Haematologica 2003 - Supplements

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esponse (50% or greater reduction in M protein) was seen in 32 patients yielding a response rate of 64% (95% CI 49-77%). If minor responses are included (25-49% reduction in M protein), the overall response rate increased to 92%. Similar results were seen in an independent trial of thalidomide plus dexamethasone in newly diagnosed patients conducted at M. D. Anderson Cancer Center. Based on these results, a randomized controlled trial comparing dexamethasone versus thalidomide plus dexamethasone was initiated by the Eastern Cooperative Oncology Group, the results of which will define the role of this combination as upfront, pre-transplant induction therapy for myeloma. Given the incurability of myeloma and the leukemogenic potential of alkylating agents, the current standard of care is to delay therapy until symptomatic disease occurs. However, patients with asymptomatic myeloma are at high risk of progression to symptomatic disease, with a median time to progression of approximately 1-2 years. With the advent of effective non-cytotoxic biologic agents, the time is right to challenge this paradigm of myeloma therapy with carefully conducted clinical trials. We hypothesized that early therapy with thalidomide may be effective in delaying progression from asymptomatic to symptomatic multiple myeloma. Therefore, we conducted a phase II trial at the Mayo Clinic to determine the response rate and time to progression with thalidomide therapy in patients with smoldering and indolent (asymptomatic; early stage) multiple myeloma. Thirty-one patients with smoldering or indolent multiple myeloma were studied at the Mayo Clinic. Two patients were deemed ineligible because they were found to have received prior therapy for myeloma and were excluded from analyses except for toxicity. Thalidomide was initiated at a dose of 200 mg/day, and escalated as tolerated to a maximum of 800 mg/day. However, the dose of thalidomide was adjusted to as low as 50 mg per day, as needed, to minimize toxicity. Of the twenty-nine eligible patients, ten (34%) had a partial response to therapy with at least 50% or greater reduction in serum and urine monoclonal (M) protein. When minor responses (25-49% decrease in M protein) were included, the response rate was 66%. Three patients had progressive disease while on therapy. Kaplan-Meier estimates of progression free survival are 80% at 1 year and 63% at 2 years. Major grade 3-4 toxicities included 2 patients with somnolence and 1 patient each with neuropathy, deep vein thrombosis, hearing loss, weakness, sinus bradycardia, and edema. Mild grade 1-2 neuropathy, sedation, and constipation were seen in 87%, 87% and 74% of patients, but these were generally amenable to appropriate dose reductions. Because of the lack of a control arm and the toxicities of early therapy, we presently do not recommend thalidomide for asymptomatic myeloma outside the setting of an approved clinical trial until randomized studies can be conducted. A phase III trial comparing zoledronic acid versus thalidomide plus zoledronic acid is due to open at the Mayo Clinic shortly, the results of which will shed light on the role of thalidomide as initial therapy for early stage myeloma. DOXIL, VINCRISTINE, DECADRON AND THALIDOMIDE (DVD-T) FOR NEWLY DIAGNOSED, AND RELAPSED/REFRACTORY MULTIPLE MYELOMA; RESPONSE TO THERAPY, AND SUPPORTIVE CARE ISSUES Mohamad A Hussein, MD The Cleveland Clinic Myeloma Research Program. The Cleveland Clinic Taussig Cancer Center, Cleveland, Ohio, USA DVd is an effective and well tolerated regimen in newly diagnosed MM patients resulting in an over all response rate of 90%, however only 10% of the patients achieve complete remission. In relapsed/refractory group of myeloma patients, only 22% and 5% achieve 50% & 90% reduction in the M-Protein respectively. Patients achieving >90% decrease in the M-Protein on DVd had a durable response. Thal/Dex in a similar group of patients results in 60% overall response with rare cases achieving 90% reduction in the M-protein. Thalidomide modulates integrins thus interrupting the myeloma cell-stroma interaction results in the malignant cell becoming sensitized to therapy as well as a significant decrease in the supportive cytokine environment. We evaluated the role of Thalidomide in combination with DVd with the objectives is to enhance the quality of response in the newly diagnosed patients, i.e., complete remission, and near complete remission rate, and in the relapsed refractory group enhance the response rate as well as the quality of response, in addition to assessing the tolerability of the combination. In both groups the regimen was administered as follows. On day 1 Doxil was given at 40 mg/ m2 IVPB; Vincristine at 2 mg IVP & reduced dose decadron at 40 mg PO daily X 4 days. Thalidomide was started at 50 mg a day, to be increased by 50 mg a day q week to maximum tolerated dose and not to exceed 400 mg a day. DVd was repeated q4 W, for a minimum of 6 cycles & 2 cycles after best response. Patients achieving a plateau phase were maintained on prednisone 50 mg qod & the maximal tolerated dose of Thalidomide until disease progression. All patients were screened for vitamin B12 and folate deficiency, and were allowed to use erythropoietin and bisphosphonate therapy for anemia, and bony disease respectively. Response was assessed according to SWOG criteria. However, for (CR) we required in addition to the standard SWOG criteria, the BM to show polyclonal PC’s by immune staining. Following an increased incidence of neutropenia, infections, oral herpes simplex, increased incidence of neuropathy & Deep venous Thrombosis (DVT’s) in the first group of patients; the protocol was amended to initiate all patients on prophylactic amoxicillin 250mg BID, acyclovir 400 mg BID until completion of chemotherapy, GM-CSF or G-CSF if the total WBC was less than 5000/µL on day 1, & Aspirin 81mg daily. The vincristine dose reduction algorhythm was further modified to be more aggressive in response to grades 1 and 2 neuropathy. 35 newly diagnosed, and 50 relapsed/refractory myeloma patients are currently enrolled. 70 patients (25 newly and 45 relapsed/refractory) will be reported for response, and 71 for toxicity. All patients enrolled had progressive disease, and none of the relapsed/refractory group was non-responder/nonprogressor. Patients’ demographics and prognosticators are outlined in table 1. Table 1 Newly diagnosed Relapsed/refractory Age 60 63 PS < 3 < 3 β2 2.9 6.6 Albumin 3.8 3.2 S4
The overall response rate was noted in 22 (88%) and 34 (76%) patients; with CR (Disappearance of the M-protein by immune fixation, & the presence of polyclonal plasma cells in the bone marrow by immune staining) is achieved in 6 (24%) and 5(11%) patients who were newly diagnosed or relapsed/refractory correspondingly. The break down of the different responses by M-protein values is outlined in table 2. Table 2 CR NCR > 75%- < 90% Newly 6 4 3 (24%) Relapsed 5 (11%) (16%) 15 (33%) > 50%- < 75% 9 (12%) (36%) 4 (9%) 10 (22%) SD 2 (8%) 4 (9%) PD 1 (4%) 7 (15%) Toxicity prior to amending the protocol included 21 of 35 patients with Grade 3/4 neutropenia, 7 cases of pneumonia requiring IV antibiotic therapy, 1 septic arthritis, 2 GI bleeds. Following the amendments these cytopenia related complications has been reduced to only 1/19 grade 3 neutropenia & fevers. Grade 3 neuropathy was reduced from 18 of the first 31 patients to none after the amendments. Even though no excessive deep venous thrombosis was noted in our protocols that utilized thalidomide as a single agent or in combination with steroids or non anthracyclines combination regimens; in the current protocol deep venous thrombosis was significantly increased with the newly diagnosed patients more likely to be afflicted than relapsed/refractory (newly diagnosed 50% vs 10% & relapse/refractory 26% vs 10%). Activated protein C resistance (APCR), factor V Leiden (FVL), platelet aggregation activity (PA), & von Willebrand factor (vWF) were measured in 28 newly diagnosed & 51 relapsed/refractory MM patients before & after each cycle of DVd-T. 3 patients with prior DVT, 1 pt on Warfarin for mechanical heart valve & 1 pt on ASA prior to the study were excluded from the analysis. Patients were grouped in 2 categories: 39 patients received ASA & 35 patients did not at the start of therapy. None of the patients had homozygous Factor V Leiden. 14 treatment-related DVT occurred with a mean of 85.6 days post-therapy. 3 with post-therapy DVT in the ASA group stopped ASA (mean= 11 days) prior to their DVT. Excluding these 3 patients, the difference between DVT rates in non-ASA group (10/35) and ASA group (1/36) is statistically significant (p=0.003).With intent-to-treat, the ASA group continued to have a lower incidence of DVT (p=0.04). after the addition of ASA, the relapsed/refractory group of patients showed a trend towards less incidence of DVT (5/46) as compared to newly diagnosed patients (6/25) (p=0.144). Compared to pre-therapy levels, vWF (p=0.03) & PA to ristocetin 1500 mcg/ml (p=0.04) were significantly elevated at day 30 after start of DVd-T. In summary DVd-T following supportive care modifications is well tolerated. The addition of low dose aspirin reduced the incidence of deep venous thrombosis to what is noted in historical data, and did not result in any increase incidence of bleeding. Compared to historical data in a similar pt population receiving DVd or Thal/Dex, the quality of response in both groups of patients, and& the response rate in the relapsed/refractory patients is significantly enhanced by combining both regimens, & reducing steroids. ROLE OF IMMUNOMODULATORY DRUGS IN MULTIPLE MYELOMA Kenneth C. Anderson, M.D. Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Boston, MA 02115 We have carried our preclinical and clinical studies of the immunomodulatory drug (IMiD) Revimid. It induces growth arrest or apoptosis of drug resistant multiple myeloma (MM) cell lines and patient cells; abrogates binding of MM cells to bone marrow stromal cells (BMSCs) and extracellular matrix proteins; inhibits production cytokines (IL-6, IGF-1, VEGF) which confer growth, survival, and drug resistance in the BM; and stimulates patient anti-MM NK cell and ADCC. Revimid triggers activation of caspase 8, enhances MM cell sensitivity to Fas-induced apoptosis, and downregulates NF-B activity as well as expression of cellular inhibitor of apoptosis protein-2 and FLICE inhibitor protein. It potentiates the activity of TRAIL/Apo2L, dexamethasone, and proteasome inhibitor PS-341. Revimid activates PI3-K/PKCand NF-AT2, with resultant nuclear translocation of NF-AT2 and upregulation of IL-2 transcription in T cells. It induces phosphorylation of CD28 on T cells, and increases proliferation of T cells following activation via CD3 or dendritic cells. When MM cells are injected subcutaneously into SCID mice in the context of matrigel, Revimid inhibits growth of human MM cells and associated angiogenesis, as well as prolongs survival. Phase I trial showed no constipation, neuropathy, or somnolence, and established the MTD of 25mg daily. Remarkably, >25% MM paraprotein decreases were observed in 63% patients with relapsed refractory MM, and stable paraprotein or better was achieved in 80% patients in this phase I trial. A phase II trial has examined 30mg once daily versus 15 mg twice a day in patients with relapsed refractory MM. Preliminary analysis reveals thrombocytopenia requiring dose reduction in 25% patients, more commonly in patients receiving the twice daily drug regimen. Importantly, 38 of 46 (85%) patients either stabilized their disease or responded, including complete responses. A multicenter phase III trial of Dexamethasone and placebo versus Dexamethasone and Revimid is ongoing in an attempt to achieve 50% prolongation of time to progression. Given its remarkable clinical activity in advanced relapsed and refractory MM, Revimid is being evaluated in treatment protocols for newly diagnosed MM, and as maintenance therapy to prolong progression free survival after high dose therapy and stem cell transplantation. THALIDOMIDE (THAL), REVIMID (REV) AND VELCADE (VEL) IN ADVANCED MULTIPLE MYELOMA Bart Barlogie, Joth Jacobson , Choon-Kee Lee, Maurizio Zangari, Ashraf Badros, John Shaughnessy and Guido Tricot The Myeloma Institute for Research and Therapy (MIRT), University of Arkansas for Medical Sciences, Little Rock, AR and Cancer Research And Biostatistics (CRAB), Fred Hutchinson Cancer Research Center, Seattle , WA. Myeloma relapsing after high dose therapy (HDT) has a poor prognosis, especially if response duration is short and cytogenetic abnormalities (CA) are present at relapse. THAL represented the first-effective therapy for such post-HDT relapses, no longer responsive to standard DEX or chemotherapy such as DCEP. An update is provided of 169 patients receiving a dose-escalation schedule of THAL (200 mg with escalation of 200 mg q 2 weeks, according to tolerance, to a maximum of 800 mg). Seventy-six percent had relapsed from 1 and 53% from 2 cycles of HDT; 67% exhibited CA including 37% with del 13. By 8 months from S5
Page 1 and 2: Focussed Symposia Arsenic trioxide
Page 3: assess whether such a program will
Page 7 and 8: Figure 5A Table 1: VEL + THAL for R
Page 9 and 10: naturally occurring OPG. Present tr
Page 11 and 12: 0.505). Finally, the multiple event
Page 13 and 14: CLINICOPATHOLOGICAL DEFINITION OF W
Page 15 and 16: Plenary Sessions 1. Development of
Page 17 and 18: clonotypic IgH VDJ signature confir
Page 19 and 20: 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
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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
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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
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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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