NK Cell Activity Influences Long Term Outcome of Pediatric Leucemias After T Cell Depleted Stem Cell Transplantation,

Abstract 4141

T cell depletion with magnetic microbeads can effectively reduce GvHD rates after stem cell transplantation from both mismatched related donors as well as from matched or partially matched unrelated donors. However, T cell recovery is markedly delayed after this procedure and T cell mediated antileukemic effects may be reduced. Thus, we focused on the rapidly regenerating donor derived NK cell system and addressed the question, whether its functional activity would influence the probability of relapse in a long term analysis. Temporal development of NK cell activity was monitored in 47 pediatric patients with leukemias (ALL, AML, CML, JMML) and myelodysplastic syndromes after transplantation of T cell depleted stem cells from matched unrelated (n=18) and mismatched related (haploidentical, n=29) donors with a median follow up of 7.4 years (2.1–12). 38 patients had CR1-3, 9 patients had active disease at time of transplantation. EFS and relapse rate at 5 years for the entire group were 36% and 40%, respectively (EFS and relapse rate for ALL patients in CR1-3: 50% and 36%; EFS and relapse rate for AML/MDS patients: 22% and 30%). CD34+ selection with magnetic microbeads resulted in 8×10³/kg residual T cells. No posttransplant immune suppression was given. 89% of the patients had no GvHD, 9% had GvHD grade I and only 2 patients had GvHD grade II or III. NK cells recovered rapidly after transplantation (300 CD56+/μL at day 30, median), whereas T cell recovery was delayed (median: 12 CD3+/μL at day 90). NK activity was measured as specific lysis of K562 targets several times after transplantation (mean: 3 assays per patient). Four temporal patterns of lytic activity could be differentiated: consistently low, consistently high, decreasing and increasing activity. Patients with consistently high or increasing activity had significantly lower relapse probability than patients with consistently low or decreasing levels (0.18 vs 0.73 at 5 years, p<0.05). The subgroup of patients with ALL showed similar results (0.75 vs 0.14 at 5 years, p<0.05). Speed of T cell recovery had no influence. These data suggest that both achieving and maintaining a high level of NK activity may contribute to prevent relapse. Thus, this model comprises direct functional data in the form of NK cell activation levels which are likely to be influenced by the presence of different cytokines in each patient. Our observations may have some clinical implications: immunomagnetic depletion of T cells prevents GvHD and can be performed in pediatric leukemias in remission without excessive increase in relapse rates. High levels of NK activity seem to be of importance. Since NK activity could be markedly increased by in vitro stimulation with Interleukin 2 (IL-2), in vivo administration should be considered.