Graft-versus-tumor effect according to type of graft-versus-host disease defined by National Institutes of Health consensus criteria and associated outcomes.
ABSTRACT The impact of National Institutes of Health consensus criteria (NCC) graft-versus-host disease (GVHD) on survival has rarely been investigated in a large cohort of patients with GVHD presenting before and after day 100 posttransplantation. We retrospectively investigated 775 patients who underwent allogeneic stem cell transplantation and assessed the GVHD effects on survival by the time-dependent covariates in Cox proportional hazards regression models. Using the NCC, the patients were classified into 4 groups: (1) no GVHD (n = 251); (2) acute GVHD (aGVHD) only (n = 199), including 26 patients with late aGVHD; (3) classic chronic GVHD (cGVHD; n = 232); and (4) overlap syndrome (OS; n = 93). Multivariate analyses showed that classic cGVHD (hazard ratio [HR], 0.46; 95% confidence interval [CI], 0.27-0.77) and OS (HR, 0.52; 95% CI, 0.28-0.96) were associated with significantly decreased risk of relapse, whereas aGVHD only was not associated with relapse rate (HR, 1.11; 95% CI, 0.76-1.63). All aGVHD events, including the period of aGVHD in patients who developed cGVHD after aGVHD, also did not affect the risk of relapse (HR, 0.74; 95% CI, 0.49-1.12). All types of GVHD were significantly associated with higher nonrelapse mortality in common. Finally, patients with aGVHD only had significantly lower overall survival and disease-free survival compared with those without GVHD, in contrast to favorable survival outcomes in patients with cGVHD without previous aGVHD. This study demonstrates that NCC GVHD type is associated with different graft-versus-tumor effects. Further studies are needed to investigate risk factors, pathogenesis, and biomarkers for each type of NCC GVHD.
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ABSTRACT: Acute graft-vs-host disease (GVHD) is a major complication of allogeneic hematopoietic cell transplantation (HCT), and the main cause of non-relapse mortality (NRM) during the first 100 days post-transplant. While GVHD can be prevented by extensive removal of mature donor T cells from the donor hematopoietic stem cell population, doing so eliminates any potential allogeneic graft-vs.- tumor (GVT) effect also mediated by donor T cells, and results in unacceptable rates of cancer relapse. One potential solution to this problem of separating GVHD development from a GVT response is to prevent T cell mediated GVHD in the intestinal tract (IT), while preserving systemic anti-host alloreactivity of donor T cells which target residual tumor cells expressing host alloantigens. We examined the ability of the anti-inflammatory Rho Kinase inhibitor, fasudil, given orally and intraperitoneally, to prevent GVHD in a C3H → B6C3F1 mouse model of MHC-haploidentical bone marrow transplantation. Fasudil treated recipients of anti-thy-1 mAb + C' treated bone marrow (ATBM) cells plus T cells had a 73% 90-day survival compared with 25% among untreated ATBM + T cell recipients (p < 0.0001). Severe initial weight loss was similar in the two groups, but less diarrhea was observed among treated animals, and fasudil treated survivors recovered more weight than untreated survivors. Skin inflammation occurred and resolved between weeks 2 and 8 with similar severity and kinetics in both treated and untreated surviving animals, indicating persistent alloreactivity. Day 10 post-transplantation splenocytes from fasudil treated-mice, containing mature donor T cells, and day 98 splenocytes, containing mature donor and de novo thymus-derived T cells, exhibited alloreactivity against host parental antigens, as assessed by in vitro IFN-γ production, and rounds of allo-stimulated proliferation, respectively. These data support the idea that targeted treatment of the IT with Rho kinase inhibitors can ameliorate lethal GVHD while preserving systemic alloreactivity. They also suggest that similar mechanisms of IT-specific tolerance or resistance to GVHD operate in fasudil treated and untreated long term survivors of allogeneic ATBM + T cells.Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 05/2014; · 3.15 Impact Factor
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ABSTRACT: OBJECTIVES: For patients with acute myeloid leukemia in first complete remission (AML CR1) lacking HLA-matched sibling donors (MSD), 8/8-mateched unrelated donors (URD) are mostly used in cases with poor risk features. For AML CR1 with intermediate cytogenetics, however, the benefit of 8/8-mateched URD should be compared with non-allogeneic therapies as well as MSD METHODS: To address this issue, we assessed the transplantation outcomes of 8/8-matched URD (n=54) compared with MSD (n=145) or autologous transplantation (n=89) for AML CR1 with intermediate cytogenetics. RESULTS: In multivariate analyses, 8/8-matched URD had comparable 6-year overall survival (OS, P=0.997), disease-free survival (DFS, P=0.951), and relapse (P=0.672) to MSD, whereas 8/8-matched URD had a higher OS (P=0.070) and DFS (P=0.035) with lower relapse (P=0.009) than autologous transplantation. No difference in non-relapse mortality was observed according to donor type. Notably, these equivalent or superior outcomes of 8/8-matched URD compared with MSD or autologous transplantation, respectively, were particularly evident in patients without poor risk features (n=200), such as older age, hyperleukocytosis at diagnosis, and myelodysplasia-related changes, who are not usual candidates for URD transplantation. CONCLUSIONS: These results indicate that 8/8-matched URD are feasible next option in AML CR1 with intermediate cytogenetics, when lacking MSD, even in patients without poor risk features. © 2013 John Wiley & Sons A/S.European Journal Of Haematology 02/2013; · 2.55 Impact Factor
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ABSTRACT: The aim of this study was to evaluate the impact of marrow blasts at transplant in adult acute myeloid leukemia (AML) patients. We analyzed 478 patients who underwent allogeneic stem cell transplantation (SCT). All patients were divided into five subgroups according to the percentage of blasts: <2 % (n = 361), ≥2 to<3 % (n = 64), ≥3 to <5 % (n = 28), ≥5 to <12 % (n = 11), and ≥12 % (n = 4). After a median follow-up of 59.5 months (range 3.3-125.9 months) for survivors, patients with higher marrow blasts at transplant showed lower overall survival (OS) and disease-free survival (DFS). In multivariate analyses, OS and DFS did not show significant differences with blast counts up to 12 %, compared with blast counts of <2 %; by contrast, the presence of >12 % marrow blasts was associated with significantly poorer OS and DFS. In the separate multivariate analyses by cytogenetic risk group, the impact of >12 % marrow blast on survival outcomes was observed in all risk groups. Thus, pre-transplant bone marrow status is an important prognostic factor for AML patients. In addition, the higher relapse rate in patients with >12 % marrow blasts may provide insights into the tolerable blast cell burden that can be overcome by the graft-versus leukemia effect.International journal of hematology 03/2013; · 1.17 Impact Factor