P-067 Vedolizumab in Treatment of Severe Intestinal Graft Versus Host Disease

Abstract

Background: Grade III-IV graft versus host disease (GvHD) after allogeneic bone marrow transplantation is associated with poor outcome and high mortality. Steroids are first line treatment, followed by several options for treatments with suboptimal effect and evidence. Furthermore, treatment modalities involve systemic immunosuppression, with risk of mortality due to infections. Vedolizumab, a monoclonal antibody targeting the homing of T cells to the intestinal endothelium through inhibition of the binding of integrin a4b7 to MadCAM, is effective in the treatment of inflammatory bowel disease. We here report use of vedolizumab in 6 patients with steroid refractory, severe intestinal GvHD. Methods: We treated 6 patients in an open-label, investigator initiated case series. All were informed about the off-label use of vedolizumab. Patients 1 and 2 had been through therapy with several modalities without resolution of the severe GvHD. Patients 3 to 6 were given vedolizumab as second line therapy after steroid failure. Vedolizumab was given as described for IBD with 300 mg i.v. week 0, 2 and 6, followed by infusions every 8 weeks. Results: All patients (except number 4 that had multi-organ failure before receiving vedolizumab, and died soon thereafter) exhibited clinical response within 7-10 days after start of treatment with decrease in abdominal pain and watery diarrhoea. Serial endoscopies were performed in remaining patients, and revealed rapid improvement in the upper GI-tract. In the colon, improvement was gradual, the caecum and distal ileum exhibited the slowest rate of repair. After 3 doses of vedolizumab, most patients could taper systemic corticosteroid therapy. All patients, except patient 4, were on oral medication including immunosuppressants (oral cyclosporin-A or MMF). Patient 1 is in continued clinical remission of GvHD. Patient 2 experienced a molecular relapse of acute promyelocytic leukemia and his GvHD relapsed after cessation of immunosuppression. Patient 3 developed skin GvHD after cessation of immunosuppression and died of an opportunistic infection following treatment of high dose steroids. Patient 4 had multi-organ failure prior to start of treatment with vedolizumab and died. Patients 5 and 6 have no symptoms of serious GvHD after 2 and 3 doses of vedolizumab. Four out of 6 patients could be discharged from hospital. Immunophenotyping of peripheral blood revealed initial high levels of CD25+ Treg cells in 4 out of 6 evaluable patients and the values showed a decline into normal range after start of therapy and with signs of clinical effect. Conclusions: This case series suggests that targeting integrin a4b7 is feasible, safe and gives clinical responses in steroid refractory intestinal GvHD. The mechanism of action is not known, but may be due to the inhibition of alloreactive T-cells homing to the intestinal mucosa. The mechanism behind the Treg patterns is unclear. One might speculate that the initially high levels of Tregs are part of the physiologic reaction to the alloreactive inflammation in the intestinal mucosa.