TY - JOUR
T1 - Phase II Trial of Costimulation Blockade With Abatacept for Prevention of Acute GVHD
AU - Watkins, Benjamin
AU - Qayed, Muna
AU - McCracken, Courtney
AU - Bratrude, Brandi
AU - Betz, Kayla
AU - Suessmuth, Yvonne
AU - Yu, Alison
AU - Sinclair, Shauna
AU - Furlan, Scott
AU - Bosinger, Steven
AU - Tkachev, Victor
AU - Rhodes, James
AU - Tumlin, Audrey Grizzle
AU - Narayan, Alexandria
AU - Cribbin, Kayla
AU - Gillespie, Scott
AU - Gooley, Ted A.
AU - Pasquini, Marcelo C.
AU - Hebert, Kyle
AU - Kapoor, Urvi
AU - Rogatko, Andre
AU - Tighiouart, Mourad
AU - Kim, Sungjin
AU - Bresee, Catherine
AU - Choi, Sung W.
AU - Davis, Jeffrey
AU - Duncan, Christine
AU - Giller, Roger
AU - Grimley, Michael
AU - Harris, Andrew C.
AU - Jacobsohn, David
AU - Lalefar, Nahal
AU - Norkin, Maxim
AU - Farhadfar, Nosha
AU - Pulsipher, Michael A.
AU - Shenoy, Shalini
AU - Petrovic, Aleksandra
AU - Schultz, Kirk R.
AU - Yanik, Gregory A.
AU - Waller, Edmund K.
AU - Levine, John E.
AU - Ferrara, James L.
AU - Blazar, Bruce R.
AU - Langston, Amelia
AU - Horan, John T.
AU - Kean, Leslie S.
N1 - Publisher Copyright:
© 2021 by American Society of Clinical Oncology.
PY - 2021/6/10
Y1 - 2021/6/10
N2 - 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.
AB - 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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UR - http://www.scopus.com/inward/citedby.url?scp=85107605861&partnerID=8YFLogxK
U2 - 10.1200/jco.20.01086
DO - 10.1200/jco.20.01086
M3 - Article
C2 - 33449816
AN - SCOPUS:85107605861
SN - 0732-183X
VL - 39
SP - 1865
EP - 1877
JO - Journal of Clinical Oncology
JF - Journal of Clinical Oncology
IS - 17
ER -