Myeloid Blast Crisis Research Articles

Monosomy 7 in a girl with Ph 1 positive chronic granulocytic leukemia

A case is reported of an 11-year-old girl with Ph 1-positive chronic granulocytic leukemia. Very early in her illness the original 46,XX,t(9:22) cell population in the marrow became replaced by a second abnormal cell line, 45,XX,−7. This hypodiploid clone then remained dominant in the marrow until her death from myeloid blast crisis over 3 years later. It is suggested that the 45,XX,−7 cell line may have been induced by chemotherapy, and this possibility is discussed with particular reference to similar changes seen in secondary ANLL following treatment for lymphomas and other hematological malignancies.

A unique antigen expressed on myeloid cells and acute leukemia blast cells defined by a monoclonal antibody.

A murine hybridoma-derived monoclonal antibody, PM-81, was obtained from a fusion of cells of the NS-1 myeloma cell line with cells from a mouse immunized with the HL-60 promyelocytic leukemia cell line. This cytotoxic IgM monoclonal antibody was specific for myeloid cells. Employing indirect immunofluorescence and flow cytometry, we determined that this antibody reacts strongly with normal human granulocytes, eosinophils, and monocytes but not lymphocytes (including phytohemagglutinin-activated lymphocytes), null cells, red blood cells, or platelets. Moreover, the PM-81 antibody reacts with leukemia cells from 19 of 22 patients with acute myelocytic leukemia of all FAB subclasses, three of three patients with common acute lymphocytic leukemia, four of four patients with chronic myelocytic leukemia (CML) in myeloid blast crisis (terminal transferase (TdT)-negative) but did not react with cells from two patients with CML in lymphoid blast crisis (TdT-positive) or five patients with chronic lymphocytic leukemia. The myeloid cell lines HL-60, K562, KG-1, and U937 were all reactive with PM-81. The lymphoid lines CCRF-CEM and Daudi did not express PM-81 but HSB-2 was positive. The PM-81 antigen was absent on myeloid and erythroid progenitor cells as determined by their insusceptibility to complement-dependent lysis. In addition, only PM-81-unreactive cells were capable of colony formation. Furthermore, the PM-81 antibody does not appear to induce modulation of the antigen to which it binds. Thus, this monoclonal antibody appears to fulfill several criteria for clinical utility in the diagnosis and treatment of both acute myelocytic and acute lymphocytic leukemia.

Monoclonal antiglycophorin as a probe for erythroleukemias

A monoclonal antibody (LICR.LON.R10) specific for the major sialoglycoprotein of the erythroid cell membrane, glycophorin A (alpha), has been used to test the possibility that “cryptic” erythroleukemia may be diagnosed as acute lymphoblastic leukemia (ALL) or acute myeloblastic leukemia (AML). In addition to 27 overt erythroleukemias, 724 leukemias, including 329 ALL (103 in relapse), 205 AML, and 109 blast crises of Ph1-positive chronic myeloid leukemia, were analyzed. Twenty cases with a significant proportion of glycophorin-A-positive (gA+) cells were found; 8 of these (5 AML and 3 blast crises of chronic myeloid leukemia, CML) had an obvious erythroid component, but 12 others were diagnosed as AML (2), AMML (1), CML in myeloid blast crisis (4) or megakaryoblastic blast crisis (1), acute megakaryoblastic leukemia (2), or acute lymphoblastic leukemia (2). The latter two patients had no immunologic evidence supporting a diagnosis of ALL and were resistant to chemotherapy. We conclude that AML and ALL only very rarely express gA, and these are probably genuine “cryptic” erythroleukemias. Other gA+ leukemias (megakaryoblastic and CML blast crises) may arise from bi- or pluripotent stem cells and contain distinct and separable blast cell populations.

Monoclonal Antiglycophorin as a Probe for Erythroleukemias

A monoclonal antibody (LICR.LON.R10) specific for the major sialoglycoprotein of the erythroid cell membrane, glycophorin A (alpha), has been used to test the possibility that "cryptic" erythroleukemia may be diagnosed as acute lymphoblastic leukemia (ALL) or acute myeloblastic leukemia (AML). In addition to 27 overt erythroleukemias, 724 leukemias, including 329 ALL (103 in relapse), 205 AML, and 109 blast crises of Ph1-positive chronic myeloid leukemia, were analyzed. Twenty cases with a significant proportion of glycophorin-A-positive (gA+) cells were found; 8 of these (5 AML and 3 blast crises of chronic myeloid leukemia, CML) had an obvious erythroid component, but 12 others were diagnosed as AML (2), AMML (1), CML in myeloid blast crisis (4) or megakaryoblastic blast crisis (1), acute megakaryoblastic leukemia (2), or acute lymphoblastic leukemia (2). The latter two patients had no immunologic evidence supporting a diagnosis of ALL and were resistant to chemotherapy. We conclude that AML and ALL only very rarely express gA, and these are probably genuine "cryptic" erythroleukemias. Other gA+ leukemias (megakaryoblastic and CML blast crises) may arise from bi- or pluripotent stem cells and contain distinct and separable blast cell populations.

The Expression of Myeloid-Specific Antigens on Myeloid Leukemia Cells: Correlations With Leukemia Subclasses and Implications for Normal Myeloid Differentiation

The expression of three distinct myeloid-specific cell surface antigens detected by monoclonal antibodies (PMN 6, PMN 29, and AML-2-23) on acute and chronic myeloid leukemia cells is correlated with blast cell morphology and normal myeloid cell antigen display. In studies on normal peripheral blood cells, monoclonal antibodies PMN 6 and PMN 29 have previously been shown to react exclusively with neutrophils while AML-2-23 reacts with both neutrophils and monocytes. The present report demonstrates that these antigens are absent from blast cells of patients with acute myelocytic leukemia (AML) classified as M1 and M2 in the French-American-British system and chronic myelocytic leukemia in myeloid blast crisis. However, leukemia cells with myelomonocytic morphology (M4) expressed all three antigens, while cells with pure monocytic features (M5) were generally only positive for AML-2-23. Based on the absence of these antigens on both leukemic and normal myeloblasts and granulocyte-monocyte progenitors and their characteristic patterns of display on more differentiated leukemic and normal cells, we propose a modified concept of normal myelopoiesis. In this hypothesis, the myeloblast is an uncommitted cell that gives rise to a series of intermediate precursors that acquire committment to either the granulocytic or monocytic lineage marked by the acquisition of specific cell surface markers.

The expression of myeloid-specific antigens on myeloid leukemia cells: correlations with leukemia subclasses and implications for normal myeloid differentiation

The expression of three distinct myeloid-specific cell surface antigens detected by monoclonal antibodies (PMN 6, PMN 29, and AML-2–23) on acute and chronic myeloid leukemia cells is correlated with blast cell morphology and normal myeloid cell antigen display. In studies on normal peripheral blood cells, monoclonal antibodies PMN 6 and PMN 29 have previously been shown to react exclusively with neutrophils while AML-2–23 reacts with both neutrophils and monocytes. The present report demonstrates that these antigens are absent from blast cells of patients with acute myelocytic leukemia (AML) classified as M1 and M2 in the French-American-British system and chronic myelocytic leukemia in myeloid blast crisis. However, leukemia cells with myelomonocytic morphology (M4) expressed all three antigens, while cells with pure monocytic features (M5) were generally only positive for AML-2–23. Based on the absence of these antigens on both leukemic and normal myeloblasts and granulocyte-monocyte progenitors and their characteristic patterns of display on more differentiated leukemic and normal cells, we propose a modified concept of normal myelopoiesis. In this hypothesis, the myeloblast is an uncommitted cell that gives rise to a series of intermediate precursors that acquire committment to either the granulocytic or monocytic lineage marked by the acquisition of specific cell surface markers.

Differentiation patterns in the blastic phase of chronic myeloid leukemia

The surface antigen phenotype of 30 patients with the blast phase of chronic myeloid leukemia (CML) was determined using a panel of monoclonal antibodies recognizing differentiation antigens of normal myeloid, erythroid, megakaryocyte, and lymphoid cells. Ten patients' cells expressed a phenotype corresponding to an immature myeloid cell and were felt to have "myeloid" blast crisis. None of these myeloid leukemias were TdT+ or responded to vincristine (V) and prednisone (P). Eleven patients expressed a phenotype similar to acute lymphoblastic leukemia cells and probably reflect maturation to an early B lymphocyte. All of these "lymphoid" leukemias were TdT+, and 67% of evaluable patients had a complete response to V and P. One leukemia had the phenotype of an erythroleukemia, one patient's cells expressed the phenotype of megakaryoblastic leukemia, and one leukemia had populations of both myeloid and lymphoid blasts. Six leukemias did not express surface markers characteristic of any lineage and were termed "undifferentiated." This group was heterogeneous with respect to TdT expression, but no patient had a complete response to V and P. Determination of surface antigen phenotype in CML blast crisis thus provides clinically useful information for the structuring of treatment protocols.

Diagnostic information derived from immunotyping 1000 patients with leukemia and lymphoma

Immunotyping analysis has been performed on cells from 1000 patients with leukemia or lymphoma using 14 markers of cell lineage or differentiation stage over a 4 yr period. Results showed considerable heterogeneity of cell type among these groups of malignant diseases not readily apparent by morphology and histochemistry. Immunotyping contributed additional diagnostic information in 30% of patients and should be a routine procedure in 8 disease categories. These are: acute leukemia, cell type not determined; acute lymphoblastic leukemia; lymphocytosis of undetermined origin; chronic myeloid leukemia-terminal blast crisis; chronic lymphocytic leukemia; malignant lymphoma-leukemic phase; Sézary syndrome, mycosis fungoides and chronic T cell leukemia; malignant lymphoma and lymphadenopathy- ? lymphoma. Immunotyping provided information on cell lineage and differentiation stage of major leukemic cell populations. Abnormal monoclonal proliferations of B lymphocytes and the presence of primitive cells amongst normally mature tissue cells were identified. Disturbances in normal lymphoid and monocytic cell populations in blood, marrow or tissues could also be demonstrated. Many of the reagents used in this period are now replaced by monoclonal antibody reagents to human lineage and differentiation antigens. These are expected to increase diagnostic usefulness of these techniques.

Variant Ph 1 translocations in CML and their incidence, including two cases with sequential lymphoid and myeloid crises

A serial cytogenetic study of 110 cases of chronic myelogenous leukemia (CML) has been performed with G- and/or Q-banding techniques with the following results. (1) Seven out of the 110 cases were karyotypically normal. (2) A variant Ph 1 translocation was observed in three cases. In one case, the leukemic cells contained two reciprocal translocations, i.e., a t(3;9) (q21;q34) and a t(17;22)(q21;q11); therefore, a Ph 1 chromosome was masked by a translocation of the deleted material from the 17q onto the band q11 of the long arm of a chromosome No. 22. In the second case, a variant Ph 1 translocation involved chromosomes No. 9, 20, and 22, resulting in a karyotype interpreted as 46,XX,t(9q+;20q+;22q−); in this rearrangement, one of the segments, i.e., 9q31 or 9q33, seemed to be interstitially deleted and inserted into the interstitial region (q11) of a chromosome No. 20 and the 22q11→qter was translocated onto the 9q. This is the first case in which chromosome No. 20 was involved in a variant Ph 1 translocation. In the third case, the karyotype of leukemic cells was interpreted as 46,XY,t(5;9;22)(q13;q34;q11). (3) The frequency of Ph 1-negative CML and that of Ph 1-positive CML with various types of Ph 1 translocation from 15 studies reported as series of 25 or more cases, including the present study, have been tabulated. The incidence of a variant Ph 1 translocation was 4.1% (42/1027 cases of Ph 1-positive CML); of the 42, 13 were of a simple type and 29 of a complex type. (4) In one case of the present study, a masked Ph 1 by a translocation of material onto the short arm of the 22q− was observed in the blastic crisis but not in the chronic phase. From the present study and a review of the published cases, it appears that the incidence of such a “masked” Ph 1, which cannot be detected by conventional Giemsa staining, is less than 0.6% in CML cases. (5) The first and the second cases with a variant Ph 1 translocation mentioned above developed a myeloid blastic crisis after the induction of remission of a lymphoid blastic crisis. For the present, it is unclear whether the occurrence of such blast cells in the two cases and the cytogenetic findings are coincidental. However, the evidence supports the notion of “lymphoid-myeloid” multipotentiality of certain leukemic cells.

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.

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.

High levels of 5′-nucleotidase activity in blastic chronic myelogenous leukemia with common all-antigen

The activity of 5′-nucleotidase (5′-N) on the surface of leukemia cells was determined in 44 patients with blast crisis of chronic myelogenous leukemia (CML) and in 52 patients with acute myeloblastic (AML) or acute lymphoblastic (ALL) leukemia. The phenotype of blast cells was classified according to immunological surface markers, including the common ALL-antigen (cALLA). High 5′-N activities were found in the presence of cALLA, whereas low to undetectable levels were characteristic for cALLA-negative leukemias, the difference being highly significant ( p ≦ 0.0001). While there was a certain overlap of 5′-N levels between cALLA-positive ALL and cALLA-negative AML, no overlap of 5′-N was observed between cALLA-positive lymphoid and cALLA-negative myeloid blast crisis of CML. Thus, 5′-N affords an additional easily-testable biochemical marker that may have its diagnostic and prognostic value especially in the case of blastic chronic myelogenous leukemia.

N‐Alkaline Phosphatase: a Potential Disease Marker for Lymphoproliferative Disorders

A characteristic alkaline phosphatase (orthophosphoric monoester hydrolase, alkaline pH optimum, EC 3.1.3.1) was detected in the sera of most patients with infectious mononucleosis, acute and chronic lymphatic leukaemia, non-Hodgkin's lymphoma, Burkitt's lymphoma and nasopharyngeal carcinoma. The enzyme was also present in the sera of nine out of 26 patients with cancer of the cervix. N-APase in these cases counted 30-100% of the total alkaline phosphatase activity. N-APase was absent from the sera of healthy individuals and of patients with acute and chronic granulocytic leukaemia, breast cancer, colon cancer, rheumatoid arthritis, ulcerative colitis, systemic lupus erythematosis, hepatitis and obstructive jaundice. Only three of 22 patients with Hodgkin's disease showed n-apase activity in the serum. In infectious mononucleosis the presence of N-APase activity was well correlated with the clinical course. In 13 cases studied, the clinical improvement was associated with the decrease or disappearance of N-APase activity. N-APase activity could not be detected in white cells of acute myeloid leukaemic patients, nor in the cells of myeloid blastic crisis of chronic granulocytic leukaemia. It was present in the cells of lymphoid blastic crisis of chronic granulocytic leukaemia.

Characterization of a Xenoantiserum Produced Against Three Molar KCl-Solubilized Antigens Obtained from a Non-T, Non-B (Pre-B) Acute Lymphoblastic Leukemia Cell Line

Abstract Antisera were produced in rabbits to 3 M KCl solubilized antigens of a recently established leukemia cell line. The cell line (NALM-6-M1) was established from an individual with acute lymphoblastic leukemia (ALL), and has the characteristics of a pre-B cell, i.e., it is cytoplasmic IgM+, surface immunoglobulin-, anti-thymocyte serum- (CIgM+, SIg-, ATS-). One unabsorbed antiserum did not react with T cells, and after a single absorption with a B lymphoblastoid cell line (positive for p23,30, an Ia-like antigen), the antiserum reacted with cells from eight of 10 patients with non-T, non-B ALL and cells from two of two patients with chronic myelogenous leukemia in lymphoid blast crisis (CML-LBC). The absorbed antiserum did not react with surface immunoglobulin+ chronic lymphocytic leukemia (SIg+ CLL) cells; acute myelogenous leukemia (AML) cells; anti-thymocyte serum+, E rosette+, acute lymphoblastic leukemia (ATS+, E+ ALL) cells; cells from patients with chronic myelogenous leukemia in myeloid blast crisis (CML-MBC); normal peripheral blood T cells; PHA-induced blasts; leukemia T cell lines; or B lymphoblastoid cell lines. The specificity of the absorbed antiserum suggests that it was detecting antigens of non-T, non-B ALL and CML-LBC, and may be recognizing a “common” ALL antigen. We conclude that 3 M KCl solubilization of membrane antigens from the NALM-6-M1 leukemia cell line provides an effective immunogen for producing antisera reactive with non-T, non-B ALL and CML-LBC. This offers an approach to the biochemical characterization of the antigen(s) common to these two leukemias and allows further evaluation of the relationship between the common ALL antigen and antigens of normal and malignant cells of the pre-B phenotype.

New cancer chemotherapy drugs in Europe

In this short review attention is drawn to promising new drugs and to promising new information on old drugs. The information may concern clinical results or pertain to preclinical data. The selection of drugs is arbitrary and no claim of completeness of listing is made. Hormones have not been considered. for which chemotherapy is poor today, such as neuroblastoma, uterus cervix cancer, larynx tumours, and chronic myeloid leukaemia blastic crisis. De Barbieri et al. (1977) are developing a large series of di-(2-chloroethyl) glycopeptides, some of which give promising resuits on sarcoma 180 and L1210 leukaemia.

Differentiation linked expression of p28,33 (Ia-like) structures on human leukaemic cells.

Summary. A differentiation linked expression of ‘Ia‐like’ (B cell associated) structures was detected by heterologous antisera against p28,33 antigen on human leukaemic cells in immunofluorescence test. A double fluorochrome immunofluorescence test was used to distinguish Ia+ (p28,33, +) leukaemic cells from B lymphocytes. Leukaemic cells with varying intensities of anti‐p28,33 staining were separated using the Fluorescence Activated Cell Sorter. The results indicate that p28,33 is very strongly expressed on undifferentiated blast cells from Philadelphia chromosome (Ph1) positive ‘lymphoid’ blast crisis and non‐T,non‐B acute lymphoid leukaemia. In Ph1 positive myeloid blast crisis and in acute myeloid leukaemia the p28,33 antigen was only moderately strongly expressed on myeloblasts and virtually absent on promyelocytes. The p28,33 antigen was also absent on the relatively more mature cells during the chronic phase of chronic myeloid leukaemia. Non‐leukaemic samples such as bone marrow samples from fetus, and from patients with severe megaloblastic anaemia or myeloid hyperplasia (due to hypersplenism in Felty syndrome) were also found to contain p28,33 positive (and membrane immunoglobulin negative) immature blast cells.On the basis of these observations the hypothesis is proposed that ‘Ia‐like’ antigens on leukaemic cells reflect the origin of these leukaemias from haemopoietic stem cells which are themselves Ia positive. The corollary of this view is that ‘Ia‐like’ membrane structures may play an important role not only in immunological responses of B cell, but also in the regulation of early haemopoietic cell differentiation.

Adenosine deaminase activity in leukaemia.

Adenosine deaminase (EC 3.5.4.4., ADA) has been measured in the blast cells of 36 patients with acute lymphoblastic, acute myeloid, chronic myeloid and chronic myeloid blast crisis leukaemia. Particularly high levels were found in acute lymphoblastic and chronic myeloid blast crisis patients. The measurement of ADA may be useful diagnostically in the undifferentiated acute leukaemias and in detecting the early onset of blast crisis in chronic myeloid leukaemia. Possible reasons for the elevation of ADA in malignant cells are discussed.