hemoglobin. Hemoglobin levels were, on average, 0.79 g/dL lower in those with albuminuria between 30-300 when compared to those with no albuminuria (A1, P=0.005). For those with SCA and albuminuria greater than 300 (A3), the sample size was small (n=28) and hemoglobin levels were 0.61 g/dl lower compared to those without albuminuria but this was not statistically significant (p=0.12). For those with variant compound heterozygous SCD and A2 albuminuria, hemoglobin levels were not statistically significantly different from those without albuminuria. However, high-grade albuminuria (A3) was associated with hemoglobin levels which were, on average, 1.86 g/dL lower than those in group A1 (P=0.004). Interestingly, the association between reduced hemoglobin and albuminuria was seen in both variant and SCA genotypes in the context of a preserved creatinine (<1.0 mg/dL). Using a multisite registry we demonstrate the need to develop strategies to assist providers and patients with adherence to guideline based recommendations for routine screening for chronic kidney disease in adults with SCD. The early association of albuminuria with worsening anemia, even in the absence of elevated creatinine levels, suggests an added urgency to screening. The causality of the association remains unclear but emphasizes the need for longitudinally followed cohorts that might help us understand the relationship between anemia and the development of CKD. Figure Disclosures Manwani: Novartis: Consultancy; Pfizer: Consultancy; GBT: Consultancy, Research Funding. Desai:Novartis: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; University of Pittsburgh: Research Funding; Ironwood: Other: Adjudication Board; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Potomac: Speakers Bureau. Field:Ironwood: Consultancy, Research Funding; Rigel: Research Funding; Prolong: Research Funding; Incyte: Research Funding. Neumayr:La Jolla Pharmaceuticals: Research Funding; Pfizer: Consultancy, Research Funding; Bayer: Consultancy; CTD Holdings: Consultancy; CDC: Research Funding; Celgene: Research Funding; Imara: Research Funding; NHLBI: Research Funding; Sangamo: Research Funding; HRSA: Research Funding; GBT: Research Funding; Emmaus: Consultancy; Apopharma: Consultancy; Sancillo: Research Funding; Novartis: Research Funding; Bluebird Bio: Research Funding; Silarus: Research Funding; Terumo: Research Funding; PCORI: Research Funding; Doris Duke Foundation: Research Funding; Seattle Children's Research Grants: Research Funding. Clay:Novartis: Speakers Bureau. Cong:Global Blood Therapeutics: Employment, Equity Ownership. Agodoa:Global Blood Therapeutics: Employment, Equity Ownership. Hoppe:Global Blood Therapeutics: Employment, Equity Ownership. Lanzkron:PCORI: Research Funding; Pfizer: Research Funding; Global Blood Therapeutics: Research Funding; Ironwood: Research Funding; HRSA: Research Funding; NIH: Research Funding. Little:Hemex Health, Inc.: Patents & Royalties; GBT: Research Funding.

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.

Phase 2 Results of Clofarabine In Combination with Etoposide and Cyclophosphamide In Pediatric Patients with Refractory or Relapsed Acute Lymphoblastic Leukemia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 866-866
Author(s):  
Nobuko Hijiya ◽  
Jo-Anne Paul ◽  
Michael J. Borowitz ◽  
Blythe Thomson ◽  
Michael Isakoff ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Board Of Directors ◽  
Research Funding ◽  
Pediatric Patients ◽  
Lymphoblastic Leukemia ◽  
Phase 2 ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership

Abstract Abstract 866 Background: Dramatic improvements have been made in treating children with newly diagnosed acute lymphoblastic leukemia (ALL). However, poor outcomes are still observed in patients who are either refractory to or who have relapsed after conventional chemotherapy. Salvage therapy options are urgently needed for this patient population. Clofarabine is approved as a single agent for treatment of pediatric ALL in second relapse. Previously we reported the safety profile and response rates from the phase 1 study assessing clofarabine in combination with etoposide and cyclophosphamide in pediatric patients with refractory/relapsed acute leukemia (Hijiya, Leukemia, 2009). Here we report the phase 2 results. Methods: Patients (pts) aged 1–21 years with refractory/relapsed ALL were treated at the recommended phase 2 dose of clofarabine 40 mg/m2/day, cyclophosphamide 440 mg/m2/day, and etoposide 100 mg/m2/day. All 3 agents were given IV daily for 5 consecutive days in induction and 4 consecutive days in consolidation. Patients could receive up to 2 induction cycles, followed by consolidation (max 8 cycles including induction). The primary endpoint was overall remission rate (ORR: complete remission [CR] and CR without platelet recovery [CRp]). Secondary endpoints were safety and tolerability, rate of partial remission (PR), duration of remission (DOR), event-free survival (EFS), 4-month EFS, and overall survival (OS). Minimal residual disease (MRD) by flow cytometry was evaluated as an exploratory endpoint. Results: Phase 2 comprised 25 pts (median follow-up 10.7 weeks [wks]): 16 males and 9 females with a median age of 14.0 years. Twenty-one pts had pre-B cell ALL, 1 pt had T cell ALL and 3 pts had an unknown immunophenotype. Fourteen pts had 2 prior induction regimens, 7 pts had 3 prior induction regimens and 4 pts had 1 prior induction regimen. Fifteen pts (60%) were refractory to their immediately preceding regimen. Four pts had received a prior hematopoietic stem cell transplant (HSCT). The investigator-assessed ORR was 44%; 7 CR (28%) and 4 CRp (16%). Additionally, 3 pts (12%) achieved PR. Eight pts were evaluable for MRD after induction, 5 were MRD negative (defined as <0.01%) and 3 were positive. Overall, 10 pts proceeded to HSCT, including 7 of 11 responders (CR + CRp). The median DOR at the last known follow-up (not censored for alternative therapy) was 15.9 wks (range: 2.9–109.6+) for pts with CR, but was not estimable for pts with CRp (range: 30.1+-67.7+). Median DOR for responders censored at alternative therapy/HSCT was not estimable as most pts received alternate therapy or transplant prior to event occurrence (range: 0.1+-10.9+ wks). Median OS censored at the last known follow-up was 10.7 wks for all patients (range: 1.0–113.1+) and 80.9 wks for responders (range: 8.1–113.1+). The median EFS for responders was 73.9 wks and 44% of all 25 pts were free of events at 4 months. The median cumulative number of clofarabine cycles received was 1 (range: 1–3), with most pts (10 of 11 responders) achieving best response after 1 cycle. The treatment-related non-hematologic adverse events (AEs) occurring in ≥25% of phase 2 pts were vomiting (88%); nausea (72%); febrile neutropenia (60%), pyrexia (52%); decreased appetite (44%); ALT increased, AST increased, hypokalemia, and hypotension (36% each), diarrhea and hyperbilirubinemia (28% each). One pt discontinued study treatment due to treatment-related fungal sinusitis which occurred 17 days after the last dose of study drug. Serious treatment-related AEs, were reported in 84% of pts. Six pts (24%) died within 30 days of receiving last dose of study treatment. Deaths were due to hepatic veno-occlusive disease (2 pts), septic shock (2 pts), pulmonary edema (1 pt) and infection (1 pt). As reported previously, after 4 of the initial 8 pts developed severe hepatotoxicity, the protocol was amended to exclude pts with prior HSCT, viral hepatitis cirrhosis, or elevated conjugated bilirubin levels at study entry (Hijiya, ASH 2008). There were no additional events of severe hepatotoxicity observed in the remaining 17 pts. Conclusions: Combination treatment with clofarabine, etoposide and cyclophosphamide in pediatric pts with refractory or relapsed ALL resulted in an ORR of 44% and negative MRD in heavily treated pts. Ten pts including 7 of 11 responders proceeded to HSCT. The safety profile is acceptable in this relapsed/refractory population. Disclosures: Hijiya: Genzyme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: Clofarabine (Clolar) is approved by the US FDA for the treatment of pediatric patients 1 to 21 years old with relapsed or refractory acute lymphoblastic leukemia after at least two prior regimens. This trial examines the use of clofarabine in combination with etoposide and cyclophosphamide. Paul:Genzyme: Employment, Equity Ownership. Borowitz:genzyme: Research Funding; becton-dickinson: Research Funding; Alexion: Consultancy; beckman-coulter: Research Funding. Isakoff:Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Silverman:Genzyme: Research Funding; Enzon : Honoraria, Membership on an entity's Board of Directors or advisory committees; EUSA: Honoraria, Membership on an entity's Board of Directors or advisory committees. Steinherz:Genzyme: Research Funding. Kadota:Genzyme: Employment, Equity Ownership. Pressey:Genzyme: Research Funding. Shen:Genzyme: Research Funding. Chu:Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Cooper:Genzyme: Research Funding. Jeha:Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Razzouk:Genzyme: Research Funding. Rytting:Genzyme: Research Funding. Barry:Genzyme: Employment, Equity Ownership. Carroll:Genzyme: Research Funding. Gaynon:Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

scholarly journals Rapid and Robust Mobilization of CD34+ HSCs without G-CSF Following Administration of Mgta-145 Alone or in Combination with Plerixafor

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1961-1961
Author(s):  
John F. DiPersio ◽  
Jonathan Hoggatt ◽  
Steven Devine ◽  
Lukasz Biernat ◽  
Haley Howell ◽  
...  
Keyword(s):  
Single Dose ◽  
Adverse Events ◽  
Board Of Directors ◽  
Preliminary Data ◽  
Research Funding ◽  
Fold Change ◽  
Employment Equity ◽  
Advisory Committees ◽  
Cd34 Cells ◽  
Equity Ownership

Background Granulocyte colony-stimulating factor (G-CSF) is the standard of care for mobilization of hematopoietic stem cells (HSCs). G-CSF requires 4-7 days of injections and often multiple aphereses to acquire sufficient CD34+ cells for transplant. The number of CD34+ HSCs mobilized can be variable and patients who fail to mobilize enough CD34+ cells are treated with the combination of G-CSF plus plerixafor. G-CSF use is associated with bone pain, nausea, headaches, fatigue, rare episodes of splenic rupture, and is contraindicated for patients with autoimmune and sickle cell disease. MGTA-145 (GroβT) is a CXCR2 agonist. MGTA-145, in combination with plerixafor, a CXCR4 inhibitor, has the potential to rapidly and reliably mobilize robust numbers of HSCs with a single dose and same-day apheresis for transplant that is free from G-CSF. MGTA-145 plus plerixafor work synergistically to rapidly mobilize HSCs in both mice and non-human primates (Hoggatt, Cell 2018; Goncalves, Blood 2018). Based on these data, Magenta initiated a Phase 1 dose-escalating study to evaluate the safety, PK and PD of MGTA-145 as a single agent and in combination with plerixafor. Methods This study consists of four parts. In Part A, healthy volunteers were dosed with MGTA-145 (0.0075 - 0.3 mg/kg) or placebo. In Part B, MGTA-145 dose levels from Part A were selected for use in combination with a clinically approved dose of plerixafor. In Part C, a single dose MGTA-145 plus plerixafor will be administered on day 1 and day 2. In Part D, MGTA-145 plus plerixafor will be administered followed by apheresis. Results MGTA-145 monotherapy was well tolerated in all subjects dosed (Table 1) with no significant adverse events. Some subjects experienced mild (Grade 1) transient lower back pain that dissipated within minutes. In the ongoing study, the combination of MGTA-145 with plerixafor was well tolerated, with some donors experiencing Grade 1 and 2 gastrointestinal adverse events commonly observed with plerixafor alone. Pharmacokinetic (PK) exposure and maximum plasma concentrations increased dose proportionally and were not affected by plerixafor (Fig 1A). Monotherapy of MGTA-145 resulted in an immediate increase in neutrophils (Fig 1B) and release of plasma MMP-9 (Fig 1C). Neutrophil mobilization plateaued within 1-hour post MGTA-145 at doses greater than 0.03 mg/kg. This plateau was followed by a rebound of neutrophil mobilization which correlated with re-expression of CXCR2 and presence of MGTA-145 at pharmacologically active levels. Markers of neutrophil activation were relatively unchanged (<2-fold vs baseline). A rapid and statistically significant increase in CD34+ cells occurred @ 0.03 and 0.075 mg/kg of MGTA-145 (p < 0.01) relative to placebo with peak mobilization (Fig 1D) 30 minutes post MGTA-145 (7-fold above baseline @ 0.03 mg/kg). To date, the combination of MGTA-145 plus plerixafor mobilized >20/µl CD34s in 92% (11/12) subjects compared to 50% (2/4) subjects receiving plerixafor alone. Preliminary data show that there was a significant increase in fold change relative to baseline in CD34+ cells (27x vs 13x) and phenotypic CD34+CD90+CD45RA- HSCs (38x vs 22x) mobilized by MGTA-145 with plerixafor. Mobilized CD34+ cells were detectable at 15 minutes with peak mobilization shifted 2 - 4 hours earlier for the combination vs plerixafor alone (4 - 6h vs 8 - 12h). Detailed results of single dose administration of MGTA-145 and plerixafor given on one day as well as also on two sequential days will be presented along with fully characterized graft analysis post apheresis from subjects given MGTA-145 and plerixafor. Conclusions MGTA-145 is safe and well tolerated, as a monotherapy and in combination with plerixafor and induced rapid and robust mobilization of significant numbers of HSCs with a single dose in all subjects to date. Kinetics of CD34+ cell mobilization for the combination was immediate (4x increase vs no change for plerixafor alone @ 15 min) suggesting the mechanism of action of MGTA-145 plus plerixafor is different from plerixafor alone. Preliminary data demonstrate that MGTA-145 when combined with plerixafor results in a significant increase in CD34+ fold change relative to plerixafor alone. Magenta Therapeutics intends to develop MGTA-145 as a first line mobilization product for blood cancers, autoimmune and genetic diseases and plans a Phase 2 study in multiple myeloma and non-Hodgkin lymphoma in 2020. Disclosures DiPersio: Magenta Therapeutics: Equity Ownership; NeoImmune Tech: Research Funding; Cellworks Group, Inc.: Membership on an entity's Board of Directors or advisory committees; Karyopharm Therapeutics: Consultancy; Incyte: Consultancy, Research Funding; RiverVest Venture Partners Arch Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; WUGEN: Equity Ownership, Patents & Royalties, Research Funding; Macrogenics: Research Funding, Speakers Bureau; Bioline Rx: Research Funding, Speakers Bureau; Celgene: Consultancy; Amphivena Therapeutics: Consultancy, Research Funding. Hoggatt:Magenta Therapeutics: Consultancy, Equity Ownership, Research Funding. Devine:Kiadis Pharma: Other: Protocol development (via institution); Bristol Myers: Other: Grant for monitoring support & travel support; Magenta Therapeutics: Other: Travel support for advisory board; My employer (National Marrow Donor Program) has equity interest in Magenta. Biernat:Medpace, Inc.: Employment. Howell:Magenta Therapeutics: Employment, Equity Ownership. Schmelmer:Magenta Therapeutics: Employment, Equity Ownership. Neale:Magenta Therapeutics: Employment, Equity Ownership. Boitano:Magenta Therapeutics: Employment, Equity Ownership, Patents & Royalties. Cooke:Magenta Therapeutics: Employment, Equity Ownership, Patents & Royalties. Goncalves:Magenta Therapeutics: Employment, Equity Ownership, Patents & Royalties. Raffel:Magenta Therapeutics: Employment, Equity Ownership. Falahee:Magenta Therapeutics: Employment, Equity Ownership, Patents & Royalties. Morrow:Magenta Therapeutics: Employment, Equity Ownership, Patents & Royalties. Davis:Magenta Therapeutics: Employment, Equity Ownership.

scholarly journals Treatment Patterns and Outcomes in Elderly Patients with Newly Diagnosed Multiple Myeloma: Results from the Connect® MM Registry

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3129-3129
Author(s):  
Hans C. Lee ◽  
Sikander Ailawadhi ◽  
Cristina Gasparetto ◽  
Sundar Jagannath ◽  
Robert M. Rifkin ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Causes Of Death ◽  
Age Groups ◽  
Treatment Patterns ◽  
Age Group ◽  
Newly Diagnosed ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership

Background: Multiple myeloma (MM) is common among the elderly, with 35% of patients (pts) diagnosed being aged ≥75 years (y). With increasing overall life expectancy, the incidence and prevalence of newly diagnosed and previously treated MM patients ≥80 y is expected to increase over time. Because elderly pts are often excluded from clinical trials, data focused on their treatment patterns and clinical outcomes are lacking. The Connect® MM Registry (NCT01081028) is a large, US, multicenter, prospective observational cohort study of pts with newly diagnosed MM (NDMM) designed to examine real-world diagnostic patterns, treatment patterns, clinical outcomes, and health-related quality of life patient-reported outcomes. This analysis reviews treatment patterns and outcomes in elderly pts from the Connect MM Registry. Methods: Pts enrolled in the Connect MM registry at 250 community, academic, and government sites were included in this analysis. Eligible pts were adults aged ≥18 y with symptomatic MM diagnosed ≤2 months before enrollment, as defined by International Myeloma Working Group criteria; no exclusion criteria were applied. For this analysis, pts were categorized into 4 age groups: <65, 65 to 74, 75 to 84, and ≥85 y. Pts were followed from time of enrollment to the earliest of disease progression (or death), loss to follow-up, or data cutoff date of February 7, 2019. Descriptive statistics were used for baseline characteristics and treatment regimens. Survival outcomes were analyzed using Cox regression. Time to progression (TTP) analysis excluded causes of death not related to MM. Results: Of 3011 pts enrolled (median age 67 y), 132 (4%) were aged ≥85 y, and 615 (20%) were aged 75-84 y at baseline. More pts aged ≥85 y had poor prognostic factors such as ISS stage III disease and reduced hemoglobin (<10 g/dL or >2 g/dL <LLN) compared with other age groups, although no notable differences between creatinine and calcium levels were observed across age groups (Table). A lower proportion of elderly pts (75-84 and ≥85 y) received triplet regimens as frontline therapy. More elderly pts received a single novel agent, whereas use of 2 novel agents was more common in younger pts (Table). The most common frontline regimens among elderly pts were bortezomib (V) + dexamethasone (D), followed by lenalidomide (R) + D, whereas those among younger pts included RVD, followed by VD and CyBorD (Table). No pt aged ≥85 y, and 4% of pts aged 75-84 y received high-dose chemotherapy and autologous stem cell transplant (vs 61% in the <65 y and 37% in the 65-74 y age group). The most common maintenance therapy was RD in pts ≥85 y (although the use was low) and R alone in other age groups (Table). In the ≥85 y group, 27%, 10%, and 4% of pts entered 2L, 3L, and 4L treatments respectively, vs 43%, 23%, and 13% in the <65 y group. Progression-free survival was significantly shorter in the ≥85 y age group vs the 75-84 y age group (P=0.003), 65-74 y age group (P<0.001), and <65 y age group (P<0.001; Fig.1). TTP was significantly shorter in the ≥85 y group vs the <65 y group (P=0.020); however, TTP was similar among the 65-74 y, 75-84 y, and ≥85 y cohorts (Fig. 2). Overall survival was significantly shorter in the ≥85 y group vs the 75-84 y, 65-74 y, and <65 y groups (all P<0.001; Fig. 3). The mortality rate was lowest (46%) during first-line treatment (1L) in pts aged ≥85 y (mainly attributed to MM progression) and increased in 2L and 3L (47% and 54%, respectively); a similar trend was observed in the younger age groups. The main cause of death was MM progression (29% in the ≥85 y vs 16% in the <65 y group). Other notable causes of death in the ≥85 y group included cardiac failure (5% vs 2% in <65 y group) and pneumonia (5% vs 1% in <65 y group). Conclusions: In this analysis, elderly pts received similar types of frontline and maintenance regimens as younger pts, although proportions varied with decreased use of triplet regimens with age. Considering similarities in TTP across the 65-74 y, 75-84 y, and ≥85 y cohorts, these real-world data support active treatment and aggressive supportive care of elderly symptomatic pts, including with novel agents. Additionally, further clinical studies specific to elderly patients with MM should be explored. Disclosures Lee: Amgen: Consultancy, Research Funding; GlaxoSmithKline plc: Research Funding; Sanofi: Consultancy; Daiichi Sankyo: Research Funding; Celgene: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Ailawadhi:Janssen: Consultancy, Research Funding; Takeda: Consultancy; Pharmacyclics: Research Funding; Amgen: Consultancy, Research Funding; Celgene: Consultancy; Cellectar: Research Funding. Gasparetto:Celgene: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; Janssen: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; BMS: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed . Jagannath:AbbVie: Consultancy; Merck & Co.: Consultancy; Bristol-Myers Squibb: Consultancy; Karyopharm Therapeutics: Consultancy; Celgene Corporation: Consultancy; Janssen Pharmaceuticals: Consultancy. Rifkin:Celgene: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Durie:Amgen, Celgene, Johnson & Johnson, and Takeda: Consultancy. Narang:Celgene: Speakers Bureau. Terebelo:Celgene: Honoraria; Jannsen: Speakers Bureau; Newland Medical Asociates: Employment. Toomey:Celgene: Consultancy. Hardin:Celgene: Membership on an entity's Board of Directors or advisory committees. Wagner:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; American Cancer Society: Other: Section editor, Cancer journal. Omel:Celgene, Takeda, Janssen: Other: Patient Advisory Committees. Srinivasan:Celgene: Employment, Equity Ownership. Liu:TechData: Consultancy. Dhalla:Celgene: Employment. Agarwal:Celgene Corporation: Employment, Equity Ownership. Abonour:BMS: Consultancy; Celgene: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Janssen: Consultancy, Research Funding.

scholarly journals Impact of Modified Thalidomide Dosing in Bortezomib/Thalidomide/Dexamethasone for Patients with Newly Diagnosed Multiple Myeloma Who Are Transplant-Eligible: A Matching-Adjusted Indirect Comparison

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4739-4739
Author(s):  
Pieter Sonneveld ◽  
Maria-Victoria Mateos ◽  
Adrián Alegre ◽  
Thierry Facon ◽  
Cyrille Hulin ◽  
...  
Keyword(s):  
Peripheral Neuropathy ◽  
Board Of Directors ◽  
Research Funding ◽  
Indirect Comparison ◽  
Employment Equity ◽  
Advisory Committees ◽  
Post Transplant ◽  
Post Induction ◽  
Adjusted Indirect Comparison ◽  
Equity Ownership

Introduction: For patients with newly diagnosed multiple myeloma (NDMM) who are transplant-eligible, bortezomib/thalidomide/dexamethasone (VTd) is a standard of care (SoC) for induction and consolidation therapy. Clinical practice has evolved to use a modified VTd dose (VTd-mod; 100 mg thalidomide daily), which is reflected in recent treatment guidelines. As VTd-mod has become a real-world SoC, a matching-adjusted indirect comparison (MAIC) of the VTd-mod dose from recent clinical trials versus the dose included in the label (VTd-label; ramp up to 200 mg thalidomide daily) was performed to understand the effect on efficacy of modified VTd dosing for patients with NDMM who are transplant-eligible. Methods: For each outcome (overall survival [OS], progression-free survival [PFS], overall response rates [ORR] post-induction and post-transplant, and rate of peripheral neuropathy), a naïve comparison and a MAIC were performed. Data for VTd-label were obtained from the phase 3 PETHEMA/GEM study (Rosiñol L, et al. Blood. 2012;120[8]:1589-1596). Data for VTd-mod were pooled from the phase 3 CASSIOPEIA study (Moreau P, et al. Lancet. 2019;394[10192]:29-38) and the phase 2 NCT00531453 study (Ludwig H, et al. J Clin Oncol. 2013;31[2]:247-255). Patient-level data for PETHEMA/GEM and CASSIOPEIA were used to generate outcomes of interest and were validated against their respective clinical study reports; aggregate data for NCT00531453 were extracted from the primary publication. Matched baseline characteristics were age, sex, ECOG performance status, myeloma type, International Staging System (ISS) stage, baseline creatinine clearance, hemoglobin level, and platelet count. Results: Patients received VTd-mod (n = 591) or VTd-label (n = 130). After matching, baseline characteristics were similar across groups. For OS, the naïve comparison and the MAIC showed that VTd-mod was non-inferior to VTd-label (MAIC HR, 0.640 [95% CI: 0.363-1.129], P = 0.121; Figure 1A). VTd-mod significantly improved PFS versus VTd-label in the naïve comparison and MAIC (MAIC HR, 0.672 [95% CI: 0.467-0.966], P = 0.031; Figure 1B). Post-induction ORR was non-inferior for VTd-mod versus VTd-label (MAIC odds ratio, 1.781 [95% CI: 1.004-3.16], P = 0.065). Post-transplant, VTd-mod demonstrated superior ORR in both the naïve comparison and MAIC (MAIC odds ratio, 2.661 [95% CI: 1.579-4.484], P = 0.001). For rates of grade 3 or 4 peripheral neuropathy, the naïve comparison and MAIC both demonstrated that VTd-mod was non-inferior to VTd-label (MAIC rate difference, 2.4 [⁻1.7-6.49], P = 0.409). Conclusions: As naïve, indirect comparisons are prone to bias due to patient heterogeneity between studies, a MAIC can provide useful insights for clinicians and reimbursement decision-makers regarding the relative efficacy and safety of different treatments. In this MAIC, non-inferiority of VTd-mod versus VTd-label was demonstrated for OS, post-induction ORR, and peripheral neuropathy. This analysis also showed that VTd-mod significantly improved PFS and ORR post-transplant compared with VTd-label for patients with NDMM who are transplant-eligible. A limitation of this analysis is that unreported or unobserved confounding factors could not be adjusted for. Disclosures Sonneveld: Takeda: Honoraria, Research Funding; SkylineDx: Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; BMS: Honoraria; Amgen: Honoraria, Research Funding; Karyopharm: Honoraria, Research Funding. Mateos:Janssen, Celgene, Takeda, Amgen, Adaptive: Honoraria; AbbVie Inc, Amgen Inc, Celgene Corporation, Genentech, GlaxoSmithKline, Janssen Biotech Inc, Mundipharma EDO, PharmaMar, Roche Laboratories Inc, Takeda Oncology: Other: Advisory Committee; Janssen, Celgene, Takeda, Amgen, GSK, Abbvie, EDO, Pharmar: Membership on an entity's Board of Directors or advisory committees; Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Takeda Oncology.: Speakers Bureau; Amgen Inc, Janssen Biotech Inc: Other: Data and Monitoring Committee. Alegre:Celgene, Amgen, Janssen, Takeda: Membership on an entity's Board of Directors or advisory committees. Facon:Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Hulin:celgene: Consultancy, Honoraria; Janssen, AbbVie, Celgene, Amgen: Honoraria. Hashim:Ingress-Health: Employment. Vincken:Janssen: Employment, Equity Ownership. Kampfenkel:Janssen: Employment, Equity Ownership. Cote:Janssen: Employment, Equity Ownership. Moreau:Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria.

scholarly journals A Phase I Trial of Janus Kinase (JAK) Inhibition with INCB039110 in Acute Graft-Versus-Host Disease (aGVHD)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 390-390 ◽  
Author(s):  
Mark A. Schroeder ◽  
H. Jean Khoury ◽  
Madan Jagasia ◽  
Haris Ali ◽  
Gary J. Schiller ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Janus Kinase ◽  
Cell Transplant ◽  
Employment Equity ◽  
Advisory Committees ◽  
Daily Dose ◽  
Equity Ownership ◽  
Grade 3 ◽  
Steroid Refractory

Abstract Background: Corticosteroids are considered standard first-line systemic therapy for patients with aGVHD, but this approach is effective in only approximately half of all cases. For patients who progress or do not respond to corticosteroids, no specific agent has been identified as standard, and regimens are typically selected based on investigator experience and patient co-morbidities. In preclinical models, JAK inhibition has been shown to impair production of cytokines as well as the differentiation and trafficking of T cells implicated in the pathogenesis of aGVHD. Retrospective studies have suggested that JAK1/JAK2 inhibition with ruxolitinib treatment provides clinical benefit in patients with steroid-refractory GVHD (Zeiser et al, Leukemia 2015;29:2062-2068). Herein, we report preliminary safety results from a prospective randomized, parallel-cohort, open-label phase 1 trial evaluating the potent and selective JAK 1 inhibitor INCB039110 in patients with aGVHD. Methods: Male or female patients 18 years or older who underwent their first allo-hematopoietic stem cell transplant (HSCT) from any donor source and developed grades IIB-IVD aGVHD were eligible for the study. Patients were randomized 1:1 to either a 200 or 300 mg oral daily dose of INCB039110 in combination with corticosteroids, and were stratified based on prior treatment status (treatment-naive [TN] versus steroid-refractory [SR]). The primary endpoint of the study was safety and tolerability; secondary endpoints included overall response rate at Days 14, 28, 56, and 100, non-relapse mortality, and pharmacokinetic (PK) evaluations. Patients were assessed through Day 28 for dose-limiting toxicities (DLTs) and response. A Bayesian approach was used for continuous monitoring of DLTs from Days 1-28. Treatment continued until GVHD progression, unacceptable toxicity, or withdrawal from the study. Acute GVHD was graded according to MN-CIBMTR criteria; adverse events (AEs) were graded according to NCICTCAE v 4.03. Results: Between January and June 2016, 31 patients (TN, n=14; SR, n= 17) were randomized. As of July 25, 2016, data were available from 30 patients who received an oral daily dose of 200 mg (n=14) or 300 mg (n=16) INCB039110 in combination with 2 mg/kg methylprednisolone (or equivalent dose of prednisone). The median durations of treatment were 60.8 days and 56.5 days for patients receiving a daily dose of 200 mg and 300 mg INCB039110, respectively. One DLT of Grade 3 thrombocytopenia was reported. The most frequently reported AEs included thrombocytopenia/platelet count decrease (26.7%), diarrhea (23.3%), peripheral edema (20%), fatigue (16.7%), and hyperglycemia (16.7%). Grade 3 or 4 AEs occurred in 77% of patients and with similar frequency across dose groups and included cytomegalovirus infections (n=3), gastrointestinal hemorrhage (n=3), and sepsis (n=3). Five patients had AEs leading to a fatal outcome, including multi-organ failure (n=2), sepsis (n=1), disease progression (n=1), and bibasilar atelectasis, cardiopulmonary arrest, and respiratory distress (n=1); none of the fatal events was attributed to INCB039110. Efficacy and PK evaluations are ongoing and will be updated at the time of presentation. Conclusion: The oral, selective JAK1 inhibitor INCB039110 can be given safely to steroid-naive or steroid-refractory aGVHD patients. The safety profile was generally consistent in both dose groups. Biomarker evaluation, PK, and cellular phenotyping studies are ongoing. The recommended phase 2 dose will be selected and reported based on PK studies and final safety data. Disclosures Schroeder: Incyte Corporation: Honoraria, Research Funding. Khoury:Incyte Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding. Jagasia:Incyte Corporation: Research Funding; Therakos: Research Funding; Janssen: Research Funding. Ali:Incyte Corporation: Research Funding. Schiller:Incyte Corporation: Research Funding. Arbushites:Incyte Corporation: Employment, Equity Ownership. Delaite:Incyte Corporation: Employment, Equity Ownership. Yan:Incyte Corporation: Employment, Equity Ownership. Rhein:Incyte Corporation: Employment, Equity Ownership. Perales:Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Chen:Incyte Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding. DiPersio:Incyte Corporation: Research Funding.

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