In this issue of Blood, Miklos et al present results from a prospective phase 1b/2 study on the Bruton tyrosine kinase (BTK) inhibitor ibrutinib in patients in need of salvage immunosuppressive treatment for chronic graft-versus-host disease (GVHD). High sustained response rates among other findings led for the first time to US Food and Drug Administration (FDA) approval of an agent in refractory chronic GVHD.1
Chronic GVHD remains the major cause of morbidity and nonrelapse mortality (NRM) after allogeneic hematopoietic cell transplantation, affecting 30% to 70% of patients. It is a pleomorphic syndrome with allo- and autoimmune features and can affect multiple organs with various degrees of severity.2,3 Most frequently, skin, oral mucosa, and eyes are involved, requiring systemic immunosuppressive treatment for symptom relief and avoidance of organ toxicities. Corticosteroids with or without calcineurin inhibitors and meticulous organ-specific care remain the mainstays of therapy.4 Corticosteroids are profoundly anti-inflammatory and broadly immunosuppressive, affecting both innate and adaptive immunity and causing serious adverse effects. Besides corticosteroids, other immunosuppressants and extracorporeal photopheresis (ECP) are commonly used, but none have been approved.5,6 With current approaches, treatment success defined as achievement of complete (CR) or partial response (PR) at 1 year without secondary systemic treatment has been observed in fewer than 20% of patients, and a vast majority require several years of systemic treatment.7
Miklos et al investigated the safety and efficacy of BTK inhibitor ibrutinib in patients with chronic GVHD in need of salvage immunosuppressive treatment. The authors must be congratulated for their huge effort and high-level study performance, enrolling 42 patients with steroid-refractory or -dependent National Institutes of Health (NIH)–defined chronic GVHD for whom 1 to 3 prior treatments had failed. Most patients had cutaneous and oral mucosal manifestations as required per protocol, and 57% had 2 organs involved. At a median follow-up of 13.9 months, best overall response rate (ORR) defined as the proportion of patients achieving a CR or PR based on NIH response criteria was 67%, including 21% achieving CR and 45% PR (see figure). Of note, 71% of responders showed a sustained response for at least 20 weeks. The most common adverse events were fatigue, diarrhea, muscle spasms, nausea, and bruising. Infectious complications were reported for 69% of patients, including 36% grade ≥3 events and 2 infectious deaths while receiving ibrutinib. In 33% of patients, adverse events led to treatment discontinuation after a median of 1.8 months. On the basis of these results, ibrutinib was approved by the FDA for treatment of adult patients with chronic GVHD after failure of ≥1 line of systemic therapy.
Considering the limited efficacy of currently available immunosuppressants, the question arises whether the evidence presented on the administration of ibrutinib as salvage treatment of chronic GVHD can be seen as the much-awaited progress in the field that has been lacking for decades. Clearly, the observed response rates are promising, and similar rates of response were observed in skin, oral mucosal, and gastrointestinal manifestations. Eighty percent of patients with ≥2 organs involved were among the cohort of responders. Prior immunosuppressive treatments such as rituximab or lack of administration of additional immunosuppressants did not affect response, although patient numbers in the various cohorts were small. One of the limitations is the predominance of cutaneous and oral mucosal involvement in enrolled patients with chronic GVHD, with no data available on other important organ manifestations such as eyes, lungs, or joints/fascia. Furthermore, cutaneous involvement was not separated into inflammatory and fibrotic features, leaving it unclear whether both responded equally well to ibrutinib. In addition to ORRs, exploratory analyses of patient-reported symptoms showed an overall improvement in Lee Chronic GVHD Symptom Scale in 61% and a decrease in chronic GVHD severity scores reported by both clinicians and patients.
In view of the detrimental effects of corticosteroids and their significant impact on survival and NRM, steroid sparing has become an important secondary end point both in clinical studies and daily clinical practice. The median prednisone dose at study enrollment was 0.31 mg/kg per day overall and 0.29 mg/kg per day in responders. By week 49, the median steroid dose had decreased to 0.12 mg/kg per day in ibrutinib responders, and 26 patients (62%) reached a steroid dose <0.15 mg/kg per day. Only 5 ibrutinib responders were able to discontinue corticosteroids. In a multicenter prospective phase 2 randomized study of ECP for treatment of steroid-refractory or -dependent chronic GVHD, >50% reduction in corticosteroid dose was achieved at weeks 12 and 24 in 25% and 39.6% of patients, respectively, in the ECP arm, and 35% of patients had a final steroid dose <10 mg per day at week 24.6 Thus, as with ECP, the administration of ibrutinib had a steroid-sparing effect in patients with chronic GVHD; however, the open-label study design could have influenced steroid-reduction policy.
During the last 5 years, our understanding of chronic GVHD pathogenesis and basic biology has substantially improved, offering the possibility of new therapeutic approaches being directed in more precise ways to target specific immunologic mechanisms and pathways.8 Chronic GVHD develops via a complex cellular and molecular network involving thymic damage and aberrant antigen presentation, leading to aberrant T- and B-cell activation and differentiation, alloantibody formation, and tissue fibrosis.8 This phase 1b/2 trial was based on a biological rationale from preclinical studies that inhibition of the BTK and interleukin-2–inducible T-cell kinase by ibrutinib would have an impact on chronic GVHD pathogenesis. Concomitant biomarker analyses in plasma revealed reductions in markers of inflammation, lymphocyte activation, and tissue fibrosis. Considering the small and heterogeneous population and the lack of correlation with response, these findings are of interest, but we must await confirmation in larger prospective studies with biologically classified patients9 to allow further assessment of the impact of ibrutinib on pathogenic pathways of chronic GVHD.
Nevertheless, the study by Miklos et al, performed according to NIH criteria, remains highly valuable. The efficacy and safety data on ibrutinib in salvage therapy support its use in first-line treatment of chronic GVHD excellently, and results of the ongoing randomized phase 3 study are awaited.
Conflict-of-interest disclosure: The author received honoraria for speakers’ bureau participation from Mallinckrodt, Novartis, and Amgen.