Haematologica 2003 - Supplements

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affects the clinical outcome. Recent developments on transplant strategies have shown that a reduction in the intensity of the conditioning can decrease the TRM while retaining an antitumor effect. However, it is still unknown if reduced-intensity regimens can offer the same opportunities of cure as myeloablative ones. We have compared the results of two clinical trials: in the first trial (myeloablative conditioning protocol, MCP) 30 patients underwent allo-SCT mainly at diagnosis, conditioning regimen consisted of busulfan 12-16 mg/kg and melphalan 140 mg/m2, all patients received peripheral blood stem cells from HLA identical siblings and immune suppression consisted of cyclosporine and short-course methotrexate; in the second trial (reduced intensity conditioning, RIC) 14 patients were treated with allo-SCT mainly with a disease relapsed or resistant to autologous stem cell transplantation. In this trial conditioning regimen consisted of thiotepa 5mg/kg, cyclophosphamide 60mg/kg and fludarabine 60mg/kg, and antithymocyte globulin 7.5mg/kg or alemtuzumab 30mg and GVHD prophylaxis consisted of cyclosporine and methotrexate. MCP patients had a median age of 48 years (range 31-55) and 15 (50%) had a chemosensitive disease at the time of transplant. RIC patients had a median age of 56 years (range 48- 69) and 6 (43%) were transplanted with a chemosensitive disease. All patients of both protocols engrafted promptly. Acute GVHD grade I°-IV° occurred in 26 (87%) of 30 MCP patients and in 4 (28%) of 14 RIC patients (P=0.008), while grade III°-IV° aGVHD occurred in 5 (17%) and 1 (7%) patients respectively (P=0.65). Chronic GVHD developed in 17/24 (71%) evaluable MCP patients and in 4/12 (33%) RIC patients (P=0.02). TRM at 100 days was 16% in MCP and 0% in RIC (P=0.10), while overall TRM was 30% in MCP and 7% in RIC (P=0.09). Median follow-up for MCP patients is 35 months (range 1-75), and 24 of them (80%) attained a complete remission (CR). Median followup for RIC patients is 12 months (range 3-27), and 5 patients (36%) attained CR: 3 of them after cyclosporine withdrawal and/or DLI. MCP seem superior to RIC in terms of attainment of CR (80% vs. 36%, P=0.006). Overall survival at 2 years is 75% for MCP and 65% for RIC. Our data on a limited series of patients suggest the following conclusions: i) there is a trend for a lower TRM in RIC transplants, especially considering that patients were older and heavily pretreated; ii) RIC with partial in vivo T-cell depletion can decrease GVHD incidence; iii) patients receiving MCP at diagnosis were more likely to attain a CR. Thus, RIC regimens appear promising and further investigation is warranted. 302 Adoptive Immunotherapy with Donor Lymphocyte Infusions (DLI) and IL-2 after High-Dose Therapy and Autologous Stem Cell Transplantation for High-Risk Multiple Myeloma. Oscar F. Ballester, Anastasios Raptis, John Hiemenz, Patricia Wilcox, Gabriela Ballester, Andrea Townsend Stem Cell Transplant Program, Medical College of Georgia, Augusta, GA, USA; Bone Marrow Transplant Program, Midwestern Regional Medical Center, Zion, IL, USA The outcome of high-dose therapy (HDT) with autologous stem cell transplantation (AutoSCT) in patients (pts) with relapsed/refractory myeloma is disappointing (median overall survival 19 months, SWOG S8993). DLI can result in a powerful graft-vs-myeloma (GvM) effect in pts who have relapsed after allogeneic transplantation. Taking advantage of the immunosuppression associated with the immediate post-transplant period, we explored the use of DLI as the means to induce a GvM effect after HDT and AutoSCT rescue. Seven pts (median age 52, range 31 to 62) with primary refractory (3.5 mcg/dL. HDT consisted of melphalan (200 mg/m2), idarubicin (45 mg/m2) and etoposide (1200 mg/m2)(MIDET) on d-9 to d-6, with AutoSCT rescue on d0. DLI (total dose of CD3+ cells 0.5 to 1 x 107/kg) was given fractionated on d+1(20%), d+5(30%) and d+10(50%), with IL-2 as a CIVI at 1 x106IU/d from d+1 to d+12. Donors were selected among relatives on the basis of best available HLA match: 3/6 (n= 4), 4/6 (n=1), 5/6 (n=1) and 6/6 (n=1). A syndrome of hyper-acute graft-versus host disease (GVHD) developed in 6 of the 7 pts, including high fevers, skin rash (Grade II skin biopsies in 5/6) and elevated serum bilirubin. No specific therapy was given for GVHD, which resolved within days. Engraftment kinetics were compared to those of 6 MM pts in 1st remission who received MIDET/AutoSCT but without DLI/IL-2 (controls). While both groups received a similar number of CD34+ cells (median 2.96 vs 3.3 x 106 /kg, pNS) and recovered neutrophils in a similar pattern (median d+13.5 vs d+12, pNS), recovery of platelets was delayed in patients receiving DLI/IL-2: d+23.5 vs d+14 in controls (p= .04). One patient failed to engraft by d+18 and received, per protocol, a backup AutoSC infusion. VNTR (sensitivity 5%) evaluated from d+7 to d+201, failed to detect donor cells in peripheral blood. One patient died from complications of a pulmonary hemorrhage on d +55, by d+46 her serum monoclonal IgG was not longer detectable. Five patients achieved a complete remission. Remarkably, with a median follow up of 36 months, all 6 remaining pts are alive and in continuous remission from 31 to 42 months post transplant. DLl/IL-2 in the setting of HDT/ASC is biologically active, resulting in self-limiting GHVD, and rarely in autologous graft rejection. An allogeneic GvM effect is suggested by the high response rate in this cohort of refractory and relapsed pts. The use of haploidentical donors could make this approach available to nearly all pts undergoing HDT/ASC for MM. 303 Long-Term Follow-Up of Previously Untreated Symptomatic Myeloma Patients Treated with Myeloablative Therapy and Sibling-Matched Allogeneic Transplantation of the SWOG Study 9321. Bart Barlogie, Jason McCoy, Hilliard Lazarus, Stephen Forman, Fred Appelbaum, Kenneth C. Anderson, Robert Kyle, John Crowley. Myeloma Institute for Research and Therapy (MIRT), University of Arkansas for Medical Sciences, Little Rock, AR, USA; Cancer Research And Biostatistics (CRAB), Fred Hutchinson Cancer Center, Seattle, WA, USA; Ireland Cancer Center, University Hospitals of Cleveland, Cleveland, Ohio; City of Hope National Medical Center, Duarte, CA, USA; Dana Farber Cancer Institute, Boston, MA, USA; Mayo Clinic, Rochester, MN, USA A long-term follow-up is provided on the myeloablative siblingmatched allotransplant arm of a multi-institutional randomized study which enrolled 38 newly diagnosed patients with symptomatic myeloma between 1994 and 1997. Patients were treated initially with 2-4 cycles of VAD followed by high-dose cyclophosphamide (4.5 g/m2) and proceeded, in the absence of progressive disease, to receive melphalan 140 mg/m2 + fractionated TBI of 1200 cGy given over 4 days, followed by infusion of marrow cells from HLA A, B, & DR matched siblings. Prevention of graft-versus-host disease (GVHD) was performed S223
with cyclosporine A and methotrexate. Of the 38 patients enrolled, 37 proceeded to allotransplant within 6 weeks following cyclophosphamide. The median age was 47 years (range: 31 - 55), 68% were male. The median survival from study enrollment is 31 months with 22 deaths, but 6-year survival is 42%. Of the 16 patients evaluable for response, 11 achieved complete remission (normal marrow; no paraprotein; negative immunofixation) or very good partial response (normal marrow; > 90% decrease in serum paraprotein; negative BJ proteinuria) and response (> 50% decrease in marrow plasmacytosis; > 75% decrease in serum paraproteins; > 90% decrease in BJ proteinuria). Seven patients relapsed during the first 3 years, with a 2-year estimate of relapse of 20%. Ten patients are event-free now for more than 5 years, with a 6-year projection of 26%. The major cause of failure, however, was transplantrelated mortality (TRM), with 13 deaths within 6 months (1-year estimate of 36%), resulting in closure of the enrollment to this arm in 1997. Of the transplant-related deaths, infection (n = 8) was the most common cause and was associated with acute GVHD. No further events after 5 years post-transplant were observed suggesting the possibility of long-term disease control, but at the expense of high initial TRM. 100% 80% 60% 40% 20% 0% Overall Survival Event-Free Survival Events / N 22 / 38 28 / 38 0 2 4 6 8 Years After Transplant 6-Year Estimate 42% 26% 304 Chronic but not acute Graft versus host disease improves outcome in multiple myeloma patients after nonmyeloablative allogeneic transplantation Pérez-Simón JA(*), Martino R, Alegre A, Tomás JF, De Leon A, Caballero D, Sureda A, Sierra J, San Miguel JF Spanish Collaborative Group for Non-myeloablative Transplantation. A graft versus myeloma effect (GVM) has been observed in MM patients after allogeneic transplantation. This effect has been used to design less toxic regimens such as non-myeloablative transplants (NMT) maintaining antitumor efficacy through the GVM effect. In the present study we have evaluated the outcome of 29 MM patients receiving fludarabine and melphalan-based NMT. Event free survival (EFS) at 24 months was 33% being significantly higher for patients who developed cGVHD as compared to those who did not (51% vs 0% respectively, p=0.02; Hazard Rate (HR) = 3.16 (95% CI=1.09-9.15, p=0.03)) as well as for patients transplanted in response (CR/PR) or stable disease (SD) as compared to those with refractory/progressive disease at transplant (43% vs 0% respectively, p=0.02). Overall survival (OS) at 24 months was 60% ranging from 72% vs 42% for patients who did and did not develop cGVHD, respectively (p=0.1) and 63% vs 41% for patients in CR/PR or SD vs refractory/progressive disease at transplant, respectively (p=0.013). After a median follow up of 366 days 13 patients are in complete or partial remission (45% overall response rate). Nine patients have died, 3 of them due to disease progression and 6 (21%) due to transplant related mortality (TRM). Actuarial incidence of TRM was 37% for patients who developed aGVHD vs 13% for those who did not (log rank p=0.04). Among patients evaluable for cGVHD, these figures were 13% and 33% for patients with and without cGVHD, respectively (log rank p=0.22). The present study suggests that graft versus myeloma (GVM) effect is the main weapon for disease control after NMT in MM patients and the efficacy of this immune effect depends on tumor burden before transplant. (Supported by Grant from Spanish FIS G03/136) 305 Results of Reduced Intensity Conditioning Allogeneic Transplantation in Myeloma – A report from the EBMT C. Crawley, R.Szydlo, M. Lalancette, G.Juliusson, A. Shimoni, A. Nagler, T Ruutu, M.Michallet, J Boiron, K.Peggs, J. Sierra, H.Einsele, R.Chopra, A. Carella, A. Zander, A. Gratwohl, H. Greinix, J. Cavenagh, F. Garban, D. Caballero, D.Niederwieser, G. Gahrton and J.Apperley For the Chronic Leukaemia Working Party of the EBMT. The more widespread use of conventional allogeneic transplant for myeloma has been limited by the substantial procedure related mortality. Reduced intensity conditioning has been widely adopted with the demonstration of its feasibility and apparent lower mortality. Evidence for efficacy is limited, as the majority of series are small and frequently diagnostically heterogeneous. Data were collected for myeloma patients from 38 EBMT centres on a total of 256 transplants performed between 11/97 and 07/00. The median age was 52 years (32-66), 61% were male of whom 43% received stem cells from a female donor. 70% had stage III disease at diagnosis. 194 were matched siblings, 40 were unrelated and 9 were from mismatched or other related donors. 73% were CMV IgG positive. At the time of transplant 7.5% were in CR, 54% PR and 29% had progressive disease. The median time to transplant was 20 months (2 months – 11 years). Conditioning regimens varied but included fludarabine in 95%. The most frequent regimens were Fludarabine + TBI, Fludarabine, Busulphan + ATG and Fludarabine, Melphalan ± Campath. The cell source was peripheral blood stem cells (PBSC) in 205 and bone marrow (BM) in 51 patients. The time to neutrophil and platelet engraftment was faster for PBSC recipients (14 and 13 days vs 17 and 21 days respectively). Acute GvHD (grade II-IV) occurred in 31% and cGvHD in 49% of 195 assessable patients (extensive in 25%). The 1 and 2 year the TRM was 23.5% and 26%. Factors associated with an increased TRM were more than one prior transplant (RR 1.9), > 1 year from diagnosis (RR2.7) and male patients with a female donor (RR 2.3). At 2 years the overall and progression free survival was 50% and 39%. Patients in remission prior to transplant had a better 2 year overall survival (1st CR/PR 74%, >1st CR/PR 49%, no remission 38% p=0.006). 2 year survival was worse in male patients receiving cells from a female donor (36% vs 54%) and in patients who had had more than one prior transplant (28% vs 54%). Similar factors were predictive for progression free survival at 2 years namely > 1 prior transplant (20% vs 45% p< 0.001) and remission status at conditioning (1st remission 62% vs no remission 35% p=0.003) Disease progression and treatment related mortality remain challenges in allogeneic transplants for myeloma even with reduced intensity conditioning. It is, however, possible to identify patients where the risk may be acceptable and who may derive real benefit. S224
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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
Page 181 and 182: 189 Factors Predicting Occult Spina
Page 183 and 184: vivo detected resonances was invest
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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
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: References Effect of dose-intensive
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 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
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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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