[Multiple primary cutaneous plasmacytoma]. / Plasmocytomes cutanés primitifs multiples.

BACKGROUND: Primary cutaneous plasmacytoma is a rare form of cutaneous B-cell lymphoma. PATIENTS AND METHODS: A 51 year-old male with an unremarkable history gradually presented erythematous papulonodular lesions that had appeared gradually over the whole body throughout a two-year period and showing histologic and immunohistochemical features of cutaneous plasmacytoma. Staging investigations confirmed the primary character of the disease, and because of this and the absence of functional impairment, we opted for therapeutic abstention. No progression was noted after 4 years of regular monitoring. DISCUSSION: Primary cutaneous plasmacytoma (PCP) is characterized by clonal proliferation of plasma cells in skin. Multiple PCPs are extremely rare and to date have been treated in most cases by chemotherapy, either with or without radiotherapy. The prognosis is poor, with 2-year survival of only 25%. The present case is original, being the only one to our knowledge in which therapeutic abstention was followed by a lack of progression after 4 years of regular follow-up. Consequently, certain indolent forms of PCP do not warrant automatic institution of chemotherapy.

Diabetes insipidus revealing acute myelogenous leukaemia with a high platelet count, monosomy 7 and abnormalities of chromosome 3: a new entity?

We describe three cases of acute myeloid leukaemia revealed by diabetes insipidus. The patients were 42, 38 and 39 yr old and they had marked hyperleukocytosis, circulating immature granular cells and a normal or elevated platelet count. The leukaemia was type AML-M2 according to the FAB classification. Cytogenetic studies showed inversion of chromosome 3 (q21;q26) in 2 cases and a translocation (3;3)(q21;q29?) in the remaining case, both associated with monosomy 7. All the cerebral CT scans were normal. Complete remission was never achieved, and all three patients survived less than 14 months. Desmopressin therapy was active but treatment could not be reduced. The association of dysmegakaryopoiesis with a chromosome 3 abnormality and diabetes insipidus is probably not fortuitous and could represent a new entity.

Humanized anti-CD20 monoclonal antibody (Rituximab) in post transplant B-lymphoproliferative disorder: a retrospective analysis on 32 patients.

BACKGROUND: B-lymphoproliferative post-transplant disorder (BLPD) is a severe complication of organ and bone marrow transplantation. The reduction of immuno-suppressive therapy or surgery for localized disease may cure some BLPDs. Other therapeutic approaches such as chemotherapy and antiviral drugs are toxic and of limited efficacy. Adoptive immunotherapy with donor T-cell infusions has yielded promising results but is, at the present time, easily applicable only in bone marrow-transplanted patients. Anti-B-cell Murine monoclonal antibodies (MoAbs) have proven effective but are no longer available for human use. We report the activity of a humanized anti CD 20 Mo Ab (Rituximab-MABTHERA Roche) in 32 episodes of BLPD treated in 14 French centers. PATIENTS AND METHODS: Between November 1997 and September 1998, 32 patients were diagnosed with BLPD. Twenty-six patients had undergone solid organ transplants (liver 8, kidney 8, heart 4, lung 3, heart lung 1, kidney-pancreas 1, liver-kidney 1) and six patients had received bone marrow transplantations. The median age of the patients was 34 years (3-67 years) and the median delay between graft and tumor 5 months (1-156 months). In organ recipients, tumors were classified as polymorphic and monomorphic in 10 and 15 cases, respectively; 4 of 6 bone marrow transplant recipients were treated without pathology documentation because of a rise in EBV load, fever and lymph node enlargement. Tumors were associated with EBV in 22 of 26 tested cases. Rituximab was used as first-line therapy in 30 patients (after reduction of immunosuppressive treatment in 27 patients) and as salvage therapy in 2 patients (after failure of chemotherapy). The median time from diagnosis of BLPD to treatment with Rituximab was 14 days (1-110 days). Two patients received eight infusions, twenty-six patients four infusions, one patient three infusions and three patients two infusions of 375 mg/m2. RESULTS: The tolerance of rituximab was good. The overall response rate was 69%, with 20 complete responses and 2 partial responses. In solid organ transplant the response rate was 65% (15 CR and 2 PR) while it was 83% in bone marrow-transplanted patients (5 CR). With a median follow-up of 8 months (1-16 months) 24 patients are still alive. The one-year projected survival is 73%. Of the 22 patients who achieved response, 15 patients (11 solid organ transplant and 4 bone marrow transplant) are alive with no evidence of disease, 4 patients relapsed a median of 7 months (3-10 months) after treatment and 3 died while in CR of concurrent diseases. Of the 10 patients who did not respond to Rituximab 5 are alive with no evidence of disease after salvage therapy. CONCLUSIONS: The use of rituximab appears to be a safe and relatively efficient therapy in BLPDs. The results need to be confirmed in a prospective multicentric trial.

Detection of membrane and soluble interleukin-6 receptor in lymphoid malignancies.

We studied the membrane expression of the gp80 chain of IL-6 receptor (IL-6R) by quantitative flow cytometry in chronic lymphocytic leukaemia (CLL) and leukaemic centrocytic lymphoma using a panel of seven monoclonal antibodies. IL-6R was detected in 18/26 CLL cases and 4/7 lymphoma cases, with a mean antigen density < 3000 molecules/cell. Multiple labelling experiments confirmed the IL-6R expression by neoplastic cells. Specific mRNA was found by RT-PCR in neoplastic cells. A specific ELISA test was designed using two anti-IL-6 receptor MAbs to measure the serum soluble IL-6R (sIL-6R) in CLL (n = 48). B-cell non-Hodgkin's lymphoma (NHL; n = 40), and monoclonal gammopathy (MG; n = 32). SIL-6R was higher in CLL (170 +/- 12.6 ng/ml) in NHL (160 +/- 12 ng/ml) and MG patients (183 +/- 23 ng/ml) than in age-matched controls (100 +/- 5.6 ng/ml; P < 0.001) and higher in high-grade than low-grade NHL. No correlation was noted with a previous treatment. Among CLL cases the patients classified as stage B according to the Binet's staging of the disease had the highest sIL-6R values, thus suggesting a link with tumour cell mass.

Leukemia-associated changes identified by quantitative flow cytometry. II. CD5 over-expression and monitoring in B-CLL.

The CD5 antigen density on B cells was studied on fetal spleen, cord blood, and adult peripheral blood (after immunomagnetic bead purification) using an indirect immunofluorescence technique. In fetal spleen, there was a continuum in CD5 expression, whereas all cord blood and less than 20% adult peripheral blood B cells were CD5+. Mean CD5 antigen density on these normal cells was low (3-6 x 10(3) molecules/cell); eight to 20 times lower than on normal T lymphocytes. In adult blood, less than 10% B cells expressed more than 3 x 10(3) CD5 molecules/cell. In chronic malignancies, 34/35 cases had a CD5 antigen density lower than on residual T cells, but mean antigen density was higher (14.8 +/- 2.1 x 10(3) molecules/cell) than on normal B cells. Sixteen cases of chronic lymphocytic leukemia (50%) expressed a CD5 density above 10 x 10(3) molecules/cell. This aberrantly high CD5 expression was used to detect neoplastic cells after dilution in normal lymphocytes, with a limit of detection between 1:100 and 1:1000. Quantitation of the CD5 antigen allows better characterization of the B1 population and should be used for the monitoring of chronic malignancies.

CD23 antigen density is related to serum gamma globulin level, bone marrow reticulin pattern, and treatment in B chronic lymphocytic leukemia.

The CD23 antigen density was evaluated by a cytofluorometric technique in 55 patients with chronic lymphocytic leukemia. The quantification method was based on the use of biological standards in indirect immunofluorescence. The CD23 antigen density was correlated with the percentage of CD23 positive cells, but antigen density appeared to be a more informative parameter. CD23 antigen density was lower in stage B than in stages A or C patients, and higher in patients undergoing chemotherapy or previously treated than in untreated patients. There was a significant negative correlation between CD23 antigen density and serum gamma globulin and IgG levels, that existed only in patients in an advanced stage of the disease. CD23 antigen density was higher in patients with abnormal bone marrow reticulin pattern. Serum gamma globulin level was lower in these patients, as well as in patients with prognostically unfavorable histologic bone marrow infiltration pattern. These data emphasize the interest of antigen density as an additional parameter and the complex relationship between CD23 expression, hypogammaglobulinemia, bone marrow histologic findings, and treatment in chronic lymphocytic leukemia.

Quantification of CD24 and CD45 antigens in parallel allows a precise determination of B-cell maturation stages: relevance for the study of B-cell neoplasias.

Quantitative expression, i.e. absolute number of monoclonal antibody molecules bound per cell, was evaluated for CD24 and CD45 by flow cytometry with standards of fluorescence intensity on a panel of normal and neoplastic B cells. The CD24 antigen was expressed at homogeneous high level in fetal bone marrow and liver. Its density decreased progressively in the other normal tissues in parallel with the B-cell maturation. The ratio between CD24 density measured on fetal bone marrow B cells and that seen on adult peripheral B cells was 6:1. The CD45 antigen density was lower on fetal bone marrow cells than in the more mature stages. Fetal spleen lymphocytes and all the mature B lymphocytes displayed the same CD45 density than that seen on normal adult peripheral T cells. The CD24/CD45 antigen density ratio was precisely related to the stage of B-cell maturation. The same pattern of variation of CD24 and CD45 antigen density was seen on B-cell neoplasias, with a significantly higher value of CD24 and lower value of CD45 in acute lymphoblastic leukemias than in chronic malignancies. CD24 and CD45 antigen levels were frequently out of the range observed in the corresponding normal population. Among ALL patients, a low CD24/CD45 antigen density ratio was associated with a good prognosis. These data confirm the interest of an absolute quantitative study for widely distributed antigens.

Cell targeting by murine recombinant retroviruses.

Cell targeting by murine retroviruses carrying recombinant genes would have numerous applications such as immortalization of under-represented cell types from complex cellular mixtures, increasing therapeutical yields in the case of gene therapy and delivery of specific genes at any location and at any moment of the life-time of living animals. To this aim, we are currently developing techniques that allow binding of viral particles to specific cell membrane markers different from the natural receptors. We have shown that biochemical bi-specific molecular adaptors able to bind both viral particles and cell surface molecules may reveal appropriate for piloting viruses toward specific cell types. More recently, we have undertaken the genetic engineering of the retroviral envelope glycoprotein in order to modify its natural tropism. This approach is discussed below.