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From 1988 to 1998 one hundred forty eight patients with acute lymphoblastic leukemia (ALL) were enrolled into prospective study. The aim of the study was to evaluate efficacy of common treatment for acute lymphoblastic leukemia and to determine risk factor for outcome. Out of 148 patients, 31 (21%) had acute nondifferentiated leukemia (according to the FAB criteria) with expression of lymphoid markers. Those patients were treated in the same way as patients with ALL. According to the type of consolidation therapy patients were divided into three groups. Chemotherapy alone received 38 (38%) patients, and 30 (31%) patients received autologous stem cell transplantation (SCT) or allogeneic STC. There were no statistical difference in sex, age, FAB subtype, number of WBC and platelets in the time of diagnosis and incidence of cytogenetic abnormalities between these three groups. Median follow-up for chemotherapy group was 68 (range 12-98) months, for allogeneic SCT 102 (range 12-120) and for autologous SCT 99 (range 12-105) months. As a condition regimen the majority of patients treated with SCT received total body irradiation followed by cyclophosphamide. There was statistically significant difference in the source of stem cell for transplantation: in 20% of autologous SCT peripheral blood was used as source of stem cells. Relapse rate was significantly higher in patients receiving chemotherapy alone than in patients receiving either autologous or allogeneic SCT (83 vs. 45 vs. 27%, p

Introduction: Previous work showed inhibitory effects of opioid pentapeptides enkephalins on cultured mouse bone marrow cells (Boranić et al., Reg Immunol 6:421,1994). Since the CD10 marker of lymphoid, myeloid and stromal cells functions as a membrane-bound enzyme processing the neuropeptides (EC 3.4.24.11, 'enkephalinase'), enkephalins and related peptides were supposed to participate in regulation of hematopoiesis. Here we describe the effects of di- and tripeptide fragments of the enkephalin molecule, as well as of the enkephalinase-inhibiting agents thiorphan and bestatin. Materials and Methods: The agents were tested in clonal and long-term cultures of mouse and human bone marrow cells. Human samples were donated by healthy volunteers or by patients with acute lymphoblastic leukemia (ALL) or non-Hodgkin lymphoma (NHL) in complete remission. The samples constituted small parts (1-2%) of the material collected and stored for allo- or autografting, respectively. Results: In clonal cultures of mouse bone marrow cells, N-terminal fragments of the enkephalin reduced the granulocyte-macrophage (GM) colony formation, like the parent molecule. Thiorphan and bestatin were suppressive as well. Opioid antagonist naloxone blocked (partly) the inhibition by the enkephalin fragments. Thiorphan increased the colony counts in cultures of normal human bone marrow cells and in approximately one-half of the ALL and NHL samples. In a long-term culture of ALL bone marrow, thiorphan promoted proliferation of cells resembling the lymphoblasts. Conclusion: The observations indicate a combination of specific (opioid receptor-mediated) and nonspecific actions of tested agents on hematopoiesis. Findings in the ALL and NHL bone marrow samples open the possibility that malignant cells respond to putative neuroendocrine regulatory mechanisms affecting the hematopoiesis.

The CD10 marker of lymphoid, myeloid and stromal cells is a membrane-bound metallo-endopeptidase processing the enkephalins and related neuropeptides (EC 3.4.24.11). Therefore, fragments of the enkephalin molecule and the inhibitors of the membrane endopeptidase CD10 wuld be expected to affect hematopoiesis. That idea was explored in short-term (clonal) and long-term cultures of mouse or human bone marrow cells. Human samples were obtained from healthy donors of bone marrow allotransplants or from the patients with acute leukemia (AL) or non-Hodgkin lymphoma (NHL) in remission. N-terminal fragments of the methionine-enkephalin molecule reduced the granulocyte-macrophage (GM) colony formation in clonal cultures of mouse bone marrow cells, thus resembling the effects of the parent molecule. The inhibition was (partly) blocked by opioid antagonist naloxone. CD10-blocking agent thiorphan increased the colony counts in cultures of normal human bone marrow cells and in approximately one-half of the AL and NHL samples. The stimulatory effects predominantly occurred in the remission bone marrow samples from the patients with T-ALL, AML or high-malignancy grade NHL. The bone marrow samples from the patients with common ALL and from the patients with low malignancy-grade NHL were refractory to thiorphan. In a long-term culture of ALL bone marrow, thiorphan promoted proliferation of undifferentiated cells resembling the lymphoblasts. The results are compatible with the idea that opioid peptides and membrane-bound metalloproteinase(s) processing them participate in the control of hematopoiesis. These observations draw attention to hematopoietic side effects of metalloproteinase-inhibiting drugs.

High-dose condiditoning regimens followed by Autologous PBSC rescue have been used for treatment of hematological malignancies and solid tumors in our hospital since 1984. In 54 patients with lymphoid malignancies (37 non-Hodgkin lymphoma, 17 Hodgkin's disease) 165 collections were performed.

alogeneic transplants, acute leukemia

malignant lymphoma and stem cell transplants

stem cell transplants, malignant lymphoma

This work was aimed at assessing the prognostic value of the colony-forming ability in vitro (the GM-CFU assay) of the bone marrow cells collected at diagnosis from 13 patients with untreated chronic lymphocytic leukemia (CLL). The GM-CFU count per 10E5 cellswas reduced in proportion to the total tumor mass (TTM score) and to the clinico-pathological staging of the disease according to the Rai criteria. A few discordant examples of low GM-CFU counts in early stages of the disease might be considered an unfavourable prognostic sign. The reduction of the bone marrow progenitor (colony-forming) cell compartment was interpreted as indicating an impairment of normal hematopoiesis by inhibitory factor(s) released from the CLL cells.