Tocilizumab for the treatment of severe steroid-refractory acute graft-versus-host disease of the lower gastrointestinal tract

Abstract

Steroid-refractory (SR) acute gastrointestinal (GI) graft-versus-host disease (GVHD) is associated with significant mortality in allogeneic hematopoietic cell transplantation recipients. We retrospectively evaluated the efficacy of tocilizumab for the treatment of SR biopsy-proven acute lower GI GVHD in 16 consecutive adult transplant recipients between October 2015 and July 2016. Tocilizumab 8 mg/kg was administered every 2 weeks until achievement of complete response, defined as resolution of all manifestations of GI GVHD, or until patients had progression or initiation of other therapy. Ten of 16 patients (62.5%; 95% CI, 0.39-82) achieved a complete response after a median time of 11 days (range, 2-28 days) from tocilizumab initiation. The median time to response onset (improvement in stage by at least 1) was 1 day (range, 1-4 days). Tocilizumab was administered at a median of 9 days (range, 3-75 days) from GVHD diagnosis and 10 days (range, 3-75 days) from initiation of high-dose steroids. At a median follow-up of 7.6 months (range, 0.8-27.7 months) from initiation of tocilizumab, 6/16 (37.5%) patients are alive and free of their underlying hematologic malignancy. Tocilizumab appears to be a highly active agent for the treatment of severe SR lower GI acute GVHD.

Acute Graft‐versus‐Host Disease: Emerging Insights and Updates into Detection, Prevention, and Treatment

“…51 Signal blockade of IL-6 is thought to block differentiation thereby reducing T-helper (Th) 1 and Th17 cell production while enhancing regulatory T cells, thus making it an ideal agent for prevention. 52 Early phase I/II data showed that by adding tocilizumab (day À1 only) to cyclosporine/methotrexate GVHD prophylaxis in HLA-matched unrelated and related allogeneic HCT recipients (N=48), incidence of acute GVHD II-IV was as low as 12%. 47 OS and progression-free survival at 2 years were 84% and 68%, respectively.…”

“…74 Other small case series have reported on mixed, but promising, activity with partial and complete responses in heavily pretreated patients. 52,70,71 In addition, early administration of tocilizumab as first-line therapy following steroid refractoriness has also shown benefit, although mostly in patients with skin and/or GI involvement. 72 Likely the strongest argument for tocilizumab was reported in a retrospective case series 52 including 16 patients with only biopsy-proven GI-associated steroidrefractory acute GVHD.…”

“…Interestingly, when measuring serum IL-6 levels pretocilizumab initiation, no association between IL-6 and the drug were found. 52 Tocilizumab is well tolerated with mild transient liver transaminase or bilirubin elevations reported. 52,70 Although there remains concern of increased infection with this agent, it is difficult within these small series to evaluate if tocilizumab is the true culprit given the concomitant immunosuppression.…”

“…52 Tocilizumab is well tolerated with mild transient liver transaminase or bilirubin elevations reported. 52,70 Although there remains concern of increased infection with this agent, it is difficult within these small series to evaluate if tocilizumab is the true culprit given the concomitant immunosuppression. Regardless, reports of CMV, BK virus, bacterial infections, and fungal infections have been described during treatment.…”

Interleukin-6 in Allogeneic Stem Cell Transplantation: Its Possible Importance for Immunoregulation and As a Therapeutic Target

“…In addition to a few case reports (156–158) and conference abstracts (159) only two published case series report the effects of tocilizumab in the treatment of acute steroid-refractory aGVHD (Table 7) (160, 161). Drobyski et al (161) described the effects in eight patients (two acute and two chronic GVHD) where tocilizumab was administered once every 3–4 weeks.…”