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Novel Scoring Criteria for the Evaluation of Ocular Graft-versus-Host Disease in a Preclinical Allogeneic Hematopoietic Stem Cell Transplantation Animal Model.

ABSTRACT: Ocular complications occur after transplantation in 60% to 90% of chronic graft-versus-host disease (GVHD) patients and significantly impair vision-related quality of life. Ocular surface inflammation and dry eye disease are the most common manifestations of ocular GVHD. Ocular GVHD can be viewed as an excellent preclinical model that can be studied to understand the immune pathogenesis of this common and debilitating disease. A limitation of this is that only a few experimental models mimic the ocular complications after hematopoietic stem cell transplantation (HSCT) and have focused on the acute GVHD process. To address this issue, we used a preclinical animal model developed by our group where ocular involvement was preceded by systemic GVHD to gain insight regarding the contributing immune mechanisms. Employing this "matched unrelated donor" model enabled the development of clinical scoring criteria, which readily identified different degrees of ocular pathology at both the ocular surface and adnexa, dependent on the level of conditioning before HSCT. As far as we are aware, we report for the first time that these clinical and immune responses occur not only on the ocular surface, but they also heavily involve the lid margin region. In total, the present study reports a preclinical scoring model that can be applied to animal models as investigators look to further explore GVHD's immunologic effects at the level of the ocular surface and eyelid adnexa compartments. We speculate that future studies will use this clinical scoring index in combination with what is recognized histologically and correlated with serum biomarkers identified in chronic/ocular GVHD.

SUBMITTER: Perez VL

PROVIDER: S-EPMC5580988 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Novel Scoring Criteria for the Evaluation of Ocular Graft-versus-Host Disease in a Preclinical Allogeneic Hematopoietic Stem Cell Transplantation Animal Model.

Perez Victor L VL Barsam Alexander A Duffort Stephanie S Urbieta Maitee M Barreras Henry H Lightbourn Casey C Komanduri Krishna V KV Levy Robert B RB

Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation 20160801 10

Ocular complications occur after transplantation in 60% to 90% of chronic graft-versus-host disease (GVHD) patients and significantly impair vision-related quality of life. Ocular surface inflammation and dry eye disease are the most common manifestations of ocular GVHD. Ocular GVHD can be viewed as an excellent preclinical model that can be studied to understand the immune pathogenesis of this common and debilitating disease. A limitation of this is that only a few experimental models mimic the ...[more]

PMID: 27492793

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Project description:Chronic graft-versus-host disease (cGVHD) is major cause of morbidity and mortality following allogeneic hematopoietic cell transplantation (HCT). Ixazomib is an oral, second-generation, proteasome inhibitor that has been shown in preclinical models to prevent GVHD. We conducted a phase I/II trial in 57 patients to evaluate the safety and efficacy of ixazomib administration for cGVHD prophylaxis in patients undergoing allogeneic HCT. Oral ixazomib was administered on a weekly basis for a total of 4 doses, beginning days +60 through +90, to recipients of matched related donor (MRD, n = 25) or matched unrelated donor (MUD, n = 26) allogeneic HCT in phase II portion of the study, once the recommended phase II dose of 4 mg was identified in phase I (n = 6). All patients received peripheral blood graft and standard GVHD prophylaxis of tacrolimus and methotrexate. Ixazomib administration was safe and well tolerated, with thrombocytopenia, leukopenia, gastrointestinal complaints, and fatigue the most common adverse events (>10%). In phase II (n = 51), the cumulative incidence of cGVHD at 1 year was 36% (95% confidence interval [CI], 19% to 54%) in the MRD cohort and 39% (95% CI, 21% to 56%) in the MUD cohort. One-year cumulative incidence of nonrelapse mortality (NRM) and relapse was 0% and 20% (95% CI, 8% to 36%) in the MRD cohort, respectively. In the MUD cohort, the respective NRM and relapse rates were 4% (0% to 16%) and 34% (17% to 52%). The outcomes on the study were compared post hoc with contemporaneous matched Center for International Blood and Marrow Transplant Research (CIBMTR) controls. This post hoc analysis showed no significant improvement in cGVHD rates in both the MRD (hazard ratio [HR] = 0.85, P = .64) or MUD cohorts (HR = 0.68, P = .26) on the study compared with CIBMTR controls. B cell activating factor plasma levels were significantly higher after ixazomib dosing in those who remained cGVHD free compared with those developed cGVHD. This study shows that the novel strategy of short-course oral ixazomib following allogeneic HCT is safe but did not demonstrate significant improvement in cGVHD incidence in recipients of MRD and MUD transplantation compared with matched CIBMTR controls. This study is registered at www.clinicaltrials.gov as NCT02250300.

Project description:BACKGROUND: Myelofibrosis is a myeloproliferative stem cell disorder curable exclusively by allogeneic hematopoietic stem cell transplantation and is associated with substantial mortality and morbidity. The aim of this study was to assess disease-specific and transplant-related risk factors that influence post-transplant outcome in patients with myelofibrosis. DESIGN AND METHODS: We retrospectively assessed 76 consecutive patients with primary (n=47) or secondary (n=29) myelofibrosis who underwent bone marrow (n=6) or peripheral blood stem cell (n=70) transplantation from sibling (n=30) or unrelated (n=46) donors between January 1994 and December 2010. The median follow-up of surviving patients was 55 ± 7.5 months. RESULTS: Primary graft failure occurred in 5% and the non-relapse mortality rate at 1 year was 28%. The relapse-free survival rate was 50% with a relapse rate of 19% at 5 years. The use of pharmacological pre-treatment and the post-transplant occurrence of chronic graft-versus-host disease were significant independent unfavourable risk factors for post-transplant survival in multivariate analysis. Using the Dynamic International Prognostic Scoring System for risk stratification, low-risk patients had significantly better overall survival (P=0.014, hazard ratio 1.4) and relapse-free survival (P=0.02, hazard ratio 1.3) compared to the other risk groups of patients. The additional inclusion of thrombocytopenia, abnormal karyotype and transfusion need (Dynamic International Prognostic Scoring System Plus) resulted in a predicted 5-year overall survival of 100%, 51%, 54% and 30% for low, intermediate-1, intermediate-2 and high-risk groups, respectively. The relapse incidence was significantly higher in the absence of chronic graft-versus-host disease (P=0.006), and pharmacological pre-treatment (n=43) was associated with reduced relapse-free survival (P=0.001). CONCLUSIONS: The data corroborate a strong correlation between alloreactivity and long-term post-transplant disease control and confirm an inverse relationship between disease stage, pharmacotherapy and outcome after allogeneic hematopoietic stem cell transplantation for myelofibrosis. The Dynamic International Prognostic Scoring System was demonstrated to be useful for risk stratification of patients with myelofibrosis who are to undergo hematopoietic stem cell transplantation.

Dataset Information

Novel Scoring Criteria for the Evaluation of Ocular Graft-versus-Host Disease in a Preclinical Allogeneic Hematopoietic Stem Cell Transplantation Animal Model.

Publications

Novel Scoring Criteria for the Evaluation of Ocular Graft-versus-Host Disease in a Preclinical Allogeneic Hematopoietic Stem Cell Transplantation Animal Model.

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