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PubMed1988

Immunophenotype of blast cells in chronic myeloid leukemia.

The immunophenotype of peripheral blood blast cells from 14 patients in the chronic phase of chronic myeloid leukemia (CML) was studied using a panel of monoclonal antibodies (McAb) directed against megakaryocytic, granulomonocytic, erythroid and lymphoid antigenic determinants. The blast cells were enriched by a simple bovine serum albumin (BSA) density-cut separation and cooled in liquid nitrogen. The study was done using the alkaline phosphatase-anti-alkaline phosphatase (APAAP) technique on the thawed blast cells. A consistent pattern of reactivity with McAb was found in all patients, showing that blast cells were heterogeneous. A minor component of the blast cells react with platelet antibodies, most of them being labelled with anti-GPIIb-IIIa McAb. Anti-GPIb and Von Willebrand factor McAb detected 4 times fewer megakaryocytic blast cells, suggesting that these cells are located very early in the differentiation scheme. Two major blast cell compartments were labelled with early myelomonocytic (anti-CD13: MY7) and early erythroid (anti-CD36: FA6-152) McAb. The CD34 (My10) and DR antigens which are expressed by immature blast cells and myeloid progenitors of human bone marrow (BM) were present on more than 50% of the CML blast cells. Thus, the blast cells of chronic phase CML patients, showed the same cellular diversity as the increased progenitor cell compartment observed in this disease, and their differentiation stages seemed to be very closely related.

Antibodies, Monoclonal↗
PubMed1994

[Treatment of promyelocytic blast crisis of chronic myelogenous leukemia with all-trans-retinoic acid].

This paper describes the treatment of promyelocytic blast crisis of chronic myelogenous leukemia with all-trans-retinoic acid (ATRA). The patient, a 22-year-old male, was diagnosed to have APL and had been treated with busulfan and then with three and half years interferon (IFN) alpha in the chronic phase. A cytogenetic study of blast cells showed the t(1;17) (p11;q11) translocation as the second chromosomal abnormality without morphological abnormality of chromosome 15. Molecular analysis showed cells to have a chimera gene consisted of PML and retinoic acid receptor alpha genes. Though maturation and differentiation of leukemic cells were seen after ATRA therapy, hematological complete remission did not occur. The ineffectiveness of ATRA may be dut to different pathological conditions from de novo APL, or progressive reduction in plasma ATRA concentration as reported by Muindi et al. When our case was compared with a similar case reported by Wiernick et al., both cases were treated with IFN alpha in the chronic phases, had no t(15;17) translocation involving No.1 chromosome abnormality and did not develop complete remission after ATRA therapy.

Adult↗
PubMed2004

The biology of CML blast crisis.

Chronic myelogenous leukemia (CML) evolves from a chronic phase characterized by the Philadelphia chromosome as the sole genetic abnormality into blast crisis, which is often associated with additional chromosomal and molecular secondary changes. Although the pathogenic effects of most CML blast crisis secondary changes are still poorly understood, ample evidence suggests that the phenotype of CML blast crisis cells (enhanced proliferation and survival, differentiation arrest) depends on cooperation of BCR/ABL with genes dysregulated during disease progression. Most genetic abnormalities of CML blast crisis have a direct or indirect effect on p53 or Rb (or both) gene activity, which are primarily required for cell proliferation and survival, but not differentiation. Thus, the differentiation arrest of CML blast crisis cells is a secondary consequence of these abnormalities or is caused by dysregulation of differentiation-regulatory genes (ie, C/EBPalpha). Validation of the critical role of certain secondary changes (ie, loss of p53 or C/EBPalpha function) in murine models of CML blast crisis and in in vitro assays of BCR/ABL transformation of human hematopoietic progenitors might lead to the development of novel therapies based on targeting BCR/ABL and inhibiting or restoring the gene activity gained or lost during disease progression (ie, p53 or C/EBPalpha).

Animals↗
PubMed1977

Inhibition of human lymphocyte stimulation by steroid hormones: cytokinetic mechanisms.

The steroid hormones estradiol, progesterone and testosterone, in addition to cortisol, inhibited stimulation of human peripheral blood lymphocytes by phytohaemagglutinin (PHA) and Con A. This effect upon lymphocyte transformation was assayed by three methods: quantitation of [3H]thymidine incorporation into acid precipitable material, microscopic assessment of blastic transformation and determination of the labelling index. Addition of steroid hormones at the initiation of culture resulted in a marked inhibition in all three parameters, which was observed with lower concentrations of cortisol than the other hormones. The inhibition was not attributable to cell death and could be partially reversed by removing hormones from the incubation medium after culture for 48-72 hr. Late addition of steroid hormones, 52 hr after addition of mitogen and 18 hr prior to pulse-labelling with [3H]thymidine, also resulted in reduced [3H]thymidine incorporation, accompanied by a nearly 50% reduction in the labelling indices and only a minimal decrease in the per cent transformed cells. Inhibition of lympohcyte stimulation by steroid hormones operates by the following cytokinetic mechanisms: (1) suppressed recruitment of cells from G3 to G1 phase of the cell cycle, as indicated by the diminished per cent blasts; (2) inhibition of progression from G1 phase into S phase, as evidenced by the reduced ratio [labelling index/blasts]; and, in the case of estradiol and progesterone, (3) reduced rate of DNA replication or altered intracellular [3H]thymidine specific activity as shown by the decreased ([3H]thymidine incorporation/labelling index) ratio. Late addition of steroid hormones to stimulated cultures reduced the per cent of cells in S phase, but did not revert previously transformed cycling lymphocytes to the G3 state.

Cell Division↗
PubMed2004

Clonal evolution in chronic myelogenous leukemia.

Clonal evolution (CE) may be a marker of disease progression in chronic myelogenous leukemia (CML) and is thought to reflect the genetic instability of the highly proliferative CML progenitors. The frequency of CE increases with advancing stage, rising from 30%in accelerated phase and up to 80% in blast crisis. Given its association with disease progression, CE is considered a feature that defines accelerated-phase CML; however, not all studies have demonstrated a uniformly poor outcome for patients with CE. Chromosomal abnormalities in Ph chromosome negative metaphases increasingly have been recognized in patients treated with imatinib. The true incidence of this phenomenon is not clear but appears to occur in 2% to 17% of imatinib-treated patients. Regardless of the precise mechanism and the long-term clinical implications, the findings described in this article underscore the importance of routine cytogenetic analysis for patients treated with imatinib. The continued study of these phenomena will help us to understand better the pathogenesis of CML and improve the long-term treatment of patients with CML.

Antineoplastic Agents↗
PubMed1987

[Bone marrow transplantation in chronic myeloid leukemia--experiences in 16 patients].

Between January 1983 and December 1986 16 patients (8 f, 8 m, median age 31.5 years, 14-41) with chronic myelocytic leukaemia (CML) received bone marrow grafts from their HLA compatible sibling donors. 11 patients were in the chronic and 4 in the accelerated phase. 1 patient was in lymphatic blast crisis. The patients were pretreated with busulfan (n = 15, total dose: 100-1000 mg, median: 225), mitobromitol (1 pat.), hydroxyurea (2 pats.), pre-irradiation of the spleen with 800 rad (1 pat.) and one patient had received 3 cycles of vincristin and prednisolone. The conditioning regimen consisted of cyclophosphamide (120 mg/kg) and total body irradiation (1000 rad, lung 800 rad). The prophylaxis against graft versus host disease (GVH-D) consisted of methotrexate (MTX) in 14 patients and of MTX in combination with cyclosporin-A in 2. At present (January 15th 1987) 9 patients survive 30 to 1210 days (median 1009) post graft (6/11 grafted in chronic, 2 of 4 in accelerated phase and 1/1 grafted in blast crisis. The causes of death were interstitial pneumonitis (CMV-associated, 2 pats.), venoocclusive disease of the liver (2 pats.), acute GVH-D and septicemia (2 pat.) and relapse (1 pat.). The Karnovsky score of 8/9 survivors is 100%, one patient has a score of 70% due to chronic GVH-D. Bone marrow transplantation for CML bears a high risk of early mortality but offers the unique option of permanent eradication of leukaemic haemopoiesis with subsequent long term survival.

Adolescent↗
PubMed1989

[Transplantation of bone marrow from unrelated donors in chronic myeloid leukemia].

Bone marrow transplantations in four patients (aged 8-28 years, median 27 years) with chronic myeloid leukaemia (CML) were performed from unrelated donors who were HLA-identical and MLC-negative. One patient was in the stage of refractory blast crisis, one in a chronic phase, and two in the second chronic phase. Conditioning treatment consisted of fractionated radiation and administration of cyclophosphamide; in the patients with their second chronic phase additionally etoposide. Cyclosporin A and methotrexate were administered to prevent graft versus host reaction. The patient in the blast crisis died on day 12 after transplantation of Candida pneumonia. The other three patients are still alive 128, 306 and 530 days, respectively, after transplantation, only a mild form of graft versus host disease having occurred. It is suggested that for patients younger then 50 years with CML in the chronic phase an unrelated donor should be searched for in the absence of a familial donor.

Bone Marrow Transplantation↗
PubMed1990

The role of the MDR-1/P-170 mechanism in the development of multidrug resistance in chronic myeloid leukemia.

We studied blood and bone marrow cells from 42 patients with Ph-chromosome positive chronic myeloid leukemia (CML) and 20 normal subjects for amplification of the multidrug resistance gene (MDR-1) by Southern blotting and for overexpression of P-glycoprotein (P-170) by immunocytochemistry on intact cells with the monoclonal antibody C219. No P-170 could be detected in normal bone marrow or buffy coat. Overexpression of P-170 without amplification of MDR-1 was found in four of 11 patients with chronic phase CML at diagnosis, seven of 16 patients treated with busulfan or hydroxyurea in chronic phase and four of 15 patients in blast crisis. The P-170 overexpression involved only cells of the granulocyte lineage and varied from weak to strong in individual patients. It did not correlate with duration of or response to treatment during chronic phase. In transformation P-170 expression was seen in differentiated cells of the granulocyte lineage but not in blast cells, although three patients had been treated intensively with lipophilic and other cytotoxic drugs to which they had become resistant. We conclude that resistance to busulfan and hydroxyurea in chronic phase and resistance of blast cells to other cytotoxic drugs in transformation are not mediated primarily through the MDR-1/P-170 pathway.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1985

Occurrence of the common acute lymphoblastic leukemia antigen on blast cells of a patient with chronic myelomonocytic leukemia in non-lymphoid blastic phase.

Leukemias showing a conspicuous lymphoid phenotype, ie, those that are HLA-DR positive, common acute lymphoblastic antigen (cALLA) positive, terminal deoxynucleotidyl transferase (TdT) negative, as well as myeloperoxidase positive (MPO), could be considered so-called mixed leukemias. Leukemias with biphenotypic blasts have to be distinguished from cases comprising two separate subpopulations that express different lineage-associated characteristics. By use of a simple new method (Immunogold Staining) we examined a case of chronic myelomonocytic leukemia in blastic phase and demonstrated simultaneous staining for MPO/alpha-naphthyl-esterase and expression of the HLA-DR-positive, cALLA-positive, and TdT-negative phenotype. The cALL antigen was detected only on mono- and myelo-monoblasts; its expression was inversely related to the MPO positivity, and it disappeared together with these types of blasts after chemotherapy. On the basis of our findings it remains obscure whether the cALL antigen at the initial presentation was due to the immature monocytic features of the leukemic cells or disclosed on additional lymphoid differentiation pattern of the blasts.

Aged↗
PubMed1982

Profile of blood coagulation and fibrinolysis in chronic myeloproliferative disorders.

Blood coagulation and fibrinolysis were studied in 65 patients with chronic myeloproliferative disorders (MPD). They consisted of 28 patients with chronic granulocytic leukemia (CGL) in chronic phase, 7 with CGL in blast crisis, 9 with polycythemia vera (PV), 13 with primary thrombocythemia (PTh) and 8 with primary myelofibrosis (MF). Hemorrhagic and thrombotic complications were observed in 19 and 8 patients, respectively. Activated partial thromboplastin time and prothrombin time were prolonged in many patients. Low factor II levels were observed in some CGL patients. Factor V was decreased in CGL patients in chronic phase and in PV patients. Fibrinogen was either normal or increased in most patients, but an elevation of fibrin/fibrinogen degradation products (FDP) was found in some patients. The VIIIR: Ag/VIII:C ratio was increased in CGL patients in blast crisis, in PV patients and in PTh patients. Antithrombin III and plasminogen were below normal in some patients. Most patients showed a decrease in alpha 2-plasmin inhibitor. These findings suggest that blood coagulation and fibrinolysis are involved in the pathogenesis of the thrombotic and hemorrhagic complications in these patients. Chronic low-grade intravascular coagulation might be present in some patients with MPD.

Adult↗
PubMed1995

Changes of nucleolar organizer regions in granulopoietic precursors during the course of chronic myeloid leukemia.

The aim of the present study was to analyze the nucleolar organizer region (AgNOR) pattern of granulopoietic precursors in chronic myeloid leukemia (CML) at diagnosis and during the course of the disease. Clusters of AgNORs and isolated dots were counted separately in 24 cases of CML at diagnosis, in 19 cases during the relapse of the chronic phase after treatment, and in 16 cases of blast crisis. For comparison, 20 cases of normal bone marrow were studied. Each cell type had its own characteristic AgNOR pattern, as has been described for normal bone marrow. There was no significant difference in the number of AgNORs between cells in the peripheral blood and bone marrow. Compared with normal granulopoiesis, myeloblasts in CML at diagnosis had lower numbers of clusters, which decreased further during relapse of chronic phase and in blast crisis. Promyelocytes and myelocytes showed significantly fewer dots. The number of AgNOR clusters correlates inversely with the duration of the cell cycle. Therefore, these findings are consistent with the progressive loss in proliferative activity of immature precursors described during the course of CML. As the number of dots indicates cellular maturation, their lower number in promyelocytes and myelocytes in CML favors the concept of a discordant maturation process described in this disease. The separate counting of clusters and dots provides a useful, simple, and cheap method of describing cytokinetic changes during the course of this myeloproliferative disorder.

Cell Differentiation↗
PubMed1992

Constitutive expression of IL-1 beta, M-CSF and c-fms during the myeloid blastic phase of chronic myelogenous leukaemia.

During the myeloid blast crisis (BC) of chronic myelogenous leukaemia (CML) non-random additional chromosome abnormalities occur in over 80% of patients. However, these cytogenetic changes have been reported to precede the clinical signs of CML-BC by several months to years suggesting that other biological events may participate in the multistep process of acute transformation of CML. The autocrine production of growth factors has been recently shown to occur in several haematological malignancies and particularly in acute myeloblastic leukaemia (AML). In the present report we demonstrate that IL-1 beta gene is expressed in almost all cases of CML in myeloid blast crisis. The secretion of IL-1 from CML blasts in culture supernatants was confirmed in all five of the patients we studied. A high proportion of cases showed constitutive expression of the M-CSF gene and many of the same patients often had a simultaneous co-expression of the proto-oncogene c-fms which encodes for the M-CSF receptor. After exposure of leukaemic cells to phorbol myristate acetate (PMA), release of M-CSF protein was documented in three of five patients studied. No significant interleukin-3 (IL-3), granulocyte-macrophage colony-stimulating factor (GM-CSF) or granulocyte colony-stimulating factor (G-CSF), was detected in these patients demonstrating that a different pattern of growth factors secretion exist in AML and CML, where distinct molecular events are likely involved in the control of leukaemic proliferation.

Adult↗
PubMed2003

Sudden onset of the blastic phase of chronic myelogenous leukemia: patterns and implications.

BACKGROUND: Therapeutic options in Philadelphia chromosome-positive chronic myelogenous leukemia (Ph-positive CML) in chronic phase include allogeneic stem cell transplantation (SCT) and treatments other than allogeneic SCT. The choice of therapy often depends on the mortality risk of allogeneic SCT. Delaying SCT until the disease demonstrates resistance to other strategies (e.g., imatinib mesylate or interferon-alpha) entails the risk of the development of a sudden blastic phase, which may not permit enough time to perform a SCT. METHODS: The current study was performed to define the incidence and patterns of sudden-onset blastic-phase CML in relation to the risk inherent in delaying allogeneic SCT. Of a study group of 1286 patients who were referred in early chronic-phase CML between 1981-2001 and who received therapies other than allogeneic SCT, 1093 patients had regular follow-up at the study institution. A sudden onset of blastic phase was defined as having its onset within 3 months from a previously documented complete hematologic response. RESULTS: Among the 1093 patients, 183 patients developed blastic-phase disease, which was of sudden onset in 46 patients (25%; 4% of the total). The incidence of sudden blastic phase was 0.4% in the first year, 1.8% in the second year, and 2.6% in the third year. Patients with sudden blastic-phase disease were found to have more often low-risk features at the time of presentation, including low incidences of blasts and thrombocytosis. Sudden blastic-phase CML was found to be associated with a higher incidence of lymphoid blastic morphology (67% vs. 22%; P < 0.0001), which resulted in a higher response rate to blastic-phase therapy (70% vs. 29%; P < 0.0001) and significantly longer survival from the onset of blastic-phase disease (median of 12 months vs. 6 months; P < 0.01). Twenty-four of the 42 patients with sudden blastic-phase disease who were treated at the M. D. Anderson Cancer Center were able to undergo allogeneic SCT in second chronic phrase (n = 13) or transformed phase (n = 11); at the time of last follow-up, 6 patients were alive without evidence of disease at a median of 18 months. CONCLUSIONS: The low rates of sudden blastic transformation in the first 3 years of the course of disease for CML and the salvage rate of these patients with allogeneic SCT should be considered in relation to the transplantation mortality in patients with early chronic-phase disease and the early promising results with imatinib mesylate therapy.

Adult↗
PubMed1991

Detection of BCR-ABL proteins in blood cells of benign phase chronic myelogenous leukemia patients.

More than 95% of patients with chronic myelogenous leukemia (CML) contain an abnormal chromosome termed the Philadelphia chromosome (Ph1). Ph1 and the resulting BCR-ABL fused genes are markers for this type of leukemia. The product of the fused BCR-ABL genes is a protein of about 2000 amino acids termed P210 BCR-ABL. Although the BCR-ABL protein can be routinely detected in blood cells from blast crisis CML patients by assaying for its activated tyrosine kinase activity, detection of P210 BCR-ABL in early stage CML patients (chronic phase) has not yet been possible (S. A. Maxwell et al., Cancer Res., 47: 1731, 1987). A procedure involving Western blotting with an anti-ABL monoclonal antibody was developed that allows detection of P210 BCR-ABL and P145 ABL in cells from chronic phase and blast crisis CML patients, but as expected only P145 ABL was found in normal white blood cells. Most chronic phase patients also contained one to two ABL proteins with a molecular weight of about 190,000. Interestingly, the ratio of BCR-ABL to ABL proteins increased in four blast crisis patients compared to 18 chronic phase patients. Also, one chronic phase patient analyzed on three separate occasions lacked P210 BCR-ABL and exhibited only the Mr 190,000 form. This assay should also be useful in other leukemias that express altered forms of the ABL protein.

Adult↗
PubMed2006

[Tyrosine kinase inhibitors in the therapy of chronic myeloid leukaemia].

Chronic myeloid leukemia (CML) is a malignant clonal disorder of hematopoietic stem cells resulting in increased myeloid and erythroid cells and platelets, and marked hyperplasia in the bone marrow. The natural history of CML is progression from a benign chronic phase, often through an accelerated phase, to a rapidly fatal blast crisis within 3-5 years. The constitutively activated ABL tyrosine kinase domain of the chimeric BCR-ABL oncoprotein is responsible for the transformation of hematopoietic stem cells and the symptoms of CML. Imatinib mesylate (Glivec), a specific small-molecule inhibitor of BCR-ABL, has become the standard drug therapy in all phases of the disease. Imatinib has greatly improved the outcome for patients with CML. Unfortunately, mutations causing resistance to imatinib are leading to relapse in some patients. Considerable progress has recently been made in understanding the structural biology of ABL and the molecular basis for resistance, facilitating the discovery and development of second- generation drugs designed to combat mutant forms of BCR-ABL. The first of these compounds to enter clinical development were dasatinib (BMS-354825) and AMN107 and, from phase I results, both of these promise a breakthrough in the treatment of imatinib-resistant CML.

Antineoplastic Agents↗
PubMed1999

ABL amplification in a patient with lymphoid blast crisis of chronic myelogenous leukaemia.

Although chronic phase myelogenous leukaemia (CML) is characterised by the Philadelphia (Ph) chromosome leading to a fusion of the BCR and ABL genes, additional genetic alterations involved in blast crisis are poorly understood. We report an at least 15-fold amplification of the ABL oncogene in a 29-year-old male patient with a variant Ph-positive t(19;22)(p13;q11.2) CML who presented in lymphoid blast crisis. Our finding suggests that an amplification of the ABL oncogene might play a part in the appearance of an aggressive phenotype in some cases of CML.

Adult↗
PubMed1981

Adenosine deaminase and ecto-5'-nucleotidase activities in various leukemias with special reference to blast crisis: significance of ecto-5'-nucleotidase in lymphoid blast crisis of chronic myeloid leukemia.

Adenosine deaminase (ADA) and ecto-5'-nucleotidase (5'-N) activities were examined in peripheral leukocytes from patients with leukemias, including nine patients with chronic myeloid leukemia (CML) in blast crisis. Four of none cases of CML in blast crisis were myeloid and the remaining lymphoid morphologically. The diagnosis of CML in lymphoid blast crisis was further contributed by the measurement of terminal deoxynucleotidyl transferase (TdT) activity. In all four cases of lymphoid blast crisis and one of myeloid blast crisis, leukemia cells had high 5'-N activity, while there was a little or no detectable activity in those from four cases of myeloid blast crisis and all of CML in chronic phase. ADA activity was high in seven of nine patients with blast crisis. Taken together, leukemia cells from two cases of lymphoid blast crisis had high ADA and 5'-N activities comparable to those in acute lymphocytic leukemia (ALL) cells. In contrast, the enzyme activities of leukemia cells from all but one patient in myeloid blast crisis were in a range similar to acute myeloid leukemia cells. The implications of these findings are as follows: (1) 5'-N may be used as a new biochemical marker of CML in lymphoid blast crisis. (2) Some lymphoid cells of CML in blast crisis have high ADA, 5'-N, and TdT activities and thus are very similar to ALL cells.

5'-Nucleotidase↗