Prognostic subgroups in B-cell chronic lymphocytic leukemia defined by specific chromosomal abnormalities.

BACKGROUND AND METHODS: Specific chromosomal abnormalities have been shown to affect the overall survival of patients with acute leukemia, but the possibility that specific chromosomal defects may influence the course of B-cell chronic lymphocytic leukemia (CLL) is controversial. We assessed this possibility as follows: blood mononuclear cells from 433 patients with B-cell CLL in five European centers were cultured with B-cell mitogens, and banded metaphases were studied. RESULTS: Three hundred ninety-one patients could be evaluated cytogenetically, and 218 had clonal chromosomal changes. The most common abnormalities were trisomy 12 (n = 67) and structural abnormalities of chromosome 13 (n = 51; most involving the site of the retinoblastoma gene) and of chromosome 14 (n = 41). Patients with a normal karyotype had a median overall survival of more than 15 years, in contrast to 7.7 years for patients with clonal changes. Patients with single abnormalities (n = 113) did better than those with complex karyotypes (P less than 0.001). Patients with abnormalities involving chromosome 14q had poorer survival than those with aberrations of chromosome 13q (P less than 0.05). Among patients with single abnormalities, those with trisomy 12 alone had poorer survival than patients with single aberrations of chromosome 13q (P = 0.01); the latter had the same survival as those with a normal karyotype. A high percentage of cells in metaphase with chromosomal abnormalities, indicating highly proliferative leukemic cells, was associated with poor survival (P less than 0.001). Cox proportional-hazards analysis identified age, sex, the percentage of cells in metaphase with chromosomal abnormalities, and the clinical stage of the disease (Binet classification system) as independent prognostic variables. CONCLUSIONS: Chromosomal analysis provides prognostic information about overall survival in addition to that supplied by clinical data in patients with B-cell CLL.

Distribution of a set of idiotopes detected by a monoclonal antibody panel in 42 cases of chronic lymphocytic leukaemia: definition of potential targets for immunotherapy.

Using a panel of 14 monoclonal V region reactive antibodies generated against a single IgG1 lambda paraprotein we have identified shared idiotopes in a group of 42 patients with chronic lymphocytic leukaemia (CLL). The specificity of cellular staining by indirect immunoperoxidase was confirmed in the majority of cases by an ELISA assay using secreted idiotypic immunoglobulin. In a few cases weak cellular binding by the panel antibodies could not be confirmed as specific for immunoglobulin. Four monoclonal antibodies specific for lambda chain determinants reacted with 5-29% of lambda expressing CLLs but the significance of this is uncertain as the antibodies may be recognizing one of the commoner V lambda subgroups. Two antibodies, which are only weakly reactive with normal serum immunoglobulin, detected heavy chain associated idiotopes which were expressed by 7% and 14% of CLL cases. One of these antibodies detects an idiotope which was expressed significantly more frequently by CLL associated immunoglobulin than by a panel of paraproteins. Such preferentially expressed idiotopes may be useful in investigating the biology of this disorder as well as providing attractive targets for immunotherapy.

Prostatic infiltration in chronic lymphatic leukaemia.

Forty six men with chronic lymphatic leukaemia (CLL) were studied for up to seven years. Six patients required surgery for prostatic outlet obstruction. Histological examination of the prostatic chippings showed variable degrees of infiltration with small mature lymphocytes in all six patients, suggestive of a leukaemic origin for the cells. Patients with chronic lymphatic leukaemia who undergo prostatectomy may have a higher incidence of leukaemic infiltration than has been previously recognised.

Clonal chromosome abnormalities in chronic lymphocytic leukemia patients revealed by TPA stimulation of whole blood cultures.

Cells from 52 patients with chronic lymphocytic leukemia and two patients with prolymphocytic leukemia were stimulated in whole blood or bone marrow culture with the polyclonal B-cell mitogen tetradecanoyl phorbol acetate (TPA). Stimulation was successful in 50 of the 54 cases. Comparison with Epstein-Barr virus and pokeweed mitogen showed them to be much less successful mitogens under the conditions used. Twenty-one patients (39%) were found to have clonal abnormalities that were probably disease-related. The most common abnormality was trisomy 12 (five patients). Four patients had a deletion of the long arm of chromosome #11 and one patient had a t(11;14). Five patients had abnormalities of the long arm of chromosome #13, with four probably having breaks in band q14. Two patients were seen with trisomy 3 as the only abnormality. Overall, the results were similar to those of other groups, which shows that considerable karyotypic information can be obtained from the use of a single mitogen on a large series of chronic lymphocytic leukemia patients.

Pyoderma gangrenosum and myelodysplasia.

Pyoderma gangrenosum has been recognized occurring in association with acute and chronic leukaemia. More recently it has been described in patients with myelodysplasia (Jacobs, Palmer & Gordon-Smith 1985). We report a case of pyoderma gangrenosum in a patient with a preceding history of myelodysplasia, illustrating the problem of controlling the skin disease in this condition and the eventual transformation of the myelodysplasia into acute leukaemia. Treatment of the leukaemia resulted in improvement of the skin lesions.

The incidence, clonal origin and secretory nature of serum paraproteins in chronic lymphocytic leukaemia.

Immuno-isoelectric focusing (IIEF) showed a 61% incidence of serum paraproteinaemia in 56 patients with chronic lymphocytic leukaemia (CLL). A strong correlation between the serum paraprotein heavy chain isotypes and those of the cytoplasmic heavy chain immunoglobulins was observed with no discrepancy noted in light chain expression. Density gradient ultracentrifugation analysis of selected sera containing monoclonal IgM showed that the IgM paraproteins were mostly 19S, secretory IgM but one patient was found to have both 19S and 8S monoclonal IgM. When the cellular origin of the IgM and IgD paraproteins found in one patient was investigated, both paraproteins were found to share the same idiotype and originate from the neoplastic clone. These findings confirm the view that there is an incomplete maturation block in chronic lymphocytic leukaemia and that in vivo secretion of paraproteins by the neoplastic cells is a relatively common occurrence.

Hypersensitivity to carbamazepine presenting as pseudolymphoma.

An unusually severe hypersensitivity reaction to carbamazepine is described, in which the patient presented with lymphadenopathy, hepatosplenomegaly, bone marrow suppression, immunosuppression and other features strongly suggestive of a lymphoma.

Surface glycoproteins as markers of the cellular status of B chronic lymphocytic leukaemia lymphocytes.

The phenotype of B CLL cells is investigated with respect to their surface glycoproteins. These glycoproteins are identified by vectorial tritiation followed by 1 and 2 dimensional gel electrophoresis, and by lectin and MoAb binding using immunoprecipitation and flow cytometry. The profiles of the CLL cells are compared with those of normal B cells, prepared from tonsils, and T cells from peripheral blood. The CLL cells show many similarities with T cells, particularly the expression of glycoproteins which bind the MoAbs gpL 115, F10-44-2 and EZB 52, and a complex set of binding sites for Helix pomatia lectin. The significance of these observations in terms of the cellular origins of the leukaemic lymphocytes is discussed.

Abnormalities in the expression of the leucocyte-common antigen in chronic lymphocytic leukaemia.

The surface glycoproteins of lymphocytes isolated from patients suffering from B cell chronic lymphocytic leukaemia (B-CLL) have been studied by radioactive labelling with impermeable probes and with MoAb. Several features not found in normal B cells have been observed. The abnormalities found in the expression of polypeptides of the leucocyte common (L-C) antigen, identified by appropriate MoAb, have been examined in detail. It has been shown by both biochemical analysis and MoAb binding that this group of polypeptides can, within a panel of B-CLL patients, range from a typical B cell pattern to the pattern resembling that normally found in T cells. The T lymphocyte profile is correlated with a poor prognosis (MVA C rating) and in the one patient where a change in the glycoprotein profile towards that of the T cell was observed, the change coincided with a clinical deterioration. The biological significance of the molecular diversity is discussed.

Histocompatibility antigen frequencies in patients with chronic lymphocytic leukaemia: possible identification of a subgroup with relatively benign disease.

A series of 57 patients with chronic lymphocytic leukaemia was typed for HLA-A, B and DR antigens and compared with a control population of equal size. There was an increased frequency of HLA-A1 and B8 in the patient group, although it was not statistically significant after allowance for the number of specificities tested. A subgroup of patients lacking both A1 and B8 differed from the others in sex ratio, degree of lymphocytosis and incidence of hypogammaglobulinaemia at presentation. This subgroup also had less need for treatment within 6 months of presentation. While these findings must be considered preliminary, it is possible that tissue typing may help to identify patients with a relatively benign form of the disease.

Hodgkin's disease presenting as idiopathic thrombocytopenic purpura.

A case of Hodgkin's disease presenting as idiopathic thrombocytopenic purpura in a 23-year-old male is reported. This is a rare presentation of Hodgkin's disease having been previously described in only two cases.

Cell marker studies in patients with newly diagnosed chronic lymphatic leukaemia.

Cell marker analysis including mouse red cell rosetting ability was carried out on 24 newly diagnosed patients with chronic lymphatic leukaemia. Using a technique not employing neuraminidase a significant difference in mouse red cell rosetting ability was noted between male and female patients. It is well accepted that females often have a milder form of disease and better longterm survival than it is suggested this might be a reflection of the difference found in mouse red cell rosetting ability between the sexes in this condition.

Thymic hypoplasia, auto-immune haemolytic anaemia and juvenile pemphigoid in an infant.

A female infant developed auto-immune haemolytic anaemia and juvenile pemphigoid, and died at the age of 10 months. Autopsy showed evidence of thymic hypoplasia and T lymphocyte deficiency. It was concluded that the two rare auto-immune diseases occurring in this child probably resulted from a lack of T cell regulation of antibody-producing B lymphocytes.

Double-blind trial of aspirin in patient receiving tranexamic acid for subarachnoid hemorrhage.

Antifibrinolytic agents have been claimed to reduce the rebleed rate in patients with subarachnoid haemorrhage from intracranial aneurysms. However, these agents may in themselves increase the incidence of delayed cerebral ischaemia in these patients. We have used aspirin in an attempt to reduce the incidence of this complication. In a prospective, double-blind trial of aspirin against placebo, 53 patients with subarachnoid haemorrhage were all treated with the antifibrinolytic agent tranexamic acid. Twenty-seven patients received aspirin and 26 patients received placebo. The morbidity and mortality was similar in each group. A further breakdown into patients who had their aneurysms clipped at craniotomy (21 patients) similarly failed to show a more favourable outcome in either group. It is concluded that aspirin does not affect the outcome in patients with subarachnoid haemorrhage treated with tranexamic acid.

Eosinophilic leukaemia in association with a double Philadelphia chromosome.

A case of eosinophilic leukaemia in association with chromosomal abnormalities including a double Philadelphia chromosome is reported. Comment is also made on the cardiological problems which arise in this condition.

Familial pseudohyperkalaemia. A new syndrome.

Inherited pseudohyperkalaemia due to an abnormal red-blood-cell potassium leak was discovered in 16 of 28 relatives of a woman with pseudohyperkalaemia. Autosomal dominance seemed to account for inheritance of this abnormality. Affected subjects were not anaemic and had normal in-vivo plasma-potassium concentrations.