Haematologica 2003 - Supplements

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expression of RANKL in MM cells and suppressed cytokineinduced production of VEGF by viable MM cells, indicating that TZDs may not only directly target MM cells, but can also abrogate their interactions with the local BM microenvironment, by inhibiting the stimulation of bone resorption and MMassociated neo-vascularization. The comprehensive direct anti-tumor sequelae and indirect microenvironmental effects of TZDs and, most importantly, their highly favorable profile of side effects, even in the setting of chronic administration of these agents, provide a strong pre-clinical and clinical rationale for trials of TZDs to improve the outcome of patients with MM. 392 ANTI-MYELOMA ACTIVITY OF HMG-CoA INHIBITORS (STATINS): FRAMEWORK FOR CLINICAL APPLICATIONS. Constantine S. Mitsiades1,2, Nicholas Mitsiades1,2, Vassiliki Poulaki3, Galinos Fanourakis1,2, Paul G. Richardson1,2, Reshma Shringarpure1,2, Masaharu Akiyama1,2, Dharminder Chauhan1,2, Teru Hideshima1,2, Steven P. Treon1,2, Nikhil C. Munshi1,2, Meletios A. Dimopoulos4 and Kenneth C. Anderson1,2. 1. Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115; 2. Department of Medicine, Harvard Medical School, Boston, MA 02115; 3. Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA 02114; 4 Dept. of Clinical Therapeutics, Alexandra Gen. Hospital, University of Athens, School of Medicine, Athens, Greece, 11527. 3-Hydroxy-3-methylgluratyl-CoA (HMG-CoA) reductase inhibitors, including lovastatin, simvastatin, and atorvastatin, have been extensively used for treatment of hypercholesterolemia, and recent studies have also suggested that this class of agents may have anti-tumor activity. The median age of patients affected with MM and WM is >60 years, an age-group where statins are extensively prescribed for hypercholesterolemia, and are well-tolerated. In this context, we studied if HMGCoA inhibitors have direct anti-tumor activity against MM or WM cells. We found that lovastatin, at low µM and sub-µM concentrations, induces growth arrest and apoptosis in tumor cells (10/10 samples) freshly isolated from relapsed refractory MM patients, including patients resistant to novel immunomodulatory thalidomide derivatives (IMiDs) or the proteasome inhibitor PS-341; in a wide panel of 25 MM cell lines, including those resistant to dexamethasone (Dex), anthracyclines, thalidomide/IMiDs, or Apo2L/TRAIL; as well as WM patient tumor cells and the WM-WSU cell line model. Importantly, lovastatin overcomes the anti-apoptotic effects conferred upon MM-1S cells by forced overexpression of bcl-2 or constitutively active Akt. Transcriptomic profiling and proteomic analysis of the signaling state of lovastatin-treated MM cells and subsequent mechanistic studies revealed that lovastatin suppresses constitutive and cytokine (IGF-1, or TNF-á)- stimulated activation of NF-êB; attenuates constitutive and cytokine (IGF-1)-induced activation of telomerase (hTERT); downregulates the levels of several intracellular inhibitors of apoptosis (IAPs); and abrogates constitutive and cytokine (IGF-1, IL-6)-induced expression of proteasome subunits and proteasome activity. Consequently, lovastatin sensitizes MM cells to other pro-apoptotic stimuli, including Dex, Doxo, Apo2L/TRAIL, and PS-341. These pre-studies in support of the anti-MM activity of statins, as well as the significant clinical experience acquired through safe long-term administration of statins for hypercholesterolemia, provide the framework for the ongoing pilot clinical trials of lovastatin therapy for MM patients, with the ultimate goal to provide the contextual framework for more extended studies on the role of this class of agents in the therapeutic management of plasma cell dyscrasias. 393 Bendamustin - new therapeutic option for relapsed and refractory multiple myeloma P.Ganeva, I. Galabova, N. Vasileva, G. Arnaudov, D. Peichev National Center of Haematology and Transfusiology - Sofia, Bulgaria Multiple myeloma ( MM) is a malignancy of terminally differentiated B- lymphocytes. It is characterized by the clonal proliferation of plasma cells that are innately resistant to standard doses of chemotherapy. Despite modern treatment modalities, including high-dose chemotherapy with stem cell support, multiple myeloma remains incurable in most cases. New treatment modalities are being evaluated to improve response rates and to achieve a cure in MM. Bendamustin is a bifunctional alkylating agent and has been evaluated mainly in the treatment of NHL, multiple myeloma, CLL and breast cancer first in Germany. We used Bendamustin/Prednisone regimen in 16 patients with relapsed and refractory disease for a 2 year period (Bendamustin 100mg /m2 day 1 and 2 plus Prednisone 60mg /m2 days 1 to 4). This regimen results in a clinical response in approximately 50% of patients and a median survival of approximately 20 months. The toxicities profile differs somewhat from that of other alkylating agents. In summary, bendamustin is an effective and well-tolerated drug in the paliative treatment of NHL, including multiple myeloma. 394 Pharmacokinetics and toxicity profile of bendamustine in myeloma patients with end-stage renal disease Preiss, R1, Teichert, J1, Pönisch, W2, Niederwieser, D2, Matthias M 3 and Merkle, Kh4 1Institute of Clinical Pharmacology and 2Department of Internal Medicine II of University of Leipzig, 3Rehabilitation Centre, Buckow, 4ribosepharm, Munich, Germany Bendamustine (4-(5-[Bis(2-chloroethyl)amino]-1-methyl-2- benzimidazolyl)butyric acid, Ribomustin®, B), a bifunctional alkylating agent with low toxicity and only partial crossresistance with other alkylating agents is of great importance in the treatment of multiple myeloma in Germany. The substance is intensively metabolized and rapidly eliminated from plasma (t1/2 0.5h) by hepatic and renal excretion, however, there are no data on its plasma kinetics and renal elimination in the event of renal dysfunction. Therefore, the aim of the present investigation was to characterize the plasma kinetics, renal elimination and the 4- week toxicity profile of B in patients with renal insufficiency. Twelve tumor patients with normal renal function (group 1) and 12 myeloma patients with severe renal impairment including 5 patients under continuous haemodialysis (group 2) received B single dose 120 mg/m2 intravenously on day 1 and 2 in 4-weekly intervals for up to 4 cycles. All patients had normal liver function. In plasma, urine and dialysate B and its metabolites (monohydroxy-B, dihydroxy-B, N-desmethyl-B and an oxidized form of B) were identified by HPLC and mass spectrometry. A strong correlation was found between creatinine clearance and renal clearance of B in patients of Group 1 and in dialysisindependent patients of Group 2. The renally eliminated amount S263
of B and its metabolites, however, was low. Only 20 and 5 % of the administered B dose were recovered in urine in patients of Group 1 and 2. B and its metabolites are dialysed in the same quantities as renally eliminated in non-dialysed patients with endstage renal disease. By means of anova, no differences were found between the two patient-groups in plasma kinetics of B and its metabolites. The toxicities that occurred were salivary gland dysfunction causing dry mouth and taste disturbances, nausea and vomiting, moderate myelotoxicity of CTC grade 2/3 leuko-and thrombocytopenia and worsening of pre-existing lymphocytopenia. These toxicities are well known and manageable. With the exception of a higher frequency of Table 1. Plasma chitotriosidase after frequent plasmapheresis with HES* Not available Patient (m/f) Age Total HES (l) HES (l/month) Creatinine clearance (ml/min) Plasma chitotriosidase (nmol/h/ml) Bone marrow biopsy 1 (f) 43 130 6.5 61 6130 Foam cells 2 (m) 54 18 3.6 88 422 n.a.* 3 (m) 68 16 3.2 73 307 Foam cells 4 (f) 54 14 4.7 84 242 Foam cells 5 (m) 23 42.5 2.2 120 206 n.a.* 6 (m) 51 33.1 4.1 112 200 n.a.* 7 (f) 54 31.5 1.4 70 165 n.a.* 8 (m) 75 10 10 119 93 Foam cells 9 (m) 31 67.5 1.6 187 78 n.a.* 10 (m) 66 25.5 1.1 85 60 Foam cells 11 (m) 34 31.5 4.5 116 59 n.a.* moderate leuko- and thrombocytopenia in patients with renal insufficiency, no difference in toxicity was observed between the two patient groups. Toxic effects of B on liver and kidney function were not observed. No dose reductions will be necessary in patients with normal liver function and end-stage renal disease, including dialysisdependent patients, thus B can be applied at 120 mg/m² iv over 30 minutes on days 1 and 2 at 4-weekly intervals. This may be an advantage over melphalan. 395 FREQUENT PLASMAPHERESIS WITH HYDROXYETHYL-STARCH (HES) IN MONOCLONAL GAMMOPATHY RESULTS IN TISSUE INFILTRATION WITH ACTIVATED FOAMY MACROPHAGES J.J.A. Auwerda1, J.H.P. Wilson2, O.P. van Diggelen3, P. Zondervan4, P. Sonneveld1 Departments of Hematology1, Internal Medicine2, Clinical Genetics3 and Pathology4 Erasmus Medical Centre, Dr Molewaterplein 40, PO-Box 2040, 3015 GD, Rotterdam, the Netherlands. Hydroxy-ethyl starch (HES, Fresenius) is a chemically modified cornstarch. Because of the reported advantages of synthetic plasma expanders, it has been suggested that HES-products might emerge as a standard replacement fluid in plasmapheresis. The kinetics of HES elimination depend on enzymatic degradation (αglucosidases/α-amylases) in blood, tissues, and the reticuloendothelial system, followed by urinary excretion. However, tissue and lysosomal storage in macrophages can occur. In Gaucher disease, similar foamy macrophages excrete chitotriosidase (CT) and the level of plasma CT reflects the extent of tissue infiltration. We have investigated the clinical applicability of plasma CT concentration as a parameter of tissue accumulation of HES in patients undergoing chronic plasmapheresis for monoclonal gammopathy or other reasons. Eleven patients receiving frequent plasmapheresis with HES were identified. The cumulative HES dose and renal function (creatinine clearance) were calculated and plasma CT was determined (table 1). When available, bone marrow aspirates were reviewed. All patients with impaired renal function, who were exposed to a high dose (liters/month) exhibited an increase in plasma CT (normal range 4-195 nmol/h/ml). Foamy macrophages were observed in all available bone marrow biopsies regardless of the plasma CT. One patient (no-1) even developed a severe acquired lysosomal storage disease causing malnutrition and weight loss, myelofibrosis, polyneuropathy, organomegaly and ascitis due to massive tissue infiltration with foamy macrophages. In this patient, plasma CT increased after a cumulative dose of 20 liters and reached the range of Gaucher disease at a cumulative dose of 85 litres. Conventional plasma expanders which had been used prior to HES exposition had not altered the normal plasma CT concentration in this patient. After cessation of HES, plasmapheresis with conventional expanders did not result in a decrease in plasma CT. This was confirmed by bone marrow biopsies performed a year later, which still revealed massive foamy macrophage infiltration. Based on these results we conclude that in patients with impaired renal function, frequent plasmapheresis with HES results in tissue infiltration with activated, CT secreting foamy macrophages. We believe that the level of plasma CT can be used to monitor tissue storage of HES. Furthermore, excessive administration of HES will result in a severe acquired lysosomal storage disease. 396 APOMINE, a Novel Inhibitor of the Mevalonate/isoprenoid Pathway, Promotes Apoptosis of Myeloma Cells In Vitro and Is Associated with a Modulation of Myeloma Disease In Vivo Claire M. Shipman (1), Gabrielle Mueller (1), Karin Vanderkerken (2), Mark Perry (3), Sandy Cordiner-Lawrie (1), Graham Russell (1), Ben Van Camp (2), Eric Niesor (4), Craig Bentzen (4), Peter I. Croucher (1) (1) Nuffield Dept. of Orthopaedic Surgery, University of Oxford, UK(2) Hematology and Immunology, Free University Brussels, Belgium(3) Medicine, Univeristy of Bristol, Bristol, UK(4) ILEX Oncology, Geneva, Switzerland The process of isoprenylation plays an important role in regulating the function of proteins that are critical in the growth and survival of myeloma cells. Inhibiting the pathways responsible for this process therefore represents a novel approach to controlling the growth of myeloma cells. APOMINE, a novel 1,1 bisphosphonate ester, increases the rate of degradation of HMGCoA reductase, thereby inhibiting the mevalonate pathway and preventing protein prenylation. The aim of the present study was to determine whether APOMINE could induce apoptosis in myeloma cells, influence osteoclast formation and bone resorption in vitro and modulate the myeloma disease in vivo. Treatment of the human myeloma cell lines NCI H929, RPMI 8226 and JJN-3 with 2-20µM APOMINE induced a dosedependent increase in apoptosis, as identified by characteristic changes in nuclear morphology and by an in situ nick translation assay (p < 0.001). APOMINE had no effect on the accumulation of cells in the S phase of the cell cycle; which we have previously seen with bisphosphonic acids. To investigate the effect of APOMINE in vivo, 5T2MM murine myeloma cells were injected intravenously into C57BL/KaLwRij mice. After 8 weeks all animals injected with tumour cells had detectable serum paraprotein and were treated with APOMINE in the diet (200mg/kg) (n=10), or vehicle (n=10) for a further 4 weeks when all animals were sacrificed. All animals injected with tumour S264
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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
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and clonal PC from MGUS, MM and PCL
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059 VEGF receptor expresion in Mult
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two HLA-A2+ myeloma patients with C
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molecules expressed on the surface
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Recognition of these antigens appea
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Diagnosis requires a single area of
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081 Incidence of solid tumors in co
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Growth Factor (VEGF), Hepatocyte Gr
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PC-AI levels of MGUS and SMM patien
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093 The predominant pathway of tran
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was associated with I.V. line, whil
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103 Vascular amyloidosis induces se
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5. Signal transduction pathways and
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integrin in IGF-1-triggered MM cell
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118 IL-6- Induced Phosphorylation o
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123 THE IGF/IGF-1R SYSTEM IS A MAJO
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human myeloma cell line (HMCL) to a
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ligation or dexamethasone (Georgii-
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6. Role of microenvironment 6.1 Cel
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141 Human myeloma cells adhere to f
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145 STUDY OF BONE MARROW ANGIOGENES
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patients, the growth of primary mye
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tibia (con=49.1±0.7mg/cm2 vs 5T2=4
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157 The Nitrogen-Containing Bisphos
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7. New prognostic criteria for clas
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atio of >3. This system has subdivi
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Patient 1 (IgG/κ);IgG - 16.5 days,
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176 Pro-inflammatory and angiogenic
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180 Clinical study on the bone lesi
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7.2 Imaging studies 185 99mTc-MIBI
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189 Factors Predicting Occult Spina
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vivo detected resonances was invest
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Support Unit (CTSU) with flexibilit
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(β2m) & C reactive protein (CRP).
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plasmids carrying the clonotypic in
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newly diagnosed multiple myeloma as
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216 Transgenic expression of Myc an
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221 Prolonged survival in the 5T2MM
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9. Chemotherapy, maintenance, treat
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229 EFFECTIVENESS OF STANDARD CHEMO
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234 Melphalan and Dexamethasone- Is
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Methods. We investigated the VECD p
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9.2 Renal complications. 243 MERIT
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cost of SRE-related care was $10,24
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those with Hb >13 g/dL. Analysis of
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sustained response, lasting from 52
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proportion of bone abnormality. IgD
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disease. The lack of response to in
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yielding a median of 3x106/kg CD34
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patients(pts) aged ≥60 yrs. We co
Page 221 and 222: PBSC mobilizing regimen utilizing C
Page 223 and 224: their leukocytes and platelets. No
Page 225 and 226: 25 Gy to marrow. The tracer dose wa
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Page 229 and 230: 296 PERIPHERAL BLOOD STEM CELL TRAN
Page 231 and 232: References Effect of dose-intensive
Page 233 and 234: with cyclosporine A and methotrexat
Page 235 and 236: 11.Role of novel therapies targetin
Page 237 and 238: 312 Thalidomide as Rescue of Relaps
Page 239 and 240: patients, light chain in 1 patients
Page 241 and 242: platelets of 207 (76-402), B2M of 3
Page 243 and 244: 325 Low Dose Thalidomide plus Dexam
Page 245 and 246: in 5 pts (11%), M protein decreased
Page 247 and 248: time from diagnosis was 3.7 years a
Page 249 and 250: 339 Thalidomide, Clarithromycin and
Page 251 and 252: 344 COMBINATION OF THALIDOMIDE, DEX
Page 253 and 254: experienced early death during the
Page 255 and 256: untreated patients with high tumor
Page 257 and 258: 357 Thalidomide protects endothelia
Page 259 and 260: 362 EOSINOPHILIA IS A VERY COMMON F
Page 261 and 262: 11.5 CC 4047, PS 341 and arsenic tr
Page 263 and 264: without chromosome 13. Mean IC50 fo
Page 265 and 266: myeloma patients. Phase I data indi
Page 267 and 268: 11.6 Other drugs 380 EFFECT OF STI5
Page 269 and 270: significant inhibition of cell prol
Page 271: which acts to prevent the synthesis
Page 275 and 276: and 10 months after start of therap
Page 277 and 278: terminal kinase (JNK) pathway which
Page 279 and 280: lymphocytes was tested by Ellispot.
Page 281 and 282: 411 Dendritic Cell-Based Idiotype V
Page 283 and 284: Author Index Abe M 74 160 Abelman W
Page 285 and 286: De La Serna J 291 De Laurenzi A P11
Page 287 and 288: Hull DR 338 Hullen C P10.2.1 Humes
Page 289 and 290: Morra E 249 280 359 Morris CM 226 M
Page 291 and 292: Siegel D 70 115 250 Sierra J 304 30
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Haematologica 2003 - Supplements

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