Abstract
Biological markers for risk stratification of chronic GvHD (cGvHD) could improve the care of patients undergoing allogeneic hematopoietic stem cell transplantation. Increased plasma levels of B-cell activating factor (BAFF), chemokine (C-X-C motif) ligand 9 (CXCL9) and elafin have been associated with the diagnosis, but not with outcome in patients with cGvHD. We evaluated the association between levels of these soluble proteins, measured by ELISA at the time of cGvHD diagnosis and before the initiation of therapy, with non-relapse-mortality (NRM). Based on the log-transformed values, factor levels were divided into tertiles defined respectively as low, intermediate, and high levels. On univariable analysis, BAFF levels were significantly associated with NRM, whereas CXCL9 and elafin levels were not. Both low (⩽2.3 ng/mL, hazard ratio (HR)=5.8, P=0.03) and high (>5.7 ng/mL, HR=5.4, P=0.03) BAFF levels were associated with a significantly higher NRM compared with intermediate BAFF level. The significant effect of high or low BAFF levels persisted in multivariable analysis. A subset of cGvHD patients had persistently low BAFF levels. In conclusion, our data show that BAFF levels at the time of cGvHD diagnosis are associated with NRM, and also are potentially useful for risk stratification. These results warrant confirmation in larger studies.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Pavletic SZ, Vogelsang GB, Lee SJ . 2014 National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: preface to the series. Biol Blood Marrow Transplant 2015; 21: 387–388.
Boyiadzis M, Arora M, Klein JP, Hassebroek A, Hemmer M, Urbano-Ispizua A et al. Impact of chronic graft-versus-host disease on late relapse and survival on 7489 patients after myeloablative allogeneic hematopoietic cell transplantation for leukemia. Clin Cancer Res 2015; 21: 2020–2028.
Arai S, Arora M, Wang T, Spellman SR, He W, Couriel DR et al. Increasing incidence of chronic graft-versus-host disease in allogeneic transplantation: a report from the Center for International Blood and Marrow Transplant Research. Biol Blood Marrow Transplant 2015; 21: 266–274.
Abou-Nassar KE, Kim HT, Blossom J, Ho VT, Soiffer RJ, Cutler CS et al. The impact of geographic proximity to transplant center on outcomes after allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2012; 18: 708–715.
Filipovich AH, Weisdorf D, Pavletic S, Socie G, Wingard JR, Lee SJ et al. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report. Biol Blood Marrow Transplant 2005; 11: 945–956.
Jagasia MH, Greinix HT, Arora M, Williams KM, Wolff D, Cowen EW et al. National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: I. The 2014 Diagnosis and Staging Working Group Report. Biol Blood Marrow Transplant 2015; 21: 389–401.e381.
Allen JL, Fore MS, Wooten J, Roehrs PA, Bhuiya NS, Hoffert T et al. B cells from patients with chronic GVHD are activated and primed for survival via BAFF-mediated pathways. Blood 2012; 120: 2529–2536.
Jacobson CA, Sun L, Kim HT, McDonough SM, Reynolds CG, Schowalter M et al. Post-transplantation B cell activating factor and B cell recovery before onset of chronic graft-versus-host disease. Biol Blood Marrow Transplant 2014; 20: 668–675.
Kitko CL, Levine JE, Storer BE, Chai X, Fox DA, Braun TM et al. Plasma CXCL9 elevations correlate with chronic GVHD diagnosis. Blood 2014; 123: 786–793.
Sarantopoulos S, Stevenson KE, Kim HT, Bhuiya NS, Cutler CS, Soiffer RJ et al. High levels of B-cell activating factor in patients with active chronic graft-versus-host disease. Clin Cancer Res 2007; 13: 6107–6114.
Yu J, Storer BE, Kushekhar K, Abu Zaid M, Zhang Q, Gafken PR et al. Biomarker panel for chronic graft-versus-host disease. J Clin Oncol 2016; 34: 2583–2590.
Chasset F, de Masson A, Le Buanec H, Xhaard A, de Fontbrune FS, Robin M et al. APRIL levels are associated with disease activity in human chronic graft-versus-host disease. Haematologica 2016; 101: e312–e315.
Parimon T, Madtes DK, Au DH, Clark JG, Chien JW . Pretransplant lung function, respiratory failure, and mortality after stem cell transplantation. Am J Respir Crit Care Med 2005; 172: 384–390.
Akpek G, Lee SJ, Flowers ME, Pavletic SZ, Arora M, Lee S et al. Performance of a new clinical grading system for chronic graft-versus-host disease: a multicenter study. Blood 2003; 102: 802–809.
Arora M, Burns LJ, Davies SM, Macmillan ML, Defor TE, Miller WJ et al. Chronic graft-versus-host disease: a prospective cohort study. Biol Blood Marrow Transplant 2003; 9: 38–45.
Arora M, Klein JP, Weisdorf DJ, Hassebroek A, Flowers ME, Cutler CS et al. Chronic GVHD risk score: a Center for International Blood and Marrow Transplant Research analysis. Blood 2011; 117: 6714–6720.
Lee SJ, Klein JP, Barrett AJ, Ringden O, Antin JH, Cahn JY et al. Severity of chronic graft-versus-host disease: association with treatment-related mortality and relapse. Blood 2002; 100: 406–414.
Palmer J, Chai X, Pidala J, Inamoto Y, Martin PJ, Storer B et al. Predictors of survival, nonrelapse mortality, and failure-free survival in patients treated for chronic graft-versus-host disease. Blood 2016; 127: 160–166.
Peus D, Newcomb N, Hofer S . Appraisal of the Karnofsky Performance Status and proposal of a simple algorithmic system for its evaluation. BMC Med Inform Decis Mak 2013; 13: 72.
Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J et al. 1994 Consensus Conference on Acute GVHD Grading. Bone Marrow Transplant 1995; 15: 825–828.
Prentice RL, Kalbfleisch JD, Peterson AV Jr, Flournoy N, Farewell VT, Breslow NE . The analysis of failure times in the presence of competing risks. Biometrics 1978; 34: 541–554.
Klein JP, Rizzo JD, Zhang MJ, Keiding N . Statistical methods for the analysis and presentation of the results of bone marrow transplants. Part 2: Regression modeling. Bone Marrow Transplant 2001; 28: 1001–1011.
Zhang MJ, Fine J . Summarizing differences in cumulative incidence functions. Stat Med 2008; 27: 4939–4949.
Ahmed SS, Wang XN, Norden J, Pearce K, El-Gezawy E, Atarod S et al. Identification and validation of biomarkers associated with acute and chronic graft versus host disease. Bone Marrow Transplant 2015; 50: 1563–1571.
Collins CE, Gavin AL, Migone TS, Hilbert DM, Nemazee D, Stohl W . B lymphocyte stimulator (BLyS) isoforms in systemic lupus erythematosus: disease activity correlates better with blood leukocyte BLyS mRNA levels than with plasma BLyS protein levels. Arthritis Res Ther 2006; 8: R6.
Kreuzaler M, Rauch M, Salzer U, Birmelin J, Rizzi M, Grimbacher B et al. Soluble BAFF levels inversely correlate with peripheral B cell numbers and the expression of BAFF receptors. J Immunol 2012; 188: 497–503.
Fujii H, Cuvelier G, She K, Aslanian S, Shimizu H, Kariminia A et al. Biomarkers in newly diagnosed pediatric-extensive chronic graft-versus-host disease: a report from the Children's Oncology Group. Blood 2008; 111: 3276–3285.
Kuzmina Z, Krenn K, Petkov V, Kormoczi U, Weigl R, Rottal A et al. CD19(+)CD21(low) B cells and patients at risk for NIH-defined chronic graft-versus-host disease with bronchiolitis obliterans syndrome. Blood 2013; 121: 1886–1895.
Whittle R, Taylor PC . Circulating B-cell activating factor level predicts clinical response of chronic graft-versus-host disease to extracorporeal photopheresis. Blood 2011; 118: 6446–6449.
Blazar BR, Murphy WJ, Abedi M . Advances in graft-versus-host disease biology and therapy. Nat Rev Immunol 2012; 12: 443–458.
Sarantopoulos S, Stevenson KE, Kim HT, Cutler CS, Bhuiya NS, Schowalter M et al. Altered B-cell homeostasis and excess BAFF in human chronic graft-versus-host disease. Blood 2009; 113: 3865–3874.
Clark WB, Brown-Gentry KD, Crawford DC, Fan KH, Snavely J, Chen H et al. Genetic variation in recipient B-cell activating factor modulates phenotype of GVHD. Blood 2011; 118: 1140–1144.
Henden AS, Hill GR . Cytokines in graft-versus-host disease. J Immunol 2015; 194: 4604–4612.
Zhang J, Roschke V, Baker KP, Wang Z, Alarcon GS, Fessler BJ et al. Cutting edge: a role for B lymphocyte stimulator in systemic lupus erythematosus. J Immunol 2001; 166: 6–10.
Vital EM, Wittmann M, Edward S, Md Yusof MY, MacIver H, Pease CT et al. Brief report: responses to rituximab suggest B cell-independent inflammation in cutaneous systemic lupus erythematosus. Arthritis Rheumatol 2015; 67: 1586–1591.
Sarantopoulos S, Ritz J . Aberrant B-cell homeostasis in chronic GVHD. Blood 2015; 125: 1703–1707.
Sarantopoulos S, Stevenson KE, Kim HT, Washel WS, Bhuiya NS, Cutler CS et al. Recovery of B-cell homeostasis after rituximab in chronic graft-versus-host disease. Blood 2011; 117: 2275–2283.
Acknowledgements
We thank the clinicians, clinical research support staff and data managers in the University of Michigan Blood and Marrow Transplant Program. We acknowledge our funding sources including: MCube, University of Michigan, Briskin/Schlafer Pediatric Oncology Investigators Fund (to CLK), University of Michigan Pediatric Hematology/Oncology Junior Faculty Grant (to CLK); and NIH (NHLBI) R01 HL 129061-01 (to SS).
Author contributions
RMS conceived and performed statistical analyses, interpreted data and wrote the manuscript; SS interpreted the data and wrote the manuscript; CLK accrued patients and discussed data, and edited the manuscript; AP, SCG and JM accrued patients and discussed data; TC and HJ collected and managed data; AA, SP and PR contributed to research discussion, DRC conceived and designed the study, collected clinical data and assured quality and wrote the manuscript.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Additional information
Supplementary Information accompanies this paper on Bone Marrow Transplantation website
Supplementary information
Rights and permissions
About this article
Cite this article
Saliba, R., Sarantopoulos, S., Kitko, C. et al. B-cell activating factor (BAFF) plasma level at the time of chronic GvHD diagnosis is a potential predictor of non-relapse mortality. Bone Marrow Transplant 52, 1010–1015 (2017). https://doi.org/10.1038/bmt.2017.73
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/bmt.2017.73