INCIDENCE OF ADENOVIRUS INFECTIONS IN PEDIATRIC AND ADULT ALLOGENEIC HEMATOPOIETIC CELL TRANSPLANT RECIPIENTS IN EUROPE Sebastian Voigt, 1 Cécile Pochon, 2 Kanchan Rao, 3 Antonio Pérez-Martínez, 4 Marco Zecca, 5 Enrikas Vainorius, 6 Tom Brundage, 6 Artak Khachatryan, 7 Essy Mozaffari, 6 Garrett Nichols 6 1 Charité-Universitätsmedizin Berlin, Department of Pediatric Oncology/Hematology/Stem Cell Transplantation, Berlin, Germany; 2 University Hospital of Nancy, Allogeneic Hematopoietic Stem Cell Transplantation Unit, Department of Hematology, Vandoeuvre-lès-Nancy, France; 3 Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom; 4 Hospital Universidad Autónoma de Madrid, Madrid, Spain; 5 Fondazione IRCCS Policlinico San Matteo, Pediatric Hematology/Oncology, Pavia, Italy; 6 Chimerix, Durham, NC, United States; 7 Analytica-Laser, London, United Kingdom 1
Disclosures SV, CP, KR, APM, and MZ are investigators in the AdVance study sponsored by Chimerix EV, TB, EM, and GN are employees of the study sponsor, Chimerix AK is an employee of Analytica-Laser, a research consultancy who conducted the study on behalf of the sponsor, Chimerix 2
Allo-HCT recipients are at increased risk of viral infection Viral infections may lead to life-threatening conditions that further complicate the management of allogeneic-hematopoietic cell transplant (allo-hct) recipients 1,2 Pediatric allo-hct patients are at particularly high risk for development of adenovirus (AdV) infections 2 Current evidence regarding AdV epidemiology after allo-hct is generally limited to single-center studies 2,3 1 Lin R and Liu Q, J Hematol Oncol. 2013;6:94. 2 Lion T. Clin Microbiol Rev. 2014;27:441-62. 3 Ison M. Clin Infect Dis. 2006;43:331-9. 3
The AdVance study AdVance is a retrospective, multicenter, multinational study of the incidence, management, and clinical outcomes of AdV infection in allo-hct recipients Data were from transplants between January 2013 and September 2015 at participating centers Quantitative and qualitative data were extracted for AdV infection, AdV viremia, and AdV viremia 1000 copies/ml within 6 months of transplant 12 10 10 1 7 9 1 o Results were stratified by age (pediatric [<18 years] vs adult) 50 centers in total 4
Objectives As part of the AdVance study, the incidence of AdV infection was evaluated in pediatric and adult allo-hct recipients Other presentations of AdVance data at EBMT 2018: The next presentation will share data on the outcomes of AdV infection Two posters are also presenting AdVance results today: o B043 shares results of a practice patterns survey o B073 presents the impact of AdV infection on hospitalization duration among pediatric allo-hct recipients 5
Baseline characteristics for pediatric patients Sex Male 1099 (63%) Age Median years 7 Underlying condition Graft type Malignant 1111 (64%) Non-malignant immunodeficient Non-malignant immunocompetent 427 (25%) 200 (11%) Bone marrow 934 (54%) Peripheral blood stem cell 549 (31%) Cord blood 255 (15%) Donor type 1 Conditioning T-cell depletion Matched-related 490 (28%) Matched-unrelated 701 (40%) Mismatched 179 (10%) Haploidentical 270 (15%) Myeloablative 1481 (85%) Non-myeloablative 257 (15%) Ex-vivo 283 (16%) Serotherapy (ATG) 753 (43%) Serotherapy (Campath) 252 (15%) None 450 (26%) Patients were from centers in Italy (431 patients), UK (388), Spain (324), France (214), Germany (214), Netherlands (91), and Czech Republic (76) n recipients (%), unless otherwise stated. 1 Non-exclusive categories Allo-HCT recipients n=1738 6
Baseline characteristics for adult patients Sex Male 1462 (58%) Age Median years 51 Underlying condition Graft type Malignant 2477 (97%) Non-malignant immunodeficient Non-malignant immunocompetent n recipients (%), unless otherwise stated. 1 Non-exclusive categories 19 (1%) 42 (2%) Bone marrow 466 (18%) Peripheral blood stem cell 1880 (74%) Cord blood 192 (8%) Allo-HCT recipients n=2538 Donor type 1 Conditioning T-cell depletion Matched-related 902 (35%) Matched-unrelated 976 (38%) Mismatched 326 (13%) Haploidentical 290 (11%) Myeloablative 1710 (67%) Non-myeloablative 828 (33%) Ex-vivo 737 (29%) Serotherapy (ATG) 728 (29%) Serotherapy (Campath) 228 (9%) None 845 (33%) Patients were from centers in France (924 patients), Spain (743), Italy (359), UK (270), Germany (239), Netherlands (2), and Czech Republic (1) 7
1 in 3 pediatric HCT recipients had an AdV infection Pediatric allo-hct recipients n=1738 Any AdV infection 1 n=558 (32%) AdV viremia 1 n=395 (23%) 93% (519/558) of AdV infections were identified as part of routine screening practices See poster B043 for more details on practice patterns AdV viremia 1000 copies/ml 1 1000 n=241 (14%) Less than half of patients with AdV infection had viremia 1000 copies/ml 1 Within 6 months of transplant 8
2 in 5 had a concurrent dsdna viral infection 1000 Of 241 pediatric allo-hct recipients with AdV viremia 1000 copies/ml: 66% had 1 concurrent infection (bacterial/fungal/viral) 1 27% had CMV coinfection 1 dsdna viral coinfection 1 n=241 CMV 65 (27%) EBV 42 (17%) BKV 22 (9%) CMV, EBV, and/or BKV 103 (43%) n recipients (%). CMV, Cytomegalovirus; EBV, Epstein Barr virus; BKV, BK virus. 1 At the time of first AdV infection identification. Non-exclusive categories 9
6% of adult HCT recipients had an AdV infection Adult allo-hct recipients n=2538 Any AdV infection 1 n=141 (6%) AdV viremia 1 n=77 (3%) 72% (101/141) of AdV infections were identified as part of routine screening practices See poster B043 for more details on practice patterns AdV viremia 1000 copies/ml 1 1000 n=39 (2%) 1 Within 6 months of transplant 10
2 in 3 had a concurrent dsdna infection 1000 Of 39 adult allo-hct recipients with AdV viremia 1000 copies/ml: 79% had 1 concurrent infection (bacterial/fungal/viral) 1 Half (51%) had CMV coinfection 1 dsdna viral coinfection 1 n=39 CMV 20 (51%) EBV 9 (23%) BKV 9 (23%) CMV, EBV, and/or BKV 26 (67%) n recipients (%). CMV, Cytomegalovirus; EBV, Epstein Barr virus; BKV, BK virus. 1 At the time of first AdV infection identification. Non-exclusive categories 11
AdV viremia 1000 copies/ml develops more quickly in pediatric patients 1000 Pediatric Adult Median time to first AdV viremia 1000 copies/ml: 26 days (IQR: 13, 56) Median time to first AdV viremia 1000 copies/ml: 61 days (IQR: 33, 91) IQR, interquartile range (1 st, 4 th ) 12
Incidence of AdV viremia 1000 copies/ml in pediatrics by transplant characteristics The highest incidence was observed in patients with Campath serotherapy or a mismatched donor Underlying condition Graft type Pediatric allo-hct recipients with AdV viremia ( 1000 copies/ml); n=241 Malignant 148/1111 (13%) Non-malignant immunodeficient Non-malignant immunocompetent 72/427 (17%) 21/200 (10%) Bone marrow 116/934 (12%) Peripheral blood stem cell 92/549 (17%) Cord blood 33/255 (13%) Pediatric allo-hct recipients with AdV viremia ( 1000 copies/ml); n=241 Allo-HCT recipients with AdV viremia 1000 copies/ml n=241 n recipients with AdV viremia 1000 copies/ml/n with baseline characteristic (%) 1 Non-exclusive categories Donor type 1 Conditioning T-cell depletion Matched-related 33/490 (7%) Matched-unrelated 100/701 (14%) Mismatched 43/179 (24%) Haploidentical 49/270 (18%) Myeloablative 202/1481 (14%) Non-myeloablative 39/257 (15%) Ex-vivo 53/283 (19%) Serotherapy (ATG) 95/753 (13%) Serotherapy (Campath) 62/252 (25%) None 31/450 (7%) 1000 13
Age Age, donor type, and use of T-cell depletion were prognostic factors for AdV viremia 1000 copies/ml Pediatric allo-hct recipients 1000 Gender Conditioning Disease Donor type T-cell Depletion 14
Incidence of AdV viremia 1000 copies/ml in adults by transplant characteristics The highest incidence was observed in those with Campath serotherapy 1000 Underlying condition Graft type Adult allo-hct recipients with AdV viremia ( 1000 copies/ml); n=39 Malignant 38/2477 (2%) Non-malignant immunodeficient Non-malignant immunocompetent 1/19 (5%) 0/42 (0%) Bone marrow 6/466 (1%) Peripheral blood stem cell 29/1880 (2%) Cord blood 4/192 (2%) Donor type 1 Adult allo-hct recipients with AdV viremia ( 1000 copies/ml); n=39 Allo-HCT recipients with AdV viremia 1000 copies/ml n=39 n recipients with AdV viremia 1000 copies/ml/n with baseline characteristic (%) 1 Non-exclusive categories Conditioning T-cell depletion Matched-related 8/902 (1%) Matched-unrelated 19/976 (2%) Mismatched 10/326 (3%) Haploidentical 0/290 (0%) Myeloablative 21/1710 (1%) Non-myeloablative 18/828 (2%) Ex-vivo 9/737 (1%) Serotherapy (ATG) 8/728 (1%) Serotherapy (Campath) 16/228 (7%) None 6/845 (1%) 15
Age, donor type, and use of T-cell depletion were prognostic factors for AdV viremia 1000 copies/ml Adult and pediatric allo-hct recipients Stepwise reduction in risk with increasing age Age 1000 16
Conclusions Pediatric Pediatric allo-hct recipients are screened routinely, with 1 in 3 (32%) having an identified AdV infection in the 6 months following their transplant 23% of recipients developed AdV viremia Just less than half of those with an AdV infection (14%) had AdV viremia 1000 copies/ml dsdna viral coinfection was common Adult Adult allo-hct recipients are less routinely screened 6% of recipients had an identified AdV infection in the 6 months following their transplant 3% developed AdV viremia 2% had AdV viremia 1000 copies/ml dsdna viral coinfection was common 17
Conclusions Pediatric and adult Adult Patient age was an independent predictor of AdV viremia 1000 copies/ml in the 6-months following allo-hct T-cell depletion and donor type are also independent risk factors These results suggest a need for re-examination of screening approaches, particularly for younger and at-risk adults 18
The AdVance centers FRANCE (10) Robert Debré Hospital, Paris CHU Angers Institut of Hematology, Lyon CHU Nancy CHU Montpellier CHU Bordeaux CHU Lyon CHU Nantes Saint Louis Hospital, Paris CHU Nice SPAIN (12) Hospital Universitario y Politécnico La Fe (2) Hospital Universitario 12 de Octubre Hospital Universitario La Paz Hospital Universitario de Salamanca Hospital Universitario Vall d'hebrón Hospital de la Santa Creu i Sant Pau (2) Hospital Universitario Reina Sofía Hospital Regional Universitario de Málaga Hospital Infantil Universitario Niño Jesús Hospital General Universitario Morales Meseguer ITALY (9) Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Centro Trapianti Midollo Osseo, Milano Hospital Casa Sollievo Sofferenza, San Giovanni Rotondo Azienda Ospedale Riuniti e Morelli Bianchi-Melacrino Centro Unico Regionale Trapianti Cellule Staminali e Terapia Cellulare, Reggio Calabria Pediatric Hematology/Oncology Department Policlinico San Matteo, Pavia GERMANY (7) Charité Campus Virchow Klinikum J. W. Goethe Universität Medizinische Hochschule Hannover Universitätsklinikum Jena Universitätsklinikum Köln Universitätsklinik Tübingen Klinikum der Universität München (LMU) UK (10) Royal Manchester Children's Hospital Bristol Royal Children s Hospital Sheffield Children's Hospital St. James's University Hospital and The General Infirmary, Leeds Great North Children's Hospital, Newcastle The NETHERLANDS (1) UMC Utrecht CZECH REPUBLIC (1) Hospital Motol, Praha 19 Great Ormond Street Hospital, London University College London Hospitals, University Hospital of Wales Cardiff The Royal Marsden Hospital, London Birmingham Children s Hospital Ospedale Civile Centro Trapianti Midollo Osseo Dip. Ematologia Medicina Trasfusionale e Biotecnologie, Pescara Pediatric Hematology/Oncology Department San Gerardo Hospital, Monza S.C. Oncoematologia Pediatrica e Centro Trapianti Regina Margherita, Torino Oncoematologia e TMO, Ospedale 'La Maddalena' Palermo Ospedale Bambin Gesù-Dip. Oncoematologia Pediatrica e Medicina Transfusionale, Roma