Ruxolitinib in GvHD (RIG) study: a multicenter, randomized phase 2 trial to determine the response rate of Ruxolitinib and best available treatment (BAT) versus BAT in steroid-refractory acute graft-versus-host disease (aGvHD) (NCT02396628)

Nikolas Von Bubnoff,Justus Duyster,Gabriele Ihorst,Nadine Röthling,Jürgen Finke,Hartmut Bertz,Olga Grishina,Robert Zeiser

doi:10.1186/s12885-018-5045-7

Abstract

BackgroundGraft-versus-Host Disease (GvHD) causes significant morbidity and mortality in patients after allogeneic stem cell transplantation. Donor T-cells cause inflammation and tissue damage in GvHD target organs such as liver, gut and skin. Cytokine receptor associated kinases JAK1 and JAK2 are critical for inflammatory cytokine response in GvHD. Ruxolitinib is a small molecule inhibitor of JAK1 and JAK2. Preliminary data indicated substantial clinical activity in patients with steroid-refractory (SR) acute and chronic GvHD.MethodsThe RIG-study is an investigator-initiated open-label, multicenter, prospective randomized controlled two-arm phase 2 study, comparing the efficacy of ruxolitinib and best available treatment (BAT) versus BAT in steroid-refractory acute GvHD (SR-aGvHD). Patients with acute skin, intestinal or liver GvHD > grade 1 and failure of previous treatment are eligible. The trial aims to include 160 patients who will be randomized in a 1:1 ratio and stratified by GvHD grade (≤ grade 3 versus grade 4) and number of previous immunosuppressive treatments (≤ 3 versus ≥4). The primary endpoint is the overall response rate at day 28, defined as: Improvement of at least one stage in the severity of acute GvHD in one organ without deterioration in any other organ, or disappearance of any GvHD signs from all organs without requirement for new systemic immunosuppressive treatment. Secondary objectives include time to response, overall survival, event-free survival, non-relapse mortality (NRM), failure-free survival, graft failure rates, quality of life and changes in serum levels of pro-inflammatory cytokines and GvHD-related biomarkers.DiscussionThis randomized prospective trial will provide further evidence if the retrospectively collected data demonstrating activity of ruxolitinib for SR-aGvHD can be reproduced. A major advantage of ruxolitinib might be the limited and predictable toxicity profile compared to other immunosuppressive therapies that mainly includes viral reactivation and cytopenias. This trial will establish candidate biomarkers to predict and monitor responses to ruxolitinib. As a next step ruxolitinib might be tested upfront against steroids or in a preemptive manner to prevent GvHD to occur.Trial registrationNCT02396628 (registration date 17.07.2015); DRKS00007939 (registration date 26.03.2015).

Highlights

Graft-versus-Host Disease (GvHD) causes significant morbidity and mortality in patients after allogeneic stem cell transplantation
The development of GvHD in humans is preceded by a dramatic change in the intestinal microflora [2, 9], which could be in part due to a massive influx of neutrophils into the intestinal immune compartment [10] because neutrophils can release proteases and antimicrobial peptides [11] that affect bacteria
In an allogeneic system we demonstrated that co-incubation with ruxolitinib strongly suppressed both the proliferation of allogeneic T cells and the production of inflammatory cytokines [17]

Summary

Introduction

Graft-versus-Host Disease (GvHD) causes significant morbidity and mortality in patients after allogeneic stem cell transplantation. Steroid-refractory GvHD constitutes the major factor for morbidity and accounts for up to one third of deaths in patients after allogeneic stem cell transplantation [1]. For these patients, there is currently no established standard treatment. The development of GvHD in humans is preceded by a dramatic change in the intestinal microflora [2, 9], which could be in part due to a massive influx of neutrophils into the intestinal immune compartment [10] because neutrophils can release proteases and antimicrobial peptides [11] that affect bacteria This neutrophil infiltration was observed at late time points after allo-HCT in patients with active GvHD [12]. It was shown that neutrophil activation is dependent on JAK 1/2 signaling [13, 14]

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