目的:尽管钙调磷酸酶抑制剂(CNIs)在异基因造血细胞移植(HCT)后预防移植物抗宿主病(GVHD)中具有公认的作用,它们的使用可能受到显著毒性的限制,这可能导致过早停止治疗。CNI不耐受患者的最佳管理是未知的。这项研究的目的是确定皮质类固醇作为CNI不耐受患者GVHD预防的有效性。
方法:这项回顾性的单中心研究包括连续的成人恶性血液病患者,这些患者接受了清髓性外周血同种异体HCT和抗胸腺细胞球蛋白,CNI,和甲氨蝶呤在艾伯塔省预防GVHD,加拿大。多变量竞争风险回归用于比较GVHD的累积发病率,复发,皮质类固醇与持续CNI预防接受者之间的非复发死亡率,多变量Cox比例风险回归用于比较总生存率,无复发生存率(RFS)和中度至重度慢性GVHD和RFS。
结果:在509名同种异体HCT接受者中,58例(11%)患者出现CNI不耐受,并在HCT后中位28天(范围1-53)转为皮质类固醇预防。与接受持续CNI预防的患者相比,接受皮质类固醇预防的患者2-4级急性GVHD的累积发生率明显更高(亚风险比[SHR]1.74,95%置信区间[CI]1.08-2.80,P=0.024),3-4级急性GVHD(SHR3.22,95%CI1.55-6.72,P=0.002),与GVHD相关的非复发死亡率(SHR3.07,95%CI1.54-6.12,P=0.001)。中度至重度慢性GVHD(SHR0.84,95%CI0.43-1.63,P=0.60)或复发(SHR0.92,95%CI0.53-1.62,P=0.78)没有显着差异,但皮质类固醇预防与显著较差的总生存率相关(风险比[HR]1.77,95%CI1.20-2.61,P=0.004),RFS(HR1.54,95%CI1.06-2.25,P=0.024),和慢性GVHD和RFS(HR1.46,95%CI1.04-2.05,P=0.029)。
结论:患有CNI不耐受的同种异体HCT受者发生急性GVHD的风险增加,尽管在CNI过早停药后采取了皮质类固醇预防措施。这种高危人群需要替代的GVHD预防策略。
Although calcineurin inhibitors (CNIs) have a well-established role in the prevention of graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (HCT), their use can be limited by significant toxicities, which may result in premature treatment discontinuation. The optimal management of patients with CNI intolerance is unknown. The objective of this study was to determine the effectiveness of corticosteroids as GVHD prophylaxis for patients with CNI intolerance.
This retrospective single-center study included consecutive adult patients with hematologic malignancies who underwent myeloablative peripheral blood allogeneic HCT with anti-thymocyte globulin, CNI, and methotrexate GVHD prophylaxis in Alberta, Canada. Multivariable competing-risks regression was used to compare cumulative incidences of GVHD, relapse, and non-relapse mortality between recipients of corticosteroid versus continuous CNI prophylaxis, and multivariable Cox proportional hazards regression was applied to compare overall survival, relapse-free survival (RFS) and moderate-to-severe chronic GVHD and RFS.
Among 509 allogeneic HCT recipients, 58 (11%) patients developed CNI intolerance and were switched to corticosteroid prophylaxis at median 28 days (range 1-53) after HCT. Compared with patients who received continuous CNI prophylaxis, recipients of corticosteroid prophylaxis had significantly greater cumulative incidences of grade 2-4 acute GVHD (subhazard ratio [SHR] 1.74, 95% confidence interval [CI] 1.08-2.80, P = 0.024), grade 3-4 acute GVHD (SHR 3.22, 95% CI 1.55-6.72, P = 0.002), and GVHD-related non-relapse mortality (SHR 3.07, 95% CI 1.54-6.12, P = 0.001). There were no significant differences in moderate-to-severe chronic GVHD (SHR 0.84, 95% CI 0.43-1.63, P = 0.60) or relapse (SHR 0.92, 95% CI 0.53-1.62, P = 0.78), but corticosteroid prophylaxis was associated with significantly inferior overall survival (hazard ratio [HR] 1.77, 95% CI 1.20-2.61, P = 0.004), RFS (HR 1.54, 95% CI 1.06-2.25, P = 0.024), and chronic GVHD and RFS (HR 1.46, 95% CI 1.04-2.05, P = 0.029).
Allogeneic HCT recipients with CNI intolerance are at increased risks of acute GVHD and poor outcomes despite institution of corticosteroid prophylaxis following premature CNI discontinuation. Alternative GVHD prophylaxis strategies are needed for this high-risk population.