Higher abatacept exposure after transplant decreases acute GVHD risk without increasing adverse events

阿巴塔克普 医学 不利影响 内科学 危险系数 人口 安慰剂 置信区间 美罗华 环境卫生 病理 替代医学 淋巴瘤
作者
Takuto Takahashi,Mahmoud Al‐Kofahi,Mutaz M. Jaber,Brandi Bratrude,Kayla Betz,Yvonne Suessmuth,Alison Yu,Donna Neuberg,Sung Won Choi,Jeffrey Davis,Christine N. Duncan,Roger Giller,Michael Grimley,Andrew C. Harris,David A. Jacobsohn,Nahal Lalefar,Nosha Farhadfar,Michael A. Pulsipher,Shalini Shenoy,Aleksandra Petrović,Kirk R. Schultz,Gregory A. Yanik,Bruce R. Blazar,John Horan,Benjamin Watkins,Amelia Langston,Muna Qayed,Leslie S. Kean
出处
期刊:Blood [American Society of Hematology]
卷期号:142 (8): 700-710 被引量:3
标识
DOI:10.1182/blood.2023020035
摘要

Abstract In the ABA2 study, the T-cell costimulation blockade agent, abatacept, was safe and effective in preventing acute graft-versus-host disease (aGVHD) after unrelated-donor hematopoietic cell transplant (HCT), leading to US Food and Drug Administration approval. Here, we performed a determination of abatacept pharmacokinetics (PK), which enabled an examination of how abatacept exposure-response relationships affected clinical outcomes. We performed a population PK analysis of IV abatacept using nonlinear mixed-effect modeling and assessed the association between abatacept exposure and key transplant outcomes. We tested the association between the trough after dose 1 (Ctrough_1) and grade (GR) 2 or 4 aGVHD (GR2-4 aGVHD) through day +100. An optimal Ctrough_1 threshold was identified via recursive partitioning and classification tree analysis. This demonstrated that abatacept PK was characterized by a 2-compartment model with first-order elimination. The ABA2 dosing regimen was based on previous work targeting a steady-state abatacept trough of 10 μg/mL. However, a higher Ctrough_1 (≥39 μg/mL, attained in ∼60% of patients on ABA2) was associated with a favorable GR2-4 aGVHD risk (hazard ratio, 0.35; 95% confidence interval, 0.19-0.65; P < .001), with a Ctrough_1 <39 μg/mL associated with GR2-4 aGVHD risk indistinguishable from placebo (P = .37). Importantly, no significant association was found between Ctrough_1 and key safety indicators, including relapse, and cytomegalovirus or Epstein-Barr virus viremia. These data demonstrate that a higher abatacept Ctrough_1 (≥39 μg/mL) was associated with a favorable GR2-4 aGVHD risk, without any observed exposure-toxicity relationships. This trial was registered at www.clinicaltrials.gov as #NCT01743131.
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