COMBINED USE OF GROWTH-FACTORS TO STIMULATE THE PROLIFERATION OF HEMATOPOIETIC PROGENITOR CELLS AFTER AUTOLOGOUS BONE-MARROW TRANSPLANTATION FOR LYMPHOMA PATIENTS

We studied the kinetic response and concentration of bone marrow (BM) progenitor cells of patients with lymphoid malignancies submitted to a utologous bone marrow transplantation (ABMT), treated with a granulocy te-colony-stimulating factor (G-CSF)/interleukin-3 (IL-3) combination. The results were compared with those of lymphoma patients receiving t he same pretransplant conditioning regimen followed by G-CSF alone. Re combinant human (rh)G-CSF was administered as a single subcutaneous (s .c.) injection at the dose of 5 mu g/kg/day from day +1 after reinfusi on of autologous stem cells, while rhIL-3 was added from day +6 at the dose of 10 mu g/kg/day s.c. (overlapping schedule). In both groups (i .e. G-CSF- and G-CSF/IL-3-treated patients), cytokine administration w as discontinued when the absolute neutrophil count was >0.5 x 10(9)/1 of peripheral blood for 3 consecutive days. Following treatment with t he CSF combination, the percentage of marrow CFU-GM and erythroid prog enitors (BFU-E) in the S phase of the cell cycle increased from 9.3 +/ - 2 to 33.3 +/- 12% and from 14.6 +/- 3 to 35 +/- 6%, respectively (p < 0.05). The number of actively cycling megakaryocyte progenitors (CFU -MK and BFU-MK) also increased. Conversely, G-CSF augmented the prolif erative rate of CFU-GM (22.6 +/- 6% compared to a baseline value of 11 .5 +/- 3%; p < 0.05) but not of BFU-E, CFU-MK or BFU-MK, and the incre ase in S-phase CFU-GM was significantly lower than that observed in th e posttreatment samples of patients receiving IL-3 in addition to G-CS F. The absolute number of both CFU-GM and BFU-E/ml of BM was significa ntly augmented after treatment with G-CSF/IL-3 but not G-CSF alone. Si milarly, administration of the cytokine combination resulted in a high er number of CD34+ cells and their concentration was significantly gre ater than that observed in the posttreatment samples of G-CSF patients . We also investigated the responsiveness to CSFs, in vitro, of highly enriched CD34+ cells, collected after priming with G-CSF in vivo (i.e . after 5 days of G-CSF administration). Our results demonstrated that pretreatment with G-CSF modified the response of BM cells to subseque nt stimulation with additional CSFs. When the hematological reconstitu tion of patients treated with G-CSF/IL-3 was compared to that of indiv iduals receiving G-CSF alone, the addition of IL-3 resulted in a signi ficant improvement in granulocyte and platelet recovery, a lower trans fusion requirement and shorted hospitalization. In conclusion, our res ults indicate that in vivo administration of two cytokines increases t he proliferative rate and concentration of BM progenitor cells better than G-CSF alone and support a role for growth factor combinations for accelerating hematopoietic recovery after high-dose chemotherapy.