Phase II Trial of Costimulation Blockade With Abatacept for Prevention of Acute GVHD. Issue 17 (10th June 2021)

• Record Type: Journal Article
• Authors: Watkins, Benjamin; Qayed, Muna; McCracken, Courtney; Bratrude, Brandi; Betz, Kayla; Suessmuth, Yvonne; Yu, Alison; Sinclair, Shauna; Furlan, Scott; Bosinger, Steven; Tkachev, Victor; Rhodes, James; Tumlin, Audrey Grizzle; Narayan, Alexandria; Cribbin, Kayla; Gillespie, Scott; Gooley, Ted A.; Pasquini, Marcelo C.; Hebert, Kyle; Kapoor, Urvi; Rogatko, Andre; Tighiouart, Mourad; Kim, Sungjin; Bresee, Catherine; Choi, Sung W.; Davis, Jeffrey; Duncan, Christine; Giller, Roger; Grimley, Michael; Harris, Andrew C.; Jacobsohn, David; Lalefar, Nahal; Norkin, Maxim; Farhadfar, Nosha; Pulsipher, Michael A.; Shenoy, Shalini; Petrovic, Aleksandra; Schultz, Kirk R.; Yanik, Gregory A.; Waller, Edmund K.; Levine, John E.; Ferrara, James L.; Blazar, Bruce R.; Langston, Amelia; Horan, John T.; Kean, Leslie S.;
• Is Part Of: Journal of clinical oncology. Volume 39:Issue 17(2021)
• Page Start: 1865
• Page End: 1877
• Publication Date: 2021-06-10
• Subjects: Oncology -- Periodicals; Cancer -- Periodicals; Oncology; Medical Oncology; Cancérologie -- Périodiques; Cancer -- Périodiques; Cancérologie; Cancer; Oncology; Oncologia; Càncer; Periodicals; 616.994
• DOI: 10.1200/JCO.20.01086
• Languages: English
• ISSNs: 0732-183X

Abstract

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.