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Reply to ‘The correlation between cotransplantation of mesenchymal stem cells and higher recurrence rates in hematologic malignancy patients: outcome of a pilot clinical study’ by Ning et al.

Leukemia volume 23, page 178 (2009)Cite this article

Ning et al.1 claim to confirm that the cotransplantation of donor origin mesenchymal stem cells (MSC) and hematopoietic stem cells results in both a significantly reduced incidence of acute and chronic graft-versus-host disease and an increased relapse rate. The data presented stem from a randomized clinical trial including 30 patients receiving either peripheral blood stem cells (PBSC), a bone marrow (BM) graft or both. Ten patients received MSC before the transplantation of the allograft and 20 patients did not receive MSC. The authors and the accompanying editorial2 conclude that through their immunosuppressive actions or as a consequence of their ‘niche function’ the MSC exert deleterious effects. Not only are we advised of the cadence of graft-versus-host disease and graft-versus-leukemia effects but also of the fact that we still are in front of a black box when discussing the clinical use of MSC.

We question these conclusions: in the study presented, PBSC and BM are used. Six of the 10 patients receiving MSC were transplanted with BM, together with PBSC (2 patients) or as sole graft. Eight of the 20 patients not receiving MSC received BM, together with PBSC (2 patients) or as sole graft. We regard the transplantation of BM as a cotransplantation of MSC, albeit before ex vivo expansion. We and others hypothesize the slightly reduced incidence of graft-versus-host disease in recipients of a BM graft when compared to PBSC3, 4 to be a consequence of the cotransplantation of MSC. The groups should be regrouped accordingly, the data from the patients with the numbers 14 (censored by the authors), 15 (censored by the authors), 16, 20, 23, 28, 29 and 30 should be analyzed as ‘received MSC’ as they received a marrow graft containing MSC. Calculated this way, the rates will shift and, for example, 3 year overall survival in the MSC group will reach 50% instead of 30% in the original calculation, compared to 66.7% in the non-MSC group (66.7%). As the authors did not find any correlation between dose of the MSC and response, we regard our grouping feasible and plausible. Furthermore, do we miss more precise disease characteristics, which impact on relapse likelihoods. Most of the patients in the analysis were suffering from an acute myeloid leukemia. How is the distribution of adverse features like complex aberrant karyotype5, 6 or FLT3 mutations? As it is much more likely for a patient with a complex aberrant karyotype in CR1 to relapse even after allogeneic stem cell transplantation than for a patient with a normal karyotype in CR1, the groups should be evenly distributed according to their relapse likelihood. This, too, applies to the other diseases included. Finally, the inclusion of pairings other than HLA matched sibling pairs is not covered by the group the authors analyzed. Results might differ if results after cotransplantation of PBSC and MSC from matched unrelated donors were analyzed, or, as suggested in the editorial,2 if third party donor MSC were cotransplanted. It is well possible that the lessons we learned from twin blood stem cell transplantation will be repeated in sibling MSC transplantation. The striking clinical results with MSC were obtained using a third party donor MSC so far.7, 8

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References

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  1. Department Internal Medicine IV, Oncology and Hematology, University Hospital Halle (Saale), Ernst-Grube-Strasse 40, Halle, Germany

    G Behre, S Theurich, T Weber & M Christopeit

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  1. G Behre
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Correspondence to M Christopeit.

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Behre, G., Theurich, S., Weber, T. et al. Reply to ‘The correlation between cotransplantation of mesenchymal stem cells and higher recurrence rates in hematologic malignancy patients: outcome of a pilot clinical study’ by Ning et al.. Leukemia 23, 178 (2009). https://doi.org/10.1038/leu.2008.150

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