ALBERT

Description: Background and objective Fludarabine in combination with cyclophosphamide (FC) plus rituximab (R) is an effective treatment for newly diagnosed as well as relapsed follicular lymphoma (Tam 2004; Keating 2005; Sacchi 2007). Maintenance treatment with R, after different induction treatments, improves overall and progression-free survival (Forstpointner 2006; van Oers 2006). Therefore, we aimed to evaluate the efficacy and safety of the FC-R regime followed by maintenance doses of R. Patients and Methods We present an intermediate report of the one-arm study in which 75 previously untreated patients with a diagnosis of follicular non-Hodgkin’s lymphoma in Ann Arbor stage II–IV were included between October 2004–2006. Seventy four were assessed for safety after receiving at least one FC-R dose (F: 3x25 mg/m2 and C: 1 g/m2; R: 375mg/m2), and 72 for response to treatment. Patients aged 53.4 years in average, one in five showed bulky disease and 72.2% Ann Arbor IV staging. FLIPI index determined 23.9% patients with low (0–1) score, 38% with intermediate (2) and 38% with poor score (3). A total of 47 patients presented some molecular alteration in PB or BM. Results Induction therapy was delivered throughout 4–6 courses, resulting in 91% complete responses (CR) and 9% partial responses (PR) (Table 1). From the patients who presented monoclonal population at diagnosis, 40 were evaluated for molecular response after induction and only 1 remained MDR positive for bcl2/IgH. Overall survival (OS) at 24 months was 87.5%, and two patients presented progressive disease within this period. The median OS has not been reached at this evaluation. To the date, 262 adverse effects grade 3–4 (32.6%) have been documented (80.9% neutropenias) and 80 infectious complications were recorded (23.8% grade 3–4). Three patients died from respiratory diseases, two from acute leukemia, and six from other causes. Table 1 EVOLUTION OF RESPONSE Evaluated Response at End of Induction Therapy Evaluated Response Post-Course 3 Assesable End Ind. (n=67) Missing End Ind. (n=5) CR: complete response; uCR: unconfirmed CR; PR: partial response; NE: not evaluated; WD: withdrawn; EX: exitus. Assesable PC3 (n=70) CRITERIA CR PR NE WD EX 14 CR 12 - 1 1 - 32 uCR 31 - 1 - - 24 PR 16 6 - - 2 2 Missing PC3 (NE) 2 - - - - 72 Total 61 6 2 1 2 Conclusions The FC-R has proven a potent antitumoral activity in untreated follicular lymphoma patients, rendering very high clinical and molecular responses. However, as reported in similar studies (Hochster 2007 ASCO), the high incidence of prolonged neutropenias and lymphopenias developed as consequence of the chemotherapy regime, questions the safety of the induction treatment.

Description: Introduction: Multiple myeloma (MM) accounts for about 20% of deaths from hematological cancers and remains incurable despite conventional and high-dose chemotherapy. Two phase III trials in patients with relapsed or refractory MM (MM-009 and MM-010) showed that lenalidomide combined with dexamethasone resulted in significantly improved response rates and significantly prolonged median time to progression (TTP) and overall survival (OS) compared with dexamethasone alone. This current sub-analysis of lenalidomide plus dexamethasone therapy assessed whether there was a survival benefit in maintaining patients on therapy after achieving their best response and what the impact of early discontinuation on TTP and OS was. Methods: Of the 353 patients from MM-009 and MM-010 treated with lenalidomide plus dexamethasone, 32 did not respond. Of the remaining 321 responding patients, 214 had a partial response (PR) or better and 107 patients had stable disease (SD). In this post-hoc sub-analysis, we first assessed the outcome of continuing treatment for ≤10 months vs. 〉10 months in all 321 patients who achieved SD or better, after they achieved their best response. In this landmark analysis, OS was measured from the time of achieving best response to death from any cause or to last contact. In a second analysis, we assessed the impact of early discontinuation due to adverse events or withdrawn consent on OS and TTP in all patients who achieved SD or better. Therefore, we excluded patients who discontinued treatment due to disease progression, death, or lack of efficacy. Patients who achieved SD or better and who continued on therapy were compared with those who discontinued. OS and TTP were assessed from time of randomization. Results: In the landmark analysis, of the 321 responding patients (≥PR, n=214; SD, n=107), 223 patients received treatment for ≤10 months after achieving their best response and 98 patients for 〉10 months after achieving their best response. Patients who continued therapy for 〉10 months after achieving their first best response had significantly longer OS vs. those who received therapy for ≤10 months (not reached vs. 23.4 months; p10 months vs. ≤10 months (93.8% vs. 48.4%, p

Description: Abstract 3873 Poster Board III-809 BACKGROUND Neuropathy in multiple myeloma, related either to the disease itself or as a result of anti-myeloma treatment, may limit patients' therapeutic options. AIMS To assess efficacy and safety of lenalidomide + dexamethasone treatment in relapsed/refractory multiple myeloma patients depending on reported neuropathy history. METHODS This subanalysis is based on pooled data from two large multi-center randomized placebo-controlled phase-3 trials (MM-009, MM-010), for patients who had received at least one prior therapy of multiple myeloma. Patients were randomized to receive either 25 mg of lenalidomide or placebo on Days 1-21 of a 28-day cycle. Both groups also received 40mg of oral dexamethasone on Days 1-4, 9-12, and 17-20 for the first four cycles, after which dexamethasone was administered only on Days 1-4. All patients who received lenalidomide + dexamethasone during the study period were included in this subanalysis (n=353). Patients with a reported history of neuropathy between time of first multiple myeloma diagnosis and date of study randomization (n=70) were compared to patients without a reported history of neuropathy (n=283). Adverse event terms included were: non-specified neuropathy, peripheral motor neuropathy, non-specified peripheral neuropathy, peripheral sensory neuropathy and non-specified polyneuropathy. Lenalidomide mean and median daily dose intensity, duration of treatment and efficacy [including complete response (CR), very good partial response (VGPR), time to progression (TTP) and overall survival (OS)] were assessed. RESULTS Lenalidomide mean daily dose intensity (excluding treatment breaks on Days 22-28 of each 28-day cycle) was not significantly different between patients with or without history of neuropathy (21.6 mg vs. 22.6 mg; p=0.1479). In addition, the median daily dose intensity was equivalent to the planned daily dose of 25mg (p=0.3857). Mean and median treatment duration were also not significantly different between the two groups (10.1 vs. 10.7 months, p = 0.5307, respectively 9.6 vs. 10.2 months, p=0.5473). Response rates were not significantly different for patients with or without history of neuropathy, with CR/VGPR of 40% vs. 33% (p=0.3116) and overall response rates of 68% vs. 64% (p=0.6174), respectively. Time to progression was not significantly different between the two groups (median TTP 14.8 vs. 12.3 months, p=0.6488), and neither was overall survival (median OS not yet reached vs. 30.6 months, p=0.7848). CONCLUSIONS With median daily dose intensities both at 25mg and a comparable mean daily dose intensity at 21.6 and 22.6 mg, lenalidomide is well tolerated in both patients with and without history of neuropathy. With a favorable tolerability profile, patients are able to continue therapy for longer, achieving desired response, longer TTP, and ultimately longer overall survival. The results of these data demonstrated that lenalidomide + dexamethasone is an optimal therapeutic choice in relapsed or refractory multiple myeloma irrespective of a patient's history of neuropathy. Disclosures: Delforge: Celgene: Honoraria, Speakers Bureau; Janssen-Cilag: Consultancy, Honoraria. Facon:Janssen Cilag: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Bravo:Celgene: Employment. Dimopoulos:Celgene: Honoraria.

Description: Abstract 4950 Background & Aims The management of elderly patients with Multiple Myeloma (MM) previously treated requiring further therapy (although in most cases palliative) is very difficult due to the presence of concomitant diseases, decreased bone marrow reserve, systemic toxicity, relatively decreased renal function and general problems of old age. As in this setting the tolerability of standard doses of conventional chemotherapy, high doses of dexamethasone or IMiDs is a concern, we report the preliminary results of the combination of tailored low doses of lenalidomide (len) and low doses of dexamethasone (dex). Methods We retrospective analyze the results of the combination of low dose lenalidomide and low dose of dexamethasone (len/dex) in 14 patients aged over 70 years with pretreated MM and progressive disease. Low doses of len (5-10 mg daily for 21days) were initially given and flexibly modified in subsequent cycles according to response and toxicity, along with low doses of dex (20-40 mg/day for 4 days) in most (12) patients. G-CSF and red cell transfusions were used when needed. Patient risk was stratified following the Salmon and Durie (S&D) score and the International Staging System (ISS). Response was assessed with the IMWG criteria. Results Median age was 80 years (70-90). All patients had received between 2-5 different previous modality treatments (m=2), including bortezomib (7), thalidomide (4) or PBSCT (2). 11 pts had IgG, m=3397mg/dl (868-4990), 2 IgA m=1460 (1050-1870) and another one BJ. 9 pts had κ and 4 » light chains. Median Hemoglobin level was 10 gr/dl (7.2-11.4) and median creatinine level 1.19 mg/dl (0.75-1.63). 11 (78%) had bone disease. 9 pts had S&D stage II, 4 stage III and another one stage I. 7 pts had ISS stage II, 4 had stage I and 2 stage III. Patients received between 2 and 13 cycles of len/dex (m=6.8). 11 pts (78%) achieved Partial Remission (PR) and 2 (14%) achieved significant, but lesser that 50%, reduction of the M-component (Stable Disease: Std). Overall response (PR+Std) occurred in 13/14 patients (92.8%). The best response occurred between 2-12 cycles of len/dex. Grade III-IV bone marrow toxicity occurred in 5 pts (35 %) and neurological toxicity (PNP) in 5 pts (35%) (all of them had received previous bortezomib or thalidomide). Treatment was stopped in 6 pts: for unrelated causes (1), due to neurological (3) or haematological (1) toxicity and in 2 pts after achieving Std and both relapsed after 3 months. Conclusions Treatment with tailored low doses of lenalidomide and low doses of dexamethasone (len/dex) is an active and tolerable option for previously treated elderly patients with symptomatic MM. Low lenalidomide doses can be flexibly modified according to the quality of the response and the hematological toxicity that is expectable and manageable. Previous treatments with bortezomib or thalidomide is associated with neurotoxicity. Disclosures No relevant conflicts of interest to declare.

Description: Plasmacytoid dendritic cells (pDCs) efficiently produce type I interferon and participate in adaptive immune responses, although the molecular interactions between pDCs and antigen-specific T cells remain unknown. This study examines immune synapse (IS) formation between murine pDCs and CD4+ T cells. Mature pDCs formed canonical ISs, involving relocation to the contact site of the microtubule-organizing center, F-actin, protein kinase C-θ, and pVav, and activation of early signaling molecules in T cells. However, immature pDCs were less efficient at forming conjugates with T cells and inducing IS formation, microtubule-organizing center translocation, and T-cell signaling and activation. Time-lapse videomicroscopy and 2-photon in vivo imaging of pDC–T-cell interactions revealed that immature pDCs preferentially mediated transient interactions, whereas mature pDCs promoted more stable contacts. Our data indicate that, under steady-state conditions, pDCs preferentially establish transient contacts with naive T cells and show a very modest immunogenic capability, whereas on maturation, pDCs are able to form long-lived contacts with T cells and significantly enhance their capacity to activate these lymphocytes.