Graft-versus-host disease (GVHD) is one of the most frequent and severe complications of allogeneic (from a donor, not from self) hematopoietic stem cell (HSC) transplantation in leukemia clinic. Mesenchymal stem cells (MSC) – another type of adult stem cells – might form a niche for HSC in the bone marrow stroma and in the same time possess some immunomodulatory properties. Based on these qualities, clinical efficacy of MSC co-transplantation with HSC was tested. Experimental and clinical data indicated that MSC increase engraftment of HSC and prevent GVHD. A few studies were published including some cases reports as well as an open-label multicenter clinical trial on 46 patients.
All the reports are very encouraging, but long-term outcome still not available. This technology was even commercialized by company Osiris Therapeutics. Their product – Prochymal™, which are allogeneic MSC, is currently on phase III (approved by FDA) of clinical trial in US.
The results of a new and the first randomized clinical trial, published in Leukemia journal, alarmed us about potential risks of MSC co-transplantation for the prevention of GVHD in patients with hematological malignancies subjected to allogeneic HSC.
A total of 30 patients were enrolled, most of them with acute myeloid leukemia, and randomized to receive HSC from an HLA-identical sibling donor with or without culture-expanded MSC from the same HSC donor, at a dose range of 0.3–15.3 times 10×5 MSC per kg. They found that only 1 out of 10 patients in the group receiving MSC developed grade II acute GVHD as compared to 8 out of 15 patients in the non-MSC group. Strikingly, the relapse rate of MSC group was significantly higher than that of non-MSC group (60 versus 20%).
The study published in this issue of Leukemia by Ning et al. is significant in that it shows in a randomized clinical trial that MSC transplantation, although beneficial, comes at a high price, as the prevention of GVHD is associated with a higher incidence of leukemia relapse. For those active in the field of HSC transplantation, these data are like a deja vu, when in the eighties we learnt that prevention of GVHD was associated with loss of GVL.
Probability of Disease-Free Survival (DFS) graph:
Probability of relapse:
These “2 faces” of MSC are unclear right now. It seems like for some reasons MSC lose graft-versus-leukemia (GVL) effect with time. If modern “leukemic stem cell (LSC) concept” explains relapses by drug-resistance of this tiny population, it’s possible that somehow MSC can support their survival and proliferation in the niche and cancer progression. On other hand, in the experimental settings, recently the independence of human acute myeloid leukemic cell engraftment from co-infused MSC in contrast with normal HSC was shown.
One possible explanation of this effect, which was pointed out by the editor of Leukemia journal, is interaction with T-cells, which remain in HSC transplant and are involved into both GVHD and GVL.
Very good editorial conclusion was made about this study:
The critical issues that we have outlined require an answer. In particular, distinguishing whether the increased relapse rate in the patients infused with MSC is the result of immunosuppression or the consequence of the ‘niche’ function is of fundamental importance for the future of MSC-based therapies.
Leukemia (2008) 22, 593–599; doi:10.1038/sj.leu.2405090