Blood cancers

Australian trial reveals tocilizumab effect in acute GVHD


Associate Professor Glen Kennedy

Hopes that the immunosuppressive drug tocilizumab would help improves outcomes for acute GVHD in patients undergoing allogeneic SCT have been dashed by an Australian study.

While the interleukin-6 inhibitor showed a trend towards benefit when used in volunteer-unrelated-donors, it not significantly reduce the incidence of grade II-IV acute GVHD, a phase 3 randomised controlled trial carried out at five Australian centres has found

Furthermore, addition of tocilizumab to standard GVHD prophylaxis did not improve long-term survival, according to the study involving 145 patients with acute-leukaemia or myelodysplasia undertaking matched-related-sibling (MSD) or volunteer-unrelated-donor (VUD) allogeneic-SCT after myeloablative or reduced-intensity conditioning.

The trial, led by Associate Professor Glen Kennedy, a haematologist at the Royal Brisbane and Women’s Hospital, aimed to investigate the encouraging results seen with tocilizumab seen in early phase trials in aGVHD. Patients received a single dose of tocilizumab or placebo on day one in addition to T-cell-replete peripheral blood stem cell (PBSC) grafts and GVHD-prophylaxis with cyclosporin/methotrexate.

At day 100 the overall incidence of grade II-IV GVHD for the entire cohort was 36% for placebo versus 27% for tocilizumab (HR 0.69; 95% CI: 0.38-1.26; p=0.23). For the VUD cohort the rates were 45% for placebo and 32% for tocilizumab.

At day 180 the overall incidence of grade II-IV aGVHD was 40% for placebo and 29% for tocilizumab (HR 0.68; CI:0.38-1.22, p=0.19). IN the VUD patients the rates were 48% for placebo and  32% for tocilizumab (HR 0.59; CI:0.30-1.16, p=0.13).

Similarly, grade II-IV acute GVHD-free survival rates at day 180 were improved by 16% with tocilizumab but the difference did not reach significance.

The study investigators also noted that , disappointingly, the reductions in acute GVHD after with tocilizumab were predominantly in moderate, grade II disease rather than in the most clinically important severe (grade III/IV) disease.

At two years post-transplant, there were no significant differences in  overall survival (79% versus 71%), transplant related mortality (8% vs 11%) or  progression free survival (75% vs 67%)  for placebo and tocilizumab groups.

Median day to neutrophil and platelet engraftment was delayed by two to three days in TCZ-treated patients while liver toxicity and infectious complications were similar between groups.

Publishing their findings in Blood, Associate Professor Kennedy and colleagues said it was disappointing to see effect sizes that  were smaller than those expected from single arm phase I/II studies, though this may have been due to lower rates of acute GVHD in the placebo cohort and a small sample size.

A follow-up study would require over 150 patients per arm to confirm an improvement in day 180 GVHD-free survival, they suggested.

“However, the fact that we did not see any reductions in the incidence of severe acute GVHD suggests that alternative strategies should be prioritised to prevent acute GVHD in the future,” they concluded.

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