Combined Use of Growth Factors to Stimulate the Proliferation of Hematopoietic Progenitor Cells after Autologous Bone Marrow Transplantation (ABMT) for Lymphoma Patients

Abstract

We studied the kinetic response and concentration of bone marrow (BM) progenitor cells of patients with lymphoid malignancies submitted to ABMT, treated with G-CSF/IL-3 combination. The results were compared with those of lymphoma patients receiving the same pretransplant conditioning regimen followed by G-CSF alone. RhG-CSF was administered as a single subcutaneous (sc) injection at the dose of 5µg/Kg/day from day +1 after reinfusion of autologous stem cells while rhIL-3 was added from day +6 at the dose of 10 lµg /Kg/day sc (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 (ANC) was > 0.5 X 109/L of peripheral blood (PB) for 3 consecutive days.

Following treatment with colony-stimulating factor (CSF) combination, the percentage of marrow granulocyte-macrophage colony forming unit (CFU-GM) and erythroid progenitors (BFU-E) in S-phase of cell cycle increased from 9.3 ± 2% to 33.3 ± 12% and from 14.6 ± 3% to 35 ± 6%, respectively (p < 0.05). Similarly, we observed an increased number of actively cycling megakaryocyte progenitors (CFU-MK and BFU-MK). 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 of S-phase CFU-GM was significantly lower than that observed in the posttreatment samples of patients recieving IL-3 in addition to G-CSF. A significant augmentation of the absolute number of both CFU-GM and BFU-E/ml of BM was reported after treatment with G-CSF/IL-3 but not G-CSF alone. Similarly, administration of the cykotine combination resulted in a higher number of CD 34+ 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 higly enriched CD 34+ 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 hermatological 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 of granulocyte and platelet recovery, a lower transfusion requirement and shorter hospitalization. In conclusion, our results indicate the in-vivo administration of 2 cytokines increase the proliferative rate and concentration of BM progenitor cells to a greater degree than G-CSF alone and support the role of growth factor combinations for accelerating hematopoietic recovery after high dose chemotherapy.