The Predictive Value of Gene Expression Profiles for Acute Graft-Versus-Host Disease after Hematopoietic Cell Transplantation with Nonmyeloablative Conditioning for Hematological Malignancy.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1079-1079
Author(s):  
Tania N. Masmas ◽  
Lennart Friis-Hansen ◽  
Jens Vilstrup Johansen ◽  
Soren Lykke Petersen ◽  
Brian T. Kornblit ◽  
...  
Keyword(s):  
Gene Expression ◽  
Graft Versus Host Disease ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Late Onset ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Graft Versus Host ◽  
Post Transplant ◽  
Acute Graft

Abstract Purpose: To test the hypothesis that global gene expression profiles of peripheral blood mononuclear cells (PBMNC) day +14 after hematopoietic cell transplantation with nonmyeloablative conditioning could predict the later occurrence of acute graft-versus-host disease (GVHD) grade II–IV. Material: Between March 2000 and Marts 2006, 100 patients with hematological malignancies received peripheral blood stem cells from an human leukocyte antigen identical sibling/mother donor or from a matched unrelated donor following nonmyeloablative conditioning with low dose fludarabine and 2 Gy of total body irradiation. Post-transplant immunosuppression consisted of cyclosporine and mycophenolate mofetil. Only patients with sustained engraftment, who did not experience late-onset acute GVHD after day +100 were included; eight patients were excluded due to graft rejection, three patients due to suboptimal RNA or lacking PBMNC samples, and further 15 patients due to late-onset acute GVHD. Seventy-four patients were then eligible for microarray analysis. Methods: RNA was precipitated from frozen PBMNC from day +14 post-transplant and gene profiling analyses were performed using Human Genome U133 Plus 2.0 GeneChip Array. The array data were normalized, RMA modelled and asinh transformed in R. The differentially regulated gene expression between the group of patients developing acute GVHD before day +40, +56 and +84 post-transplant compared to the patients never experiencing acute GVHD was identified and formed the basis for the subsequent principal component analysis (PCA) and classifying models. No patients experienced acute GVHD between day +85 and +100 post-transplant. Results: The patients experiencing acute GVHD by different time points were separated from the patients never experiencing acute GVHD by the PCA plot. Furthermore the classifying models could separate the groups correctly in up to 93% of cases in the best of the classifying model. In addition, differentially regulated genes between the two groups were identified. Conclusion: These data suggest that the pattern of gene expression profiles early post-transplant is able to predict patients with a high risk of later occurrence of acute GVHD from those never experiencing acute GVHD. This knowledge could be exploited to increase the immunosupression and thus prevent acute GVHD in patients at risk. Furthermore, candidate genes of interest for the pathogenesis of acute GVHD have been identified.

scholarly journals Comparative analysis of risk factors for acute graft-versus-host disease and for chronic graft-versus-host disease according to National Institutes of Health consensus criteria

Blood ◽  
2011 ◽  
Vol 117 (11) ◽  
pp. 3214-3219 ◽  
Author(s):  
Mary E. D. Flowers ◽  
Yoshihiro Inamoto ◽  
Paul A. Carpenter ◽  
Stephanie J. Lee ◽  
Hans-Peter Kiem ◽  
...  
Keyword(s):  
Risk Factors ◽  
Graft Versus Host Disease ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Chronic Gvhd ◽  
Human Leukocyte ◽  
National Institutes Of Health ◽  
Host Disease ◽  
Graft Versus Host ◽  
Acute Graft

Abstract Risk factors for grades 2-4 acute graft-versus-host disease (GVHD) and for chronic GVHD as defined by National Institutes of Health consensus criteria were evaluated and compared in 2941 recipients of first allogeneic hematopoietic cell transplantation at our center. In multivariate analyses, the profiles of risk factors for acute and chronic GVHD were similar, with some notable differences. Recipient human leukocyte antigen (HLA) mismatching and the use of unrelated donors had a greater effect on the risk of acute GVHD than on chronic GVHD, whereas the use of female donors for male recipients had a greater effect on the risk of chronic GVHD than on acute GVHD. Total body irradiation was strongly associated with acute GVHD, but had no statistically significant association with chronic GVHD, whereas grafting with mobilized blood cells was strongly associated with chronic GVHD but not with acute GVHD. Older patient age was associated with chronic GVHD, but had no effect on acute GVHD. For all risk factors associated with chronic GVHD, point estimates and confidence intervals were not significantly changed after adjustment for prior acute GVHD. These results suggest that the mechanisms involved in acute and chronic GVHD are not entirely congruent and that chronic GVHD is not simply the end stage of acute GVHD.

Early Onset of Acute Graft-Versus-Host Disease Indicating a Worse Prognosis in Terms of Chronic Graft-Versus-Host Disease and Survival Compared to Late Onset.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4979-4979
Author(s):  
Sang Kyun Sohn ◽  
Joon Ho Moon ◽  
Jong Gwang Kim ◽  
Yee Soo Chae ◽  
Yoon Young Cho ◽  
...  
Keyword(s):  
Graft Versus Host Disease ◽  
Early Onset ◽  
Acute Gvhd ◽  
Late Onset ◽  
Chronic Gvhd ◽  
Onset Time ◽  
Host Disease ◽  
Graft Versus Host ◽  
Grade Ii ◽  
Acute Graft

Abstract Background: Acute graft-versus-host disease (GVHD) is an important risk factor for predicting chronic GVHD. The transplant outcome can be influenced by the onset time of acute GVHD in patients who received allogeneic stem cell transplantation (SCT) Methods: The medical records of one hundred six patients with hematological malignancies who received allogeneic transplantation were retrospectively reviewed. Results: Fifty four (39.7%) patients developed grade II to IV acute GVHD within D+30 after allogeneic SCT (<D+30 group) and 13 (9.6%) patients manifested acute GVHD after D+30 (≥D+30 group). The cumulative incidence of chronic GVHD was 81.5% and 53.8% in <D+30 group and ≥D+30 group, respectively.(p<0.001) On multivariate analysis, grade II to IV acute GVHD developed before D+30 and primary diagnosis of chronic myeloid leukemia were identified as independent variables predicting chronic GVHD. The overall survival rate was significantly lower in the <D+30 group than grade 0 or I group (p<0.001). But there was no statistical difference between the group with grade 0 or I and ≥D+30 group in terms of the incidence of chronic GVHD (p=0.295). Among the 54 patients with grade II to IV acute GVHD developed at before D+30, 26 (48.1%) patients developed into quiescent chronic GVHD and 20 (37%) patients progressive chronic GVHD. The quiescent chronic GVHD showed a better survival than progressive chronic GVHD (p=0.063). Conclusion: Acute GVHD of early onset (within D+30) was regarded as a worse prognostic indicator in terms of chronic GVHD and survival.

Donor Statin Treatment Protects against Severe Acute Graft-Versus-Host Disease After Related Allogeneic Hematopoietic Cell Transplantation.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2227-2227
Author(s):  
Marcello Rotta ◽  
Barry E Storer ◽  
Rainer F Storb ◽  
Paul J Martin ◽  
Shelly Heimfeld ◽  
...  
Keyword(s):  
Cell Transplantation ◽  
Graft Versus Host Disease ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Statin Treatment ◽  
Hematopoietic Cell ◽  
Graft Versus Host ◽  
Grade 3 ◽  
Statin Use ◽  
Acute Graft

Abstract Abstract 2227 Poster Board II-204 Acute graft-versus-host disease (GVHD) contributes to morbidity and mortality after allogeneic hematopoietic cell transplantation (HCT) and more effective prevention and treatment strategies are needed. The 3-hydroxy-3-methylglutaryl coenzyme A-reductase inhibitors (statins) have been shown to possess immunomodulatory properties in vitro and in vivo. To determine whether donor or recipient statin use may affect the risk of GVHD, we retrospectively analyzed outcomes among 567 patients with hematologic malignancies who had hematopoietic cell transplantation from HLA-matched related donors at a single institution between 2001 and 2007. Compared to allografts where neither the donor nor recipient was treated with a statin at the time of transplant (n=464), statin use by the donor and not the recipient (n=75) was associated with a profoundly decreased risk of grade 3-4 acute GVHD (multivariate hazard ratio [HR], 0.28; 95= confidence interval [CI], 0.1-0.9; p=0.03) (Table). Statin use by both donor and recipient (n=12) was suggestively associated with a decreased risk of grade 3-4 acute GVHD (HR, 0.00; 95= CI, undefined; p=0.06), while statin use by the recipient and not the donor (n=16) did not confer GVHD-protection. Risks of chronic GVHD, recurrent malignancy, non-relapse mortality and overall mortality were not significantly affected by donor or recipient statin exposure. Statin-associated GVHD-protection was restricted to recipients with cyclosporine-based postgrafting immunosuppression (n=417; 74=) and was not observed among those given tacrolimus (significance of effect modification: cyclosporine vs. tacrolimus, p=0.009). These results suggest that donor statin treatment may be a promising strategy for preventing severe acute GVHD without compromising immunologic control of the underlying malignancy. Disclosures: No relevant conflicts of interest to declare.

Sirolimus, Tacrolimus and Antithymocyte Globulin Are Associated with Improved Overall Survival When Compared to Methotrexate, Tacrolimus and Antithymocyte Globulin in Mismatched Unrelated Allogeneic Hematopoietic Cell Transplantation

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2553-2553
Author(s):  
Rebecca Nelson ◽  
Janelle Perkins ◽  
Jamie Shapiro ◽  
Jongphil Kim ◽  
Binglin Yue ◽  
...  
Keyword(s):  
Cell Transplantation ◽  
Graft Versus Host Disease ◽  
Antithymocyte Globulin ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Disease Risk ◽  
Hematopoietic Cell ◽  
Allogeneic Hematopoietic Cell Transplantation ◽  
Graft Versus Host ◽  
Acute Graft

Abstract Background: Sirolimus, an inhibitor of the mammalian target of rapamycin (mTOR), is used in combination with tacrolimus as prophylaxis for acute graft-versus-host-disease (GVHD). Two published randomized trials (one single institution and a multicenter one) failed to demonstrate a survival advantage of sirolimus plus tacrolimus (SIR-TAC) vis-à-vis methotrexate plus tacrolimus (MTX-TAC) when used for acute GVHD prophylaxis in HLA-matched related or unrelated allogeneic hematopoietic cell transplantation. No data exists comparing these two regimens when combined with antithymocyte globulin (ATG) in mismatched unrelated donor (MMUD) allografting. This study aims at comparing the efficacy of SIR-TAC-ATG vs. MTX-TAC-ATG in MMUD allografting. Patients and methods: We retrospectively analyzed 122 patients allografted between 01/2006 and 08/2013 after acute GVHD prophylaxis using SIR-TAC-ATG (n=28) or MTX-TAC-ATG (n=94). All patients received 7.5 mg/kg of rabbit ATG. Conditioning regimens were myeloablative (n=94) or reduced-intensity (n=28). Patient-, disease-, and treatment-related characteristics are summarized in Table 1. Results: Patients receiving SIR-TAC-ATG were older (54 vs. 47 years, p=0.015). The median follow-up from day of cell infusion for all patients was 11.2 (0.5-84.4) months; and for patients in the sirolimus-group or methotrexate-group were 11.5 (1.8-54.9) months and 10.4 (0.5-84.4) months, respectively. The 1-year survival was superior in patients who received SIR-TAC-ATG (83% vs. 57%, p=0.012). The 100-day cumulative incidences of grade 2-4 acute GVHD were 57% in the sirolimus- and 71% in the methotrexate-group, p=0.14. Patients who received methotrexate had over two-fold higher cumulative incidence of NRM (3-year), albeit not statistically significant (37% vs. 16%, p=0.1). There were no difference in median relapse-free survival (RFS) (MTX-TAC-ATG=17.8 months vs. SIR-TAC-ATG=not reached, p=0.21) or cumulative incidence of relapse at 1-year (MTX-TAC-ATG =19% vs. 19%, p= 0.94). Use of rituximab for preemptive treatment of EBV reactivation was higher in the group treated with sirolimus (79% vs. 51%, p= 0.01). Multivariate analyses using Cox proportional-hazard model identified use of sirolimus (HR=0.28 (95%CI=0.10, 0.78), p=0.015) and low CIBMTR disease risk (Hazard ratio (HR) =0.49 (95%CI=0.27, 0.88), p=0.018) as favorable predictors of overall survival (OS); but only low CIBMTR disease risk (HR=0.47 (95%CI=0.22, 0.98), p=0.045) as predictor for lower NRM. Conclusion: This study suggests that combining SIR-TAC-ATG results in improved OS in MMUD allogeneic hematopoietic cell transplantation when compared to MTX-TAC-ATG. These findings need to be confirmed in a prospective randomized controlled trial. Table 1. Variables Sirolimus-based Methotrexate-based p-value Recipient median (range) age (years) 54 (24-67) 47(20-69) 0.015 Recipient gender Male (M) Female (F) M=46% F=54% M=63% F=37% 0.13 Conditioning regimen MAC RIC MAC=75% RIC=25% MAC=78% RIC=22% 0.80 Recipient CMVserology seropositive 75% 70% 0.81 Primary disease Myeloid Lymphoid Others 68% 11% 21% 55% 17% 28% 0.55 CIBMTR disease risk High=18% Int=36% Low=47% High=23% Int=33% Low=44% 0.78 Median CD34 cell dose (x106/kg) 8.5 (3.2-23) 8.6 (1.8-25) 0.53 Rituximab Yes 79% 51% 0.01 MAC regimens: FLU-BU (AUC5300); RIC regimens: FLU-BU (AUC3500), FLU-CY, FLU-MEL, FLU-2GyTBI; Myeloid: AML, CML, MDS; Lymphoid: ALL, CLL Disclosures Off Label Use: sirolimus for prophylaxis for acute Graft-versus-host disease; Antithymocyte globulin for prophylaxis for acute Graft-versus-host disease.

Re-Evaluation of Chronic Graft-Versus-Host Disease Using National Institute of Health Consensus Criteria.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2239-2239
Author(s):  
Dae-Young Kim ◽  
Je-Hwan Lee ◽  
Jung-Hee Lee ◽  
Se Hyung Kim ◽  
Sung-nam Lim ◽  
...  
Keyword(s):  
Graft Versus Host Disease ◽  
Scoring System ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Late Onset ◽  
Chronic Gvhd ◽  
Prognostic Significance ◽  
P Value ◽  
Host Disease ◽  
Graft Versus Host

Abstract Background: The National Institutes of Health (NIH) proposed new consensus criteria for the diagnosis and scoring of chronic graft-versus-host disease (cGVHD). Using the new system, we re-evaluated the patients with cGVHD that was diagnosed by classic criteria. Methods: Of 618 patients who underwent allogeneic hematopoietic cell transplantation (HCT) from December 1994 to April 2008 at the Asan Medical Center, Seoul, Korea, we retrieved 236 patients who had cGVHD by classic criteria from the AMC BMT Registry. Among 236 patients, 20 patients with liver-only involvement could not be diagnosed as cGVHD by the NIH criteria, thus we reclassified and graded 216 patients according to the NIH criteria. We also evaluated the ability of the NIH criteria to stratify and predict the risk of cGVHD patients, as assessed by GVHD-specific survival (GSS). Results: Twenty patients (9.3%) were reclassified as acute GVHD by NIH criteria (‘classic acute’ in 7 and ‘persistent, recurrent, or late-onset acute’ in 13) and 196 patients (90.7%) remained as chronic GVHD (‘classic chronic’ [Cl-Ch] in 170 and ‘overlap syndrome’ [Ov-Sy] in 26). Median age of 196 patients with cGVHD by NIH criteria, 119 males and 77 females, was 35.5 years (range, 15 to 57). Acute GVHD preceded cGVHD in 70 patients (35.7%). The probability of GSS at 5 years was 86.2% with 22 cGVHD-related deaths. The GSS was significantly different between two subtypes of cGVHD by NIH criteria: 88.6% for Cl-Ch vs 70.2% for Ov-Sy (p=0.002). NIH global scoring system stratified risk of cGVHD patients better than stage by classic criteria at both onset and peak of cGVHD (Table 1). We evaluated 12 variables at onset of cGVHD to determine their prognostic significance for GSS. Multivariate analysis demonstrated that NIH global score at onset (mild vs moderate, HR 6.1, p=0.027; mild vs. severe, HR 7.0, p=0.015), preceding aGVHD (no vs. yes, HR 6.2, p=0.001), and number of HLA ABDR mismatch (0 vs. 1, HR 2.0, p=0.555; 0 vs 2, HR 200.4, p=0.009) were independent predictors for GSS. Conclusion: Our results indicate that a new NIH system can provide a proper risk-stratification of patients with cGVHD and global scoring system at onset of cGVHD can predict the prognosis of patients. Table 1. GVHD-specific survival according to NIH global scoring system or stage by classic criteria Onset of cGVHD Peak of cGVHD Pt. No. GSS (5-y) P-value Pt. No. GSS (5-y) P-value NIH criteria mild 70 95.2% 0.022 36 100% 0.004 moderate 64 82.8% 42 92.2% severe 62 79.7% 118 79.6 Classic criteria limited 86 90.1% 0.305 45 97.8% 0.039 extensive 110 83.7% 151 83.0%

scholarly journals Genetic variation in the IL-10 pathway modulates severity of acute graft-versus-host disease following hematopoietic cell transplantation: synergism between IL-10 genotype of patient and IL-10 receptor β genotype of donor

Blood ◽  
2005 ◽  
Vol 106 (12) ◽  
pp. 3995-4001 ◽  
Author(s):  
Ming-Tseh Lin ◽  
Barry Storer ◽  
Paul J. Martin ◽  
Li-Hui Tseng ◽  
Bryan Grogan ◽  
...  
Keyword(s):  
Cell Transplantation ◽  
Graft Versus Host Disease ◽  
Lower Risk ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Multivariable Analysis ◽  
Hematopoietic Cell ◽  
Host Disease ◽  
Graft Versus Host ◽  
Acute Graft

We have previously shown that the interleukin 10 (IL-10)/-592*A allele of the recipient is associated with less severe acute graft-versus-host disease (GVHD) and a lower risk of nonrelapse mortality after hematopoietic cell transplantation (HCT) from an HLA-identical sibling. In the present study, we examined variation in the IL-10 receptor β gene as a further test of the hypothesis that the IL-10 pathway regulates the risk of acute GVHD. A single nucleotide polymorphism (A/G) at cDNA position 238 of the IL-10 receptor β gene (IL10RB/c238) was genotyped in 953 HC transplant recipients and their HLA-identical sibling donors. IL-10/-592 and IL10RB/c238 genotypes were tested for association with GVHD by multivariable analysis. The IL-10/-592*A allele of the recipient and IL10RB/c238*G allele of the donor were significantly associated with a lower risk of grades III-IV acute GVHD (trend P < .001 and P = .02, respectively). The donor IL10RB/c238*G allele provided protection among patients with the IL-10/-592 A/C or A/A genotypes but not among patients with the high-risk IL-10/-592 C/C genotype. These data suggest an interaction of the patient IL-10/-592 and donor IL10RB/c238 genotypes on risk of GVHD, further supporting the hypothesis that the IL-10 pathway plays an important role in controlling the severity of acute GVHD.

Sign in / Sign up

Export Citation Format

Share Document