HEMATOPOIETIC PROGENITOR AND MYELOID CELL-KINETICS IN HUMANS TREATED WITH INTERLEUKIN-3 AND GRANULOCYTE-MACROPHAGE COLONY-STIMULATING FACTOR IN COMBINATION

Patients with advanced adenocarcinoma of the colon, rectum or pancreas were entered into trials for evaluation of treatment with sequential doses of IL-3 and GM-CSF. They received 0.25 to 5 mu g IL-3/kg/d for u p to 7 days, followed by I mu g GM-CSF/kg/ day for a maximum of IO fur ther days. We assessed the kinetics of bone-marrow cell proliferation and of blood production using tritiated thymidine labelling in vitro a nd in vivo. Megakaryocytic-CFC were unaffected but proliferation rates of GM-CFC and BFU-E were increased. Progenitor cells were mobilized ( 12-fold over baseline) into the peripheral blood. The proliferative ac tivity of maturing cells in the marrow was increased (cell-cycle times were reduced by at least 30%). This translated into amplified blood c ell production (WCC similar to 30 x 10(9)/l), a 2.2-fold increase in p latelet counts and significant eosinophilia. Newly generated neutrophi ls appeared in the circulation at the normal time and their peripheral half-life was also normal. The calculated 3.2-fold amplification in n eutrophil production required nearly 2 extra divisions in the marrow, shared between the progenitors and the proliferating granulocytic cell s. The results were compared with those of a previous trial using GM-C SF only, although at a 10-fold higher dose level. Comparable levels of peripheral neutrophils were obtained in both trials but significant i neffective granulopoiesis developed in the earlier study. This was ove rcome in the present study, the priming dose of IL-3 apparently giving the latitude to utilize lower doses of GM-CSF with less risk of compl ications. (C) 1994 Wiley-Liss, Inc.