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Soluble tumor necrosis factor receptor: enbrel (etanercept) for subacute pulmonary dysfunction following allogeneic stem cell transplantation.

ABSTRACT: Subacute lung disease, manifested as either obstructive (OLD) or restrictive (RLD) lung dysfunction, is a common complication following allogeneic stem cell transplantation. In each case, therapeutic options are limited, morbidity remains high, and long-term survival is poor. Between 2001 and 2008, 34 patients with noninfectious, obstructive (25) or RLD restrictive lung dysfunction (nine) received etanercept (Enbrel®, Amgen Inc.) 0.4 mg/kg/dose, subcutaneously, twice weekly, for 4 (group A) or 12 weeks (group B). Corticosteroids (if present at study entry) were kept constant for the initial 4 weeks of therapy and then tapered as tolerated. Thirty-one of 34 (91%) subjects were evaluable for response, and 10 (32%) met primary response criteria. There was no difference in response based on the duration of treatment (29% group A versus 35% group B; P = .99), the presence of RLD or OLD (33% versus 32%; P = .73), or the severity of pulmonary disease at study onset. Estimated 5-year overall survival rates following therapy were 61% (95% confidence interval, 46%-80%) for all subjects and 90% (95% confidence level, 73%-100%) for the 10 who met the primary response criteria. Five-year survival estimates for subjects treated with RLD was 44%, compared with 67% for those treated for OLD (P = .19). Etanercept was well tolerated, with no bacteremia or viremia observed. Pathogens were noted on posttherapy bronchoalveolar lavage in two cases. These data support the development of expanded clinical trials to study etanercept as a therapeutic agent for subacute lung injury after allogeneic stem cell transplantation.

SUBMITTER: Yanik GA

PROVIDER: S-EPMC4462521 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature

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Soluble tumor necrosis factor receptor: enbrel (etanercept) for subacute pulmonary dysfunction following allogeneic stem cell transplantation.

Yanik Gregory A GA Mineishi Shin S Levine John E JE Kitko Carrie L CL White Eric S ES Vander Lugt Mark T MT Harris Andrew C AC Braun Thomas T Cooke Kenneth R KR

Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation 20111210 7

Subacute lung disease, manifested as either obstructive (OLD) or restrictive (RLD) lung dysfunction, is a common complication following allogeneic stem cell transplantation. In each case, therapeutic options are limited, morbidity remains high, and long-term survival is poor. Between 2001 and 2008, 34 patients with noninfectious, obstructive (25) or RLD restrictive lung dysfunction (nine) received etanercept (Enbrel®, Amgen Inc.) 0.4 mg/kg/dose, subcutaneously, twice weekly, for 4 (group A) or 1 ...[more]

PMID: 22155140

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Project description:BackgroundBiologic disease-modifying antirheumatic drugs, including tumor necrosis factor inhibitors such as etanercept (Enbrel®), have improved outcomes for patients with rheumatic and other inflammatory diseases, with sustained remission being the optimal goal for patients with rheumatoid arthritis. Flexible and convenient treatment options, compatible with modern lifestyle, are important in helping patients maintain treatment and manage their disease. Etanercept drug product (DP) is available in lyophilized powder (Lyo) for solution injection, prefilled syringe, and prefilled pen presentations and is typically stored under refrigerated conditions. We aimed to generate a comprehensive analytical data package from stability testing of key quality attributes, consistent with regulatory requirements, to determine whether the product profile of etanercept is maintained at ambient temperature.MethodsTest methods assessing key attributes of purity, quality, potency, and safety were performed over time, following storage of etanercept DP presentations under a range of conditions.ResultsResults and statistical analysis from stability testing (based on size exclusion high-performance liquid chromatography, hydrophobic interaction chromatography, and sodium dodecyl sulfate-polyacrylamide gel electrophoresis Coomassie) across all etanercept presentations (10 and 25 mg/vial Lyo DP; 25 and 50 mg prefilled syringe DP; 50 mg prefilled pen DP) showed key stability-indicating parameters were within acceptable limits through the alternative storage condition of 25°C±2°C for 1 month.ConclusionStability testing performed in line with regulatory requirements supports a single period of storage for etanercept DP at an alternative storage condition of 25°C±2°C for up to 1 month within the approved expiry of the product. This alternative storage condition represents further innovation in the etanercept product lifecycle, providing greater flexibility and enhanced overall convenience for patients.

Project description:Noninfectious pulmonary toxicity (NPT), a significant complication of allogeneic hematopoietic cell transplantation (alloHCT), includes idiopathic pneumonia syndrome (IPS), diffuse alveolar hemorrhage (DAH), and cryptogenic organizing pneumonia (COP), with an overall incidence ranging from 1% to 15% in different case series and a variable mortality rate. A registry study of the epidemiology and outcomes of NPT after alloHCT has not been conducted to date. The primary objective of the present study was to assess the incidence of and risk factors for IPS, DAH, and COP; the secondary objective was to assess overall survival (OS) in patients developing NPT. This retrospective study included adult patients who underwent alloHCT between 2008 and 2017 and reported to the Center for International Blood and Marrow Transplant Research. Multivariable Cox proportional hazards regression models were developed to identify the risk factors for development of NPT and for OS, by including pretransplantation clinical variables and time-dependent variables of neutrophil and platelet recovery, and acute graft-versus-host disease (GVHD) post-transplantation. This study included 21,574 adult patients, with a median age of 55 years. According to the HCT Comorbidity Index (HCT-CI), 24% of the patients had moderate pulmonary comorbidity and 15% had severe pulmonary comorbidity. The cumulative incidence of NPT at 1 year was 8.1% (95% confidence interval [CI], 7.7% to 8.5%). Individually, the 1-year cumulative incidences of IPS, DAH, and COP were 4.9% (95% CI, 4.7% to 5.2%), 2.1% (95% CI, 1.9% to 2.3%), and .7% (95% CI, .6% to .8%), respectively. Multivariable analysis showed that severe pulmonary comorbidity, grade II-IV acute GVHD, mismatched unrelated donor and cord blood transplantation, and HCT-CI score ≥1 significantly increased the risk of NPT. In contrast, alloHCT performed in 2014 or later, non-total body irradiation (TBI)- and TBI-based nonmyeloablative conditioning and platelet recovery were associated with a decreased risk. In a landmark analysis at day+100 post-transplantation, the risk of DAH was significantly lower in patients who had platelet recovery by day +100. Multivariable analysis for OS demonstrated that NPT significantly increased the mortality risk (hazard ratio, 4.2; P < .0001).

Dataset Information

Soluble tumor necrosis factor receptor: enbrel (etanercept) for subacute pulmonary dysfunction following allogeneic stem cell transplantation.

Publications

Soluble tumor necrosis factor receptor: enbrel (etanercept) for subacute pulmonary dysfunction following allogeneic stem cell transplantation.

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