Multiple myeloma. Part II: Treatment.
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Antineoplastic Combined Chemotherapy Protocols↗
Biomedical subjects
B Varet
Publications and source records attributed to B Varet.
Description of a novel FR1 IgH PCR strategy and its comparison with three other strategies for the detection of clonality in B cell malignancies.
PCR amplification of IgH gene V-D-J junctional variability (IgH PCR) is increasingly replacing Southern analysis for the detection of clonal lymphoid populations in cases presenting diagnostic difficulties. In order to determine the most efficient strategy, we have compared three known methods, using consensus primers against the VH FR3 or FR2 (FR256) regions, or a mix of six primers against the FR1 region (FR1f), with a new approach using a consensus primer against FR1 (FR1c), never previously described for diagnostic purposes, on DNA from 89 monoclonal B-cell proliferations (16 ALL, 28 CLL/PLL, 15 myelomas, 30 NHL). We obtained a detection rate of 70% for FR3, 64% for FR1f and 77% and 78% for FR256 and FR1c, respectively. Polyclonal lymphocytes and mature T cell malignancies tested negative for all systems. Differences in the detection rate were related not only to the choice of VH primer but also the JH primer(s) used and the pathological subtype. All strategies led to adequate detection of leukaemic DNA, whereas the detection rate in myeloma varied between strategies from 47 to 80% and that of follicular lymphoma from 13 to 63%. The lowest detection rates were observed in follicular lymphoma and in mature CD5 negative proliferations, reflecting the probable correlation between somatic mutation and PCR false-negativity. The combined use of FR1c and FR256 allowed detection in at least one system of 92% of cases overall and at least 75% in all pathological subtypes, thus providing a simple, reliable and rapid non-radioactive system for the detection of B cell clonality.
Alleles↗
Quantitative non-radioactive clonality analysis of human leukemic cells and progenitors using the human androgen receptor (AR) gene.
Clonal analysis of FACS-purified primitive hematopoietic stem cells and of their progeny as assessed by the progenitors obtained from long-term cultures requires PCR-based approaches, mainly because of the low number of cells available. We have developed a non-radioactive androgen receptor (AR) assay which allows a simple and quantitative evaluation of the clonality of hematopoietic cells and progenitors. In this approach 5' AR primer is labelled by fluorescein and the amplified product is run on a sequencing gel which allows evaluation of the intensity of the fluorescent peaks generated. A computer software then analyzes the reduction of the intensity of the peaks on HpaII-digested samples. In order to determine the feasibility of the technique, we analyzed the clonality of leukemic cells from a patient with an acute-phase CMML which showed a typical clonal pattern of her leukemic DNA sample (WBC = 300 x 10(9)/I) using phosphoglycerate kinase (PGK) analysis. The same sample was then analyzed with either radioactive- or fluorescein-labelled AR primers, showing a typical clonal pattern (complete disappearance of one allele after HpaII digestion). A short-term clonogenic assay was then set up on methylcellulose and clonogenic progenitors were individually analyzed. All 24 colonies tested showed a typical clonal pattern with the disappearance of the same allele on each sample after HpaII digestion, indicating that they all derived from the same leukemic stem cell. Using this approach we then analyzed 94 patients with several hematologic malignancies and quantification of their fluorescent peaks. Fifty-four percent of the patients were clearly heterozygous (ie, a difference of > or = 2 CAG repeats was present between the two copies of the gene) and could be analyzed in an automatic sequencer using the fluorescent primers. Bone marrow mononuclear cells from all patients with acute myeloid leukemia (AML) showed a clonal or oligoclonal pattern at diagnosis whereas a polyclonal pattern was seen when remission was obtained. Similarly, out of 21 patients with a diagnosis of myelodysplastic syndrome (MDS), a clonal pattern was demonstrated in 10 whereas an oligoclonal or non-clonal pattern was shown in 11. These results show that this non-radioactive and safe technology can now be used on a large scale to evaluate the clonality of highly purified hematopoietic stem cells and their progenitors in hematopoietic malignancies and this might allow new insights into the targets of clonal amplification.
Acute Disease↗
Detection of malignant B cells in peripheral blood stem cell collections after chemotherapy in patients with multiple myeloma.
Autologous transplantation after high-dose chemo or radiotherapy is now frequently used for the treatment of patients with multiple myeloma (MM). The collection of peripheral blood stem cells (PBSC) has a theoretical advantage over autologous bone marrow collection as the malignant plasmacytic contamination is believed to be lower. However, the extent of B cell contamination in PBSC has not been extensively investigated. Using an immunoglobulin heavy chain gene 'fingerprinting' technique at diagnosis and during apheresis after one cycle of chemotherapy we detected a monoclonal population in 44% of PBSC samples (9 positives in 22 studied). There was no correlation between contamination and sex, age, Durie and Salmon classification, C-reactive protein and albumin. A significant correlation was observed with beta 2 microglobulin serum level (P = 0.02). Twenty one patients were grafted and up to the present, with a mean follow-up of 12 months, 6 patients have relapsed including 4 patients with contaminating B cells. Our results suggest that PBSC contamination, defines a 'poor risk' group of patients, with poor prognosis. However, we could not exclude reinitiation of the disease by plasmacyte stem cells after grafting.
Adult↗
Expression of the Evi-1 gene in myelodysplastic syndromes.
Increased expression of the proto-oncogene Evi-1 has been shown to block the in vitro granulocytic differentiation of myeloid cells in response to granulocytic colony-stimulating factor and to interfere with the proliferation of erythroid cells in response to erythropoietin. We determined the frequency of Evi-1 expression in myelodysplastic syndromes (MDS), a disorder with altered proliferation and differentiation in the erythroid and myeloid lineages. Twenty-one patients were studied. Abnormal expression was found in 1/9 patients with refractory anemia and in 7/12 patients with refractory anemia with excess of blasts (RAEB) or in transformation (RAEBt). No correlation could be found between expression of Evi-1 and age, sex, hemoglobin level and percentage of bone marrow blasts or erythroblasts. This result suggests that the high incidence of Evi-1 expression which remains at low levels in RAEB and RAEBt is not a major determinant of ineffective erythropoiesis and myelopoiesis in MDS.
Base Sequence↗
[A hematologist's point of view].
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Anemia, Hemolytic, Autoimmune↗
[Cutaneous transformation of chronic lymphoid leukemia into immunoblastic lymphoma. Cutaneous manifestation of Richter syndrome].
INTRODUCTION: Richter's syndrome is a large-cell lymphoma occurring in patients with chronic lymphoid leukaemia (CLL). It is rarely limited to cutaneous locations. We report the case of a 61-year-old patient with CLL who developed multiple skin lesions due to immunoblastic lymphoma. CASE REPORT: Six years after onset of CLL controlled by chloraminophen, a tumoural syndrome developed and was treated by chemotherapy. A papulonecrotic cutaneous eruption was then observed on the face, the presternal area and then on the fingers. Skin biopsy revealed large-cell CD20+ CD30+ immunoblastic lymphoma. Polymerase chain reaction on the heavy chain immunoglobulins showed a band with the same size in the skin biopsy and in the circulating cells. No transformation was found in lymph node and bone marrow biopsies. The lesions disappeared after 4 treatments with VP16, cysplatin and methylprednisolone. CLL was again stabilized after the first chemotherapy sessions. DISCUSSION: Richter's syndrome is rarely discovered due to skin lesions. There have only been 4 similar cases reported in the literature. The clinical presentation of the lesions is insufficient to distinguish them from manifestations of CLL. Histological examination of the biopsy is required to make the diagnosis of high grade lymphoma. Prognosis is usually poor after discover of this type of lymphoma. This is the first observation of Richter's syndrome revealed by a skin lesion in which polymerase chain reaction suggested that the skin lymphoma and the CLL cells came from the same B clone.
Humans↗
[Collection and manipulation of human hematopoietic cell lines].
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Antigens, CD↗
A spontaneous remission of lymphoid blast crisis in chronic myelogenous leukaemia following blood transfusion and infection.
We report a case of spontaneous remission of lymphoid blast crisis in chronic myelogenous leukaemia (CML) which returned to chronic phase, without the use of cytostatic chemotherapy, following an episode of viral infection and blood transfusion. Although complete remissions of acute leukaemia have been described, this evolution is extremely rare and has never been reported in CML blast crisis. The role of hypothetical factors leading to such a rare event are briefly discussed.
Aged↗
[Erythroblastopenia: chronic idiopathic or associated with chronic lymphoid leukemia. Value of cultures of erythroblastic progenitors and therapeutic strategy].
Fifty cases of chronic pure red cell aplasia in adults (idiopathic in 32 cases, associated with chronic lymphocytic leukaemia in 18) were followed up after studying their erythroblastic precursors in vitro. Analysis of response to immunomodulators confirmed the existence, in patients with idiopathic chronic pure red cell aplasia, of a relationship between in vitro behaviour and obtention of a remission: patients with normal differentiation of erythroblasts consistently responded to treatments, whereas treatments were usually ineffective when the erythroblasts did not differentiate in vitro. When in vitro differentiation was below normal, responses to treatments were varied. In patients with chronic lymphocytic leukaemia, the erythroblastic precursors were normal in 15/18 cases, and response to immunomodulators was observed in 13/18 cases. A second objective of this study was to determine, on a large series, the most adequate immunomodulator treatment. In idiopathic chronic pure red cell aplasia the most efficient therapy was corticosteroids and cyclophosphamide administered separately or together. The antilymphocyte serum gave disappointing results. In pure red cell aplasia associated with leukaemia cyclophosphamide was the most frequently effective drug, with corticosteroids taking second rank; however, infections were frequent. The treatments to be considered when both corticosteroids and cyclophosphamide fail are discussed.
Adrenal Cortex Hormones↗
[Anemias due to erythroblastopenia].
Anaemias caused by pure red cell aplasia may regress spontaneously (acute) or remain chronic. They have multiple causes, the most frequent of which, in chronic pure red cell aplasia, is chronic lymphocytic leukaemia. It is important to find that the anaemia is due to pure red cell aplasia since this may raise hopes of cure after an immunosuppressive treatment. In patients with chronic pure red cell aplasia the in vitro study of erythroid precursors has a prognostic value.
Acute Disease↗
Erythropoietin synthesis by tumor cells in a case of meningioma associated with erythrocytosis.
While secondary erythrocytosis is often associated with tumors arising from the kidney, other tumors have been described to originate in the liver, uterus, ovary, adrenal gland, and central nervous system, among which cerebellar hemangioblastomas are involved in most instances. Two cases of meningioma associated with erythrocytosis have already been reported. We observed a 59-year-old female patient who had developed a frontal meningioma associated with erythrocytosis. Before surgery, she had a significantly elevated total red blood cell volume with a normal plasma volume. Serum erythropoietin (Epo) dosage assessed by radioimmunoassay was within the normal range. The tumor was removed and the pathologic study found a meningotheliomatous meningioma. Total RNA from the tumor was hybridized to a monkey cDNA Epo probe. A strong 1.6-kb messenger RNA (mRNA) signal was observed, which is the expected size of human Epo mRNA. In situ hybridization with the 35S-labeled Epo probe was performed on frozen tumor tissue sections. A significant hybridization was observed in all the tumor cells, whereas the stroma was negative. Therefore, in this meningioma associated with erythrocytosis, Epo was produced by the tumor cells themselves.
Erythropoietin↗
High doses of intravenous recombinant erythropoietin for the treatment of anaemia in myelodysplastic syndrome.
We studied the efficacy of high doses (100,000 IU intravenously (IV)/twice a week) of human recombinant erythropoietin (rHuEpo) in patients with transfusion dependent myelodysplastic syndromes (MDS). Rationale for such dose of IV Epo was the poor in vitro response of MDS erythroid progenitors (CFU-E) to physiological concentrations of Epo, and the usual high endogenous serum Epo levels of MDS patients. Seventeen patients (nine males, eight females) were included, five refractory anaemia (RA), six RA with blasts excess (RAEB), five RA with ringed sideroblasts (RARS). Tolerance was good, except in three patients who experienced severe flu-like syndrome after Epo injection. None of the patients showed hypertension or developed anti rHuEpo antibodies. Three patients (17.6%) with RAEB had 35-60% reduction of transfusion requirements. No progression of disease occurred. Percentage of erythroblasts, endogenous baseline Epo level and in vitro cultures of erythroid progenitors did not correlate with response to Epo treatment. This study shows that very high IV doses induce only seldom and partial improvement in the status of transfusion dependent MDS. This rate of response, not higher than described with lower dosage, probably represents the maximum expectable response to rHuEpo in this category of patients.
Adult↗
Adult acute lymphoblastic leukemia: a multicentric randomized trial testing bone marrow transplantation as postremission therapy. The French Group on Therapy for Adult Acute Lymphoblastic Leukemia.
PURPOSE: In a prospective multicenter study, we analyzed the benefits of allogeneic bone marrow transplantation (BMT) in a nonselected group of adult patients with acute lymphoblastic leukemia (ALL) and, by a randomized trial, evaluated the effectiveness of autologous BMT over chemotherapy as postremission therapy in patients younger than 50 years who were not candidates for allogeneic BMT. PATIENTS AND METHODS: After induction therapy that randomized patients to receive one of two anthracycline-containing regimens, either daunorubicin (DNR) or zorubicin (ZRB), patients were assigned to postremission treatment according to age and results of HLA typing. Patients younger than 40 years with an HLA-identical sibling (group 1) were scheduled to receive cyclophosphamide 60 mg/kg on days 1 and 2, total-body irradiation (TBI), and allogeneic BMT. Patients older than 50 years (group 2) received the chemotherapy arm composed of three monthly consolidation courses (DNR or ZRB, cytarabine, and asparaginase) followed by maintenance chemotherapy (modified L10 regimen). The remaining population (group 3) was randomly assigned to receive, after the three 1-month consolidation courses, either the chemotherapy arm or autologous BMT following a conditioning regimen similar to that of group 1. RESULTS: Of the 572 assessable patients, 436 achieved complete remission (78% +/- 2% for DNR v 74% +/- 3% for ZRB; P = .3). The estimated 3-year disease-free survival (DFS) rate for the 116 patients included in group 1 was 43% +/- 5%. Both autologous BMT (95 patients) and chemotherapy (96 patients) produced comparable 3-year DFS rates (39% +/- 5% v 32% +/- 5%) and survival durations (49% +/- 5% v 42% +/- 5%). However, late relapses after 36 months were mainly observed in the chemotherapy arm. CONCLUSION: This first interim analysis did not demonstrate a benefit of this autologous BMT procedure over classical maintenance chemotherapy in patients with ALL who received consolidation chemotherapy.
Adolescent↗
Prognostic factors of invasive pulmonary aspergillosis in leukemic patients.
The study objective was to identify prognostic factors associated with survival in patients treated for acute leukemias who developed invasive aspergillosis (IA) during induction therapy. This retrospective analysis involved 21 patients treated in two hematologic centers over a six-year period. All were treated in protective isolated rooms with high-dose amphotericin B as soon as fungal infection was suspected. Ten (45%) of the twenty-one patients died. There was no statistical difference between the patients who survived and those who died in relation to the mean time of onset of IA or the total and mean daily dose of amphotericin B. On the other hand a favourable outcome correlated strongly with complete leukemic remission (p < 0.0001): all but one of the patients with objective residual leukemia died of IA, whereas all those who achieved complete hematological remission survived. In conclusion, it seems that the main vital prognostic factor in these leukemic patients with IA was the achievement of complete remission. We were unable to control IA in 10 of 11 patients with refractory leukemia, regardless of neutropenic status, despite early administration of high-dose amphotericin B. All the patients who achieved complete remission were successfully treated with amphotericin B.
Acute Disease↗
High-dose recombinant human erythropoietin administered intravenously for the treatment of anaemia in myelodysplastic syndromes.
As the importance of recombinant human erythropoietin (r-HuEPO) therapy has been clearly demonstrated in anaemic patients with chronic renal failure (CRF), we carried out an open, non-randomized, non-placebo-controlled trial of high-dose intravenous (i.v.) r-HuEPO (100,000 U twice weekly) therapy in 14 anaemic, transfusion-dependent patients. Clinical response was defined by a rise in haemoglobin concentration to 9-11 g/dl and/or a reduction in the transfusion requirement during the treatment period compared with the 12 weeks before treatment. Eight patients completed the 12-week treatment and 4 were still under treatment, 1 at 10 weeks, 2 at 8 weeks and 1 at 4 weeks. Only those patients completing treatment were included in the efficacy evaluation. After treatment there was no significant change in haemoglobin concentrations, reticulocyte counts, or transfusion requirements. However, the number of patients included is too low to allow any definitive conclusion to be made.
Adult↗
Correlation between the biological and therapeutic effects of interferon-alpha in low-grade nodular non-Hodgkin's lymphoma: lack of in vivo down-regulation and reduced affinity of IFN-alpha receptors in unresponsive patients.
We investigated the correlations between the biological effects of interferon-alpha (IFN-alpha) and clinical responsiveness in low-grade non-Hodgkin's lymphomas (NHL). In this disease, 40-50% of cases respond to IFN-alpha therapy. Patients with nodular NHL were selected for a phase II trial in which they were treated daily with 9 x 10(6) U of IFN-alpha 2a. Binding experiments with [125I]IFN-alpha 2a showed the presence of IFN-alpha receptors on tumor B-cells isolated from lymph nodes before therapy in 9 out of 10 patients. Receptor levels were not related to the subsequent clinical responses. However, no specific binding was detected in one patient who turned out to be unresponsive to IFN-alpha treatment. Single injections of IFN-alpha 2a before beginning the therapeutic protocol resulted in down-regulation of IFN-alpha receptors without change in their affinity in peripheral blood leukocytes from only patients who subsequently responded to therapy (4/10). In 4/5 non-responders and one patient displaying a minor response, receptor numbers did not decrease but Kd values rose markedly in all six cases. These results indicate that lack of in vivo IFN-alpha receptor down-regulation and reduced receptor affinity, as detected before therapy, may be correlated with failure of IFN-alpha therapy in nodular NHL.
2',5'-Oligoadenylate Synthetase↗