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A Summary of the Sixth International Symposium Held in Schloss Ellmau, Germany, January 22–24, 2004

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A Summary of the Sixth International Symposium Held in Schloss Ellmau, Germany, January 22–24, 2004 Bone Marrow Transplantation (2004) 34, 767–780 & 2004 Nature Publishing Group All rights reserved 0268-3369/04 $30.00 www.nature.com/bmt Meeting report An update on graft-versus-host and graft-versus-leukemia reactions: a summary of the sixth International Symposium held in Schloss Ellmau, Germany, January 22–24, 2004 R Munker1, C Schmid2, JA Madrigal3 and HJ Kolb2,4 1Division of Hematology/Oncology, Louisiana State University Health Sciences Center, Shreveport, LA, USA; 2Medizinische Klinik III der Ludwig-Maximilians-Universita¨t (Klinikum Grosshadern), Munich, Germany; 3The Antony Nolan Research Institute, London, UK; and 4GSF Clinical Cooperative Group for Hematopoietic Cell Transplantation, Munich, Germany Summary: Clinical results of donor lymphocyte infusions (DLI) The Sixth International Symposium on Graft-versus-Host Cesare Guglielmi (Rome, Italy) presented the EBMT data and Graft-versus Leukemia Reactions was held in Schloss of DLI for relapsed chronic myelogenous leukemia (CML). Ellmau (near Garmisch-Partenkirchen, Germany) be- In a retrospective study, 298 patients with CML who had tween January 21 and 24, 2004. A total of 110 invited DLI before January 1999 were analyzed.1 The major aim of participants (scientists and clinicians working in the area the study was to determine how the initial dose of DLI of allogeneic stem cell transplantation) discussed current affected the ultimate outcome. Three groups of patients topics. Major topics of the 2004 meeting were: clinical were compared (median dose 0.1 vs 1 vs 3.5 Â 108/kg). results of donor lymphocyte infusions, basic biology, Overall, graft-versus-host disease (GVHD) was observed in immunogenetics, function and clinical relevance of natural 46% of patients, myelosuppression in 19% and any killer cells, haplo-identical stem cell transplantation, response in 74%. The first group had the best survival, immune monitoring and immune modulation. Further showing a significant difference from the other groups up to highlights were: adoptive immunotherapy, vaccination 9 months after DLI. The data shown by Guglielmi and antibody-mediated strategies. As can be seen in the demonstrate that patients with relapsed CML who start summaries of the individual presentations, important DLI with a dose higher than 0.2 Â 108 mononuclear cells advances have occurred in our understanding of GVH (MNC)/kg are exposed to significant morbidity and and GVL reactions. Each session was followed by an mortality. The incidence of major side effects can be animated discussion, which resulted in new ideas, insights markedly reduced by starting with a cell dose inferior or and projects both for basic research and clinical equal to 0.2 Â 108 MNC/kg. He also presented a current transplantation. This year’s symposium (‘From Marrow protocol of the EBMT Chronic Leukemia Working Party Transplantation to Cell Therapy’) was jointly organized for CML relapse after transplant in which escalating doses by the Ludwigs-Maximilians-University of Munich (Son- of DLI are compared to 12 months of imatinib, followed by derforschungsbereich 455), GSF (National Research the same escalating doses of DLI. Center for Environment and Health) and the EBMT Christoph Schmid (Munich, Germany) reviewed the Immunobiology Working Party. The organizers and results of adoptive immunotherapy in acute myelogenous authors of the conference proceedings would like to leukemia (AML). In contrast to CML, adoptive immu- extend their gratitude to all participants for sharing their notherapy using donor cells (DLI) has been less effective in ideas, slides and manuscripts and making this event the treatment of AML relapse post allo-transplant. In a possible. retrospective analysis by the EBMT, data on 120 patients Bone Marrow Transplantation (2004) 34, 767–780. were analyzed in order to define risk factors for response doi:10.1038/sj.bmt.1704667 and outcome.2 The overall complete remission rate was Published online 13 September 2004 42%, and the duration of remission post transplant, the use Keywords: leukemia; stem cell transplantation; allo- of chemotherapy prior to or with DLI, and the develop- geneic; GVH reactions; GVL reactions ment of acute GVHD of Xgrade II had a significant influence on response. Responding patients showed a median disease-free survival of 304 days, and a 1-year survival of 55%. Interestingly, the use of chemotherapy by itself was not associated with better survival. Experi- Correspondence: Dr R Munker, Division of Hematology/Oncology, ments were performed to improve antigen presentation LSU Health Sciences Center, 1501 Kings Highway, Shreveport, LA 71130, USA; E-mail: [email protected] in vitro by treating leukemic blasts with distinct cytokine Received 13 April 2004; accepted 15 June 2004 cocktails containing GM-CSF and interleukin-4. With Published online 13 September 2004 this technique, leukemia-derived dendritic cells showing GVH-GVL Symposium Ellmau 2004 R Munker et al 768 immunophenotypic and functional properties of profes- ma (HL). In the past, allogeneic transplantation for sional antigen-presenting cells (APCs) could be generated.3 relapsed or refractory HL had a high transplant-related This approach was translated into a clinical trial using mortality and resulted in few cures according to the mobilized donor blood cells and systemic application of IBMTR data. The UK group performed reduced intensity GM-CSF for treatment of AML relapse post transplant in conditioning transplants in 49 patients using alemtuzumab, 24 patients. The response rate was 67%, and long-term fludarabine and melphalan as conditioning.8 DLI were remissions could be induced.4 More recently, DLI were also given for progression (16 cases) or mixed chimerism (three used prophylactically after allo-transplants for high-risk cases) following the transplant. According to Peggs and his AML. In all, 12 patients have been treated so far in Munich collaborators, reduced-intensity transplants have a low using an escalating dose regimen. Toxicity was very low, toxicity especially if a related fully matched donor is used and the patients showed a 2 year DFS of 82% (manuscript and potentially lead to lasting responses. Responses to DLI in preparation). In conclusion, DLI may also be effective in provide evidence for a GVT effect in HL. Further AML, but candidates probably will have to be selected exploration of reduced-intensity transplants in HL appears according to defined risk factors. Improvement may also warranted. come from immune-modulatory strategies using cytokines Ju¨rgen Finke (Freiburg, Germany) reviewed the results or growth factors, and from the use of DLI in a and perspectives of DLI in multiple myeloma.9–11 So far prophylactic or minimal residual disease situation.5 only a limited number of patients have been treated with Bart Nijmeijer (Leiden, The Netherlands) discussed DLI. An overall response of up to 50% (including complete experimental studies on DLI for acute lymphoblastic responses in 22–40% of the patients) was reported. The leukemia (ALL) using a mouse model in which immune- main toxicity was GVHD. High numbers of transfused T deficient NOD/SCID mice were engrafted with primary cells (up to 3 Â 108/kg) as well as effective disease control human ALL blasts. The mouse model had been established prior to allo-transplantation and DLI were associated with earlier and was demonstrated to permit the monitoring of better response. Repeated DLI and dose escalation seemed leukemic progression in vivo6 as well as monitoring of the to improve the results. Protocols using prophylactic DLI antileukemic efficacy of human effector cells.7 After for prevention of relapse post transplant were effective but leukemic engraftment, human donor lymphocytes were had a slow response, reminiscent of the pattern seen in infused and the blood of the animals was continuously CML. Prophylactic DLI led to a significant survival monitored for leukemic cells and effector cells. Clinically, advantage in a study using DLI after T-cell-depleted ALL and lymphoid blast crisis in general respond poorly to primary transplantation. A complete or partial response DLI after allogeneic stem cell transplantation (SCT). The had a 30–40% relapse rate. In some patients, a relapse at underlying reasons are likely to be multifactorial and may extramedullary sites was observed. So far, the mechanisms include disease progression, GVHD and lack of co- of the graft-versus-myeloma effect are not well understood. stimulatory molecules. In vitro, Nijmeijer and his colleagues Identification of target antigens as idiotypes, tumor- could generate conventional MHC-restricted T-cell re- associated antigens, MAGE or other neo-antigens might sponses against ALL cells in HLA-disparate settings, enhance the efficacy of the procedure. In the clinical setting, demonstrating that, in a situation of high antigenic reducing the tumor burden prior to allo-transplantation disparity, the establishment of conventional T-cell re- using high-dose chemotherapy and autologous stem cell sponses against ALL cells is feasible. Also, in vivo in rescue (‘auto-allo tandem protocol’) appears promising. leukemic animals T-cell responses against HLA-identical Anthony D Ho (Heidelberg, Germany) analyzed the and non-HLA-identical lymphoid blast cells were observed relationship between GVHD and allogeneic antitumor after DLI. However, these responses displayed a distinctly effects in multiple myeloma. He started by reviewing the limited expansion potential, and T-cell proliferation data in CML, where graft-versus-tumor
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