Ruxolitinib as the first post-steroid treatment for acute and chronic graft-versus-host disease

ABSTRACTIntroduction Acute and chronic graft-versus-host disease (GvHD) are potentially life-threatening complications occurring after allogeneic stem cell transplantation (allo-HSCT). Although steroids represent the first-line treatment for both conditions, in those patients who do not adequately benefit from steroid therapy, standardized treatment algorithms are lacking. In recent years, ruxolitinib has emerged as the most promising agent for the second-line therapy of steroid-refractory (SR)-GvHD.Areas covered This review will summarize the biological properties and the mechanistic aspects that justify the therapeutic role of ruxolitinib in GvHD. In addition, current treatment options for SR-GvHD will be briefly discussed. Finally, results of the most relevant clinical trials on the use of ruxolitinib for SR-GvHD will be analyzed, with a particular focus on two phase-III randomized trials in which ruxolitinib demonstrated its superiority in comparison with the best available therapy.Expert opinion Ruxolitinib has considerably improved the outcome of patients with SR-acute/chronic-GvHD and should be regarded as the standard-of-care option when corticosteroids fail or cannot be tapered. Nevertheless, a number of questions still remain unanswered and significant room for improvement exists. Additional observations derived from a longer follow-up will certainly increase our expertise in the management of this powerful therapy.KEYWORDS: acute-GvHDchronic-GvHDcorticosteroid-dependent GvHDcorticosteroid-refractory GvHDHSCTJAK1/2 inhibitorREACH studiesruxolitinib Article highlights The treatment of steroid-refractory (SR) and steroid-dependent (SD) GvHD has been a major unmet medical need for a long time, given the absence of established second-line therapeutic options.Ruxolitinib, a JAK1/2 inhibitor, has a pleiotropic effect, interfering with multiple pathways that contribute to development and maintenance of both acute and chronic GvHD.Ruxolitinib has been proven to be convincingly more effective than best available therapy (BAT) in two phase III randomized trials conducted in both acute and chronic GvHD, respectively.Ruxolitinib is well tolerated with manageable adverse events, mostly reversible hematological toxicity; incidence of infections is not greater than that observed with BAT.Pre-clinical data suggest that ruxolitinib does not impair GvL effect. However, further clinical studies are needed to confirm this hypothesis in vivo.After the achievement of FDA and EMA approval, and on the basis of the positive results of two phase III trials, ruxolitinib should be regarded as the standard-of-care option for the treatment of both acute and chronic GvHD when corticosteroids fail or cannot be tapered. However, additional studies and longer follow-up are warranted to further elucidate the therapeutic effect of ruxolitinib in the context of GvHD.Declaration of interestF Locatelli: Amgen: Speakers Bureau; Neovii: Speakers Bureau; Medac: Speakers Bureau; BlueBird bio: Speakers Bureau; Miltenyi: Speakers Bureau; Novartis: Honoraria, Speakers Bureau; SOBI: Speakers Bureau; Jazz Pharmaceuticals: Honoraria. M Algeri: Vertex Pharmaceuticals advisory board and steering committee membership. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.Reviewer disclosuresPeer reviewers on this manuscript have no relevant financial or other relationships to disclose. Novartis provided a scientific accuracy review at the request of the journal editor.Additional informationFundingThis paper was not funded.