兔ATG PK对小儿血液恶性肿瘤TCR-αβ/CD19贫化后同种异体造血干细胞移植结果的影响

IF 7.4 1区 医学 Q1 HEMATOLOGY Blood advances Pub Date : 2024-12-10 DOI:10.1182/bloodadvances.2024012670
Christopher C Dvorak, Janel R Long-Boyle, Lucia Holbrook-Brown, Hisham Abdel-Azim, Alice Bertaina, Anant Vatsayan, Julie-An Talano, Nancy Bunin, Eric Anderson, Allyson Flower, Nahal Lalefar, Christine S Higham, Neena Kapoor, Orly Klein, Maryanne C Odinakachukwu, Soohee Cho, David A Jacobsohn, Willem Collier, Michael A Pulsipher
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引用次数: 0

摘要

我们假设,在接受αβ/CD19-T细胞耗竭(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,无病生存期(DFS)较差的原因是过度暴露于兔抗胸腺细胞球蛋白(rATG;Thymoglobulin®)。2015-2023 年间,9 个中心的 163 名中位数年龄为 13 岁(范围为 0.4-27.4)的患者在两项前瞻性试验中接受了 AB-TCD 单倍体 HCT,以治疗 ALL(98 人)、AML/MDS(49 人)或其他恶性肿瘤(16 人)。采用经过验证的药代动力学(PK)模型预测了rATG在HCT前后的暴露量。使用 ROC 曲线确定与结果相关的 rATG 暴露的最佳目标窗口。我们确定了 rATG 暴露的四个象限--象限 1(n=52):HCT 前 AUC 高(≥50 AU*day/mL ),HCT 后 AUC 低(≥50 AU*day/mL )。
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Effect of rabbit ATG PK on outcomes after TCR-αβ/CD19-depleted pediatric haploidentical HCT for hematologic malignancy.

Abstract: 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.

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来源期刊
Blood advances
Blood advances Medicine-Hematology
CiteScore
12.70
自引率
2.70%
发文量
840
期刊介绍: Blood Advances, a semimonthly medical journal published by the American Society of Hematology, marks the first addition to the Blood family in 70 years. This peer-reviewed, online-only, open-access journal was launched under the leadership of founding editor-in-chief Robert Negrin, MD, from Stanford University Medical Center in Stanford, CA, with its inaugural issue released on November 29, 2016. Blood Advances serves as an international platform for original articles detailing basic laboratory, translational, and clinical investigations in hematology. The journal comprehensively covers all aspects of hematology, including disorders of leukocytes (both benign and malignant), erythrocytes, platelets, hemostatic mechanisms, vascular biology, immunology, and hematologic oncology. Each article undergoes a rigorous peer-review process, with selection based on the originality of the findings, the high quality of the work presented, and the clarity of the presentation.
期刊最新文献
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