H.D. Yun, E.K. Waller / Biol Blood Marrow Transplant 19 (2013) 505e508
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Finding the Sweet Spot for Donor Lymphocyte Infusions Hyun Don Yun 1, 2, Edmund K. Waller 1, * 1 2
Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia Division of Hospital Medicine, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia
Article history: Received 9 February 2013 Accepted 11 February 2013
In this issue of Biology of Blood and Marrow Transplantation, Krishnamurthy et al. [1] report very favorable clinical outcomes after preemptive donor lymphocyte infusion (pDLI) or therapeutic donor lymphocyte infusion (tDLI) in patients with low levels of donor chimerism or relapsed disease, respectively, after allogeneic hematopoietic stem cell transplantation (HSCT). Patients were conditioned with regimens containing alemtuzumab or antithymocyte globulin, producing in vivo T cell depletion (TCD). Thirty-two of 62 patients (52%) received pDLI within 6 months, and these patients had a 5-year overall survival of 80% and an eventfree survival of 65%. Fifty-one patients with relapsed or persistent disease who received tDLI had a 5-year overall survival of 40%. Survival was better in patients who received tDLI at more than 6 months after HSCT compared with those who did so at less than 6 months after HSCT. The surprising results from this study, in which more than half of the patients received pDLI within 6 months after undergoing HSCT, are the relatively low incidence of graftversus-host disease (GVHD; 31% after pDLI versus 45% after tDLI) and the low rate of GVHD-related deaths (3% after pDLI versus 2% after tDLI). Furthermore, only 7 deaths (11%) due to disease relapse occurred in the patients who received pDLI, despite the low number of donor T cells in the DLI (median dose, 1.5 106 donor T cells/kg). In contrast to Krishnamurthy et al., Liga et al. [2] recently reported severe GVHD in 47% of pDLI recipients treated for high-risk disease or for mixed chimerism after HSCT with an alemtuzumab-containing conditioning regimen. In that series, GVHD was the major factor in death in 27% of the patients who received DLI. In the more than 50 years since the first HSCT, there have been significant improvements in care, with various strategies to overcome treatment-related mortality; nonetheless, enhancing the graft-versus-tumor (GVT) reaction without increasing GVHD remains the greatest challenge in the field. Using a preclinical murine model and in a phase 1 clinical trial, we have shown that DLI consisting of allogeneic T cells treated with low-dose irradiation preserved GVT effects without increased GVHD, owing to retention of short-term cytotoxicity without the potential for clonal expansion of irradiated T cells [3].
Financial disclosure: See Acknowledgments on page 508. * Correspondence and reprint requests: Edmund K. Waller, M.D., Ph.D., FACP, Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, 1365B Clifton Rd NE, Atlanta, GA 30322. E-mail address:
[email protected] (E.K. Waller). 1083-8791/$ e see front matter Ó 2013 American Society for Blood and Marrow Transplantation. http://dx.doi.org/10.1016/j.bbmt.2013.02.005
The use of regulatory T (Treg) cells in DLI may reduce the risk of GVHD from conventional T (Tcon) cells. For example, in one study, 28 patients treated with CD34-selected, haploidentical, HLA-mismatched grafts received ex vivo CD4þCD25þ Treg cells, followed by Tcon infusion on day 0 [4]. Surprisingly, only 8% of patients developed GVHD, and 92% of patients achieved remission, with an overall survival of 46% at 1 year [4]. Other strategies for limiting the potential for DLI to cause GVHD while retaining GVT activity include the sequential administration of graded doses of donor lymphocytes [5], the use of high-dose cyclophosphamide as pharmacologic GVHD prophylaxis after DLI in haploidentical HSCT [6] and the administration of DLI depleted of CD8 T cells [7-9]. Interpreting these different DLI strategies and choosing the optimum approach for each individual patient is confounded by factors that strongly influence whether the infusion of additional donor Tcells will cause GVHD. These factors include (1) intensity of the conditioning regimen, (2) use of in vivo TCD (alemtuzumab or antithymocyte globulin serotherapy) or ex vivo TCD (CD34þ selection and/or TCD), (3) timing of DLI after allo-HSCT, (4) Tcell dose and Tcell subsets in the DLI (CD4 versus CD8 T cells), (5) degree of donorerecipient HLA mismatch, (6) type and amount of residual cancer (eg, acute myelogenous leukemia, acute lymphocytic leukemia, chronic myelogenous leukemia, or multiple myeloma), (7) intensity of posttransplantation immunosuppression, and (8) level of donor chimerism at the time of DLI. The appropriate use of pDLI and tDLI in the setting of in vivo TCD and reduced-intensity conditioning must be informed by an understanding of how these factors impact the observed incidence and severity of GVHD. Figure 1 describes the interaction of some of the effects of the time from initial transplant to DLI, T cell dose, TCD, and HLA mismatch on the degree of GVHD that might occur after DLI. The risk of GVHD after DLI is classified as low (50%). In patients who underwent allogeneic HSCT with in vivo TCD (as in the study of Krishnamurthy et al.), DLI therapy is predicted to result in more GVHD for a given T cell dose compared with patients who received conventional T cellereplete transplantations and less GVHD compared with patients who received grafts depleted of donor T cells through ex vivo manipulation [8-12]. The idea that the degree of GVHD caused by DLI varies according to the level of TCD in the initial transplantation is based on a wide variation of intrinsic alloreactivity across different donorerecipient pairs with the same level of HLA mismatch. In a given population of allograft recipients, those with high donorerecipient alloreactivity are more likely to develop acute GVHD posttransplantation and are excluded from DLI therapy. The intrinsic level of donorerecipient alloreactivity is lower in the remaining patients without posttransplantation GVHD, leading to a low incidence of severe GVHD when DLI is administered for mixed chimerism or relapsed disease. In contrast, the intrinsic donorerecipient alloreactivity is untested in patients who do not develop GVHD after receiving a CD34-selected allograft (containing
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H.D. Yun, E.K. Waller / Biol Blood Marrow Transplant 19 (2013) 505e508
REFERENCES
Figure 1. Risks of developing GvHD determined by interplay between timing, T cell doses of DLI, types of TCD, and degree of HLA mismatch. As an example, data for the timing, cell dose and use of in vivo TCD from the report in pDLI of Krishnamurthy et al. is shown as an “X” on the figure.
essentially no T cells). Thus, DLI administered after a T celledepleted graft is predicted to lead to higher rates of GVHD compared with DLI administered to recipients of a T cellereplete graft. From this perspective, strategies to define the safe dose of donor T cells and the optimal time of administration in defined cohorts of patients treated with uniform conditioning regimens and GVHD prophylaxis are needed. The study by Krishnamurthy et al. advances our knowledge in this field. ACKNOWLEDGMENTS Financial disclosure: The authors have no conflicts to disclose.
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