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Mechanisms of graft-versus-leukemia effects after allogeneic stem cell transplantation: effects on the leukemia stem cell?

Leukemia Supplements volume 3, pages S16–S17 (2014)Cite this article

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Total body irradiation (TBI) was originally thought to be capable of eradicating leukemia, but with time it became apparent that we cannot eradicate this disease with TBI.1 Today we know that graft-versus-leukemia effects are more important than previously thought. Strong evidence came from the depletion of T cells from the graft for the prevention of graft-versus-host disease (GVHD): the rate of relapses increased particularly in chronic myelogenous leukemia (CML),2 and in some patients the graft was even rejected. However, some patients with refractory acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) were treated with intensive chemotherapy and a single dose of TBI and are alive and in remission today more than 30 years later. Therefore, the question arises whether immune therapy with lymphocytes from the stem cell donor can eradicate leukemia stem cells without the help of high-dose TBI or stem-cell toxic chemotherapy. The best clinical evidence for leukemia stem cells is provided by the occurrence of late relapses presumably arising from radio- and chemo-resistant, quiescent stem cells. Late relapses after allogeneic stem cell transplantation were observed in patients treated for CML3 and less frequently in those treated for AML and ALL.4 In these patients stem cells of leukemia may have been recruited from a quiescent state and may have given rise to open relapse.

It is known that hematopoiesis is the first target of the GVH reaction, leukemia cells of the host may be eliminated by donor T cells without severe sequelae, as the hematopoiesis of the host is replaced by donor hematopoiesis. To determine the optimal conditions for eliminating residual hematopoiesis of the host, we performed studies on dogs. In dogs, transplantation of anti-thymocyte globulin-treated (T-lymphocyte depleted) bone marrow from dog leukocyte antigen-identical littermates showed mixed chimerism and development of GVHD was prevented. Transfusion of donor lymphocytes (DLTs) produced fatal GVHD, if given within 60 days of marrow transplantation.5 After this time, DLT could be given without GVHD. Nevertheless, the degree of chimerism increased to complete chimerism in dogs given DLT, whereas those not given DLT remained mixed chimeras until the end of the observation period 8 years after transplantation. It is well established that after bone marrow transplantation complete chimerism is required to avoid recurrence of leukemia. This form of treatment, which was proven successful in dogs, was also thought to be applicable to humans. The treatment strategy included (i) allogeneic stem cell transplantation with T-cell depletion, (ii) establishment of chimerism and tolerance, (iii) adoptive immunotherapy with donor lymphocytes. Prior to preemptive DLT we studied the treatment of leukemia relapse after transplantation with DLT. Two of three patients treated for recurrent CML6 are still in molecular remission more than 20 years later, one patient relapsed 20 years after treatment of relapse with DLT. In an EBMT study,7 it was shown that CML in hematological relapse and cytogenetic relapse showed the best response toward DLT; 70–80% of patients experienced cytogenetic remission. Relapse in transformed phase was less responsive and responses were not durable. In patients with progressive and relapsing MMY response rates were around 50%, but responses were also not durable. Response rates were less in AML and least in ALL patients.

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Acknowledgements

CF and AM received grant support from the German Research Foundation (DFG TransRegio SFB 36, B8) and Integrated Research and Treatment Center Transplantation (IFB-Tx). The symposium and publication of this supplement were sponsored by the Division of Hematology / Oncology at the Warren Alpert Medical School of Brown University and NIH Center of Biomedical Research Excellence (COBRE) for Stem Cells Biology at Rhode Island Hospital.

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Authors and Affiliations

  1. Department of Medicine III, Clinical Cooperative Group Haematopoietic Cell Transplantation, University of Munich, Munich, Germany

    H-J Kolb, H Schmetzer, C Schmid, I Bigalke, R Buhmann, A Moosmann, C Falk, S Reuther, F Schuster & A Borkhardt

  2. Helmholtz Zentrum Muenchen—German Research Center for Environmental Health, Munich, Germany

    H-J Kolb, H Schmetzer, C Schmid, I Bigalke, R Buhmann, A Moosmann, C Falk, S Reuther, F Schuster & A Borkhardt

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  1. H-J Kolb
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Correspondence to H-J Kolb.

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H-JK and SH have received lecture fees from Neovii Fresenius Biotech EBMT and TEVA education. RB declares no conflict of interest.

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Kolb, HJ., Schmetzer, H., Schmid, C. et al. Mechanisms of graft-versus-leukemia effects after allogeneic stem cell transplantation: effects on the leukemia stem cell?. Leukemia Suppl 3 (Suppl 1), S16–S17 (2014). https://doi.org/10.1038/leusup.2014.9

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