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Peng Y. et al: Allo-HSCT in Extranodal LymphomaRESEARCH ARTICLEDOI: 10.4274/tjh.galenos.2021.2020.0438Turk J Hematol 2021;38:126-137Allogeneic Hematopoietic Stem Cell Transplantation in ExtranodalNatural Killer/T-cell LymphomaEkstranodal Doğal Öldürücü/T-hücreli Lenfomada Allojeneik Hematopoetik HücreTransplantasyonuYin-yin Peng 1 , Yi-ying Xiong 1 , Li-xia Zhang 1 , Jing Wang 1 , Hong-bin Zhang 1 , Qing Xiao 1 , Shu-liang Guo 21First Affiliated Hospital of Chongqing Medical University, Department of Hematology, Chongqing, China2First Affiliated Hospital of Chongqing Medical University, Department of Respiratory Medicine, Chongqing, ChinaAbstractObjective: Extranodal NK/T-cell lymphoma (ENKL) is aggressiveand resistant to chemotherapy and radiotherapy. Allogeneichematopoietic stem cell transplantation (allo-HSCT) is a potentiallycurative treatment for high-risk lymphomas owing to its associatedgraft-versus-lymphoma (GVL) effect. However, its application to ENKLis limited. We aim to summarize the characteristics of allo-HSCT forENKL and, more importantly, evaluate whether allo-HSCT could offerany benefits for ENKLMaterials and Methods: A systematic review and data analysis wereperformed to evaluate the performance of allo-HSCT in the treatmentof ENKL using studies obtained from PubMed, Medline, and Embasefrom January 2000 to December 2019 in the English language.Results: A total of 136 cases from 17 eligible publications wereincluded in this study. It was found that after allo-HSCT, withan average follow-up time of 34 months (range: 1-121 months),37.5% (52) of 136 patients had acute graft-versus-host disease(GVHD) and 31.6% (43) had chronic GVHD. Furthermore, 35.3%(48) of the patients were reported to have relapsed, but 2 of thoserelapsed only locally and achieved complete remission (CR) again withadditional irradiation, chemotherapy, and donor lymphocyte infusionsfor one and rapid tapering and discontinuation of cyclosporine forthe other, earning more than one year of extra survival. Finally,of the 136 patients, 51.5% (70) died because of primary diseaseprogression (42.9%), infection (20.0%), GVHD (11.4%), organ failure(7.1%), hemorrhage (4.3%), and other causes (not specified/unknown)(14.3%).Conclusion: Allo-HSCT may be a treatment option for advancedor relapsed/refractory ENKL, but its role still requires more rigorousfuture studies.Keywords: Extranodal NK/T-cell lymphoma, Chemotherapy,Radiotherapy, Allogeneic hematopoietic stem cell transplantationÖzAmaç: Ekstranodal NK/T-hücreli lenfoma (ENKL) agresiftir vekemoterapi ve radyoterapiye dirençlidir. Allojenik hematopoetik kökhücre transplantasyonu (allo-HSCT), ilişkili graft-lenfoma (GVL) etkisinedeniyle, yüksek riskli lenfomalara yönelik potansiyel olarak iyileştiricibir tedavidir. Bununla birlikte, ENKL’ye uygulanması sınırlıdır. Buçalışmada ENKL için allo-HSCT’nin/AHKHN’nin özelliklerini özetlemeyive daha da önemlisi allo-HSCT’nin ENK için herhangi bir fayda sağlayıpsağlamayacağını değerlendirmeyi amaçlıyoruz.Gereç ve Yöntemler: Ocak 2000’den Aralık 2019’a kadar İngilizcedilinde PubMed, Medline ve Embase literatürleri kullanılarakallo-HSCT’nin ENKL’ye performansını değerlendirmek için sistematikbir inceleme ve veri analizi gerçekleştirildi.Bulgular: Bu çalışmaya 17 uygun yayından toplam 136 olgu dahiledildi. 1) allo-HSCT’den sonra, 34 aylık ortalama takip süresine göre(aralık: 1-121 ay), 136 hastanın %37,5’inde (52) akut graft-versushosthastalığı (GVHD), %31,6’sında (43) kronik GVHD vardı; 2) raporedildiğinde, hastaların %35,3’ünde (48) relaps vardı, ancak bunlardanikisi sadece lokal olarak nüks etti ve bunlardan birine ek ışınlama,kemoterapi, donör lenfosit infüzyonu ile tekrar tam remisyon (CR)sağladı, diğerine siklosporinin hızlı azaltılması ve kesilmesi bir yıldanfazla ekstra sağkalım kazandırdı; 3) 136 hastanın %51,5’i (70) primerhastalık ilerlemesi (%42,9), enfeksiyon (%20,0), GVHD (%11,4), organyetmezliği (%7,1), kanama (%4,3) ve diğerleri (belirtilmedi/bilinmiyor)(%14,3) nedeniyle öldü.Sonuç: Allo-HSCT, ilerlemiş veya nükseden/refrakter ENKL için birtedavi seçeneği olabilir, ancak rolü hala daha titiz gelecek çalışmalarıgerektirmektedir.Anahtar Sözcükler: Ekstranodal NK/T-hücreli lenfoma, Kemoterapi,Radyoterapi, Allojeneik hematopoetik kök hücre nakli©Copyright 2021 by Turkish Society of HematologyTurkish Journal of Hematology, Published by Galenos Publishing HouseAddress for Correspondence/Yazışma Adresi: Yin-yin Peng, M.D., First Affiliated Hospital of Chongqing MedicalUniversity, Department of Hematology, Chongqing, ChinaPhone : 86-15123312126E-mail : pengyinyin802320@163.com ORCID: orcid.org/0000-0002-7978-4826Received/Geliş tarihi: July 30, 2020Accepted/Kabul tarihi: January 29, 2021126
Turk J Hematol 2021;38:126-137Peng Y. et al: Allo-HSCT in Extranodal LymphomaIntroductionNatural killer cell tumors are categorized as extranodal NK/Tcelllymphoma (ENKL), aggressive NK-cell leukemia and chronicNK-cell lymphoproliferative disorders according to the 2016World Health Organization (WHO) classification [1]. Among them,ENKL is relatively more common. ENKLs include both nasal andextra-nasal ENKL categories of disease in the current 2016 WHOclassification [2]. It is rarely diagnosed in Western countries butrelatively more common in East Asian countries, being closelyassociated with Epstein-Barr virus (EBV). Pathologically, ENKLshows a highly aggressive clinical behavior. It usually involvesthe nasal cavity, nasopharynx, upper aerodigestive tract,skin, gastrointestinal tract, or other parts of the body, whichhave poorer survival. Limited-stage ENKL responds relativelymuch better to radiotherapy or to concurrent radiation andchemotherapy than advanced or relapsed/refractory ENKL. Sofar, there is no standard management for relapsed or refractorydisease.Although ENKL’s clinical features and prognostic factorshave been well characterized in the last decades, optimaltreatment strategies still remain unclear. The tumorcells lack L-asparagine synthetase and are susceptibleto L-asparaginase, which depletes L-asparagine in NKlymphoma cells [1]. Regimens containing L-asparagine wereeffective for limited-stage ENKL; however, when used inpatients with advanced-stage disease, these regimens werenot so satisfactory. Some studies showed that the completeremission (CR) rate with the L-asparagine, etoposide, anddexamethasone (AspaMetDex) regimen for patients withadvanced-staged disease was 30%, and the 5-year survivalrate with the L-asparagine, vincristine, and dexamethasone(LVD) regimen was only 25% [3,4]. As advanced-stage orrelapsed/refractory ENKL is highly progressive and sometimesmultidrug-resistant, L-asparaginase-based therapy is still achallenge [5].Allogeneic hematopoietic stem cell transplantation (allo-HSCT)is a potentially curative treatment for high-risk lymphomapatients owing to its associated graft-versus-lymphoma (GVL)effect. Furthermore, ENKL cells almost invariably express EBVantigens, providing an alloreactive target to enhance the GVLeffect [1]. Although allo-HSCT is an effective way to treathematologic tumors, its applications for ENKL remain limited.Some small series of studies have demonstrated a disease-freesurvival (DFS) of 30%-50%, but with high transplant-relatedmortality of about 25% [1,6-9]. Problems still remain: (1)undoubtedly, both infection and acute graft-versus-host disease(GVHD) during allo-HSCT often cause death; (2) the heavypsychological pressure during allo-HSCT is still overwhelming;(3) and, furthermore, human leukocyte antigen (HLA) donorsand patients are still hard to match for allo-HSCT. Therefore, inthis study we aim to summarize the characteristics of allo-HSCTfor ENKL and, more importantly, evaluate whether allo-HSCTcould offer any benefits for ENKL.Materials and MethodsLiterature ReviewWe searched PubMed, Medline, and Embase for publicationsin the English language from January 2000 to December 2019.The following terms were used: “natural killer/T-cell tumors” or“natural killer/T-cell neoplasm” or “natural killer/T-cell lymphoma”or “extranodal natural killer/T-cell lymphoma” or “extranodalnatural killer/T-cell lymphoma nasal type” or “angiocentriclymphoma” and “hematopoietic stem cell transplantation” or“transplantation” or “therapy” or “treatment.”Study SelectionStudies were considered eligible in the analysis if they met thefollowing inclusion criteria: (1) patients were diagnosed withENKL according to REAL and WHO classifications; (2) patients didnot suffer from a second primary malignancy before or togetherwith ENKL; (3) patients were treated with allo-HSCT; (4) studiesprovided data including overall survival (OS), progression-freesurvival (PFS), and/or DFS or other markers describing thesurvival outcome.Studies that met any of the following criteria were excluded: (1)non-English literature; (2) repeated studies; (3) studies withoutrelevant outcome indicators.Data ExtractionData were extracted by two independent authors and checkedby another. Disagreements were resolved in consultation withthe third author. For each study, the following informationwas extracted: (1) basic information such as the author, date,country, patient numbers and characteristics, etc.; (2) specificintervention details; (3) outcome indicators and measures suchas OS, PFS, and DFS.Data AnalysisThe measurement data were expressed in percentages andcomposition ratios and then the “average age” and “averagefollow-up time” after allo-HSCT were calculated. The “averageage” is only an average value of the “referred ages” of all thereferences. “Referred age” here means the “mean age” or “medianage” in different papers, which are not identical. Theoretically,if all references calculate “mean age” of patients in their casestudies, our “average value” of their “referred ages” in this studyshould equal the mean age of the 136 patients. However, somereferences calculated “median age” and we had no opportunityto obtain their original data. Thus, we had to take the “medianages” as approximate indicators of the mean ages and finally127
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