Extended mycophenolate mofetil and shortened cyclosporine failed to reduce graft-versus-host disease after unrelated hematopoietic cell transplantation with nonmyeloablative conditioning

in Biology of Blood & Marrow Transplantation (2007), 13(9), 1041-1048

We previously reported data from 103 patients with hematologic malignancies (median age 54 years) who received peripheral blood stem cell (PBSC) grafts from HLA-matched unrelated donors after ... [more ▼]

We previously reported data from 103 patients with hematologic malignancies (median age 54 years) who received peripheral blood stem cell (PBSC) grafts from HLA-matched unrelated donors after nonmycloablative conditioning and were given postgrafting immunosuppression consisting of mycophenolate mofetil (MMF; administered from day 0 until day + 40 with taper through day + 96) and cyclosporine (CSP; given from day -3 to day + 100, with taper through day 180) (historical patients). The incidences of grade II-IV acute and extensive chronic graft-versus-host disease (aGVHD, cGVHD) were 52% and 49%, respectively, and the 1-year probabilities of relapse, nonrelapse mortality (NRM), and progression-free survival (PFS) were 26%, 18%, and 56%, respectively. Here, we treated 71 patients with hematologic malignancies (median age 56 years) with unrelated PBSC grafts and investigated whether postgrafting immunosuppression with an extended course of NMF, given at full dosing until day + 150 and then tapered through day + 180, and a shortened course of CSP, through day + 80, would promote tolerance induction and reduce the incidence of GVHD (current patients). We observed 77% grade ll-1V aGVHD and 45% extensive cGVHD (P =.03, and P =.43, respectively, in current compared to historical patients). The 1-year probabilities of relapse, NRM, and PFS were 23%, 29%, and 47%, respectively (P =.89, P =.02, and P =.08 compared to the historical patients). We conclude that postgrafting immunosuppression with extended MMF and shortened CSP failed to decrease the incidence of GVHD among unrelated PBSC recipients given nonmyeloablative conditioning. (c) 2007 American Society for Blood and Marrow Transplantation [less ▲]

Unrelated donor status and high donor age independently affect immunologic recovery after nonmyeloablative conditioning

in Biology of Blood & Marrow Transplantation (2006), 12(11), 1176-1187

The risk of cytomegalovirus (CMV) infection is higher after HLA-matched unrelated donor (URD) than after HLA-matched related donor (MRD) nonmyeloablative hematopoietic cell transplantation (HCT). We ... [more ▼]

The risk of cytomegalovirus (CMV) infection is higher after HLA-matched unrelated donor (URD) than after HLA-matched related donor (MRD) nonmyeloablative hematopoietic cell transplantation (HCT). We therefore investigated factors affecting immune recovery in 94 patients given HCT from MRDs (n = 51) and URDs (n = 43) after 2-Gy total body irradiation with or without fludarabine and postgrafting immunosuppression with mycophenolate mofetil and cyclosporine. CD4 T cells counts remained below normal values during the first year after HCT in both patient groups. This included abnormally low counts each of naive CD4 T cells and memory CD4 T cells. Conversely, CD8 T cell counts reached the 10th percentile of normal 6 months after HCT in MRD and URD recipients. On day 30 after HCT, URD recipients had lower counts of B cells (P = .02), naive CD4 T cells (P = .04), memory CD4 T cells (P = .005), memory CD8 T cells (P = .005), and CMV-specific T helper cells (P = .007) than had MRD recipients. This delay in CMV-specific immune reconstitution translated into increased frequency of CMV antigenemia among URD recipients during the first 100 days after HCT. Older donor age was associated with low counts of naive CD4 T cells on days 180-365 after HCT (P = .003). Further, low numbers of T cells and CD34(+) cells in the graft and development of acute graft-versus-host disease were associated with impaired immune recovery of naive CD4 T cells and B cells. In summary, immunologic recovery was poor the first year after nonmyeloablative conditioning and was delayed among URD recipients in comparison with MRD recipients. Other factors significantly associated with delayed immune recovery were advanced donor age, low numbers of CD34 and T cells in the graft, and development of graft-versus-host disease. (C) 2006 American Society for Blood and Marrow Transplantation. [less ▲]

Kinetics of engraftment in patients with hematologic malignancies given allogeneic hematopoietic cell transplantation after nonmyeloablative conditioning.

in Blood (2004), 104(8), 2254-62

We analyzed the kinetics of donor engraftment among various peripheral blood cell subpopulations and their relationship to outcomes among 120 patients with hematologic malignancies given hematopoietic ... [more ▼]

We analyzed the kinetics of donor engraftment among various peripheral blood cell subpopulations and their relationship to outcomes among 120 patients with hematologic malignancies given hematopoietic cell transplantation (HCT) after nonmyeloablative conditioning consisting of 2 Gy total body irradiation (TBI) with or without added fludarabine. While patients rapidly developed high degrees of donor engraftment, most remained mixed donor/host chimeras for up to 180 days after HCT. Patients given preceding chemotherapies and those given granulocyte colony-stimulating factor-mobilized peripheral blood mononuclear cell (G-PBMC) grafts had the highest degrees of donor chimerism. Low donor T-cell (P = .003) and natural killer (NK) cell (P = .004) chimerism levels on day 14 were associated with increased probabilities of graft rejection. High T-cell chimerism on day 28 was associated with an increased probability of acute graft-versus-host disease (GVHD) (P = .02). Of 93 patients with measurable malignant disease at transplantation, 41 achieved complete remissions a median of 199 days after HCT; 19 of the 41 were mixed T-cell chimeras when complete remissions were achieved. Earlier establishment of donor NK-cell chimerism was associated with improved progression-free survival (P = .02). Measuring the levels of peripheral blood cell subset donor chimerisms provided useful information on HCT outcomes and might allow early therapeutic interventions to prevent graft rejection or disease progression. [less ▲]