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M.M. Cuadrado et al.
into a female recipient. This finding was unexpected because female recipients of male grafts had either full donor chimerism or stable mixed chimerism prior to CD34+-selected infusion (6/14 [30%] full donor and 8/14 [57%] stable mixed chimerism). This finding would be consistent with the concept of ‘split tolerance’ identified in animal models in which hematopoietic chimeras with mixed T-cell chimerism can nevertheless reject other donor tissues, including other hematopoietic cells.19 It will therefore be important to track for evidence of anti-HY antibodies and HY-specific cytotoxic T lymphocytes either prior to or following infusion of male grafts into female recipients. Potential strategies that could be consid- ered in future trials would be the use of nonmyeloablative conditioning prior to CD34+-selected infusion, or the co- transfer of regulatory T cells;20 in the latter case, the regu- latory T cells may be particularly important in providing immune privileged sites for HSC within the bone marrow.21
The minority of patients showing no recovery or only partial recovery following CD34+-selected infusion had worse overall survival, mostly explained by non-relapse deaths in the first 18 months following treatment (12/14 [86%] of patients with no or partial recovery died due to non-relapse causes, in the first 18 months). It will be cru- cial to implement alternative strategies in such patients including a second allogeneic SCT; in this case, use of the
same donor can afford the opportunity to use less toxic regimens, even though these procedures still carry a high risk in patients who may have accumulated additional problems such as infection.
In conclusion, we confirm that CD34+-selected donor infusion without conditioning is an important therapeutic option that should be considered in patients with poor graft function following allogeneic SCT. Our findings also indicate that this approach can be applied in patients with stable mixed chimerism, a group excluded from previous studies. The low risk of the procedure means that this strategy can be adopted even in patients with risk factors for lower rates of recovery (e.g., in patients with active infection, of whom 1 in 2 patients will still respond). However, the overall heterogeneity of response is indica- tive that multiple factors (both intrinsic and extrinsic) influence graft integrity and highlight the critical need for further investigation of mechanisms underlying poor graft function. The information gained could be used to define the role of emerging treatments such as thrombopoietin- receptor agonists,22 which are the subject of ongoing trials. In the future, trials investigating combination therapies involving CD34+-selected infusion and co-transfer of mes- enchymal cells to improve niche function23 or regulatory T cells to augment immune tolerance of transferred HSC should be conducted.
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