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Is there really a specific graft-versus-leukaemia effect?

Bone Marrow Transplantation volume 51, pages 1413–1415 (2016)Cite this article

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There is recent considerable interest and data in persons with leukaemia receiving allotransplants from HLA-haplotype-matched-related donors. These data were not included in our prior analyses (reviewed in Bacigalupo and Sica4 and Kanakry et al.5). One approach to preventing acute and chronic GvHD in this setting is to give high doses of cyclophosphamide immediately post transplant. This intervention markedly reduces the risk of being diagnosed with chronic GvHD; the impact on reducing acute GvHD is less dramatic. Because chronic GvHD was associated with the lowest leukaemia relapse risk in our prior analyses, we wondered whether using post-transplant cyclophosphamide in this setting was associated with an increased risk of leukaemia relapse. The answer seems no. For example, persons with AML receiving an HLA-haplotype-matched transplant and post-transplant cyclophosphamide have a significantly lower incidence of chronic GvHD than recipients of HLA-matched unrelated transplants, but no increase in leukaemia relapse risk.6 Similarly, a lower incidence of chronic GvHD with no increase in leukaemia relapse risk was reported in a cohort of subjects receiving a HLA-haplotype-matched transplant with post-transplant cyclophosphamide compared with recipients of HLA-identical sibling transplants for lymphoma.7 One possible explanation why decreasing the proportion of persons diagnosed with chronic GvHD did not result in more leukaemia relapses is the direct anti-leukaemia activity of cyclophosphamide given post transplant. This seems unlikely as the amount of cyclophosphamide given pre- and post transplant did not differ between persons with AML receiving HLA-haplotype-matched transplants compared with those receiving HLA-matched unrelated transplant after conventional conditioning regimens of cyclophosphamide and total-body radiation or busulfan.

Although these data do not exclude the possibility of an alloimmune effect that decreases leukaemia relapse risk but is distinct from chronic GvHD, it is most consistent with an immune-mediated specific anti-leukaemia effect distinct from chronic GvHD reasonably termed GvL. Whether these persons might have undiagnosed chronic GvHD or some other alloimmune response to disparate HLA and non-HLA histocompatibility antigens is unknown and probably unknowable. Regardless of the mechanism of action, cells mediating this effect seem relatively resistant to high-dose cyclophosphamide. This contrasts with susceptibility of the cells mediating chronic GvHD. Another possibility is recipient-derived immune cells with specific anti-leukaemia activity survive pretransplant conditioning and are activated in an allogeneic milieu to eradicate leukaemia cells without causing diagnosable GvHD, perhaps until these cells are eliminated by the non-specific graft-versus-host reaction (as distinct from diagnosed GvHD). For example, host T cells were reported to effect anticancer immunity after non-myeloablative allotransplants, donor lymphocyte infusion and vaccination in a mouse model of breast cancer.8 Others report specific anti-leukaemia effects of T-cells recognising neoantigens on CLL cells.9 A third possibility is that donor natural-killer cells in the HLA-haplotype-matched graft or developing post transplant have an anti-leukaemia effect unassociated with GvHD. And there are other more convoluted explanations.

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Acknowledgements

Professor Hillard Lazarus kindly reviewed the typescript. RPG acknowledges support from the National Institute of Health Research (NIHR) Biomedical Research Centre funding scheme. EJF acknowledges support from P01 CA15396 from the US National Cancer Institute.

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  1. Department of Medicine, Division of Experimental Medicine, Haematology Research Centre, Imperial College London, London, UK

    R P Gale

  2. Department of Medicine, Division of Hematologic Malignancies, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA

    E J Fuchs

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Correspondence to R P Gale.

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Gale, R., Fuchs, E. Is there really a specific graft-versus-leukaemia effect?. Bone Marrow Transplant 51, 1413–1415 (2016). https://doi.org/10.1038/bmt.2016.183

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