The Influence of ATG on the Outcomes of Patients With AML at the Time of Unrelated Donor Transplantation

Abstract

Objectives: Anti-thymos globulin (ATG) can potentially eliminate alloreactive donor T-cells and reduce the graft-versus-host disease (GVHD). As a result of this, increased disease relapse and reduced overall survival can be observed in ATG recipients. In addition, the presence of pre- allogeneic hematopoietic stem cell transplantation (allo-HSCT) measurable residual disease has been associated with an increased risk of acute myeloid leukemia (AML) relapse in multiple studies. Herein, we aimed to investigate the impact of ATG on the outcomes of patients with AML stratified by flow cytometric minimal residual disease (MRD) status who underwent allo-HSCT from unrelated donor. Materials and Methods: This was a retrospective single-center analysis using the data set of our institutional database. Eligibility criteria for this analysis included 83 adult patients with AML who underwent allo‐HSCT from either an HLA 10/10 matched (n=34) or 9/10 mismatched (n=41) UD, between October 2012 and June 2019. Results: A total of 83 consecutive patients with AML who underwent allo-HSCT from a UD were evaluated. There were 44 MRD- and 18 MRD+ patients and 21 patients who were transplanted in the setting of active disease were also included in this analysis. We investigated the influence of ATG on transplant outcomes separately in MRD-, MRD+ and active disease cohorts. As expected, lowest incidence of relapse was observed in MRD- groups [MRD-; 29.5% (13/44) vs MRD+; 44.4% (8/18); p=0.17]. MRD status at the time of allo-HSCT impacted the progression free survival significantly: MRD- (not reached) or MRD+ [median 17.3 (95% confidence interval (CI), 6.3-28.3)] or active disease [median 11 months (%95 CI, 3,9-18,1)] (p=0.02). In multivariate cox regression analyses; we could demonstrate the negative effect of detection of MRD [Hazard ratio (HR): 1.8; %95 GA: 0.7-4.8; p=0.02] and active disease (HR: 3.6; %95 GA: 1.4-8.7; p=0.006) on PFS. Conclusion: Based on this single-center study, the use of ATG was associated with a lower incidence of chronic GVHD. Most importantly, ATG could increase the risk of disease relapse or mortality in patients with pre-transplant MRD+ and active diseases. However, further prospective, randomized studies on a large number of patients are warranted to clarify these findings.

Keywords

• Acute Myeloid Leukemia
• Allogeneic Hematopoietic Stem Cell Transplantation
• Measurable Residual Disease
• ATG

Akut Myeloid Lösemi Tanısı ile Akraba Dışı Vericiden Allojeneik Hematopoietik Kök Hücre Nakli Yapılan Hastalarda ATG Kullanımının Nakil Sonuçlarına Etkisi

Abstract

Amaç: Anti-timosit globülinin (ATG) alloreaktif verici T-hücrelerini yok ederek graft versus lösemi (GVL) etkisini azaltma olasılığı bilinmektedir. Bunun sonucu olarak da ATG kullanılanlarda; hastalık nüksünde artış ve tüm sağ kalımda azalma gözlenebilmektedir. Ayrıca nakil öncesi ölçülebilir kalıntı hastalık (ÖKH) varlığı ile akut miyeloid lösemi (AML) riskinde artış olduğu birçok çalışmada gösterilmiştir. Biz de bu çalışmamızda, akraba dışı vericiden allojeneik hematopoietik kök hücre nakli (AHKHN) yapılan AML hastalarında, akan hücre ölçer yöntemi ile değerlendirilen ÖKH varlığını dikkate alarak, ATG’nin nakil sonuçlarına olan etkisini retrospektif olarak değerlendirmeyi planladık. Gereç ve Yöntem: Bu çalışma retrospektif, tek merkezli ve kendi veri tabanımız kullanılarak yapılmıştır. Ekim 2012 ile Haziran 2019 arasında 10/10 (n=39) ya da 9/10 (n=44) doku grubu antijenleri uyuşumlu akraba dışı vericiden nakil yapılan 83 erişkin AML hastası çalışmaya dahil edildi. Bulgular: Akraba dışı vericiden ardışık AHKHN yapılan 83 AML hastası çalışmamıza dahil edildi. Kırk dört hasta ÖKH-, 18 hasta ÖKH+, 21 hasta da aktif hastalık ile nakile alınmıştır. ATG’nin nakil sonuçlarına etkisi ÖKH-, ÖKH+ ve aktif hastalıklı hastalarda ayrı ayrı incelenmiştir. Beklendiği gibi, en düşük nüks oranı ÖKH- grupta (13/44, %29,5) görülmüştür (ÖKH+ grupta 8/18, %44,4, p=0,17). AHKHN aşamasındaki ÖKH durumu progresyonsuz sağkalımı (PFS) istatistiksel olarak anlamlı derecede etkilemektedir: ÖKH- grupta henüz ulaşılmamışken ÖKH+ grupta ortanca 17,3 ay [%95 güven aralığı (GA), 6,3-28,3] ve aktif hastalıklı olan grupta ortanca 11 ay (%95 GA, 3,9-18,1) (p=0,02). Çoklu değişkenli multivariate cox regresyon analizinde sadece hastaların ÖKH+ [tehlike oranı (HR): 1,8; %95 GA: 0,7-4,8; p=0,02] ve aktif hastalık varlığının (HR: 3,6; %95 GA: 1,4-8,7; p=0,006) PFS üzerine olumsuz etkileri gösterilebilmiştir. Sonuç: Bu tek merkezli çalışmanın sonuçlarına göre, ATG kullanımı kronik GvHH gelişme oranını azaltmaktadır. Çalışmamızın en önemli sonucu ise; ATG içeren hazırlama rejimleri ile nakile alınan AML hastalarının, ÖKH+ veya aktif hastalığı olması nüks ve mortalite riskini artırabilmektedir. Bu bulguları doğrulamak amacıyla gelecekte daha fazla hasta içeren prospektif, randomize çalışmaların planlanması gerekmektedir

Keywords

• Akut Myeloid Lösemi
• Allojeneik Hematopoetik Kök Hücre Nakli
• Ölçülebilir Kalıntı Hastalık
• ATG

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