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3. High risk of relapsed disease in patients with NK/T cell chronic active Epstein-Barr virus disease outside of Asia

Author

Saldaña, Blachy J Dávila, John, Tami D, Bonifant, Challice L, Buchbinder, David, Chandra, Sharat, Chandrakasan, Shanmuganathan, Chang, Weni, Chen, Leon, Elfassy, Hannah L, Geerlinks, Ashley V, Giller, Roger H, Goyal, Rakesh Kumar, Hagin, David, Islam, Shahidul, Mallhi, Kanwaldeep K, Miller, Holly K, Owen, William C, Pacheco, Martha, Patel, Niraj, Querfeld, Christiane, Quigg, Troy, Richard, Nameeta, Schiff, Deborah E, Shereck, Evan, Stenger, Elizabeth O, Jordan, Michael B, Heslop, Helen E, Bollard, Catherine M, and Cohen, Jeffrey I

Subjects
Lymphoma, Stem Cell Research, Stem Cell Research - Nonembryonic - Human, Cancer, Clinical Research, Hematology, Transplantation, Rare Diseases, Regenerative Medicine, Good Health and Well Being, Asia, Chronic Disease, Epstein-Barr Virus Infections, Herpesvirus 4, Human, Humans, Lymphoproliferative Disorders, Natural Killer T-Cells, Retrospective Studies, United States
Abstract

Chronic active Epstein-Barr virus (EBV) disease (CAEBV) is characterized by high levels of EBV predominantly in T and/or natural killer cells with lymphoproliferation, organ failure due to infiltration of tissues with virus-infected cells, hemophagocytic lymphohistiocytosis, and/or lymphoma. The disease is more common in Asia than in the United States and Europe. Although allogeneic hematopoietic stem cell transplantation (HSCT) is considered the only curative therapy for CAEBV, its efficacy and the best treatment modality to reduce disease severity prior to HSCT is unknown. Here, we retrospectively assessed an international cohort of 57 patients outside of Asia. Treatment of the disease varied widely, although most patients ultimately proceeded to HSCT. Though patients undergoing HSCT had better survival than those who did not (55% vs 25%, P < .01), there was still a high rate of death in both groups. Mortality was largely not affected by age, ethnicity, cell-type involvement, or disease complications, but development of lymphoma showed a trend with increased mortality (56% vs 35%, P = .1). The overwhelming majority (75%) of patients who died after HSCT succumbed to relapsed disease. CAEBV remains challenging to treat when advanced disease is present. Outcomes would likely improve with better disease control strategies, earlier referral for HSCT, and close follow-up after HSCT including aggressive management of rising EBV DNA levels in the blood.

Published
2022

4. Immunophenotypic predictors of influenza vaccine immunogenicity in pediatric hematopoietic cell transplant recipients

Author

Naik, Swati, Williams, Christopher, Russo, Michael, Goyal, Rakesh, Blum, Samantha, Shoemaker, Lauren, Lacombe, Kirsten, Smith, Hannah, Allison, Kim J., Truong, Kenny, Dvorak, Christopher, Hamdan, Lubna, Batarseh, Einas, Haddadin, Zaid, Stewart, Laura S., Stahl, Anna, Potter, Molly, Rahman, Herdi, McHenry, Rendie, Bender, Margaret, Barto, Shari, Amarin, Justin Z., Dulek, Daniel E., Simmons, Joshua, Hayek, Haya, Chappell, James D., Nochowicz, Cindy Hager, Kitko, Carrie L., Schuster, Jennifer E., Muñoz, Flor M., Bocchini, Claire E., Moulton, Elizabeth A., Coffin, Susan E., Freedman, Jason L., Ardura, Monica I., Wattier, Rachel L., Maron, Gabriela, Grimley, Michael, Paulsen, Grant, Danziger-Isakov, Lara, Carpenter, Paul A., Englund, Janet A., Halasa, Natasha B., Spieker, Andrew J., and Kalams, Spyros A.

Published
2024
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6. Effect of Different MQL Parameters on the Surface Quality of Aluminum Alloy During Face Milling

Author

Singh, Kamaljeet, Sharma, Vijay Kumar, Singh, Talvinder, Rana, Mohit, Goyal, Rakesh, Chaari, Fakher, Series Editor, Gherardini, Francesco, Series Editor, Ivanov, Vitalii, Series Editor, Cavas-Martínez, Francisco, Editorial Board Member, di Mare, Francesca, Editorial Board Member, Haddar, Mohamed, Editorial Board Member, Kwon, Young W., Editorial Board Member, Trojanowska, Justyna, Editorial Board Member, Li, Xianguo, editor, Rashidi, Mohammad Mehdi, editor, Lather, Rohit Singh, editor, and Raman, Roshan, editor

Published
2023
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8. Investigation of Manual Material Tasks Performed by Workers in North Indian Manufacturing Industries

Author

Singh, Jaswinder, Singh, Kulwinder, Molla, K. Z., Goyal, Rakesh, Gupta, Rupesh, Cavas-Martínez, Francisco, Series Editor, Chaari, Fakher, Series Editor, Gherardini, Francesco, Series Editor, Haddar, Mohamed, Series Editor, Ivanov, Vitalii, Series Editor, Kwon, Young W., Series Editor, Trojanowska, Justyna, Series Editor, di Mare, Francesca, Series Editor, Dubey, Avanish Kumar, editor, Sachdeva, Anish, editor, and Mehta, Munish, editor

Published
2022
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9. Optimization and Validation of Material Removal Rate During EDM of HSLA Steel

Author

Singh, Kulwinder, Goyal, Rakesh, Singh, Jaswinder, Gupta, Rupesh, Madan, Manuj, Cavas-Martínez, Francisco, Series Editor, Chaari, Fakher, Series Editor, Gherardini, Francesco, Series Editor, Haddar, Mohamed, Series Editor, Ivanov, Vitalii, Series Editor, Kwon, Young W., Series Editor, Trojanowska, Justyna, Series Editor, di Mare, Francesca, Series Editor, Dubey, Avanish Kumar, editor, Sachdeva, Anish, editor, and Mehta, Munish, editor

Published
2022
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11. Related and unrelated donor transplantation for β-thalassemia major: results of an international survey

Author

Li, Chunfu, Mathews, Vikram, Kim, Soyoung, George, Biju, Hebert, Kyle, Jiang, Hua, Li, Changgang, Zhu, Yiping, Keesler, Daniel A, Boelens, Jaap Jan, Dvorak, Christopher C, Agarwal, Rajni, Auletta, Jeffery J, Goyal, Rakesh K, Hanna, Rabi, Kasow, Kimberly, Shenoy, Shalini, Smith, Angela R, Walters, Mark C, and Eapen, Mary

Subjects
Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Immunology, Regenerative Medicine, Clinical Research, Transplantation, Adolescent, Adult, Age Factors, Child, Child, Preschool, Hematopoietic Stem Cell Transplantation, Histocompatibility, Humans, Myeloablative Agonists, Surveys and Questionnaires, Survival Analysis, Tissue Donors, Transplantation Conditioning, Transplantation, Homologous, Unrelated Donors, Young Adult, beta-Thalassemia, Cardiovascular medicine and haematology
Abstract

We studied 1110 patients with β-thalassemia major aged ≤25 years who received transplants with grafts from HLA-matched related (n = 677; 61%), HLA-mismatched related (n = 78; 7%), HLA-matched unrelated (n = 252; 23%), and HLA-mismatched unrelated (n = 103; 9%) donors between 2000 and 2016. Ninety percent of transplants were performed in the last decade. Eight-five percent of patients received ≥20 transfusions and 88% were inadequately chelated. All patients received myeloablative-conditioning regimen. Overall and event-free survival were highest for patients aged ≤6 years and after HLA-matched related and HLA-matched unrelated donor transplantation. The 5-year probabilities of overall survival for patients aged ≤6 years, 7 to 15 years, and 16 to 25 years, adjusted for donor type and conditioning regimen were 90%, 84%, and 63%, respectively (P < .001). The corresponding probabilities for event-free survival were 86%, 80%, and 63% (P < .001). Overall and event-free survival did not differ between HLA-matched related and HLA-matched unrelated donor transplantation (89% vs 87% and 86% vs 82%, respectively). Corresponding probabilities after mismatched related and mismatched unrelated donor transplantation were 73% vs 83% and 70% vs 78%. In conclusion, if transplantation is considered as a treatment option it should be offered early (age ≤6 years). An HLA-matched unrelated donor is a suitable alternative if an HLA-matched relative is not available.

Published
2019

15. Long-term follow-up of IPEX syndrome patients after different therapeutic strategies: An international multicenter retrospective study.

Author

Barzaghi, Federica, Amaya Hernandez, Laura Cristina, Neven, Benedicte, Ricci, Silvia, Kucuk, Zeynep Yesim, Bleesing, Jack J, Nademi, Zohreh, Slatter, Mary Anne, Ulloa, Erlinda Rose, Shcherbina, Anna, Roppelt, Anna, Worth, Austen, Silva, Juliana, Aiuti, Alessandro, Murguia-Favela, Luis, Speckmann, Carsten, Carneiro-Sampaio, Magda, Fernandes, Juliana Folloni, Baris, Safa, Ozen, Ahmet, Karakoc-Aydiner, Elif, Kiykim, Ayca, Schulz, Ansgar, Steinmann, Sandra, Notarangelo, Lucia Dora, Gambineri, Eleonora, Lionetti, Paolo, Shearer, William Thomas, Forbes, Lisa R, Martinez, Caridad, Moshous, Despina, Blanche, Stephane, Fisher, Alain, Ruemmele, Frank M, Tissandier, Come, Ouachee-Chardin, Marie, Rieux-Laucat, Frédéric, Cavazzana, Marina, Qasim, Waseem, Lucarelli, Barbarella, Albert, Michael H, Kobayashi, Ichiro, Alonso, Laura, Diaz De Heredia, Cristina, Kanegane, Hirokazu, Lawitschka, Anita, Seo, Jong Jin, Gonzalez-Vicent, Marta, Diaz, Miguel Angel, Goyal, Rakesh Kumar, Sauer, Martin G, Yesilipek, Akif, Kim, Minsoo, Yilmaz-Demirdag, Yesim, Bhatia, Monica, Khlevner, Julie, Richmond Padilla, Erick J, Martino, Silvana, Montin, Davide, Neth, Olaf, Molinos-Quintana, Agueda, Valverde-Fernandez, Justo, Broides, Arnon, Pinsk, Vered, Ballauf, Antje, Haerynck, Filomeen, Bordon, Victoria, Dhooge, Catharina, Garcia-Lloret, Maria Laura, Bredius, Robbert G, Kałwak, Krzysztof, Haddad, Elie, Seidel, Markus Gerhard, Duckers, Gregor, Pai, Sung-Yun, Dvorak, Christopher C, Ehl, Stephan, Locatelli, Franco, Goldman, Frederick, Gennery, Andrew Richard, Cowan, Mort J, Roncarolo, Maria-Grazia, Bacchetta, Rosa, and Primary Immune Deficiency Treatment Consortium (PIDTC) and the Inborn Errors Working Party (IEWP) of the European Society for Blood and Marrow Transplantation (EBMT)

Subjects
Primary Immune Deficiency Treatment Consortium (PIDTC) and the Inborn Errors Working Party (IEWP) of the European Society for Blood and Marrow Transplantation, Humans, Genetic Diseases, X-Linked, Diabetes Mellitus, Type 1, Immune System Diseases, Diarrhea, Disease-Free Survival, Hematopoietic Stem Cell Transplantation, Survival Rate, Retrospective Studies, Follow-Up Studies, Mutation, Adolescent, Adult, Child, Child, Preschool, Infant, Female, Male, Forkhead Transcription Factors, Allografts, Immunosuppression Therapy, FOXP3, IPEX, Treg cells, enteropathy, genetic autoimmunity, hematopoietic stem cell transplantation, immunosuppression, neonatal diabetes, primary immune deficiency, rapamycin, Clinical Research, Stem Cell Research, Regenerative Medicine, Pediatric, Genetics, Transplantation, Aetiology, 2.1 Biological and endogenous factors, Immunology, Allergy
Abstract

BackgroundImmunodysregulation polyendocrinopathy enteropathy x-linked (IPEX) syndrome is a monogenic autoimmune disease caused by FOXP3 mutations. Because it is a rare disease, the natural history and response to treatments, including allogeneic hematopoietic stem cell transplantation (HSCT) and immunosuppression (IS), have not been thoroughly examined.ObjectiveThis analysis sought to evaluate disease onset, progression, and long-term outcome of the 2 main treatments in long-term IPEX survivors.MethodsClinical histories of 96 patients with a genetically proven IPEX syndrome were collected from 38 institutions worldwide and retrospectively analyzed. To investigate possible factors suitable to predict the outcome, an organ involvement (OI) scoring system was developed.ResultsWe confirm neonatal onset with enteropathy, type 1 diabetes, and eczema. In addition, we found less common manifestations in delayed onset patients or during disease evolution. There is no correlation between the site of mutation and the disease course or outcome, and the same genotype can present with variable phenotypes. HSCT patients (n = 58) had a median follow-up of 2.7 years (range, 1 week-15 years). Patients receiving chronic IS (n = 34) had a median follow-up of 4 years (range, 2 months-25 years). The overall survival after HSCT was 73.2% (95% CI, 59.4-83.0) and after IS was 65.1% (95% CI, 62.8-95.8). The pretreatment OI score was the only significant predictor of overall survival after transplant (P = .035) but not under IS.ConclusionsPatients receiving chronic IS were hampered by disease recurrence or complications, impacting long-term disease-free survival. When performed in patients with a low OI score, HSCT resulted in disease resolution with better quality of life, independent of age, donor source, or conditioning regimen.

Published
2018

16. High risk of relapsed disease in patients with NK/T-cell chronic active Epstein-Barr virus disease outside of Asia

Author

Dávila Saldaña, Blachy J., John, Tami, Bonifant, Challice, Buchbinder, David, Chandra, Sharat, Chandrakasan, Shanmuganathan, Chang, Weni, Chen, Leon, Elfassy, Hannah L., Geerlinks, Ashley V., Giller, Roger H., Goyal, Rakesh, Hagin, David, Islam, Shahidul, Mallhi, Kanwaldeep, Miller, Holly K., Owen, William, Pacheco, Martha, Patel, Niraj C., Querfeld, Christiane, Quigg, Troy, Richard, Nameeta, Schiff, Deborah, Shereck, Evan, Stenger, Elizabeth, Jordan, Michael B., Heslop, Helen E., Bollard, Catherine M., and Cohen, Jeffrey I.

Published
2022
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18. Numerical Analysis and Experimental Study for Fatigue Life Behavior of HSLA and UHSS Welded Joints

Author

Goyal, Rakesh, El-zein, Mohamad, Cavas-Martínez, Francisco, Series Editor, Chaari, Fakher, Series Editor, Gherardini, Francesco, Series Editor, Haddar, Mohamed, Series Editor, Ivanov, Vitalii, Series Editor, Kwon, Young W., Series Editor, Trojanowska, Justyna, Series Editor, Seetharamu, S., editor, Jagadish, Thimmarayappa, editor, and Malagi, Ravindra, editor

Published
2021
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19. Prediction of refractive index of 1-butyl-1-methylpyrrolidinium dicyanamide and water ionic liquid mixture: An application of machine learning.

Author

Sirohi, Archana, Upmanyu, Arun, Kumar, Pankaj, Singh, Harjeet, Goyal, Rakesh, and Pandey, Krishna Kumar

Subjects
REGRESSION analysis, REFRACTIVE index, IONS, LIQUID mixtures, CONCENTRATION functions
Abstract

Machine Learning tool is employed to predict the refractive index of 1-butyl-1-methyl pyrrolidinium dicyanamide and Water ionic liquid mixture at different concentration and temperatures. The calculated values are are in good agreement with experimental ones. In this article, polynomial regression equation as a function of concentration of mixture has also been generated at different temperatures. The variation of refractive index with respect to concentration (X1) at different temperatures has been utilized to explore the molecular interactions prevalent in the system. This study reveals that the intra molecular (A-A) interactions between the molecules of ionic liquids are dominate over the inter molecular (A-B) interactions between ionic liquid and water for 01<0.8. Additionally refractive mixing rules viz., Lorentz-Lorentz, Gladstone-Dale, Wiener, Heller and Arago – Biot are tested for the given system under study. It is observed that all the five mixing rules are in excellent agreement with the experimental value. [ABSTRACT FROM AUTHOR]

Published
2024
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21. Abnormal B-cell maturation in the bone marrow of patients with germline mutations in PIK3CD

Author

Florea, Alina E Dulau, Braylan, Raul C, Schafernak, Kristian T, Williams, Kelli W, Daub, Janine, Goyal, Rakesh K, Puck, Jennifer M, Rao, V Koneti, Pittaluga, Stefania, Holland, Steven M, Uzel, Gulbu, and Calvo, Katherine R

Subjects
Biomedical and Clinical Sciences, Immunology, Adolescent, B-Lymphocytes, Bone Marrow Cells, Cell Differentiation, Child, Child, Preschool, Class I Phosphatidylinositol 3-Kinases, Female, Germ-Line Mutation, Hematologic Diseases, Humans, Male, Precursor Cells, B-Lymphoid, Young Adult, Allergy
Abstract

Patients with germline mutations in PIK3CD, immunodeficiency, lymphoproliferation, and autoimmunity show a distinct pattern of abnormal B-cell maturation in the bone marrow.

Published
2017

23. IoT for Indian Power Sector

Author

Goyal, Rakesh Kumar, Angrisani, Leopoldo, Series Editor, Arteaga, Marco, Series Editor, Panigrahi, Bijaya Ketan, Series Editor, Chakraborty, Samarjit, Series Editor, Chen, Jiming, Series Editor, Chen, Shanben, Series Editor, Chen, Tan Kay, Series Editor, Dillmann, Rüdiger, Series Editor, Duan, Haibin, Series Editor, Ferrari, Gianluigi, Series Editor, Ferre, Manuel, Series Editor, Hirche, Sandra, Series Editor, Jabbari, Faryar, Series Editor, Jia, Limin, Series Editor, Kacprzyk, Janusz, Series Editor, Khamis, Alaa, Series Editor, Kroeger, Torsten, Series Editor, Liang, Qilian, Series Editor, Martin, Ferran, Series Editor, Ming, Tan Cher, Series Editor, Minker, Wolfgang, Series Editor, Misra, Pradeep, Series Editor, Möller, Sebastian, Series Editor, Mukhopadhyay, Subhas, Series Editor, Ning, Cun-Zheng, Series Editor, Nishida, Toyoaki, Series Editor, Pascucci, Federica, Series Editor, Qin, Yong, Series Editor, Seng, Gan Woon, Series Editor, Speidel, Joachim, Series Editor, Veiga, Germano, Series Editor, Wu, Haitao, Series Editor, Zhang, Junjie James, Series Editor, Pillai, Reji Kumar, editor, Ghatikar, Girish, editor, Seethapathy, Ravi, editor, Sonavane, Vijay L., editor, Khaparde, S. A., editor, Yemula, Pradeep Kumar, editor, and Chaudhuri, Samir, editor

Published
2020
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29. Corrigendum: Natural Killer Cells from Patients with Recombinase-Activating Gene and Non-Homologous End Joining Gene Defects Comprise a Higher Frequency of CD56bright NKG2A+++ Cells, and Yet Display Increased Degranulation and Higher Perforin Content

Author

Dobbs, Kerry, Tabellini, Giovanna, Calzoni, Enrica, Patrizi, Ornella, Martinez, Paula, Giliani, Silvia Clara, Moratto, Daniele, Al-Herz, Waleed, Cancrini, Caterina, Cowan, Morton, Bleesing, Jacob, Booth, Claire, Buchbinder, David, Burns, Siobhan O, Chatila, Talal A, Chou, Janet, Daza-Cajigal, Vanessa, de Bruin, Lisa M Ott, de la Morena, Maite Teresa, Di Matteo, Gigliola, Finocchi, Andrea, Geha, Raif, Goyal, Rakesh K, Hayward, Anthony, Holland, Steven, Huang, Chiung-Hui, Kanariou, Maria G, King, Alejandra, Kaplan, Blanka, Kleva, Anastasiya, Kuijpers, Taco W, Lee, Bee Wah, Lougaris, Vassilios, Massaad, Michel, Meyts, Isabelle, Morsheimer, Megan, Neven, Benedicte, Pai, Sung-Yun, Parvaneh, Nima, Plebani, Alessandro, Prockop, Susan, Reisli, Ismail, Soh, Jian Yi, Somech, Raz, Torgerson, Troy R, Kim, Yae-Jean, Walter, Jolan E, Gennery, Andrew R, Keles, Sevgi, Manis, John P, Marcenaro, Emanuela, Moretta, Alessandro, Parolini, Silvia, and Notarangelo, Luigi D

Subjects
natural killer cells, recombinase-activating genes, non-homologous end joining, immunodeficiency, CD56, interferon-gamma, degranulation, interferon-γ, Immunology, Medical Microbiology
Abstract

[This corrects the article on p. 798 in vol. 8, PMID: 28769923.].

Published
2017

30. Natural Killer Cells from Patients with Recombinase-Activating Gene and Non-Homologous End Joining Gene Defects Comprise a Higher Frequency of CD56bright NKG2A+++ Cells, and Yet Display Increased Degranulation and Higher Perforin Content

Author

Dobbs, Kerry, Tabellini, Giovanna, Calzoni, Enrica, Patrizi, Ornella, Martinez, Paula, Giliani, Silvia Clara, Moratto, Daniele, Al-Herz, Waleed, Cancrini, Caterina, Cowan, Morton, Bleesing, Jacob, Booth, Claire, Buchbinder, David, Burns, Siobhan O, Chatila, Talal A, Chou, Janet, Daza-Cajigal, Vanessa, de Bruin, Lisa M Ott, de la Morena, Maite Teresa, Di Matteo, Gigliola, Finocchi, Andrea, Geha, Raif, Goyal, Rakesh K, Hayward, Anthony, Holland, Steven, Huang, Chiung-Hui, Kanariou, Maria G, King, Alejandra, Kaplan, Blanka, Kleva, Anastasiya, Kuijpers, Taco W, Lee, Bee Wah, Lougaris, Vassilios, Massaad, Michel, Meyts, Isabelle, Morsheimer, Megan, Neven, Benedicte, Pai, Sung-Yun, Parvaneh, Nima, Plebani, Alessandro, Prockop, Susan, Reisli, Ismail, Soh, Jian Yi, Somech, Raz, Torgerson, Troy R, Kim, Yae-Jaen, Walter, Jolan E, Gennery, Andrew R, Keles, Sevgi, Manis, John P, Marcenaro, Emanuela, Moretta, Alessandro, Parolini, Silvia, and Notarangelo, Luigi D

Subjects
Genetics, Rare Diseases, Stem Cell Research, Regenerative Medicine, Transplantation, Stem Cell Research - Nonembryonic - Human, natural killer cells, recombinase-activating genes, non-homologous end joining, immunodeficiency, CD56, interferon-gamma, degranulation, interferon-γ, Immunology, Medical Microbiology
Abstract

Mutations of the recombinase-activating genes 1 and 2 (RAG1 and RAG2) in humans are associated with a broad range of phenotypes. For patients with severe clinical presentation, hematopoietic stem cell transplantation (HSCT) represents the only curative treatment; however, high rates of graft failure and incomplete immune reconstitution have been observed, especially after unconditioned haploidentical transplantation. Studies in mice have shown that Rag-/- natural killer (NK) cells have a mature phenotype, reduced fitness, and increased cytotoxicity. We aimed to analyze NK cell phenotype and function in patients with mutations in RAG and in non-homologous end joining (NHEJ) genes. Here, we provide evidence that NK cells from these patients have an immature phenotype, with significant expansion of CD56bright CD16-/int CD57- cells, yet increased degranulation and high perforin content. Correlation was observed between in vitro recombinase activity of the mutant proteins, NK cell abnormalities, and in vivo clinical phenotype. Addition of serotherapy in the conditioning regimen, with the aim of depleting the autologous NK cell compartment, may be important to facilitate engraftment and immune reconstitution in patients with RAG and NHEJ defects treated by HSCT.

Published
2017

39. TNF-Receptor Inhibitor Therapy for the Treatment of Children with Idiopathic Pneumonia Syndrome. A Joint Pediatric Blood and Marrow Transplant Consortium and Children's Oncology Group Study (ASCT0521)

Author

Yanik, Gregory A, Grupp, Stephan A, Pulsipher, Michael A, Levine, John E, Schultz, Kirk R, Wall, Donna A, Langholz, Bryan, Dvorak, Christopher C, Alangaden, Keith, Goyal, Rakesh K, White, Eric S, Collura, Jennifer M, Skeens, Micah A, Eid, Saada, Pierce, Elizabeth M, and Cooke, Kenneth R

Subjects
Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Clinical Sciences, Pediatric, Lung, Rare Diseases, Hematology, Clinical Research, Clinical Trials and Supportive Activities, Pneumonia & Influenza, 6.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, Adolescent, Adrenal Cortex Hormones, Bronchoalveolar Lavage Fluid, Child, Child, Preschool, Cytokines, Drug Therapy, Combination, Etanercept, Female, Hematologic Neoplasms, Hematopoietic Stem Cell Transplantation, Humans, Idiopathic Interstitial Pneumonias, Immunoglobulin G, Immunosuppressive Agents, Infant, Male, Receptors, Tumor Necrosis Factor, Respiration, Artificial, Siblings, Survival Analysis, Transplantation, Homologous, Treatment Outcome, Unrelated Donors, Bone marrow transplantation, Idiopathic pneumonia syndrome, Immunology, Cardiovascular medicine and haematology
Abstract

Idiopathic pneumonia syndrome (IPS) is an acute, noninfectious lung disorder associated with high morbidity and mortality after hematopoietic cell transplantation. Previous studies have suggested a role for TNFα in the pathogenesis of IPS. We report a multicenter phase II trial investigating a soluble TNF-binding protein, etanercept (Enbrel, Amgen, Thousand Oaks, CA), for the treatment of pediatric patients with IPS. Eligible patients were < 18 years old, within 120 days after transplantation, and with radiographic evidence of a diffuse pneumonitis. All patients underwent a pretherapy broncho-alveolor lavage (BAL) to establish the diagnosis of IPS. Systemic corticosteroids (2.0 mg/kg/day) plus etanercept (.4 mg/kg twice weekly × 8 doses) were administered. Response was defined as survival and discontinuation of supplemental oxygen support by day 28 of study. Thirty-nine patients (median age, 11 years; range, 1 to 17) were enrolled, with 11 of 39 patients nonevaluable because of identification of pathogens from their pretherapy BAL. In the remaining 28 patients, the median fraction of inspired oxygen at study entry was 45%, with 17 of 28 requiring mechanical ventilation. Complete responses were seen in 20 (71%) patients, with a median time to response of 10 days (range, 1 to 24). Response rates were higher for patients not requiring mechanical ventilation at study entry (100% versus 53%, P = .01). Overall survival at 28 days and 1 year after therapy were 89% (95% confidence interval [CI], 70% to 96%) and 63% (95% CI, 42% to 79%), respectively. Plasma levels of proinflammatory cytokines were significantly increased at onset of therapy, subsequently decreasing in responding patients. The addition of etanercept to high-dose corticosteroids was associated with high response rates and survival in children with IPS.

Published
2015

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