Haematologica 2003 - Supplements

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matched study from the European Group for Blood and Marrow Transplantation. Blood 1996; 88:4711-8. 3. Corradini P CM, Lokhorst H, Martinelli G, Russel N, Majolini M, Boccadoro M, Samson D, Bacigalupo A, Voena C, Terragna C, Gahrton G. Molecular remissions are frequently achieved in myeloma patients undergoing allografting with peripheral blood stem cells. Bone Marrow Transplantation 2001; 27:S39. 4. Gahrton G, Svensson H, Cavo M, et al. Progress in allogenic bone marrow and peripheral blood stem cell transplantation for multiple myeloma: a comparison between transplants performed 1983--93 and 1994--8 at European Group for Blood and Marrow Transplantation centres. Br J Haematol 2001; 113:209-16. 5. Alyea E, Weller E, Schlossman R, et al. T-cell-- depleted allogeneic bone marrow transplantation followed by donor lymphocyte infusion in patients with multiple myeloma: induction of graft-versus-myeloma effect. Blood 2001; 98:934-9. 6. Maloney D, Sahebi F, Stockerl-Goldstein K, et al. Combining an allogeneic graft-vs-myeloma effect with high-dose autologous stem cell rescue in the treatment of multiple myeloma. Blood 2001; 98:434a. P11.1.2 WHAT IS THE ROLE OF ALLOGENEIC TRANSPLANTATION IN MM? BOLOGNA EXPERIENCE Michele Cavo, Claudia Cellini, Francesca Bonifazi, Paola Tacchetti, Elena Zamagni, Delia Cangini, Patrizia Tosi, Giuseppe Bandini, Sante Tura, Michele Baccarani Institute of Hematology and Medical Oncology “Seràgnoli; University of Bologna, Italy Clinical studies aimed at investigating the feasibility and toxicity of allogeneic stem cell transplantation for the treatment of MM were pionereed by our group (1) and other groups in the early 1980s. Initial studies mostly included heavily pretreated patients with refractory disease and provided demonstration that chemo(radio)therapy administered at myeloablative doses overcame chemoresistance and induced complete remission (CR), even in patients who failed on prior conventional chemotherapy. The first patient who received an allotransplant at our centre for relapsing MM is still in serological and molecular CR 19 years after transplant. Following initial encouraging reports, interest in the use of allotransplants has grown over the years and more than 2000 patients have been performed worlwide. In 1983, a registry of allotransplants performed in Europe was opened; since then, several updates of registry data were reported by the European Group for Blood and Marrow Transplantation (EBMT) (2, 3). Moreover, additional studies on single-centre experiences were also published by other groups (4, 5). From the analysis of all these studies it appears evident that the most crucial issue related to the use of allogeneic stem cell transplantation for MM was the high treatment related mortality (TRM) that exceeded 40% in most series (4). In a retrospective case-matched study performed by the EBMT group and aimed at comparing autologous and allogeneic bone marrow transplants reported to the registry between 1983 and 1994, TRM was significantly higher in the allografted group (41% vs 13% for autotransplants) and did not change appreciably over the time period analyzed (6). Based on these observations, indications for the use of allogeneic stem cell transplantation for MM patients have been for a long time the matter of debate and controversies still exist. In an attempt to investigate whether the outcome of allogeneic stem cell transplantation was improved in more recent years, we retrospectively analyzed a series of 84 consecutive patients (median age, 43 years; stage III, 64%; refractory or progressive, 67%) who received allotransplants from HLA-identical sibling donors (n=79) or HLA-matched unrelated donors (n=5) at our centre between 1990 and 2002. Patients were divided into 3 groups according to the period in whom allotransplants were performed (group 1, from 1990 to 1993; group 2, from 1994 to 1995; group 3, from 1996 to 2002). Notably, conditioning regimens and treatments used to prevent graft-versus-host disease (GVHD) were different over the periods of the study. More specifically, patients in group 1 (n=20) received a combination of busulfan (total dose, 16 mg/kg) and cyclophosphamide (CTX) (total dose, 200 mg/kg), whereas patients in groups 2 (n=14) and 3 (n=50) were mostly treated with combined total body irradiation (TBI), CTX and melphalan (MEL) (total dose, 100- 120 mg/m2). Cyclosporine + methotrexate (CsA + MTX) were used to prevent GVHD in patients included in groups 1 and 3, whereas patients in group 2 received a T-cell depleted marrow. Bone marrow was the only source of repopulating hematopoietic stem cells used from 1990 to 1995 (groups 1 and 2), while approximately 75% of transplants performed after 1995 (group 3) were performed with peripheral blood (PB) stem cells. TRM rate at 1 year was significantly lower among patients included in group 3 (16%), as compared with patients in group 2 (43%) and in group 1 (30%) (P=0.0002). Notably, the decreased TRM observed in recent years was not related to a more favorable selection of the patients (stage III, 70%; refractory/progressive, 66%). At the opposite, comparison between the 3 groups showed that patients in group 3 were transplanted earlier than the others (median time interval from diagnosis to transplant: 13 months vs. 18 and 20 months for patients in groups 2 and 1, respectively). Posttransplant mortality due to infections was 8% among patients in group 3, as opposed to 36% for patients who received TBIincluding regimens and a T-cell depleted marrow (group 2). As a result of the lower TRM rate, overall survival for patients in group 3 was significantly longer than that for the other groups (66% projected at 4 years, as opposed to 35% for group 2 and 20% for group 1) (P=0.001). Similarly, the progression-free survival for patients in group 3 was significantly longer than that for the other groups (41% projected at 4 years, as opposed to 21% and 15% for groups 2 and 1, respectively) (P=0.008). These results compare favorably with those of a recent study carried out by the EBMT registry demonstrating that TRM during the period 1994-1998 was significantly reduced in comparison with earlier time periods (21% as opposed to 38% observed before 1994), mainly as a result of a significant decrease in the frequency of deaths due to interstitial pneumonia or bacterial and fungal infections (7). As in the EBMT study, also in the present analysis we were unable to demonstrate any improvement over time in the response to transplant. On an intent-to-treat basis, the CR rate was 38% in group 1, 43% in group 2 and 44% in group 3. Overall, the 4-year and 7-year projected probabilities of relapse were 33% and 46%, respectively. Due to several relapses occurring as late as 9 and 10 years following transplantation, there was no apparent plateau in the relapse-free survival curve. This finding raises the issue of whether allotransplant has the potential ability to cure MM. To address this poorly investigated issue, we recently used a polymerase chain reaction-based (PCR) strategy to retrospectively analyze the presence of residual myeloma cells in serial posttransplant bone marrow samples obtained from a series of patients in sustained CR following allogeneic stem cell transplantation (8). For this purpose, patientspecific primers were generated from complementarity determining regions 2 and 3 of the rearranged IgH gene. It was S66
found that 75% of patients who were analyzed remained persistently PCR negative for a median of 3 years. In some of these patients PCR negative results were documented up to 4-10 years after allotransplants. It is concluded that allogeneic stem cell transplantation is associated with a graft-versus-myeloma (GVM) effect which results in more frequent molecular CR and decreased probability of relapse as compared with autotransplant(s). Mortality due to treatment-related complications, mainly infective, has been significantly reduced over the last years, as a result of earlier timing of the procedure and better supportive care. The challenge for clinical investigators will be to furtherly reduce the mortality associated with allotransplants and to increase the rate of sustained CR. Transplants with low-intensity, nonablative regimens aimed at decreasing early toxic complications, even in heavily pretreated patients, while retaining a GVM effect to induce CR are currently under investigation. Moreover, molecular profiling may help identify high-risk patients who do not benefit from autotransplant(s) and for whom allotransplants deserve further investigation. REFERENCES Tura S, Cavo M, Baccarani M, Ricci P, Gobbi M. Bone marrow transplantation in multiple myeloma. Scand J Haematol 1986; 36: 176-9. Gahrton G, Tura S, Ljungman P, et al. Allogeneic bone marrow transplantation in multiple myeloma. N Engl J Med 1991; 325: 1267-73. Gahrton G, tura S, Ljungman P, et al. Prognostic factors in allogeneic bone marrow transplantation for multiple myeloma. J Clin Oncol 1995; 13: 1312-22. Bensinger WI, Buckner CD, Anasetti C, et al. Allogeneic marrow transplantation for multiple myeloma: an analysis of risk factors on outcome. Blood 1996; 88: 2787-93. Cavo M, Bandini G, Benni M, et al. High-dose busulfan and cyclophosphamide are an effective conditioning regimen for allogeneic bone marrow transplantation in chemosensitive multiple myeloma. Bone Marrow Transplant 1998; 22: 27-32. Bjorkstrand B, Ljungman P, Svensson H, et al. Allogeneic bone marrow transplantation versus autologous stem cell transplantation in multiple myeloma: a retrospective casematched study from the European Group for Blood and Marrow transplantation. Blood 1996; 88: 4711-18. Gahrton G, Svensson H, Cavo M, et al. Progress in allogeneic bone marrow and peripheral blood stem cell transplantation for multiple myeloma. A comparison between transplants performed 1983-1993 and 1994-1998 at EBMT centres. Br J Haematol 2001; 113: 209-16 Cavo M, Terragna C, Martinelli G, et al. Molecular monitoring of minimal residual disease inpatients in long-term complete remission after allogeneic stem cell transplantation for multiple myeloma. Blood 2000; 96: 355-7. P11.1.3 THE ROLE OF DONOR T CELLS IN THE TREATMENT OF MYELOMA Henk M. Lokhorst, Christine M. Segeren, Leo F. Verdonck,, Bronno van der Holt, Anton VMB. Schattenberg, Nigel Russell, Reinier Raymakers, Marinus HJ. van Oers, Renee MY. Barge, Harry C. Schouten, Petra HM. Westveer, Monique MC. Steijaert, Jan J. Cornelissen, Pieter Sonneveld. Upfront Myeloablative Allo-SCT. The necessity of performing Allo-SCT in MM is disputed. Median OS in different reports varies from 18 to 28 months from transplantation. A survival advantage for patients receiving an Allo-SCT compared to patients with matched characteristics who were treated with Auto-SCT and no SCT at all has not been shown. 1 We have determined in a prospective study the efficacy, toxicity and long term outcome of upfront myeloablative Allo-SCT. 2 In the prospective phase III study HOVON 24 MM , 53 patients with an HLA-identical sibling (median age at Tx 48 yrs, range 31-56) were allocated to a partial T-cell depleted Allo-SCT after induction therapy. The overall response after Allo-SCT was 89% (47/53) including 19% (10/53) of patients with a complete remission (CR). Five patients achieved a CR only after Allo-SCT. Five of 7 (71%) primary refractory patients obtained a response to Allo-SCT, all of which had a PR. With a median follow-up of 38 months (range 25-61), 20 patients are alive since Allo-SCT, 33 patients have died, of whom 14 from progressive disease, 18 (34%) from Treatment Related Mortality (TRM) and one from another cause. Occurrence of acute Graft versus Host Disease grades II-IV predicted for higher TRM in a time-dependent analysis. Median progression-free survival after Allo-SCT was 18 months. Median overall survival after Allo-SCT was 25 months or 29 months since start of therapy (figure 1). The outcome of Allo-SCT patients was inferior as compared to a comparable group (age) of patients who received autologous stem cell transplantation or α-Interferon maintenance as part of the HOVON 24 trial. These patients had a comparable PFS but their overall survival was significantly longer (47 months vs 25 months) due to a much lower TRM (5%). Figure 1: Kaplan-Meier curve of overall survival from partially T-cell depleted Allo transplantation, with TRM and death due to progression/other cause as competing risks Donor lymphocyte infusions Contrary to T cell depleted Allogeneic Stem Cell Transplantation as part of first line treatment, a Graft versus Myeloma (GVM) effect is strongly induced by Donor Lymphocyte Infusions (DLI) administered to patients with relapsed MM. 3 In a recent retrospective update of 50 patients with relapsed disease, remissions were induced in 56% of patients including 23% of patients with a CR. Reinduction therapy was administered to 25 patients including 10 patients in which this was part of a recently started prospective trial. In order to increase response rate and reduce toxicity by limiting GVHD, we now prospectively evaluate the strategy in which all patients are re-induced with VAD Patients with chemo-sensitive disease are treated with low dose of DLI (1x10 7 T cells/kg) followed by dose escalation in case of no response; patients with chemo-resistant disease receive high dose DLI (1x10 8 T cells/kg). Both low and high dose DLI are combined with α-Interferon to augment the GVM effect. Both results from the retrospective and prospective analysis show that S67
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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,
Page 21 and 22: immunofluorescence staining for DKK
Page 23 and 24: P2.3 DEVELOPMENT OF A MULTIPLE MYEL
Page 25 and 26: P2.5 MOLECULAR CYTOGENETICS OF MYEL
Page 27 and 28: clear that the biggest challenge fo
Page 29 and 30: esponse and have demonstrated that
Page 31 and 32: variable region of the idiotypic im
Page 33 and 34: 4. From MGUS to symptomatic MM Fig.
Page 35 and 36: (MRI); some have claimed that level
Page 37 and 38: P4.5 CYTOKINES IN MGUS: THERAPEUTIC
Page 39 and 40: preventing phosphorylation of p70S6
Page 41 and 42: transducing component of the interl
Page 43 and 44: survive initial drug exposure and a
Page 45 and 46: quiescent counterpart, the human um
Page 47 and 48: transcriptional activity of NF-êB;
Page 49 and 50: manifestations and anomalous protei
Page 51 and 52: P7.4 ROLE OF SERUM FREE LIGHT CHAIN
Page 53 and 54: P7.6 IMMUNOPHENOTYPIC INVESTIGATION
Page 55 and 56: presumably through the circulation,
Page 57 and 58: 9. Chemotherapy, maintenance treatm
Page 59 and 60: stratified according to their antim
Page 61 and 62: explore higher doses of zoledronic
Page 63 and 64: initial therapy. However, the role
Page 65 and 66: P10.2.2 SINGLE VERSUS TANDEM HIGH D
Page 67 and 68: With a median follow-up of 38 month
Page 69 and 70: cells could be harvested following
Page 71: 11. What is the role of allogeneic
Page 75 and 76: patients with responsive disease 3
Page 77 and 78: 9. Giralt S, Estey E, Albitar M, et
Page 79 and 80: Badros A, Barlogie B, Siegel E, et
Page 81 and 82: Figure 3b. Event-free Survival 4-Ye
Page 83 and 84: improve patient outcome in MM. Impo
Page 85 and 86: myeloma and in 40% of previously un
Page 87 and 88: degrade OPG in the same way as myel
Page 89 and 90: P12.2.5 MONOCLONAL ANTIBODY THERAPY
Page 91 and 92: myeloma. Blood 2001; 98:210-216. 6.
Page 93 and 94: MHC molecules, in effectively prese
Page 95 and 96: mice demonstrate that class II-spec
Page 97 and 98: detected in 293 and NIH3T3 cells. S
Page 99 and 100: hypothesis that (1) CCND1 and FGFR3
Page 101 and 102: patient samples. In addition, the p
Page 103 and 104: 016 NEUTRAL ENDOPEPTIDASE (CD10) KN
Page 105 and 106: 2. Genetic heterogeneity in MM: imp
Page 107 and 108: evidence from two t(11;14) cases wh
Page 109 and 110: immunoglobulin heavy chain (IgH) lo
Page 111 and 112: 034 Instability of Pericentromeric
Page 113 and 114: clusters were found, the first was
Page 115 and 116: MGUS but most likely not crucial fo
Page 117 and 118: Objective: To compare the impact on
Page 119 and 120: 4 patients had MMSET/IgH but did no
Page 121 and 122: 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
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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
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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