Factors associated with early molecular remission after T cell-depleted allogeneic stem cell transplantation for chronic myelogenous leukemia

Abstract

Eighty patients with chronic myeloid leukemia (CML) underwent T cell-depleted stem cell transplantation from an HLAidentical sibling, with add-back of donor T cells on days 30 to 45 and days 60 to 100 in patients in whom grade 2 or greater acute graft-versus-host disease (GVHD) developed. The outcomes for 54 patients with chronic-phase (CP) and 26 with advanced-phase (AP) disease were as follows: overall survival, 85% ؎ 5% versus 36% ؎ 10%; transplantation-related mortality (TRM), 13% ؎ 5% versus 43% ؎ 11%; and current leukemia-free survival, 76% ؎ 6% versus 34% ؎ 9%. The day-30 lymphocyte count (LC30) was strongly associated with outcome. For patients in CP with counts greater than the median of 0.30 ؋ 10 9 /L, survival was 100% versus 70% ؎ 9% (P ‫؍‬ .003); current LFS 100% versus 56% ؎ 9% (P ‫؍‬ .002); and TRM 0% versus 26% ؎ 8% (P ‫؍‬ .006). Higher-than-median LC30 correlated significantly with molecular remission (MR) at 3, 6, and 12 months and with higher CD34 doses. Lymphocyte subset analysis performed in 20 patients available for phenotyping showed that LC30 was highly correlated with absolute CD56 ؉ CD3 ؊ natural killer cell numbers (NK30), which also predicted for survival and MR. CD34 cell dose, LC30, and NK30, but not day-30 CD3 ؉ cell count, were highly correlated and were significant predictors of transplantation outcome. These results suggest that transplanted CD34 cell doses greater than 5 ؋ 10 6 /kg may improve outcomes by increasing the early recovery of NK cells. (Blood. 2006;107: 1688-1695)

Fully functional NK cells after unrelated cord blood transplantation

“…Shilling et al 26 show that patients who have a delay on NK reconstitution after HLA-matched SCT presented more severe clinical complications than those who reconstituted more rapidly. In the same line, Savani et al 35 suggested that early NK recovery was a main predictor of molecular remission in Chronic myelogenous leukemia patients undergoing HLA-matched T-cell-depleted transplants. More recently, we and other groups have also reported an altered NK reconstitution after haploidentical SCT, having potential impact on GvL effect.…”

“…20,37 The maturation of NK cells occurs under the influence of the microenvironment and the host marrow stromal cells. 34, 35 Lucas et al 38 show that the intensity and quality of NK-cell cytotoxic response depend on the cytokine microenvironment as well as on immune system interactions. Several publications have focused on the newly described crosstalk between NK cells and dendritic cells or T lymphocytes, occurring in secondary compartments such as lymph nodes.…”

Rapid natural killer cell recovery determines outcome after T-cell-depleted HLA-identical stem cell transplantation in patients with myeloid leukemias but not with acute lymphoblastic leukemia

“…7,8 Although NK-mediated effects after SCT have largely been ascribed to KIR-MHC ligand mismatching in the context of haploidentical transplants ('missing-self' hypothesis), 9 there is also widespread evidence in vitro and in vivo for NK-related effects in HLA-matched SCT. 3,[10][11][12][13][14][15] Thus, the conditions required for donor NK alloreactivity cannot be entirely explained by the missing KIR hypothesis. Several models have been proposed to explain NK alloreactivity in HLA-mismatched and -matched SCT.…”

“…[1][2][3][4][5][6] It is believed that NK alloreactivity following allogeneic stem cell transplantation (SCT) is regulated by quantitative differences in activating and inhibitory signals (mediated by activating and inhibitory killer cell immunoglobulin-like-receptors (KIR)). 7,8 Although NK-mediated effects after SCT have largely been ascribed to KIR-MHC ligand mismatching in the context of haploidentical transplants ('missing-self' hypothesis), 9 there is also widespread evidence in vitro and in vivo for NK-related effects in HLA-matched SCT.…”

Lymphocyte subset recovery following allogeneic bone marrow transplantation: CD4+-cell count and transplant-related mortality

“…This report was confirmed and built on their prior study of 20 CML patients whose NK reconstitution was associated with molecular remission. 15 As mentioned above, Berger et al 14 reported the kinetics of lymphocyte subset recovery from 758 allograft patients with a 5-year follow-up. In this study, 2 3 of the donors were matched sibling donors and the rest were family-mismatched or unrelated donors.…”