Naive T-Cell Depletion to Prevent Chronic Graft-Versus-Host Disease

Author(s):  
Marie Bleakley ◽  
Alison Sehgal ◽  
Stuart Seropian ◽  
Melinda A. Biernacki ◽  
Elizabeth F. Krakow ◽  
...  

PURPOSE Graft-versus-host disease (GVHD) causes morbidity and mortality following allogeneic hematopoietic cell transplantation. Naive T cells (TN) cause severe GVHD in murine models. We evaluated chronic GVHD (cGVHD) and other outcomes in three phase II clinical trials of TN-depletion of peripheral blood stem-cell (PBSC) grafts. METHODS One hundred thirty-eight patients with acute leukemia received TN-depleted PBSC from HLA-matched related or unrelated donors following conditioning with high- or intermediate-dose total-body irradiation and chemotherapy. GVHD prophylaxis was with tacrolimus, with or without methotrexate or mycophenolate mofetil. Subjects received CD34-selected PBSC and a defined dose of memory T cells depleted of TN. Median follow-up was 4 years. The primary outcome of the analysis of cumulative data from the three trials was cGVHD. RESULTS cGVHD was very infrequent and mild (3-year cumulative incidence total, 7% [95% CI, 2 to 11]; moderate, 1% [95% CI, 0 to 2]; severe, 0%). Grade III and IV acute GVHD (aGVHD) occurred in 4% (95% CI, 1 to 8) and 0%, respectively. The cumulative incidence of grade II aGVHD, which was mostly stage 1 upper gastrointestinal GVHD, was 71% (95% CI, 64 to 79). Recipients of matched related donor and matched unrelated donor grafts had similar rates of grade III aGVHD (5% [95% CI, 0 to 9] and 4% [95% CI, 0 to 9]) and cGVHD (7% [95% CI, 2 to 13] and 6% [95% CI, 0 to 12]). Overall survival, cGVHD-free, relapse-free survival, relapse, and nonrelapse mortality were, respectively, 77% (95% CI, 71 to 85), 68% (95% CI, 61 to 76), 23% (95% CI, 16 to 30), and 8% (95% CI, 3 to 13) at 3 years. CONCLUSION Depletion of TN from PBSC allografts results in very low incidences of severe acute and any cGVHD, without apparent excess risks of relapse or nonrelapse mortality, distinguishing this novel graft engineering strategy from other hematopoietic cell transplantation approaches.

2022 ◽  
pp. 106002802110681
Author(s):  
Rémi Tilmont ◽  
Ibrahim Yakoub-Agha ◽  
Nassima Ramdane ◽  
Micha Srour ◽  
Valérie Coiteux ◽  
...  

Background Defibrotide is indicated for patients who develop severe sinusoidal obstructive syndrome following allogeneic hematopoietic cell transplantation (allo-HCT). Preclinical data suggested that defibrotide carries a prophylactic effect against acute graft-versus-host disease (aGVHD). Objective The purpose of this study was to investigate the effect of defibrotide on the incidence and severity of aGVHD. Methods This single-center retrospective study included all consecutive transplanted patients between January 2014 and December 2018. A propensity score based on 10 predefined confounders was used to estimate the effect of defibrotide on aGVHD via inverse probability of treatment weighting (IPTW). Results Of the 482 included patients, 64 received defibrotide (defibrotide group) and 418 did not (control group). Regarding main patient characteristics and transplantation modalities, the two groups were comparable, except for a predominance of men in the defibrotide group. The median age was 55 years (interquartile range [IQR]: 40-62). Patients received allo-HCT from HLA-matched related donor (28.6%), HLA-matched unrelated donor (50.8%), haplo-identical donor (13.4%), or mismatched unrelated donor (7.0%). Stem cell source was either bone marrow (49.6%) or peripheral blood (50.4%). After using IPTW, exposure to defibrotide was not significantly associated with occurrence of aGVHD (HR = 0.97; 95% CI 0.62-1.52; P = .9) or occurrence of severe aGVHD (HR = 1.89, 95% CI: 0.98-3.66; P = .058). Conclusion and Relevance Defibrotide does not seem to have a protective effect on aGVHD in patients undergoing allo-HCT. Based on what has been reported to date and on these results, defibrotide should not be considered for the prevention of aGVHD outside clinical trials.


Blood ◽  
2011 ◽  
Vol 117 (5) ◽  
pp. 1734-1744 ◽  
Author(s):  
Martin Giroux ◽  
Jean-Sébastien Delisle ◽  
Simon-David Gauthier ◽  
Krista M. Heinonen ◽  
Julie Hinsinger ◽  
...  

Abstract Gene expression profiling of human donor T cells before allogeneic hematopoietic cell transplantation revealed that expression of selected genes correlated with the occurrence of graft-versus-host disease (GVHD) in recipients. The gene with the best GVHD predictive accuracy was SMAD3, a core component of the transforming growth factor-β signaling pathway, whose expression levels vary more than a 6-fold range in humans. The putative role of SMAD3 in the establishment of graft-host tolerance remained elusive. We report that SMAD3-KO mice present ostensibly normal lymphoid and myeloid cell subsets. However, the lack of SMAD3 dramatically increased the frequency and severity of GVHD after allogeneic hematopoietic cell transplantation into major histocompatibility complex-identical recipients. Lethal GVHD induced by SMAD3-KO donors affected mainly the intestine and resulted from massive tissue infiltration by T-bet+ CD4 T cells and granulocytes that caused tissue damage by in situ release of Th1 cytokines and oxidative-nitrosative mediators, respectively. Our report reveals the nonredundant roles of SMAD3 in the development of tolerance to the host. Furthermore, our data support the concept that SMAD3 levels in donor cells dictate the risk of GVHD and that SMAD3 agonists would be attractive for prevention of GVHD.


Blood ◽  
2009 ◽  
Vol 114 (5) ◽  
pp. 1099-1109 ◽  
Author(s):  
Holbrook E. Kohrt ◽  
Brit B. Turnbull ◽  
Kartoosh Heydari ◽  
Judith A. Shizuru ◽  
Ginna G. Laport ◽  
...  

A hematopoietic cell transplantation regimen was adapted from a preclinical model that used reduced-intensity conditioning (RIC) and protected against graft-versus-host disease (GVHD) by skewing residual host T-cell subsets to favor regulatory natural killer T cells. One hundred eleven patients with lymphoid (64) and myeloid (47) malignancies received RIC using total lymphoid irradiation (TLI) and antithymocyte globulin (ATG) followed by the infusion of granulocyte colony-stimulating factor-mobilized grafts. Included were 34 patients at least 60 years of age, 32 patients at high risk of lymphoma relapse after disease recurrence following prior autologous transplantation, and 51 patients at high risk of developing GVHD due to lack of a fully human leukocyte antigen (HLA)–matched related donor. Durable chimerism was achieved in 97% of patients. Cumulative probabilities of acute GVHD (grades II-IV) were 2 and 10% of patients receiving related and unrelated donor grafts. Nonrelapse mortality (NRM) at 1 year was less than 4%. Cumulative incidence of chronic GVHD was 27%. The 36-month probability of overall and event-free survival was 60% and 40%, respectively. Disease status at start of conditioning and the level of chimerism achieved after transplantation significantly impacted clinical outcome. The high incidence of sustained remission among patients with active disease at time of transplantation suggests retained graft-versus-tumor reactions. Active trial registration currently at clinicaltrials.gov under IDs of NCT00185640 and NCT00186615.


Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 30-31
Author(s):  
Lars Klingen Gjærde ◽  
Sisse Rye Ostrowski ◽  
Niels Smedegaard Andersen ◽  
Lone Smidstrup Friis ◽  
Brian Kornblit ◽  
...  

Introduction: Suppression of tumorigenicity 2 (ST2) is a prognostic plasma marker of non-relapse mortality (NRM) after allogeneic hematopoietic cell transplantation (allo-HCT) when measured at day +14 [Vander Lugt MT et al., N Engl J Med, 2013] and at day +7 in combination with regenerating islet-derived 3α (REG3α) [Hartwell MJ et al., JCI Insight, 2017]. We hypothesized that also pre-transplantation ST2 levels would be associated with NRM in the first 6 months after allo-HCT. Methods: We studied 112 adult patients who underwent allo-HCT with myeloablative conditioning at Rigshospitalet between July 2015 and August 2018 (Table 1). ST2 levels were measured by enzyme-linked immunosorbent assays using stored EDTA plasma samples obtained at the patients' scheduled pre-transplantation visit around day -23 (±11 days) and post-transplantation at days +7 and +14 (±3 days, n = 76 and 66). Univariable linear models and Spearman's ρ were used to evaluate associations and correlations between pre-transplantation ST2 levels and patient characteristics and other prognostic markers, respectively. Cause-specific Cox regression models were used to estimate hazard ratios (HR) with 95% confidence intervals (CI) for NRM in the first 6 months after allo-HCT (relapse as competing risk) and grade II-IV acute graft-versus-host disease (GvHD) in the first 100 days after allo-HCT (NRM and relapse as competing risks) according to pre-transplantation ST2 levels. Gray's test was used to test differences in the cumulative incidence of NRM in the first 6 months after allo-HCT according to quartiles of pre-transplantation ST2 levels. Results: The median pre-transplantation plasma ST2 level was 19.9 ng/mL (inter-quartile range: 14.6-25.7 ng/mL, Figure Panel A); levels were higher in males (β = 8.7 ng/mL, p < 0.01), but did not differ by age (p = 0.81) or by being transplanted for acute leukemia (p = 0.89). ST2 was correlated with C-reactive protein (ρ = 0.24, p = 0.01), the endothelial activation and stress index (EASIX, calculated as creatinine x lactate dehydrogenase/thrombocytes, ρ = 0.27, p < 0.01) and ferritin (ρ = 0.28, p < 0.01). Longitudinally, pre-transplantation ST2 levels were strongly correlated with ST2 levels on day +7 (ρ = 0.57, p < 0.01) and day +14 (ρ = 0.48, p < 0.01). The cumulative incidence of NRM at 6 months was 11% (n = 12); causes of death were organ failure (75%), acute graft-versus-host disease (GvHD, 17%) and infection (8%). Higher pre-transplantation ST2 levels were associated with increased hazard of NRM in the first 6 months after allo-HCT (HR 1.73 per 10 ng/mL increase, 95% CI: 1.28-2.33, p < 0.01, area under the receiver operating characteristics curve = 0.61). Despite a significantly higher NRM in patients with pre-transplantation ST2 levels in the highest quartile (cumulative incidence at 6 months: 21% vs. 7% in patients with levels in the three lower quartiles, p = 0.03), there was no overall significant difference in NRM according to quartiles of pre-transplantation ST2 levels (p = 0.15, Figure Panel B). No significant association was found between pre-transplantation ST2 levels and grade II-IV acute GvHD (HR 0.88, 95% CI: 0.61-1.26, p = 0.48). Conclusion: Pre-transplantation ST2 levels were associated with increased NRM in the first 6 months after myeloablative allo-HCT, mainly driven by higher NRM in patients with pre-transplantation ST2 levels in the highest quartile. Larger studies are warranted to validate pre-transplantation ST2 levels as a prognostic marker of NRM after allo-HCT, which potentially could be used to support the choice of conditioning intensity. Disclosures No relevant conflicts of interest to declare.


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