SEQUENTIAL ADMINISTRATION OF INTERLEUKIN-3 AND GRANULOCYTE-MACROPHAGECOLONY-STIMULATING FACTOR FOLLOWING INTENSIFIED, ACCELERATED CEE (CYCLOPHOSPHAMIDE, EPIRUBICIN, ETOPOSIDE) CHEMOTHERAPY IN PATIENTS WITH SOLID TUMORS - CYTOKINETIC EFFECTS ON BONE-MARROW HEMATOPOIETIC PROGENITORS

The biological mechanisms by which the association of interleukin-3 (I L-3) and granulocyte-macrophage colony-stimulating factor (GM-CSF) is expected to effectively reduce the hematological toxicity associated w ith chemotherapy (CT) are not completely elucidated. We exploited the cell kinetic changes of the bone marrow CD34(+) cell subset after CT f ollowed by the IL-3+GM-CSF together with the clinical effects of this association. Eighteen patients with advanced cancers and normal hemato poiesis were treated with an intensified CT course (mg/m(2): CTX 1100, epirubicin 100, VP-16 200; iv day 1). Six cycles were planned at 14-d ay intervals with the support of IL-3 (5 mu g/kg/day; from day 2 to 6) sequenced with GM-CSF (same dose; from day 7 to 11). DNA content and bromodeoxyuridine incorporation were evaluated using flow cytometry on immunomagnetically-sorted bone marrow CD34(+) cells, at baseline and at different times (days 5, 6, 7, 8, 11 and 14) after CT followed by I L-3+GM-CSF. Treatment with IL-3 induced a marked increase in the % of myeloid precursors with respect to the baseline and in the % of CD34() cells in S-phase. However, while the first parameter remained elevat ed until day 14, the enhanced proliferative activity of the CD34(+) ce ll subset decreased after IL-3 was stopped and remained significantly low during GM-CSF administration. These data suggest a negative reboun d effect on CD34(+) cell proliferation after IL-3 discontinuation whic h is maintained during GMCSF, that led to kinetic refractoriness of th e hyperplastic marrow. In the 99 courses completed a rapid neutrophil and platelet recovery was obtained without cumulative multilineage tox icity. The modifications of CD34(+) cell cycling after CT followed by IL-3+GM-CSF could provide additional myeloprotection during multicycli c, dose-intensive programs.