Haematologica 2003 - Supplements

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169 SOLUBLE CD138: A NEW IMPORTANT MARKER IN DIAGNOSIS OF MULTIPLE MYELOMA Vladimir Maisnar, Miroslava Touskova, Miloslav Kmonicek, Jan Krejsek, Pavel Zak, Otakar Kopecky, Jaroslav Maly Department of Haematology and Institute for Clinical Immunology and Allergy, Charles University Teaching Hospital Hradec Kralove, Czech Republic Objectives: Multiple myeloma (MM) is a B-cell malignancy characterised by the progressive accumulation of clonal malignant plasma cells. Previous studies have shown that syndecan-1 (sCD138) is shed from the surface of myeloma cells into serum and that this marker is a new independent prognostic parameter in MM. Methods: In our study we evaluated value of sCD138 in serum samples drawn at diagnosis from 14 MGUS patients and 37 MM patients, 17 patients were treated by high-dose chemotherapy regimen. For determination of sCD138 level we used a rapid and simple ELISA procedure (Diaclone, France). Results: Mean serum levels of sCD138 in MGUS patients were 32.4 (median 35.1) ng/ml and 1004.4 (median 202.1) ng/ml in MM patients (p500 ng/ml) had worse prognosis (p = 0.049) despite of good response to chemotherapy in some of them. Conclusions: We present our first experience with the use of the new important prognostic marker in diagnosis of MM. We verified its very strong prognostic significance. In our opinion the determination of sCD138 can also be recommended as helpful marker for differential diagnosis of monoclonal gammopathies. 170 Serum free light chain concentrations and their use for disease monitoring in multiple myeloma patients with intact immunoglobulin monoclonal proteins Mead GP, Carr-Smith H, Drayson M and Bradwell AR. The Binding Site111 Dale RoadBirminghamUKB29 6AY Introduction: Automated serum assays specific for free immunoglobulin light chains (flc), have shown elevated serum flc concentrations in all of 224 cases of light chain multiple myeloma and 68% of 28 cases of nonsecretory multiple myeloma. In this retrospective study, we determined the proportion of myeloma patients producing intact immunoglobulin monoclonal proteins who also had elevated levels of serum flc. In addition, flc levels in some of these patients, were measured during the course of cytotoxic chemotherapy and their changes compared with those of other disease markers. Materials & Methods: Flc levels were measured in presentation sera from 492 subjects entered into the UK MRC myeloma trials (314 IgG, 142 IgA & 36 IgD) and compared with levels in 282 normal individuals. Assays were also performed on 37 sera from patients being treated for Waldenstrom’s macroglobulinaemia (WM) and 5 IgE myeloma sera. Flc levels in serial serum samples from 17 myeloma trial patients (12 IgG & 5 IgA) were measured and where possible, compared with measures of total immunoglobulins, monoclonal immunoglobulins (by electrophoresis and densitometry), 2 microglobulin and bone marrow plasma cell counts. The intervals between samples varied from 3 weeks to 1 year. All flc assays were performed on the Behring NephelometerTMII. Results: In the presentation sera, elevated flc levels were observed in 84% (265/314) of the IgG myelomas, 92% (130/142) of the IgA, 94% (34/36) IgD, 100% (5/5) IgE and 89% of the WM sera. In the serial samples, all patients showed some fall in their monoclonal immunoglobulins, total immunoglobulins and flc after initial chemotherapy. The range of change in the flc concentrations was typically several-fold greater than for the intact immunoglobulin. For the majority of IgG myelomas, the timing of the samples revealed that flc concentrations stabilised within the normal range in advance of the intact immunoglobulin but this was apparent in only 1 of 5 IgA patients. There was an initial fall in 2 microglobulin levels in only 5/17 patients but the speed of normalisation matched that of the flc. In 5 patients, bone marrow plasma cell counts had been made while the flc concentration was within the normal range but monoclonal IgG was still present by electrophoresis; in all these cases the plasma cell counts were
Patient 1 (IgG/κ);IgG – 16.5 days, free κ - 5 days Patient 2 (IgG/λ; IgG – 10 days, free λ - 5 days Patient 3 (IgA/κ); IgA - 2.5 days, free κ5days Patient 4 (IgA/ λ;IgA – 3.5 days, free λ - 1.5 days The estimated half-lives for the free light chain were always shorter than for the intact immunoglobulin. This difference was greatest for the IgG monoclonal proteins in accordance with the known serum half lives in normal individuals (IgG1,IgG2 & IgG4, 12 -21 days; IgG3, 7–8 days; IgA, 6 days and free light chain 2-6 hours). The shorter half-life of the free light chains should provide a more accurate estimation of the rate of tumour kill. Half-life estimates were quite different between the 4 patients but the relationship to prognosis has yet to be established. In two patients, the melphalan treatment produced no reduction in the concentration of the alternate (non-tumour) light chain while in a third, the concentrations of both light chains decreased at the same rate. By monitoring the concentrations of both light chain types, it should be possible to gain an estimate of the differential killing rates of the tumour and non-tumour plasma cells. It was notable that the flc half lives in the patients producing IgG monoclonal proteins were considerably longer than in the patients with IgA monoclonal proteins. Further patients need to be examined to determine whether this is chance or a consistent finding. 172 Prognostic significance of immuneparesis in progression of solitary bone plasmacytoma Rabin N, Kyriakou C, Peggs K, Ardeshna K, Yong K, D’Sa S. Department of Haematology, Mount Vernon Hospital, Rickmansworth Road, Northwood, Middlesex, HA6 2RN, UK, and Department of Haematology, University College London Hospitals, Grafton Way, London, WC1E 3BG, UK. Prognostic factors for patients with plasmacytoma are not fully understood. This study aims to further define factors predicting outcome for patients diagnosed with a solitary plasmacytoma. Twenty -nine patients were studied retrospectively, including 23 with solitary bone plasmacytoma (SBP) and 6 with solitary extramedullary plasmacytoma (SEP). Median age was 54 years (range 21 to 81) and 70 years (range 52 to 88) respectively. Thirteen patients with SBP had axial disease (56 %). All patients with SBP received radiotherapy (median dose 40 Gy range 20 to 50 Gy), 10 had prior surgery and 4 prior VAD chemotherapy. Five of 6 SEP patients received radiotherapy (median dose 48 Gy; range 27 – 50 Gy) and 1 had oral melphalan chemotherapy. Results: SBP patients: Serum paraprotein was present in 16 of 22, BJP in 4 of 16 and immuneparesis in 5 of 21 evaluable patients. β2 microglobulin was normal in 14 of 15 patients, and raised in 1. Local relapse occurred in 2 patients at 8 and 31 months. Radiotherapy dose, diagnostic paraprotein level, disappearance of paraprotein at 1 year, and immuneparesis at diagnosis did not predict relapse. Eight patients progressed to MM at a median of 18 months (range 6 to 48 months), including one patient with a distant relapse at 18 months, progressing to MM at 4 years. Median follow up from progression to MM is 20 months. Immuneparesis at diagnosis predicted progression to MM (p=0.0112). Of 5 patients with immuneparesis 4 progressed to MM the other to amyloidosis. Paraprotein disappeared at one year following treatment in 3 patients, none of whom developed MM (not significant). Axial site of disease, radiotherapy dose, serum paraprotein at diagnosis and β2 microglobulin did not predict progression to MM. Twenty-one of 23 patients remain alive at a median of 3 years (range 2 months to 11 years). Two patients died. One died of unrelated causes. One progressed to MM (at 6 months, died at 10 months). SEP patients: M protein was present in 2 patients (1 serum, 1 BJP), 3 were non-secretory, and 1 not assessed. None were immuneparesed. BJP disappeared in 1 patient; follow up paraproteins were not recorded in the other patients. Three died of unrelated causes. Three patients are alive at a median of 18 years (range 2 to 22 years). Relapse occurred in 2 patients. One had local relapse at 15 years (treated with radiotherapy), and remains alive at 18 years after diagnosis. The other patient relapsed with multifocal plasmacytomas, spanning 2 to 13 years following diagnosis and remains alive at 22 years (treated with radiotherapy and chemotherapy). Neither has evidence of MM, and both are disease free. Conclusion: Results support immuneparesis at diagnosis as predicting progression to MM. Site of disease (axial skeleton), radiotherapy dose, level of serum paraprotein, disappearance of paraprotein and beta 2 microglobulin did not predict disease progression. The long overall survival of this group of patients, including those with disease relapse or progression to MM underscores the responsiveness to treatment and indolent nature of SBP and SEP. 173 CYCLIN D1 OVEREXPRESSION IS NOT AN ADVERSE PROGNOSTIC VARIABLE FOR NEWLY DIAGNOSED MULTIPLE MYELOMA PATIENTS TREATED WITH HIGH-DOSE CHEMOTHERAPY Simona Soverini, Michele Cavo, Carolina Terragna, Deborah Ruggeri, Nicoletta Testoni, Claudia Cellini, Antonio de Vivo, Antonino Neri,* Sonia Fabris,* Marilina Amabile, Tiziana Grafone, Emanuela Ottaviani, Barbara Giannini, Patrizia Tosi, Elena Zamagni, Francesca Bonifazi, Delia Cangini, Sante Tura, Michele Baccarani, Giovanni Martinelli. Institute of Hematology and Medical Oncology “Seragnoli”, University of Bologna, Bologna, Italy;* Ospedale Maggiore IRCCS, University of Milan, Milan, Italy. In the present study we analyzed the frequency and the clinical and prognostic relevance of cyclin D1 expression, as evaluated by a real-time RT-PCR assay, in a series of 74 patients with de novo multiple myeloma (MM) who were randomized to receive either single (Tx-1) or double (Tx-2) PBSC autotransplants (see Cavo et al, IX International Workshop on MM) as primary therapy for their malignancy. In 46 patients for whom sufficient material was available, conventional cytogenetic and/or FISH analyses were performed in an attempt to investigate the presence of chromosome 11 and 13 abnormalities. Patients harboring the t(11;14) had significantly higher cyclin D1 mRNA levels than those with trisomy 11 (P=0.001). Both these subgroups significantly overexpressed cyclin D1 in comparison to patients with no evidence of 11q abnormalities ( P
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Focussed Symposia Arsenic trioxide
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assess whether such a program will
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The overall response rate was noted
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Figure 5A Table 1: VEL + THAL for R
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naturally occurring OPG. Present tr
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0.505). Finally, the multiple event
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CLINICOPATHOLOGICAL DEFINITION OF W
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Plenary Sessions 1. Development of
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clonotypic IgH VDJ signature confir
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can be considered as two entities,
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immunofluorescence staining for DKK
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P2.3 DEVELOPMENT OF A MULTIPLE MYEL
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P2.5 MOLECULAR CYTOGENETICS OF MYEL
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clear that the biggest challenge fo
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esponse and have demonstrated that
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variable region of the idiotypic im
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4. From MGUS to symptomatic MM Fig.
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(MRI); some have claimed that level
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P4.5 CYTOKINES IN MGUS: THERAPEUTIC
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preventing phosphorylation of p70S6
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transducing component of the interl
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survive initial drug exposure and a
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quiescent counterpart, the human um
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transcriptional activity of NF-êB;
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manifestations and anomalous protei
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P7.4 ROLE OF SERUM FREE LIGHT CHAIN
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P7.6 IMMUNOPHENOTYPIC INVESTIGATION
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presumably through the circulation,
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9. Chemotherapy, maintenance treatm
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stratified according to their antim
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explore higher doses of zoledronic
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initial therapy. However, the role
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P10.2.2 SINGLE VERSUS TANDEM HIGH D
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With a median follow-up of 38 month
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cells could be harvested following
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11. What is the role of allogeneic
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found that 75% of patients who were
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patients with responsive disease 3
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9. Giralt S, Estey E, Albitar M, et
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Badros A, Barlogie B, Siegel E, et
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Figure 3b. Event-free Survival 4-Ye
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improve patient outcome in MM. Impo
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myeloma and in 40% of previously un
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degrade OPG in the same way as myel
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P12.2.5 MONOCLONAL ANTIBODY THERAPY
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myeloma. Blood 2001; 98:210-216. 6.
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MHC molecules, in effectively prese
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mice demonstrate that class II-spec
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detected in 293 and NIH3T3 cells. S
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hypothesis that (1) CCND1 and FGFR3
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patient samples. In addition, the p
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016 NEUTRAL ENDOPEPTIDASE (CD10) KN
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2. Genetic heterogeneity in MM: imp
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evidence from two t(11;14) cases wh
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immunoglobulin heavy chain (IgH) lo
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034 Instability of Pericentromeric
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clusters were found, the first was
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MGUS but most likely not crucial fo
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Objective: To compare the impact on
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4 patients had MMSET/IgH but did no
Page 121 and 122: and clonal PC from MGUS, MM and PCL
Page 123 and 124: 059 VEGF receptor expresion in Mult
Page 125 and 126: two HLA-A2+ myeloma patients with C
Page 127 and 128: molecules expressed on the surface
Page 129 and 130: Recognition of these antigens appea
Page 131 and 132: Diagnosis requires a single area of
Page 133 and 134: 081 Incidence of solid tumors in co
Page 135 and 136: Growth Factor (VEGF), Hepatocyte Gr
Page 137 and 138: PC-AI levels of MGUS and SMM patien
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Page 143 and 144: 103 Vascular amyloidosis induces se
Page 145 and 146: 5. Signal transduction pathways and
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Page 149 and 150: 118 IL-6- Induced Phosphorylation o
Page 151 and 152: 123 THE IGF/IGF-1R SYSTEM IS A MAJO
Page 153 and 154: human myeloma cell line (HMCL) to a
Page 155 and 156: ligation or dexamethasone (Georgii-
Page 157 and 158: 6. Role of microenvironment 6.1 Cel
Page 159 and 160: 141 Human myeloma cells adhere to f
Page 161 and 162: 145 STUDY OF BONE MARROW ANGIOGENES
Page 163 and 164: patients, the growth of primary mye
Page 165 and 166: tibia (con=49.1±0.7mg/cm2 vs 5T2=4
Page 167 and 168: 157 The Nitrogen-Containing Bisphos
Page 169 and 170: 7. New prognostic criteria for clas
Page 171: atio of >3. This system has subdivi
Page 175 and 176: 176 Pro-inflammatory and angiogenic
Page 177 and 178: 180 Clinical study on the bone lesi
Page 179 and 180: 7.2 Imaging studies 185 99mTc-MIBI
Page 181 and 182: 189 Factors Predicting Occult Spina
Page 183 and 184: vivo detected resonances was invest
Page 185 and 186: Support Unit (CTSU) with flexibilit
Page 187 and 188: (β2m) & C reactive protein (CRP).
Page 189 and 190: plasmids carrying the clonotypic in
Page 191 and 192: newly diagnosed multiple myeloma as
Page 193 and 194: 216 Transgenic expression of Myc an
Page 195 and 196: 221 Prolonged survival in the 5T2MM
Page 197 and 198: 9. Chemotherapy, maintenance, treat
Page 199 and 200: 229 EFFECTIVENESS OF STANDARD CHEMO
Page 201 and 202: 234 Melphalan and Dexamethasone- Is
Page 203 and 204: Methods. We investigated the VECD p
Page 205 and 206: 9.2 Renal complications. 243 MERIT
Page 207 and 208: cost of SRE-related care was $10,24
Page 209 and 210: those with Hb >13 g/dL. Analysis of
Page 211 and 212: sustained response, lasting from 52
Page 213 and 214: proportion of bone abnormality. IgD
Page 215 and 216: disease. The lack of response to in
Page 217 and 218: yielding a median of 3x106/kg CD34
Page 219 and 220: patients(pts) aged ≥60 yrs. We co
Page 221 and 222: PBSC mobilizing regimen utilizing C
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their leukocytes and platelets. No
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25 Gy to marrow. The tracer dose wa
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non-CR after the first transplant a
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296 PERIPHERAL BLOOD STEM CELL TRAN
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References Effect of dose-intensive
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with cyclosporine A and methotrexat
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11.Role of novel therapies targetin
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312 Thalidomide as Rescue of Relaps
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patients, light chain in 1 patients
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platelets of 207 (76-402), B2M of 3
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325 Low Dose Thalidomide plus Dexam
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in 5 pts (11%), M protein decreased
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time from diagnosis was 3.7 years a
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339 Thalidomide, Clarithromycin and
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344 COMBINATION OF THALIDOMIDE, DEX
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experienced early death during the
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untreated patients with high tumor
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357 Thalidomide protects endothelia
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362 EOSINOPHILIA IS A VERY COMMON F
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11.5 CC 4047, PS 341 and arsenic tr
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without chromosome 13. Mean IC50 fo
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myeloma patients. Phase I data indi
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11.6 Other drugs 380 EFFECT OF STI5
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significant inhibition of cell prol
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which acts to prevent the synthesis
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of B and its metabolites, however,
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and 10 months after start of therap
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terminal kinase (JNK) pathway which
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lymphocytes was tested by Ellispot.
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411 Dendritic Cell-Based Idiotype V
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Author Index Abe M 74 160 Abelman W
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De La Serna J 291 De Laurenzi A P11
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Hull DR 338 Hullen C P10.2.1 Humes
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Morra E 249 280 359 Morris CM 226 M
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Siegel D 70 115 250 Sierra J 304 30
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