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      Lineage-specific chimerism analysis in nucleated cells, T cells and natural killer cells after myeloablative allogeneic hematopoietic stem cell transplantation

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          Abstract

          Background

          Chimerism analysis is an important tool for assessing the origin of hematopoietic cells after allogeneic stem cell transplantation (allo-SCT) and can be used to detect impending graft rejection and the recurrence of underlying malignant or nonmalignant diseases.

          Methods

          This study included 24 patients who underwent myeloablative allo-SCT. DNA was extracted from nucleated cells (NCs), T cells, and natural killer (NK) cells, and the chimerism status of these cell fractions was determined by STR-PCR performed using an automated fluorescent DNA analyzer.

          Results

          Twenty-three out of the 24 patients achieved engraftment. Mixed chimerism (MC) in NCs, but not in T cells and NK cells, was significantly correlated with disease relapse. MC in all cell fractions was correlated with mortality. Ten patients (41.6%) developed extensive chronic GVHD. Six patients had MC in T cells, and 3 of them had chronic GVHD. Four patients with MC and relapse received donor lymphocyte infusion (DLI), and among them, 3 had secondary relapse. Further, the chimerism status differed among different cell lineages in 6 patients with myeloid malignancies.

          Conclusion

          The implications of MC in lymphocyte subsets are an important area for future research. Chimerism analysis in lineage-specific cells permits detection of relapse and facilitates the monitoring of therapeutic interventions. These results can provide the basic data for chimerism analysis after myeloablative SCT.

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          Most cited references28

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          Hematopoietic cell transplantation in older patients with hematologic malignancies: replacing high-dose cytotoxic therapy with graft-versus-tumor effects.

          Toxicities have limited the use of allogeneic hematopoietic cell transplantation (HCT) to younger, medically fit patients. In a canine HCT model, a combination of postgrafting mycophenolate mofetil (MMF) and cyclosporine (CSP) allowed stable allogeneic engraftment after minimally toxic conditioning with low-dose (200 cGy) total-body irradiation (TBI). These findings, together with the known antitumor effects of donor leukocyte infusions (DLIs), led to the design of this trial. Forty-five patients (median age 56 years) with hematologic malignancies, HLA-identical sibling donors, and relative contraindications to conventional HCT were treated. Immunosuppression involved TBI of 200 cGy before and CSP/MMF after HCT. DLIs were given after HCT for persistent malignancy, mixed chimerism, or both. Regimen toxicities and myelosuppression were mild, allowing 53% of eligible patients to have entirely outpatient transplantations. Nonfatal graft rejection occurred in 20% of patients. Grades II to III acute graft-versus-host disease (GVHD) occurred in 47% of patients with sustained engraftment. With median follow-up of 417 days, survival was 66.7%, nonrelapse mortality 6.7%, and relapse mortality 26.7%. Fifty-three percent of patients with sustained engraftment were in complete remission, including 8 with molecular remissions. This novel allografting approach, based on the use of postgrafting immunosuppression to control graft rejection and GVHD, has dramatically reduced the acute toxicities of allografting. HCT with the induction of potent graft-versus-tumor effects can be performed in previously ineligible patients, largely in an outpatient setting. Future protocol modifications should reduce rejection and GVHD, thereby facilitating studies of allogeneic immunotherapy for a variety of malignancies. (Blood. 2001;97:3390-3400)
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            Monitoring of donor chimerism in sorted CD34+ peripheral blood cells allows the sensitive detection of imminent relapse after allogeneic stem cell transplantation.

            Analysis of donor chimerism is an important diagnostic tool to assess the risk of relapse after allogeneic stem cell transplantation, especially in patients lacking a specific marker suitable for monitoring of minimal residual disease. We prospectively investigated the predictive value of donor chimerism analyses in sorted CD34(+) peripheral blood cells in 90 patients with acute leukemia and myelodysplastic syndrome. The cumulative incidence of relapse after four years was significantly increased in cases with decreasing or incomplete CD34(+) donor chimerism (57% vs. 18%, p=0.0001). Multivariate analysis confirmed decreasing CD34(+) donor chimerism as an independent predictor of relapse and inferior survival. The interval between a decrease of CD34(+) chimerism of less than 80% and hematologic relapse was 61 days (range 0-567). Monitoring of CD34(+) donor chimerism in the peripheral blood allows prediction of imminent relapse after allogeneic stem cell transplantation even when a disease-specific marker is lacking.
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              How and when should we monitor chimerism after allogeneic stem cell transplantation?

              Chimerism analysis has become an important tool for the peri-transplant surveillance of engraftment. It offers the possibility to realize impending graft rejection and can serve as an indicator for the recurrence of the underlying malignant or nonmalignant disease. Most recently, these investigations have become the basis for treatment intervention, for example, to avoid graft rejection, to maintain engraftment and to treat imminent relapse by pre-emptive immunotherapy. This invited review focuses on the clinical implications of characterization of hematopoietic chimerism in stem cell transplantation.
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                Author and article information

                Journal
                Korean J Hematol
                KJH
                The Korean Journal of Hematology
                Korean Society of Hematology; Korean Society of Blood and Marrow Transplantation; Korean Society of Pediatric Hematology-Oncology; Korean Society on Thrombosis and Hemostasis
                1738-7949
                2092-9129
                March 2011
                15 March 2011
                : 46
                : 1
                : 18-23
                Affiliations
                [1 ]Department of Laboratory Medicine, Dong-A University College of Medicine, Busan, Korea.
                [2 ]Department of Internal Medicine, Dong-A University College of Medicine, Busan, Korea.
                Author notes
                Correspondence to Jin-Yeong Han, M.D., Ph.D. Department of Laboratory Medicine, Dong-A University College of Medicine, 1, 3-ga, Dongdaesin-dong, Seo-gu, Busan 602-715, Korea. Tel: +82-51-240-5323, Fax: +82-51-255-9366, jyhan@ 123456dau.ac.kr
                Article
                10.5045/kjh.2011.46.1.18
                3065621
                21461299
                9474886b-e4a7-4934-90b2-dfbd7069f451
                © 2011 Korean Society of Hematology

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 24 February 2010
                : 08 February 2011
                : 08 February 2011
                Categories
                Original Article

                Hematology
                myeloablative stem cell transplantation,natural killer cells,t cells,lineage-specific chimerism

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