Adult Bone Marrow Transplant Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York; Department of Medicine, Weill Cornell Medical College, New York, New York.
Department of Pharmacy, Memorial Sloan Kettering Cancer Center, New York, New York.
Biol Blood Marrow Transplant. 2019 Aug;25(8):1526-1535. doi: 10.1016/j.bbmt.2019.02.021. Epub 2019 Mar 1.
Antithymocyte globulin (ATG) use mitigates the risk of graft rejection and graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (allo-HCT), but ATG overexposure in the setting of lymphopenia negatively affects immune recovery. We hypothesized that standard empiric weight-based dosing of ATG, used to prevent graft rejection in ex vivo CD34-selected allo-HCT, may lead to serious adverse consequences on outcomes in certain patients. We evaluated 304 patients undergoing myeloablative-conditioned ex vivo CD34-selected allo-HCT with HLA-matched donors for the treatment of hematologic malignancies. Patients received rabbit ATG at a dose of 2.5 mg/kg/day i.v. on days -3 and/or -2. An ATG dosing cutoff of 450 mg was used for statistical analyses to assess the relationship between ATG and overall survival (OS). Among all patients, median total ATG dose was 360 mg (range, 130 to 510 mg); 279 (92%) received a total dose of ATG ≤450 mg, and 25 (8%) received a total dose >450 mg. On the first day of ATG administration (day -3), the median absolute lymphocyte count was .0 K/µL. For patients who received a total dose of ATG >450 mg or ≤450 mg, the incidences of acute and late-acute GVHD grade II-IV were statistically similar. At 3 years post-HCT, for patients who received a total dose of ATG >450 mg or ≤450 mg, nonrelapse mortality (NRM) rates were 35% and 18%, respectively (P = .029), disease-free survival (DFS) rates were 37% and 61%, respectively (P = .003), and OS rates were 40% and 67%, respectively (P = .001). Among all patient and HCT characteristics in multivariable analyses, receipt of a total dose of ATG >450 mg was associated with an increased risk of NRM (hazard ratio [HR], 2.9; P = .01), shorter DFS (HR, 2.0; P = .03), and inferior OS (HR, 2.1; P = .01). In summary, the use of weight-based ATG at a time of relative lymphopenia before ex vivo CD34-selected allo-HCT results in overdosing in heavier patients, leading to higher NRM and lower DFS and OS. Further pharmacokinetic investigation in this setting is critical to determining the optimal dosing strategy for ATG.
抗胸腺细胞球蛋白（ATG）可降低同种异体造血细胞移植（allo-HCT）后移植物排斥和移植物抗宿主病（GVHD）的风险，但在淋巴细胞减少的情况下，ATG 过度暴露会对免疫恢复产生负面影响。我们假设，用于预防体外 CD34 选择的 allo-HCT 中移植物排斥的标准经验性体重为基础的 ATG 给药剂量，可能会对某些患者的结果产生严重的不良后果。我们评估了 304 名接受同种异体 HLA 匹配供体的清髓性条件下体外 CD34 选择的 allo-HCT 治疗血液系统恶性肿瘤的患者。患者在 -3 天和/或 -2 天接受 2.5mg/kg/天的兔 ATG 静脉注射。使用 ATG 剂量 450mg 进行统计分析，以评估 ATG 与总生存率（OS）之间的关系。在所有患者中，中位总 ATG 剂量为 360mg（范围 130-510mg）；279 名（92%）接受的总 ATG 剂量≤450mg，25 名（8%）接受的总 ATG 剂量>450mg。在 ATG 给药的第一天（-3 天），绝对淋巴细胞计数的中位数为 0.0K/µL。对于接受总剂量 ATG>450mg 或≤450mg 的患者，急性和迟发性急性 GVHD II-IV 级的发生率无统计学差异。在移植后 3 年，对于接受总剂量 ATG>450mg 或≤450mg 的患者，非复发死亡率（NRM）分别为 35%和 18%（P=0.029），无病生存率（DFS）分别为 37%和 61%（P=0.003），总生存率分别为 40%和 67%（P=0.001）。在多变量分析中，所有患者和 HCT 特征中，接受 ATG 总剂量>450mg 与 NRM 风险增加相关（风险比[HR]，2.9；P=0.01）、DFS 更短（HR，2.0；P=0.03）和 OS 更差（HR，2.1；P=0.01）。总之，在体外 CD34 选择的 allo-HCT 前相对淋巴细胞减少时，基于体重的 ATG 会导致较重患者过度给药，从而导致更高的 NRM 发生率、DFS 和 OS 率降低。在这种情况下进一步的药代动力学研究对于确定 ATG 的最佳给药策略至关重要。
