Characteristics of Late Fatal Infections after Allogeneic Hematopoietic Cell Transplantation

Maxim Norkin; Bronwen E. Shaw; Ruta Brazauskas; Heather R. Tecca; Helen L. Leather; Juan Gea-Banacloche; Rammurti T. Kamble; Zachariah DeFilipp; David A. Jacobsohn; Olle Ringden; Yoshihiro Inamoto; Kimberly A. Kasow; David Buchbinder; Peter Shaw; Peiman Hematti; Raquel Schears; Sherif M. Badawy; Hillard M. Lazarus; Neel Bhatt; Biljana Horn; Saurabh Chhabra; Kristin M. Page; Betty Hamilton; Gerhard C. Hildebrandt; Jean A. Yared; Vaibhav Agrawal; Amer M. Beitinjaneh; Navneet Majhail; Tamila Kindwall-Keller; Richard F. Olsson; Helene Schoemans; Robert Peter Gale; Siddhartha Ganguly; Ibrahim A. Ahmed; Harry C. Schouten; Jane L. Liesveld; Nandita Khera; Amir Steinberg; Ami J. Shah; Melhem Solh; David I. Marks; Witold Rybka; Mahmoud Aljurf; Andrew C. Dietz; Usama Gergis; Biju George; Sachiko Seo; Mary E.D. Flowers; Minoo Battiwalla; Bipin N. Savani; Marcie L. Riches; John R. Wingard

doi:10.1016/j.bbmt.2018.09.031

Characteristics of Late Fatal Infections after Allogeneic Hematopoietic Cell Transplantation

Maxim Norkin, Bronwen E. Shaw, Ruta Brazauskas, Heather R. Tecca, Helen L. Leather, Juan Gea-Banacloche, Rammurti T. Kamble, Zachariah DeFilipp, David A. Jacobsohn, Olle Ringden, Yoshihiro Inamoto, Kimberly A. Kasow, David Buchbinder, Peter Shaw, Peiman Hematti, Raquel Schears, Sherif M. Badawy, Hillard M. Lazarus, Neel Bhatt, Biljana HornSaurabh Chhabra, Kristin M. Page, Betty Hamilton, Gerhard C. Hildebrandt, Jean A. Yared, Vaibhav Agrawal, Amer M. Beitinjaneh, Navneet Majhail, Tamila Kindwall-Keller, Richard F. Olsson, Helene Schoemans, Robert Peter Gale, Siddhartha Ganguly, Ibrahim A. Ahmed, Harry C. Schouten, Jane L. Liesveld, Nandita Khera, Amir Steinberg, Ami J. Shah, Melhem Solh, David I. Marks, Witold Rybka, Mahmoud Aljurf, Andrew C. Dietz, Usama Gergis, Biju George, Sachiko Seo, Mary E.D. Flowers, Minoo Battiwalla, Bipin N. Savani, Marcie L. Riches, John R. Wingard

Internal Medicine

Research output: Contribution to journal › Article › peer-review

44 Scopus citations

Abstract

We analyzed late fatal infections (LFIs) in allogeneic stem cell transplantation (HCT) recipients reported to the Center for International Blood and Marrow Transplant Research. We analyzed the incidence, infection types, and risk factors contributing to LFI in 10,336 adult and 5088 pediatric subjects surviving for ≥2 years after first HCT without relapse. Among 2245 adult and 377 pediatric patients who died, infections were a primary or contributory cause of death in 687 (31%) and 110 (29%), respectively. At 12 years post-HCT, the cumulative incidence of LFIs was 6.4% (95% confidence interval [CI], 5.8% to 7.0%) in adults, compared with 1.8% (95% CI, 1.4% to 2.3%) in pediatric subjects; P <.001). In adults, the 2 most significant risks for developing LFI were increasing age (20 to 39, 40 to 54, and ≥55 years versus 18 to 19 years) with hazard ratios (HRs) of 3.12 (95% CI, 1.33 to 7.32), 3.86 (95% CI, 1.66 to 8.95), and 5.49 (95% CI, 2.32 to 12.99) and a history of chronic graft-versus-host disease GVHD (cGVHD) with ongoing immunosuppression at 2 years post-HCT compared with no history of GVHD with (HR, 3.87; 95% CI, 2.59 to 5.78). In pediatric subjects, the 3 most significant risks for developing LFI were a history of cGVHD with ongoing immunosuppression (HR, 9.49; 95% CI, 4.39 to 20.51) or without ongoing immunosuppression (HR, 2.7; 95% CI, 1.05 to 7.43) at 2 years post-HCT compared with no history of GVHD, diagnosis of inherited abnormalities of erythrocyte function compared with diagnosis of acute myelogenous leukemia (HR, 2.30; 95% CI, 1.19 to 4.42), and age >10 years (HR, 1.92; 95% CI, 1.15 to 3.2). This study emphasizes the importance of continued vigilance for late infections after HCT and institution of support strategies aimed at decreasing the risk of cGVHD.

Original language	English
Pages (from-to)	362-368
Number of pages	7
Journal	Biology of Blood and Marrow Transplantation
Volume	25
Issue number	2
DOIs	https://doi.org/10.1016/j.bbmt.2018.09.031
State	Published - Feb 2019

Bibliographical note

Publisher Copyright:
© 2018

Funding

Financial disclosure: The CIBMTR is supported primarily by Public Health Service Grant/Cooperative Agreement 5U24CA076518 from the National Cancer Institute (NCI), the National Heart, Lung and Blood Institute (NHLBI), and the National Institute of Allergy and Infectious Diseases; Grant/Cooperative Agreement 4U10HL069294 from the NHLBI and NCI; Contract HHSH250201200016C with the Health Resources and Services Administration; Grants N00014-17-1-2388 and N0014-17-1-2850 from the Office of Naval Research; and grants from *Actinium Pharmaceuticals; *Amgen; *Amneal Biosciences; *Angiocrine Bioscience; Anonymous donation to the Medical College of Wisconsin; Astellas Pharma US; Atara Biotherapeutics; Be the Match Foundation; *bluebird bio; *Bristol Myers Squibb Oncology; *Celgene; Cerus; *Chimerix; Fred Hutchinson Cancer Research Center; Gamida Cell; Gilead Sciences; HistoGenetics; Immucor; *Incyte; Janssen Scientific Affairs; *Jazz Pharmaceuticals; Juno Therapeutics; Karyopharm Therapeutics; Kite Pharma; Medac; MedImmune; Medical College of Wisconsin; *Mediware; *Merck & Company; *Mesoblast; MesoScale Diagnostics; Millennium, the Takeda Oncology Company; *Miltenyi Biotec; National Marrow Donor Program; *Neovii Biotech NA; Novartis Pharmaceuticals; Otsuka Pharmaceuticals; PCORI; *Pfizer; *Pharmacyclics; PIRCHE; *Sanofi Genzyme; *Seattle Genetics; Shire; Spectrum Pharmaceuticals; St. Baldrick's Foundation; *Sunesis Pharmaceuticals; Swedish Orphan Biovitrum; Takeda Oncology; Telomere Diagnostics; and University of Minnesota. The views expressed in this article do not reflect the official policies or positions of the National Institutes of Health, Department of the Navy, Department of Defense, Health Resources and Services Administration, or any other agency of the US Government. *Corporate members. Conflict of interest statement: There are no conflicts of interest to report. Authorship statement: M.N., B.E.S., R.B., H.R.T., M.E.F., M.B., B.N.S., M.L.R., J.G.B., and J.R.W. designed the study and interpreted the results. R.B. and H.R.T. performed data analysis. All authors participated in writing and reviewing the manuscript. Financial disclosure: The CIBMTR is supported primarily by Public Health Service Grant/Cooperative Agreement 5U24CA076518 from the National Cancer Institute (NCI), the National Heart, Lung and Blood Institute (NHLBI), and the National Institute of Allergy and Infectious Diseases; Grant/Cooperative Agreement 4U10HL069294 from the NHLBI and NCI; Contract HHSH250201200016C with the Health Resources and Services Administration; Grants N00014-17-1-2388 and N0014-17-1-2850 from the Office of Naval Research; and grants from *Actinium Pharmaceuticals; *Amgen; *Amneal Biosciences; *Angiocrine Bioscience; Anonymous donation to the Medical College of Wisconsin; Astellas Pharma US; Atara Biotherapeutics; Be the Match Foundation; *bluebird bio; *Bristol Myers Squibb Oncology; *Celgene; Cerus; *Chimerix; Fred Hutchinson Cancer Research Center; Gamida Cell; Gilead Sciences; HistoGenetics; Immucor; *Incyte; Janssen Scientific Affairs; *Jazz Pharmaceuticals; Juno Therapeutics; Karyopharm Therapeutics; Kite Pharma; Medac; MedImmune; Medical College of Wisconsin; *Mediware; *Merck & Company; *Mesoblast; MesoScale Diagnostics; Millennium, the Takeda Oncology Company; *Miltenyi Biotec; National Marrow Donor Program; *Neovii Biotech NA; Novartis Pharmaceuticals; Otsuka Pharmaceuticals; PCORI; *Pfizer; *Pharmacyclics; PIRCHE; *Sanofi Genzyme; *Seattle Genetics; Shire; Spectrum Pharmaceuticals; St. Baldrick's Foundation; *Sunesis Pharmaceuticals; Swedish Orphan Biovitrum; Takeda Oncology; Telomere Diagnostics; and University of Minnesota. The views expressed in this article do not reflect the official policies or positions of the National Institutes of Health, Department of the Navy, Department of Defense, Health Resources and Services Administration, or any other agency of the US Government.

Funders	Funder number
Amneal Biosciences, *Angiocrine Bioscience
Angiocrine Bioscience
Department of the Navy
US Government Accountability Office
National Institutes of Health (NIH)
U.S. Department of Defense
Office of Naval Research Naval Academy
National Heart, Lung, and Blood Institute (NHLBI)
National Childhood Cancer Registry – National Cancer Institute	U24CA076518
National Childhood Cancer Registry – National Cancer Institute
National Institute of Allergy and Infectious Diseases	HHSH250201200016C, N00014-17-1-2388, N0014-17-1-2850, 4U10HL069294
National Institute of Allergy and Infectious Diseases
Health Resources and Services Administration
Minnesota State University-Mankato
Actinium Pharmaceuticals Incorporated

Keywords

Adults
Hematopoietic cell transplantation
Infection
Late fatal infection
Pediatrics

ASJC Scopus subject areas

Hematology
Transplantation

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10.1016/j.bbmt.2018.09.031

Cite this

Norkin, M., Shaw, B. E., Brazauskas, R., Tecca, H. R., Leather, H. L., Gea-Banacloche, J., T. Kamble, R., DeFilipp, Z., Jacobsohn, D. A., Ringden, O., Inamoto, Y., A. Kasow, K., Buchbinder, D., Shaw, P., Hematti, P., Schears, R., Badawy, S. M., Lazarus, H. M., Bhatt, N., ... Wingard, J. R. (2019). Characteristics of Late Fatal Infections after Allogeneic Hematopoietic Cell Transplantation. Biology of Blood and Marrow Transplantation, 25(2), 362-368. https://doi.org/10.1016/j.bbmt.2018.09.031

@article{8e1666af86c6452aaf3c3849efe2250a,

title = "Characteristics of Late Fatal Infections after Allogeneic Hematopoietic Cell Transplantation",

abstract = "We analyzed late fatal infections (LFIs) in allogeneic stem cell transplantation (HCT) recipients reported to the Center for International Blood and Marrow Transplant Research. We analyzed the incidence, infection types, and risk factors contributing to LFI in 10,336 adult and 5088 pediatric subjects surviving for ≥2 years after first HCT without relapse. Among 2245 adult and 377 pediatric patients who died, infections were a primary or contributory cause of death in 687 (31\%) and 110 (29\%), respectively. At 12 years post-HCT, the cumulative incidence of LFIs was 6.4\% (95\% confidence interval [CI], 5.8\% to 7.0\%) in adults, compared with 1.8\% (95\% CI, 1.4\% to 2.3\%) in pediatric subjects; P <.001). In adults, the 2 most significant risks for developing LFI were increasing age (20 to 39, 40 to 54, and ≥55 years versus 18 to 19 years) with hazard ratios (HRs) of 3.12 (95\% CI, 1.33 to 7.32), 3.86 (95\% CI, 1.66 to 8.95), and 5.49 (95\% CI, 2.32 to 12.99) and a history of chronic graft-versus-host disease GVHD (cGVHD) with ongoing immunosuppression at 2 years post-HCT compared with no history of GVHD with (HR, 3.87; 95\% CI, 2.59 to 5.78). In pediatric subjects, the 3 most significant risks for developing LFI were a history of cGVHD with ongoing immunosuppression (HR, 9.49; 95\% CI, 4.39 to 20.51) or without ongoing immunosuppression (HR, 2.7; 95\% CI, 1.05 to 7.43) at 2 years post-HCT compared with no history of GVHD, diagnosis of inherited abnormalities of erythrocyte function compared with diagnosis of acute myelogenous leukemia (HR, 2.30; 95\% CI, 1.19 to 4.42), and age >10 years (HR, 1.92; 95\% CI, 1.15 to 3.2). This study emphasizes the importance of continued vigilance for late infections after HCT and institution of support strategies aimed at decreasing the risk of cGVHD.",

keywords = "Adults, Hematopoietic cell transplantation, Infection, Late fatal infection, Pediatrics",

author = "Maxim Norkin and Shaw, \{Bronwen E.\} and Ruta Brazauskas and Tecca, \{Heather R.\} and Leather, \{Helen L.\} and Juan Gea-Banacloche and \{T. Kamble\}, Rammurti and Zachariah DeFilipp and Jacobsohn, \{David A.\} and Olle Ringden and Yoshihiro Inamoto and \{A. Kasow\}, Kimberly and David Buchbinder and Peter Shaw and Peiman Hematti and Raquel Schears and Badawy, \{Sherif M.\} and Lazarus, \{Hillard M.\} and Neel Bhatt and Biljana Horn and Saurabh Chhabra and \{M. Page\}, Kristin and Betty Hamilton and Hildebrandt, \{Gerhard C.\} and Yared, \{Jean A.\} and Vaibhav Agrawal and \{M. Beitinjaneh\}, Amer and Navneet Majhail and Tamila Kindwall-Keller and Olsson, \{Richard F.\} and Helene Schoemans and Gale, \{Robert Peter\} and Siddhartha Ganguly and \{A. Ahmed\}, Ibrahim and Schouten, \{Harry C.\} and \{L. Liesveld\}, Jane and Nandita Khera and Amir Steinberg and Shah, \{Ami J.\} and Melhem Solh and Marks, \{David I.\} and Witold Rybka and Mahmoud Aljurf and Dietz, \{Andrew C.\} and Usama Gergis and Biju George and Sachiko Seo and Flowers, \{Mary E.D.\} and Minoo Battiwalla and Savani, \{Bipin N.\} and Riches, \{Marcie L.\} and Wingard, \{John R.\}",

note = "Publisher Copyright: {\textcopyright} 2018",

year = "2019",

month = feb,

doi = "10.1016/j.bbmt.2018.09.031",

language = "English",

volume = "25",

pages = "362--368",

number = "2",

}

Norkin, M, Shaw, BE, Brazauskas, R, Tecca, HR, Leather, HL, Gea-Banacloche, J, T. Kamble, R, DeFilipp, Z, Jacobsohn, DA, Ringden, O, Inamoto, Y, A. Kasow, K, Buchbinder, D, Shaw, P, Hematti, P, Schears, R, Badawy, SM, Lazarus, HM, Bhatt, N, Horn, B, Chhabra, S, M. Page, K, Hamilton, B, Hildebrandt, GC, Yared, JA, Agrawal, V, M. Beitinjaneh, A, Majhail, N, Kindwall-Keller, T, Olsson, RF, Schoemans, H, Gale, RP, Ganguly, S, A. Ahmed, I, Schouten, HC, L. Liesveld, J, Khera, N, Steinberg, A, Shah, AJ, Solh, M, Marks, DI, Rybka, W, Aljurf, M, Dietz, AC, Gergis, U, George, B, Seo, S, Flowers, MED, Battiwalla, M, Savani, BN, Riches, ML & Wingard, JR 2019, 'Characteristics of Late Fatal Infections after Allogeneic Hematopoietic Cell Transplantation', Biology of Blood and Marrow Transplantation, vol. 25, no. 2, pp. 362-368. https://doi.org/10.1016/j.bbmt.2018.09.031

TY - JOUR

T1 - Characteristics of Late Fatal Infections after Allogeneic Hematopoietic Cell Transplantation

AU - Norkin, Maxim

AU - Shaw, Bronwen E.

AU - Brazauskas, Ruta

AU - Tecca, Heather R.

AU - Leather, Helen L.

AU - Gea-Banacloche, Juan

AU - T. Kamble, Rammurti

AU - DeFilipp, Zachariah

AU - Jacobsohn, David A.

AU - Ringden, Olle

AU - Inamoto, Yoshihiro

AU - A. Kasow, Kimberly

AU - Buchbinder, David

AU - Shaw, Peter

AU - Hematti, Peiman

AU - Schears, Raquel

AU - Badawy, Sherif M.

AU - Lazarus, Hillard M.

AU - Bhatt, Neel

AU - Horn, Biljana

AU - Chhabra, Saurabh

AU - M. Page, Kristin

AU - Hamilton, Betty

AU - Hildebrandt, Gerhard C.

AU - Yared, Jean A.

AU - Agrawal, Vaibhav

AU - M. Beitinjaneh, Amer

AU - Majhail, Navneet

AU - Kindwall-Keller, Tamila

AU - Olsson, Richard F.

AU - Schoemans, Helene

AU - Gale, Robert Peter

AU - Ganguly, Siddhartha

AU - A. Ahmed, Ibrahim

AU - Schouten, Harry C.

AU - L. Liesveld, Jane

AU - Khera, Nandita

AU - Steinberg, Amir

AU - Shah, Ami J.

AU - Solh, Melhem

AU - Marks, David I.

AU - Rybka, Witold

AU - Aljurf, Mahmoud

AU - Dietz, Andrew C.

AU - Gergis, Usama

AU - George, Biju

AU - Seo, Sachiko

AU - Flowers, Mary E.D.

AU - Battiwalla, Minoo

AU - Savani, Bipin N.

AU - Riches, Marcie L.

AU - Wingard, John R.

PY - 2019/2

Y1 - 2019/2

N2 - We analyzed late fatal infections (LFIs) in allogeneic stem cell transplantation (HCT) recipients reported to the Center for International Blood and Marrow Transplant Research. We analyzed the incidence, infection types, and risk factors contributing to LFI in 10,336 adult and 5088 pediatric subjects surviving for ≥2 years after first HCT without relapse. Among 2245 adult and 377 pediatric patients who died, infections were a primary or contributory cause of death in 687 (31%) and 110 (29%), respectively. At 12 years post-HCT, the cumulative incidence of LFIs was 6.4% (95% confidence interval [CI], 5.8% to 7.0%) in adults, compared with 1.8% (95% CI, 1.4% to 2.3%) in pediatric subjects; P <.001). In adults, the 2 most significant risks for developing LFI were increasing age (20 to 39, 40 to 54, and ≥55 years versus 18 to 19 years) with hazard ratios (HRs) of 3.12 (95% CI, 1.33 to 7.32), 3.86 (95% CI, 1.66 to 8.95), and 5.49 (95% CI, 2.32 to 12.99) and a history of chronic graft-versus-host disease GVHD (cGVHD) with ongoing immunosuppression at 2 years post-HCT compared with no history of GVHD with (HR, 3.87; 95% CI, 2.59 to 5.78). In pediatric subjects, the 3 most significant risks for developing LFI were a history of cGVHD with ongoing immunosuppression (HR, 9.49; 95% CI, 4.39 to 20.51) or without ongoing immunosuppression (HR, 2.7; 95% CI, 1.05 to 7.43) at 2 years post-HCT compared with no history of GVHD, diagnosis of inherited abnormalities of erythrocyte function compared with diagnosis of acute myelogenous leukemia (HR, 2.30; 95% CI, 1.19 to 4.42), and age >10 years (HR, 1.92; 95% CI, 1.15 to 3.2). This study emphasizes the importance of continued vigilance for late infections after HCT and institution of support strategies aimed at decreasing the risk of cGVHD.

AB - We analyzed late fatal infections (LFIs) in allogeneic stem cell transplantation (HCT) recipients reported to the Center for International Blood and Marrow Transplant Research. We analyzed the incidence, infection types, and risk factors contributing to LFI in 10,336 adult and 5088 pediatric subjects surviving for ≥2 years after first HCT without relapse. Among 2245 adult and 377 pediatric patients who died, infections were a primary or contributory cause of death in 687 (31%) and 110 (29%), respectively. At 12 years post-HCT, the cumulative incidence of LFIs was 6.4% (95% confidence interval [CI], 5.8% to 7.0%) in adults, compared with 1.8% (95% CI, 1.4% to 2.3%) in pediatric subjects; P <.001). In adults, the 2 most significant risks for developing LFI were increasing age (20 to 39, 40 to 54, and ≥55 years versus 18 to 19 years) with hazard ratios (HRs) of 3.12 (95% CI, 1.33 to 7.32), 3.86 (95% CI, 1.66 to 8.95), and 5.49 (95% CI, 2.32 to 12.99) and a history of chronic graft-versus-host disease GVHD (cGVHD) with ongoing immunosuppression at 2 years post-HCT compared with no history of GVHD with (HR, 3.87; 95% CI, 2.59 to 5.78). In pediatric subjects, the 3 most significant risks for developing LFI were a history of cGVHD with ongoing immunosuppression (HR, 9.49; 95% CI, 4.39 to 20.51) or without ongoing immunosuppression (HR, 2.7; 95% CI, 1.05 to 7.43) at 2 years post-HCT compared with no history of GVHD, diagnosis of inherited abnormalities of erythrocyte function compared with diagnosis of acute myelogenous leukemia (HR, 2.30; 95% CI, 1.19 to 4.42), and age >10 years (HR, 1.92; 95% CI, 1.15 to 3.2). This study emphasizes the importance of continued vigilance for late infections after HCT and institution of support strategies aimed at decreasing the risk of cGVHD.

KW - Adults

KW - Hematopoietic cell transplantation

KW - Infection

KW - Late fatal infection

KW - Pediatrics

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UR - http://www.scopus.com/inward/citedby.url?scp=85055972080&partnerID=8YFLogxK

U2 - 10.1016/j.bbmt.2018.09.031

DO - 10.1016/j.bbmt.2018.09.031

M3 - Article

C2 - 30287390

AN - SCOPUS:85055972080

SN - 1083-8791

VL - 25

SP - 362

EP - 368

JO - Biology of Blood and Marrow Transplantation

JF - Biology of Blood and Marrow Transplantation

IS - 2

ER -

Characteristics of Late Fatal Infections after Allogeneic Hematopoietic Cell Transplantation

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