Interleukin-1 blockade does not prevent acute graft-versus-host disease: results of a randomized, double-blind, placebo-controlled trial of interleukin-1 receptor antagonist in allogeneic bone marrow transplantation

Blood ◽  
2002 ◽  
Vol 100 (10) ◽  
pp. 3479-3482 ◽  
Author(s):  
Joseph H. Antin ◽  
Daniel Weisdorf ◽  
Donna Neuberg ◽  
Roberta Nicklow ◽  
Shawn Clouthier ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Receptor Antagonist ◽  
Graft Versus Host Disease ◽  
Interleukin 1 ◽  
Double Blind ◽  
Host Disease ◽  
Double Blind Placebo ◽  
Graft Versus Host ◽  
Acute Graft

Acute graft-versus-host disease (GVHD) is thought to derive from direct T-cell injury of target tissues through perforin/granzyme, Fas/FasL interactions, and the effects of inflammatory cytokines. Animal models and some clinical trials support the notion that inhibition of inflammatory mediators such as interleukin-1 (IL-1), tumor necrosis factor α, and interferon γ may ameliorate or prevent GVHD. We hypothesized that blockade of IL-1 during the period of initial T-cell activation would reduce the risk of severe GVHD. We tested this hypothesis in a double-blind, placebo-controlled randomized trial of recombinant human IL-1 receptor antagonist (IL-1Ra) in 186 patients undergoing allogeneic stem cell transplantation. Randomization was stratified by degree of histocompatibility and stem cell source. All patients were conditioned with cyclophosphamide and total body irradiation. GVHD prevention consisted of cyclosporine and methotrexate in all patients. Recombinant human IL-1Ra or saline placebo was given from day −4 to day +10. Randomization was stratified according to GVHD risk. The 2 groups were well-matched for pretreatment characteristics. Moderate to severe GVHD (grades B-D) developed in 57 (61%) of 94 patients receiving IL-1Ra and in 51 (59%) of 86 patients on placebo (P = .88). There was no difference in hematologic recovery, transplantation-related toxicity, event-free survival, or overall survival. We conclude that blockade of IL-1 using IL-1Ra during conditioning and 10 days immediately after transplantation is not sufficient to reduce GVHD or toxicity or to improve survival.

Thymic Recovery among Pediatric Stem Cell Recipients.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1422-1422
Author(s):  
Helena Olkinuora ◽  
Tanja Kaartinen ◽  
Sanna Siitonen ◽  
Kimmo Talvensaari ◽  
Ulla Pihkala ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Graft Versus Host Disease ◽  
Host Disease ◽  
Graft Versus Host ◽  
Post Transplant ◽  
Real Time Quantitative Pcr ◽  
Stem Cell Rescue ◽  
Autologous Stem Cell Rescue ◽  
Acute Graft

Abstract BACKGROUND: Thymic recovery is an essential part of immune reconstitution post stem cell transplantation. The process is affected by the age of the recipient, use of radiotherapy in conditioning and graft versus host disease. The duration of impaired T cell function depends mainly on thymic recovery and is associated with an increased risk of complications such as infections. The aim of this study was to evaluate thymic recovery post-transplant in pediatric patients. And also to detect differencies in thymic recovery between recipients of autologous stem cell rescue and those of allogeneic grafts from sibling and unrelated donors MATERIAL AND METHODS: Between 8/2001–8/2005 a total of 66 patients with a mean age of 7 yrs with either a malignant or non-malignant disease were studied. 31 received a matched unrelated, 21 a sibling graft and 14 were given autologous stem cell rescue. Thymic function was evaluated by quantifying TREC (T cell receptor excision circles) levels in peripheral blood mononuclear cells by real time quantitative PCR once prior to transplant and once every three months during the first year and at 18 months post-transplant. FOXP3 levels were evaluated simultaneously with those of TREC by real time quantitative PCR. The data was related to the clinical status of patients and the recovery of peripheral blood T cell numbers. In 29% (6/21) of the recipients of sibling grafts and 65% (20/31) of recipients of unrelated grafts had clinically significant (Gr II–IV) acute graft versus host disease. About 30 % in both groups developed chronic graft versus host disease. RESULTS: Comparison of TREC levels in children following SCT indicated that thymic recovery was brisk among recipients of autologous stem cell rescue by the 6 months and within the allogeneic group the recovery was significantly better in recipients of sibling grafts than in recipients of unrelated grafts (Figure 1.0). There was an significant negative association between the values of TREC and the occurrence of chronic graft versus host disease from 6 months to 18 months post-transplant. Children with low (below median) TREC values had increased mortality. Patients with low TREC experienced more infections during first six months post-transplant than children with high (above median) TREC values. Blood numbers of CD4 naive cells (CD45RA+) and CD27+ cells correlated significantly with TREC values. FOXP3 values were associated at three months post-transplant with acute graft versus host disease and with its chronic form at 12 and 18 months post-transplant. FOXP3 correlated with blood CD4 naive cells (CD45RA+) and CD27+ cells at 12 and 18 months post-transplant. There was a significant correlation between levels of TREC and FOXP3 at 12 and 18 months post stem cell transplant. CONCLUSIONS: Our data may indicate a difference in the kinetics of thymic recovery post-transplant between recipients of sibling and URD grafts and those of autologous stem cell rescue. Chronic GVHD seems to associate with thymic dysfunction and herpesviral infections with the pace of thymic recovery. Figure Figure

scholarly journals Effect of Early Post-Transplantation Tacrolimus Concentration on the Risk of Acute Graft-Versus-Host Disease in Allogenic Stem Cell Transplantation

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 613
Author(s):  
Nidhi Sharma ◽  
Qiuhong Zhao ◽  
Bin Ni ◽  
Patrick Elder ◽  
Marcin Puto ◽  
...  
Keyword(s):  
Stem Cell ◽  
Graft Versus Host Disease ◽  
Tacrolimus Concentration ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host ◽  
The Impact ◽  
Risk Of Relapse ◽  
Acute Graft

Acute graft versus host disease (aGVHD) remains a leading cause of morbidity and mortality in allogeneic hematopoietic stem cell transplant (allo-HSCT). Tacrolimus (TAC), a calcineurin inhibitor that prevents T-cell activation, is commonly used as a GVHD prophylaxis. However, there is variability in the serum concentrations of TAC, and little is known on the impact of early TAC levels on aGVHD. We retrospectively analyzed 673 consecutive patients undergoing allo-HSCT at the Ohio State University between 2002 and 2016. Week 1 TAC was associated with a lower risk of aGVHD II–IV at TAC level ≥10.15 ng/mL (p = 0.03) compared to the lowest quartile. The cumulative incidence of relapse at 1, 3 and 5 years was 33%, 38% and 41%, respectively. TAC levels at week 2, ≥11.55 ng/mL, were associated with an increased risk of relapse (p = 0.01) compared to the lowest quartile. Subset analysis with acute myeloid leukemia and myelodysplastic syndrome patients showed significantly reduced aGVHD with TAC level ≥10.15 ng/mL at week 1 and a higher risk of relapse associated with week 2 TAC level ≥11.55 ng/mL (p = 0.02). Hence, achieving ≥10 ng/mL during the first week of HCT may mitigate the risk of aGVHD. However, levels (>11 ng/mL) beyond the first week may be associated with suppressed graft versus tumor effect and higher relapse.

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