Correlation Between the Kinetics of CD3+ Chimerism and the Incidence of Graft-Versus-Host Disease in Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation

Department of Hematology, Poznan University of Medical Sciences, Poznan, Welkopolska, Poland.
Transplantation Proceedings (Impact Factor: 0.98). 06/2011; 43(5):1915-23. DOI: 10.1016/j.transproceed.2011.02.011
Source: PubMed


Graft-versus-host disease (GvHD) remains a significant complication after allogeneic hematopoietic stem cell transplantation (HSCT). Early diagnosis and treatment may improve patient outcomes. A prospective study to investigate the relationship between chimerism kinetics and the development of acute or chronic GvHD was carried out. Split chimerism in association with the onset of GvHD was also analyzed.
Thirty-three patients with hematologic diseases treated with allogeneic HSCT were analyzed. They were conditioned with myeloablative or reduced intensity regimens and grafted with peripheral blood (PB) or bone marrow stem cells. GvHD prophylaxis consisted of cyclosporine and methotrexate. Chimerism evaluation was performed on PB mononuclear cells and purified cell subsets consisting of separated CD3(+) T cells, monocytes (CD14(+)), and granulocytes (CD15(+)). Chimerism analysis was performed at 30, 60, 120, and a median of 200 days after HSCT.
Acute GvHD was diagnosed in 19 patients and chronic GvHD in 16. On day 30, no relation was found between the level of donor chimerism and aGvHD. Upon univariate analysis, decreasing mixed chimerism among CD3(+) and infused CD34(+) cell numbers was significantly correlated with acute GvHD development, while the PB stem cell source, reduced-intensity conditioning regimen, and female donor sex were associated with an increased risk of chronic GvHD. In multivariate analysis, the risk of acute GvHD correlated only with the CD34(+) cell dose, while the risk of extensive chronic GvHD was associated with high CD3(+) donor chimerism on day 30. Patients with versus without split chimerism (T cell vs myeloid lines) did not differ statistically in their incidence of acute GvHD or chronic GvHD.
Our results supported the belief that chimerism kinetics or longitudinal chimerism evaluation is of greater significance than isolated absolute values of the percentage of chimerism at a single point after HSCT. The observations suggest that longitudinal monitoring of chimerism in CD3(+) T-cell subsets is an acceptable method to predict the development of GvHD among patients undergoing HSCT.

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    • "It has been proposed that lineage-specific chimerism analysis can highlight relapse, or impending loss of engraftment, earlier than whole blood analysis, thus enabling the clinician to initiate salvage therapy (Bader et al, 2005b; Mossallam et al, 2009; Rupa-Matysek et al, 2011; Breuer et al, 2012). It is beyond the scope of these recommendations to suggest which lineages should be investigated in which diseases; rather we will concentrate on the technical aspects of cell separation that must be taken into consider- ation. "
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    ABSTRACT: Analysis of short tandem repeats (STR) is the predominant method for post-transplant monitoring of donor engraftment. It can enable early detection of disease relapse, level of engraftment and provide useful information on the graft-versus-host disease (GVHD)/graft-versus-tumour (GVT) effect, facilitating therapeutic intervention. Harmonization and standardization of techniques and result interpretation is essential to reduce the impact of laboratory variability on both clinical management and the results of multi-centre clinical trials. However, the United Kingdom National External Quality Assessment Service for Leucocyte Immunophenotyping (UK NEQAS LI) has highlighted significant issues inherent in STR testing that impact upon inter- and intra- laboratory variation. We present here consensus best practice guidelines and recommendations for STR chimerism testing, data interpretation and reporting that have been drawn up and agreed by a consortium of 11 UK and Eire clinical laboratories. This document uses data obtained from the UK NEQAS LI Post-Stem Cell Transplant (SCT) Chimerism Monitoring Programme.
    Full-text · Article · Aug 2014 · British Journal of Haematology
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    ABSTRACT: Background: Chimerism defines the amount of donor versus recipient hematopoiesis following allogeneic stem cell transplant (SCT). PCR-based analyses of short tandem repeats (STRs) are commonly used and are accurate and applicable to allogeneic transplant recipients. These analyses are performed on blood and marrow aspirates, but it is unknown if analyses of both are required. We performed a retrospective analysis of 42 consecutive adult allogeneic SCT recipients at our institution to determine if both sample types are needed. Methods: Chimerism status was determined by multiplex PCR and capillary electrophoresis of STRs. Analyses were performed at 30, 60, and 90days after SCT on both unfractionated blood and unfractionated marrow aspirate. Results: PCR analyses of STRs for chimerism performed on unfractionated blood highly correlated with results obtained using unfractionated marrow aspirates at 30, 60, or 90days following transplant (p<0.0001 for each time point). Overall and relapse-free survival of patients experiencing full donor chimerism was not statistically different from patients demonstrating mixed chimerism at days 30, 60, and 90 following SCT. Conclusions: PCR-based chimerism analyses on blood provide similar information as marrow aspirate analyses. These are unique results suggesting that chimerism analyses may be assessed on peripheral blood alone.
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    ABSTRACT: Double umbilical cord blood (dUCB) allogeneic transplantation following low dose Total body irradiation, Cyclophosphamide and Fludarabine (TCF regimen)-based reduced-intensity conditioning regimen (RIC) is increasingly used in adults lacking a suitable related or unrelated donor. Currently, there is little data regarding the impact on long-term outcome of CD3+ T cell chimerism (TCC) in this particular setting. Thirty-six adults with various hematological diseases and who received dUCB allogeneic transplant conditioned with TCF were included in this retrospective study. Peripheral blood CD3+ TCC was considered until day +100 post-tranplant in order to determine the impact of full versus mixed chimerism on long-term outcomes. Twenty-nine and 7 patients were documented with full and mixed CD3+ TCC, respectively, within the first 100 days post-transplant. With a median follow-up of 36 months, 3 year-overall survival (OS), disease-free survival (DFS), and cumulative incidence of relapse (CIR) were 61%, (95% CI: 43-75); 50% (95% CI: 32.5-66) and 28% (95% CI: 16-44), respectively. In univariate analysis, a full CD3+ TCC was associated with a better 3-year DFS : 59% (95% CI: 39-75.5) vs 14% (95% CI: 7-46), (HR=0.24 [0.09-0.65], p=0.005) and a lower CIR: 24% (95% CI: 21.5-57) vs 78% (95% CI: 52-99), (HR=0.18 [0.05-0.5], p=0.004). In multivariate analysis, a full CD3+ TCC remained associated with a lower CIR (HR=0.17 [0.028-0.99], p=0.049). CD3+ TCC has no impact on graft versus host disease and non-relapse mortality in this study. In conclusion, here, full CD3+ TCC was independently associated with a lower risk of relapse in adults receiving a dUCB TCF RIC allogeneic transplant. This highlights the need to develop immunotherapy approaches allowing for early conversion to full chimerism after this type of transplant.
    No preview · Article · Dec 2014 · Biology of Blood and Marrow Transplantation
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