Haematologica 2003 - Supplements

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esponse was 8 (2 – 12) months. To date, 4 patients are alive: 3 with stable MM and 1 with progressive disease. The median overall survival was 8 months (1 – 16). We have analysed the clinical pattern of relapsed/progressed disease in our series. Out of the 7 relapses, 3 cases presented untested and very extended pulmonary (2) and frontal bone (1) plasmocytomas. The remaining 4 patients presented progressive increase of paraprotein levels associated with plasmacytic BM infiltration and new osteolytic lesions. The extramedullary manifestation were treated with radiotherapy and in all relapsers a weekly dose (500 mg) of cyclofosphamide was added to the current therapy. All relapsers died after 2 (1 – 3) months. Out of the 5 patient with disease progression, 4 presented the typical haematological features and 1 a large plasmacytoma, extended from the 5th lumbar spine to the iliac region. This patient, alive from 15 months, received radiotherapy, weekly cyclofosphamide and regular courses of dex, as above reported, achieving a partial control of disease, lasting from 5 months. Median survival after progression was 2 (1 – 15) months. Although the small number of patients, the occurrence of extramedullary disease, found in 4/12 (33%) patients, suggests a role of a resistant and more aggressive clone, who has lacked the regulatory adhesion molecule-mediated mechanisms, causing metastasis to distant sites, as the lung, maybe favoured by its fine microcirculation. Our experience, outlining the poor prognosis of the relapsed/progressed MM patients receiving the reported salvage therapy, suggests the need of further studies on the efficacy of new drugs in modifying the clinical history of the advanced MM. 337 The combination therapy of thalidomide, incadronate and dexamethasone (TID) for relapsed or refractory multiple myeloma Naoya Ochiai *1, Ryo Uchida *1, Shin-ichi Fuchida *1, Akira Okano *1, Mayumi Hatsuse *2, Masashi Okamoto *1, Eishi Ashihara *1, Tohru Inaba *1, Naohisa Fujita *1, Masao Nakagawa *1 and Chihiro Shimazaki *1 *1: Second Department of Medicine, Kyoto Prefectural University of Medicine, Japan; *2: Syakaihoken Kyoto Hospital, Kyoto, Japan Introduction: Thalidomide has proven to be a useful drug for treatment of refractory and relapsed MM patients and the efficacy has been reported up to 35% in several clinical trials. Thalidomide has been reported to restore the sensitivity of myeloma cells to other drugs and to enhance the anti-myeloma activity of dexamethasone, and in clinical study the combination of thalidomide with dexamethasone have been more effective than thalidomide alone. It is reported that nitrogen-containing bisphosphonates, such as incadronate, have direct anti-myeloma effect, and inhibit the mevalonate pathway and prevent posttranslational prenylation of GTP-binding proteins for example Ras. Based on these observations, we investigated the combination effect of thalidomide, incadronate and dexamethasone (TID therapy) as clinical phase 2 trial for relapsed or refractory MM patients, in order to assess its efficacy and toxicity. Patients and methods: Nine patients with relapsed or refractory MM were treated after informed consent was obtained from patients. The protocol scheduled the administration of thalidomide at doses from 100mg to 300mg/day, incadronate at 10mg/day iv weekly and dexamethasone at 12mg/day four days every three weeks. Patients’ median age was 69 years (range: 52 to 75 years) and five were male. In myeloma subtypes, five were IgG, two were IgA and two were Bence Johnes protein type. All of patients were relapsing despite combination chemotherapy contained high dose dexamethasone and two or more treatment regimens were administrated before therapy. One patient was highly aggressive relapsed after tandem auotologous peripheral blood stem cell transplantation. Results: All of nine patients achieved over 25% reduction of M- protein after 1 cycle of TID therapy but in two patients it was stopped because of severe somnolence. Of seven patients evaluable for response after 3 cycles of therapy, five patients achieved 50% reduction, one patient 25% reduction of M-protein and one patient progressive disease. Toxicities TID therapy was equally effective in patients with or without prior-resistance to dexamethasone-based regimens. These data suggest that TID is a feasible and promising therapeutic approach for advanced multiple myeloma patients. 338 Clarithromycin, Dexamethasone and low dose Thalidomide (CDT) is effective therapy in relapsed/refractory myeloma; a Phase II study and quality of life survey. TCM Morris, DR Hull**, C Boyd**, FCG Jones, PJ Kettle, M Drake, R McLoughlin*, J Quinn*. Haematology Department, Belfast City Hospital, *Clinical Trials Unit, Belfast City Hospital, Haematology Department, **Craigavon, Area Hospital, Northern Ireland. We have previously shown that Clarithromycin has a modest anti myeloma effect1 and more recently a combination of Clarithromycin, Dexamethasone and Thalidomide has been shown to have significant activity in patients with myeloma2. We report a very high response rate in a phase II trial of this combination in which the object was to minimise the doses of both Thalidomide and Dexamethasone. Sixteen patients (10 M, 6 F) with relapsed (12) or refractory (4) myeloma, age range 52 – 83, from whom informed consent was obtained, were given Clarithromycin 250mg bd continuously, Dexamethasone 10 mg daily for 4 days, once every 4 weeks and Thalidomide 50 mg nocte. An additional 4 days of 10 mg of Dexamethasone was given on days 15–18 only. Dose escalation of Thalidomide to 200mg by 50mg increments was permitted but only 3 patients reached 150mg and 3 patients 100mg. All patients received IV bisphosphonates once every four weeks. Results: Three patients had complete remission, 2 very good partial response, 8 partial response and 2 minimal response and there was one non responder whose paraprotein fall failed to reach the criteria for minimal response. The median response duration is 25 weeks. The median overall survival has not been reached but is greater than 9 months. Most patients had one or more cytopenia at the onset of therapy. Eight patients had thrombocytopenia (median 89 x 109/l, range 14-134); all had significant rises in the platelet count, 7 to normal levels. Seven of 11 patients with anaemia had haemoglobin increments of >1 g/dl, 5 reaching normal levels; of 7 patients with neutropenia
339 Thalidomide, Clarithromycin and Bisphosphonates in a Unique Maintenance Chemotherapy in Patients with Multiple Myeloma Katakkar, Suresh B. Arizona Hematology Oncology, 1845 W Orange Grove Road, Bldg 2, Tucson, Arizona 85704 USA Introduction: The majority of multiple myeloma patients relapse within 3 years. By using less toxic agents as maintenance we hope to improve the survival rate. Methodology: All patients with multiple myeloma from 1999 until present, once induced in remission, were maintained on Thalidomide 200mg/day p.o. Bisphosphonates I.V. every fourth week. Clarithromycin 500mg/day p.o. Both bisphosphonates were used in standard doses. The addition of Clarithromycin to Thalidomide has helped to change the pharmacodynamics of Thalidomide. Basically it will interfere with it’s excretion. Results: 22 patients were eligible. There were 12 males and 10 females. There was an average age of 62 years for the males, and 60 years for the females. Eight patients have been taking this combination for greater than 3 years without any adverse effects. The longest follow-up has been 4 years. Three patients were dropped, 2 due to neuropathy and 1 due to syncope. 3 patients have died, 2 with unrelated causes, and 1 with myeloma. Of 19 patients, including the 3 who died, only one patient has active disease. All others are in remission with a median of 18 months. Conclusion: The Thalidomide, Clarithromycin, and Bisphosphonates are an effective combination in patients with multiple myeloma in regard to keeping these patients in remission. 340 Thalidomide and Celecoxib for patients with multiple myeloma (MM) – a promising combination LM Mileshkin1, HM. Prince1,7, JJ Biagi1, JF Seymour1, R Ramsay1, D Westerman1, A Roberts2, C. Underhilll3, V Ganju4, R Bell5, P Briggs6, J Zeldis8. Depts of Haematology and Medical Oncology; Peter MacCallum Cancer Institute1, Royal Melbourne Hospital2, Border Medical Oncology3, Frankston Hospital4, The Geelong Hospital5, Monash Medical Centre6, Cabrini Hospital7, Victoria, Australia. Celgene Corporation8, New Jersy, USA. Tel: 61-3-96561700, Fax: 61-3- 96561408, Email: Miles.Prince@petermac.org Introduction: Thalidomide (Thal) has proven efficacy in the management of MM. However response rate (RR) when used as a single agent is low. Thal has been shown to downregulate COX-2 mRNA, and COX-2 inhibitors have anti-angiogenic effects. Commencing August 2001, we performed a prospective Phase-II open-label, multi-centre(n=7) study combining Thal and Celecoxib (Thal/Cel) in patients(pts) with relapsed/refractory MM. The primary objective was to determine the RR and compare this with our previous trial using single agent Thal ± interferon (Mileshkin et al, Blood in press). Further objectives were to determine event-free (EFS) and overall survival (OS), as well as the toxicity profile. Methods: Eligible pts had relapsed or refractory MM, platelets ≥50 x 109/L and serum creatinine ≤ 1.5 x upper limit of normal. Pts commenced Cel 400mg bid plus Thal 200 mg/d. After 14 days, Thal was escalated by 200 mg/d every 14d to a maximum of 800 mg/d, or an individually maximum tolerated dose (iMTD)
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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
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
Page 223 and 224: their leukocytes and platelets. No
Page 225 and 226: 25 Gy to marrow. The tracer dose wa
Page 227 and 228: non-CR after the first transplant a
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: time from diagnosis was 3.7 years a
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 and 272: which acts to prevent the synthesis
Page 273 and 274: of B and its metabolites, however,
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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