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

•We demonstrate a favorable exposure-response relationship between the Ctrough_1 of abatacept and a lower risk of gr 2or 4 aGVHD.•No association was found between abatacept Ctrough_1 and key safety outcomes, including relapse, cytomegalovirus, or Epstein-Barr virus viremia. [Display omitted] In the...

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Published in:Blood 2023-08, Vol.142 (8), p.700-710
Main Authors: Takahashi, Takuto, Al-Kofahi, Mahmoud, Jaber, Mutaz, Bratrude, Brandi, Betz, Kayla, Suessmuth, Yvonne, Yu, Alison, Neuberg, Donna S., Choi, Sung W., Davis, Jeffrey, Duncan, Christine, Giller, Roger, Grimley, Michael, Harris, Andrew C., Jacobsohn, David, Lalefar, Nahal, Farhadfar, Nosha, Pulsipher, Michael A., Shenoy, Shalini, Petrovic, Aleksandra, Schultz, Kirk R., Yanik, Gregory A., Blazar, Bruce R., Horan, John T., Watkins, Benjamin, Langston, Amelia, Qayed, Muna, Kean, Leslie S.
Format: Article
Language:English
Subjects:
Abatacept - adverse effects
Epstein-Barr Virus Infections - etiology
Graft vs Host Disease - etiology
Graft vs Host Disease - prevention & control
Hematopoietic Stem Cell Transplantation - adverse effects
Herpesvirus 4, Human
Humans
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Summary:•We demonstrate a favorable exposure-response relationship between the Ctrough_1 of abatacept and a lower risk of gr 2or 4 aGVHD.•No association was found between abatacept Ctrough_1 and key safety outcomes, including relapse, cytomegalovirus, or Epstein-Barr virus viremia. [Display omitted] 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
ISSN:0006-4971
1528-0020
1528-0020
DOI:10.1182/blood.2023020035