A phase 2a randomized clinical trial of intravenous vedolizumab for the treatment of steroid-refractory intestinal acute graft-versus-host disease

Yngvar Fløisand,Chunlin Chen,Mark A Schroeder,Andrejus Parfionovas,Yi-Bin Chen,Johan Jansson,Steven Devine,Ibrahim Yakoub-Agha,Mona Akbari,Mohamad Mohty,Syed Quadri,Anne S Renteria,Dominik Selleslag,Patrice Chevallier

doi:10.1038/s41409-021-01356-0

Abstract

Steroid-refractory (SR) acute graft-versus-host disease (aGvHD) remains a significant complication after allogeneic hematopoietic cell transplantation. Systemic corticosteroids are first-line therapy for aGvHD, but apart from ruxolitinib, there are no approved treatments for SR aGvHD. Vedolizumab is approved for treatment of ulcerative colitis and Crohn’s disease, and may be effective for treatment of SR intestinal aGvHD. We conducted a phase 2a trial (NCT02993783) to evaluate the clinical efficacy, tolerability, and safety of vedolizumab 300 and 600 mg for SR intestinal aGvHD. This study was terminated before full enrollment was completed because early results failed to demonstrate positive proof-of-concept in efficacy. Before termination, 17 participants had enrolled and an early response in intestinal aGvHD was observed in 11 and eight participants at days 15 and 28, respectively. All adverse events observed were consistent with those expected in a population with SR intestinal aGvHD. Overall, vedolizumab did not meet the primary efficacy endpoint (overall response at day 28), likely owing to premature study drug discontinuation, lack of efficacy, and the competing risks inherent with a population with advanced SR intestinal aGvHD. Nevertheless, this study provides valuable insights into the considerations needed when conducting studies in patients with SR intestinal aGvHD.

Highlights

Allogeneic hematopoietic cell transplantation is an important and potentially curative therapy for many hematologic
Four participants (30.8%) discontinued owing to ‘other’ reasons, including death (n = 3) and withdrawal (n = 1), three participants (23.1%) owing to a treatment-emergent serious adverse events (TEAEs), and one participant (7.7%) owing to progression of an underlying malignancy. Of those who discontinued for reasons other than unsatisfactory therapeutic response or progression of acute graft-versus-host disease (aGvHD) (n = 8), at the last study assessment only two were recorded as having no intestinal aGvHD involvement, suggesting that most had not responded to treatment at the time that they discontinued the study drug
While early clinical benefit (64.7% overall response (OR) rate at day 15) was observed in approximately two-thirds of participants, less than half obtained an OR in intestinal aGvHD by day 28, with a significant number (n = 8) of participants dying from complications of aGvHD

Summary

Introduction

Acute GvHD (aGvHD), which generally occurs in the first few months after allogeneic hematopoietic stem cell transplantation, typically involves the skin, liver, and/or intestine [2,3,4]. After conventional allogeneic hematopoietic cell transplantation, the incidence of aGvHD ranges from 10% to 80% (dependent on certain clinical risk factors) in patients receiving T-cell-replete allogeneic grafts, despite standard measures of prophylaxis [5,6,7]. Hematology Oncology, Cellular and Gene Therapy, ICON Clinical Research Service, New York, NY, USA. Hematopoietic Cell Transplant and Cellular Therapy Program, Massachusetts General Hospital, Boston, MA, USA. We present data from a phase 2a clinical trial (NCT02993783), which prospectively investigated the clinical efficacy, tolerability, and safety of vedolizumab for the treatment of SR intestinal aGvHD

Study design

Results

Discussion

Compliance with ethical standards