Turkish Journal of Hematology Volume: 37 Issue: 1 / 2020

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RESEARCH ARTICLEDOI: 10.4274/tjh.galenos.2019.2019.0139Turk J Hematol 2020;37:20-29Predictive Values of Early Suppression of Tumorigenicity 2 forAcute GVHD and Transplant-related Complications after AllogeneicStem Cell Transplantation: Prospective Observational StudyAllojenik Kök Hücre Transplantasyonu Sonrası Akut GVHD ve Transplantasyonla İlişkiliKomplikasyonlar İçin Tümörjenisite 2’nin Erken Baskılanmasının Prediktif Değeri: ProspektifGözlemsel ÇalışmaAyako Matsumura 1 , Takuya Miyazaki 1 , Takayoshi Tachibana 1 , Taiki Ando 2 , Megumi Koyama 2 , Satoshi Koyama 2 ,Yoshimi Ishii 2 , Hiroyuki Takahashi 1 , Yuki Nakajima 1 , Ayumi Numata 2 , Wataru Yamamoto 2 , Kenji Motohashi 2 ,Maki Hagihara 1 , Kenji Matsumoto 1 , Shin Fujisawa 2 , Hideaki Nakajima 11Yokohama City University Graduate School of Medicine, Department of Stem Cell and Immune Regulation, Kanagawa, Japan2Yokohama City University Medical Center, Department of Hematology, Kanagawa, JapanAbstractObjective: A soluble form of suppression of tumorigenicity 2(sST2) has emerged as a biomarker for acute graft-versus-hostdisease (GVHD) and non-relapse mortality (NRM). We prospectivelymonitored sST2 levels during the early phase of hematopoietic stemcell transplantation (HSCT) and evaluated the clinical association withtransplant-related complications including acute GVHD.Materials and Methods: Thirty-two adult Japanese patients whoreceived a first allogeneic HSCT were enrolled in this study. Levels ofsST2 were measured at fixed time points (pre-conditioning, day 0, day14, day 21, and day 28).Results: The median age was 50.5 years (range=16-66). With amedian follow-up of 21.5 months (range=0.9-35.4), 9 patientsdeveloped grade II-IV acute GVHD. Median sST2 levels on the dayof HSCT were higher than baseline and reached the maximum value(92.7 ng/mL; range=0-419.7) on day 21 after HSCT. The optimal cutoffvalue of sST2 on day 14 for predicting grade II-IV acute GVHD wasdetermined as 100 ng/mL by ROC analysis. The cumulative incidenceof acute GVHD was 56.7% and 16.5% in the high- and low-sST2groups, respectively (p<0.01). Multivariate analyses showed thathigh sST2 levels at day 14 were associated with a higher incidence ofacute GVHD (hazard ratio=9.35, 95% confidence interval=2.92-30.0,p<0.01). The cumulative incidence of NRM was increased in the highsST2group (33% vs 0%, p<0.01), but all the patients died of non-GVHDcomplications. Among 6 patients in the high-sST2 group withoutgrade II-IV GVHD, 5 patients developed veno-occlusive disease (VOD)and one also had thrombotic microangiopathy (TMA).Conclusion: The early assessment of sST2 after HSCT yielded predictivevalues for the onset of acute GVHD and other transplant-relatedcomplications including VOD and TMA.Keywords: Suppression of tumorigenicity 2, Graft-versus-host disease,Biomarker, Hematopoietic stem cell transplantationÖzAmaç: Akut graft-konakçı hastalığı (GVHD) ve relaps dışı mortalite(NRM) için bir biyobelirteç olarak, tümör oluşumu 2’nin baskılanmasının(sST2) çözünür bir formu ortaya konulmuştur. Hematopoietik kökhücre transplantasyonunun (HSCT) erken safhasında sST2 düzeyleriniprospektif olarak izledik ve akut GVHD dahil transplantla ilişkilikomplikasyonlarla klinik ilişkisini değerlendirdik.Gereç ve Yöntemler: Bu çalışmaya ilk allojenik HSCT’si olan 32yetişkin Japon hasta alındı. sST2 seviyeleri sabit zaman noktalarında(hazırlık rejimi öncesi, 0. gün, 14. gün, 21. gün ve 28. gün) ölçüldü.Bulgular: Ortanca yaş 50,5 idi (aralık=16-66). Ortalama 21,5 aylıktakip süresi (aralık= 0,9-35,4) ile 9 hastada Grade II-IV akut GVHDgelişti. Nakil gününde ortanca sST2 seviyeleri bazal değerlerden dahayüksekti ve HSCT’den sonraki 21. günde maksimum değere (92,7 ng/mL;aralık=0-419,7) ulaştı. Grade II-IV akut GVHD’yi tahmin etmek için 14.günde sST2’nin optimal eşik değeri, ROC analizi ile 100 ng/mL olarakbelirlenmiştir. Akut GVHD’nin kümülatif insidansı yüksek ve düşüksST2 gruplarında sırasıyla %56,7 ve %16,5 idi (p<0,01). Çok değişkenlianalizler 14. günde yüksek sST2 düzeylerinin daha yüksek akut GVHDinsidansı ile ilişkili olduğunu göstermiştir (tehlike oranı=9, 35, %95güven aralığı=2,92-30,0, p<0,01). NRM’nin kümülatif insidansı yükseksST2 grubunda artmıştır (%33’e karşı %0, p<0,01), ancak tüm hastalarGVHD dışı komplikasyonlardan öldü. Yüksek sST2 grubunda grade II-IVGVHD olmayan 6 hastadan 5’inde veno-oklüzif hastalık (VOD) geliştive birinde trombotik mikroanjiyopati (TMA) vardı.Sonuç: HSCT sonrası sST2’nin erken değerlendirmesi, akutGVHD’nin başlangıcı ve VOD ve TMA dahil transplantla ilişkili diğerkomplikasyonlar için prediktif değerler vermiştir.Anahtar Sözcükler: Tümör oluşumu 2’nin baskılanması, Akutgraft-konakçı hastalığı, Biyomarker, Hematopoietik kök hücretransplantasyonu©Copyright 2020 by Turkish Society of HematologyTurkish Journal of Hematology, Published by Galenos Publishing HouseAddress for Correspondence/Yazışma Adresi: Takuya Miyazaki, M.D., Yokohama City University Graduate School ofMedicine, Department of Stem Cell and Immune Regulation, Kanagawa, JapanPhone : +81 45 787 2800E-mail : takuya_m@yokohama-cu.ac.jp ORCID: orcid.org/0000-0003-1884-4757Received/Geliş tarihi: April 2, 2019Accepted/Kabul tarihi: August 28, 201920
Turk J Hematol 2020;37:20-29Matsumura A, et al: ST2 for Transplant-related ComplicationsIntroductionAcute graft-versus-host disease (GVHD) is one of the majorcomplications after allogeneic hematopoietic stem celltransplantation (HSCT) and remains the leading cause of nonrelapsemortality (NRM) [1,2]. Identifying useful biomarkers forpredicting onset or severity of acute GVHD at the early phaseof HSCT may help in the development of a more individualizedtreatment strategy for GVHD. Recent studies show severalplasma biomarkers that correlate with acute GVHD: suppressionof tumorigenicity 2 (ST2) [3,4], interleukin (IL)-2 receptor α[5], tumor necrosis factor receptor 1 (TNFR1) [5], hepatocytegrowth factor [5], IL-8 [5], and IL-6 [6] for systemic GVHD;elafin for skin GVHD [7]; and regenerating islet-derived 3-α[8] and T-cell immunoglobulin mucin-3 for gastrointestinalGVHD [8,9,10,11,12]. Among these biomarkers, ST2 has emergedas a promising biomarker for onset or steroid-resistant acuteGVHD and NRM [3,4,12,13,14]. In addition, recent studies havedemonstrated that high ST2 levels are associated with thedevelopment of thrombotic microangiopathy (TMA) and venoocclusivedisease (VOD) after HSCT [15,16].ST2 is a membrane receptor expressed on several immune celltypes that belong to the IL-1 receptor family. ST2 induces Thelper type 2 (Th2) and Treg immune responses, which playimportant roles in GVHD [17]. A soluble form of ST2 (sST2)is a decoy receptor for IL-33, which blocks the IL-33/ST2pathway and drives Th2 cells toward a Th1 cell phenotype, andit is thought to be important in the pathophysiology of GVHD[18,19]. In murine models, the ST2/IL-33 axis has been reportedas a potential therapeutic target for GVHD [20,21].Despite the accumulating evidence that higher sST2 levels areassociated with increased GVHD risk and subsequent mortality,a clinical role of sST2 during the early phase of transplantationhas not been fully elucidated. We performed a multicenter,prospective, observational study monitoring the serial changesin sST2 levels before and early after HSCT with the aim ofdetermining the diagnostic and prognostic values for acuteGVHD, other transplant-related complications, and mortality.Materials and MethodsPatients and Transplant ProcedurePatients who received first allogeneic HSCT for hematologicaldiseases were enrolled consecutively between February 2014 andJuly 2015 at Yokohama City University Hospital or YokohamaCity University Medical Center. The selection of donor sourceand conditioning regimen was based on patients’ hematologicaldiagnosis, donor availability, and patients’ clinical status.Conditioning regimens were classified into myeloablativeconditioning (MAC) and reduced-intensity conditioning (RIC)according to the definitions previously reported [22]. Thepre-transplant risk category was defined as standard or highaccording to the diagnosis and the disease stage at the time oftransplantation, as described previously [23].Written informed consent was obtained from all the patientsenrolled in this study before the start of the trial. This study wasapproved by the institutional review boards of our universityhospital and medical center and was conducted in accordancewith the Declaration of Helsinki. All authors vouched for theaccuracy and completeness of the reported data, analyses, andadherence to the study protocol.Peripheral Blood SamplesSamples were collected prospectively before conditioning, onthe day of HSCT (day 0), and on days 14, 21, and 28 after HSCT.Serum sST2 and IL-33 levels were measured by ELISA (HumanST2/IL-1 R4 ELISA Kit and Human IL-33 ELISA Kit; R&D Systems,Minneapolis, MN, USA). Absorbance was measured using amicroplate reader (Powerscan HT, DS Pharma Biomedical, Osaka,Japan).Transplant-related ComplicationsAcute GVHD was diagnosed clinically with histologicalconfirmation when available. The classification of acute GVHDwas based on the diagnostic criteria of the 1994 ConsensusConference on Acute GVHD Grading [24]. GVHD prophylaxisconsisted of cyclosporine or tacrolimus with short-termmethotrexate. Anti-thymocyte globulin was administeredfor HLA-serological mismatched transplant based on eachinstitution’s criteria.Other transplant-related complications were diagnosed asfollows: TMA was diagnosed according to the Blood and MarrowClinical Trials Network and European Group for Blood andMarrow Transplantation guidelines [25,26]. VOD was diagnosedbased on the Baltimore and Seattle criteria [27,28].Statistical AnalysisFisher’s exact test and the Mann-Whitney U test were used toassess the categorical and continuous variables, respectively.The receiver operating characteristics (ROC) curve fromlogistic regression models with the area under the curve(AUC) was used to present the correlation between sST2 andother biomarkers. The Pearson test was used to determine thecorrelation between sST2 and other biomarkers. The Kaplan-Meier method was used to assess overall survival (OS) using thelog-rank test. For multivariate analysis, the Cox proportionalhazards method was used to assess the OS. The Gray test andFine-Gray test were used to assess the cumulative incidenceof GVHD and NRM. The competing risks were GVHD and deathprior to GVHD. Values of p<0.05 were considered statisticallysignificant. All analyses were performed using EZR version 1.3621
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