Vascular biomarkers reveal a unique toxicity profile of posttransplant cyclophosphamide: secondary analysis of BMT CTN 0402 and 1202

Blood Vessels, Thrombosis & Hemostasis Pub Date : 2024-07-26 DOI:10.1016/j.bvth.2024.100020

Laura F. Newell , Najla El Jurdi , Brian C. Betts , Corey Cutler , Joseph H. Antin , John E. Levine , Angela Panoskaltsis-Mortari , Shernan G. Holtan

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Abstract

Posttransplant cyclophosphamide (PTCy)–based graft-versus-host disease (GVHD) prophylaxis regimens are associated with very low rates of severe acute and chronic GVHD after hematopoietic cell transplant (HCT). However, concerns about cardiac and other organ toxicities persist. This study aimed to compare the vascular biomarker profile of PTCy with other GVHD regimens, including tacrolimus/sirolimus (Tac/Sir) and tacrolimus/methotrexate (Tac/MTX), to generate hypotheses for toxicity mitigation strategies. Plasma samples from day +28 after transplant were analyzed against pretransplant baseline measurements in patients receiving PTCy-based GVHD prophylaxis as part of Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 1202 (n = 112) vs Tac/MTX (n = 98) and Tac/Sir (n = 95) regimens from BMT CTN 0402. Compared with Tac/MTX, PTCy was associated with increasing angiopoietin-2 levels and decreasing epidermal growth factor levels at day +28. In contrast, Tac/Sir displayed increasing follistatin and endoglin levels and decreasing vascular endothelial growth factor receptor 2 (VEGFR2) plasma levels after HCT. Across all cohorts, increasing epidermal growth factor was protective from nonrelapse mortality, and decreasing VEGFR2 was associated with subsequent development of extensive chronic GVHD. These distinct biomarker profiles offer insights that could guide strategies to mitigate unique GVHD prophylaxis–associated toxicities.

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血管生物标志物揭示了移植后环磷酰胺的独特毒性特征：对 BMT CTN 0402 和 1202 的二次分析

摘要基于环磷酰胺（PTCy）的移植后移植物抗宿主病（GVHD）预防方案与造血细胞移植（HCT）后极低的严重急性和慢性 GVHD 发生率有关。然而，对心脏和其他器官毒性的担忧依然存在。本研究旨在比较PTCy与其他GVHD方案（包括他克莫司/西罗莫司（Tac/Sir）和他克莫司/甲氨蝶呤（Tac/MTX））的血管生物标志物谱，从而为减轻毒性策略提出假设。在血液和骨髓移植临床试验网络（BMT CTN）1202（n = 112）与BMT CTN 0402的Tac/MTX（n = 98）和Tac/Sir（n = 95）方案中，对接受以PTCy为基础的GVHD预防治疗的患者移植后第+28天的血浆样本与移植前基线测量值进行了对比分析。与 Tac/MTX 相比，PTCy 与 HCT 后血管生成素-2 水平升高和表皮生长因子水平降低有关；相比之下，Tac/Sir 与 HCT 后绒毛素和内皮素水平升高和血管内皮生长因子受体 2 (VEGFR2) 血浆水平降低有关。在所有队列中，表皮生长因子的升高对非复发死亡率具有保护作用，而血管内皮生长因子受体2的降低与随后出现的广泛慢性GVHD有关。这些不同的生物标志物特征提供了深入的见解，可以指导减轻独特的 GVHD 预防相关毒性的策略。

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Blood Vessels, Thrombosis & Hemostasis

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