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Higher Abatacept Exposure Decreases Acute GVHD Risk Without Increasing Adverse Events.

Takuto TakahashiMahmoud Al-KofahiMutaz JaberBrandi BratrudeKayla M BetzYvonne SuessmuthAlison YuDonna S NeubergSung Won ChoiJeffrey H DavisChristine DuncanRoger H GillerMichael S GrimleyAndrew C HarrisDavid A JacobsohnNahal Rose LalefarNosha FarhadfarMichael A PulsipherShalini ShenoyAleksandra PetrovicKirk R SchultzGregory A YanikBruce R BlazarJohn T HoranBenjamin WatkinsAmelia A LangstonMuna QayedLeslie S Kean
Published in: Blood (2023)
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 transplantation (URD HCT), leading to FDA approval. Here, we performed a detailed determination of abatacept pharmacokinetics (PK), which enabled an examination of how abatacept exposure-response (E-R) relationships impacted key clinical outcomes. To accomplish this, we performed a population PK analysis of intravenous abatacept using nonlinear mixed-effect modeling, and assessed the association between abatacept exposure (dosed at 10 mg/kg on Days -1,+5,+14,+28) and key transplant outcomes. We tested the association between the trough concentration after dose 1 (Ctrough_1) and Grade 2-4 acute GVHD (Gr 2-4 AGVHD) through Day+100 as the primary outcome in 184 HCT patients. An optimal Ctrough_1 threshold was identified by recursive partitioning and classification tree analysis. This demonstrated that abatacept PK was characterized by a two-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 (≥39μg/mL, attained in ~60% of ABA2 patients) was associated with a favorable Gr 2-4 AGVHD risk (HR:0.35, 95%CI:0.19-0.65, p<0.001), with a Ctrough_1 <39μg/mL associated with Gr 2-4 AGVHD risk indistinguishable from placebo (p=0.37). Importantly, no significant association was found between Ctrough_1 and key safety indicators, including relapse, CMV viremia, and EBV viremia. These data demonstrate that, compared to a previously reported target Ctrough_1 of 10 μg/mL, a higher abatacept Ctrough_1 (≥39 μg/mL) was associated with a favorable Gr 2-4 AGVHD risk, without any observed exposure-toxicity relationships. Clinical trial NCT01743131.
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