Cognitive function in the acute course of allogeneic hematopoietic stem cell transplantation for hematological malignancies.

The aim of the study was to assess cognitive performance in patients with hematological malignancies before, and 3 months after, allogeneic hematopoietic stem cell transplant (HSCT). A consecutive sample of 39 patients was assessed before admission with a comprehensive neuropsychological test battery and health-related quality-of-life (HRQoL) questionnaires; 19 of these patients were retested around 100 days post HSCT. Test results were compared with normative data and revealed minimal differences at both time points in the level of group-means. One parameter - simple reaction time - was significantly worse (prolonged) at second measurement after HSCT. According to the definition of an impairment score (more than three impaired functions), 26% of patients were classified as impaired before as well as after HSCT. Neuropsychological test results did not vary systematically according to medical variables such as extent of pretreatment, graft-versus-host-disease (GvHD) and kind of conditioning protocol. As a dimension of HRQoL, self-rated cognitive function was in the normal range before and after HSCT. Significant correlations between HRQoL and neuropsychological parameters were related to symptom scales. This study showed impairments of neuropsychological performance for a subgroup of patients before and after allogeneic HSCT. Systematic effects of conditioning, medical variables or self-rated HRQoL could not be observed.

Inhibition of CFU-C growth by VP-16 containing plasma samples obtained from patients after conditioning therapy for bone marrow transplantation.

The introduction of VP-16 into high-dose therapy regimens used for conditioning before BMT or PBSCT has resulted in higher remission rates and prolonged disease-free survival, even in high risk patients. VP-16 levels have been measured in plasma at the time of transplantation. The question is, is there a biological activity that corresponds with the risk of delayed engraftment or graft failure? We investigated the inhibitory effects of plasma samples obtained from patients under high-dose VP-16 therapy on the growth of human bone marrow progenitor cells. Bone marrow cells from healthy donors were exposed to the plasma samples and seeded into methylcellulose-culture (CFU-C-assay). We found a dose dependent CFU-C inhibition related to VP-16 plasma levels at the time of transplantation (k = 0.769, P < 0.01). There were signs of a correlation between CFU-C growth inhibition at the time of BMT and haematological recovery (k = 0.656, P < 0.05) between CFU-C inhibition and the time until leucocytes reached 0.2 x 10(9)/l. Patients with CFU-C growth inhibition at the time of BMT may show delayed engraftment of leucocytes and that there might be a correlation with VP-16 levels, but further investigation is necessary to determine the significance of the latter thesis and if VP-16 plasma levels could lead to failure of engraftment. We recommend a minimum time interval between VP-16 infusion and graft transplantation of 72 h.

Comparison of the content and subpopulations of CD3 and CD34 positive cells in bone marrow harvests and G-CSF-mobilized peripheral blood leukapheresis products from healthy adult donors.

Recombinant human granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood stem/progenitor cells (PBPC) have replaced bone marrow (BM) harvests for autologous transplantation after myeloablative therapy in cancer patients. G-CSF-mobilized PBPC from healthy donors contain one log excess of T lymphocytes representing a potential risk for graft-versus-host disease (GVHD). However, recent pilot clinical studies of G-CSF-mobilized allogeneic PBPC transplantation have shown rapid haematological recovery and no severe acute GVHD except in a very few cases. Therefore, the risk of inducing severe acute GVHD is not as high as was expected during the pioneering period of allogeneic PBPC transplantation. The present study was performed to address the possible reasons for the rapid haematological recovery and the absence of severe acute GVHD observed after allogeneic PBPC transplantation by comparing the contents and subsets of CD3+ and CD34+ G-CSF-mobilized PBPC (n = 31) with those of BM (n = 26) allografts from healthy adult donors. The present results revealed that the phenotypic profiles of CD3+ and CD34+ cells differ between PBPC and BM allografts. The single PBPC leukapheresis product contained 10 times more mononuclear cells, 1.5 times more CD34+ cells, 5.5 times more CD3+ T lymphocytes, 3 times more CD19+ B lymphocytes and 3.8 times more CD14+ monocytes than the single BM harvest. Both CD34+CD33+ myeloid progenitor cells and CD34+HLA-DR-long-term reconstituting haemopoietic stem cells were significantly increased in the CD34+ G-CSF-mobilized PBPC compared with the CD34+ BM cells; median 73.1% and 30.4% vs 60.6% and 5.0%, respectively, P < 0.01. The percentage of CD3+ cells coexpressing CD4 (T helper/inducer) was similar in both PBPC and BM allografts, 47.2% and 45.6%, respectively, whereas the percentage of CD3+ cells coexpressing CD8 (T suppressor/cytotoxic) was significantly decreased in PBPC compared with BM; 37.0% vs 55.9%, p < 0.01. The rapid haematological recovery after allogeneic PBPC transplantation could be due to the increased content of CD34+CD33+ myeloid committed cells and the CD34+HLA-DR-long-term reconstituting haemopoietic stem cells in the PBPC allografts. Also, the absence of an increased risk of severe acute GVHD after allogeneic PBPC transplantation could be due to the increased T lymphocyte ratio of CD4+/CD8+ in the PBPC allografts. In conclusion, rapid haematological recovery without an increased risk of severe acute GVHD can be achieved using G-CSF-mobilized PBPC rather than BM for allogeneic transplantation.

Factors influencing the haematological recovery after allogeneic bone marrow transplantation in leukaemia patients treated with methotrexate-containing GVHD prophylaxis: a single-centre experience.

In the present single institution study of 66 leukaemia patients (28 AML, 23 ALL, 15 CML), the factors influencing haematological recovery after allogeneic bone marrow transplantation (alloBMT) were analysed retrospectively in order to identify the optimal conditions required for a rapid haematological recovery after alloBMT. All patients received GVHD prophylaxis with cyclosporine A plus methotrexate. The mean number of days required to achieve > or = 0.5 x 109/l neutrophil count after alloBMT was 17 (median 17, range 9 to 27 days) and 19 patients (28.8%) had rapid neutrophil recovery within 15 days after alloBMT. The haematological recovery was more rapid in the 38 patients without GVHD or with only grade I GVHD. Furthermore, 50% and 40% of patients receiving 10 (n = 18) or 5 (n = 20) micrograms/kg/day G-CSF had rapid neutrophil recovery within 15 days after alloBMT, versus only 7.1% of patients not receiving G-CSF post-transplant (n = 28), p < 0.001. The neutrophil recovery was similar in patients receiving either fresh or cryopreserved allografts and either TBI-containing or busulfan-containing conditioning regimen. A significant correlation was found between neutrophil recovery and either the MNC or CFU-GM content of the allografts, r = 0.33, p < 0.01. The mean number of days required for neutrophil recovery was only 16 days (median 16, range 9 to 24 days) in patients receiving allografts containing > 1 x 10(5) CFU-GM/kg (n = 28) versus 19 days (median 19, range 13 to 27 days) in patients receiving allografts containing < 1 x 10(5) CFU-GM/kg (n = 35). Three patients receiving allografts containing less than 0.5 x 10(5) CFU-GM/kg had primary neutrophil engraftment failure. The mean number of days required to achieve 20 x 109/l platelet count was 21 (median 20, range 11 to 50 days) and 30 patients (46.9%) had platelet recovery within 20 days after alloBMT. The platelet recovery after alloBMT was not significantly affected by the type of leukaemia, conditioning regimen, or G-CSF administration. The mean number of days required for platelet recovery after alloBMT was only 20 days (median 18 days) in patients receiving allografts containing > 1.0 x 10(5) BFU-E/kg (n = 35) versus 23 days (median 20 days) in patients receiving allografts containing < 1.0 x 10(5) BFU-E/kg (n = 24). Seven patients receiving allografts containing less than 0.5 x 10(5) BFU-E/kg had primary platelet engraftment failure. The present study has identified the high number of progenitor cells in the allografts infused and the daily administration of G-CSF post-transplant as the optimal combination for a rapid neutrophil recovery after alloBMT. More significantly, the number of BFU-E in allografts was the most significant factor to determine platelet recovery after alloBMT. The development of GVHD of grade II or more during the first weeks after alloBMT was associated with slower haematological recovery and longer period of fever during neutropenia and hospitalisation.

Neuropsychological function in high-risk breast cancer survivors after stem-cell supported high-dose therapy versus standard-dose chemotherapy: evaluation of long-term treatment effects.

BACKGROUND: Studies on cognitive functioning in breast cancer patients point out that a subset of women exhibit chemotherapy-related neuropsychological impairment. Thereby, high-dose therapy may elevate the risk of cognitive dysfunctions. The primary purpose of the study was to evaluate the impact of high-dose versus standard-dose chemotherapy on the late neuropsychological outcome in randomized assigned high-risk breast cancer survivors. Next to focusing prevalence, function specificity and extent of cognitive impairment, the question as to whether doses-dependent group differences occur was investigated. PATIENTS AND METHODS: Twenty-four high-dose and 23 standard-dose patients 5 years, on average, after treatment underwent a comprehensive neuropsychological assessment. In addition, 29 early-stage breast cancer patients matched for age, education and time since treatment were recruited as a comparison group. RESULTS: Global cognitive impairment was observed in 8% of high-dose versus 13% of standard-dose compared with 3% of early-stage breast cancer patients. Compared with normative data, all patient groups performed worse on one attention subtest measuring the simple reaction time (P < 0.001 in each case). By contrast, no significant between-group differences on the late neuropsychological outcome were found. CONCLUSIONS: Five years after treatment, standard-dose patients were slightly, but not significantly, more impaired in cognitive performance than high-dose patients.