LAUSR

Background Isolated mixed T-cell chimerism in otherwise fully engrafted recipients of TCDHCT has been associated, in some series, with risk of graft rejection or relapses and an indication for DLI. Thereto, we have analyzed the impact of donor chimerism on outcomes in a prospective clinical trial of conditioning regimens used with CD34+ selected TCDHCT. Methods The trial (NCT0119066) compares A) HFTBI, Thiotepa and cyclophosphamide with B) Busulfex, melphalan and fludarabine or C) Clofarabine, melphalan and thiotepa as conditioning for CD34+ TCDHCT used to treat high risk hematologic malignancies. As part of the trial, we sequentially assessed lineage-specific donor chimerism in the marrow and the myeloid cells and T-cells in blood by analysis of donor and host-specific STRs in cell fractions isolated by immunotype. In the landmark analysis, quartiles of donor chimerism were compared for T-cell levels, and clinical outcomes. Results 283 consecutive patients, transplanted between 5/13/2010 and 12/31/2016 (106 in Arm A, 144 in Arm B, 33 in Arm C). All engrafted by day 10-11. While 3 pts in Arm B and 1 in C had late graft failure, all others from 3 mos on had full donor chimerism in marrow and myeloid blood cells. However, at 3 mos median donor CD3+ T-cell chimerism (MDTC), was mixed in each arm but significantly lower in Arm B (10%) vs A (50%) and C (63%) (p To assess the impact of this sustained mixed chimerism, we did a landmark analysis at 3 months, comparing subsequent T-cell recovery and clinical outcomes for pts in the first (lowest) and fourth (highest) quartile of T-cell chimerism in Arms A and B. As shown in Table 1, CD3+ and CD8+ T-cells in both arms were significantly higher in Q1, as were CD3+CD4+ cells in Arm B. Non-relapse mortality (NRM) at 2 yrs was also significantly lower for Q1 pts in both arms but relapse risks were not. In Arm B, but not A, 2yr OS and DFS were also significantly better in Q1 vs Q4. Conclusions Conditioning with Bu/Mel/Flu (Arm B) secured durable engraftment and hematopoietic reconstitution but a high proportion of pts have isolated and persistent mixed T-cell chimerism. However, surviving host T-cells can expand, persist and contribute significantly to earlier T-cell recovery and long-term reduction of NRM without increasing risk of graft rejection, relapse or need for DLI.