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Efficacy of tocilizumab add-on treatment to prevent acute GvHD after HLA-matched allogeneic stem cell transplantation: results from a phase III study

Dec 21, 2019

Interleukin-6 (IL-6) has been shown to be a key mediator of graft- versus-host disease (GvHD) in experimental models of allogeneic stem cell transplantation (SCT). 1,2The anti-IL-6 receptor monoclonal antibody, tocilizumab (TCZ), which is approved for the treatment of rheumatoid arthritis, 3binds to both transmembrane and soluble IL-6 receptors and blocks all IL-6 signaling. 4A phase I/II study of add-on TCZ conducted in 48 patients receiving standard GvHD prophylaxis after allogeneic SCT (allo-SCT) generated promising efficacy signals, with low rates of acute GvHD, high rates of engraftment, and no specific safety signals reported. 4

To further investigate the efficacy of TCZ in preventing acute GvHD after HLA-matched allo-SCT, a phase III study was initiated in five Australian transplant centers. The aim of this trial was to determine whether TCZ can prevent grade 2–4 acute GvHD in patients with acute leukemia or myelodysplasia undergoing allo-SCT after myeloablative (MAC) or reduced intensity (RIC) conditioning, using matched sibling donors (MSD) or matched unrelated donors (MUD). The results from this study were presented in December 2019 at the 61 stAmerican Society of Hematology Meeting & Exposition, Orlando, FL, US, by Glen Kennedy, Royal Brisbane and Women’s Hospital, Brisbane, Australia. 5

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Study design

  • Randomized, double-blind, placebo-controlled study
  • Patient eligibility: aged 18–70 years; diagnosed with acute leukemia, myelodysplastic syndrome, or chronic myelomonocytic leukemia; Eastern Cooperative Oncology Group performance status ≤2; adequate organ function
  • Treatment:
    • Conditioning:RIC patients all received fludarabine and melphalan (Flu/Mel) while MAC patients received cyclophosphamide and total body irradiation (Cy/TBI) or busulfan/cyclophosphamide (Bu/Cy)
    • GvHD prophylaxis:All patients received T-replete peripheral blood progenitor cell grafts and standard GvHD prophylaxis with cyclosporine A (5mg/kg daily from day -1 to day 1, then 3mg/kg daily to maintain levels at 140-300ng/ml) and methotrexate (15mg/m 2on day 1 then 10mg/m 2on days 3,6,11). Patients were randomized 1:1 to receive intravenous TCZ 8mg/kg (max. dose 800mg) or placebo on day -1 of conditioning
  • Endpoints:
    • Primary endpoint: incidence of grade 2–4 acute GvHD at day 100. The study was powered to detect a 50% reduction in grade 2-4 acute GvHD incidence
    • Secondary endpoints: incidence of grade 2–4 GvHD at day 180, grade 2–4 acute GvHD free-survival (GvHD-FS) at day 180, grade 3–4 GvHD, transplant-related mortality (TRM), progression-free survival (PFS) at 24 months, overall survival (OS) at 24 months, time to engraftment, and rate of infection
    • A subgroup analysis in MUD transplanted patients was included


The addition of TCZ to standard prophylaxis GvHD prophylaxis resulted in non-significant trends towards a reduced incidence of grade 2–4 GvHD and improved GvHD-FS in recipients of MUD transplantation, but no improvements in survival were observed ( Table 1)

  • 145 (50 MSD and 95 MUD) transplanted patients were randomized
  • Median follow up was 746 days (range 369–1525 days)

Table 1.Efficacy of TCZ when added to standard GvHD prophylaxis in patients undergoing HLA-matched allo-SCT


Placebo(n= 73)

TCZ(n= 72)

HR (95% CI)

Grade 2–4 GvHD at day 100


MUD subgroup







0.69 (0.38–1.26)

p= 0.23

0.61 (0.31–1.22)

p= 0.16

Grade 2–4 GvHD at day 180


MUD subgroup







0.68 (0.38–1.22)

p= 0.19

0.59 (0.30–1.16)

p= 0.13

Grade 3–4 GvHD at day 100


MUD subgroup







1.04 (0.42–2.61)

p= 0.93

1.42 (0.41–4.95)

p= 0.59

GvHD-FS in MUD subgroup



1.70 (0.86–3.37)

p= 0.13




1.37 (0.47–3.94)

p= 0.56




1.44 (0.78–2.63)

p= 0.24




0.69 (0.35–1.34)

p= 0.27

CI, confidence interval; GvHD, graft- versus-host-disease; GvHD-FS, day 180 grade 2–4 acute GvHD-free-survival; HR, hazard ratio; MUD; matched unrelated donor; TRM, transplant-related mortality

  • Time to neutrophil engraftment was significantly delayed in TCZ-treated patients, with a median time to a neutrophil count of ≥0.5x10 9on three consecutive days of 15 days (range, 11–24 days) for placebo-treated patients vs18 days (range, 9–35 days) for TCZ-treated patients (median difference 3 days; 95% CI, 1.3–4.7; p= 0.001)
  • Time to platelet engraftment was also significantly delayed in TCZ-treated patients, with a median time to a post-nadir platelet count of ≥20x10 9/L on five consecutive days of 16 days (range, 9–36 days) for placebo-treated patients vs19 days (range, 11–389 days) for TCZ-treated patients (median difference 3 days; 95% CI, 0.4–5.6; p= 0.022)
  • The median time to neutrophil and platelet engraftment in TCZ-treated patients were each two days slower in the MUD cohort (p= 0.016 and p= 0.22 for neutrophils and platelets, respectively)
  • Two TCZ-treated patients died at day 31 and 32 with incomplete neutrophil recovery
  • The incidence of grade ≥3 liver toxicity was similar between groups, occurring in 14% of placebo-treated patients vs15% of TCZ-treated patients (odds ratio [OR]= 1.14; 95% CI, 0.45–2.88; p= 0.79)
  • The incidence of grade ≥2 infection adverse events occurred in 64% of placebo-treated patients vs71% of TCZ-treated patients (OR= 1.34; 95% CI, 0.67–2.71; p= 0.41)


This study confirmed that TCZ administered at day -1 was associated with a trend towards a reduced incidence of grade 2–4 GvHD – with a one-third reduction – and a trend towards an improved day 180 grade 2–4 GvHD-FS in the MUD subgroup – with a 16% increase. There was no reduction in severe (grade 3–4) GvHD or organ-specific acute GvHD, and there was a median delay of 2–3 days in neutrophil and platelet engraftment. No improvements in TRM, PFS, or OS were observed. According to the investigators, at the final analysis, the study had been underpowered to detect a benefit of TCZ because of lower rates of acute GvHD in the control group and a smaller effect size than had been anticipated.

  1. Chen X. et al., Blockade of interleukin-6 signaling augments regulatory T-cell reconstitution and attenuates the severity of graft-versus-host disease. Blood. 2009 Jul 23;114(4):891–900. DOI: 10.1182/blood-2008-08-175448
  2. Tawara I. et al., Interleukin-6 modulates graft-versus-host responses after experimental allogeneic bone marrow transplantation. Clin Cancer Res. 2011 Jan 1;17(1):77-88. DOI: 10.1158/1078-0432.CCR-10-1198
  3. RoActemra (tocilizumab) Summary of Product Characteristics. Roche Registration GmbH.[Accessed December 9, 2019]
  4. Kennedy G.A. et al., Addition of interleukin-6 inhibition with tocilizumab to standard graft-versus-host disease prophylaxis after allogeneic stem-cell transplantation: a phase 1/2 trial. Lancet Oncol. 2014 Dec;15(13):1451–1459. DOI: 10.1016/S1470-2045(14)71017-4
  5. Kennedy G.A. et al. Results of a Phase III Double-Blind Study of the Addition of Tocilizumab Vs. Placebo to Cyclosporin/Methotrexate Gvhd Prophylaxis after HLA-Matched Allogeneic Stem Cell Transplantation. Oral Abstract #368. 2019 Dec 8. 61 stAmerican Society of Hematology (ASH) Annual Meeting & Exposition, Orlando, FL