Engraftment Kinetics

The engraftment kinetics after a nonmyeloablative conditioning regimen were first analyzed by Childs et al.38 The authors studied chimerism evolution in 15 patients conditioned with cyclophosphamide and flu-darabine. Postgrafting immunosuppression was carried out with CSP alone. The patterns of engraftment varied considerably among their patients, but most often full donor chimerism was achieved earlier in T cells than in granulocytes, and the achievement of full donor T-cell chimerism preceded GvHD and antitumor responses. The kinetics of B-cell recovery were distinct from those of myeloid and T-cell lineages, while NK-cell chimerism was closely correlated with T-cell chimerism.

Ueno et al. studied chimerism evolution in 23 patients, with metastatic tumors transplanted after a reduced-intensity conditioning regimen combining fludarabine and melphalan.42 Postgrafting immunosuppression consisted of tacrolimus and short MTX. All patients showed 100% T-cell and granulocyte chimerisms on days 30 and 100 after the transplant.

Keil et al. analyzed the impact of day 28 chimerism on outcome after nonmyeloablative HCT in 38 patients conditioned with fludarabine followed by low-dose (2 Gy) TBI.43 Postgrafting immunosuppression was carried out with MMF and CSP. Generally, donor T-cell chimerism lagged behind myeloid chimerism. In addition, patients with <90% donor T cells on day 28 after the transplant had significantly higher risks of graft rejection and relapse and significantly worse progression-free survival than patients with >90% donor T cells.

Baron et al. analyzed T-cell chimerism in 35 patients conditioned with TBI (2 Gy) alone (n = 15), TBI (2 Gy) and fludarabine (n = 13), or fludarabine and cyclophosphamide (n = 7). Patients received either unmanipu-lated (n = 18), CD8-depleted (n = 11), or CD34-selected G-PBMC (n = 6). Median donor T-cell contributions on days 28, 60, 100, 180, and 365 in recipients of unmanipulated G-PBMC were 75, 85, 87, 90, and 100%, respectively. Evolution of donor T-cell chimerism did not differ significantly between recipients of unmanipulated and CD8-depleted G-PBMC, while CD34 selection resulted in significantly decreased donor T-cell chimerism.44

We analyzed the kinetics of donor engraftment in peripheral blood hematopoietic subpopulations from 120 patients conditioned with 2 Gy TBI +/ — fludara-bine and postgrafting immunosuppression with MMF and CSP.45 On day 14 posttransplant, the highest degree of donor chimerism was noted in the NK-cell fraction, followed by lymphocytes, monocytes, and granulocytes. By day 28, donor granulocyte chimerism had surpassed those in the remaining cell populations. Most patients remained mixed chimeras for at least 180 days posttransplant, with greater than 60% donor chimerism in each subpopulation except in patients with CML or MDS, who had lower percentages of donor T-cell chimerisms. Patients receiving G-PBMC had higher degrees of donor T-cell chimerism than recipients of marrow. Greater intensity of therapy before HCT was also associated with higher degrees of donor chimerisms. Low donor T-cell chimerism on day 14 (<50% CD3+ T cells) was strongly associated with a higher risk of graft rejection.

Taken altogether, these results suggest that the engraftment kinetics after nonmyeloablative or reduced-intensity conditioning HCT depend on the intensity of pretransplant chemotherapy, the intensity of the preparative regimens, and whether the grafts have been depleted of T-cells or not. Moreover, monitoring mixed chimerism early after transplant may predict transplantation outcomes and/or allow early intervention to prevent graft rejection or disease progression.

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