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PubMed1996

The dual expression of minor and major bcr/abl chimeric mRNA in blast crisis of chronic myelogenous leukemia.

The hypothesis that minor bcr/abl fusion mRNA is produced in blast crisis of chronic myelogenous leukemia (CML) is examined. The RNA transcripts encoding the minor and major bcr/abl fused protein were detected by polymerase chain reaction (PCR) using RNA from peripheral blood or bone marrow cells of eight patients with blast crisis or accelerated phase of CML. The mRNA encoding for major bcr/abl was detected in all eight cases. In four patients, however, transcripts encoding for minor bcr/abl mRNA were detected, as well as major bcr/abl mRNA. The presence of minor bcr/abl mRNA was verified with the hybridization with a junction-specific probe and DNA sequencing analysis of PCR products. The appearance of minor bcr/abl fusion mRNA was associated with the lymphoblastic immunophenotype of the blast cells. In two of these four patients, samples of initial diagnosis of chronic phase of CML were available, which did not show minor bcr/abl transcript. We conclude that the appearance of minor bcr/abl mRNA transcript is associated with the terminal evolution of CML in lymphoblastic crisis.

Adolescent↗
PubMed1992

Treatment of chronic myeloid leukemia with allogeneic bone marrow transplantation after preparation with BuCy2.

One hundred fifteen patients with chronic myelocytic leukemia (CML) were administered busulphan 4 mg/kg for 4 days and cyclophosphamide 60 mg/kg on each of 2 days (BuCy2) followed by allogeneic bone marrow transplantation from histocompatible sibling donors. For 62 patients in chronic phase, 26 in accelerated phase, and 27 in blast transformation, the actuarial survival at 3 years was 58%, 41%, and 25%, respectively. Actuarial probability of relapse was 3%, 12%, and 27%, respectively. Only two patients in chronic phase showed a transient cytogenetic relapse and one of these died from subsequent transplant-related complications, whereas the other remains cytogenetically normal 697 days posttransplant. Patients who were transplanted within 1 year of diagnosis in chronic phase had a survival of 70% compared with 40% when transplanted beyond 1 year from diagnosis. This significant difference in survival was due to transplant-related complications and was correlated with previous exposure to high doses of busulphan. This study indicates that BuCy2 is a useful conditioning regimen for marrow transplantation in patients with CML and results in similar survival statistics and transplant-related mortality as would be expected with conditioning regimens containing total body irradiation. It is possible that relapse after BuCy2 may be lower than expected with regimens containing total body irradiation, but larger analyses are required.

Adolescent↗
PubMed1980

Thymidine as a chemotherapeutic agent: pharmacologic, cytokinetic, and biochemical studies in a patient with T-cell acute lymphocytic leukemia.

Biochemical studies suggested that leukemia T-cells have low levels of TTP-catabolizing enzyme activity and are uniquely sensitive to thymidine (dThd). A child with T-cell acute lymphocytic leukemia (ALL), whose peripheral blood lymphoblasts manifested very low TTP catabolic capacity, was treated with 75 g dThd/m2/day by constant iv infusion for two courses of 5 and 8 days. The dThd caused an initial accumulation of peripheral blood blasts in S-phase at the expense of cells in G1, followed by a rapid reversal of this pattern consistent with a block in late G1 and/or early S. Concurrently, a prompt reduction of blasts was found in the peripheral blood. However, dThd treatment neither decreased the number of lymphoblasts in the cerebrospinal fluid (CSF) nor cleared the marrow. No major toxicity was observed, but the effect of dThd on normal marrow elements could not be evaluated in this patient. Blood concentrations of dThd were 1.4-3.0 mM, and concentrations of thymine were in the same range; beta half-life for dThd was 48 minutes. Steady-state CSF dThd was 9% of the simultaneous serum level. Clearance measurements demonstrated that catabolism of dThd was saturated and that renal clearance was a major determinant of total body clearance during high-dose dThd infusion. A good correlation was found between biochemical and cytokinetic parameters and response to dThd for the peripheral blood lymphoblasts. However, dThd did not produce a useful remission in this case of T-cell ALL.

Antineoplastic Agents↗
PubMed1987

Effects of cytapheresis on cell cycle distribution of peripheral blood and bone marrow cells in some hematological malignancies.

Feulgen-DNA cytophotometry and 3H-thymidine autoradiography were used to evaluate therapeutic cytapheresis effects on cell cycle distributions of peripheral blood leukemic cells in 15 acute leukemia, 5 CML and 8 CLL patients and of bone marrow erythroblasts in 18 PV patients. Both individual cytapheresis procedures and a long-term program of cytapheresis altered cell cycle distributions and biochemistry which may be summarized as follows: An increase in percentage of cells in S-phase (acute leukemia, CML); a decrease in the differences between values of S-cell number obtained by cytophotometry and autoradiography (acute leukemia, CML, PV); a decrease in some cases in enlarged fraction of cells in G2 (blast crisis of CML, PV); an activation of G0----G1 transition and an increase in the PAS-positive lymphocyte fraction in CLL patients. An apparent increase of blasts in S-phase was found after a pheresis in acute leukemia patients who responded to subsequent chemotherapy. In "nonresponders", a pheresis had no effect on cell cycle distributions. The results of the study demonstrate that despite the wide variability of individual responses, cytapheresis activates cell proliferation and metabolic processes in patients with hematological malignancies.

Blast Crisis↗
PubMed1998

Expression of the leptin receptor in human leukaemic blast cells.

The leptin receptor is a member of the cytokine receptor superfamily, and is expressed in CD34 haemopoietic stem cells. We examined expression of the leptin receptor in fresh human leukaemia cells. Northern blot analysis showed the leptin receptor was expressed in leukaemic cells from patients with acute myeloblastic leukaemia, acute lymphoblastic leukaemia and chronic myeloid leukaemia (CML). In CML, higher expression was observed in blast crisis than in chronic phase. The expression of leptin receptor decreased during in vitro differentiation of leukaemic blast cells. It appeared that expression of the leptin receptor was associated with immature leukaemic blast cells. Our findings may indicate the possibility that leptin has some role in leukaemia.

Acute Disease↗
PubMed1978

Characterization of rat bone marrow lymphoid cells. I. A study of the distribution parameters of sedimentation velocity, volume and electrophoretic mobility.

Various cell populations in rat bone marrow were characterized by means of a two dimensional separation using velocity sedimentation and free flow electrophoresis and by electrical sizing of the separated cells. Up to 4.5 mm/hr five different populations with discrete distributions in volume (coefficient of variation 10% to 13%) and sedimentation velocity (coefficient of variation 6% to 10%) were observed. Three of the small sized populations represented lymphocytes and small normoblasts and two of the larger sized populations represented myeloid cells. Almost all of these cells were in the G0/G1 cycle phase. In the faster sedimenting fractions which contained immature myeloid, erythroid and undefined blast cells and two S phase populations, discrete volume distributions were not evaluated. The cell populations with homogeneous volume (particularly the small lymphocytes) showed high density variations which condiserably impair the separation resolution. The cells sedimenting slower than 3.5 mm/hr were further separated by means of free flow electrophoresis into three peaks differing in electrophoretic mobility (EPM). The peaks of low and high EPM contained two populations and the peak of medium EPM contained three populations all characterized by normal volume distributions of uniform coefficient of variation between 11% and 14%. The small cells in the peaks of high and medium EPM were normolblasts and the other cells were lymphocytes. The biological significance of these results is discussed.

Animals↗
PubMed1993

Bone marrow transplantation for chronic myeloid leukemia: long-term results. Chronic Leukemia Working Party of the European Group for Bone Marrow Transplantation.

The data on 1480 bone marrow transplants for chronic myeloid leukemia (CML), performed between 1979 and 1990 were reported to the registry of the European Group for Bone Marrow Transplantation (EBMT). Of these, 1082 patients were transplanted in first chronic phase, 88 in subsequent chronic phase, 251 in accelerated phase and 59 during blast crisis. For these four disease stages leukemia-free survival (LFS) at 5 years is 39%, 22%, 22% and 0%, respectively. A more detailed analysis was performed for 947 patients receiving a first transplant in first chronic phase of their disease from an HLA-identical sibling donor. Survival at 8 years is 47%. At 5 years, relapse incidence (RI) is 33% and the transplant-related mortality rate (TRM) is 42%. The major prognostic factors are patient age (LFS, TRM), T cell depletion (LFS, RI), time from diagnosis to transplant (LFS, TRM), white blood cell count (RI) and donor-recipient sex combination (LFS, TRM). This first report on long-term results of a large cohort of transplanted CML patients confirms and extends previous findings. Stage of disease at time of transplant is the most important prognostic factor. Fifty per cent of all patients transplanted for CML in chronic phase can be expected to be alive at 8 years post-transplant, 40% alive and free of the disease. This number increases to > 60% for patients given cyclosporin and methotrexate without T cell depletion as GVHD prophylaxis. However, there is no plateau phase and late relapses and late transplant-related deaths occur in all subcategories.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed2004

[Therapy of chronic myelogenous leukemia in 2004].

Chronic myelogenous leukemia constitutes a clinical model for other neoplastic diseases. The cytogenetic hallmark of CML, the Ph chromosome with the molecular juxtaposition of BCR and ABL genes and the multistep pathogenesis with the stable chronic phase, the accelerated phase and the terminal blast crisis provide the background for the translation of molecular-cytogenetic findings into clinical practice. The systematic development of the selective BCR-ABL inhibitor imatinib was based on the discovery of the molecular pathogenesis of CML. Promising preclinical data were confirmed in phase I-III trials. Concerning hematologic and cytogenetic response and adverse effects imatinib is superior to interferon alpha. Open questions are treatment duration in patients with good response, long term side effects, persistence of minimal residual disease in almost all patients, development of resistance after long term therapy, and the efficacy of combination treatments. Prospective clinical trials, e. g. CML study IV of the German CML Study Group, should answer these questions. The impact of the various treatment modalities (imatinib, interferon alpha, ara-C, allogeneic stem cell transplantation) will be elucidated. The recruitment of newly diagnosed CML patients into CML-study IV is recommended.

Antineoplastic Agents↗
PubMed1989

Effect of recombinant human granulocyte-macrophage colony-stimulating factor in patients with myelodysplastic syndrome with excess blasts.

As part of a broad phase I study of recombinant human granulocyte-macrophage colony-stimulating factor (rh GM-CSF), four patients were treated who had myelodysplastic syndrome (MDS) with excess blasts. The GM-CSF was given daily as an intravenous injection over a period of 30 min for 5 days. A total of 11 cycles were conducted. Each patient received at least two different dose levels. In three patients, three different dosages were delivered. The treatment course was interrupted by a 10-day rest period. Rh GM-CSF was well tolerated, with only minor side effects seen, which included bone discomfort at the lower back, sternum and ribs, and constitutional symptoms such as low grade fever, nausea/vomiting, and mild myalgias. Whereas no increases in platelet and reticulocyte counts were recorded, elevations of absolute neutrophil counts above 100 cells/microliters occurred in all patients. The most striking finding was, however, the development of increases in the number of circulating and bone marrow blast counts that were observed particularly when doses of greater than or equal to 500 micrograms/m2 of body surface area were administered. In line with data demonstrating in vitro induction of proliferation of leukemic blast cells by rh GM-CSF, one may take advantage of blastogenesis induced in vivo that may favor the use of a therapeutic strategy by recruiting quiescent cells into the mitotic cycle which would then represent optimum targets for a subsequent cycle-specific cytotoxic chemotherapy. Such an approach could form the basis for new clinical trials in MDS.

Adult↗
PubMed1999

Abnormalities of the p53 gene in juvenile myelomonocytic leukaemia.

Juvenile chronic myelomonocytic leukaemia (JMML) is a rare myeloproliferative disorder of childhood. Fewer than 30% of cases of JMML terminate in a blast crisis; however, its molecular mechanism is unknown. Since mutation and/or deletion of the p53 gene has been reported to be associated with disease progression in a wide variety of human cancers, including adult-type chronic myelogenous leukaemia, we studied the p53 gene in 20 patients with JMML (16 samples in chronic phase and seven at blast crisis). Exons 4-8 of the p53 gene, which cover all the hot spots of point mutations, were amplified by the polymerase chain reaction (PCR) method and subjected to mutation screening by single-strand conformation polymorphism analysis. No mobility shift of single-strand DNA of PCR products in polyacrylamide gel electrophoresis, indicating point mutations, was found in 19/20 patients. DNA of the remaining patient in the chronic phase failed to be amplified by PCR and Southern blot analysis with XbaI-digested genomic DNA revealed a gross rearrangement (presumed deletion) of the p53 gene. These data indicate that abnormalities of the p53 gene are rare in JMML and not responsible for acute transformation, but could be involved in the pathogenesis of some cases of JMML.

Blotting, Southern↗
PubMed2001

Phase II study of combination human recombinant GM-CSF with intermediate-dose cytarabine and mitoxantrone chemotherapy in patients with high-risk myelodysplastic syndromes (RAEB, RAEBT, and CMML): an Eastern Cooperative Oncology Group Study.

A Phase II study of GM-CSF with intermediate-dose cytarabine and mitoxantrone was conducted in patients with high-risk myelodysplastic syndrome. It was designed to evaluate if priming with growth factor could increase the efficiency of chemotherapy. In this older population only two of 10 patients achieved a bone marrow CR, including one patient whose leukemic blasts had an "S" phase increase of 2.55x at 48 hr. Unexpected hepatotoxicity was noted. This regimen cannot be recommended for this elderly population of patients.

Aged↗
PubMed1987

Lymphocyte subpopulations, activation phenotypes, and spontaneous proliferation in tuberculous pleural effusions.

The state of lymphocyte activation in tuberculous pleural effusions was studied. The proportion of cells at and beyond the G1 phase of the cell cycle displaying interleukin-2 receptor, transferrin receptor or gp 40/80 glycoprotein in avidin-biotin-peroxidase complex (ABC) staining was 6 +/- 2 percent, 8 +/- 3 percent, and 14 +/- 4 percent of all pleural fluid mononuclear cells, respectively. These findings imply that only a fraction of pleural fluid lymphocytes is activated in tuberculosis. The proportion of autoradiographically visualized 3H-thymidine incorporating blasts at the S phase of the cell cycle was 1.2 +/- 0.3 percent. This phenomenon further confirms the impression that, in spite of activation, most of the pleural fluid mononuclear cells are resting cells. The T4/T8 ratio in the functionally active blast cell population determined by a double labeling method combining ABC staining with autoradiography was similar to the total T4/T8 ratio (2.3 +/- 0.7 vs 2.7 +/- 0.8, p greater than 0.05) calculated for all pleural fluid mononuclear cells.

Humans↗
PubMed1993

Genetic alterations in the p53 gene in the blast crisis of chronic myelogenous leukemia: analysis by polymerase chain reaction based techniques.

Rearrangements of the c-abl protooncogene and the bcr-gene are found in > 90% of patients in chronic phase of chronic myelogenous leukemia (CML). The molecular events leading to blast crisis, however, have not been well characterized. Gross alterations of the p53 gene have been detected in 30% of patients with blast crisis. Since point mutations in the p53 gene appear to be important in the process of transformation in many epithelial tumors, we looked for these mutations in the critical regions of the p53 gene (exons 4, 5, 6, 7, and 8). We used the polymerase chain reaction (PCR), direct sequencing, differential PCR, and single strand conformation polymorphism (SSCP) analysis to detect mutations of the p53 gene in samples from 21 patients with CML blast crisis. Two of 21 patients exhibited an intragenic deletion or rearrangement in p53. In addition, these patients were homozygous for the mutant p53 allele. No mutations were found in the p53 gene of the remaining 19 patients. However, sequencing of the CML blast crisis cell line, K562, revealed an insertion of a C at base position 956 within the fifth exon, causing a frame shift mutation and an early translational stop at codon 148. We conclude that, in contrast to solid tumors, mutations in exons 4-8 of p53 are not frequently seen in primary samples from CML blast crisis. However, deletions and/or rearrangements within the p53 gene do occur and may contribute to the progression from chronic phase to blast crisis in a limited number of patients with CML.

Base Sequence↗
PubMed1993

DNA image analysis in childhood acute lymphoblastic leukemia.

DNA index (DI) and percentages of cells in S and G2/M phase were determined in Feulgen stained nuclei of blasts from 31 cases of childhood ALL at diagnosis. In 6 cases the results of DNA analysis and cytogenetics were concordant showing hyperdiploidy. Two other cases with normal karyotype were revealed as DNA aneuploid with image analysis. Cases with cytogenetic abnormalities like translocation, deletion or presence of single or double supernumerary chromosomes had DI within normal ranges. Nine ALL cases (29%) were found to be DNA aneuploid--8 hyperdiploid and 1 hypodiploid. The percentages of cells in S and G2/M phase for blasts from bone marrow (mean 17.6%) were significantly higher than those estimated in the peripheral blood (mean 1.57%). We conclude that analysis by image cytometry can detect aneuploid DNA content even in cases, which showed a normal karyotype and provides new information concerning the biological aspects of leukemic blasts.

Adolescent↗
PubMed1975

Heterogeneity of morphological, cytochemical, and cytogenetic features in the blastic phase of chronic granulocytic leukemia.

Possible predictive criteria of the refractoriness to therapy of the blastic phase of Ph-1-positive chronic granulocytic leukemia (CGL) have been sought. Eight cases in the blastic phase were studied. The blasts were noted to be of two types: some displayed a high nuclear:cytoplasmic ratio with deep blue cytoplasm, while others had a comparatively low nuclear:cytoplasmic ratio and bluish gray cytoplasm containing a few small granules. Electron microscopic studies showed a variety of features, including defective organelles and giant mitochondria. Cytochemical staining revealed the majority of blast cells to be peroxidase- and Sudan black-negative; granular PAS positivity was the rule. Serial cytogenetic studies demonstrated increasing aneuploidy. Bone marrow biopsy showed myelofibrotic changes in two cases. Two patients entered complete remission with prednisone and vincristine and with Ara-C and thioguanine, respectively. It is concluded that the blastic phase of CGL may manifest heterogeneity.

Acute Disease↗
PubMedDate not supplied

[The comparative characteristics of the clinico-hematological indices in patients with different forms of myelodysplasias].

Clinical findings were analyzed as were parameters of the peripheral blood and bone marrow in 102 patients presenting with hematodysplasias with regard to a form of the disorder and in comparison with healthy subjects. Used for the analysis was the computer system "GEMA" (Saint-Petersburg). Correlations were analyzed between the studied parameters. Differential-diagnostic differences were revealed between refractory anemia, blast surplus refractory anemia, and refractory anemia with blast surplus in the phase of transformation into acute leukosis. The results obtained can be used for their differential diagnosis, prediction of the disease course, choice of therapeutic alternatives.

Acute Disease↗
PubMed1988

[Cytogenetic study of cell sub-populations in human leukemias (AML, CML) sorted by flow cytometry].

Multivariate analysis, flow cytometry and sorting were used to distinguish and enrich subpopulations of bone marrow cells in cases of acute myeloblastic leukemia and blast crisis of chronic myelocytic leukemia: blast cells with a high rate of S/G2-M phase of the cell cycle; non-blast cells or blasts with a low rate of S/G2-M. These populations were separated on the basis of their forward angle and large angle light scatter of the laser beam, and of their Hoechst 33342 fluorescence intensity. About one million cells of each population were sorted and sorting purity was controlled by cytometry and microscope examination. Cell viability was good. Karyotypes of sorted cell populations were carried out using a cell synchronisation technique and showed different chromosomal markers.

Bone Marrow Cells↗