Beyond ruxolitinib in steroid‐refractory acute graft‐versus‐host disease

Abstract

Steroid-refractory acute graft-versus-host disease (SR-aGVHD) is a debilitating complication of allogeneic haematopoietic cell transplantation (HCT) and is associated with high mortality. Until recently, there has been no accepted standard-of-care treatment for SR-aGVHD. Treatment options have included extracorporeal photopheresis (ECP), anti-TNF-a antibodies, anti-thymocyte globulin (ATG), and anti-IL-2R antibodies, amongst others. While initially effective, durable treatment responses are difficult to achieve and each therapy is frequently complicated with toxicity. SR-aGVHD often leads to death primarily attributed to GVHD progression, infection, or cancer recurrence. As such, treatments for SR-aGVHD have been tailored based upon physicians’ experience, patients’ comorbidities, and potential drug toxicities. In May 2019, ruxolitinib became the first FDA-approved front-line treatment for SR-aGVHD in adult and paediatric patients ≥12 years old, based upon data from the REACH1 study. Following this pivotal trial, the phase III randomized study of ruxolitinib versus best available therapy (BAT) for the treatment of SR-aGVHD (REACH2) continued to demonstrate a superior day 28 overall response of 62% and day 56 durable overall response of 40% compared to BAT. Adverse events mainly consisted of anaemia and thrombocytopenia, and overall led to the discontinuation of ruxolitinib treatment in 11% of patients. Otherwise, lack of efficacy leading to treatment discontinuation occurred in 21% of patients. While REACH2 allowed cross-over of patients onto ruxolitinib treatment on or after day 28 after failure of BAT, the study was not designed to evaluate outcomes following subsequent SR-aGVHD treatments, following ruxolitinib failure or intolerance. In this issue of British Journal of Haematology, Abedin and colleagues use real-world data to report on treatment responses and survival to next line of treatment following ruxolitinib resistance or intolerance in SR-aGVHD. The majority of patients had a response to ruxolitinib treatment with a rate similar to those published in the REACH trials. However, as expected, responses to salvage treatments after discontinuing ruxolitinib were limited and survival was poor, indicating that effective SR-aGVHD therapy beyond ruxolitinib is still an unmet need. It is noteworthy to mention that this study cohort consisted mainly of patients with high-risk features of aGVHD, including a high proportion of stage III/ IV disease with gastrointestinal (GI) involvement. In addition, among the 64 patients who had discontinued ruxolitinib, only 15 (23%) received ruxolitinib as front-line therapy for SR-aGVHD, again indicating a baseline high-risk population as a majority of the patients failed front-line therapy for SR-aGVHD. Among the 48 of 64 patients who were ruxolitinib-resistant, 33 patients received next line of treatment as a single agent or concurrently with ruxolitinib and 12 patients (36%) had a response, with most being partial responses. Similarly, only half of the patients who were deemed ruxolitinib-intolerant and received next line of therapy had at most partial response. Given the relatively small number of patients and study design, independent predictors for ruxolitinib failure could not be determined. The authors also acknowledge the need to study a larger number of patients who received ruxolitinib as front-line therapy for SR-aGVHD to truly determine the incidence of ruxolitinib resistance or intolerance, response to next line therapies, and longer-term outcomes in modernday practice. Nonetheless, their results suggest a need to develop clinical trials testing novel agents for SR-aGVHD following ruxolitinib. Correspondence: Catherine J. Lee, Utah Transplantation & Cellular Therapy Program, Huntsman Cancer Institute at University of Utah, Salt Lake City, UT, USA. E-mail: [email protected] commentary