Chronic Graft-versus-Host Disease: A Long Road Ahead

Chronic graft-versus-host disease (GVHD) remains a significant contributor to long-term morbidity and mortality after allogeneic hematopoietic cell transplantation (HCT). Up to half of all HCT patients will develop chronic GVHD, and patients with moderate to severe disease require systemic immunosuppressive therapy (IST) [1,2]. In their study, Lee et al. [3] closely follow the pattern of IST use in clinical practice in a single-center cohort of 250 chronic GVHD patients enrolled in their prospective observational study. After a median follow-up of 5.6 years, only about one third of survivors were alive and off IST, whereas one third remained on IST (with half past third-line therapy) and one third relapsed or died. The most remarkable finding was that only a minority of patients were alive and off IST years after allogeneic HCT, highlighting the suboptimal efficacy of current chronic GVHD treatment.

This study further assessed the success rate of individual first and subsequent lines of IST by failure-free survival, defined as no additional systemic therapy and no relapse or death in 6 months. For any given agent in any line of therapy, the failure-free survival rate was quite low ranging, from 10% to 30%, and the majority of patients received 3 or more lines of therapy. The pattern of IST discontinuation was also examined in this study; only half of all patients underwent an initial attempt at IST discontinuation. After stopping IST the first time, about half the patients had to restart IST at a median of 3.4 months. Subsequent attempts to stop IST were met with one third of patients having to restart therapy at a median of 6 months. Increased length of time from transplant was identified as a predictor for successfully stopping IST, while oral and skin manifestations were associated with restarting IST. In a subset analysis of patients enrolled within 3 months of chronic GVHD diagnosis, the median time to permanent IST discontinuation was 69 months. This detailed clinical data illustrate the protracted, complex treatment course experienced by patients with chronic GVHD.

In summary, this study by Lee et al. provides clinically useful natural history data about the expected time course and chance of success with standard chronic GVHD therapy including attempts at discontinuation of IST. This paper affirms what we convey to patients when we consent them for HCT: one has about a 15% chance of suffering on the long and unrelenting road of chronic GVHD. Importantly, this article also points to the fact that half of the patients who respond well to initial therapy will have chronic GVHD relapse within 3 months of IST taper. Although further study is needed to draw guidelines, these data suggest that we should consider lifelong IST or immunomodulatory therapy in patients after first chronic GVHD relapse.

In their article, by affirming the suboptimal efficacy and prolonged course of current mainstay treatments, the authors also reinforce the need for chronic GVHD prevention. Strategies to avert moderate-severe chronic GVHD must be weighed against opposing risk of graft rejection, added infectious risk, and increased risk of cancer relapse. We know we can do this using in vivo T cell depletion with anti-thymocyte globulin, but the cost in terms of tumor relapse remains highly controversial [4,5]. Emerging data with haploidentical transplants and bone marrow products also appear promising [6–9]. B cell depletion early after HCT appears to prevent chronic GVHD in those patients capable of robust B cell recovery [10]. Recent advances in understanding the pathobiology and genesis of chronic GVHD will continue to guide the development of novel treatment strategies such as inhibition of the Janus kinase, Bruton tyrosine kinase, and spleen tyrosine kinase pathways [11,12]. Prospective trials of these and other novel agents are underway, and findings from these trials are urgently needed to identify more effective treatment strategies for chronic GVHD that provide long term clinical benefit. Trials addressing use of chronic GVHD–directed agents to prevent chronic GVHD must now also be designed.