ALBERT

Description: Abstract 1689 Poster Board I-715 Introduction The use of the proteasome inhibitor bortezomib has demonstrated activity in multiple myeloma and lymphomas. The HDAC inhibitor romidepsin is being evaluated in CTCL and PTCL, though its activity in B-cell lymphomas is less clear. We hypothesized that the combination of bortezomib and romidepsin would result in synergistic apoptosis in different B-cell NHL cell lines based upon the observed activity of this combination in more mature B-cell malignancies such as myeloma. Experimental Design Daudi, HT, Ramos and SUDHL-4 cell lines were exposed to different concentrations of bortezomib and romidepsin, separately, concurrently, and sequentially. Cell viability was assessed using MTT-assay, induced apoptosis was evaluated using Annexin V and PI staining from 24-48 hours. Apoptosis was also evaluated using western blot analysis of caspases and PARP cleavage. LC3 and HDAC6 level expressions were performed to determine if the effect of the combination was a result of the aggresome or autophagy pathway. Cell cycle studies were also performed to study if there were any changes after treating cells with the combination. Results The combination of bortezomib and romidepsin resulted in synergistic B-cell apoptosis as measured by MTT-assay with combination indices of 〈 0.5. This was associated with increased caspases and PARP cleavage as early as 24 hours after exposure. Order of addition experiments demonstrated definite sequence specificity. When romidepsin was added first, and 6 hours later followed by bortezomib, apoptosis was enhanced, compared to both agents being given concurrently or when bortezomib was administered first. Cell cycle analysis studies demonstrated that pretreatment of cells with romidepsin for 6 hours followed by the addition of bortezomib arrested the cells in G2M phase. HDAC6 expression was significantly reduced following combination therapy, and LC3-I was cleaved to LC3-II in treated cells suggesting that the combination affected aggresome formation and autophagy. Conclusion The combination of romidepsin and bortezomib at low nanomolar concentrations suggests that this may be an important clinical combination to test in patients with relapsed or refractory B-cell malignancies. Sequence of administration data is currently being tested to determine if the effect is a result of autophagy inhibition as is seen in myeloma cell lines. Additional mechanistic studies will be presented with the goals of identifying predictors of response that can then be validated in prospective clinical trials. Disclosures Lechowicz: Gloucester: Consultancy. Kaufman:Millennium: Consultancy; Genzyme: Consultancy; Celgene: Consultancy; Merck: Research Funding; Celgene: Research Funding. Lonial:Gloucester: Research Funding; Novartis: Consultancy; BMS: Consultancy; Millennium: Consultancy, Research Funding; Celgene: Consultancy. Flowers:Millennium: Research Funding.

Description: Background: Bortezomib-containing combination chemotherapy regimens are effective in non-Hodgkin's lymphoma (NHL), although there are limited data on toxicity in the front-line setting for indolent NHL when combined with reduced-dose vincristine-containing chemotherapy. Our group (Sinha et al, Cancer 2012) reported outcomes from a phase I study of bortezomib combined with rituximab, cyclophosphamide, doxorubicin, modified vincristine, and prednisone (VR-CHOP) and found a maximum tolerated dose (MTD) of bortezomib (V) of 1.6mg/m2 with vincristine capped at 1.5 mg with an overall response rate (ORR) of 100%. Herein we report the results of our phase II study of this regimen. Patients and Methods: Eligible patients had untreated indolent NHL (small lymphocytic lymphoma [SLL], marginal zone lymphoma [MZL], or follicular lymphoma [FL] grades 1-3) meeting standard criteria for treatment or with FL international prognostic index (FLIPI) ≥3. Patients received V administered at a dose of 1.6mg/m2 on days 1 and 8 as well as rituximab (R) 375mg/m2, cyclophosphamide 750mg/m2, doxorubicin 50mg/m2, and vincristine 1.4mg/m2 (capped at 1.5mg/dose) on day 1 and prednisone 100mg on days 1-5 of a 21-day cycle. Patients received at least 6 cycles and up to 8 cycles of therapy at the discretion of the treating physician. Patients who achieved a complete response (CR) after induction were assigned to receive maintenance R 375mg/m2 every 12 weeks for 2 years while patients with a partial response (PR) or stable disease received R 375mg/m2 along with V 1.6mg/m2 (VR), both administered weekly for 4 weeks every 6 months for up to 2 years. Response was assessed by Cheson 1999 criteria, and toxicity assessed by CTCAE version 3.0. One FL patient discontinued study therapy after cycle 2 when a central pathology review revised the diagnosis to diffuse large B-cell lymphoma. This patient was not included in the efficacy analysis but is included in the safety reports. CR rate and ORR were determined at the conclusion of induction therapy, and progression-free survival (PFS) and overall survival (OS) were evaluated by the Kaplan-Meier method from the date of study entry. Results: Thirty patients received at least 1 treatment of VR-CHOP, including 16 males and 14 females. The median age was 58 (range: 31-71), and histologies included MZL (n=5), SLL (n=4), and FL (Grade 1, n=7; Grade 2, n=12; Grade 3, n=2). FLIPI score for patients with FL were 1 (n=2), 2 (n=4), 3 (n=12), and 4 (n=3). Twenty-nine were evaluable for response, including 19 patients with CR and 10 patients with PR at the conclusion of induction therapy (CR rate of 66%; ORR of 100%). For 20 evaluable patients with FL, the CR rate was 75%. Twenty-five patients proceeded with maintenance therapy, including 6 patients who received VR and 19 patients who received R alone. Three patients with PR to induction converted to CR after maintenance with VR. Four patients received no maintenance due to refusal/lost to follow-up (n=2), toxicity (n=1), and progression (n=1). Three patients with PR received only R due to neuropathy. Four patients have relapsed or progressed on therapy, including 1 patient prior to starting maintenance, 2 patients during VR maintenance, and 1 patient who achieved a PR but was receiving R maintenance. One additional patient progressed after completing R maintenance. With a median follow-up of 39 months, 3-year PFS rate is 85.8%, and the 3-year OS rate is 96.4% (Figure). Grade ≥3 peripheral neuropathy was noted in 2 patients (7%), while grade 1-2 neuropathy occurred in 17 patients (57%). Grade 3-4 hematologic toxicities included neutropenia (n=14, 47%), thrombocytopenia (n=3, 10%), anemia (n=1, 3%), and febrile neutropenia (n=1, 3%). Eight patients experienced additional grade 3 non-hematologic toxicities, including the following which occurred in more than 1 patient: vomiting (n=3, 10%), abdominal pain (n=2, 7%), fatigue (n=2, 7%), hyperglycemia (n=2, 7%), hypokalemia (n=2, 7%), and nausea (n=2, 7%). Conclusion: VR-CHOP is highly efficacious in the front-line setting for management of patients with untreated indolent NHL, and toxicities are expected and manageable. Incidence of grade 3 peripheral neuropathy is low with incorporation of a decreased dose of vincristine, and the PFS compares favorably with previously reported outcomes in FL and indolent NHL for R-CHOP, R-Bendamustine, and R-CHOP plus maintenance R. Figure 1 Figure 1. Disclosures Cohen: Janssen: Research Funding; BMS: Research Funding; Seattle Genetics: Consultancy; Pharmacyclics: Consultancy. Off Label Use: Bortezomib is not currently approved for follicular lymphoma, marginal zone lymphoma, or small lymphocytic lymphoma and is being evaluated in combination with a standard induction regimen.. Kaufman:Millennium: Consultancy; Janssen: Consultancy. Nastoupil:TG Therapeutics: Research Funding; Celgene: Honoraria; Genentech: Honoraria; Janssen: Research Funding. Lechowicz:Millennium: Consultancy. Lonial:Millennium, Celgene, Novartis, BMS, Onyx: Consultancy, Research Funding. Flowers:Gilead, Spectrum, Millennium, Janssen: Research Funding; Celgene, Prescription Solutions, Seattle Genetics, Millennium (unpaid), Genentech (unpaid) : Consultancy.

Description: Abstract 2686 Background: DLBCL is the most commonly occurring form of non-Hodgkin lymphoma and is a highly curable disease, but one that is universally fatal if untreated or improperly treated. In a series of studies, we have reported racial disparities in the clinical presentation and the treatment outcomes for patients (pts) with DLBCL in the United States (Shenoy Cancer 2010; Flowers CEBP 2012). These studies showed that black pts with DLBCL are diagnosed at an age a decade younger than whites, are more likely to have advanced stage disease, and are less likely to survive 5 years. One explanation is that black patients in the US less often receive standard of care therapy (Flowers CEBP 2012). However, in a cohort study of 533 white and 144 black patients with DLBCL managed at Emory and University of Alabama-Birmingham (UAB) black race predicted worse overall survival (OS) even when black and white pts received the same therapy (CHOP; Hazard ratio [HR] 1.8, p 60 years of age (p=0.04), 73% had stage III/IV disease vs. 56% (p=0.03), and 77% had an LDH〉ULN vs. 51% (p=0.04). There were no significant differences between the two racial groups in terms of sex, ECOG PS, presence of B-symptoms (38% vs. 29%p=0.46), extranodal sites (50% vs. 78% ≤ 1, p=0.27), IPI risk, or treatment received (RCHOP 46% vs. 40% p=0.93). By the Hans, Natkunam, Tally, and Choi algorithms black patients more commonly presented with the poor-risk ABC/non-GCB subtype (by Choi black 64% ABC vs. white 37%; p= 0.01, Table). After controlling for clinical confounders including age, sex, stage, LDH, performance status, presence of B-symptoms, race, treatment (RCHOP vs. other), and ABC subtype, being 〉60 years of age [HR 3.1 95% CI 1.3–7.2], being black (HR 3.5 95% CI 1.5–8.2), and receiving treatment other than RCHOP (HR 12.8, 95% CI 3.2–50.6) were associated with inferior OS. Conclusions: The rate of ABC DLBCL is significantly higher in black pts compared to white pts in this university-based cohort from the Southern United States. Additional studies confirming these findings in larger populations and examining the mutations associated with these differences are underway to address biological differences intrinsic to DLBCL that may in part explain comparatively adverse features and outcomes for black pts with DLBCL. Disclosures: Flowers: Celgene, Spectrum, Millennium, Gilead, Janssen: Research Funding; Genentech/Roche (unpaid), Millennium (unpaid), Celgene: Consultancy. Bernal-Mizrachi:Empire Genomics (not related to current work): Patents & Royalties. Sinha:Celgene: Research Funding. Jaye:Millenium Pharmaceuticals (For single lecture on immunohistochemical subtyping of large B cell lymphomas): Honoraria.

Description: Abstract 2947 Poster Board II-923 Introduction: DLBCL occasionally presents in leukemic phase, and the prognostic significance of circulating lymphoma cells is unknown. We herein report characteristics and outcomes of newly diagnosed DLBCL presenting in leukemic phase at 2 Institutions. Methods: Flow cytometry database analysis and retrospective chart reviews were carried out with IRB-approval for cases accrued between 2001 and 2008. Leukemic phase DLBCL patients were matched on a 3:1 basis with control DLBCL with no circulating lymphoma cells based on IPI, year of diagnosis, and age ± 10 years. Results: 18 patients, median age 48 years (range 34-80), ECOG PS-1 (22%), 2(38%) and 3(40%), and IPI - 3(56%), 4(40%) and 5(4%) presented in leukemic phase. Extranodal sites included bone marrow (100%), spleen (83%), pleura (61%) and CSF (22%). 61% had B symptoms, and LDH was 6xULN (range, 1-56). WBC was 13,000/microL (range, 7,100-127,400), with 50% lymphoma cells (range, 2-92); these cells were immunophenotypically similar to those in the histologically confirmed DLBCL node, and co-expressed CD19, CD20, CD22, CD38, CD45, HLA-DR and FMC7 in 〉90% of cases, and kappa or lambda light chain restriction in 〉 50%. Karyotype was abnormal and complex in 61%. One patient expired before treatment began. Treatment consisted of R-CHOP (10), R-HCVAD (6), and single agent rituximab (1). 8 (44%) achieved CR (5 R-HCVAD and 3 R-CHOP), 5 (28%) PR, and 4 (22%) had resistant disease. 1 patient was autografted in CR1 and remains in remission. With a median follow-up of 32 months, 2 relapsed in leukemic phase, 1 of whom achieved CR2, but relapsed at the time of conditioning for a consolidative allograft. 10 (56%) patients died from progressive disease, 2 (11%) were lost to follow-up and 6 (33%) remain alive in remission. Overall (Panel A) and progression-free (Panel B) survival curves the 18 leukemic (solid line) and 54 non-leukemic phase (dashed line) DLBCL are depicted in the Figure. Conclusion: DLBCL presenting with circulating lymphoma cells is associated with chemo-resistance (44% CR) and poor outcomes with the exception of those who achieve complete remission. These patients are candidates for alternative therapies. Disclosures: Kaufman: Millenium: Consultancy; Genzyme: Consultancy; Celgene: Consultancy, Research Funding; Merck: Research Funding. Lonial:Millennium: Consultancy, Research Funding; Celgene: Consultancy; BMS: Consultancy; Novartis: Consultancy; Gloucester: Research Funding. Armitage:Eisa: Consultancy; Allo: Consultancy; Ziopharm: Consultancy.

Description: Abstract 905 Introduction: Though dose-intensive strategies using chemoimmunotherapy have significantly improved mantle cell lymphoma (MCL) outcomes with prolonged progression-free survival (PFS), most patients still relapse over time. In the relapsed setting, MCL patients often develop chemoresistance and have a poor overall prognosis. The immunomodulatory agent lenalidomide has demonstrated tumoricidal and antiproliferative effects in MCL and clinical activity and safety in multiple phase II studies in aggressive non-Hodgkin's lymphoma. The objective of the MCL-001 “EMERGE” study was to examine the safety and efficacy of single-agent lenalidomide in subjects with MCL who relapsed or were refractory to bortezomib. Methods: This phase II, multicenter, single-arm, open-label study examined single-agent lenalidomide administered at 25 mg/d PO on days 1–21 of a 28-day cycle until disease progression, unacceptable toxicity, or voluntary withdrawal. The subjects were required to have had prior treatment with rituximab, cyclophosphamide and anthracycline (or mitoxantrone), and to have relapsed or progressed (

Description: Abstract 1628 Introduction: Historically, relapsed DLBCL and HL has been associated with a high cure rate with salvage regimens followed by high dose chemotherapy and stem cell transplant (ASCT). However, patients (pts) who relapse early following upfront chemotherapy and pts who fail to respond to salvage have a poor overall response rate (ORR) with additional salvage regimens and a poor prognosis even when consolidated with ASCT (von Tresckow & Engert, 2011; Gisselbrecht et al., 2010). At present there is no standard therapy in the third-line setting for pts with DLBCL and HL. We designed a regimen: vinorelbine (30mg/m2) & paclitaxel (175mg/m2) given on day 1; etoposide (100mg/m2) & cisplatin (20mg/m2) given on days 2–5; and cytarabine (2000mg/m2) on days 4 and 5 (VTEPA) for treatment of lymphoma pts with 1° refractory disease or relapse following salvage. In phase 1, VTEPA was safe with a 33% ORR following 1 cycle (Lonial et al, 2006). Design and Methods: To examine the effectiveness of VTEPA, we conducted an IRB approved retrospective review of consecutive cases of relapsed/refractory DLBCL and HL identified from our database from 1999–2011. All pts had evidence of primary refractory disease or stable or progressive disease following first line salvage therapy. Responses following salvage VTEPA were retrospectively assessed using International Working Group Criteria (JCO 1999) for all pts. Responding pts proceeded to ASCT. Survival curves were constructed using the Kaplan-Meier method and compared with the log-rank test. Results: 74 pts (44 DLBCL and 30 HL) with a median age at diagnosis of 30 years (range 18–63) for HL and 49 years (range 20–68) for DLBCL were included. 67% of HL pts had primary refractory disease and 33% of pts had relapsed disease; 60% were stage III/IV at diagnosis. 75% of DLBCL pts had primary refractory disease and 25% of pts had relapsed disease; 73% stage III/IV. Pts received a median of 2 prior therapies (range 1–4). 63% pts with HL received prior salvage therapy with ifosfamide, carboplatin, and etoposide (ICE) and 13% with other regimens. 16 pts with HL received 1 cycle of VTEPA, 13 received 2 cycles and 1 pt received 3 cycles of VTEPA. 70% pts with DLBCL had received prior salvage therapy with rituximab (R) + ICE and 16% received other salvage regimens. 32 pts with DLBCL received 1 cycle of R-VTEPA and 12 pts received 2 cycles. The most common reported grade 3/4 toxicities were pancytopenia (97%), nausea/vomiting (58%), fatigue (30%), infectious complications (26%), diarrhea (24%), electrolyte imbalance (19%), and mucositis (16%). 70 pts (43 DLBCL and 27 HL) were evaluable for response. The ORR for DLBCL pts was 44% (9% CR and 35% PR) while that for HL pts was 70% (26% CR and 44% PR, p=0.04). 4 DLBCL pts had treatment related mortality. 34 pts went on to collect ≥2 × 106 CD34+ cells/kg; 3 pts had inadequate stem cell collection. In 23 pts collection was not attempted, and 14 pts collected stem cells prior to R+/−VTEPA. 37 pts (47%) went onto planned ASCT, and 4 pts underwent allogeneic transplantation. The PFS at 2 years for pts with HL was 68% vs. 49% for pts with DLBCL (p

Description: Copper deficiency has long been recognized as cause of hematopoietic dysfunction, and diagnosis is straightforward if it is pursued. Over a three year period, we diagnosed copper deficiency in seven pts referred to our university-based hematology and BMT outpatient clinics for evaluation and treatment of myelodysplastic syndrome (MDS) or neutropenia/anemia. This represents approximately 3% of new outpatient referrals carrying an ICD-9 code corresponding to MDS or neutropenia. Patient characteristics are shown in Table 1. Three of the seven pts carried a presumptive diagnosis of MDS, and one had received several months of decitabine therapy. Two patients were actually referred for consideration of stem cell transplantation; the others were referred for evaluation of cytopenias. Six of the seven patients had been evaluated by a hematologist prior to referral. Only 3 of 7 pts in our series had recognized risk factors for copper deficiency such as prior gastric bypass or other GI dysfunction; postulated risk factors in the other pts are included in Table1. All pts in our series were anemic and leukopenic, with absolute neutropenia at presentation. In contrast, platelet counts were normal or elevated in all pts, consistent with most previous reports. Five of the seven pts in our series had neuropathy or myelopathy of variable severity. The hematologic abnormalities responded rapidly and completely to oral and/or IV copper replacement in all pts, although neurologic recovery was slow and incomplete. Conclusions: Our experience indicates that copper deficiency is a relatively common cause of neutropenia and anemia, and the consequences of missing the diagnosis may be substantial, including performance of unnecessary transfusion, chemotherapy, and even stem cell transplantation. Normal or elevated platelet counts and concomitant neuropathy or myelopathy are important clues to the diagnosis. Furthermore, copper deficiency must be considered even in pts without obvious GI absorption abnormalities. Serum copper and ceruloplasmin assays should be incorporated into the routine evaluation of most pts with cytopenias and suspected MDS. Age/gender Ref. diagnosis Risk factor Associated symptoms Serum copper (80–155 mcg/dl) Ceruloplasmin (21–53 mg/dl 53F MDS–RAEB unknown Severe sensory-motor neuropathy 29 7 43F MDS–RA Excess carbonated soda intake? Severe sensory-motor neuropathy 2

Description: Background: Recent concerns regarding the risks of cancer and cancer-related death due to radiation from computed tomography (CT) scans (Brenner, NEJM 2007) and the lack of data demonstrating a survival advantage for surveillance CT scans following lymphoma therapy have raised questions regarding their benefit. We compared the radiation-related lifetime cancer incidence (LCI) and mortality risks (LCMR) associated with CT scans for staging and surveillance of non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL) with the cumulative probability of lymphoma death (CPLD) during monitoring. Methods: Using 2008 NCCN Guidelines for HL and NHL, we estimated that the average number of scans a patient would need during 5 years of treatment and follow-up would be 10. We utilized published estimates of the cumulative organ-specific radiation doses from full-body CT scans (Brenner, Radiology 2004) and calculated the LCI and LCMR using sex-, age-, and organ-dependent cancer risks per 0.1Gy provided by the Biological Effects of Ionizing Radiations VII report. Site-specific cancer risks were summed to yield the overall LCI and LCMR as described by Brenner (Med Phys 2001). Surveillance, Epidemiology, and End Results (SEER) data were used to identify cases between 2000 and 2005 from 17 SEER Registries and calculate CPLD for specified cohorts. Results: LCI and LCMR were lower for males and were markedly less than the CPLD at 5 years for most patients, but relevant for younger women with HL given their low risk of HL death (Table 1). The relationship between LCMR and the number of CT scans is shown in Figure 1. Additional implications of surveillance strategies on specific cancer risks will be presented. Conclusion: While the LCMR from CT scans is small compared to lymphoma-related deaths for most subgroups, these data should be discussed with patients in formulating plans for surveillance following lymphoma therapy. Table 1 LCI and LCMR due to CT scans compared with CPLD for lymphoma subtypes by age at diagnosis and gender Lymphoma Subtype (Age at Diagnosis) LCI from CT* LCMR from CT* 5-year Cumulative Probability of Lymphoma Death** Males Females Males Females Males Females * per person exposed to the cumulative radiation dose associated with 10 full-body CT scans during 5 years from diagnosis ** Age group studied were HL (20–29 & 80–84), DLBCL (60–79), FL (60–79), NHL (60–79) NHL (70 yrs) 0.0044 0.0057 0.0032 0.0044 0.31 0.28 FL (70 yrs) 0.22 0.18 DLBCL (70 yrs) 0.39 0.37 HL (20 yrs) 0.0133 0.0242 0.0070 0.0108 0.07 0.07 HL (80 yrs) 0.0022 0.0030 0.0019 0.0026 0.47 0.55 Figure 1 LCMR due to CT scans by age at diagnosis of lymphoma and gender Figure 1. LCMR due to CT scans by age at diagnosis of lymphoma and gender

Description: Background: Perifosine is an oral AKT inhibitor which exerts a marked cytotoxic effect on human tumor cell lines. It is currently being tested in several phase II trials for the treatment of major cancers including multiple myeloma. While the proposed mechanism of action relates to downregulation of AKT expression, overepxression of constitutively active AKT does not abrogate perifosine induced cell death suggesting alternative mechanisms. Hypothesis: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL, Apo2 ligand) effectively kills multiple myeloma cells in vitro after binding to their membrane specific receptors TRAIL-R1 (DR4) and TRAIL-R2 (DR5). It is our hypothesis that DR4/DR5 upregulation occurs in response to perifosine treatment, and thus may be additive with exogenous TRAIL. Materials and Methods: TRAIL-sensitive myeloma cell lines (MM.1S, RPMI8226, MM.1R) and TRAIL- resistant myeloma cell lines (U266) were used in this study. Apoptosis was assessed by annexin-V binding assay using flow-cytometry and cell death was assessed by MTT assay. Recombinant human TRAIL, chimeras of DR4 and DR5 were obtained from R&D systems. Results: Perifosine alone(5μM and 10μM) induced apoptosis of MM.1S in 40% and 50% of the treated cells as measured by flow cytometry, that increased to 81% and 91% when 50ng/ml of TRAIL was added to 5μM and 10 μM of perifosine. TRAIL alone induced only nominal apoptosis. Use of the TRAIL resistant U266 cell line showed only minimal apoptosis in response to perifosine, TRAIL, or the combination of both agents. Perifosine also induced DR4 and DR5 expression in less than 2hrs upon the Perifosine exposure in MM.1S as shown by RT-PCR. The combination of perifosine and TRAIL was not sequence specific. Furthermore, we observed that the enhanced apoptosis induced by perifosine and TRAIL in combination was almost or partially blocked by the administration of the DR4 and DR5 blocking antibodies only in the case of MM.1S, MM.1R, RPMI8226 TRAIL sensitive cells lines. Apoptosis was completely blocked in the case of U266 TRAIL resistant cell line when the chimera antibodies were used with perifosine alone or in combination with TRAIL. Conclusion and future directions: Perifosine, an agent proposed to function via inhibition of p-AKT and PDK-1, may have other effects on cell cycle regulation and it pro-apoptotic effects may be partially related to the TRAIL pathway. Our data suggests that an additional mechanism of action relates to the effect perifosine has on DR4 and DR5 expression thus directly effecting apoptosis via the TRAIL mediated effects. The limited response the trail resistant cell line U266 cells suggest that the TRAIL resistant myeloma cells have less DR4 or DR5 surface receptors as compared to the TRAIL sensitive cell lines, MM.1S, MM.1R, and RPMI8226 further validating this alternative mechanism. Further experiments such as inhibition of DR4, DR5, and FADD by small interfering RNAs, RT-PCR, the response in primary myeloma cells and also using more TRAIL resistant cell lines to support our preliminary observations are currently in progress.

Description: Abstract 3708 Background: Rituximab maintenance (RM) following induction therapy has been demonstrated to increase PFS in randomized trials in both first-line and relapsed settings (ECOG 1496, EORTC 20981, and most recently, PRIMA), and RM has been frequently used in clinical practice in the U.S. and other countries. We examined the various RM approaches used by practicing physicians in the U.S., factors that predicted whether RM was used, and compared the “real-world” effectiveness of RM to the outcomes of observation (Obs) following front-line R-based induction in FL patients (pts). Methods: The National LymphoCare Study is a prospective, multi-center, longitudinal, observational study that collects data on treatment and outcomes for pts diagnosed with FL in the U.S. from 2004–2007. Pts who achieved complete response (CR), partial response (PR) or stable disease (SD) following initial treatment with R-based therapy and who did not initiate second line therapy during the 215-day period following the date of last dose of initial therapy were categorized as Obs. Pts meeting the same criteria who started maintenance R treatment in the 215-day period comprise the RM group. Multivariable logistic regression analyses were performed to identify characteristics related to receiving RM. We compared RM and Obs groups in progression-free survival (PFS), time to next treatment (TTNT), and overall survival (OS) using Cox proportional hazards models controlling for confounding factors of clinical interest (sex, FLIPI risk group, treatment setting [academic vs. community], and induction therapy). PFS was defined as the number of days from the 215 day period following induction that defined the Obs and RM groups up to and including the date of disease progression as assessed by the treating physician or death from any cause. Pts who had not yet experienced a PFS event at the time of analysis were censored at the date of the most recent response assessment. Results: Of the 2,732 pts enrolled in NLCS, 1,536 pts completed R-based induction therapy. Among these,1,236 pts achieved CR/PR/SD and met other criteria described above to be included in analysis. 557 pts started RM treatment in the 215-day post-induction work up period (128 following R and 429 following R-chemo), and 679 pts were observed (125 following R and 554 following R-chemo). The mean duration of RM was 528 days, and the mean number of RM doses received was 13. 23% received Rx4 every 6 months, 20% Rx1 every 2 or 3 months, and 57% received another schedule. 14% of pts discontinued RM early (n=79). The most common reasons for early discontinuations were disease progression (29%), toxicity (11%), or death (7%). Pts who received R induction were more likely to receive RM than those who received R-chemo as induction (51% vs. 44%). Pts treated in community practices were slightly more likely to receive RM compared with those who were treated in academic centers (46% vs. 40%). In multivariable models, the most significant predictors of receiving RM were grade (I/II), stage (III/IV), geographic region (other than West), community practice setting, and R induction treatment (all p