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B-Cell Activating Factor (BAFF) Plasma Level at the Time of Chronic Gvhd Diagnosis Is a Potential Predictor of Non-Relapse Mortality

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B-Cell Activating Factor (BAFF) Plasma Level at the Time of Chronic Gvhd Diagnosis Is a Potential Predictor of Non-Relapse Mortality Bone Marrow Transplantation (2017) 52, 1010–1015 © 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved 0268-3369/17 www.nature.com/bmt ORIGINAL ARTICLE B-cell activating factor (BAFF) plasma level at the time of chronic GvHD diagnosis is a potential predictor of non-relapse mortality RM Saliba1,7, S Sarantopoulos2,7, CL Kitko3, A Pawarode4, SC Goldstein4, J Magenau4, AM Alousi1, T Churay4, H Justman4, S Paczesny5, P Reddy4 and DR Couriel6 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 (45.7 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. Bone Marrow Transplantation (2017) 52, 1010–1015; doi:10.1038/bmt.2017.73; published online 8 May 2017 INTRODUCTION diagnosis, before the initiation of systemic therapy for cGvHD, Chronic GvHD (cGvHD) remains the main long-term limitation to when clinical manifestations are potentially reversible and successful allogeneic hematopoietic stem cell transplantation risk-adapted treatment is most likely to be successful. (HSCT).1–3 The signs and symptoms of cGvHD are often insidious. Thus, diagnosis and treatment typically occur after clinical manifestations are advanced. In addition, management of cGvHD PATIENTS AND METHODS may be suboptimal after discharge from the transplant Study population center as patients are often followed by local oncologists From January 2007 through December 2010, 341 consecutive adult unfamiliar with the clinical features of cGvHD.4 Development of patients underwent their first allogeneic HSCT at the University of a much needed diagnostic and severity scoring system based Michigan. Of these, a total of 287 survived beyond post-HSCT day on clinical manifestations of cGvHD is challenging because (D100); 158 patients who developed cGvHD and had not been diagnosed of the complex and pleomorphic nature of the disease.5,6 with progression of their underlying malignancy before the onset of cGvHD were included in this analysis. All patients provided informed In this context, validation of biological markers that would fi consent to participate in an institutional review board-approved, long-term facilitate risk strati cation and a more personalized approach to follow-up study. Patient cGvHD data were prospectively collected into the the management of cGvHD has the potential to improve University of Michigan Bone Marrow Transplant Program database. outcomes.1,6 A number of potentially viable biomarkers in cGvHD have been identified through proteomics. Of these, soluble B-cell activating Assessment of cGvHD and additional risk factors for NRM factor (BAFF), chemokine (C-X-C motif) ligand 9 (CXCL9) and elafin Clinical cGvHD data were adjudicated by two clinicians with expertise in fi have been associated with the diagnosis of cGvHD7–12 but their the eld (CLK and DRC), and diagnosis and scoring were based on National Institutes of Health (NIH) Consensus Criteria.5 Lung score calculation was potential association with outcome remains unknown. In this based on results of pulmonary function tests performed within 4 weeks of study, we evaluate the association of these three soluble factors the diagnosis of cGvHD per published recommendations.13 The date of with non-relapse mortality (NRM) in a cohort of newly diagnosed cGvHD diagnosis was defined as the time when NIH Consensus Criteria cGvHD patients. We focused our assessment on the time of cGvHD were first reached. 1Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 2Division of Cell Therapy and Hematologic Malignancies, Duke Cancer Institute, Duke University Durham, NC, USA; 3Department of Pediatrics, Division of Hematology-Oncology, Vanderbilt University Medical Center, Nashville, TN, USA; 4Adult Blood and Marrow Transplant Program, University of Michigan, Ann Arbor, MI, USA; 5Department of Pediatrics, Microbiology and Immunology, Indiana University School of Medicine, Melvin and Bren Simon Cancer Center, Indianapolis, IN, USA and 6Blood and Marrow Transplantation Program, Huntsman Cancer Institute, University of Utah Hospital, Salt Lake City, UT, USA. Correspondence: Professor DR Couriel, Blood and Marrow Transplantation Program, Division of Hematology, Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope, 2151, Salt Lake City, UT 84112, USA. E-mail: [email protected] 7These authors contributed equally to this work. Received 15 August 2016; revised 14 January 2017; accepted 25 January 2017; published online 8 May 2017 BAFF levels at cGVHD onset predict mortality RM Saliba et al 1011 Previously reported risk factors for NRM after HSCT were examined.14–18 19 Table 1. GvHD characteristics at the time of cGvHD diagnosis of the Karnofsky Performance Status (KPS) was assessed as 470 or ⩽ 70%. = = Acute GvHD was scored by modified Glucksberg criteria.20 study (N 158) cohort and of the subset of patients (N 112) evaluable for BAFF assessment Measurement of potential protein biomarkers Characteristics N = 158 (%) N = 112 (%) ELISA was used to determine plasma concentrations of BAFF, CXCL9 and elafin as previously described.9 Plasma samples were collected at the time Days from transplant to 189 (132,273) 167 (126,207) cGvHD diagnosis, of cGvHD diagnosis before the initiation of treatment for cGvHD and at fi median (interquartiles) 3 months interval thereafter. BAFF, CXCL9 and ela n levels were available History of grade 34/40/20 21%/ 29/24 26%/21% in 112 (71%), 110 (70%) and 109 (69%) patients, respectively. All three I/II/III–IV aGvHD 25%/13% /11 /10% protein levels were available for 105 of the 158 patients. cGvHD onset presentation De novo 64 41% 48 43% Statistical approach Quiescent 60 38% 35 31% NRM was defined as death because of any cause not related to progression Progressive 34 21% 29 26% or persistence of the underlying malignancy. NRM, overall survival (OS), progression-free survival (PFS) and progression of malignancy after cGvHD Global NIH-CC severity Mild 23 15% 16 14% diagnosis were assessed by landmark analysis starting on the day of Moderate 79 50% 54 48% diagnosis of cGvHD. According to the inclusion criteria, none of the Severe 56 35% 42 37% patients had experienced progression of the underlying malignancy before the onset of cGvHD. Therefore, in this study all reference to ‘progression of Organ involvement according to NIH-CC malignancy’ pertains to progression occurring after cGvHD diagnosis. Skin Actuarial OS and PFS were estimated by the Kaplan–Meier method. The None 78 49% 54 48% cumulative incidence method accounting for competing risks21 was used Mild 32 20% 26 23% Moderate 26 16% 16 14% to estimate the incidence of NRM (considering progression of the Severe 22 14% 16 14% underlying malignancy or death with persistent malignancy as competing Mouth risks), and the incidence of progression of the underlying malignancy None 25 16% 12 11% (considering NRM as a competing risk). Mild 113 71% 85 76% We evaluated the association between NRM and each of the plasma Moderate 18 11% 14 12% factors using Cox proportional hazards regression analysis on univariable Severe 2 1% 1 1% and multivariable analysis. NRM-specific hazard ratios (HRs) were Eye None 111 70% 80 71% generated accounting for progression of the underlying malignancy or Mild 35 22% 25 22% death with persistent malignancy as they occurred after cGvHD Moderate 11 7% 6 5% diagnosis.22,23 Each plasma factor was initially evaluated in two separate Severe 1 1% 1 1% Cox models in which the log-transformed values were divided into Gastrointestinal quartiles or into tertiles. The goodness-of-fit test (based on the Cox–Snell None 128 81% 88 79% residuals) confirmed the superiority of the Cox model evaluating plasma Mild 25 16% 20 18% values in tertiles. Therefore, all results pertaining to plasma factors were Moderate 5 3% 4 4% fi fi Liver presented based on the tertile classi cation. The rst, second and third None 68 43% 48 43% tertiles were defined as low, intermediate and high levels, respectively. Mild 40 25% 28 25% To identify potential confounding factors in the association between Moderate 27 17% 16 14% plasma factors and NRM, we assessed patient sociodemographic, Severe 23 15% 20 18% transplantation and GvHD-related factors as predictors of NRM. Patient, Lung (evaluable in 154/158 patients) transplantation or cGvHD factors that were associated with NRM at the None 63 41% 45 41% 0.003 (P-value adjusted based on Bonferroni correction to account for Mild 74 48% 51 47% Moderate 15 10% 11 10% multiple comparisons) level on univariable analysis were considered in Severe 2 1% 2 2% multivariable analysis. First-degree interaction effects were tested and Joint were not found to be significant. Categorical variables were compared None 148 94% 105 94% using the χ2 and Fisher’s exact tests and continuous variables were Mild 9 6% 7 6% compared using the Wilcoxon rank-sum rest.
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