Selected CD34 blood cell allografts for older patients: low transplant-related mortality, graft failure and acute GvHD.

BACKGROUND: Early transplant mortality is related to acute GvHD, which this study in older patients (40 to 60 years) decreased by reducing the graft T-cell number while maintaining a high CD34 cell number--by positive CD34 cell selection. Potential increased risk of relapse is addressed by giving donor leucocyte infusion (DLI) post-transplant. METHODS: CD34 cells selected by Isolex devices from leukophereses obtained from Filgrastim-treated matched sibling donors were transplanted and DLI given later if there was no GvHD. RESULTS: Selection of CD34 cells achieved a median of 5.2 million cells/kg, with minimum target for transplantation achieved in 17 of 21 donors. Median CD3 cell number was 0.24 million/kg. Engraftment was rapid and graft failure rare. Transplant-related mortality was low (6% at 3 months). Acute GvHD of >or=Grade 2 occurred in only two patients (12.5%). DLI were given to only six patients who had resolved Grade 1 or no GvHD. Eight of the 17 patients relapsed, including three of the six who had DLI. Extensive chronic GvHD developed in six of 12 evaluable patients, two of these had received DLI. Seven of the 17 patients (41%) are alive at median follow-up of 56 months. CONCLUSION: CD34 selection allows transplantation of high numbers of CD34 cells with low CD3 cell count, reducing early mortality in patients 40-60 years old because of rapid hemopoietic reconstitution and low acute GvHD incidence. Administration of DLI was often precluded by low-grade acute GvHD.

Granulocyte colony-stimulating factor (G-CSF) dose-dependent efficacy in peripheral blood stem cell mobilization in patients who had failed initial mobilization with chemotherapy and G-CSF.

For 10 consecutive patients in our unit who did not show a significant rise in blood progenitor cells within 14 days following chemotherapy and G-CSF, we increased the G-CSF dose from 5 to 10 microg/kg/day (n = 9) or from 10 to 15 microg/kg/day (n = 1). As a result, there were significant increases in total yield as well as yield per apheresis of mononuclear cells, CD34+ cells and CFU-GM (P < 0.025, <0.01 and <0.005, respectively). After G-CSF dose escalation, six of the 10 patients had sufficient CD34+ cells for performing transplantation. These results demonstrate a dose-dependent response of progenitor cell mobilization by G-CSF when used in combination with chemotherapy. Moreover, increasing the dose of G-CSF as late as the third week of mobilization may still provide sufficient cell yield even with patients who did not show a significant mobilization with conventional doses of G-CSF.

An incremental response to high-dose therapy in multiple myeloma.

Results of conventional chemotherapy for multiple myeloma are disappointing. High-dose chemoradiotherapy with auto-transplantation is increasingly reported and some results are encouraging. We report the results of peripheral blood stem cell transplantation (PBSCT) for multiple myeloma at a single institution over a 6-year period. Forty patients, including 18 de novo patients, received debulking chemotherapy consisting of vincristine, adriamycin, and dexamethasone or methyl-prednisolone followed by stem cell mobilization with high-dose cyclophosphamide. Twenty-nine patients received PBSCT following high-dose chemoradiotherapy. Following PBSCT 92% of evaluable patients obtained at least a partial remission and 29% reached complete remission. Objective treatment responses, defined as at least a 50% reduction in serum paraprotein or marrow plasma cells, were observed following each treatment step of debulking chemotherapy, mobilization and PBSCT in 50, 42 and 71% of patients, respectively. The median overall survival from diagnosis in patients transplanted was 50 months and the median overall and progression-free survivals following transplant were 26 and 18 months, respectively. Median follow-up was 28 months. Overall treatment-related mortality was 20% but was significantly lower in de novo vs previously treated patients at 6 and 33% respectively (P = 0.027). De novo patients were more likely to obtain complete remission and had a longer overall survival following transplant but overall survival from diagnosis was similar to previously treated patients. A low serum B2M before mobilization predicted a longer progression-free survival. PBSCT needs to be considered early following diagnosis to maximise treatment response and reduce the high treatment-related mortality seen in heavily pretreated patients. In this treatment program a dose response effect in multiple myeloma was observed possibly suggesting that more intensive therapy than a single transplant may effect greater disease response.

Collection efficiency on the Fenwal CS3000 when using filgrastim (recombinant methionyl human granulocyte colony-stimulating factor) as a peripheral blood stem cell mobilization agent.

The collection efficiency (CE) of the Fenwal CS3000 in collecting peripheral blood stem cells during post-chemotherapy recovery phase ranges from 58% to 73%. Recently filgrastim (recombinant methionyl human granulocyte colony-stimulating factor [G-CSF]) has also been shown to be effective as a mobilization agent although mobilization occurs during elevated and not low normal leukocyte counts. We compared the mononuclear cell (MNC) CE and the myeloid progenitor cell (CFU-GM) CE among 11 patients with G-CSF mobilization (33 procedures) and 19 patients during recovery following myelosuppression chemotherapy (93 procedures). Pre-apheresis leukocyte, neutrophil, MNC, and PB CFU-GM counts were significantly higher in the G-CSF group, while the granulocyte percentage in the apheresis products was similar in both groups. Both MNC CE (81.8 +/- 4.5% vs. 64 +/- 2.4%) and CFU-GM CE (79.5 +/- 10.5% vs. 55.8 +/- 3.5%) were higher in the G-CSF group. Only the pre-apheresis MNC count showed an independently significant correlation for both CE (P < .001). The higher CE in the G-CSF group can only be partly explained by a rise in MNC count during apheresis. These data suggest that the blood cell separator works better with leukocytosis, and especially with a higher MNC count. The improvement in CE is another benefit of G-CSF mobilization over chemotherapy mobilization.

Immune reconstitution following peripheral blood stem cell transplantation, autologous bone marrow transplantation and allogeneic bone marrow transplantation.

The rate and pattern of recovery of total lymphocytes, T cell subsets, B cells and NK cells were compared for 12 months following recovery phase peripheral blood stem cell (PBSC) autotransplantation (n = 49), autologous (n = 7) and allogeneic BMT (n = 11). The PBSC group had a significantly faster recovery of total lymphocyte count, total T cells (CD3+ cells), CD8 cells and CD4 cells than the allogeneic BMT group. The pattern of earlier recovery of CD8 cells than CD4 cells was the same for each type of transplant. Reconstitution following autologous BMT was intermediate between PBSC and allogeneic BMT. Multivariate analysis identified type of transplant, number of mononuclear cells transplanted and conditioning regimen as significantly influencing immune recovery.

A comparison of peripheral blood stem cell mobilisation after chemotherapy with cyclophosphamide as a single agent in doses of 4 g/m2 or 7 g/m2 in patients with advanced cancer.

We used cyclophosphamide at a dose of 7 g/m2 in patients with advanced cancer and compared the efficacy of this treatment to generate peripheral blood stem cells (PBSC) with the previously reported regimen of cyclophosphamide 4 g/m2 in a similar group of patients. None of these patients received haemopoietic growth factors. Twenty-two patients received 7 g/m2 and 37 received 4 g/m2. PBSC were collected by apheresis after the leukocyte count recovered to 1.0 x 10(9)/L. The yield of colony forming unit-granulocyte macrophage (CFU-GM) was higher for the 7 g/m2 group with a median of 35 x 10(4)/kg versus 15 x 10(4)/kg body weight (BW) (p < 0.05) and higher mononuclear cell yield with medians of 4.2 x 10(8)/kg compared with 3.1 x 10(8)/kg BW (p < 0.001). The percentage of patients achieving the minimum safe level of > 15 x 10(4) CFU-GM/kg BW was higher in the 7 g/m2 cyclophosphamide group (82%) than the 4 g/m2 cyclophosphamide group (51%). The duration of significant neutropaenia was a median of 11 compared with nine days (p < 0.004) and all patients receiving 7 g/m2 required admission to hospital and intravenous antibiotic therapy compared with 44% in the 4 g/m2 group. There was one death during the period of neutropaenia after cyclophosphamide in each group. Nineteen per cent of patients required platelet transfusions after cyclophosphamide 7 g/m2 compared with 18% after 4 g/m2. We conclude that the 7 g/m2 cyclophosphamide gives a higher yield of haemopoietic progenitor cells than the 4 g/m2 but at increased clinical toxicity.