Leukemia In Blastic Phase Research Articles

Differential expression of CD54/intercellular adhesion molecule-1 in myeloid leukemias and in lymphoproliferative disorders

Indirect immunofluorescence staining with monoclonal antibody (MoAb) CL203.4 of malignant cells from 269 patients with hematologic malignancies showed a heterogeneous expression of CD54/intercellular adhesion molecule-1 (ICAM-1). This marker was expressed by malignant cells of 57 out of 118 patients with myeloid malignancies and 69 out of 135 with B-lymphoid malignancies. On the other hand, CD54 was not detected on malignant cells of 16 patients with T-lymphoid malignancies. In myeloid malignancies, CD54 is preferentially expressed by “stem cell-derived” malignancies, being detectable on blast cells from almost all patients affected by chronic myelogenous leukemia in blast phase or myelodysplastic syndromes and by only 34% of patients with de novo acute myeloid leukemia (AML). The expression of CD54 did not correlate with any specific myeloid FAB subtype, although three cases of highly undifferentiated AML (FAB MO) displayed maximal levels of the antigen. The expression of CD54 in AML was significantly associated with that of CD34 and HLA-DR antigens. In B-lymphoid malignancies, CD54 expression appears to correlate with the differentiation stage of malignant cells, since B-origin acute lymphoblastic leukemias and conventional B-chronic lymphocytic leukemias (B-CLL; ie, “dim SIg” CLL) expressed lower levels of CD54 than more mature lymphoproliferative disorders (“bright SIg” CLL, prolymphocytic leukemias, and lymphoplasmacytic tumors). “High-grade” B- cell non-Hodgkin‧s lymphomas (B-NHL) express in general a higher level of CD54 than “low-grade” ones. This finding in conjunction with the expression of CD54 in all 17 patients with “bright SIg” CLL investigated (characterized by marked organomegaly and poor prognosis) suggest that the differential expression of CD54 in lymphoproliferative disorders may also relate to their degree of malignancy.

Continuous infusion mitoxantrone in relapsed acute nonlymphocytic leukemia

Mitoxantrone is a substituted anthraquinone with considerable activity against human acute leukemia. The authors' goal was to treat patients with continuous infusion mitoxantrone in order to maintain cytotoxic steady state levels with acceptable toxicity and to assess the results. Daily mitoxantrone levels showed a mean steady state plasma level of 16.8 +/- 1.4 ng/ml (range, 9.1-25.1) with a systemic clearance of 519 +/- 47 ml/minute/m2. No drug accumulation occurred. Mitoxantrone was undetectable 24 hours postinfusion. All patients, including two patients with chronic myelogenous leukemia in blast phase, had greater than 90% reduction in leukemia cell mass (marrow cellularity X percent leukemia cells) by day 6. However, six patients received 3 days of etoposide at that point because of residual acute nonlymphocytic leukemia (ANLL). Overall four patients (36%) had a complete remission; one additional patient had a bone marrow remission but also had a persistent granulocytic sarcoma. Toxicities included severe but tolerable myelosuppression, mucositis, and hepatic dysfunction. There was no correlation between mitoxantrone levels, toxicity, or clinical response. Continuous infusion produces cytotoxic plasma mitoxantrone levels and rapid clearing of ANLL from bone marrow. Further dose escalation may be possible.

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.

Occurrence of the Common Acute Lymphoblastic Leukemia Antigen on Blast Cells of a Patient with Chronic Myelomonocytic Leukemia in Non-Lymphoid Blastic Phase

Abstract 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.

Coexistence of cells with unmasked and masked Ph 1 in a case of chronic myeloid leukemia in blastic phase

Bone marrow from a patient with chronic myeloid leukemia in blastic phase at diagnosis showed cells with t(9;22), as well as others with a 22q+ marker. The marker was due to t(8;22), and consequently, these cells presented a masked Ph 1: t(8;9;22) (q24.2;q34;q11). The marrow contained a wide variety of abnormal clones, which formed an evolutionary pedigree. The pedigree allowed location of the stage of evolution at which masking of the Ph 1 had taken place.

Lonidamine in the treatment of chronic lymphoid leukemia.

Blood and/or bone marrow cells from patients with hematological malignancies, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia in blastic phase, acute lymphoid leukemia, acute myeloid leukemia, prolymphocytic leukemia, multiple myeloma and myelofibrosis, were incubated with Lonidamine at different concentrations (50, 100 and 160 micrograms/ml) for 1-2 h. B lymphocytes of CLL had the highest sensitivity to the drug: a decrease of more than 30% in the viable nucleated cells was recorded in 8 out of 10 experiments. Subsequent in vivo studies were performed to investigate the effectiveness of Lonidamine in the treatment of CLL. The drug was administered orally for a period of 7 days to 19 selected patients, both previously treated and untreated, in different stages of the disease. Only 5 patients responded: 2 of them had a significant decrease (greater than 30%) in the lymphocyte count, and the remaining 3 showed an appreciable reduction of the spleen (1 case) and of the lymph node size (2 cases). Generalized myalgia was the most common side effect induced by Lonidamine.

Enrichment of cell populations containing terminal deoxynucleotidyl transferase activity by free flow electrophoresis.

Terminal deoxynucleotidyl transferase (TdT) is an enzyme that has been utilized as a biochemical marker for following certain leukemia patients during treatment and remission. The potential usefulness of this enzyme in predicting the onset of relapse before any morphological indications has been demonstrated in chronic myelogenous leukemia patients in blast phase of the disease. In order to be able to detect low levels of TdT activity, especially during remission phase, we have used the technique of free flow electrophoresis to enrich cell populations containing TdT. With this technique we have achieved up to 20-fold enrichment of TdT-positive cell populations from normal human bone marrow, cells from patients with acute lymphoblastic leukemia and chronic myelogenous leukemia in blast phase of the disease. TdT positive cells were not detected in patients with acute myelogenous leukemia and B cell lines. This technique should prove to be useful in early detection of relapse in patients in remission and for enrichment of cell populations containing other biochemical markers.

Enrichment of terminal deoxynucleotidyl transferase activity by cell separation.

Terminal deoxynucleotidyl transferase is a unique DNA polymerase that can carry out DNA synthesis on an initiator molecule in the absence of a template. The usefulness of this enzyme as a biological marker for following patients during treatment and remission has been suggested. The potential usefulness of this enzyme in predicting the onset of relapse before any morphological indications has been demonstrated in chronic myelogenous leukemia patients in blast phase of the disease. In order to be able to detect low levels of TdT activity especially during remission phase, we have used cell separation techniques which can enrich cell populations containing TdT activity. A number of cell separation techniques have been developed to separate different cell types. We have used the techniques of unit gravity sedimentation and free flow electrophoresis to achieve enrichment of TdT positive cell populations. Our results show that up to 20 fold enrichment of TdT activity in normal human bone marrow can be accomplished by using cell separation techniques. With the use of free flow electrophoresis, we have achieved enrichment of TdT positive cell populations from normal human bone marrow, cells from patients with acute lymphoblastic leukemia and chronic myelogenous leukemia in blast phase of the disease. No TdT positive cells were detected in patients with acute myelogenous leukemia. These cell separation techniques should prove to be useful in early detection of relapse in patients in remission.

Different cell clones in bone marrow and spleen of a patient with chronic myelocytic leukemia (CML) in blastic phase

The chromosome study of a patient with chronic myelocytic leukemia in blastic phase revealed a 46,XY,Ph1/47,XY,Ph1,+8 cytogenetic constitution in bone marrow cells and a 46,XY,Ph1/48,XY,2Ph1,+19 cytogenetic constitution in spleen cells. As the cell clones exhibiting chromosome abnormalities in addition to the Ph1 chromosome evolved apparently independently, it is suggested that the acute transformation had a bifocal, myeloid and splenic origin.

Antiserum Against Leukemia Cell Ferritin as a Diagnostic Tool for Malignant Neoplasms2

The specific antiserum against a type of ferritin that is especially common to leukemia cells and the placenta was used to test, by countercurrent immunoelectrophoresis, sera from humans with various diseases. The best results were obtained with leukemia; patients with chronic myelogenous leukemia in blastic phase, acute myelogenous leukemia, lymphogenous leukemia, and unclassifiable juvenile leukemia frequently showed a positive reaction, but patients with chronic myelogenous leukemia in static phase did not. The average incidence of positive reaction among all leukemia patients was 54.0%. Patients with other malignant tumors (i.e., multiple myeloma, malignant lymphoma and carcinomas of the stomach, rectum, and liver) also often showed a positive reaction. The average incidence of positive reaction among all the patients with malignant diseases of the hematopoietic system, except for leukemia, was 34.3%, and that among patients with nonhematologic malignant neoplasms was 36.8%. However, the incidence of a positive reaction in patients with benign diseases and healthy individuals was less than 3%.