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PubMed1986

Lymphokine induction of NK-like cytotoxicity in T cells from B-CLL.

T cells from patients with B cell chronic lymphocytic leukemia (B-CLL) exhibit defective natural killer (NK) activity. In this study, we have analyzed the cytotoxic-inducer effects of gamma interferon (gamma-IFN) and supernatants containing interleukin 2 (IL 2 sup). T cells from patients with B-CLL were incubated with gamma-IFN or IL 2 sup. gamma-IFN did not modulate the very low or undetectable levels of NK activity present in the T cell population. However, the IL 2 sup induced a potent cellular cytotoxicity against NK-sensitive and NK-resistant tumoral target cells. This cytotoxic inducer effect (a) was present in lectin-free IL 2 sup and in a 15,000- to 20,000-dalton molecular weight fraction obtained by gel filtration chromatography of this supernatant; (b) was directed against NK-sensitive and NK-resistant target cells; (c) was not correlated with the basal levels of NK activity; and (d) was not associated with a development or augmentation of the proportion of lymphocytes with classic NK cell phenotype. Taken together, these results demonstrate that unstimulated T cells from B-CLL patients, incubated briefly (18 hours) with IL 2 sup but not gamma-IFN, have strong NK-like cytotoxicity, despite the lack of classic NK activity.

Aged↗

PubMed1987

Effects of recombinant interferon-alpha and -gamma on B-CLL cells in serum-free medium: expression of activation, differentiation, and CALLA antigens.

Chronic B-lymphocytic leukemia (B-CLL) cells from 10 patients were cultured serum-free with recombinant interferon (rIFN)-alpha 2, rIFN-gamma, or phorbol ester (TPA) for 5 days. All three agents induced functional differentiation, as evidenced by IgM secretion, without concomitant proliferation. A panel of monoclonal antibodies was used to detect changes in cell surface antigens defining pre-B cells (CALLA), resting B cells (HH1), early (4F2, MHM6) and late (anti-Tac, OKT9) B cell activation, and terminally differentiated B cells (OKT10). The activation markers 4F2, MHM6, and anti-Tac and the plasma cell marker T10 were all significantly induced with TPA, rIFN-alpha 2, an rIFN-gamma, whereas the expression of HH1 decreased. CALLA was detected on substantial proportions of differentiated (4-38%) but not resting (0-4%) B-CLL cells. The CALLA-positive B-CLL cells were negative for nuclear terminal deoxynucleotidyl transferase (TdT). The T9 antigen was expressed on TPA-treated cells (1-16%) only. The present findings indicate novel properties of IFN-alpha and IFN-gamma in inducing terminal differentiation of human monoclonal B cells without prior activation.

Antigens, Surface↗

PubMed1988

Immunohistochemical study of bone marrow sections in CLL.

T lymphocytes and dendritic reticulum cells (DRC) were studied in frozen-cut bone marrow sections of 35 patients with chronic lymphocytic leukemia (CLL) (infiltration patterns: interstitial 8, nodular 6, mixed 9, diffuse 12) and 13 cases of low grade non Hodgkin's lymphoma (NHL) (centroblastic/centrocytic 7, centrocytic 3, lymphoplasmacytoid 3) with bone marrow involvement. In contrast to the usual findings in normal bone marrow, in CLL and low grade NHL CD4 positive cells were more numerous than CD8 positive cells. Whereas in NHL CDR were large and occupied all the nodule, in CLL were small and located in the center of the nodule. These findings can be of interest in the study and differential diagnosis of lymphoproliferative disorders.

Antigens, Differentiation, T-Lymphocyte↗

PubMed1988

CD4, CD8 and NK subsets in B-CLL.

Although B-CLL is a hematological disorder characterized by clonal proliferation of B-cells, in most cases an increase in absolute numbers of T cells is observed. This increase is probably polyclonal in nature, since most data indicate that T lymphocytes are not progeny of the malignant clone in B-CLL. As CD4, CD8 and NK cells correspond to heterogeneous populations, in this work we tried to better define these subpopulations. Thus, CD4 subpopulations were displayed by using double labelling techniques into helper inducer subset (CD4+CDW29+) and suppressor inducer subset (CD4+CD45R+). CD8 subpopulations were delineated according to density expression of CD8 and reactivity with CD16 and CD11b in: suppressive cells defined by high density (HD) CD8 and reactivity with CD11b; NK cells defined by low density (LD) CD8 and binding to CD16; CTL cells by LD or HD CD8 and absence of expression of CD16 and CD11b. Our results concerning 47 normal control donors and 27 B-CLLs indicated that: although percentages of cells expressing CD3, CD4, CD8 and NK markers are decreased, absolute values of these subpopulations were increased; there exists an imbalance concerning CD4 and CD8, given by a more important increase of CD8 than CD4 subpopulations, but both are significantly augmented when compared to the normal range; within CD4 subpopulations, there is an important increase of CD4 CDW29 subset (helper inducer) whereas the CD4 CD45R (suppressor inducer) is not augmented in stage A patients and decreases in stage C patients; all the 3 identified CD8 subpopulations (NK, suppressors and CTLs) appeared to be increased; in 3 cases of clonal remission CLL studied, all T cell and NK subpopulations were recovering to normal percentages.

Antigens, Differentiation, T-Lymphocyte↗

PubMed1986

An unusual variant of T-CLL: evidence for the existence of a hitherto unrecognized T cell subset.

A case of T-cell chronic lymphocytic leukaemia (T-CLL) with an unusual mature membrane phenotype: E+, CD3+, CD4+, CD8-, M1+, Leu-15+, Fc gamma+, is described. The cells were large granular lymphocytes with slight immature features. Functionally these cells lacked helper, suppressor and NK activity but possessed normal levels of K activity. These findings demonstrate several features not previously described in T-CLL: the coexpression of the antigens detected by T4, M1 and Leu-15 the presence of Fc gamma receptors on CD4+ lymphocytes and the lack of NK activity in M1+, Fc gamma+ cells. This study broadens the known heterogeneity of T-CLL and suggests the existence of a hitherto unrecognized normal T-lymphocyte subset with the same functional and phenotypic characteristics as in the case described here.

Antibodies, Monoclonal↗

PubMed1979

T-cell-subset characterization of human T-CLL.

Circulating peripheral blood tumor cells in four cases of chronic lymphoproliferative disease were immunologically characterized. By the use of T-cell-specific heteroantisera and indirect immunofluorescence, all were shown to involve proliferation of malignant T cells. Three cases demonstrated morphologic and clinical features consistent with chronic lymphocytic leukemia (CLL), and one case presented as a lymphosarcoma cell leukemia. Antisera specific for normal human T-cell subsets defined the malignant T cells in each case as arising from the TH2--subset. This subset normally constitutes approximately 80% of human peripheral blood T cells. Terminal deoxynucleotidyl transferase (TdT) was not detected in any of the T-cell CLL cases, thus supporting the notion that T-cell CLL represents a malignancy of a mature phenotype. The one patient with lymphosarcoma whose tumor cells were TdT-positive subsequently developed T-cell acute lymphoblastic leukemia (ALL). Moreover, la-like antigen (p23,30) was detected on two of these tumor cell populations. In addition, it was shown that not all tumor cells were E-rosette-positive, since only cells from 3 of 4 patients were capable of forming spontaneous rosettes. These findings demonstrate that heteroantisera can provide an additional important tool for dissecting the heterogeneity of T-cell leukemias and for relating them to more differentiated normal T cells.

Adult↗

PubMedDate not supplied

Treatment of lymphoid neoplasias with interferon. II. Human leucocyte alpha-interferon in chronic lymphatic leukemia (CLL). PHase I-II trial.

Nine patients with chronic lymphoid leukemia (CLL) were treated with subcutaneous human (leukocyte) interferon a (IF a). In the first part of the study, 7 patients received intermittent 10 day courses, with free intervals of 10 to 15 days and with dose escalation in the same patient from cycle to cycle from 1.5 to 6 X 10(6) units daily, if tolerated. As we observed a decrease of peripheral lymphocytosis with low doses, and as high doses gave more side-effect in the second part of the study, 4 patients (including two who has previously received intermittent courses) were treated for three months or more at a dose of 1.5 X 10 units daily. Tumor mass reduction was seen in only three patients. However, a significant decrease in peripheral lymphocytosis was seen in 7 patients who were sustained in the continuous treatment group; with relapse at treatment discontinuation in one patient and despite continuation in another. Immune monitoring with currently available T, B, NK and macrophage tests, showed a good correlation between NK cell activity and clinical response, in this group of patients. Further studies are warranted to determine the best modalities of treatment, the population of patients likely to benefit from such treatment, the possible special respective indications of IF, and also the other treatments of CLL. One can already consider as a reasonable indication CLL presentations with myeloid insufficiency as IF is not myelotoxic, contrary to chemotherapy.

Aged↗

PubMed1983

[Prognostic relevancy of histomorphological bone marrow findings in chronic lymphocytic leukemia (CLL)].

Punctures of the pelvic crest made in 45 patients with CLL (25 men, 20 women, mean age 58.7 years) were classified according to the type of lymphatic bone-marrow infiltrations which can be identified histomorphologically. Four different types were distinguished: 1. interstitial type (lymphatic infiltration of bone-marrow tracts, with lipocytes being present) - 11 cases 2. nodular type (nodular infiltration, free bone-marrow tracts) - 5 cases 3. mixed type (combination of interstitial and nodular type) - 11 cases 4. diffuse type (original haematopoiesis and fat cells have been displaced, type A: purely diffuse type; type B: diffuse + nodular) - 18 cases The statistical analysis of survival curves reveals significant differences in the probability for survival to be met with in types with morphologically limited bone-marrow infiltration in the sense of a proceeding deterioration of prognosis in the following order: interstitial, nodular, mixed, and diffuse type. In addition, a statistically significant correlation existing between the non-diffuse infiltration types and clinical early stages (RAI 0 to II) on the one hand, and the diffuse type and clinical late stages (RAI III and IV) on the other hand, could be identified. In the course of CLL the different types of lymphatic bone-marrow infiltration apparently reflect different degrees of lymphocyte accumulation or proliferation respectively. Because of their significance the histomorphological bone-marrow findings should be included in the therapy planning for CLL.

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PubMed1984

Study of cell-surface markers in chronic lymphocytic leukaemia (CLL).

There are new possibilities to characterize lymphocytes of the so-called immunoproliferative disorders, e.g. chronic lymphocytic leukaemia. Cell marker studies help to phenotype and differentiate several entities within the CLL-syndrome. Test of rosette formation with mouse erythrocytes together with the surface membrane immunoglobulin detection by immunofluorescence technique proved to be very useful in diagnosing B-CLL and in distinguishing it from other B-lymphoproliferative disorders. In three patients with atypical B-CLL the number of dual-marked (D)-lymphocytes were increased significantly. The prognostic value of this phenomenon is still uncertain.

Animals↗

PubMed1981

Antigenic characterization of a T-CLL with heteroantisera and monoclonal antibodies: evidence for the T cell lineage of an Ia-positive, Fc-IgG--positive, suppressor-cell subpopulation.

In a previous report, peripheral blood mononuclear T cells from a patient with T-chronic lymphocytic leukemia (T-CLL) were shown to bear receptors for the Fc portion of IgG (T gamma). Moreover, the ability of these cells to rosette with sheep erythrocytes was strongly inhibited by a preincubation of the cells with theophylline. These data indicated that they represent a highly purified subpopulation of Fc-IgG receptor-positive, low-affinity rosetting cells with in vitro suppressor activity on lectin-induced proliferation of normal lymphocytes. They also were reactive in antibody-dependent cell-mediated cytotoxicity but had no reactivity in natural killer cell assays. These cells were studied in this report with several heteroantisera and monoclonal antibodies. Results indicate that these T-CLL cells express a T cell antigenic pattern (OKT-3+) and the majority are Ia positive. They also react with the OKT-8 reagent (a reagent detecting the subset of T cells that contains the cytotoxic/suppressor cells), whereas they are negative with OKT-4 (which reacts with the subset of T cells that contains helper cells) and OKT-6 (thymocyte) antibodies. Heteroantisera also support the results obtained with monoclonal reagents. Despite some recent evidence showing that a high percentage of T gamma cells may belong to the monocyte-myeloid lineage, these T-CLL cells were negative with OKM-1, a monoclonal antibody reported to detect a monomyeloid antigen. These results suggest that a distinct subpopulation of suppressor T cells can be identified by membrane-marker phenotyping.

Adult↗

PubMed1984

Benign monoclonal B cell lymphocytosis--a benign variant of CLL: clinical, immunologic, phenotypic, and cytogenetic studies in 20 patients.

From 1951 through 1978, we have seen 20 cases of stage O chronic lymphocytic leukemia (CLL) without disease progression for 6.5-24 years. The cohort included 7 males and 13 females, aged 48-77 years at the time of diagnosis. None presented with anemia, thrombocytopenia, or neutropenia nor developed cytopenias during follow-up. Mean total lymphocyte count in these patients was 20,100/microL, with ranges from 10,000 to 43,700 at the time of diagnosis, and was 20,600, with ranges from 1,000 to 47,200, at last follow-up. Of 12 patients studied, 8 and 4 were phenotyped as heavy chain mu delta- and mu-type, respectively, with 7 kappa- and 4 gamma-type (no light chain was detectable in one patient). Of 13 patients studied, one had a slightly elevated IgG level and two had slightly depressed serum IgA and IgM levels. All patients had positive delayed hypersensitivity responses to at least one of five skin test antigens. Each of seven patients studied for an in vitro leukocyte thymidine uptake had a low level of [3H]thymidine incorporation. Nine of 12 patients studied had elevated total T cells, and the remaining 3 had normal T cell counts. In vitro unseparated lymphocyte response to phytohemagglutinin showed normal kinetics of DNA synthesis, with a peak response on day 3 or 4 of culture in 4 and slightly or moderately depressed and/or delayed kinetics in 8 patients studied. Cytogenetic analyses by Q- or G-banding techniques of polyclonal B cell mitogen-stimulated lymphocytes in all six patients studied showed normal karyotypes. These data are consistent with a previously undescribed syndrome involving a monoclonal B cell lymphocytosis, a prolonged asymptomatic or benign clinical course, and essentially normal humoral and cellular immunity and normal karyotype. Our observations indicate that these 20 patients with stage O CLL have a benign clinical course and that they may also be designated as benign monoclonal B cell lymphocytosis ( BMBL ), a benign variant of CLL.

Aged↗

PubMed1984

Cell electrophoretic characterization of peripheral blood lymphocyte subpopulations enriched by rosette formation, from normal individuals and CLL patients.

Peripheral blood lymphocytes from healthy subjects and patients with chronic lymphatic leukemia (CLL) were isolated and their subpopulations enriched through formation of spontaneous rosettes with sheep or mouse red blood cells, respectively. Electrophoretic measurements were performed in unseparated as well as in fractionated cell populations. Normal blood lymphocytes showed two clearly distinguishable populations of different electrophoretic mobilities. After separation by SRBC rosette formation the rosette-forming cells could be identified as high mobility cells. CLL lymphocytes showed in most cases an unimodally distributed cytopherogram, the mean electrophoretic mobility being intermediate between the low and high mobility cells of control persons. After separation through mouse erythrocytes rosette formation these cells contained two cell fractions differing in their electrophoretic mobility: a fraction of slower mouse rosette-forming cells and a fraction of the non-MRFC which contained mainly cells of higher mobility that could be identified as enriched T cells. These both fractions showed unimodal distributions. This study shows that CLL lymphocyte subpopulations can be further characterized by surface charge density.

Animals↗

PubMed1993

Prognostic features and survival in young adults with early/intermediate chronic lymphocytic leukemia (B-CLL): a single institution study.

Information regarding natural history and prognostic factors for early/intermediate B-cell chronic lymphocytic leukemia (B-CLL) in young adults is limited. We analysed 62 young adults (< or = 50 years old) with early/intermediate B-CLL who were seen at our institution during initial diagnosis over a 15-year period. These patients had been followed for a median duration of 7 years. Median age for the entire group was 44 years and 72% were > or = 40 years old. Actuarial median survival from initial diagnosis for the entire group was 140 months. Upon univariate analysis, significant survival advantage was observed in patients with Rai stages 0 and 1 versus stage II disease (median survival 140 versus 60 months, p = 0.01) and in those with lymphocyte doubling time (LDT) of > 1 year versus < or = 1 year (median survival 150+ versus 94 months, p = 0.06). Similarly there was a trend towards longer survival in patients with a leucocyte count of < or = 50,000/microliters when compared to those with higher counts although the difference was not statistically significant. The bone marrow infiltration pattern was not prognostically useful. Upon multivariate analysis, only Rai stage and LDT were prognostically useful. Patients who did not respond to initial therapy with alkylating agents had the worst prognosis, with a median survival of only 19 months. Assessment of presenting clinical stage, LDT, and degree of initial treatment response may prompt earlier consideration of alternative therapeutic modalities such as purine nucleoside analogs or bone marrow transplantation in younger patients with early/intermediate B-CLL.

Adolescent↗

PubMed1995

Karyotypic evolution in CLL: identification of a new sub-group of patients with deletions of 11q and advanced or progressive disease.

Chronic lymphatic leukaemia (CLL) is the most common leukaemia and is characterized by long-term survival. Previous studies have shown that karyotypic abnormalities are relatively stable and that certain abnormalities may be associated with a poor prognosis. In a prospective 5-year study of 45 patients with typical CLL, sequential karyotypic studies were undertaken every 6-12 months. Clonal karyotypic abnormalities were identified in 62% of patients, either at diagnosis or during the study period with 38% (17/45) exhibiting clonal evolution. In patients with no clinical disease progression, 13q abnormalities were most commonly detected compared with 11q deletions in patients with progressive disease. Karyotypic evolution was significantly associated with progressive disease (12/16, 75% vs 5/29, 17%; P < 0.001, chi2). Thus, karyotypic evolution is not uncommon in CLL, is usually associated with disease progression and deletions of 11q are the commonest detected abnormalities.

Adult↗

PubMed1997

Prophylactic strategies to meet infectious complications in fludarabine-treated CLL.

Fludarabine has emerged as salvage therapy in chlorambucil-resistant CLL. However, encouraging response rates have been compromised by a high incidence of serious infectious complications. Prophylactic measures to reduce the frequency of infections are needed, but up to now, there are no established standards for supportive therapy in fludarabine-treated CLL. Clinicians have observed an increasing frequency of life-threatening opportunistic infections but only some of these may be explained by fludarabine-induced impairment of cell-mediated immunity. Neutrocytopenia commonly found during initial fludarabine treatment may not have been addressed sufficiently as risk factor for infections. Thus, G-CSF supplementation may improve the rate of infectious complications by reducing the duration of fludarabine-induced neutrocytopenia. The changing spectrum of infectious complications should stimulate additional trials on the value of IVIG replacement in fludarabine-treated CLL patients and on the role of low-dose co-trimoxazole in patients at high risk of Pneumocystis carinii infections.

Antibiotic Prophylaxis↗

PubMed1998

A case report: CD8 expression in B-cell chronic lymphocytic leukemia (B-CLL). Prognostic significance of the aberrant CD8 expression.

The human CD8 molecule is usually expressed on T lymphocytes or natural killer cells but not on normal B cells. Over a course of 5 years, we followed a case of B-CLL which aberrantly expressed the CD8 molecule. During this period, the clinical and hematological conditions of the patient were stable. This B-CLL presented a typical immunophenotype (HLA DR+, CD19+, CD5+, CD23+) with monotypic expression of surface immunoglobulin light chain kappa. We confirmed the CD8 expression on these leukemia cells by using double labelling and different antibodies directed against this antigen. We measured the quantitative expression of the CD8 molecule. The number of CD8 molecules per cell was clearly lower on these malignant B cells than on normal T lymphocytes. In order to evaluate the prognostic significance of this CD8 expression, we quantitated in parallel other markers such as CD5, CD23, CD22, CD11c. During 5 years, this aberrant CD8 expression persisted and was associated with an increase of the CD23 and a decrease of CD22 levels, known to correlate with a good prognosis in agreement with the karyotype analysis. Altogether our results led us to conclude that the aberrant CD8 expression in this case of B-CLL may correlate with a non-aggressive form of lymphoproliferative disorder.

CD8 Antigens↗

PubMed2005

Chronic lymphocytic leukemia (CLL): first-line treatment.

For the past ten years, there has been a dynamic development of new therapeutic compounds and prognostic parameters for chronic lymphocytic leukemia (CLL). Hematologists and oncologists are challenged to use these new possibilities for an optimized, risk- and fitness-adapted treatment strategy, with the goal of achieving long-term remissions and preserving a good quality of life. This review is intended to summarize the current knowledge on first-line treatment of CLL.

Anemia↗

PubMed2003

Tumor lysis syndrome (TLS) following fludarabine therapy for chronic lymphocytic leukemia (CLL): case report and review of the literature.

Adenosine deaminase inhibitors have proven superior to alkylating agent-based therapies in inducing clinical and hematologic remissions in treated and previously untreated chronic lymphocytic leukemia (CLL) patients, and they have become increasingly accepted as a standard for therapy. We report the case of a 66-year-old patient with a 7-year history of CLL who had been previously treated with alkylating agents. Upon presentation with abdominal lymphadenopathy, a 5-day course of the nucleoside analogue, fludarabine, was administered. Two days after completion, the patient developed acute tumor lysis syndrome (TLS) that induced renal failure with hyperkalemia and hyperuricemia. This resulted in critical, life-threatening complications requiring hospitalization, aggressive hemodialysis and fluid replacement therapy. While only 5 other cases of TLS associated with fludarabine therapy have been reported since 1989, we recommend that adenosine deaminase inhibitor therapy be initiated with the addition of allopurinol, and that hydration with copious amounts of oral fluids during therapy be encouraged in order to help protect against the renal effects of potential TLS induced by these agents.

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