NATURAL-KILLER-CELL REGENERATION AFTER TRANSPLANTATION WITH MAFOSFAMIDE PURGED AUTOLOGOUS BONE-MARROW

Autologous bone marrow transplantation (ABMT) is used increasingly for the treatment of acute leukemias, lymphomas and solid tumors. Since ABMT is burdened by high risk of relapse, mafosfamide or 4-hydroperoxycyclophosphamide chemical marrow purging is employed. Mafosfamide acts by exerting a potent cytotoxic effect and by promoting apoptosis of leukemic cells. A third proposed mechanism of action involves an effect on immune regeneration in vivo. It was the aim of this study to investigate natural killer (NK) cell regeneration in a group of patients undergoing mafosfamide-purged ABMT. Fifteen patients (8 acute myelogenous leukemia, AML; 4 acute lymphoblastic leukemia, ALL; 3 non-Hodgkin's lymphoma, NHL) were treated with high-dose chemotherapy followed by transplantation with marrow purged with mafosfamide. Prior to ABMT and at different intervals thereafter, NK cell number and function were studied by evaluating the percentage of circulating CD16 positive cells and cytotoxic activity against the leukemic cell line, K562, In comparison to pre-ABMT values, AML patients showed a significant increase in cytotoxic activity, expressed as percentage of chromium release (42.5 +/- 3 vs 32.5 +/- 6, P less than or equal to 0.025 at 4 months) which still persisted at 12 months post-ABMT (54 +/- 6, P less than or equal to 0.05). The behavior of NK functional activity was paralleled by an increase of the percentage of CD16-positive cells (8.4 +/- 2.2 vs 5 +/- 1.3, P less than or equal to 0.05 at 4 months; 12.8 +/- 2.4, P less than or equal to 0.005 at 12 months post-ABMT). Similar significant and longlasting increments in NK cells were also found in NHL patients. In contrast, no changes in either the cytotoxic activity nor in the percentage of CD16-positive cells were detected in ALL patients after mafosfamide purged ABMT. These data suggest that in NHL and AML, but not in ALL, mafosfamide might act as an activator of NK cell regeneration. Since these mechanisms are likely to be involved in the control of minimal residual disease and could therefore serve to reduce the rate of relapse after ABMT further evaluation in prospective randomised studies, comparing the use of purged and unpurged marrow, should be undertaken.