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 autologous bone marrow transplantation (ABMT), treated with a granulocyte-colony-stimulating factor (G-CSF)/interleukin-3 (IL-3) combination. The results were compared with those of lymphoma patients receiving the same pretransplant conditioning regimen followed by G-CSF alone. Recombinant human (rh)GCSF was administered as a single subcutaneous (s.c.) injection at the dose of 5 μg/kg/day from day +1 after reinfusion of autologous stem cells, while rhIL-3 was added from day +6 at the dose of 10 μg/kg/day s.c. (overlapping schedule). In both groups (i.e. G-CSF- and G-CSF/IL-3-treated patients), cytokine administration was discontinued when the absolute neutrophil count was > 0.5 x 10⁹/l of peripheral blood for 3 consecutive days. Following treatment with the CSF combination, the percentage of marrow CFU-GM and erythroid progenitors (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 proliferative 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 increase in S-phase CFU-GM was significantly lower than that observed in the posttreatment samples of patients receiving IL-3 in addition to G-CSF. The absolute number of both CFU-GM and BFU-E/ml of BM was significantly augmented after treatment with G-CSF/IL-3 but not G-CSF alone. Similarly, administration of the cytokine combination resulted in a higher number of CD34+ cells and their concentration was significantly greater 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 subsequent stimulation with additional CSFs. When the hematological reconstitution of patients treated with G-CSF/IL-3 was compared to that of individuals receiving G-CSF alone, the addition of IL-3 resulted in a significant improvement in granulocyte and platelet recovery, a lower transfusion requirement and shorted hospitalization. In conclusion, our results indicate that in vivo administration of two cytokines increases the 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.