TY - JOUR
T1 - Prognostic Biomarkers for Hepatic Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome in Myeloablative Allogeneic Hematopoietic Cell Transplantation
T2 - Results from the Blood and Marrow Transplant Clinical Trials Network 1202 Study
AU - Putta, Santosh
AU - Young, Bradford A.
AU - Levine, John E.
AU - Reshef, Ran
AU - Nakamura, Ryotaro
AU - Strouse, Christopher
AU - Perales, Miguel Angel
AU - Howard, Alan
AU - Pine, Polly
AU - Shi, Ju
AU - Zhang, Peixin
AU - Ho, Vincent T.
AU - Saber, Wael
N1 - Funding Information:
Conflict of interest statement: S.P. has consulted for Jazz Pharmaceuticals. B.A.Y. is the Senior Principal Consultant for B.A.Y. Strategic Consulting (dba B.A.Y. Biotech Consulting) and has consulted for Jazz Pharmaceuticals. J.E.L. has consulted for Bluebird Bio, Incyte, Jazz Pharmaceuticals, Mesoblast, Novartis, Omeros, OncoImmune, and Talaris. R.R. has consulted for Gilead, Bristol Myers Squibb, Novartis, Bayer, TScan, Regeneron, Synthekine, Jasper, and Atara. R.N. has served as an advisor to and received honoraria from Kadmon, Viracor, and Magenta; has consulted for NapaJen, Omeros, Bluebird Bio, and Jazz Pharmaceuticals; and has received institutional research funding from Miyarisan. C.S. has received honoraria from Bristol Myers Squibb. M-A.P. has received honoraria from AbbVie, Astellas, Bristol Myers Squibb, Celgene, Equilium, Incyte, Karyopharm, Kite/Gilead, Merck, Miltenyi Biotec, MorphoSys, Novartis, Nektar Therapeutics, Omeros, Takeda, VectivBio AG, and Vor Biopharma; serves on data safety and monitoring boards for Cidara Therapeutics, Medigene, Sellas Life Sciences, and Servier; serves on the scientific advisory board of NexImmune; has ownership interests in NexImmune and Omeros; has received research support for clinical trials from Incyte, Kite/Gilead, Miltenyi Biotec, and Novartis; and serves in a volunteer capacity as a member of the Board of Directors of the American Society for Transplantation and Cellular Therapy and Be The Match (National Marrow Donor Program), as well as on the Center for International Blood and Marrow Transplant Research Cellular Immunotherapy Data Resource Executive Committee. P.P. and J.S. are employees of and hold stock ownership in Jazz Pharmaceuticals. P.Z. was an employee of Jazz Pharmaceuticals at the time the study was conducted and holds stock and/or stock options in Jazz Pharmaceuticals. C.S. has received honoraria from Bristol Myers Squibb. V.T.H. has consulted for Jazz Pharmaceuticals, Janssen, Alexion, AlloVir, and Omeros Pharmaceuticals. A.H. and W.S. have no conflicts to disclose.
Funding Information:
Financial disclosure: This study was supported by Jazz Pharmaceuticals. Support for this study was also provided by Grants U10HL069294 and U24HL138660 to the Blood and Marrow Transplant Clinical Trials Network from the National Heart, Lung, and Blood Institute and the National Cancer Institute. The content of this study is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Medical writing and editorial assistance were provided by Oghenetega Umukoro, PhD, of Lumanity Scientific, Inc, and were financially supported by Jazz Pharmaceuticals.
Publisher Copyright:
© 2022 The American Society for Transplantation and Cellular Therapy
PY - 2023/3
Y1 - 2023/3
N2 - Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a potentially life-threatening complication of hematopoietic cell transplantation (HCT). This study aimed to determine a blood biomarker signature early post-HCT that identifies patients at high risk for VOD/SOS. A set of 23 plasma biomarkers, selected from the VOD/SOS literature, was measured on days 0, 7, and 14 after myeloablative HCT using blood samples from patients enrolled in the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) Protocol 1202. Eligible cases were diagnosed with VOD/SOS in BMT CTN 1202 using the Baltimore criteria. Controls (without VOD/SOS) were matched to cases for conditioning regimen and age. Significant biomarkers were identified using the Bonferroni-adjusted Wilcoxon rank-sum test (P ≤ .002). Thirty-three patients with mild or severe VOD/SOS were identified (cases) and matched to 107 controls. Two, 8, and 5 biomarkers measured from the plasma of these patients were significantly associated with the development of VOD/SOS at days 0, 7, and 14, respectively, with the strongest associations on days 7 and 14. Biomarker associations were stronger for severe VOD/SOS risk and were stronger prognostic markers for VOD/SOS cases occurring within 28 days of HCT. Hyaluronan was most strongly associated with VOD/SOS risk, with an area under the receiver operating characteristic curve (AUC) of .81 on day 7 and .79 on day 14. Multivariate models of up to 5 biomarkers generated AUCs ranging from .82 to .85. All associations with VOD/SOS risk were independent of clinical risk factors. This study confirms previously identified biomarkers of VOD/SOS risk and identified novel prognostic biomarker signatures that identify patients at risk for VOD/SOS shortly after HCT. Multivariate analysis suggests that a combination of up to 5 of these protein biomarkers may provide a prognostic tool for identifying patients at risk for VOD/SOS.
AB - Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a potentially life-threatening complication of hematopoietic cell transplantation (HCT). This study aimed to determine a blood biomarker signature early post-HCT that identifies patients at high risk for VOD/SOS. A set of 23 plasma biomarkers, selected from the VOD/SOS literature, was measured on days 0, 7, and 14 after myeloablative HCT using blood samples from patients enrolled in the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) Protocol 1202. Eligible cases were diagnosed with VOD/SOS in BMT CTN 1202 using the Baltimore criteria. Controls (without VOD/SOS) were matched to cases for conditioning regimen and age. Significant biomarkers were identified using the Bonferroni-adjusted Wilcoxon rank-sum test (P ≤ .002). Thirty-three patients with mild or severe VOD/SOS were identified (cases) and matched to 107 controls. Two, 8, and 5 biomarkers measured from the plasma of these patients were significantly associated with the development of VOD/SOS at days 0, 7, and 14, respectively, with the strongest associations on days 7 and 14. Biomarker associations were stronger for severe VOD/SOS risk and were stronger prognostic markers for VOD/SOS cases occurring within 28 days of HCT. Hyaluronan was most strongly associated with VOD/SOS risk, with an area under the receiver operating characteristic curve (AUC) of .81 on day 7 and .79 on day 14. Multivariate models of up to 5 biomarkers generated AUCs ranging from .82 to .85. All associations with VOD/SOS risk were independent of clinical risk factors. This study confirms previously identified biomarkers of VOD/SOS risk and identified novel prognostic biomarker signatures that identify patients at risk for VOD/SOS shortly after HCT. Multivariate analysis suggests that a combination of up to 5 of these protein biomarkers may provide a prognostic tool for identifying patients at risk for VOD/SOS.
KW - Biomarkers
KW - Defibrotide
KW - Sinusoidal obstruction syndrome
KW - Veno-occlusive disease
UR - http://www.scopus.com/inward/record.url?scp=85147115413&partnerID=8YFLogxK
U2 - 10.1016/j.jtct.2022.11.024
DO - 10.1016/j.jtct.2022.11.024
M3 - Article
C2 - 36574581
AN - SCOPUS:85147115413
SN - 2666-6375
VL - 29
SP - 166.e1-166.e10
JO - Transplantation and Cellular Therapy
JF - Transplantation and Cellular Therapy
IS - 3
ER -