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INCIDENCE OF ADENOVIRUS INFECTIONS IN PEDIATRIC AND ADULT ALLOGENEIC

HEMATOPOIETIC CELL TRANSPLANT RECIPIENTS IN EUROPE

Sebastian Voigt,1 Cécile Pochon,2 Kanchan Rao,3Antonio Pérez-Martínez,4 Marco Zecca,5 Enrikas Vainorius,6 Tom Brundage,6

Artak Khachatryan,7 Essy Mozaffari,6 Garrett Nichols6

1Charité-Universitätsmedizin Berlin, Department of Pediatric Oncology/Hematology/Stem Cell Transplantation, Berlin, Germany; 2University Hospital of Nancy, Allogeneic Hematopoietic Stem Cell Transplantation Unit, Department of Hematology, Vandoeuvre-lès-Nancy, France;

3Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom; 4Hospital Universidad Autónoma de Madrid, Madrid, Spain;

5Fondazione IRCCS Policlinico San Matteo, Pediatric Hematology/Oncology, Pavia, Italy; 6Chimerix, Durham, NC, United States;

7Analytica-Laser, London, United Kingdom

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

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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) recipients1,2

Pediatric allo-HCT patients are at particularly high risk for development of adenovirus (AdV) infections2

Current evidence regarding AdV epidemiology after allo-HCT is generally limited to single-center studies2,3

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1Lin R and Liu Q, J Hematol Oncol. 2013;6:94. 2Lion T. Clin Microbiol Rev. 2014;27:441-62. 3Ison M. Clin Infect Dis. 2006;43:331-9.

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 transplanto Results were stratified by age

(pediatric [<18 years] vs adult)

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10

12

9

10

17

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50 centers in total

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

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Baseline characteristics for pediatric patients

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Sex Male 1099 (63%)

Age Median years 7

Underlying condition

Malignant 1111 (64%)

Non-malignantimmunodeficient 427 (25%)

Non-malignant immunocompetent 200 (11%)

Graft type

Bone marrow 934 (54%)

Peripheral blood stem cell 549 (31%)

Cord blood 255 (15%)

Donor type1

Matched-related 490 (28%)

Matched-unrelated 701 (40%)

Mismatched 179 (10%)

Haploidentical 270 (15%)

ConditioningMyeloablative 1481 (85%)

Non-myeloablative 257 (15%)

T-cell depletion

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. 1Non-exclusive categories

Allo-HCT recipients n=1738

Baseline characteristics for adult patients

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n recipients (%), unless otherwise stated. 1Non-exclusive categories

Sex Male 1462 (58%)

Age Median years 51

Underlying condition

Malignant 2477 (97%)

Non-malignantimmunodeficient 19 (1%)

Non-malignant immunocompetent 42 (2%)

Graft type

Bone marrow 466 (18%)

Peripheral blood stem cell 1880 (74%)

Cord blood 192 (8%)

Donor type1

Matched-related 902 (35%)

Matched-unrelated 976 (38%)

Mismatched 326 (13%)

Haploidentical 290 (11%)

ConditioningMyeloablative 1710 (67%)

Non-myeloablative 828 (33%)

T-cell depletion

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)

Allo-HCT recipients n=2538

Pediatric allo-HCT recipientsn=1738

Any AdV infection1

n=558 (32%)

AdV viremia1

n=395 (23%)

AdV viremia ≥1000 copies/mL1

n=241 (14%)≥1000

1 in 3 pediatric HCT recipients had an AdV infection

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1Within 6 months of transplant

93% (519/558) of AdV infections were identified as part of routine screening practices

• See poster B043 for more details on practice patterns

Less than half of patients with AdV infection had viremia ≥1000 copies/mL

2 in 5 had a concurrent dsDNA viral infection

Of 241 pediatric allo-HCT recipients with AdV viremia ≥1000 copies/mL:• 66% had ≥1 concurrent infection (bacterial/fungal/viral)1

• 27% had CMV coinfection1

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dsDNA viral coinfection1

n=241CMV 65 (27%)EBV 42 (17%)BKV 22 (9%)CMV, EBV, and/or BKV 103 (43%)

≥1000

n recipients (%). CMV, Cytomegalovirus; EBV, Epstein–Barr virus; BKV, BK virus. 1At the time of first AdV infection identification. Non-exclusive categories

Adult allo-HCT recipientsn=2538

Any AdV infection1

n=141 (6%)

AdV viremia1

n=77 (3%)

AdV viremia ≥1000 copies/mL1

n=39 (2%)

6% of adult HCT recipients had an AdV infection

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1Within 6 months of transplant

≥1000

72% (101/141) of AdV infections were identified as part of routine screening practices

• See poster B043 for more details on practice patterns

2 in 3 had a concurrent dsDNA infection

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 coinfection1

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dsDNA viral coinfection1

n=39CMV 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. 1At the time of first AdV infection identification. Non-exclusive categories

≥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)

AdV viremia ≥1000 copies/mL develops more quickly in pediatric patients

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IQR, interquartile range (1st, 4th)

≥1000

Incidence of AdV viremia ≥1000 copies/mL in pediatrics by transplant characteristics

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The highest incidence was observed in patients with Campath serotherapy or a mismatched donor

Pediatric allo-HCT recipients with AdV viremia (≥1000 copies/mL); n=241

Underlying condition

Malignant 148/1111 (13%)

Non-malignantimmunodeficient 72/427 (17%)

Non-malignant immunocompetent 21/200 (10%)

Graft type

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

Donor type1

Matched-related 33/490 (7%)

Matched-unrelated 100/701 (14%)

Mismatched 43/179 (24%)

Haploidentical 49/270 (18%)

ConditioningMyeloablative 202/1481 (14%)

Non-myeloablative 39/257 (15%)

T-cell depletion

Ex-vivo 53/283 (19%)

Serotherapy (ATG) 95/753 (13%)

Serotherapy (Campath) 62/252 (25%)

None 31/450 (7%)n recipients with AdV viremia ≥1000 copies/mL/n with baseline characteristic (%) 1Non-exclusive categories

≥1000

Allo-HCT recipients with AdV viremia ≥1000 copies/mL n=241

Age, donor type, and use of T-cell depletion were prognostic factors for AdV viremia ≥1000 copies/mL

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≥1000

Pediatric allo-HCT recipientsAge

Disease

Donor type

T-cell Depletion

Conditioning

Gender

Incidence of AdV viremia ≥1000 copies/mL in adults by transplant characteristics

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The highest incidence was observed in those with Campath serotherapy

Adult allo-HCT recipients with AdV viremia (≥1000 copies/mL); n=39

Underlying condition

Malignant 38/2477 (2%)

Non-malignantimmunodeficient 1/19 (5%)

Non-malignant immunocompetent 0/42 (0%)

Graft type

Bone marrow 6/466 (1%)

Peripheral blood stem cell 29/1880 (2%)

Cord blood 4/192 (2%)

Adult allo-HCT recipients with AdV viremia (≥1000 copies/mL); n=39

Donor type1

Matched-related 8/902 (1%)

Matched-unrelated 19/976 (2%)

Mismatched 10/326 (3%)

Haploidentical 0/290 (0%)

ConditioningMyeloablative 21/1710 (1%)

Non-myeloablative 18/828 (2%)

T-cell depletion

Ex-vivo 9/737 (1%)

Serotherapy (ATG) 8/728 (1%)

Serotherapy (Campath) 16/228 (7%)

None 6/845 (1%)n recipients with AdV viremia ≥1000 copies/mL/n with baseline characteristic (%) 1Non-exclusive categories

≥1000

Allo-HCT recipients with AdV viremia ≥1000 copies/mL n=39

Age, donor type, and use of T-cell depletion were prognostic factors for AdV viremia ≥1000 copies/mL

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≥1000

Stepwise reduction in risk with increasing age

Adult and pediatric allo-HCT recipients

Age

Conclusions

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Pediatric allo-HCT recipients are screened routinely, with 1 in 3 (32%) having an identified AdV infection in the 6 months following their transplant23% of recipients developed AdV

viremiaJust less than half of those with an

AdV infection (14%) had AdV viremia ≥1000 copies/mL

• dsDNA viral coinfection was common

Adult allo-HCT recipients are less routinely screened6% of recipients had an identified AdV

infection in the 6 months following their transplant3% developed AdV viremia2% had AdV viremia ≥1000 copies/mL • dsDNA viral coinfection was common

Pediatric Adult

Conclusions

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AdultPediatric and 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

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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

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

• Great Ormond Street Hospital, London

• University College London Hospitals,

• University Hospital of Wales Cardiff

• The Royal Marsden Hospital, London

• Birmingham Children’s Hospital

The NETHERLANDS (1)• UMC Utrecht

GERMANY (7)• Charité Campus Virchow Klinikum• J. W. Goethe Universität• Medizinische Hochschule Hannover• Universitätsklinikum Jena• Universitätsklinikum Köln• Universitätsklinik Tübingen• Klinikum der Universität München (LMU)

CZECH REPUBLIC (1)• Hospital Motol, Praha

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

• 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

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

The AdVance centers