Phase 1 clinical trial evaluating abatacept in patients with steroid-refractory chronic graft-versus-host disease

Blood. 2018 Jun 21;131(25):2836-2845. doi: 10.1182/blood-2017-05-780239. Epub 2018 Mar 16.

Abstract

Steroid-refractory chronic graft-versus-host disease (SR-cGVHD) remains a major cause of morbidity and mortality after allogeneic stem cell transplantation. Innovative immunotherapeutic strategies are urgently needed for the treatment of SR-cGVHD. We conducted a phase 1 clinical trial to evaluate the safety, efficacy, and immune effects of abatacept, a novel immunomodulatory drug that acts as an inhibitor of T-cell activation via costimulatory blockade, in the treatment of SR-cGVHD. The study followed a 3+3 design with 2 escalating abatacept doses: 3 mg/kg and 10 mg/kg, with an expansion cohort treated at 10 mg/kg. Abatacept was well-tolerated with no dose-limiting toxicities. Of the 16 evaluable patients, 44% achieved a clinical partial response per 2005 National Institutes of Health Consensus Criteria. Importantly, abatacept resulted in a 51.3% reduction in prednisone usage in clinical responders (mean baseline, 27 vs 14 mg; P = .01). Increased PD-1 expression on circulating CD4 (P = .009) and CD8 (P = .007) T cells was observed in clinical responders. In summary, abatacept was safe and led to a marked improvement in National Institutes of Health cGVHD scores and a significant reduction in prednisone use. In this cohort of heavily pretreated patients, the results suggest abatacept may be a promising therapeutic agent for SR-cGVHD, and a phase 2 trial has been initiated. This trial was registered at www.clinicaltrials.gov as #NCT01954979.

Publication types

  • Clinical Trial, Phase I
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abatacept / administration & dosage
  • Abatacept / adverse effects
  • Abatacept / therapeutic use*
  • Adult
  • Aged
  • Chronic Disease
  • Cohort Studies
  • Female
  • Glucocorticoids / administration & dosage
  • Glucocorticoids / therapeutic use
  • Graft vs Host Disease / drug therapy*
  • Graft vs Host Disease / immunology
  • Graft vs Host Disease / pathology
  • Hematopoietic Stem Cell Transplantation / adverse effects
  • Humans
  • Immunosuppressive Agents / administration & dosage
  • Immunosuppressive Agents / adverse effects
  • Immunosuppressive Agents / therapeutic use*
  • Male
  • Middle Aged
  • Prednisone / administration & dosage
  • Prednisone / therapeutic use
  • Programmed Cell Death 1 Receptor / analysis
  • Programmed Cell Death 1 Receptor / immunology
  • T-Lymphocytes / drug effects*
  • T-Lymphocytes / immunology
  • T-Lymphocytes / pathology
  • Transplantation, Homologous / adverse effects
  • Young Adult

Substances

  • Glucocorticoids
  • Immunosuppressive Agents
  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor
  • Abatacept
  • Prednisone

Associated data

  • ClinicalTrials.gov/NCT01954979