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

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.

SUBMITTER: Takahashi T

PROVIDER: S-EPMC10797507 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature

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

Takahashi Takuto T Al-Kofahi Mahmoud M Jaber Mutaz M Bratrude Brandi B Betz Kayla K Suessmuth Yvonne Y Yu Alison A Neuberg Donna S DS Choi Sung W SW Davis Jeffrey J Duncan Christine C Giller Roger R Grimley Michael M Harris Andrew C AC Jacobsohn David D Lalefar Nahal N Farhadfar Nosha N Pulsipher Michael A MA Shenoy Shalini S Petrovic Aleksandra A Schultz Kirk R KR Yanik Gregory A GA Blazar Bruce R BR Horan John T JT Watkins Benjamin B Langston Amelia A Qayed Muna M Kean Leslie S LS

Blood 20230801 8

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 non ...[more]

PMID: 37319437

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Project description:Thrombocytopenia is common in preterm neonates and can be associated with hemorrhage. Most platelet transfusions are prophylactic. Previously, higher platelet-count thresholds were recommended for neonates, but this recommendation has been questioned in recent studies. In the PlaNeT2 trial, mortality and serious bleeding were more frequent in neonates with the highest platelet-count threshold than in others. Following this trial, we changed our platelet transfusion practice by lowering the platelet-count threshold for prophylactic transfusion from 50,000 to 25,000/mm3. We conducted a before-after retrospective cohort study to quantify the frequency of platelet transfusions and assess the new protocol by analyzing death and serious hemorrhage events. This retrospective monocentric study included neonates born before 37 weeks of gestation with platelet count < 150,000/mm3 during the 2 years preceding the new platelet transfusion protocol (high prophylactic transfusion threshold, 50,000/mm3) and during the 2 years after the new platelet transfusion protocol (low prophylactic transfusion threshold, 25,000/mm3). The primary outcome was the proportion of neonates receiving at least one platelet transfusion in both groups. We also compared the proportion of deaths and severe hemorrhage events. A total of 707 neonates with thrombocytopenia were identified. In the high-threshold group, 99/360 (27.5%) received at least one platelet transfusion as compared with 56/347 (16.1%) in the low-threshold group (p < 0.001). The groups did not differ in proportion of deaths or severe hemorrhage events.ConclusionsA reduced platelet-count threshold for transfusion allowed for a significant reduction in the number of platelet transfusions without increasing severe hemorrhage events.What is known• A recent randomized trial suggested that restrictive platelet-count thresholds for platelet transfusion could be beneficial for preterm neonates.What is new• On lowering the platelet-count threshold for transfusion from 50,000 to 25,000/mm3, the number of transfusions significantly decreased without increasing severe hemorrhage events in a neonatal intensive care unit.

Project description:ImportanceLow socioeconomic status (SES) has been associated with higher risk of rejection and graft loss in pediatric heart transplant (HT) recipients. The association of SES with other posttransplant morbidities is unknown.ObjectiveTo assess whether low SES is associated with higher risk of a major adverse transplant event (MATE) among pediatric HT recipients.Design, setting, and participantsRetrospective single-center cohort study at a children's hospital in Boston with consecutive primary HT recipients from 2006 to 2019 and follow-up through 2022. Data were analyzed from June 2023 to March 2024.ExposureVery low or low, moderate, and high or very high Childhood Opportunity Index (COI) for neighborhood (census tract) of patient residence.Main outcomes and measuresPrimary outcome was 3-year MATE-6 score assessed in 6-month survivors as cumulative burden of acute cellular rejection, antibody-mediated rejection, coronary vasculopathy, lymphoproliferative disease, kidney dysfunction, and infection, each as an ordinal score from 0 to 4 (24 for death or retransplant). Secondary outcomes were freedom from rejection during first 6 months, freedom from death or retransplant, MATE-3 score for events 1 to 3 (under immune suppression) and events 4 to 6 (chronic immune suppression effects), and each MATE component.ResultsOf 153 children analyzed, the median (IQR) age at HT was 7.2 (1.5-14.8) years, 99 (65%) were male, 16 (10%) were Black, 17 (11%) were Hispanic, and 106 (69%) were White. Fifty patients (33%) lived in very low or low, 17 (11%) in moderate, and 86 (56%) in high or very high COI neighborhoods. There was no significant group difference in mean (SD) 3-year MATE-6 score (very low or low COI, 3.4 [6.5]; moderate COI, 2.4 [6.3]; and high or very high COI, 4.0 [6.9]). Furthermore, there was no group difference in mean (SD) MATE-3 scores for underimmune suppression (very low or low COI, 1.9 [3.5]; moderate COI, 1.2 [3.2]; and high or very high COI, 2.2 [3.6]), chronic immune suppression effects (very low or low COI, 1.6 [3.3]; moderate COI, 1.1 [3.2]; and high or very high COI, 1.8 [3.6]), individual MATE components, rejection during the first 6 months, or death or retransplant.Conclusions and relevanceIn this cohort study of pediatric HT recipients, there was no difference in posttransplant outcomes among recipients stratified by SES, a notable improvement from prior studies. These findings may be explained by state-level health reform, standardized posttransplant care, and early awareness of outcome disparities.

Project description:PurposeSevere (grade 3-4) acute graft-versus-host disease (AGVHD) is a major cause of death after unrelated-donor (URD) hematopoietic cell transplant (HCT), resulting in particularly high mortality after HLA-mismatched transplantation. There are no approved agents for AGVHD prevention, underscoring the critical unmet need for novel therapeutics. ABA2 was a phase II trial to rigorously assess safety, efficacy, and immunologic effects of adding T-cell costimulation blockade with abatacept to calcineurin inhibitor (CNI)/methotrexate (MTX)-based GVHD prophylaxis, to test whether abatacept could decrease AGVHD.MethodsABA2 enrolled adults and children with hematologic malignancies under two strata: a randomized, double-blind, placebo-controlled stratum (8/8-HLA-matched URD), comparing CNI/MTX plus abatacept with CNI/MTX plus placebo, and a single-arm stratum (7/8-HLA-mismatched URD) comparing CNI/MTX plus abatacept versus CNI/MTX CIBMTR controls. The primary end point was day +100 grade 3-4 AGVHD, with day +180 severe-AGVHD-free-survival (SGFS) a key secondary end point. Sample sizes were calculated using a higher type-1 error (0.2) as recommended for phase II trials, and were based on predicting that abatacept would reduce grade 3-4 AGVHD from 20% to 10% (8/8s) and 30% to 10% (7/8s). ABA2 enrolled 142 recipients (8/8s, median follow-up = 716 days) and 43 recipients (7/8s, median follow-up = 708 days).ResultsIn 8/8s, grade 3-4 AGVHD was 6.8% (abatacept) versus 14.8% (placebo) (P = .13, hazard ratio = 0.45). SGFS was 93.2% (CNI/MTX plus abatacept) versus 82% (CNI/MTX plus placebo, P = .05). In the smaller 7/8 cohort, grade 3-4 AGVHD was 2.3% (CNI/MTX plus abatacept, intention-to-treat population), which compared favorably with a nonrandomized matched cohort of CNI/MTX (30.2%, P < .001), and the SGFS was better (97.7% v 58.7%, P < .001). Immunologic analysis revealed control of T-cell activation in abatacept-treated patients.ConclusionAdding abatacept to URD HCT was safe, reduced AGVHD, and improved SGFS. These results suggest that abatacept may substantially improve AGVHD-related transplant outcomes, with a particularly beneficial impact on HLA-mismatched HCT.

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

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

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