losartan-potassium and Blast-Crisis

We analyzed prognostic factors of response, response duration, and possible impact on survival of epoetin alpha, epoetin beta, or darbepoetin alpha (DAR) with or without granulocyte colony-stimulating factor in 403 myelodysplastic syndrome (MDS) patients. Sixty-two percent (40% major and 22% minor) and 50% erythroid responses were seen, and median response duration was 20 and 24 months according to IWG 2000 and 2006 criteria, respectively. Significantly higher response rates were observed with less than 10% blasts, low and int-1 International Prognostic Scoring System (IPSS), red blood cell transfusion independence, serum EPO level less than 200 IU/L, and, with IWG 2006 criteria only, shorter interval between diagnosis and treatment. Significantly longer response duration was associated with major response (IWG 2000 criteria), IPSS low to INT-1, blasts less than 5%, and absence of multilineage dysplasia. Minor responses according to IWG 2000 were reclassified as "nonresponders" or "responders" according to IWG 2006 criteria. However, among those IWG 2000 minor responders, response duration did not differ between IWG 2006 responders and nonresponders. Multivariate adjusted comparisons of survival between our cohort and the untreated MDS cohort used to design IPSS showed similar rate of progression to acute myeloid leukemia in both cohorts, but significantly better overall survival in our cohort, suggesting that epoetin or DAR treatment may have a favorable survival impact in MDS.

Topics: Aged; Blast Crisis; Cohort Studies; Disease-Free Survival; Erythrocyte Transfusion; Erythropoietin; Female; Granulocyte Colony-Stimulating Factor; Humans; Male; Myelodysplastic Syndromes; Predictive Value of Tests; Survival Rate; Time Factors

P39/Tsugane is a myelomonocytoid cell line derived from a patient with myelodysplastic syndrome (MDS). The cells readily undergo apoptosis in response to various agents, and the cell line has been suggested as a useful model to study apoptosis in MDS. The aims of the present study were to assess differentiation and apoptosis induced with all-trans retinoic acid (ATRA) and etoposide, to characterize the mode of apoptosis in these two model systems, and to assess the influence of granulocyte colony-stimulating factor (G-CSF), which in combination with erythropoietin has been shown to inhibit apoptosis in MDS. ATRA induced differentiation and apoptosis in a concentration- and time-dependent manner. Differentiated cells were partially rescued (by 50%) from apoptosis with G-CSF. Etoposide induced apoptosis in a concentration- and time-dependent manner, but no signs of preceding maturation or G-CSF rescue were detected. ATRA- and etoposide-induced apoptosis were both mediated through the caspase pathway and were partially blocked with the general caspase inhibitor zVAD-fmk. Simultaneous treatment with G-CSF and zVAD-fmk additively blocked ATRA-induced apoptosis. However, the two pathways differed in terms of substrate cleavage during apoptosis. ATRA-induced apoptosis caused actin cleavage, which was not affected by G-CSF, and Bcl-2 downregulation. Etoposide induced a caspase-dependent cleavage of Bcl-2, while actin remained intact. The Fas system did not seem to play a major role in any of these apoptotic pathways. Our results may provide new tools to study the mechanisms of apoptosis in MDS.

Topics: Actins; Acute Disease; Amino Acid Chloromethyl Ketones; Antibodies, Monoclonal; Apoptosis; Blast Crisis; Caspase Inhibitors; Caspases; Cell Differentiation; Cysteine Proteinase Inhibitors; Cytoskeleton; Erythropoietin; Etoposide; fas Receptor; Granulocyte Colony-Stimulating Factor; Humans; Leukemia, Myeloid; Myelodysplastic Syndromes; Neoplasm Proteins; Proto-Oncogene Proteins c-bcl-2; Signal Transduction; Tretinoin; Tumor Cells, Cultured

Topics: Aged; Blast Crisis; Erythropoietin; Female; Hemoglobins; Humans; Leukemia, Myelomonocytic, Chronic; Male; Middle Aged; Recombinant Proteins; Reticulocytes

We have previously demonstrated that malignant hematopoietic colony-forming units (CFUs) may be purged from normal CFU by exposure to c-myb antisense oligodeoxynucleotides (oligomers). This novel strategy appeared particularly promising for patients with chronic myelogenous leukemia (CML) in blast crisis, since in some cases complete elimination of bcr-abl-expressing cells was accomplished. We have examined 11 additional patients, including seven in chronic phase, in order to extend these initial observations. We sought in particular to determine if elimination of bcr-abl-expressing clones was a usual event. Exposure of CML cells to c-myb antisense oligomers resulted in inhibition of CFU-granulocyte, macrophage (CFU-GM)-derived colony formation in eight of 11 (73%) cases evaluated. Inhibition was antisense sequence-specific, dose-dependent, ranged between 58% and 93%, and was statistically significant (P less than or equal to .03) in seven of the eight cases. In two cases, CFU-granulocyte, erythrocyte, monocyte, megakaryocyte (CFU-GEMM)-derived colony formation was also examined and found to be inhibited by the c-myb antisense oligomers in a sequence-specific manner. To determine whether CML CFU had been reduced or eliminated after exposure to the antisense oligomers, we examined cells in the residual colonies for bcr-abl mRNA expression using a reverse transcription-polymerase chain reaction detection technique (RT-PCR). Eight cases were evaluated and in each case where antisense myb inhibited growth, bcr-abl expression as detected by RT-PCR was either greatly decreased or nondetectable. No residual leukemic CFU were demonstrable on replating of treated cells. These results suggest that c-myb antisense oligomers substantially inhibit the growth and survival of CML CFU in both chronic and blast phase of disease. They may therefore prove useful for both ex vivo and in vivo treatment of CML.

Topics: Actins; Adult; Aged; Base Sequence; Blast Crisis; Cloning, Molecular; Codon; Erythropoietin; Female; Fusion Proteins, bcr-abl; Granulocyte-Macrophage Colony-Stimulating Factor; Growth Substances; Hematopoietic Stem Cells; Humans; Interleukin-3; Leukemia, Myeloid, Chronic-Phase; Leukocytes, Mononuclear; Male; Middle Aged; Molecular Sequence Data; Oligonucleotides, Antisense; Oncogenes; Polymerase Chain Reaction; RNA, Messenger; Tumor Stem Cell Assay

The effects of recombinant human erythropoietin (rEp) on murine hematopoietic progenitors were studied using a serum-free culture. A high concentration of rEp stimulated the formation of mixed erythroid-megakaryocyte colonies (EM colonies) and blast cell colonies, as well as erythroid colonies, erythroid bursts, and megakaryocyte colonies from normal mouse bone marrow cells. Direct effects of rEp on EM colony, megakaryocyte colony, and erythroid burst formation were confirmed by depletion of accessory cells such as T cells, B cells, and macrophages from crude bone marrow cells, and inhibition of the colonies by the addition of rabbit anti-rEp antibody to the culture in a dose-dependent fashion. Replating experiments were performed to confirm the differentiating ability of blast cell colonies grown in the presence of rEp. Most of the blast cell colonies yielded not only secondary erythroid colonies but also megakaryocyte colonies in the presence of 2 IU/mL rEp. Some of the blast cell colonies produced secondary EM colonies in the presence of 16 IU/ml rEp of 2 IU/mL rEp plus interleukin-3, although no granulocyte-macrophage colonies were found in the secondary culture. These results suggest that Ep acts not only as a late-acting factor that is specific for erythroid progenitors, but also as a bipotential EM-stimulating factor for murine hematopoietic cells.

Topics: Animals; Antibodies; Blast Crisis; Bone Marrow Cells; Cells, Cultured; Cholesterol; Culture Media; Dose-Response Relationship, Drug; Erythrocytes; Erythroid Precursor Cells; Erythropoiesis; Erythropoietin; Female; Hematopoiesis; Hematopoietic Stem Cells; Lymphocyte Depletion; Megakaryocytes; Mice; Phosphatidylcholines; Recombinant Proteins

A chronic myeloproliferative disorder associated with monosomy 7 is described in a 3 1/2-year-old boy. His presenting features closely resembled those of juvenile chronic myeloid leukaemia (JCML). Cytogenetic study of bone marrow cells showed that all of the metaphases examined had chromosome 7 deletions. He developed an erythroblastic phase, characterized by anaemia, marked erythroid hyperplasia of bone marrow and the appearance of nucleated red blood cells in the peripheral blood. During the erythroblastic phase, blood transfusion resulted in a suppression of erythropoiesis as evidenced in both the peripheral blood and bone marrow. The in vitro culture studies showed that the erythroid precursor was dependent upon erythropoietin (Ep) for differentiation and proliferation during the erythroblastic phase. However, the Ep dose-response curve showed that a peak of erythroid colony formation occurred at a lower concentration than in the healthy controls. These findings suggest that although the erythroid precursor remains under the control of Ep, it has an increased sensitivity to Ep during the erythroblastic phase of monosomy 7.

Topics: Blast Crisis; Blood Transfusion; Child, Preschool; Chromosome Deletion; Chromosomes, Human, Pair 7; Erythropoiesis; Erythropoietin; Humans; Karyotyping; Male; Monosomy; Myeloproliferative Disorders

The bone marrow of a patient with acute undifferentiated leukemia developed unique colonies after a 14-day culture in erythropoietin (EPO)-containing methylcellulose. The colonies consisted of 20 to 200 nonhemoglobinized large blast cells. Cytogenetic analysis of single colonies revealed hypotetraploid karyotypes with several marker chromosomes that were identical to those found in directly sampled bone marrow. The concurrently formed erythroid bursts showed only normal karyotypes. No leukemic colony formation was observed in other culture systems with either colony-stimulating activity (CSA) or phytohemagglutinin-stimulated leukocyte-conditioned medium (PHA-LCM). The leukemic colonies exhibited a complete EPO-dose dependency similar to that of the patient's normal BFU-E. Although cytochemical and immunologic marker studies of the bone marrow cells failed to clarify the cell lineage of the leukemic cells with extraordinarily large cell size, ultrastructural study revealed erythroid differentiation such as siderosome formation in the cytoplasm and ferritin particles in the rhophecytosis invaginations. These findings indicate that the patient had poorly differentiated erythroid leukemia and that some of the clonogenic cells might respond to EPO in vitro. Corresponding to this biological feature, the leukemic cells were markedly decreased in number in response to repeated RBC transfusions, and partial remission was obtained. These observations suggest that erythroid leukemia distinct from erythroleukemia (M6) with a myeloblastic component, can develop as a minor entity of human acute leukemia.

Topics: Acute Disease; Blast Crisis; Cells, Cultured; Erythropoietin; Hematopoietic Stem Cells; Humans; Karyotyping; Leukemia; Male; Microscopy, Electron; Middle Aged