A phase 3 double-blind study of the addition of tocilizumab vs placebo to cyclosporin/methotrexate GVHD prophylaxis

Abstract

We determined the efficacy of tocilizumab (TCZ) in preventing grade II-IV acute GVHD (aGVHD) in patients with acute-leukemia or myelodysplasia undertaking matched-related-sibling (MSD) or volunteer-unrelated-donor (VUD) allogeneic-SCT after myeloablative or reduced-intensity conditioning across five Australian centers. 145 patients (50 MSD, 95 VUD) were randomly assigned to placebo or TCZ on day-1. All patients received T-cell-replete PBSC grafts and GVHD-prophylaxis with cyclosporin/methotrexate. A planned sub-study analyzed the VUD cohort. With a median follow up of 746 days, the incidence of grade II-IV aGVHD at day 100 for the entire cohort was 36% versus 27% for placebo versus TCZ (HR 0.69; CI:0.38-1.26, p=0.23) and 45% versus 32% (HR 0.61; CI:0.31-1.22, p=0.16) for the VUD subgroup. The incidence of grade II-IV aGVHD at day 180 for the entire cohort was 40% versus 29% for placebo versus TCZ (HR 0.68; CI:0.38-1.22, p=0.19) and 48% versus 32% (HR 0.59; CI:0.30-1.16, p=0.13) for the VUD subgroup. Reductions in aGVHD were predominantly in grade II disease. A trend to improved aGVHD-free survival (aGVHD-FS) was noted in the TCZ-treated VUD subgroup, 52% versus 68% for placebo versus TCZ (p=0.13). For the entire cohort, transplant-related-mortality occurred in 8% versus 11% of placebo versus TCZ-treated patients respectively (p=0.56) and overall-survival was 79% versus 71% (p=0.27). Median day to neutrophil and platelet engraftment was delayed by 2-3 days in TCZ-treated patients while liver toxicity and infectious complications were similar between groups. In this phase-3 randomized, double-blind trial (ACTRN12614000266662), tocilizumab showed non-significant trends to reduced incidence of grade II-IV aGVHD and improved aGVHD-FS in recipients of HLA-matched VUD donors, but no improvements in long term-survival.

Acute Graft-Versus-Host Disease, Prophylaxis and Therapy

“…-For entire cohort, overall-survival was 79% versus 71% (p=0.27) respectively. Hence, while Toci had a non-significant trend towards mostly grade II aGVHD and GVHD-FS, there was no improvement in overall survival [55](Table 3). CSA and TAC are considered equivalent and there has been discussions on the target serum concentrations.…”

“…Immunologic analysis revealed control of T-cell activation in abatacept treated patients (Table 3). A phase III double-blind trial with Tocilizumab (Toci) or placebo with MTX/CNI in 145 patients (50 matched related donor (MRD) and 95 matched unrelated donor (MUD)) was recently published [55]. The incidence of grade II-IV aGVHD at day 180 for the entire cohort was 40% placebo versus 29% Toci (p=0.…”

T Cell Subsets in Graft Versus Host Disease and Graft Versus Tumor

“…Anti-IL-6 tocilizumab was used in a single dose before allo-matched HCT, which showed low incidence of aGVHD with treatment, and called for further study of this method in GVHD prophylaxis (167). However, a more recent randomized phase 3 trial evaluating the addition of tocilizumab to cyclosporin and methotrexate for aGVHD prophylaxis, did not show statistically significant reduction in grade II-IV aGVHD or long-term survival (168).…”

“…The phase III double-blinded study of the addition of Tocilizumab vs. Placebo to cyclosporin/methotrexate GVHD Prophylaxis after HLA-Matched allo-HCT failed to meet the primary endpoint (168).…”

Immunomodulatory Therapies for the Treatment of Graft-versus-host Disease

“… 72 A phase III trial (ACTRN12614000266662) investigated the beneficial effect of tocilizumab added to cyclosporine/methotrexate GvHD prophylaxis in MDS and AML patients after allo-HCT. 72 Grade II–IV acute GvHD at day +100 was decreased in the tocilizumab versus placebo group; however, treatment-related mortality was slightly increased upon tocilizumab treatment, and neutrophil and platelet engraftment was delayed. 72 In summary, tocilizumab partly reduced GvHD severity, but could not improve long-term survival.…”