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Autologous stem cell transplantation is considered the standard of care for multiple myeloma patients aged < 65 years with no relevant comorbidities. The addition of drugs acting both on bone marrow microenvironment and on neoplastic plasma cells has significantly increased the proportion of patients achieving a complete remission after induction therapy, and these results are mantained after high-dose melphalan, leading to a prolonged disease control. Studies are being carried out in order to evaluate whether short term consolidation or long-term maintenance therapy can result into disease eradication at the molecular level thus increasing also patients survival. The efficacy of these new drugs has raised the issue of deferring the transplant after achiving a second response upon relapse. Another controversial point is the optimal treatment strategy for high-risk patients, that do not benefit from autologous stem cell transplantation and for whom the efficacy of new drugs is still matter of debate. [ABSTRACT FROM AUTHOR]

Lipoplatin is a novel liposomal cisplatin formulation with reduced adverse side effects compared with its parental compound, cisplatin. The aims of this preclinical study were to compare lipoplatin and cisplatin cytotoxicity in vitro in established cell lines derived from non-small cell lung cancer, renal cell carcinoma, and in normal hematopoietic cell precursors, and to identify biological markers associated with sensitivity and resistance. Our results showed a superior cytotoxicity in all tumor cell models and a much lower toxicity in normal cells for lipoplatin compared with cisplatin, suggesting a higher therapeutic index for the liposomal compound. Moreover, RT-PCR analysis of molecular markers known to be related to cisplatin resistance showed a direct correlation between cisplatin and lipoplatin resistance and ERCC1 and LRP expression. In conclusion, lipoplatin showed a higher antitumor activity in both tumor histotypes investigated and was found to be safer than the parent compound, cisplatin. Moreover, ERCC1 and LRP expression levels would seem to be valid predictors of sensitivity or resistance to these drugs.

In the present study we investigated the proliferative response of megakaryocyte progenitor cells (CFU-MK) derived from peripheral blood stem cell (PBSC) collections of patients with haematological malignancies and normal donors. Highly purified CD34+ cells and mononuclear cell fractions were assayed in the presence of recombinant interleukin-3 (IL-3) and pegylated-recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF), alone or in combination, and megakaryocyte colony formation was evaluated in the plasma clot. In comparison, steady-state bone marrow samples from normal donors were highly enriched in CD34+ cells and tested with the cytokines studied. Our results showed that IL-3 was able to stimulate CFU-MK colony formation from bone marrow and peripheral blood CD34+ cells. Similarly, PEG-rHuMGDF stimulated, in a dose-response manner, CD34+ cells from the bone marrow. However, normal mobilized peripheral blood CD34+ cells were not induced to generate CFU-MK colonies by PEG-rHuMGDE The same lack of response was observed when patients peripheral blood CD34+ cells primed with chemotherapy plus G-CSF or with G-CSF alone were assessed. In contrast, PEG-rHuMGDF stimulated CFU-MK growth when mononuclear cells, either from the bone marrow or from mobilized peripheral blood, were grown in plasma clot. Moreover, we analysed by flow cytometry the expression of Mpl receptor on the cell membrane of normal mobilized peripheral blood and normal steady-state bone marrow CD34+ cells. Our results showed a reduced expression of Mpl receptor on mobilized peripheral blood progenitor cells in comparison with bone marrow cells.

Background and Objective: Transplantation of mobilized allogeneic peripheral blood stem cells (PBSC) has recently been reported by several groups. However, few patients receiving an allograft in the early stage of their disease have been described so far., Design and Methods: Fifteen patients with early stage hematologic malignancies were transplanted with cryopreserved allogeneic PBSC from HLA-identical siblings. PBSC were collected after priming with 10 micrograms/kg/day of glycosylated granulocyte colony-stimulating factor (G-CSF, lenograstim). Outcomes were compared to a historical control group of 15 patients who received conventional bone marrow transplantation (BMT) from HLA-identical sibling donors. The two groups were matched for diagnosis, stage of disease, age, preparative regimen, graft-versus host (GVHD) prophylaxis, patients' and donors' gender and cytomegalovirus (CMV) serology. Diagnoses in both groups were: chronic myelogenous leukemia (CML) in first chronic phase (= 5), acute leukemia in first complete remission (CR) (= 5), non-Hodgkin's lymphoma in CR (= 1) and multiple myeloma (MM) with sensitive disease (= 4). All patients were given cyclosporin-A (CsA) and methotrexate (MTX) for GVHD prophylaxis. Preparative regimens varied according to diagnosis and included either busulfan/cyclophosphamide combination (BU/Cy) or total body irradiation/cyclophosphamide +/- melphalan (TBI/Cy +/- Mel)., Results: The patients in the PBSC group showed a more rapid hematopoietic reconstitution with a significant difference in the median times to 1 x 10(9) neutrophils/L (19 days vs. 26 days; p = 0.03) and to platelet transfusion independence (18 days versus 22 days; p = 0.02). This finding was associated with a significantly shorter hospitalization (28 days versus 33 days after transplantation; p = 0.01). In the PBSC series, grade II-IV acute GVHD occurred in 3 patients (20%) and grade III-IV in 1 patient (7%). In the BMT control group, grade II-IV aGVHD was reported in 2 cases (13%; p = NS) and 1 case had grade III-IV GVHD. Chronic GVHD developed in 7 patients (47%) (limited = 6; extensive = 1) undergoing PBSC transplantation and 5 patients (33%) (limited = 4; extensive = 1) in the BMT series (p = NS). No difference was found in the incidence of grade II-IV (according to the World Health Organization) mucositis, whereas PBSC recipients did have a significantly lower incidence of additional severe (grade III-IV) organ toxicity. After a median follow-up of 300 days (range 180-630), all PBSC patients are still alive with a median Karnofsky score of 100% (range 80%-100%). Thirteen patients are in CR and 2 myeloma patient are in good partial remission (PR). Also, in the BMT group the peritransplant mortality was absent; two MM patients died due to progressive disease at day +796 and +1,023, respectively; one leukemic patient died of chronic GVHD 407 days after transplantation and one additional leukemic individual relapsed 1,140 days after BMT., Interpretation and Conclusions: This retrospective comparison suggests that allogeneic PBSC transplantation performed in the early stage of the disease is safe and may be associated with a more rapid hematopoietic reconstitution than BMT, as well as lower transplant-related toxicity and earlier hospital discharge with apparently no increased risk of acute and chronic GVHD.

Unlabelled: In this paper we describe an experimental model for ex vivo purging of contaminating tumor cells from peripheral blood stem cell (PBSC) collections obtained from patients with acute myeloblastic leukemia (AML). We studied the combination of the alkylating agent nitrogen mustard (NM; concentrations ranging from 0.25 to 1.25 microg/mL) and etoposide (VP-16; constant dose of 20 microg/mL), and the conventional cyclophosphamide (Cy)-derivative mafosfamide (concentrations: 20-175 microg/mL)., The Aims of Our Study Were: 1) To compare the toxicity of the purging protocols on bone marrow (BM) and circulating trilineage precursors collected from normal donors after priming with granulocyte colony-stimulating factor (G-CSF) or after complete remission (CR) consolidation chemotherapy and G-CSF (leukemic patients); 2) to demonstrate the survival of very primitive hematopoietic progenitors (LTC-IC) in the peripheral blood (PB) and the BM after pharmacological treatment; and 3) to evaluate the antineoplastic efficacy of purging protocols on PBSC collections using 3 well-established leukemic cell lines. Our results demonstrated that the toxicity on BM and PB progenitor cells could be correlated with the complete killing of committed granulocyte-macrophage colony-forming units (CFU-GMs) and erythroid precursors (BFU-Es), a condition reached at the concentration of 1.5 microg/mL of NM (in addition to 20 microg/mL of VP-16) and 175 microg/mL of mafosfamide. Notably, early and late megakaryocyte progenitor cells (CFU-MKs and BFU-MKs, respectively) showed higher sensitivity to NM/VP-16, but not to mafosfamide, than did CFU-GMs and BFU-Es. The dose of NM capable of inhibiting 95% of CFU-MKs and BFU-MKs (ID95) was 0.75 microg/mL. After incubation with the same dose of NM, the recovery of CFU-GMs and BFU-Es was 20 +/- 8% SD and 25 +/- 10% SD, respectively (p < 0.05). Long-term liquid cultures showed the recovery of primitive hematopoietic cells after incubation with the highest concentrations of NM/VP-16 and mafosfamide, with no significant differences between PB and BM samples. Under the same experimental conditions, we observed a more than 5-log reduction of contaminating leukemic cell lines (i.e., K-562, KG-1, and HL-60). In conclusion, we demonstrated that NM/VP-16 and mafosfamide purging agents are capable of killing leukemic cell lines that contaminate leukapheresis products from patients with AML, whereas an acceptable proportion of primitive LTC-IC is spared. Moreover, despite the different kinetic and functional profile of mobilized and steady-state BM progenitors, we did not observe any difference in toxicity of antineoplastic agents on hematopoietic cells at different levels of differentiation. These data suggest that pharmacological strategies developed for eliminating minimal residual disease (MRD) from BM autografts can be effectively and safely applied to circulating stem cell harvests.

Clonal chromosome aberrations observed in patients who have relapsed after autologous bone marrow transplantation (ABMT) are usually related to the cytogenetic abnormalities observed at diagnosis. In order to assess this relationship, we evaluated 30 acute non-lymphocytic leukemia (ANLL) patients who underwent ABMT at out institution and had evaluable serial cytogenetic studies before and after ABMT. Seventeen patients (57%) showed no chromosome aberrations after ABMT in any of the studies performed, while 13 patients (43%) carried abnormalities. In eight out of 30 patients (27%0 the abnormal karyotype after ABMT was associated with hematologic relapse. The cytogenetic abnormalities were: (1) the same as at diagnosis without additional abnormalities in five patients; (2) the same as at diagnosis but with additional abnormalities in three patients. In one patient a different karyotype from that of diagnosis was detected and a myelodysplastic syndrome was clinically evaluable. Furthermore, occasional and single cell chromosome abnormalities were observed in four patients (13%), none of whom relapsed. The new and additional clonal cytogenetic abnormalities observed after ABMT were found in eight patients (27%), suggesting that this event may not be so frequent, that is presumably associated regimen. The re-appearance of the chromosome aberrations after ABMT and the relationship with the risk of relapse are discussed.

We evaluated the role of ABMT in late 1st CR AML adult patients using busulfan plus cyclophosphamide as preparative regimen. Fifty-one adult patients (mean age 36 years, range 15-59) with AML underwent ABMT in 1st CR. Three of them had a prior diagnosis of myelodysplastic syndrome; one patient had a secondary leukemia. The median interval between CR and ABMT was 8 months (range 4-20). Patients received busulfan, 4 mg/kg/day for 4 days plus cyclophosphamide 50 mg/kg/day for 4 days or 60 mg/kg/day for 2 days. No maintenance chemotherapy was administered after ABMT. Median days to reach 0.5 x 10(9)/I PMN and 20 x 10(9)/I platelets were 26 (range 12-250) and 74 (range 16-740), respectively. No transplant-related deaths were observed. Five-year actuarial overall survival rate is 76.9%; actuarial leukemia-free survival rate is 70.6%. Mean follow-up from ABMT is 35 months. Leukemia-free survival of this group was compared with that of 38 non-transplanted patients younger than 60 years, who maintained a CR longer than 8 months in the same period. This analysis shows a statistically significant difference in favor of ABMT patients. These results suggest that, even if performed late after 1st CR as post-remission intensification, ABMT can improve the outcome of AML patients.