asta-z-7557 and Leukemia

Topics: Adolescent; Adult; Animals; Bleomycin; Bone Marrow; Bone Marrow Transplantation; Cell Separation; Child; Child, Preschool; Clinical Trials as Topic; Cyclophosphamide; Drug Evaluation; Etoposide; Graft vs Host Disease; Hematopoietic Stem Cells; Humans; Leukemia; Leukemia, Lymphoid; Lymphoma; Lysophosphatidylcholines; Methylprednisolone; Neoplasms, Experimental; Phospholipid Ethers; Pyrimidinones; Transplantation, Autologous; Transplantation, Isogeneic

Topics: Adolescent; Adult; Animals; Bleomycin; Bone Marrow; Bone Marrow Transplantation; Cell Separation; Child; Child, Preschool; Clinical Trials as Topic; Cyclophosphamide; Drug Evaluation; Etoposide; Graft vs Host Disease; Hematopoietic Stem Cells; Humans; Leukemia; Leukemia, Lymphoid; Lymphoma; Lysophosphatidylcholines; Methylprednisolone; Neoplasms, Experimental; Phospholipid Ethers; Pyrimidinones; Transplantation, Autologous; Transplantation, Isogeneic

The sensitivity of human myeloblastic leukemic (CFU-L) and normal hemopoietic stem cells (CFU-GM and BFU-e) to Asta Z 7557 (INN Mafosfamide) was studied with regard to autologous bone marrow transplantation (ABMT) with cleansed marrow for consolidation therapy in adult patients with acute leukemia (AL) in remission. Establishment of the dose-response curves for CFU-GM (n = 37), BFUe (n = 11), and myeloblastic CFU-L (n = 9) demonstrated a wide range of sensitivity from patient to patient for all three progenitors. Whereas CFU-L, CFU-GM, and BFU-e grown in semisolid cultures disclosed similar sensitivities to Asta Z 7557, long-term culture (LTC) studies (n = 41) indicated a higher resistance of early progenitors. In an effort to achieve a maximum tumor cell kill and yet spare a sufficient amount of normal stem cells to ensure consistent engraftment, we defined the optimal dose for marrow cleansing as the dose sparing 5% CFU-GM (LD95). This dose was established from a preincubation test (PIT) realized on a 10-mL marrow aspirate taken 15 days before marrow collection in each individual patient. Twenty-four adult patients while in remission of AL (20 in complete remission, four in partial remission) were consolidated by cyclophosphamide 60 mg/kg X 2 and total body irradiation at 10 Gy followed by ABMT with marrow cleansed by Asta Z 7557 according to the specification described above. Patients were divided in two groups: group 1, unfavorable prognosis (11 patients); group 2, standard prognosis [13 patients in first complete remission (CR)]. All patients engrafted on leukocytes (median day for recovery to 10(9)/L: day 30), patients with ALL recovered faster than patients with ANL (median day 19 v 34). Similarly, recovery of platelets to 50.10(9)/L occurred sooner in patients with ALL (median day 67, range day 23 through 90) whereas three patients with acute nonlymphoblastic leukemia (ANLL) in group 2 had to be supported with platelet transfusions for more than one year. In group 1, six patients had recurrent tumor within six months; three patients died from toxicity with no evidence of tumor. Two patients are still disease-free with a short follow-up (nine and ten months). In group 2, two patients died from toxicity with no evidence of leukemia three and 16 months post-ABMT. One patient with a M5 ANLL and one patient with ALL relapsed at six and 15 months, respectively. Nine patients have remained in CR or are disease-free with a median follow-up of 22 months.(A

Topics: Adolescent; Adult; Bone Marrow Transplantation; Cell Separation; Clinical Trials as Topic; Colony-Forming Units Assay; Cyclophosphamide; Erythroblasts; Female; Granulocytes; Humans; Leukemia; Liver; Male; Middle Aged; Stem Cells

Ammonium trichloro(dioxoethylene-O,O')tellurate (AS101) has been shown previously to provide radioprotective effects when given to mice 24 h prior to irradiation and to protect mice from lethal and sublethal doses of cyclophosphamide (CTX). In this study we examined the ability of AS101 to protect mice bone marrow colony forming units-granulocyte-macrophage treated in vitro with various doses of ASTA-Z 7557, a potent derivative of cyclophosphamide. We demonstrate that prior incubation with AS101 protects colony forming units-granulocyte-macrophage from toxic effects of ASTA-Z. This protection can also be conferred by injection of mice with AS101 prior to incubation of their bone marrow in vitro with ASTA-Z. Prior incubation with AS101 was shown not to protect K562 leukemic cells or HL-60 cells from the toxic effects of ASTA-Z. We show that AS101 protection from the toxic effects of ASTA-Z in vitro and CTX in vivo can be partially ascribed to increased aldehyde dehydrogenase (ALDH) activity induced by AS101. This was shown directly by measuring cellular ALDH activity and indirectly by measuring the toxicity of ASTA-Z and CTX in the presence of cyanamide, an inhibitor of ALDH. AS101 is also demonstrated in this study to protect spleen cells from the toxic effects of 5-fluorouracil, probably through a different mechanism. These properties of AS101 make it a useful candidate for increasing the qualitative potential of bone marrow used for autologous transplantation after purging with ASTA-Z. In addition, the results suggest an increase in ALDH activity by AS101 as one of the mechanisms of protection from the toxic effects of ASTA-Z and CTX. However, the chemoprotectiveness of AS101 was found not to be restricted to cyclophosphamide, since as shown in this study, AS101 helped by other mechanisms to reconstitute the number of spleen cells after 5-fluorouracil treatment.

Topics: Aldehyde Dehydrogenase; Animals; Bone Marrow; Bone Marrow Purging; Colony-Forming Units Assay; Cyanamide; Cyclophosphamide; Dose-Response Relationship, Drug; Drug Resistance; Ethylenes; Fluorouracil; Granulocytes; Leukemia; Male; Mice; Mice, Inbred BALB C; NAD; Spleen; Tumor Cells, Cultured

Fourteen adult patients in first complete remission of acute leukemia (A.L.) [6 with acute lymphoblastic leukemia (ALL), 8 with acute non lymphoblastic leukemia (ANLL)] were consolidated with high dose cyclophosphamide and total body irradiation followed by autologous bone marrow transplantation (ABMT) with marrow cleansed in vitro by Asta Z 7557. According to our previously described protocol showing evidence for a wide range of sensitivity from patient to patient, the marrow of each individual patient was incubated with the highest tolerable dose of Asta Z 7557. This dose, individually determined, was defined as the dose sparing between 0 and 10% of CFU-GM (CFU-GM DL95). ABMT was not followed by maintenance therapy. Hematological reconstitution was significantly faster in ALL patients when compared to ANLL patients. Out of these 14 patients: 2 relapsed on months 5 and 15 respectively after ABMT, and 2 died in complete remission on months 3 and 16 respectively, of veno-occlusive disease and encephalitis. Ten patients (70%) remain in complete remission up to a median of 15 months +, with 4 patients over 24 months +.

Topics: Acute Disease; Adult; Bone Marrow; Bone Marrow Transplantation; Combined Modality Therapy; Cyclophosphamide; Female; Humans; Leukemia; Male; Middle Aged

Ex vivo bone marrow treatment prior to autologous bone marrow transplantation for acute leukemia or solid tumors (known for their frequent medullary metastatic dissemination) has provoked a great deal of hope and enthusiasm. If, as in most cases, the feasibility of various methods (exposure to chemical products, monoclonal antibodies and complement-dependent cytolysis, immuno-magnetic procedures) has been confirmed, no study to date has shown the efficacy. Only randomized studies will result in such a proof, on the condition that all the specific technical parameters of each method have been perfectly defined. The clinical results of pilot evaluation studies for the prevention of graft-versus-host reaction through the elimination of T lymphocytes in the donor graft have been encouraging. They have shown the feasibility and efficacy of different methods of T cell depletion. One point however remains controversial: is it necessary or not to eliminate all T lymphocytes? After a depletion which is too efficient, the difficulties involved in grafting the donor's hematopoietic cells on the recipient represent a new problem, e.g., in allogenic grafts for acute leukemia (host-versus-graft). In order to resolve the problem of these take failures (10 to 20% of the published series except for Royal Free Hospital and Besançon) it appears necessary to redefine the conditioning regimen prior to allogenic bone marrow transplantation.

Topics: Antibodies, Monoclonal; Antigens, Neoplasm; Bone Marrow; Bone Marrow Cells; Bone Marrow Transplantation; Cell Separation; Centrifugation, Density Gradient; Cyclophosphamide; Graft vs Host Disease; Humans; Lectins; Leukemia; Lymphocyte Depletion; Methylprednisolone; Neoplasms; Neprilysin; Pilot Projects; Plant Lectins; Ricin; Soybean Proteins; T-Lymphocytes; Transplantation, Autologous; Transplantation, Homologous

The chromosomal anomaly t(4;11) is closely related to a specific type of acute leukemia: occurrence in young children, hyperleukocytosis with a particular immunologic phenotype, and poor response to therapy. Allogeneic bone marrow (BM) transplantation has been done in a few cases. We report a case in which a complete remission was obtained after intensive therapy. Because no donor was available, an autologous BM transplantation was performed after purge ex vivo of the BM collection by Asta-Z. Relapse occurred at day 45.

Topics: Bone Marrow; Bone Marrow Transplantation; Chromosomes, Human, 4-5; Chromosomes, Human, 6-12 and X; Cyclophosphamide; Female; Humans; Infant; Leukemia; Translocation, Genetic

The lymphocyte subset reconstitution after high-dose chemotherapy and total body irradiation followed by autologous bone marrow transplantation (ABMT) has been studied in ten patients with acute leukemia (AL) (6 ALL and 4 ANLL) in complete remission (CR). Bone marrow was treated in vitro with high-dose ASTA Z 7557, individually determined according to CFU-GM sensitivity. The different peripheral blood lymphocyte subsets were characterized by means of monoclonal antibodies (indirect immunofluorescence assay) belonging to the following classes of differentiation: OKT11-T11 (CD2), OKT3-T3 (CD3), OKT4-T4 (CD4), OKT8-T8 (CD8), OKIal-I2 (HLA-DR), Leu7 (natural killer/killer) and by means of polyspecific antiimmunoglobulin sera (direct immunofluorescence assay). Data in these ten patients were compared with those of a control group of 21 normal donors and with a control group of 14 patients in CR without ABMT. Our results showed a marked depression of the T4:T8 ratio in patients with AL before ABMT, compared with normal donors who had respective values of 1.02 and 1.33 (p less than 0.01). This depression was increased and prolonged up to day 515 after ABMT, with a value of 0.32 (p less than 0.01 compared with the pregraft situation; p less than 0.001 compared with normal donors). This T4:T8 ratio imbalance was related to the depletion of the T4+ population and to the increase of the T8+ subset. This imbalance was emphasized after ABMT. The Leu 7+ population was also increased in grafted patients compared with normal donors (p less than 0.01). The B-cell population remained unchanged throughout the study. We conclude that patients autografted with marrow treated in vitro by high-dose ASTA Z 7557 may experience a long-term T-cell subset imbalance.

Topics: Acute Disease; Adult; Bone Marrow; Bone Marrow Transplantation; Cyclophosphamide; Female; Humans; Killer Cells, Natural; Leukemia; Lymphocytes; Male; T-Lymphocytes; Transplantation, Autologous

Topics: Adult; Bone Marrow; Bone Marrow Transplantation; Chromosome Aberrations; Cyclophosphamide; Humans; Leukemia; Transplantation, Autologous

Topics: Animals; Bone Marrow; Bone Marrow Transplantation; Burkitt Lymphoma; Cell Line; Cell Separation; Cyclophosphamide; Hematopoietic Stem Cells; Humans; Leukemia; Leukemia, Experimental; Mice; Rats

Thirty human bone marrow (BM) suspensions from patients with acute leukaemia patients in remission were processed with the Haemonetics 30 flow cell separator in order to separate buffy-coats and to treat them in vitro with a derivative of cyclophosphamide (ASTA Z 7557). After processing, the volumes of BM suspensions were reduced to 25%. Recoveries of leucocytes, CFUc and BFUe were respectively 62, 85 and 84%. In vitro treatment with doses of ASTA Z ranging from 50 to 140 micrograms/2 X 10(7) leucocytes (according to the CFUc sensitivity of each patient) destroyed 95 +/- 5% of initial CFUc. After freezing and thawing, recovery of CFUc from treated BM was poor (24%) in comparison to that obtained with untreated BM (79%).

Topics: Acute Disease; Bone Marrow; Bone Marrow Transplantation; Cell Separation; Colony-Forming Units Assay; Cyclophosphamide; Freezing; Humans; In Vitro Techniques; Leukemia; Tissue Preservation; Transplantation, Autologous

Topics: Acute Disease; Cyclophosphamide; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells; Humans; Leukemia

Cyclophosphamide (CPA) is widely used against leukemic and lymphoproliferative diseases, but in vitro studies on response to this agent so far have been limited to instable derivatives with poor galenic properties. ASTA Z 7557 is a newly synthesized "activated cyclophosphamide" that circumvents the need for hepatic activation and has good stability. The critical cytotoxic lesions after exposure to bifunctional alkylating agents presumably are DNA interstrand crosslinks (ISC). We have, therefore, examined the formation and apparent removal of ISC after in vitro treatment with ASTA Z 7557 by use of the highly sensitive alkaline elution technique. Survival of murine L1210 cells was determined after 1 hour in vitro exposure with a D 37 value of 5.7 micrograms/ml (from the initial shoulder part of the survival curve) and a Do value of 1.5 micrograms/ml (from the exponential part of the curve). Previous labelling of L1210 cells by 125IUdR simplified the alkaline elution procedure but there was some cytotoxicity of the radiochemical itself with a reduction of cloning efficiency from 77% to 61%. The maximum of ISC was observed at 6 h after initiation of treatment with much of the damage apparently removed at 24 h. The simultaneous presence of DNA single strand breaks (SSB), however, confounds the analysis of DNA damage at 24 h and early cytolysis and unaided death of human lymphocytes often preclude the analysis of macromolecular damage at this time. Human peripheral blood cells isolated from patients with leukemic or lymphoproliferative diseases showed a remarkable heterogeneity with regard to the formation of ISC at 3 h.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Cell Survival; Cells, Cultured; Cross-Linking Reagents; Cyclophosphamide; DNA Repair; DNA, Neoplasm; DNA, Single-Stranded; Humans; Kinetics; Leukemia; Leukemia L1210; Mice