[HTML][HTML] Phase II trial of costimulation blockade with abatacept for prevention of acute GVHD
B Watkins, M Qayed, C McCracken… - Journal of clinical …, 2021 - ncbi.nlm.nih.gov
B Watkins, M Qayed, C McCracken, B Bratrude, K Betz, Y Suessmuth, A Yu, S Sinclair…
Journal of clinical oncology, 2021•ncbi.nlm.nih.govPURPOSE Severe (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 …
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 …
Abstract
PURPOSE
Severe (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.
METHODS
ABA2 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).
RESULTS
In 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.
CONCLUSION
Adding 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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