The 2019 Transplantation and Cellular Therapy (TCT) Meetings of American Society for Transplantation and Cellular Therapy (ASTCT) and Center for International Blood & Marrow Transplant Research (CIBMTR) showcased the latest developments in the field. One of the major complications of allogeneic transplantation is graft-versus-host disease (GVHD). A variety of end-organ effects can occur including skin rashes, colitis, etc. After first-line treatment with corticosteroids, there are limited options for those patients who become refractory. Thus, this remains a significant unmet clinical need and an area of active research.
Notable presentations at the 2019 TCT Meetings in the realm of GVHD includes exciting preliminary data presented by Joseph Pidala, MD, PhD from the Moffitt Cancer Center in Tampa, FL. This was a single-arm, multicenter, phase II trial conducted by the Chronic GvHD Consortium examining the efficacy of ixazomib in chronic GVHD. Ixazomib is a proteasome inhibitor currently approved by the Food and Drug Administration (FDA) for use in multiple myeloma. The primary objective was to evaluate treatment failure by six months, defined as death, relapse, or need for a new line of immune suppressive therapy. Additional objectives included responses at 3 and 6 months, overall survival, non-relapse mortality (NRM), relapse, and failure-free survival (FFS). A total of 50 patients, who had been treated with at least three previous lines of therapy were included. Ixazomib was given at a dose of 4 mg weekly for three weeks out of a 28-day cycle for up to six total cycles. About half (or 52 percent) of patients received all six cycles and close to a third (or 38 percent) of patients had a serious adverse event.
Compared to historical controls, the treatment failure rate had significantly improved (28 percent vs. 44 percent). I think the most interesting elements from this trial are that ixazomib led to a dose reduction in corticosteroid use and had a fairly robust response rate in a heavily pre-treated population. Ideally, I would have liked to see more than half of the patients complete the planned six cycles from a safety and tolerability standpoint.
In the acute GVHD setting, Madan Jagasia, MD from the Vanderbilt-Ingram Cancer Center presented results from the phase II REACH1 trial. This was a single-arm, open-label, multicenter study examining the combination of ruxolitinib with corticosteroids in steroid-refractory acute GVHD. Ruxolitinib, a Janus kinase (JAK)1/JAK2 inhibitor, is currently FDA approved for polycythemia vera. Patients received ruxolitinib 5mg BID with an optional increased to 10mg BID if no cytopenias were present. The primary endpoint was day 28 overall response rate (ORR); secondary endpoint was 6-month duration of response (DOR). A total of 71 patients were enrolled. ORR at day 28 was 55 percent with 27 percent in complete remission (CR). Median DOR was 345 days. The most frequent hematologic treatment-related adverse events included anemia, thrombocytopenia, and neutropenia. I feel this study is a natural evolution of the treatment paradigm in acute GVHD as the combination of ruxolitinib and corticosteroids showed rapid and durable responses. Moreover, the adverse events were expected with this regimen and well tolerated. A larger cohort to confirm these findings and to better isolate which organ systems (liver, gastrointestinal, or skin) benefit the most from this regimen is warranted.
Finally, Dr. Pidala also presented the results of the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 1501 study. This was a randomized, open-label, multicenter study comparing sirolimus versus prednisone for the upfront treatment of acute GVHD. Specifically, they included standard risk acute GVHD patients as per the refined Minnesota Criteria who require systemic therapy; those with a biomarker Ann Arbor Risk status of 1/2 were allowed to continue with randomization. 64 patients were enrolled on the prednisone arm and 58 on the sirolimus arm. Sirolimus as compared to prednisone provided a similar day 28 CR/PR response in acute GVHD. Moreover, upfront use of sirolimus resulted in less total steroid exposure over time, with a similar NRM and OS. This study is notable for also demonstrating that initial risk stratification incorporating a central biomarker assessment is feasible. I would like to see additional data in follow-up reporting on this study on the secondary and exploratory objectives including treatment failures, use of topical agents as part of therapy, and immune suppression discontinuation. Finally, detailed information on sirolimus- and corticosteroid-associated complications will be essential to better see how well a steroid-free regimen is tolerated.
These studies provide a snapshot of where we are headed in the management of GVHD, both in the upfront and steroid-refractory settings. Incorporation of biomarkers in particular, of which some data was also presented at the 2019 TCT Meetings, will also be integral in not only risk-stratifying patients, but helping decide the optimal treatment strategy. Finally, the clinical need for novel agents in steroid-refractory GVHD remains present, but hopefully, I will be able to share more updates in the months to come in this area.
Sagar S. Patel, MD is a fellow in Blood & Marrow Transplantation and Experimental Hematology at the Cleveland Clinic, Taussig Cancer Institute in Cleveland, Ohio.
Illustration by April Brust.