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Clinical Trial
. 2018 Apr;103(4):717-727.
doi: 10.3324/haematol.2017.183434. Epub 2018 Jan 19.

Tocilizumab, Tacrolimus and Methotrexate for the Prevention of Acute Graft- versus-host Disease: Low Incidence of Lower Gastrointestinal Tract Disease

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Free PMC article
Clinical Trial

Tocilizumab, Tacrolimus and Methotrexate for the Prevention of Acute Graft- versus-host Disease: Low Incidence of Lower Gastrointestinal Tract Disease

William R Drobyski et al. Haematologica. .
Free PMC article

Abstract

We conducted a phase 2 study in which patients undergoing allogeneic hematopoietic stem cell transplantation received tocilizumab in addition to standard immune suppression with tacrolimus and methotrexate for graft-versus-host disease prophylaxis. Thirty-five patients were enrolled between January 2015 and June 2016. The median age of the cohort was 66 (range: 22-76). All patients received busulfan-based conditioning, and were transplanted with human leukocyte antigen-matched related or matched unrelated bone marrow or peripheral stem cell grafts. The cumulative incidences of grades II-IV and III-IV acute graft-versus-host disease were 14% (95% CI 5-30) and 3% (95% CI 0-11) at day 100, and 17% (95% CI 7-31) and 6% (95% CI 1-16) at day 180, respectively. Notably, there were no cases of graft-versus-host disease of the lower gastrointestinal tract within the first 100 days. A comparison to 130 matched controls who only received tacrolimus and methotrexate demonstrated a lower cumulative incidence of grades II-IV acute graft-versus-host disease (17% versus 45%, P=0.003) and a significant increase in grades II-IV acute graft-versus-host disease-free survival at six months (69% versus 42%, P=0.001) with tocilizumab, tacrolimus and methotrexate, which was the primary endpoint of the study. Immune reconstitution was preserved in patients treated with tocilizumab, tacrolimus and methotrexate, as T-cell and B-cell subsets recovered to near normal levels by 6-12 months post-transplantation. We conclude that tocilizumab has promising activity in preventing acute graft-versus-host disease, particularly in the lower gastrointestinal tract, and warrants examination in a randomized setting.

Figures

Figure 1.
Figure 1.
Engraftment, GvHD, disease-free survival, and overall survival. (A). Cumulative incidence of achieving an absolute neutrophil count >500/mm3 for three consecutive days. (B). Cumulative incidence of patients that achieved an unsupported platelet count > 20,000/mm3. Five patients never dropped their platelet count below 20,000. (C,D). Cumulative incidence of grades II-IV and grades III-IV aGvHD. (E). Cumulative incidence of grades II-IV aGvHD in patients that received myeloablative (MA) versus reduced intensity (RIC) preparative regimens. (F). Cumulative incidence of NIH-defined cGvHD. (G) Probability of disease-free survival and (H) overall survival in patients that received Toc/Tac/MTX as GvHD prophylaxis. Dashed gray lines indicate 95% confidence interval bands.
Figure 2.
Figure 2.
Cytokine levels in control population that received tacrolimus and methotrexate for GvHD prophylaxis. Concentration of IL-6, sIL-6R, IL-2, IL-4, IL-10, IL-17, TNF-α, and IFN-g in the serum of patients (n=11) who received Tac/MTX for the prevention of aGvHD prior to the start of conditioning, and at days 7, 14 and 28. *P<0.05, ***P<0.001. IL: interleukin; sIL: soluble interleukin; TNF-α: tumor necrosis factor α; IFN-γ: interferon γ.
Figure 3.
Figure 3.
Effect of tocilizumab administration on interleukin 6 and soluble interleukin 6 receptor levels based on conditioning regimen. (A). Concentration of IL-6 in the serum from patients that were treated with tocilizumab and received myeloablative or reduced intensity conditioning. (B). Concentration of soluble IL-6 receptor in the serum from patients that were treated with tocilizumab and received myeloablative or reduced intensity conditioning. ***P<0.001. IL: interleukin; sIL: soluble interleukin; RIC: reduced intensity conditioning.
Figure 4.
Figure 4.
Comparative analysis of serum cytokine production in tocilizumab-treated versus patients that received Tac/MTX only. Concentration of IL-6, sIL-6R, IL-2, IL-4, IL-10, IL-17, IFN-γ, and TNF-α in the serum of patients that were treated with Toc/Tac/MTX (●, n=35) or Tac/MTX (control) (○, n=11) for the prevention of aGvHD prior to the start of conditioning and at days 7, 14 and 28. *P<0.05, **P<0.01, ***P<0.001. IL: interleukin; sIL: soluble interleukin; TNF-α: tumor necrosis factor α; IFN-γ: interferon γ.
Figure 5.
Figure 5.
Reconstitution of major lymphocyte subsets in patients who received tocilizumab for GvHD prophylaxis. (A,B). The absolute number of cells per mm3 (i.e., microliter) is shown in panel A, and the percentage of the gated cells is shown in panel B. Data are shown for individual patients together with the median and 25th and 75th quartiles (red bars). Gray shading represents the upper and lower range expected for healthy control subjects. Samples were obtained at one month (n=33), three months (n=29), six months (n=22), and 12 months (n=13). Lymphocytes were gated on total CD45+ white blood cells, and all other subsets were gated on lymphocytes. NK: natural killer.
Figure 6.
Figure 6.
GvHD and transplant outcomes in patients treated with tocilizumab versus a matched CIBMTR control population. (A). Cumulative incidence of grades II-IV aGvHD in patients treated with tocilizumab versus the matched control cohort. (B). Probability of grades II-IV aGvHD-free survival. (C). Cumulative incidence of cGvHD, (D) transplant-related mortality, and (E) relapse. (F) Probability of disease-free survival in patients treated with tocilizumab versus the matched control cohort. Toc: tocilizumab: Tac: tacrolimus; MTX: methotrexate.

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