Sinha, Rajni

Abstract Certain normal and malignant B-cells rely upon “tonic” B-cell receptor (BCR)-mediated survival signals. BCR signaling induces the phosphorylation of the associated Ig alpha and beta proteins and the recruitment and activation of spleen tyrosine kinase (SYK); thereafter, SYK initiates downstream events and amplifies the original BCR signal. A subset of DLBCL exhibits coordinate overexpression of BCR pathway components, including SYK, and relies upon tonic BCR signaling. FosD is an orally available inhibitor of SYK under development for rheumatoid arthritis, and has demonstrated significant in vitro activity against BCR-dependent NHLs. We have performed the first clinical trial of the oral SYK inhibitor, FosD, in patients (pts) with a variety of relapsed or refractory B-cell non-Hodgkin’s lymphomas. We first enrolled 13 pts in a Phase I component, exploring two dose levels (200 and 250 mg BID) of FosD. Pts (Follicular [FL], 5; CLL/SLL, 2; mantle [MCL], 3; DLBCL, 3) were heavily pretreated. On the first day of FosD dosing at 200 mg and 250 mg, the maximum plasma concentrations were 668 ± 258 ng/mL and 1020 ± 781 ng/mL, and the AUC0–4 estimates were 1800 ± 602 ng*h/mL and 2590 ± 1900 ng*h/mL, respectively. Plasma concentrations increased approximately 2-fold with continued administration, but beyond Day 29 there was no apparent change in FosD concentrations measured over time. Dose limiting toxicity in Phase I was neutropenia; and 200 mg BID was chosen for Phase II evaluation. We then enrolled 68 pts with relapsed/refractory NHL in 3 separate disease cohorts: DLBCL (23); FL (21) and other B-cell NHL (24) including SLL/CLL (11), MCL (9) marginal zone/MALT (3) and lymphoplasmacytic NHL (1). The median age of pts in phase II was 61 (range 41–87); pts received a median of 5 prior therapies, including ASCT (16; 12 with DLBCL) and radioimmunotherapy (8). FosD was overall very well tolerated; there were 4 cases of febrile neutropenia reported. Eight pts required dose modification for neutropenia (2), hypertension (2), liver function test abnormalities (2), fever (1) and mucositis (1). Six pts withdrew before initial response evaluation (AE, 5; noncompliance, 1). Best responses by disease were: DLBCL 21% (4PR; 1CR); SLL/CLL 54% (6PR); FL 10% (2PR); MCL 11% (1PR). Stable disease was observed in an additional 23 patients, including 12 with FL, 4 with DLBCL, 4 with MCL, 2 with CLL/SLL and 1 with MALT. As of 7/15/08, 16 pts were treated for more than 200 days, and 14 pts remain on study. Median PFS is 4.5 months, and only 5 pts have died (4 with DLBCL of disease progression and 1 with CLL of infection following therapy). Several pts with CLL/SLL experienced a transient increase in circulating lymphocytes in the setting of responding nodal disease. Of the 6 responding pts with CLL, Zap-70 status was positive (3), negative (1) and unknown (2); cytogenetics were trisomy 12 (1), del13 (1), normal (1), complex (1) and unknown (2). We conclude that disrupting BCR-induced signaling by inhibiting SYK kinase represents a safe and well-tolerated novel therapeutic approach to NHL. In addition to significant responses in DLBCL and CLL/SLL, prolonged stable disease was observed in pts with FL. FosD should be developed further, as a single agent and in rational combinations, for BCR-dependent B-cell NHLs.

8534 Background: Lenalidomide, an immunomodulatory agent with antitumor and antiproliferative effects, demonstrated rapid and durable efficacy in patients with relapsed/refractory mantle cell lymphoma (MCL) post-bortezomib in the phase II multicenter MCL-001 study. The objective of this analysis was to explore the efficacy of lenalidomide across patient subgroups. Methods: Single-agent lenalidomide was administered at 25 mg/d PO on days 1-21 of a 28-day cycle until disease progression or intolerability; primary endpoints were overall response rate (ORR) and duration of response (DOR) determined by an independent central review committee per modified IWG criteria. Exploratory analyses of ORR and DOR for subgroups were predefined and prospectively conducted. Results: Patients with relapsed/refractory MCL (N=134) had a median age of 67 y, with a median of 4 prior therapies (range, 2-10). The ORR was 28% (7.5% CR/CRu) and DOR was 16.6 months (95% CI, 7.7-26.7). Lenalidomide treatment provided consistent ORR and DOR across all subgroups analyzed by demographics, baseline disease status and prior therapy (Table). High vs normal baseline LDH was the only significant factor by univariate and multivariate logistic regression analysis of ORR (odds ratio=0.193; p=0.002). Conclusions: Single-agent lenalidomide provided consistent clinical benefit in patients with relapsed/refractory MCL post-bortezomib irrespective of patient subgroups at baseline with the exception of LDH. Clinical trial information: NCT00737529. [Table: see text]

8533 Background: Mantle cell lymphoma (MCL) is an aggressive form of non-Hodgkin lymphoma (NHL) with poor prognosis. The immunomodulatory agent lenalidomide shows consistent activity with tolerable safety in multiple phase II studies of relapsed/refractory aggressive NHL (NHL-002 and NHL-003) and MCL post-bortezomib (MCL-001). This pooled analysis further examined the efficacy and safety of single-agent lenalidomide in patients with relapsed/refractory MCL. Methods: Single-agent lenalidomide was given 25 mg/d PO on days 1-21 of 28-day cycles as tolerated for 52 weeks (NHL-002) or until disease progression (NHL-003 and MCL-001). All MCL patients received ≥1 prior treatment, including bortezomib in MCL-001. Efficacy data were examined by independent central review for MCL-001 and NHL-003 and by investigators for NHL-002. Results: 206 patients with relapsed/refractory MCL were studied. The median age was 67 y (range 33-84; 63% ≥65 y), 91% stage III/IV disease and 51% had received ≥4 prior regimens (76% prior bortezomib). Overall response rate (ORR) with lenalidomide was 32% (10% CR/CRu), with a median time to response of 2.1 months and median duration of response (DOR) of 16.6 months (not yet reached in patients with CR/CRu; Table). Kaplan-Meier estimates for median PFS and OS were 5.4 and 23.9 months, respectively. Mean daily dose of lenalidomide was 21 mg. Grade 3/4 AEs included neutropenia (44%), thrombocytopenia (29%), anemia (11%), and fatigue (7%). Other any-grade AEs included tumor flare reaction (7%), venous thromboembolic events (7%), and invasive second primary malignancies (3%). Conclusions: Lenalidomide produced rapid and durable responses in patients with relapsed/refractory MCL, and exhibited a predictable safety profile among 3 phase II studies of lenalidomide in heavily pretreated patients, including prior treatment with bortezomib. Clinical trial information: MCL-001: NCT00737529; NHL-002: NCT00179660; NHL-003: NCT00413036. [Table: see text]

Abstract Abstract 775 Introduction: WW has been an initial strategy for advanced stage FL because randomized trials showed no clear benefit for immediate initiation of therapy with single agent alkylators when compared to deferring therapy (Brice, JCO 1997; Ardeshna, Lancet 2003), although a recent trial raises questions about WW in the era of rituximab (R) based frontline therapies (Ardeshna, ASH Meeting 2010). Methods: The NLCS is a prospective, multicenter, observational study collecting data on 2,738 newly diagnosed pts with FL diagnosed from 2004–2007 at 265 US sites (80% non-academic). Initial management decisions were made by the treating physician and were categorized as WW (for pts who did not receive therapy in the 90 period following diagnoses and were coded by physicians as WW) or active therapy (AT) including: R alone, R-chemotherapy (RChemo), or other. Baseline clinical factors and treatment setting were compared for WW and AT pts using multivariable logistic regression. Kaplan-Meier (KM) estimation and Cox models were used to evaluate progression-free survival (PFS), time to 2nd and 3rd line management strategy (TT2, TT3), transformation-free survival (TFS), PFS following 1st AT, and overall survival (OS). Due to differences between WW and AT groups, adjusted Cox regression models are presented for the primary analysis of study endpoints controlling for sex, community vs. academic practice site, FL grade, and FLIPI. All time to event analyses were calculated from the 90 day period following diagnosis to allow enrollment in WW, and PFS was calculated from the starting point to the clinician's recording of progressive disease (PD) or death. Results: Among 1,737 pts presenting with stage III/IV FL in the analysis population, 237 underwent WW and 1,500 received AT immediately following diagnosis including: 241 pts treated with R, 1046 with RChemo, 26 with radiation, and 187 other therapies. Multivariable logistic regression demonstrated that the following pt characteristics were predictive of selection of WW rather than initial AT: age > 60 years, no B-symptoms, FL grade 1 or 2, ECOG PS = 0, ≤1 extranodal sites involved, and LDH ≤ULN (all p < 0.05). Median PFS and TT2 were 27 and 35 months for WW, and 64 months and not reached for AT. With a median follow-up of 55 months, 17% of WW pts and 19% of AT pts have died, with no significant difference in OS between WW and AT (p = 0.31). Compared with WW, RChemo improved PFS: adjusted Hazard Ratio (HR) = 0.36, TFS: HR=0.65, TT2: HR=0.48, and TT3: HR=0.53, all p<0.01. For most of the 145 WW pts that later initiated an AT, PD was recorded as the reason for treatment (83%). ATs following WW were: R (51, 35%), RCVP (21, 14%), RCHOP (16, 11%), R + other chemo (23, 16%), investigational (15, 10%), chemo alone (9, 6%), radiation (8, 6%), BMT (1, 1%), or other therapy (1, 1%). The median PFS for R was 42 months when given at diagnosis and 55 months when given following WW. The median PFS for RChemo was 71 months when given at diagnosis and 37 months when given following WW. After adjustment for FLIPI, FL grade, sex, practice setting, and type of treatment, WW adversely affected PFS following 1st AT, H=2.02, p <0.0001. Conclusions: FL pts in the US who undergo initial WW are treated at a median of nearly 3 years. Median PFS following RChemo, but not R is shorter when utilized after period of WW than at diagnosis – albeit in different clinical circumstances. Additional follow-up is needed to assess the tradeoff of this time without therapy with as yet no observable differences in OS. Disclosures: Sinha: CELGENE: Research Funding. Friedberg:Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees. Link:Genentech: Consultancy. Flowers:Spectrum: Consultancy, Research Funding; Millennium/Takeda: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Genentech/Roche (unpaid): Consultancy; Novartis: Research Funding; Seattle Genetics: Consultancy.

Abstract Abstract 97 Background: There is no consensus or standard of care for front-line therapy for FL as demonstrated by our initial publication of the National LymphoCare Study (NLCS) showing that strategies used in newly diagnosed FL patients (pts) in the US included: watchful waiting (17.7%), rituximab (R) with chemotherapy (51.9%), R alone (13.9%), radiation therapy (5.6%), chemotherapy (3.2%), or a clinical trial (6.1%). Given the lack of observational data comparing the effectiveness of front-line R-chemotherapy regimens, we examined the outcomes for patients with stage III/IV FL receiving R with cyclophosphamide, vincristine, and prednisone (RCVP), R with cyclophosphamide, doxorubicin, vincristine, and prednisone (RCHOP), or R with a fludarabine-based regimen (RFlu) as first-line therapy. Methods: The NLCS is a prospective, multicenter, observational study collecting data on 2,738 previously untreated patients (pts) with FL diagnosed from 2004 to 2007 at 265 sites in the US. Initial management decisions were made by the treating physician without protocol-specified treatment assignments. Descriptive statistics for the baseline characteristics of pts who received RCVP, RCHOP, and RFlu were compared using Pearson Chi-square tests. A generalized logistic model was used to identify baseline factors of clinical interest (FLIPI, sex, practice setting [academic vs. community]) that were correlated with treatment. Kaplan–Meier estimation was used to evaluate progression-free survival (PFS) and overall survival (OS) for the treatment regimens; comparisons for the 2-year landmark estimates were obtained using a Wald statistic. PFS was defined as the number of days from diagnosis up to and including the date of progressive disease (PD) as assessed by the treating physician or death from any cause. Pts who had not yet experienced PD at the time of analysis were censored at the date of the most recent response assessment. To evaluate the effects of treatment on PFS and OS, Cox proportional hazards models were used controlling for FLIPI, sex, community or academic practice setting, and maintenance R or observation following treatment. Results: Of the 2,738 pts enrolled in NLCS, 926 pts were identified as having stage III/IV FL and having received the regimens of interest. Within this cohort 60% received RCHOP (n=558), 27% received RCVP (n=247) and the remaining 13% received RFlu (n=121). Baseline characteristics were correlated with induction treatment and whether a patient received subsequent R maintenance. Women (odds ratio [OR]=1.50, 95%CI 1.05–2.13) and pts aged >60 years (OR=2.36, 95%CI 1.64–3.38) more commonly received RCVP than RCHOP, and pts with LDH > upper limit of normal (OR=1.75, 95%CI 1.02–3.03) more commonly received RCHOP than RFlu. A greater % of pts receiving RCVP (61%) had poor-risk FLIPI (3–5) vs. RCHOP (49%) or RFlu (44%). In this cohort, 60% of RCVP, 43% of RCHOP, and 46% of RFlu pts received maintenance R. The overall response rates for RCVP, RCHOP, and RFlu were 88%, 94%, and 96%, respectively, and 2-year PFS was 72% (95% CI 66–78%) for RCVP, 78% (95%CI 74–81%) for RCHOP, and 76% (95%CI 67–-83%) for RFlu. There were no significant differences in PFS between treatments after adjustment (p= 0.07). However, with a median follow-up of 58 months there were significant differences in unadjusted OS (p=0.03), with 2-year OS probabilities of 88% (95%CI 84–92%) for RCVP, and 91% (84–95%) for RFlu, and 94% (92–96%) for RCHOP (Figure A). After adjustment for sex, FLIPI, practice setting, and maintenance use, the OS benefits of RCHOP persisted over RCVP HR=1.67 (95%CI 1.15–2.42) but not RFlu HR=0.94 (0.53–1.68). The benefits of RCHOP were even more pronounced in poor risk FLIPI pts (Figure B). Conclusions: First-line R-chemotherapy regimens in clinical practice have high overall response rates and high 2-year PFS and OS. With 4.75 years of follow-up in this large pt cohort, these regimens appear similar in response rates and early PFS and OS with suggestions that RCHOP may provide benefits over RCVP particularly for poor risk patients. Disclosures: Sinha: Celgene: Research Funding. Friedberg:Genentech: Consultancy; astellas: ; Lilly:; Abbott/Trubion:; Seattle Genetics: Honoraria; Cephalon: Consultancy. Hirata:Roche: Equity Ownership; Genentech Inc/Roche: Employment. Flowers:Seattle Genetics: Consultancy; Millennium/Takeda: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Genentech/Roche (unpaid): Consultancy; Novartis: Research Funding; Spectrum: Consultancy, Research Funding.

Abstract 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<0.05). After adjusting for FLIPI risk group, induction treatment, and clinical factors, RM significantly improved PFS (HR= 0.72; p= 0.010) and TTNT (HR= 0.74; p= 0.03). At 4 years of follow-up, 11% of pts in the combined population have died and there was no significant difference in OS between RM and Obs groups. 22% (n=124) of RM pts had received 2nd line treatment at the time of analysis, of whom 36% received R alone and 31% received R-chemo. The response rate for 2nd treatment was similar between RM and Obs groups (60% CR/PR for both groups). Conclusions: RM following front-line R-based induction was common in this period. However, a large percentage of pts received a RM schedule that was not consistent with standard published schedules reflecting variation among community practices. Nevertheless, RM use in clinical practice produced significant differences in PFS and TTNT compared to Obs. Importantly, response to second-line treatment was similar between RM and Obs groups. Additional followup is needed to determine whether RM produces OS benefits in this context. Disclosures: Sinha: Celgene: Research Funding. Zhou:RTI-HS: Employment; Novartis: Research Funding. Friedberg:Genentech: Consultancy; astellas: ; Lilly: ; Abbott/Trubion: ; Seattle Genetics: Honoraria; Cephalon: Consultancy. Hirata:Genentech Inc/Roche: Employment; Roche: Equity Ownership. Flowers:Spectrum: Consultancy, Research Funding; Millennium/Takeda: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Genentech/Roche (unpaid): Consultancy; Novartis: Research Funding; Seattle Genetics: Consultancy.

Abstract 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<0.001) suggesting a biological basis for some disparities(Flowers Leuk Lymph 2012). To address these findings, we examined whether known prognostic biological variants within DLBCL [germinal center B-cell-like (GCB) and activated B-cell like (ABC)] occurred differentially between black and white pts. Methods: DLBCL pts within our Emory-UAB cohort study provided formalin fixed material available for construction of tissue microarrays (TMAs). All pts were diagnosed with DLBCL from 1990–2010 and met the following criteria: age ≥18 years at diagnosis and available information on demographics, race, gender, initial clinical features at presentation, treatment, and treatment outcomes. H&E slides from each block for each case were reviewed to identify the appropriate zone(s) for cores. Sections placed in TMAs underwent immunohistochemistry (IHC) staining with BCL6, GCET1, CD10, FOXP1, and LMO2 antibodies. The percentages of positive cells were scored in 10% increments for each antibody, and recorded for each case by 3 hematopathologists blinded to the clinical and demographic data. The Choi algorithm was used to classify all patients into ABC and GCB subsets; other IHC algorithms were used as a backup. Descriptive statistics for the baseline characteristics of black and white pts were compared using Chi-square tests. Kaplan–Meier estimation was used to evaluate OS for the two groups and compared with the log-rank test. To evaluate prognostic factors and the effects of treatment on OS, Cox proportional hazards models were used controlling for age, sex, stage, LDH, performance status, presence of B-symptoms, race, treatment (R-CHOP vs. other), and ABC subtype. Results: Tissues for 26 black pts and 63 white pts meeting all eligibility criteria were evaluated in the TMA. There were significant differences in baseline characteristics between the two groups; 23% of black pts vs. 46% of whites were > 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.

Abstract 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 (<12 months) after or were refractory to bortezomib. The primary endpoints were overall response rate (ORR) and duration of response (DOR); secondary endpoints included complete response (CR), PFS, time to progression (TTP), overall survival (OS) and safety. Efficacy data were measured by investigators and an independent central review committee according to modified International Working Group criteria and analyzed by SAS. Results: 134 subjects with relapsed or refractory MCL who were heavily pretreated (no limitation in number of prior therapies) were enrolled. The median age was 67 y (range, 43–83), two-thirds of them being 65 y or older and 93% with advanced stage disease (stage III-IV). The median number of prior therapies was 4 (range, 2– 10) with 78% of subjects having received ≥ 3 prior lines of treatment. The ORR to single-agent lenalidomide was 28% (CR/CRu 8%; Table 1) by independent central review, with a median DOR of 16.6 mo (95% CI, 7.7–26.7; Figure 1). The ORR was 32% (CR/CRu 16%) by investigator assessment, with a median DOR of 18.5 mo. Median time to response (central review) was 2.2 mo (3.7 mo to achieve CR). The median PFS was 4.0 mo (95% CI, 3.6–5.6); median OS was 19.0 mo (95% CI, 12.5–23.9). Subjects received an average dose of 20 mg/d of lenalidomide. Lenalidomide was dose reduced in 38% of subjects; treatment discontinuation due to an adverse event (AE; primarily myelosuppression) was reported in 19% of subjects. The most common grade 3/4 AEs were neutropenia (43%), thrombocytopenia (28%), anemia (11%), pneumonia (8%) and fatigue (7%). Other AEs (any grade) included tumor flare reaction (13 subjects, 10%), deep vein thrombosis (5 subjects, 4%), pulmonary embolism (3 subjects, 2%) and invasive second primary malignancies (3 subjects, 2%). Conclusions: The EMERGE study demonstrated rapid and durable efficacy of lenalidomide in MCL subjects who relapsed or progressed after or were refractory to bortezomib. These results in heavily pretreated MCL subjects (median of 4 prior treatments), and with an expected toxicity profile support single-agent lenalidomide in subjects with relapsed or refractory MCL after bortezomib. Disclosures: Goy: Pfizer: Advisory board member, Advisory board member Other; Seattle Genetics: Advisory board member Other; J&J: Advisory board member, Advisory board member Other; Pharmacyclics: Advisory board member, Advisory board member Other; Millenium: Advisory board member, Advisory board member Other, Speakers Bureau; Celgene: Advisory board member Other. Off Label Use: This is a phase 2 clinical study of safety and efficacy for lenalidomide in patients with MCL. Sinha:Celgene: Research Funding. Williams:Celgene: Clincial Trial Research Support, Advisory Boards, Data Safety Committee Member, Consultant Other, Consultancy. Drach:Celgene: Speakers Bureau; Janssen: Speakers Bureau; Roche: Research Funding. Ramchandren:Seattle Genetics: Speakers Bureau. Herbrecht:Pfizer: Advisory board member Other. Zhang:Celgene: Employment. Cicero:Celgene: Employment. Fu:Celgene: Employment. Witzig:Celgene : Research Funding.

SummaryTo examine the effectiveness of an initial management strategy of watchful waiting for follicular lymphoma (FL) in clinical practice, we compared outcomes for patients diagnosed 2004–2007 in the United States initially managed with watchful waiting with outcomes following initial rituximab monotherapy and chemoimmunotherapy. In total, 1754 stage II–IV patients in the National LymphoCare Study underwent watchful waiting (n = 386), rituximab monotherapy (n = 296) or rituximab plus chemotherapy (n = 1072) as initial management strategy. Female patients and those who received treatment in the Northeast or in an academic setting more commonly underwent watchful waiting versus initial chemoimmunotherapy; whereas patients with grade 3 histology, anaemia, elevated lactate dehydrogenase, extranodal involvement, B symptoms or performance status ≥1 more commonly received chemoimmunotherapy. Although time to new treatment and progression‐free survival following first‐ and second‐line therapy were improved with chemoimmunotherapy, and time to chemotherapy was improved with rituximab monotherapy, there were no differences in overall survival between watchful waiting and chemoimmunotherapy or rituximab monotherapy. With 8‐year overall survival estimates of 74%, initial management with watchful waiting in the context of sequential therapy remains a viable option for FL patients in the modern era. This trial was registered at www.clinicaltrials.gov (NCT00097565).

BACKGROUNDThe authors examined the “real‐world” effectiveness of rituximab (R) maintenance therapy (R‐maintenance) compared with observation after R‐based induction therapy in patients with previously untreated follicular lymphoma (FL) in the United States.METHODSThe National LymphoCare Study is a prospective, multicenter, observational study that enrolled > 2700 untreated patients with FL diagnosed from 2004 to 2007 at 265 sites in the United States. Among these, patients who achieved at least stable disease after R‐based induction therapy were eligible for the current analysis. Patients who initiated R‐maintenance within 215 days of completing induction therapy were categorized as the R‐maintenance group, and those who did not initiate therapy during this period were categorized as the observation group. The objective of the current study was to determine the effect of R‐maintenance on progression‐free survival (PFS), time to next treatment (TTNT), and overall survival (OS).RESULTSA total of 1439 patients completed R‐based induction therapy, 1186 of whom met all inclusion criteria (541 patients received R‐maintenance and 645 patients were observed). Characteristics that were found to be predictive of receiving R‐maintenance were histology grade (1/2), Ann Arbor stage of disease (III/IV), geographic region (region other than the West), and practice setting (community practice). With a median follow‐up of 5.7 years, R‐maintenance was associated with superior PFS (hazards ratio [HR], 0.68; 95% confidence interval [95% CI], 0.56‐0.84 [P = .0003]) and TTNT (HR, 0.66; 95% CI, 0.52‐0.84 [P = .0007]). No significant difference in OS was observed (HR, 0.81; 95% CI, 0.58‐1.14 [P = .23]).CONCLUSIONSR‐maintenance in patients with FL and at least stable disease after R‐based induction therapy provided significantly longer PFS and TTNT in comparison with observation, but no significant difference in OS was observed with 5‐years of follow‐up. This comparative effectiveness study aligns with the results of randomized trials suggesting that similar outcomes occur with R‐maintenance in FL with the treatment variations observed in clinical practice. Cancer 2014;120:1830–1837. © 2014 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.