Factors affecting hemopoietic recovery after high-dose therapy and autologous peripheral blood progenitor cell transplantation: a single center experience.

BACKGROUND AND OBJECTIVE: While the minimum number of CD34+ cells required for complete and long-lasting engraftment is quite well established, there is not general agreement about the optimal number of CD34+ per kg needed in order to obtain engraftment as rapidly as possible. In the present study we assess factors affecting hemopoietic recovery and the optimal peripheral blood progenitor cell (PBPC) number for rapid engraftment in patients treated with high-dose therapy. DESIGN AND METHODS: We enrolled 80 consecutive patients affected by hematologic and non-hematologic malignancies treated with a median of 10 chemotherapy courses (range 3-38). PBPC collection was performed after mobilization with high-dose chemotherapy and G-CSF 5 micrograms/kg/day. The circulating and harvested CD34+ cells were recognized in the cytofluorimetric CD45+/CD14- lymphocyte gate. After myeloablative therapy, PBPC infusion was followed by G-CSF 5 micrograms/kg/day from day +5 until WBC > or = 5.0 x 10(9)/L. Univariate and multivariate Cox analyses were performed to investigate factors affecting hemopoietic recovery. The Kaplan-Meier probabilities of hemopoietic reconstitution were compared by log-rank test to assess the optimal CD34+ cell number for rapid engraftment. RESULTS: We performed a median of two apheresis (range 1-4) per patient and we infused a median of 6.1 x 10(6) CD34+ cells/kg (range 0.5-30.5). Absolute neutrophil count (ANC) > 0.5 x 10(9)/L was reached after 11 days (range 8-15). The only factor affecting granulocyte recovery proved to be the CD34+ cell number; 5.0 to 7.8 x 10(6) CD34+ cells/kg allowed a significantly faster granulocyte recovery than < 2.5 x 10(6) CD34+ cells/kg (p = 0.0312). Platelet transfusion independence (> 20 x 10(9)/L) and 50 x 10(9)/L platelets were reached after 12 (range 8-24) and 15 days (range 9-40), respectively. The CD34+ cell number was also the only factor affecting platelet recovery; the number of 5.0 to 7.8 CD34+ cells/kg allowed a significantly faster platelet recovery than the lower dose, whereas a higher number did not. No late graft failures were observed. Patients receiving 5.0 to 7.8 x 10(9) CD34+ cells/kg had a significantly shorter duration of neutropenia, fewer platelet transfusions and less time spent in hospital than those receiving lower number did, whereas patients transplanted with a higher number had no advantage. INTERPRETATION AND CONCLUSIONS: When G-CSF is employed both for PBPC mobilization and after PBPC transplantation, the CD34+ cell number is the only factor that affects hemopoietic recovery. Moreover, > 5.0 x 10(6) CD34+ cells/kg is the optimal number for obtaining rapid platelet recovery and reducing the costs of HDT but there is no advantage exceeding the threshold of 7.8 x 10(6) CD34+ cells/kg.

Addition of erythropoietin to granulocyte colony-stimulating factor after priming chemotherapy enhances hemopoietic progenitor mobilization.

Hemopoietic progenitor cell mobilization intended for autotransplantation is now feasible in many patients, following the administration of single cytokines (G-CSF, GM-CSF, IL-3) or their combination. Erythropoietin (EPO) is a cytokine which showed an interesting activity also on non-erythroid progenitors, however the clinical relevance of this activity has not been sufficiently investigated yet. This retrospective study has attempted to assess the effectiveness of the combination of EPO plus G-CSF after priming chemotherapy to increase the number of blood progenitor cells, as compared to the results obtained by G-CSF alone. Thirty-four patients underwent priming chemotherapy followed by cytokine administration: 18 patients received G-CSF 5 micrograms/kg/day and 16 patients G-CSF plus EPO 50 U/kg/day. The two groups were homogeneous as regards the main clinical characteristics which are thought to affect BPC mobilization. As for hemopoietic progenitor cell mobilization, we observed that the combination of EPO and G-CSF was more effective in comparison with G-CSF alone, with a median of 1.9-fold for circulating MNC, 4.0-fold for CFU-GM, 4.7-fold for BFU-E and 2.8-fold increase for CD34+ cells. The results of apheresis collections revealed that the same group of patients showed better results for total blood progenitor cells/kg. The difference was statistically significant both for BPC mobilization and collection. Our findings suggest that EPO has a synergistic activity with G-CSF in mobilizing hemopoietic progenitors; the good results obtained, despite our pretreated patients, suggest that this cytokine combination has both biologic and clinical relevance.

DHAP regimen plus G-CSF as salvage therapy and priming for blood progenitor cell collection in patients with poor prognosis lymphoma.

We studied 14 patients affected by lymphoma to assess the toxicity, efficacy and mobilization capability of salvage DHAP regimen followed by G-CSF 5 micrograms/kg/day. Ten patients were affected by intermediate-grade NHL and 4 by HD; all of them were in relapse or in PR. We administered a total of 34 courses of DHAP plus G-CSF (median 2 per patient; range 1-5) and did not observe either life-threatening extrahematologic toxicity or severe infections during the short neutropenic period. A significant tumor burden reduction was observed in 86% of patients (50% CR, 36% PR). A total of 35 aphereses were performed (median 3 per patient; range 1-5). The hemopoietic progenitors showed a very rapid increase from day +11 with a synchronous and impressive peak on day +13. We collected a median of 2.6 x 10(6)/kg CD34+ cells, 10 x 10(4)/kg CFU-GM, 5 x 10(4)/kg BFU-E and 0.5 x 10(4)/kg CFU-GEMM per apheresis. All patients transplanted with PBPC had a rapid and sustained hematological recovery. The DHAP regimen followed by G-CSF proved to be a very effective and well-tolerated schedule for debulking disease before transplantation and for enhancing progenitor cell mobilization.

Optimization of the yield of PBSC for autotransplantation mobilized by high-dose chemotherapy and G-CSF: proposal for a mathematical model.

We analyzed the results of 71 leukapheresis procedures performed in 21 patients to identify the best predictive factors affecting the yield of peripheral blood progenitors after high-dose chemotherapy followed by G-CSF administration. An average of 1 +/- 1 x 10(8) MNC/kg, 5 +/- 6 x 10(4) CFU-GM/kg and 4 +/- 6 x 10(6) CD34+ cells/kg was collected for each leukapheresis. When we defined > or = 5 x 10(4)/kg as the minimum number of CFU-GM per procedure for a 'satisfactory' collection, multiparameter analysis of clinical features and laboratory findings showed that the only factors that predicted the numbers of CFU-GM collected were prior treatment with the MOPP regimen and the number of mononuclear cells identified in the basophil channel of the H*1 = Technicon. A logistic regression analysis performed to generate a mathematical model revealed four predictive factors: the number of previous cycles of chemotherapy, previous MOPP chemotherapy, the interval from latest chemotherapy and the number of mononuclear cells/microliter. This model was valuable in defining the optimal time for the first leukapheresis procedure. In contrast, the number of circulating CD34+ cells did not correlate with CFU-GM numbers collected whereas the numbers of mononuclear cells did provide a simple and reliable index. Thus the principal factor affecting the efficiency of peripheral blood stem cell collection was prior therapy with MOPP.

PBSC collection after high dose chemotherapy followed by G-CSF in patients with malignancies: analysis of results regarding factors affecting the yield of hemopoietic progenitors.

High-dose non ablative chemotherapy followed by growth factors efficiently mobilizes and amplifies Peripheral Blood stem Cells (PBSC). Cytofluorimetric PBSC monitoring reduces the number of leukapheresis needed to collect sufficient amounts of progenitors to restore hemopoiesis after myeloablative therapy. Twenty-eight patients, affected by lymphoproliferative disorders, were primed with non myeloablative chemotherapy followed by G-CSF 5 micrograms/kg/die subcutaneously, until leukapheresis. A total number of 90 leukaphereses was performed (median: 3 per patient) using blood cell separator CS 3000 Plus Baxter; we collected 1 +/- 0.8 x 10(8)/kg mononuclear cells (MNC), 6 +/- 9 x 10(4)/kg CFU-GM and 4 +/- 5 x 10(6) CD34+ cells for each procedure. The statistical analysis showed that the number of progenitors collected was dependent on the age, number and type of previous chemotherapies and interval between the last chemotherapy and the priming; the type of priming, type and status of disease, sex, and bone marrow involvement were not significant. Duration of neutropenia after megachemotherapy was very short; in two cases platelet support was necessary and only two patients needed hospitalization. Our experience shows that high-dose non ablative chemotherapy followed by G-CSF is safe and yields large amounts of PBSC; several factors influence the quality of collections mainly regarding age and the previous treatment.

[Differentiating agents in myelodysplastic syndromes. Analysis of personal cases]. / Agenti differenzianti nelle mielodisplasie. Analisi della casistica personale.

The Myelo-Dysplastic Syndromes are a heterogeneous group of diseases which includes patients with different prognosis. There is no agreement about the management and the therapeutic strategy must be based on many individual parameters, particularly the age of the patients and their performance status. The therapeutic options range from no cytotoxic therapy for low-risk patients up to more aggressive treatment for high-risk patients, with disappointing results except for the very few cases eligible for allogenic bone marrow transplantation. The leukaemic cell can be induced to differentiate, so losing its self-maintenance potential; different drugs such as Interferon, vitamin D3, retinoids and arabinosyl-cytosine (low doses) have shown a differentiating action on myeloid blasts in "vitro". We summarize the general strategy in the treatment of myelo-dysplastic syndromes based on literature data, and on our results about the efficacy and tolerance of a combination of the above mentioned differentiating drugs, in a group of 27 elderly patients affected by myelodysplastic syndrome with poor prognosis. We obtained 14 objective responses (52%), and the median overall survival of these patients have been compared with that of 25 patients with severe myelodysplastic syndrome treated with a conventional regimen. In the 27 patients receiving the differentiating combination the median survival was found to be 14.7 months, versus 8.4 months for the control group. The results obtained are encouraging about the tolerance and the efficacy of this combination in elderly patients with a poor MDS prognosis. Further randomized studies are necessary to establish whether this treatment can really improve the survival in this group of patients.