Plasma Cell Leukemia Patients Research Articles

Clinical Efficacy of Bortezomib Based Therapy in Plasma Cell Leukemias.

Introduction Plasma Cell Leukemia (PCL) is characterized by a high number of plasma cells in peripheral blood (>2 × 109/L) and more than 20% of circulating plasmocytes on differential count. Primary PCL or secondary form, after previous multiple myeloma (MM), represent the most aggressive forms of clonal gammapathy with very poor outcome from both conventional chemotherapy and autologous or allogeneic transplant. For this reasons new effective treatment approaches are required. The proteasome inhibitor Bortezomib has been shown to be effective in advanced MM with a rapid response but few reports have been published regarding its potential role on PCL. We report here the clinical results of a serie of PCL patients that received proteasome inhibitor, Bortezomib (Velcade®), as induction therapy.Patients and Clinical Results We describe 10 patients with PCL treated with Bortezomib. Median age was 58 y (30–70). 4 cases were primary, de novoPCL and 6 cases were secondary forms of relapsed or progressive MM. Patients with secondary PCL had received a median of 3 previous lines of therapy including autologous transplantation (5 cases). Bortezomib at standard dose iv: 1.3 mg/m2 days 1,4, 8,11 every 21 days were used alone in 2 patients and in combination with high dose of Dexamethasone +/− Adryamicin in the rest. 3 cases recived the BDD scheme (Bortezomib iv, Pegylated Doxorrubicin iv and oral Dexamethasone). 9 patients were evaluable for drug efficacy with 7 cases showing some grade of favourable response with the first cycle, including 3 cases of CR. 4 patients have died: 1 during first weeks and 3 for progression, 2–3 months after initial response. 3 cases received allogeneic transplant with related donor and reduced conditioning and are alive 12, 14 and 30 months postransplant. The median follow up since PCL diagnosis of 6 alive patients is 14 months (3–39 months). 3 patients received maintenance therapy that included low dose thalidomide. Grade 2 thrombopenia, neutropenia and gastrointestinal symptoms were the main secondary toxicity. No complicated tumoral lysis syndrome were observed.Conclusions and Comments Bortezomib has been shown to be effective by several mechanisms in patients with MM resistant to multiple previous treatments and as induction therapy alone or in combination with other drugs. The favourable responses observed in these cases of PCL; including de novo patients, and the biological ex vivo results in PCL cell lines, suggest the potential efficacy of this agent combined with dexamethasone and doxorubicin. Although more experience is necessary these data support future trials with Bortezomib combined with other drugs for example BDD scheme in the induction treatment of PCL. The role of allogeneic intensification therapy has also to be investigated in young patients after control of PCL with this approach. For maintenance of response, the role of this drug or other new drugs as thalidomide or lenalidomide has to be investigated.

Fluorescence In Situ Hybridization Studies in 22 Cases of Plasma Cell Leukemia.

Background Plasma cell leukemia (PCL) is a rare malignant plasma cell disorder that usually carries an aggressive course with a rapidly fatal outcome. Cytogenetic studies performed on plasma cell disorder are scarce and difficult because of the low proliferation rate of plasma cells. Fluorescence in situ hybridization (FISH) analysis is an attractive alternative for evaluation of numerical and structural chromosomal changes in PCL.Methods Interphase FISH (I-FISH) and two different specific probes for the regions containing 13q14.3 (D13S319) or 14q32 (IGHC/IGHV) were used to detect 13q14 deletion [del(13q14)] or IgH rearrangement in 22 PCL patients. For patients with IgH rearrangement, probes for IgH(JH) and 11q13 (CCND1) or 4p16 (FGFR3) were used to detect t(11;14)(q13;q32) or t(4;14)(p16;q32).Results Molecular cytogenetic aberrations were found in 19 of 22 (86.4%) PCL patients. Del(13q14) was detected in 13 cases (59.1%), and IgH rearrangement in 17 (77.3%) patients including 7 with t(11;14) and 3 with t(4;14). 14q32 rearrangement and 13q14 deletion were found concurrently in 11 cases (50%).Conclusions Chromosomal abnormalities are frequent in PCL. The most frequent aberrations among the cases was the 14q32 rearrangement and 13q14 deletion. I-FISH technique is useful to detect molecular cytogenetic aberrations and should be used in the routine evaluation of PCL.

CD32B on Clonal Plasma Cells in Systemic Light-Chain Amyloidosis (AL) and Multiple Myeloma (MM): A Target for Immunotherapy in Both Disorders and a Prognostic Marker in MM.

Despite stem cell transplant and new therapies, nearly all patients with AL and MM die of disease or complications of treatment. Novel approaches that selectively kill clonal plasma cells are needed. CD32B, the inhibitory Fcγ receptor IIB, is a member of the Fc receptor (FcR) family on chromosome 1q. B-cells and some monocytes and dendritic cell subtypes express cell-surface CD32B, which has a cytoplasmic inhibitory motif important in regulating immune responses. Unlike the CD32B2 isoform on myeloid cells, CD32B1 on B-cells is not internalized, making it a suitable target for monoclonal antibody (MAb) therapy (Blood 2006Jun6 Epub). CD32B has not previously been found on AL and MM plasma cells. We used purified CD138+ marrow and blood cells from AL, MM and plasma cell leukemia (PCL) patients, and 5 human MM cell lines, to evaluate CD32B gene and cell-surface expression with gene expression profiles (GEP) (Affymetrix U133 PLUS 2.0), RT-PCR for CD32B1 and B2, and flow-cytometry with the 2B6 MAb for CD32B. In AL, GEP showed that CD32B expression was significantly higher than other FcR genes (p<0.01), RT-PCR showed that CD32B1 was prominently expressed on CD138+ cells from both newly diagnosed and relapsed AL patients, and flow cytometry showed intense cell-surface staining for CD32B on >98% of all AL plasma cells. In MM, public GEP data (http://lambertlab.uams) showed that CD32B expression was significantly higher than other FcR genes while RT-PCR showed CD32B1 message in CD138+ MM and PCL specimens but not in the RPMI 8226 cell line. Cytogenetic analysis then showed that 8226 cells lack t(4;14) but have 4 copies of 1q, implicating segmental uniparental tetrasomy of a mutant allele in the lack of CD32B message. Flow cytometry showed median 96% CD32B expression on CD138+ marrow cells from patients with normal or hyperdiploid cytogenetics, but significantly lower expression (median 69%, p=0.01) in patients with unfavorable cytogenetics (del 13, t(4;14)). CD32B expression was lower still on PCL specimens (median 10%) and nil on MM cell lines. We then investigated the GEP of sorted CD138+/CD32B+ and CD32B− fractions from MM patients. In CD138+/CD32B+ cells, CD45C and CXCR4 were overexpressed. In CD138+/CD32B− cells, genes on chromosome 1q were overexpressed, including those for cancer testis antigens and others possibly associated with biologic aggressivity (Cancer Cell 2006; 9:313). Notably, the CD32B-specific MAb 2B6 directs human mononuclear cell cytotoxicity against CD32B+ cell lines, reduces tumor growth and improves tumor-free survival in a mouse xenograft model. Moreover, an Fc-engineered humanized variant of 2B6 elicits ADCC-mediated specific cytotoxicity against a low-level CD32B+ MM cell line in vitro. In sum, these data show that CD32B is important in AL and MM; that CD32B on AL and the majority of MM plasma cells provides a target for MAb therapy; and that, given the results in MM, PCL and MM cell lines, CD32B expression is inversely related to biologic aggressivity. Genetic instability of chromosome 1q may provide a direct basis for this relationship thereby mechanistically linking CD32B expression in MM to prognosis. These data support further evaluation of CD32B and clinical studies of anti-CD32B MAb therapy in AL and MM.

Clonal plasma cells from monoclonal gammopathy of undetermined significance, multiple myeloma and plasma cell leukemia show different expression profiles of molecules involved in the interaction with the immunological bone marrow microenvironment

The immunological bone marrow (BM) microenvironment plays a major role in controlling growth and survival of clonal plasma cells (PC); this might translate into different patterns of expression of molecules involved in immune responses on PC from different types of monoclonal gammopathies (MG). We have studied the expression of a group of nine such molecules on both BMPC and the plasma of 61 newly diagnosed MG patients (30 MG of undetermined significance (MGUS), 27 multiple myeloma (MM) and four plasma cell leukemia (PCL)) and five normal individuals. Clonal PC from all MG displayed significantly increased levels of CD56, CD86 and CD126, and decreased amounts of CD38 (P<0.001). Additionally, HLA-I and beta2-microglobulin were abnormally highly expressed in MGUS, while CD40 expression was decreased in MM and PCL (P<0.05). Interestingly, a progressive increase in the soluble levels of beta2-microglobulin was found from MGUS to MM and PCL patients (P=0.03). In contrast, all groups showed similar surface and soluble amounts of CD126, CD130 and CD95, except for increased soluble levels of CD95 observed in PCL. Overall, those phenotypic differences are consistent with increased antigen presentation and costimulatory capacities in MGUS, which progressively deteriorate in malignant MG (MM and PCL).

C-kit Receptor (CD117) Expression on Plasma Cells in Monoclonal Gammopathies

The surface expression of CD117 antigen (c-kit) on plasma cells from 158 multiple myeloma (MM), 12 plasma cell leukemia (PCL), 7 MGUS, 7 IgM lymphoplasmacytic lymphoma patients and 10 healthy subjects has been analyzed by flow cytometry using triple staining with the monoclonal antibodies CD138, CD117 and CD38. The antigen expression intensity was calculated as relative fluorescence intensity (RFI) and for direct quantitative analysis the QuantiBRITE test (Becton Dickinson) was applied. Antibody bounding capacity (ABC) was calculated using QuantiCALC software. CD117 antigen was present in 49/158 MM, 5/12 PCL and 5/7 MGUS patients. The RFI values ranged from 0.2 to 20.2 in particular MM patients (mean: 11.0 ± 5.3; median 11.5) while the number of CD117 binding sites (ABC) on MM plasma cells ranged from 637 to 6217 (mean: 3029 ± 1568; median 2946) (r = 0.8328). In responsive to chemotherapy c-kit positive MM patients the percentage of CD117 + plasma cells in the bone marrow decreased significantly while in c-kit negative MM patients the percentage of CD117 + cells in bone marrow did not change and remained in the normal limits. When comparing the clinical and biological disease characteristics (monoclonal protein isotype, albumin, β2-microglobulin, lactate dehydrogenase, stage of disease, response to chemotherapy, survival time) of c-kit positive and c-kit negative cases, no significant differences were found. In CD117 positive PCL cases expression of CD117 was detected in bone marrow plasma cells as well as in peripheral blood plasma cells. Normal plasma cells and those in IgM lymphoplasmacytic lymphoma did not show reactivity for the CD117 antigen. We conclude that it may be rationale to consider usefulness of therapy with tyrosine kinase inhibitors in the management of c-kit positive plasma cell proliferations. In one third of MM and PCL patients c-kit antigen could be considered as a "tumor associated marker" and together with CD38 and CD138 it may be of value for the identification of the malignant clone in minimal residual disease as it was first suggested by Spanish authors.

Cytogenetic and fluorescence in situ hybridization studies in 60 patients with multiple myeloma and plasma cell leukemia

We report cytogenetic results in a series of 60 patients affected with multiple myeloma (MM) and plasma cell leukemia (PCL) and compare the results with those previously reported. In our series, a total of 41% of MM patients and 71% of PCL patients displayed chromosome abnormalities. To evaluate the clinical value of monosomy 18, we obtained fluorescence in situ hybridization results (using centromeric probe for chromosome 18) of 22 MM patients who displayed a normal karyotype. Monosomy 18 was present in 3 of 22 patients (14%). Using conventional cytogenetics, we detected monosomy 18 in one patient affected with PCL. Two of four cases with monosomy 18 followed an aggressive course, with overall survival of 1 and 9 months. The remaining two are in follow-up and remain stable. The association of monosomy 18 with IgA subtype predominance and poor prognosis was not observed in this series of MMs and PCLs. Although these results do not confirm our previous hypothesis, further observations of this group of patients (with monosomy 18) regarding malignant transformation is warranted.

A possible role of the P53 gene deletion as a prognostic factor in multiple myeloma.

The role of P53 gene abnormalities in the pathogenesis of multiple myeloma (MM) and their potential use as prognostic indicators remain uncertain. To further define this question, we studied genomic DNA from 50 MM and one plasma cell leukemia patients by polymerase chain reaction single-strand conformation polymorphism and sequencing, and fluorescence in situ hybridization in order to detect P53 mutation and deletion, respectively. Kaplan-Meier survival curves and the log-rank test were used to analyze the survival data. No P53 mutation was detected in our patients. In contrast, P53 deletion, predominantly monoallelic, was detected in 8 of 51 (15.7%) patients. Similar frequencies of P53 deletion were observed in patients stratified by age ( P=0.71), gender ( P=0.44), status, and stage of the disease ( P=0.70 and P=0.23, respectively). However, patients with P53 deletion had significantly shorter median overall survival compared with those without a deletion (7.4 vs 139.0 months, P<0.0001). On univariate regression analysis, P53 deletion was a parameter for predicting shortened survival ( P=0.02). We concluded that P53 mutation may be seen as a prognostic indicator of limited value in MM. In contrast, P53 deletion may be seen as a prognostic indicator of poor outcome. However, as the cohort of patients is rather limited for a prognostic analysis, these results should be confirmed by further studies with larger sized samples.

Differences in genetic changes between multiple myeloma and plasma cell leukemia demonstrated by comparative genomic hybridization.

To analyze the genomic differences between multiple myeloma (MM) and plasma cell leukemia (PCL), a total of 30 cases were studied by comparative genomic hybridization (CGH). In five cases with a low proportion of plasma cells (PC) in bone marrow, an enrichment of PC was performed by using immunomagnetic beads conjugated with the monoclonal antibody B-B4. In 24 out of the 25 MM (96%) and in all five PCL (100%) patients DNA copy number changes were identified by CGH analysis; in the MM case without chromosomal imbalances, the immunomagnetic enrichment of PC had failed. The most recurrent changes in MM patients were gains at chromosomes 15q (48%), 11q (44%), 3q (40%), 9q (40%) and 1q (36%). By contrast, all PCL patients showed gains in 1q. Losses of chromosomal material were significantly more frequent in PCL than in MM patients (P = 0.03): losses on 13q in 80% of PCL vs 28% of MM; and on chromosome 16 in 80% vs 12%, respectively. In addition, PCL patients showed losses of 2q and 6p that were not present in MM. The CGH data show differences in chromosomal imbalances between MM and PCL.

Expression of PRAD1/cyclin D1 in plasma cell malignancy: incidence and prognostic aspects.

We analysed PRAD1/cyclin D1 expression in 20 patients with plasma cell malignancy by Northern analysis. 6/17 multiple myeloma patients and 3/3 plasma cell leukaemia patients showed PRAD1/cyclin D1 expression. This incidence appeared to be higher than the expected incidence based on previous studies. Southern analysis did not show rearrangement of the bcl-1 region. Although there was no statistical difference, the PRAD1/cyclin D1 negative group showed a 1-year survival of 81.8%, 3-year survival of 45.5% and 5-year survival of 22.7%, and those for the PRAD1/cyclin D1 positive group were 63.5%, 16.9% and 16.9%, respectively. Further study is required to determine whether PRAD1/cyclin D1 expression is a prognostic factor.

Primary Plasma Cell Leukemia: Clinical, Immunophenotypic, DNA Ploidy, and Cytogenetic Characteristics

AbstractWe report on a series of 26 patients diagnosed with primary (de novo) plasma cell (PC) leukemia (PCL) in whom we analyzed the clinicobiologic characteristics of the disease together with the immunophenotype, DNA cell content, proliferative index, and numeric chromosomal aberrations of the neoplastic PC, and compared them with 664 multiple myeloma (MM) patients at diagnosis. The median age, sex ratio, and bone lesion extension were similar, but PCL cases displayed a higher prevalence of clinical stage III, extramedullary involvement, and Bence Jones cases, with fewer IgA cases than for MM patients. In addition, according to several prognostic indicators (β2-microglobulin serum level, proportion of S-phase PCs, proteinuria, calcium serum level, lactate dehydrogenase [LDH] and renal function), the incidence of adverse prognostic factors was significantly higher in PCL versus MM. Immunophenotypic expression was similar for CD38, CD138, CD2, CD3, CD16, CD10, CD13, and CD15, but PCL differed from MM in the expression of CD56, CD9 HLA-DR, CD117, and CD20 antigens. Twenty-two PCL cases were diploid and one was hypodiploid, while most MM cases (57%) showed DNA hyperdiploidy. With the fluorescent in situ hydridization (FISH) technique, 12 of 13 PCL cases displayed the numeric aberrations, −13 (86%), ±1 (57%), +18 (43%), and −X in women (25%), but they lacked several numeric aberrations usually found in MM such as +3, +6, +9, +11, and +15. PCL cases had a lower overall response to therapy than MM cases (38% v 63%, P = .01332). Among PCL patients, a trend for a worse response was observed in cases treated with melphalan and prednisone (MP) versus polychemotherapy. Overall survival was significantly worse in PCL versus MM patients (8 v 36 months,P < .0001), but it was significantly better in PCL patients treated with polychemotherapy versus MP (18 v 3 months,P = .0137). By contrast, MM patients did not show significant differences in overall survival according to the treatment used, MP or polychemotherapy. Ten variables seemed to predict survival in PCL patients, but only the β2-microglobulin level and S-phase PCs retained an independent value in multivariate analysis. In summary, our study illustrates that PCs from PCL display singular phenotypic, DNA cell content, and cytogenetic characteristics that lead to a different disease evolution versus MM.

Primary Plasma Cell Leukemia: Clinical, Immunophenotypic, DNA Ploidy, and Cytogenetic Characteristics

We report on a series of 26 patients diagnosed with primary (de novo) plasma cell (PC) leukemia (PCL) in whom we analyzed the clinicobiologic characteristics of the disease together with the immunophenotype, DNA cell content, proliferative index, and numeric chromosomal aberrations of the neoplastic PC, and compared them with 664 multiple myeloma (MM) patients at diagnosis. The median age, sex ratio, and bone lesion extension were similar, but PCL cases displayed a higher prevalence of clinical stage III, extramedullary involvement, and Bence Jones cases, with fewer IgA cases than for MM patients. In addition, according to several prognostic indicators (β2-microglobulin serum level, proportion of S-phase PCs, proteinuria, calcium serum level, lactate dehydrogenase [LDH] and renal function), the incidence of adverse prognostic factors was significantly higher in PCL versus MM. Immunophenotypic expression was similar for CD38, CD138, CD2, CD3, CD16, CD10, CD13, and CD15, but PCL differed from MM in the expression of CD56, CD9 HLA-DR, CD117, and CD20 antigens. Twenty-two PCL cases were diploid and one was hypodiploid, while most MM cases (57%) showed DNA hyperdiploidy. With the fluorescent in situ hydridization (FISH) technique, 12 of 13 PCL cases displayed the numeric aberrations, −13 (86%), ±1 (57%), +18 (43%), and −X in women (25%), but they lacked several numeric aberrations usually found in MM such as +3, +6, +9, +11, and +15. PCL cases had a lower overall response to therapy than MM cases (38% v 63%, P = .01332). Among PCL patients, a trend for a worse response was observed in cases treated with melphalan and prednisone (MP) versus polychemotherapy. Overall survival was significantly worse in PCL versus MM patients (8 v 36 months,P &lt; .0001), but it was significantly better in PCL patients treated with polychemotherapy versus MP (18 v 3 months,P = .0137). By contrast, MM patients did not show significant differences in overall survival according to the treatment used, MP or polychemotherapy. Ten variables seemed to predict survival in PCL patients, but only the β2-microglobulin level and S-phase PCs retained an independent value in multivariate analysis. In summary, our study illustrates that PCs from PCL display singular phenotypic, DNA cell content, and cytogenetic characteristics that lead to a different disease evolution versus MM.

Multiple myeloma associated with serum amino acid disturbance and high output cardiac failure

We experienced a plasma cell leukemia (PCL) patient complicated with high output cardiac failure (HOCF), proved as his elevated cardiac index and pulmonary artery wedge pressure and decreased systemic vascular resistance index in a hemodynamic study. We found no possible causes of HOCF. Interestingly, HOCF was improved as PCL responded to intensive chemotherapy. On the other hand, he showed consciousness disturbance, and had frequent attacks of generalized seizure. His electroencephalogram showed slow waves, and a spike and wave complex. Hyperammonemia and abnormal amino acid distribution were also found. This abnormal serum amino acid distribution, especially elevated glycine level, was different from that seen in chronic liver failure, and he had no hepatic disease. After intensive chemotherapy, the serum ammonia level and glycine level decreased. In this patient, PCL seemed to be responsible for HOCF, hyperammonemia, and abnormal amino acid distribution. We experienced two more cases of multiple myeloma (MM) with HOCF, hyperammonemia, abnormal serum amino acid distribution, and consciousness disturbance of unknown origin. Those two cases showed slow waves in the electroencephalogram. Improvement was seen in their HOCF, hyperammonemia, and abnormal amino acid levels after chemotherapy. The possibility of MM as a cause of HOCF is discussed. Am. J. Hematol. 57:77–81, 1998. © 1998 Wiley-Liss, Inc.

MDM2 Protein Overexpression Promotes Proliferation and Survival of Multiple Myeloma Cells

AbstractThe murine double minute 2 (MDM2) protein facilitates G1 to S phase transition by activation of E2F-1 and can enhance cell survival by suppressing wild-type p53 (wtp53) function. In this study, we examined MDM2 expression and function in multiple myeloma (MM) cells. MDM2 is strongly and constitutively expressed in MM cell lines (ARH-77, RPMI 8226, and OCI-My5) and in the cells of plasma cell leukemia (PCL) patients, but is not expressed in normal bone marrow mononuclear cells (BM MNCs). Treatment of MM cells with MDM2 antisense, but not sense, nonsense, or scrambled, oligodeoxyribonucleotides (ODNs) decreased DNA synthesis and cell viability; it also induced G1 growth arrest, as evidenced by propidium iodide (PI) staining and induction of retinoblastoma protein (pRB) to E2F-1 binding. Moreover, inhibition of MDM2 using antisense ODNs also triggered MM cell apoptosis as evidenced by acridine orange–ethidium bromide staining. We next studied the association of MDM2 with wtp53 and/or mutant p53 (mtp53), E2F-1, CDK4, and p21. MDM2 constitutively binds to E2F-1 in all MM cells, to both wtp53 and mtp53, and to p21 in tumor cells lacking p53. These data suggest that MDM2 may enhance cell-cycle progression in MM cells both by activating E2F-1 and by downregulating cell-cycle inhibitory proteins (wtp53 and p21). Overexpression of MDM2 may therefore contribute to both growth and survival of MM cells, suggesting the potential utility of treatment strategies targeting MDM2 in MM.

Expression of cytoadhesion molecules (CD56, CD54, CD18 and CD29) by myeloma plasma cells

Recently we reported the expression of the human natural killer cell associated antigen CD56 (Leu 19/NKH1) in plasma cells of a majority of multiple myeloma (MM) patients. CD56 is known to be an isoform of the human neural adhesion molecule N-CAM which is involved in homotypic adhesive interactions. By immunophenotyping using four CD56 specific monoclonal antibodies and immunoprecipitation analysis we here confirm that the Leu 19 antigen expressed by myeloma plasma cells is identical to N-CAM and corresponds to the 145 kDa isoform. Because of the possible biological role of adhesion molecules on myeloma cells, we compared the expression of N-CAM with the intercellular adhesion molecule 1 (ICAM-1) and the beta 1 and beta 2 integrins. By immunogold-silver staining of cytospin preparations of mononuclear cell suspensions, bone marrow plasma cells of 17 MM patients were analysed. Plasma cells expressed N-CAM (CD56) in 14 patients. ICAM-1 (CD54) in 16 patients, and beta 2 integrins (CD18) in eight patients. beta 1 integrins (CD29) were expressed in all patients. The expression of beta 2 integrins was always very weak while N-CAM, ICAM-1 and the beta 1 integrins showed a moderate to strong positivity. The plasma cells of five haematological normal individuals lacked significant N-CAM expression but were positive for ICAM-1 and both integrin subgroups. One plasma cell leukaemia patient and two out of four end-stage MM patients showed no expression of N-CAM or beta 2 integrins on their circulating plasma cells. Among 11 previously established myeloma cell lines, surface expression of ICAM-1 and the integrins was detected in most cases, while N-CAM was present in only four lines. Most cell lines showed coexpression of the fibronectin receptors (VLA-4 and VLA-5) and the laminin receptor (VLA-6). The collagen receptor (VLA-2) was not expressed. The N-CAM negative cell lines included four cell lines that were derived from plasma cell leukaemia patients. These results indicate that the expression of adhesion molecules is an intrinsic part of the biology of multiple myeloma.

Surface antigen expression of human neoplastic plasma cells includes molecules associated with lymphocyte recirculation and adhesion

The surface phenotype of neoplastic plasma cells from peripheral blood of plasma cell leukaemia patients and bone marrow of patients with myelomatosis was investigated with two monoclonal antibody panels including 50 selected from the B cell panel of the IVth International Workshop on Leucocyte Differentiation Antigens. The majority of myelomas expressed CD24 (HB8 epitope only), CD38, CD44, CD54, and the antigen recognized by the monoclonal antibody 8A. A range of other antigens may also be expressed including CD10, CD32 (FcR II), CD19, CD20 and MHC Class II. Antigens expressed by myeloma plasma cells can be considered in three groups: (a) antigens associated with lymphocyte and plasma cell differentiation: (b) antigens which are not lineage specific: and (c) molecules concerned with lymphocyte recirculation and intercellular adhesion (CD44 and CD54). The significance of CD44 and CD54 expression by plasma cells and the potential interaction of plasma cells with T lymphocytes and monocytes is discussed.

Differential response of malignant human B-cells to anti-IgM immunoglobulin (anti-mu) and B-cell growth factor: unique direct cytotoxicity of anti-mu on prolymphocytic leukemia cells

We examined in vitro tritiated thymidine uptake by B cells from seven prolymphocytic leukemia (PLL), seven chronic lymphocytic leukemia (CLL), and four plasma cell leukemia (PCL) patients in response to culture with anti-human IgM antibody (anti-mu) and B-cell growth factor (BCGF). In contrast to the stimulatory effect observed in normal B-cell cultures, the divalent F(ab')2 anti-mu antibody uniquely inhibited the autonomous proliferation and induced marked cytotoxicity in six of seven PLL cell cultures independent of complement or Fc-receptor- mediated mechanisms. There was neither stimulation or inhibition of the slgM+ CLL or the slgM- PCL cells. The inhibitory effect on the PLL cells was observed at an anti-mu concentration below the stimulatory threshold for normal B cells. Significant impairment of trypan blue exclusion was delayed until 48 hours, with morphological cellular changes suggestive of a programmed cell death mechanism or apoptosis. The cytotoxicity was independent of the slgM-staining intensity or the autonomous and BCGF-augmented DNA synthetic activity of the PLL cells and was similar in patients with de novo PLL or with prolymphocytic transformation of CLL. Cells from a PLL patient were separated by elutriation into two fractions, a BCGF-unresponsive large “transformed” cell fraction with marked autonomous DNA synthesis and a smaller lymphoid cell subset with low 3H-thymidine uptake that could be augmented by BCGF. Both fractions were equally susceptible to the cytotoxic effect of anti-mu. These data suggest that certain slgM- bearing malignant B cells are susceptible to anti-mu-triggered cytotoxicity. They may represent the malignant counterpart of a “tolerogenic” normal B-cell subset, and the unique direct cytotoxicity of anti-mu may provide a therapeutic strategy specifically for PLL.

Differential Response of Malignant Human B-Cells to Anti-IgM Immunoglobulin (Anti-µ) and B-Cell Growth Factor: Unique Direct Cytotoxicity of Anti-µ on Prolymphocytic Leukemia Cells

We examined in vitro tritiated thymidine uptake by B cells from seven prolymphocytic leukemia (PLL), seven chronic lymphocytic leukemia (CLL), and four plasma cell leukemia (PCL) patients in response to culture with anti-human IgM antibody (anti-mu) and B-cell growth factor (BCGF). In contrast to the stimulatory effect observed in normal B-cell cultures, the divalent F(ab')2 anti-mu antibody uniquely inhibited the autonomous proliferation and induced marked cytotoxicity in six of seven PLL cell cultures independent of complement or Fc-receptor-mediated mechanisms. There was neither stimulation or inhibition of the slgM+ CLL or the slgM- PCL cells. The inhibitory effect on the PLL cells was observed at an anti-mu concentration below the stimulatory threshold for normal B cells. Significant impairment of trypan blue exclusion was delayed until 48 hours, with morphological cellular changes suggestive of a programmed cell death mechanism or apoptosis. The cytotoxicity was independent of the slgM-staining intensity or the autonomous and BCGF-augmented DNA synthetic activity of the PLL cells and was similar in patients with de novo PLL or with prolymphocytic transformation of CLL. Cells from a PLL patient were separated by elutriation into two fractions, a BCGF-unresponsive large "transformed" cell fraction with marked autonomous DNA synthesis and a smaller lymphoid cell subset with low 3H-thymidine uptake that could be augmented by BCGF. Both fractions were equally susceptible to the cytotoxic effect of anti-mu. These data suggest that certain slgM-bearing malignant B cells are susceptible to anti-mu-triggered cytotoxicity. They may represent the malignant counterpart of a "tolerogenic" normal B-cell subset, and the unique direct cytotoxicity of anti-mu may provide a therapeutic strategy specifically for PLL.