Severe deficiency of B lymphocytes in peripheral blood from multiple myeloma patients.

Pilarski, Linda M.; Mant, Michael J.; Ruether, Bernard A.; Belch, Andrew R.

doi:10.1172/jci111540

Cited by 58 publications

(37 citation statements)

References 24 publications

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“…This is particularly true in haematology, as shown by the various lymphoma or leukaemia classifications. The following experimental evidence (Kubagawa et al, 1979;Pilarski et al, 1985;Caligaris-Cappio et al, 1985Epstein et al, 1990) (Fitz et al, 1984;Carter et al, 1987;San Miguel et al, 1987;Paule et al, 1988;Pasqualetti et al, 1990;Greipp, 1992) Gahrton et al, 1991;Jagannath et al, 1990;Attal et al, 1992;Gore et al, 1989;Dimopoulos et al, 1993;Fernand et al, 1993;Johnson and Selby, 1994;Guillemin et al, 1995) have considered TR as a prognostic factor because of its demonstrated importance on survival and on response to further therapies (Dimopoulos et al, 1993;Fernand et al, 1993). A recent report showed that myeloablative therapies are useless for MM patients in the following three conditions: resistant relapse, primary resistance longer than 1 year and relapse in consolidation therapy of a late remission.…”

Section: Discussionmentioning

confidence: 94%

A prognostic index for multiple myeloma

Grignani

Gobbi²,

Formisano³

et al. 1996

Br J Cancer

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Summary The current prognostic systems have failed to identify multiple myeloma (MM) patients who require aggressive therapy. These staging systems do not reliably distinguish patients with different prognoses. This paper explores the possibility of improving the prognostic forecast in MM by considering some clinical characteristics at diagnosis together with response to first-line chemotherapy. A total of 231 patients were prospectively randomised in a multicentre trial to no therapy vs melphalan + prednisone (MP) for stage I, MP in stage II, and MP vs peptichemio, vincristine and prednisone for stage III. The clinical features of these groups were evaluated for prognostic variables predictive of overall survival by means of univariate and multivariate analysis. The independently significant variables were incorporated into a model that identified three groups of patients with different risks of death and different overall survival. Three variables retained statistical significance: the staging system proposed by the British Medical Research Council, a composite parameter integrating the percentage of bone marrow plasma cells with cytological features of the infiltrating elements (plasma cell vs plasmablast), and response to 6 months of first-line chemotherapy. These three variables led the proposal of a scoring system able to identify three different risk classes (with median overall survival of 52, 28 and 13 months respectively) and to estimate individual patient prognosis more flexibly. The proposed risk classes, drawn from both diagnostic and therapeutic parameters, are thought to be a clinical and investigational instrument for separating MM patients into comparable groups, for selecting the best available therapy and for evaluating response with respect to the disease of each new patient.

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Section: Discussionmentioning

confidence: 94%

A prognostic index for multiple myeloma

Grignani

Gobbi²,

Formisano³

et al. 1996

Br J Cancer

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“…The second supposition cannot be ruled out but gives no explanation for the existence of a proliferating B lymphocyte population, which has been observed carrying the same idiotype and the same gene rearrangement as the plasmocytic cells and which have been recognized as malignant progenitor cells by various investigators (5, (,,8,22,31,40-42,4(,,48,53). There are studies showing that, in MM, a population of pre-B cells is the target for an oncogenic event, which does not block differentiation to plasmocytic cells ( 12,17,22,23,27,32,37,43,45,47). The third possiblity is equivocal but may be correct.…”

Section: Discussionmentioning

confidence: 99%

S‐Phase cells of the lymphoplasmocytic compartment in hyperdiploid multiple myeloma are diploid cells

et al. 1995

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In vivo S-phase cell labeling with iododeoxyuridine (IdUrd) was performed in six multiple myeloma (MM) patients. Myeloma cells from four patients were hyperploid. In three out of four patients, DNNIdUrd flow cytometry revealed that most of the labeled cells, which had divided during the period, elapsed between flash labeling and sampling, had returned to the diploid GO/Gl compartment and not to the hyperdiploid peak. To eliminate contaminating cells belonging to the normal hematopoiesis, plasmocytic and lymphocytic cells were fractionated and analyzed separately. Cell enrichment was performed with use of murine monoclonal antibodies (MoAbs) against plasmocytic and lymphocytic cell markers and subsequent magnetic activated cell sorting with immunobeads, i.e., polysterene magnetic particles coated with sheep anti-mouse IgG. The purified plasmocytic cells were mainly hyperdiploid and largely unlabeled. The lymphocytic cells appeared to belong chiefly to the diploid cell population. The IdUrd-labeled cells were predominantly lymphocytic cells, returning after mitosis to the diploid GO/G1 peak. Although this pattern of S-phase cells in hyperdiploid MM, belonging to the diploid cell compartment, was observed in three out of four hyperploid cases and although the number of observations is small, S-phase cells may demonstrate an aspect of tumor cell kinetics in hyperploid MM, which has been debated for many years and which indicates the existence of a non-plasmocytic stem cell compartment that feeds the plasmocytoma. The behavior of the labeled cells as observed in a few cases of MM provides another, hitherto undescribed, argument that, at least in some MM patients, a part of the proliferating tumor cells may be diploid lymphocytic (precursor) cells. These findings should be considered when targeting and monitoring treatment of MM and also in purging procedures of bone marrow in patients to be treated by ablative cytotoxic therapy and autologous bone marrow transplantation. 0 1995 Wiley-Liss, Inc.Key terms: Multiple myeloma, precursor cells, iododeoxyuridine (IdUrd), in vivo IdUrd labeling, immunomagnetic cell separation, DNA/IdUrd flow cytometryIn the majority of patients with multiple myeloma (MM), the tumor cells, or at least a large part of them, are aneuploid (1 1,34,35,53). Evaluation of cellular DNA content by flow cytometry (FCM) has revealed the existence of an aneuploid plasma cell population in 65-75% of the MM bone marrow samples with a median DNA index of 15% above normal (2,3,9,11,34,35,53). Most aneuploid tumor cells show a cell marker that is consistent with differentiated B cells, but subpopulations of tumor cells have been observed that express pre-B, early-B, or T lymphocytic, and even myelomonocytic or erythroid, features (16,17,22,23). Differentiation and lineage infedilities of plasmocytic cells in MM suggest that the malignant transformation involves a more pluripotent lymphoplasmacytoid precursor cell with a flexible pattern of gene expression.In 1974, Pileri and Tarocco (45) demonstrated the non...

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“…The underlying mechanism is sufficiently powerful to suppress even monoclonal gammopathies unrelated to the myeloma (2,3). Although most multiple myeloma patients have greatly reduced numbers of B lymphocytes (4)(5)(6)(7), it is not clear whether the decreased serum polyclonal Ig is due to lack of B compared the number of surface IgM' (sIgM+)' B cells in peripheral blood, the frequency with which B cells from myeloma patients are transformed by Epstein-Barr virus (EBV) to produce IgM-secreting clones in vitro (10)(11)(12)(13) Peripheral blood lymphocytes (PBL) were purified by centrifugation over Ficoll-paque (Pharmacia Fine Chemicals, Piscataway, NJ), and the composition of the resulting cell population was determined by a differential count using Giemsa stain. Aliquots were characterized for number of sIg' and sIgM' B cells by indirect immunofluorescence (IF) (4).…”

Section: Introductionmentioning

confidence: 99%

“…After washing, the cell pellet was resuspended in 50 MlI of a 1/20 dilution of F(ab')2 fragments of sheep anti-mouse Ig labeled with fluorescein isothiocyanate (FITC) (Tago Inc., Burlingame, CA), incubated for 60 min at 4°C, and washed twice. Cells were then resuspended in warm saline and incubated for 10 min at 370C to allow cap formation (4) followed by fixation of cells in 1% formalin. The patients analyzed for this study include the set of patients analyzed previously (4) where B cells were defined by their expression of HLA -DR, and of 41H * 16, a marker for mature B cells (14).…”

Section: Introductionmentioning

confidence: 99%

“…Supernatants were collected at 3 wk and tested for IgM activity as described below. The frequency of transformed cells within an EBVinfected E-population was defined as the reciprocal of the cell number at which 37% of the microculture wells in the limiting dilution series were negative; on average each well receives one transformed B cell at this cell concentration (1 [1][2][3][4][5][6][7][8][9][10][11][12][13] (15,(26)(27)(28)(29), but like other cases of agammaglobulinemia (15,(29)(30)(31), the defect in myeloma patients is extrinsic to the B cell rather than an intrinsic genetic block, since these B cells are fully able to transcribe and translate genes for IgM and to secrete IgM after EBV transfor- (36,37) and in murine model systems (38), its reversal might lead to a better prognosis for myeloma patients. Experiments are in progress to determine the mechanism(s) mediating B lineage differentiation arrest in myeloma, with particular emphasis on a search for suppressor T cells.…”

Section: Introductionmentioning

confidence: 99%

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