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Clinical Trial
. 2021 Jun 10;39(17):1865-1877.
doi: 10.1200/JCO.20.01086. Epub 2021 Jan 15.

Phase II Trial of Costimulation Blockade With Abatacept for Prevention of Acute GVHD

Benjamin Watkins  1 , Muna Qayed  1 , Courtney McCracken  2 , Brandi Bratrude  3 , Kayla Betz  3 , Yvonne Suessmuth  1 , Alison Yu  3 , Shauna Sinclair  4 , Scott Furlan  5 , Steven Bosinger  6 , Victor Tkachev  3 , James Rhodes  7 , Audrey Grizzle Tumlin  7 , Alexandria Narayan  5 , Kayla Cribbin  4 , Scott Gillespie  2 , Ted A Gooley  5 , Marcelo C Pasquini  8 , Kyle Hebert  8 , Urvi Kapoor  9 , Andre Rogatko  10 , Mourad Tighiouart  10 , Sungjin Kim  10 , Catherine Bresee  10 , Sung W Choi  11 , Jeffrey Davis  12 , Christine Duncan  3 , Roger Giller  13 , Michael Grimley  14 , Andrew C Harris  15 , David Jacobsohn  16 , Nahal Lalefar  17 , Maxim Norkin  18 , Nosha Farhadfar  19 , Michael A Pulsipher  20 , Shalini Shenoy  21 , Aleksandra Petrovic  4 , Kirk R Schultz  12 , Gregory A Yanik  11 , Edmund K Waller  22 , John E Levine  9 , James L Ferrara  9 , Bruce R Blazar  23 , Amelia Langston  22 , John T Horan  3 , Leslie S Kean  3
Affiliations
Clinical Trial

Phase II Trial of Costimulation Blockade With Abatacept for Prevention of Acute GVHD

Benjamin Watkins et al. J Clin Oncol. .

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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Conflict of interest statement

Benjamin WatkinsConsulting or Advisory Role: Bristol Myers SquibbPatents, Royalties, Other Intellectual Property: Patent pending for “Method to prevent relapse after transplant” Muna QayedConsulting or Advisory Role: Novartis, MesoblastTravel, Accommodations, Expenses: Novartis Steve BosingerResearch Funding: GlaxoSmithKline Victor TkachevTravel, Accommodations, Expenses: Regeneron Ted A. GooleyConsulting or Advisory Role: Kiadis Pharma, Pharmacyclics, REGiMMUNE Marcelo C. PasquiniConsulting or Advisory Role: Pfizer, Medigene, Celgene, AmgenResearch Funding: Kite/Gilead, Novartis, Celgene, Bristol Myers Squibb Roger GillerResearch Funding: Bristol-Myers Squibb, Jazz Pharmaceuticals, Atara Maxim NorkinResearch Funding: Celgene Nosha FarhadfarConsulting or Advisory Role: IncyteResearch Funding: CSL Behring Michael A PulsipherHonoraria: Amgen, Bellicum Pharmaceuticals, Miltenyi BiotecConsulting or Advisory Role: Novartis, CSL Behring, Jasper Therapeutics, NovartisSpeakers' Bureau: NovartisResearch Funding: Adaptive Biotechnologies, Miltenyi BiotecTravel, Accommodations, Expenses: Medac, Bellicum Pharmaceuticals, Miltenyi Biotec Shalini ShenoyHonoraria: Novartis, JazzConsulting or Advisory Role: as listed previously, California Institute of Regenerative MedicineTravel, Accommodations, Expenses: as listed above Aleksandra PetrovicConsulting or Advisory Role: Orchard, CSL Behring Kirk R. SchultzHonoraria: ShireConsulting or Advisory Role: MesoScale Discovery, Juno TherapeuticsTravel, Accommodations, Expenses: Jazz Pharmaceuticals Gregory A. YanikResearch Funding: Jazz Pharmaceuticals Edmund K. WallerEmployment: Cambium Medical TechnologiesLeadership: Cambium Medical Technologies, Cambium Oncology, Cambium OncologyStock and Other Ownership Interests: Cambium Medicl Technologies, Cambium Oncology, Cerus, ChimerixHonoraria: Novartis, Partners, Verastem, Kite Pharma, Pharmacyclics, KaryopharmaConsulting or Advisory Role: Novartis, Verastem, Pharmacyclics, Karyopharm Therapeutics, Partners Healthcare, Kite PharmaResearch Funding: Novartis, Amgen, Juno Therapeutics, Verastem, Partners Healthcare, Partners HealthcarePatents, Royalties, Other Intellectual Property: Received Royalties from patent on preparing platelet lysate that has been licensed to Cambium Medical TechnologiesTravel, Accommodations, Expenses: Pharmacyclics John E. LevineConsulting or Advisory Role: Incyte, Novartis, Talaris, Bluebird Bio, MesoblastResearch Funding: Incyte, Kamada, BiogenPatents, Royalties, Other Intellectual Property: GVHD biomarkers patent licensed to Viracor James L. FerraraHonoraria: Incyte, Mallinckrodt, Equillium, KamdaConsulting or Advisory Role: OmerosResearch Funding: Kamada, IncytePatents, Royalties, Other Intellectual Property: Royalties from an IP licenseTravel, Accommodations, Expenses: Incyte Bruce R. BlazarStock and Other Ownership Interests: Five Prime Therapeutics, BlueRock Therapeutics, Tmunity Therapeutics, Inc, Magenta TherapeuticsHonoraria: Kadmon, REGiMMUNE, Dr Reddy's Laboratories, Incyte, GT Biopharma, bioverativConsulting or Advisory Role: Kadmon, BlueRock Therapeutics, Magenta TherapeuticsResearch Funding: Tmunity Therapeutics, Inc, Fate Therapeutics, BlueRock Therapeutics, Alpine Immune Sciences, RXI Pharmaceuticals, AbbvieTravel, Accommodations, Expenses: Incyte, Magenta Therapeutics, Dr Reddy's Laboratories, bioverativ, Intellia Therapeutics, Rheos Amelia LangstonResearch Funding: Chimerix, Astellas Pharma, Incyte, Takeda, Jazz Pharmaceuticals, Kadmon, Novartis Leslie S. KeanHonoraria: Gilead SciencesConsulting or Advisory Role: HiFiBio, Forty Seven, EMD SeronoResearch Funding: Magenta Therapeutics, Bluebird Bio, Kyocera, Regeneron, Gilead Sciences, BEAM Therapeutics, Bristol Myers SquibbPatents, Royalties, Other Intellectual Property: Licensing Fees for ABA2 clinical trial dataNo other potential conflicts of interest were reported.

Figures

FIG 1.
FIG 1.
CONSORT diagrams. (A) 7/8 stratum. (B) 8/8 stratum. aPatients were randomly assigned between March 1, 2013, and December 9, 2014. Following a protocol amendment, subjects in the 7/8 cohort were nonrandomly assigned to receive abatacept. The remaining 7/8 patients were randomly assigned between December 19, 2014, and November 30, 2016. bPatient determined to be ineligible because of disease progression prior to day 1. cPatient excluded because of confirmation of Li-Fraumeni Syndrome prior to day 1.
FIG 2.
FIG 2.
Key GVHD outcomes. (A) 7/8 Cohort, cumulative incidence of grade 3-4 AGVHD. Number of patients at risk and censored are listed below the graph. (B) 8/8 Cohort, cumulative incidence of grade 3-4 AGVHD. Number of patients at risk and censored are listed below the graph. (C) 7/8 Cohort, cumulative incidence of grade 2-4 AGVHD. Number of patients at risk and censored are listed below the graph. (D) 8/8 Cohort, cumulative incidence of grade 3-4 AGVHD. Number of patients at risk and censored are listed below the graph. (E) 7/8 Cohort: cumulative incidence of severe AGVHD-free-survival (SGFS). Number of patients at risk and censored are listed below the graph. (F) 8/8 Cohort: cumulative incidence of SGFS. Number of patients at risk and censored are listed below the graph. (G) 7/8 Cohort: cumulative incidence of moderate-severe CGVHD. Number of patients at risk and censored are listed below the graph. (H) 8/8 Cohort: Cumulative incidence of moderate-severe CGVHD. Number of patients at risk and censored are listed below the graph. 7/8 Cohort: Blue: CIBMTR control cohort. Solid red: 7/8 abatacept cohort, matched to the CIBMTR controls. Dashed red: 7/8 intention-to-treat (ITT) cohort. P values represent comparison of 7/8 abatacept cohort and CIBMTR control cohort. 8/8 Cohort: Blue: placebo. Red: abatacept. ABA, abatacept; AGVHD, acute graft-versus-host disease; ATG, anti-thymocyte globulin; CGVHD, chronic GVHD; CIBMTR, Center for International Blood and Marrow Transplant Research.
FIG 3.
FIG 3.
Key transplant outcomes. (A) 7/8 Cohort, cumulative incidence of nonrelapse mortality (NRM). Number of patients at risk and censored are listed below the graph. (B) 8/8 Cohort, cumulative incidence of NRM. Number of patients at risk and censored are listed below the graph. (C) 7/8 Cohort, cumulative incidence of relapse-free survival (RFS). Number of patients at risk and censored are listed below the graph. (D) 8/8 Cohort, cumulative incidence of RFS. Number of patients at risk and censored are listed below the graph. (E) 7/8 Cohort, cumulative incidence of. Number of patients at risk and censored are listed below the graph. (F) 8/8 Cohort, cumulative incidence of OS. Number of patients at risk and censored are listed below the graph. 7/8 Cohort: Blue: CIBMTR control cohort. Solid red: 7/8 abatacept cohort, matched to the CIBMTR controls. Dashed red: 7/8 intention-to-treat (ITT) cohort. P values represent comparison of 7/8 abatacept cohort and CIBMTR control cohort. 8/8 Cohort: Blue: Placebo. Red: Abatacept. ABA, abatacept; ATG, anti-thymocyte globulin; CIBMTR, Center for International Blood and Marrow Transplant Research; OS, overall survival.
FIG 4.
FIG 4.
Post-transplant immunologic analysis. (A) Percent of CD4+ naive T cells (compared with total CD4+ T cells). ANOVA P value = .00004; 8/8 ABA versus 7/8 ABA P = .99; 8/8 ABA versus 8/8 placebo P = .0001; 7/8 ABA versus 8/8 placebo P = .0016. (B) Percent of CD4+ effector-memory T cells (compared with total CD4+ T cells). ANOVA P value = .0052; 8/8 ABA versus 7/8 ABA P = .52; 8/8 ABA versus 8/8 Placebo P = .0034; 7/8 ABA versus 8/8 placebo P = .18. (C) Percent of CD4+ naive T cells (compared with total CD4+ T cells), dichotomized by grade 3-4 AGVHD. ABA patients with no grade 3-4 GVHD versus ABA patients with grade 3-4 GVHD P = .024. In A-C, data are shown as the percentage ± SEM. In A-B, dashed red = 7/8 ABA intent-to treat; solid red = 8/8 ABA; solid blue = 8/8 placebo; in C, dashed red = 8/8 ABA with grade 3-4 AGVHD; solid red = 8/8 ABA without grade 3-4 AGVHD; dashed blue: 8/8 placebo with grade 3-4 AGVHD; solid blue = 8/8 placebo without grade 3-4 AGVHD. (D) Transcriptomic analysis pipeline. (E) Weighted gene coexpression network analysis heatmap. Heatmap demonstrates the correlation (using a blue-red false color scale) of weighted gene coexpression network analysis gene modules (colored turquoise, blue, green, and red) in transcriptomic samples grouped by clinical metadata. Row or column order is determined by hierarchical clustering of the module eigengene with clinical metadata for each sample. (F) Gene set enrichment analysis of the turquoise WGCNA module in a ranked list of differentially expressed genes between patients receiving abatacept (left) and patients receiving standard prophylaxis (right). The gene list was generated with a cutoff of FDR < 0.001 by gene-set permutation testing. (G) Ingenuity pathway analysis of the 93-gene subset of the turquoise module. Yellow: proliferation genes; black: apoptosis genes; blue: checkpoint genes; green: metabolism genes; red: T-cell activation genes. Solid lines: direct interactions; dashed lines: indirect interactions. ABA, abatacept; AGVHD, acute graft-versus-host disease; CMV, Cytomegalovirus; EBV, Epstein-Barr virus; FDR, False Discovery Rate; HC, hematopoietic cell; NRM, nonrelapse mortality.
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References

    1. Bunin N, Carston M, Wall D, et al. Unrelated marrow transplantation for children with acute lymphoblastic leukemia in second remission Blood 993151–31572002 - PubMed
    1. Bunin NJ, Davies SM, Aplenc R, et al. Unrelated donor bone marrow transplantation for children with acute myeloid leukemia beyond first remission or refractory to chemotherapy J Clin Oncol 264326–43322008 - PMC - PubMed
    1. Lee SJ, Klein J, Haagenson M, et al. High-resolution donor-recipient HLA matching contributes to the success of unrelated donor marrow transplantation Blood 1104576–45832007 - PubMed
    1. Shaw PJ, Kan F, Woo Ahn K, et al. Outcomes of pediatric bone marrow transplantation for leukemia and myelodysplasia using matched sibling, mismatched related, or matched unrelated donors Blood 1164007–40152010 - PMC - PubMed
    1. Woolfrey A, Klein JP, Haagenson M, et al. HLA-C antigen mismatches are associated with worse outcomes in unrelated donor peripheral blood stem cell transplantation Biol Blood Marrow Transplant 17885–8922011 - PMC - PubMed

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