Division of Pediatric Allergy, Immunology, and Bone Marrow Transplantation, Department of Clinical Pharmacy, University of California San Francisco Benioff Children's Hospitals, San Francisco, CA.
Division of Hematology and Oncology, Section of Transplantation Intermountain Primary Children's Hospital, Huntsman Cancer Institute, Spencer Fox Eccles School of Medicine at The University of Utah, Salt Lake City, UT.
Blood Adv. 2024 Dec 10;8(23):6003-6014. doi: 10.1182/bloodadvances.2024012670.
We hypothesized that the inferior disease-free survival (DFS) seen in older patients who underwent αβ-T-cell/CD19-depleted (AB-TCD) haploidentical hematopoietic cell transplantation (HCT) for hematologic malignancies is caused by excessive exposure to rabbit antithymocyte globulin (rATG; Thymoglobulin). Between 2015 and 2023, 163 patients with a median age of 13 years (range, 0.4-27.4) underwent AB-TCD haploidentical HCT for the treatment of acute lymphoblastic leukemia (n = 98), acute myeloid leukemia/myelodysplastic syndrome (n = 49), or other malignancies (n = 16) at 9 centers in 2 prospective trials. Exposures to rATG before and after HCT were predicted using a validated pharmacokinetic model. Receiver operating characteristic curves were used to identify the optimal target windows for rATG exposure in terms of outcomes. We identified 4 quadrants of rATG exposure, namely quadrant 1 (n = 52) with a high pre-HCT area under curve (AUC; ≥50 arbitrary units [AU] per day per milliliter) and a low post-HCT AUC (<12 AU per day per liter); quadrant 2 (n = 47) with a low pre- and post-HCT AUC; quadrant 3 (n = 13) with a low pre-HCT and a high post-HCT AUC; and quadrant 4 (n = 51) with a high pre- and post-HCT AUC. Quadrant 1 had a 3-year DFS of 86.5%, quadrant 2 had a DFS of 64.6%, quadrant 3 had a DFS of 32.9%, and for quadrant 4 it was 48.2%. An adjusted regression analysis demonstrated additional factors that were associated with an increased hazard for worse DFS, namely minimal residual disease (MRD) positivity and cytomegalovirus (CMV) R+/D- serostatus. Nonoptimal rATG exposure exhibited the strongest effect in unadjusted and adjusted (MRD status or CMV serostatus) analyses. High exposure to rATG after HCT was associated with inferior DFS following AB-TCD haploidentical HCT for pediatric patients with hematologic malignancies. Model-based dosing of rATG to achieve optimal exposure may improve DFS. These trials were registered at www.ClinicalTrials.gov as #NCT02646839 and #NCT04337515.
我们假设，在接受 αβ-T 细胞/CD19 耗尽（AB-TCD）单倍体造血细胞移植（HCT）治疗血液系统恶性肿瘤的老年患者中，较低的无病生存（DFS）是由于过度暴露于兔抗胸腺球蛋白（rATG；Thymoglobulin）引起的。在 2015 年至 2023 年期间，在 9 个中心的 2 项前瞻性试验中，有 163 名中位年龄为 13 岁（范围 0.4-27.4）的患者因急性淋巴细胞白血病（n = 98）、急性髓系白血病/骨髓增生异常综合征（n = 49）或其他恶性肿瘤（n = 16）接受 AB-TCD 单倍体 HCT 治疗。使用经过验证的药代动力学模型预测 HCT 前后 rATG 的暴露情况。使用接收者操作特征曲线确定 rATG 暴露在疗效方面的最佳目标窗口。我们确定了 rATG 暴露的 4 个象限，即象限 1（n = 52），其预 HCT 曲线下面积（AUC；每毫升每天每毫克≥50 个任意单位[AU]）高，后 HCT AUC 低（<12 AU 每天每升）；象限 2（n = 47）预和后 HCT AUC 均较低；象限 3（n = 13）预 HCT 低，后 HCT AUC 高；象限 4（n = 51）预和后 HCT AUC 均较高。象限 1 的 3 年 DFS 为 86.5%，象限 2 的 DFS 为 64.6%，象限 3 的 DFS 为 32.9%，象限 4 的 DFS 为 48.2%。调整后的回归分析表明，其他与较差 DFS 风险增加相关的因素包括微小残留病（MRD）阳性和巨细胞病毒（CMV）R+/D-血清状态。非最佳 rATG 暴露在未调整和调整（MRD 状态或 CMV 血清状态）分析中表现出最强的效果。HCT 后 rATG 暴露过高与儿科血液系统恶性肿瘤患者接受 AB-TCD 单倍体 HCT 后 DFS 较差相关。基于模型的 rATG 剂量给药以实现最佳暴露可能会改善 DFS。这些试验在 www.ClinicalTrials.gov 上注册，分别为 #NCT02646839 和 #NCT04337515。
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