Approaches to Targeting Acute and Chronic GVHD

John F. DiPersio, MD, PhD

During a satellite symposium at the 2017 BMT Tandem Meetings (the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation [ASBMT]), presenters reviewed the experience of using new and emerging therapies for treating patients with acute and chronic graft-versus-host disease (GVHD). The presenters detailed the existing options, including B-cell depletion, interleukin (IL)-2, T-cell trafficking modulators (ie, inhibitors of JAK1/JAK2, JAK1-specific inhibitors), extracorporeal photopheresis (ECP), and ibrutinib (Imbruvica), the Bruton’s tyrosine kinase inhibitor.

Initial treatment for acute GVHD is prednisone, according to ASBMT’s 2012 guidelines, but steroid-refractory acute GVHD remains a problem. No approach has been associated with improved GVHD control or overall survival (OS) compared with second-line therapy with high-dose steroids.

The first portion of the session was delivered by John F. DiPersio, MD, PhD, chief, Division of Oncology, Washington University School of Medicine in St. Louis, Missouri, on new targets for acute GVHD. JAK1 and JAK2 are mediators of interferon gamma receptor signaling; in mouse models, pharmacologic inhibition with JAK1/2 inhibitors decreased expression of the chemokine receptor CXCR3, reduced the incidence of GVHD, and improved survival after allogeneic hematopoietic stem cell transplant.¹

In a retrospective survey of 19 stem cell transplant centers in the United States and Europe, outcomes data from 95 patients who had received ruxolitinib (Jakafi) as salvage therapy for steroid-refractory GVHD showed an overall response rate (ORR) of 81.5% and a complete response (CR) rate of 46.3% for acute GVHD, and an ORR of 85.4% for chronic GVHD. One-year OS in the overall population of 95 patients (acute and chronic GVHD) was 92.7%, and the estimated median OS was not reached.²

The IL-6 pathway appears to be mediated by JAK1/2 signaling, and blockade of this pathway has an important effect on mitigating GVHD, said DiPersio. Tocilizumab (Actemra), an IL-6 inhibitor, was associated with very low rates of acute GVHD and high survival rates when administered with standard prophylaxis in patients undergoing T-replete HLA-matched allogeneic hematopoietic stem cell transplant (HSCT).³

Integrin inhibitors are undergoing investigation as another strategy to improve GVHD control; alpha-4 is involved in GVHD pathology, likely by facilitating the migration of alloreactive T cells to GVHD target organs. Selective inhibition of the alpha4beta1 integrin was recently shown to be effective in preventing GVHD in a mismatched allogeneic HSCT model.⁴

New approaches to treating chronic GVHD were discussed by David Miklos, MD, PhD, associate professor of medicine, Blood and Marrow Transplantation, Stanford University Medical Center. The incidence of chronic GVHD is increasing as early transplant-related mortality is falling, requiring long-term therapy and being associated with quality of life and functional deficits. Corticosteroids remain the initial therapy for chronic GVHD. Alternatives have failed to improve outcomes.

“There is no current consensus on optimal second-line treatment,” Miklos said. Many retrospective and prospective studies suggest high response rates with ECP, rituximab (Rituxan), imatinib (Gleevec), mycophenolate mofetil, and mTOR inhibitors in the second-line setting, but the results are difficult to interpret because of suboptimal study designs.

ECP plus standard therapy in patients with cutaneous chronic GVHD manifestations not adequately controlled by steroids showed that the surface area of involved skin at week 12 decreased by 14.5% compared with 8.5% with standard treatment alone.⁵Some 8.3% of patients in the ECP group had ≥50% reduction in steroid doses from baseline and ≥25% reduction in Total Skin Score compared with 0% of the patients with standard therapy. “One of our goals is to find and identify steroid-sparing therapies,” Miklos said.

Because the B cell has a role in the pathogenesis of chronic GVHD, B-cell depletion with rituximab 375 mg/m2/week for 4 weeks was studied in 21 patients who had extensive steroid-refractory chronic GVHD. The ORR was 70% at 1 year, and the median steroid dose was reduced from 40 mg/day at study entry to 10 mg/day following rituximab (P <.001).6 Significant changes were also reported for skin involvement, the oral pharyngeal score, ocular Schirmer&rsquo;s test, and rheumatologic symptoms.

The rationale for use of low-dose IL-2 is that impairment of regulatory T-cell (Treg) function is associated with chronic GVHD and IL-2 is critical for normal Treg development, expansion, activity, and survival. In 35 patients with extensive refractory chronic GVHD, partial responses (PRs) occurred in 61% and were observed in the liver, skin, lung, joint/fascia, and gastrointestinal system.⁷

Ibrutinib may selectively target chronic GVHD pathogenic cells while preserving cytotoxic T cells and Tregs, Miklos said, noting the results of a multicenter open-label phase II study of ibrutinib given after failure of corticosteroids in 42 patients with chronic GVHD. In that study, investigators observed an ORR of 67%, with 9 CRs, 19 PRs, and a sustained response rate at &ge;20 weeks of 71%.8 Only 3 patients had chronic GVHD progression, and 14 came off therapy due to treatment-emergent adverse events.

A supplemental new drug application for ibrutinib as a treatment for patients with chronic graft-versus-host-disease after failure of &ge;1 lines of systemic therapy is pending with the FDA. The agent previ- ously received a breakthrough therapy designation in this setting.