Ratanatharathorn V, Nash R A, Przepiorka D, Devine S M, Klein J L, Weisdorf D, Fay J W, Nademanee A, Antin J H, Christiansen N P, van der Jagt R, Herzig R H, Litzow M R, Wolff S N, Longo W L, Petersen F B, Karanes C, Avalos B, Storb R, Buell D N, Maher R M, Fitzsimmons W E, Wingard J R
University of Michigan, Ann Arbor; Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
Blood. 1998 Oct 1;92(7):2303-14.
We report the results of a phase III open-label, randomized, multicenter trial comparing tacrolimus/methotrexate to cyclosporine/methotrexate for graft-versus-host disease (GVHD) prophylaxis after HLA-identical sibling marrow transplantation in patients with hematologic malignancy. The primary objective of this study was to compare the incidence of moderate to severe (grade II-IV) acute GVHD. Secondary objectives were to compare the relapse rate, disease-free survival, overall survival, and the incidence of chronic GVHD. Patients were stratified according to age (<40 v >/=40) and for male recipients of a marrow graft from an alloimmunized female. There was a significantly greater proportion of patients with advanced disease randomized to tacrolimus arm (P = . 02). The incidence of grade II-IV acute GVHD was significantly lower in patients who received tacrolimus than patients in the cyclosporine group (31.9% and 44.4%, respectively; P = .01). The incidence of grade III-IV acute GVHD was similar, 17.1% in cyclosporine group and 13.3% in the tacrolimus group. There was no difference in the incidence of chronic GVHD between the tacrolimus and the cyclosporine group (55.9% and 49.4%, respectively; P = .8). However, there was a significantly higher proportion of patients in the cyclosporine group who had clinical extensive chronic GVHD (P = . 03). The relapse rates of the two groups were similar. The patients in the cyclosporine arm had a significantly better 2-year disease-free survival and overall survival than patients in the tacrolimus arm, 50.4% versus 40.5% (P = .01) and 57.2% versus 46.9% (P = .02), respectively. The significant difference in the overall and disease-free survival was largely the result of the patients with advanced disease, 24.8% with tacrolimus versus 41.7% with cyclosporine (P = .006) and 20.4% with tacrolimus versus 28% with cyclosporine (P = .007), respectively. There was a higher frequency of deaths from regimen-related toxicity in patients with advanced disease who received tacrolimus. There was no difference in the disease-free and overall survival in patients with nonadvanced disease. These results show the superiority of tacrolimus/methotrexate over cyclosporine/methotrexate in the prevention of grade II-IV acute GVHD with no difference in disease-free or overall survival in patients with nonadvanced disease. The survival disadvantage in advanced disease patients receiving tacrolimus warrants further investigation.
我们报告了一项III期开放标签、随机、多中心试验的结果，该试验比较了他克莫司/甲氨蝶呤与环孢素/甲氨蝶呤在血液系统恶性肿瘤患者接受 HLA 相同的同胞骨髓移植后预防移植物抗宿主病（GVHD）的效果。本研究的主要目的是比较中度至重度（II-IV 级）急性 GVHD 的发生率。次要目的是比较复发率、无病生存率、总生存率以及慢性 GVHD 的发生率。患者根据年龄（<40岁与≥40岁）以及接受来自同种免疫女性的骨髓移植的男性受者进行分层。随机分配到他克莫司组的晚期疾病患者比例显著更高（P = 0.02）。接受他克莫司治疗的患者中II-IV级急性 GVHD 的发生率显著低于环孢素组患者（分别为31.9%和44.4%；P = 0.01）。III-IV级急性 GVHD 的发生率相似，环孢素组为17.1%，他克莫司组为13.3%。他克莫司组和环孢素组慢性 GVHD 的发生率无差异（分别为55.9%和49.4%；P = 0.8）。然而，环孢素组中出现临床广泛慢性 GVHD 的患者比例显著更高（P = 0.03）。两组的复发率相似。环孢素组患者的2年无病生存率和总生存率显著优于他克莫司组患者，分别为50.4%对40.5%（P = 0.01）和57.2%对46.9%（P = 0.02）。总生存率和无病生存率的显著差异主要是晚期疾病患者导致的，他克莫司组为24.8%，环孢素组为41.7%（P = 0.006），他克莫司组为20.4%，环孢素组为28%（P = 0.007）。接受他克莫司治疗的晚期疾病患者因方案相关毒性导致的死亡频率更高。非晚期疾病患者的无病生存率和总生存率无差异。这些结果表明，在预防II-IV级急性 GVHD 方面，他克莫司/甲氨蝶呤优于环孢素/甲氨蝶呤，非晚期疾病患者的无病生存率或总生存率无差异。接受他克莫司治疗的晚期疾病患者的生存劣势值得进一步研究。
