ORLANDO – Tocilizumab plus standard immune suppression appears to drive down the risk for graft-versus-host disease (GVHD), according to results from a phase II study of 35 adults undergoing allogeneic stem cell transplants.
The effect was particularly pronounced for prevention of GVHD in the colon, William Drobyski, MD, reported at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.
The incidence rate of grades II-IV and III-IV acute GVHD was 12% at day 100 in patients given standard prophylaxis of tacrolimus/methotrexate (Tac/MTX) and 3% in patients given Tac/MTX plus 8 mg/kg of tocilizumab (Toc, capped at 800 mg), said Dr. Drobyski of the Medical College of Wisconsin, Milwaukee.
To provide further context to the results, Dr. Drobyski and his colleagues performed a matched case-control analysis using contemporary controls in the Center for International Blood & Marrow Transplant Research from 2000 to 2014. The same eligibility criteria used for the trial were applied to the matched controls except for the use of Tac/MTX as GVHD prophylaxis. Patients were otherwise matched based on age, performance score, disease, and donor type.
The incidence of grades II-IV acute GVHD at day 100 was significantly lower in the Toc/Tac/MTX group than in the Tac/MTX control population (12% vs. 41%). The incidence of grades III-IV acute GVHD was slightly lower with tocilizumab, but the difference between the groups was not statistically significant, Dr. Drobyski said.
The probability of grade II-IV acute GVHD–free survival, which was the primary endpoint of the study, was significantly higher in the Toc/Tac/MTX group (79% vs 52%), he said.
Five patients developed grade 2 acute GVHD of the skin or upper GI tract, and one patient died of grade 4 acute GVHD of the skin in the first 100 days. Notably, there were no cases of acute GVHD of the lower GI tract during that time, although two cases did occur between days 130 and 180, he said.
“There was no difference in transplant-related mortality, relapse, disease-free survival, or overall survival,” he said, adding that preliminary data suggest there were no differences in chronic GVHD between the groups.
Causes of death also were similar between the two cohorts with respect to disease- and transplant-related complications.
Patients in the tocilizumab study were enrolled between January 2015 and June 2016; the median age was 66 years. Diseases represented in the cohort included de novo acute myeloid leukemia (13 patients), AML (6 patients), chronic myelomonocytic leukemia (6 patients), acute lymphoblastic leukemia (4 patients), myelodysplastic syndrome (3 patients), and T-cell lymphoma, chronic myeloid leukemia, and NK/T cell lymphoma (in 1 patient each). Most patients were classified as high risk (9 patients) or intermediate risk (22 patients) by the disease risk index.
Conditioning was entirely busulfan based. Myeloablative conditioning was with busulfan and cyclophosphamide (Cytoxan) in 5 patients, or fludarabine and 4 days of busulfan in 10 patients, and reduced-intensity conditioning was with fludarabine and 2 days of busulfan in 18 patients. Transplants were with either HLA-matched related or unrelated donor grafts. Most patients (29 of 35) received peripheral stem cell grafts.
Tocilizumab, an interleuken-6 receptor blocker that is approved for treatment of rheumatoid arthritis, was administered after completion of conditioning and on the day prior to stem cell infusion.
In a pilot clinical trial of tocilizumab for the treatment of steroid-resistant acute GVHD in patients who had primarily had lower GI tract disease, “we were able to demonstrate responses in a majority of these patients,” Dr. Drobyski said, noting that a recent study presented at the 2016 annual meeting of the American Society of Hematology also showed efficacy in the treatment of lower tract GI GVHD, “providing evidence that tocilizumab had activity in acute GVHD, and perhaps in the treatment of steroid-refractory lower GI GVHD.”
Elevated IL-6 levels in the peripheral blood are correlated with an increased incidence and severity of GVHD; administration of an anti-IL-6 receptor antibody has been shown in preclinical studies to protect mice from lethal GVHD. The current open-label study was performed to “try to advance this concept” by assessing whether inhibition of IL-6 signaling could also prevent acute GVHD.
The findings confirm those of a 2014 study by Kennedy et al. in Lancet Oncology (2014;15:1451-9), and imply that tocilizumab warrants a randomized trial as prophylaxis for acute GVHD, he concluded.
Dr. Drobyski reported having no disclosures.