Raising the bar for chronic GVHD trials

In this issue of Blood, Martin et al propose a new primary endpoint for clinical studies on chronic graft-versus-host disease (GVHD). Their results from a prospective multicenter observational study are helpful for designing future clinical trials in the treatment of chronic GVHD because the endpoint was shown to be associated with clinical benefit for the patient.¹ 

Since the first report 60 years ago, allogeneic stem cell transplantation has become a widely accepted treatment approach for numerous malignant and nonmalignant diseases and has saved several thousands of lives. However, almost half of the patients depending on donor and transplant characteristics will experience some form of chronic GVHD, which is the major cause of late morbidity and mortality after stem cell transplantation with severe impact on the quality of life.²  The first report on chronic GVHD in survivors after allogeneic stem cell transplantation was described by Shulman et al in 1978.³  In 1981, corticosteroids were introduced as treatment of chronic GVHD,⁴  and since then, despite improvement in preventing chronic GVHD,⁵  no clinical relevant progress in the treatment of chronic GVHD has been made.⁶ 

In two National Institutes of Health conferences in 2005 and 2014, experts in the field developed recommendations (some later confirmed, some rejected) on chronic GVHD regarding diagnosis, scoring, histopathology, response criteria, biomarkers, supportive care, and clinical trials, which resulted in numerous publications (summarized by Lee⁷ ), led to a harmonization of language, and enabled more meaningful clinical research via standardization of terms. How does the paper of Martin and colleagues improve the field? At first glance, defining a new primary endpoint with clinical benefit sounds less than exciting because a careful reader would expect any endpoint of a clinical study to ultimately result in a meaningful benefit for the patient. However, despite the major achievements in developing criteria for clinical trials in chronic GVHD,⁸  a uniform standard primary endpoint for studies on chronic GVHD has not yet been established, and any of the proposed endpoints could not convincingly demonstrate a clinical benefit for the patients. Thus, studies in chronic GVHD, either as salvage after steroid failure or as first-line therapy investigating new compounds, differ with respect to the primary endpoint and are hard to compare. In the past, it was believed that absence of secondary systemic treatment, nonrelapse mortality, and recurrent underlying malignancy would be a suitable composite endpoint for clinical studies. However, in the presented prospective, observational study, which included 328 patients, the authors were able to show that absence of secondary systemic treatment alone is not a reliable marker for adequate control of chronic GVHD, and only the inclusion of complete and partial response at 1 year into the composite endpoint was associated with a clinical benefit. Those patients who achieved a partial or complete remission according to National Institutes of Health criteria at 1 year without secondary systemic treatment had a lower mortality and an earlier termination of systemic treatment. One might suggest 6 months might be enough to determine clinical benefit. However, even if a substantial number of patients were lost to follow-up at 1 year and others were not evaluable for response assessment, measuring outcome according to response and absence of secondary systemic treatment at 6 months was too early because secondary systemic treatment as well as partial response or complete response occurred frequently between 6 and 12 months after the start of treatment. Unfortunately, but not unexpectedly, <20% of the patients achieved this new composite endpoint. The new composite endpoint resulted in clinical benefit, highlighting the major unmet clinical need for an effective and clinically relevant treatment option for chronic GVHD. It is hardly surprising that until now neither the US Food and Drug Administration nor the European Medicines Agency has approved any agent for treatment of chronic GVHD. The proposed primary new endpoint is certainly timely because new insights and advances in understanding pathogenesis of chronic GVHD are able to target signaling pathways such as Bruton tyrosine kinase, Janus kinase, and spleen tyrosine kinase, and such inhibitors among many novel agents are currently promising agents to treat chronic GVHD more effectively.⁹  Overall, in these exciting times with new mechanism-driven treatment options for chronic GVHD, the composite endpoint for prospective clinical trials in chronic GVHD is another step forward. For the first time, the outcome includes a measurable improvement for the patient, not just an improvement in the disease.