FLIPI Score Research Articles

A Randomized Phase II Study Comparing Consolidation With a Single Dose Of 90y Ibritumomab Tiuxetan (Zevalin®) (Z) Vs. Maintenance With Rituximab (R) For Two Years In Patients With Newly Diagnosed Follicular Lymphoma (FL) Responding To R-CHOP. Preliminary Results At 36 Months From Randomization

▪Patients with FL can have long time of survival, but disease progression typically occurs 3-5 years after initial treatment. Consolidation with Z after initial therapy has shown to improve progression-free survival (PFS) mainly in the pre-R era, whereas maintenance with R also has demonstrated a substantial benefit in terms of PFS in patients treated with immunochemotherapy. In this setting, the Spanish intergroup PETHEMA/GELTAMO/GELCAB started a randomized phase 2 trial in order to compare the use of consolidation with Z vs. R maintenance in patients with FL responding to R-CHOP. From June 2008 to July 2010, 146 patients (66M/80F; median age, 55 years) were enrolled from 25 Spanish institutions in the randomized phase 2 trial ZAR2007 (ClinicalTrials.gov, number NCT00662948). Main inclusion criteria were: FL grade 1, 2 or 3a, age 18-75 years, stages II-IV and need of treatment according to modified GELF criteria. Patients with FL grade 3b or transformed to DLBCL were excluded. In addition, patients with platelet count <150x109/L or bone marrow infiltration>25% before randomization were also excluded. Main end-point of the trial was PFS from randomization. The distribution according to the FLIPI score was as follows: low-risk 14%, intermediate 47%, and high 39%. After R-CHOP, 124 patients in CR (n=56), CR[u] (13) or PR (55) were randomized 1:1 (stratified by response) to arm A (90Y ibritumomab tiuxetan 0.4 mCi/kg IV; total dose of 90Y was capped at 32 mCi) vs. arm B (1 infusion of R 375 mg/m2 every 8 weeks for 2 years). Sixty three (51%) patients were assigned to arm A (Z) and 61 (49%) to arm B (R). Twenty two patients were not randomized due to response <PR, low neutrophil or platelets counts or patient decision. After a median follow-up of 37 months from randomization (range, 26 to 56), 31 patients eventually progressed/relapsed with a 36-month PFS of 64% (95% confidence interval [CI] 52-76) for patients in arm A (consolidation with Z) (22 events) and 86% (95% CI 77-95) for patients in the R maintenance (9 events) (p=0.01; HR=0.38, 95%CI 0.17-0.83) as shown in the figure. The number of patients in PR after R-CHOP who reached CR during maintenance were 14 of 28 (50%) and 12 of 26 (46%) for arms A and B, respectively. Two patients developed transformation to DLBCL at 8 (arm A) and 39 months (arm B) after randomization. During the maintenance period, patients receiving Z showed grade 3-4 neutropenia in 6 of 63 cases and grade 3-4 thrombocytopenia in 5 of 63, whereas these figures were 1 of 61 and 0 of 61 (p=0.05) for patients in arm B, respectively. No unexpected late toxicities have been reported. Five patients have died during the follow-up due to the progression of lymphoma in all cases, with no differences between the arms (36-month OS, 98% vs. 95% for arms A and B, respectively). In conclusion, in patients with FL in response after R-CHOP, maintenance with R was superior to consolidation with Z in terms of PFS, with no differences in OS with the current follow-up. [Display omitted] Disclosures:Lopez-Guillermo:Roche: Membership on an entity's Board of Directors or advisory committees. Briones:F. Hoffmann-La Roche: Honoraria.

B-Cell Receptor Selection Pattern and Natural History Of Follicular Lymphoma

Follicular lymphoma (FL) is initiated by the t(14:18) that places the anti-apoptotic proto-oncogene BCL2 under transcriptional control of the immunoglobulin heavy chain (IgH) locus during primary VDJ recombination. Neoplastic FL B cells are arrested at the germinal center stage with ongoing somatic hypermutation of B-cell receptor (BCR) genes by activation-induced deaminase (AID). Antigen recognition by the clonal BCR may facilitate malignant growth upon entry of t(14;18)-immortalized naïve B cells into secondary lymphoid organs. We have reported at ASH 2012 that FL may be classified according to the AID-mediated BCR evolution pattern into two distinct subgroups: A predominantly IgM-expressing subgroup with evidence for antigen-driven affinity maturation, and a subgroup selected for BCR sequence preservation that has often undergone class switch recombination.To investigate whether these BCR selection patterns were correlated to clinical outcome, we retrospectively analyzed somatic hypermutation of multiple BCR sequences in 66 patients (median age: 49; range: 29-75 years) with advanced-stage FL that had undergone a research tumor rebiopsy after inclusion into our prospective idiotype vaccination program (Blood, 2011) with informed consent. Biopsies were performed at a median interval of 20.1 months from diagnosis (range: 0-171 months). At rebiopsy, 43 patients had not yet received systemic cytoreductive therapy (chemotherapy, antibody therapy, or radiation therapy); 14 and 9 patients had been treated with one or two prior regimens, respectively.IgH transcripts were cloned with an unbiased anchored PCR strategy with nested constant region-specific primers. A median of 8 clonal IgH sequences was subjected to bioinformatic analysis for BCR selection patterns by the focused test (Hershberg et al., 2008). 22 patients (33.3%) were classified as having evidence (focused test: p>0) for positive BCR selection through antigen-driven affinity maturation; 44 patients (66.6%) belonged to the BCR preservation category defined by p<0. Clinical risk according to the FLIPI was evenly distributed among both groups (BCR selection: 5 cases low FLIPI, 15 intermediate, 2 high; BCR preservation: 15, 22, 7). The BCR category distribution of app. 1:2 did not change with increasing time from diagnosis to biopsy or after prior therapy.Among 39 patients who were managed initially with a “watch and wait” policy (36 of these underwent rebiopsy prior to initiation of therapy), BCR selection was associated with superior progression-free survival with a median of 87.7 months versus 16.9 months in the BCR preservation group (log-rank test: p=0.024). The treatment-free interval during which the rebiopsy was taken was longer in the BCR selection category for all patients (median 102.0 versus 31.0 months; p=0.030) and for patients with initial “watch and wait” policy (median 103.4 versus 21.0 months; p=0.049). Transformations to aggressive lymphoma occurred exclusively in the BCR preservation group (n=4). At a median total follow-up from diagnosis of 101.6 months, 8 patients (36,4%) in the BCR selection group and 7 patients (15,9%) of the BCR preservation group have not yet received any cytoreductive therapy. When death or transformation were defined as competing events, median event-free survival was not reached in either group with 2 events in the BCR selection group and 8 events in the BCR preservation group (p=0.10).The BCR selection pattern as defined by the focused test through analysis of multiple BCR sequences may represent a novel prognostic factor for the natural history of FL in the pre-treatment phase. A focused test-based categorization could be readily incorporated into the diagnostic work-up of FL and could potentially complement clinical prognostication by means of the FLIPI score. Since the retrospective design of this study cannot entirely exclude possible selection bias, the hypothesis that antigen-driven BCR affinity maturation defines a favorable FL subgroup calls for validation in a prospective study. The relationship of the BCR selection pattern with the established prognostic role of the tumor microenvironment warrants investigation. In summary, we propose that BCR selection may govern the natural history of follicular lymphoma in treatment-free periods, thereby lending further support to the concept that BCR signaling plays an important causal role in FL lymphomagenesis. Disclosures:No relevant conflicts of interest to declare.

Tolerability and activity of combinations of the PI3Kδ inhibitor idelalisib (GS-1101) with rituximab and/or bendamustine in patients with previously treated, indolent non-Hodgkin lymphoma (iNHL): Updated results from a phase I study.

8500 Background: PI3K-delta signaling is critical for activation, proliferation and survival of B cells, and is hyperactive in many B-cell malignancies. Idelalisib is a first-in-class, selective, oral inhibitor of PI3Kδ that has shown considerable monotherapy activity in recurrent iNHL (Kahl, ICML 2011), as well as combination therapy (Fowler, ASCO 2012). Methods: This phase I study evaluated the activity of continuous (48 weeks) idelalisib (Id), 100/150 mg BID, in combination with rituximab (R) (375 mg/m2 weekly x 8 doses) (Id+R), with bendamustine (B) (90 mg/m2 x 2, for 6 cycles) (Id+B), or in combination with R (375 mg/m2 monthly x 6) and B (90 mg/m2 x 2), for 6 cycles (Id+BR). Investigators assessed response according to standard criteria (Cheson 2007). Patients who continued to benefit were able to enroll on an extension study. Results: Study enrolled 78 pts with relapsed/refractory iNHL, with 34 (44%) pts continuing on treatment in the ongoing extension protocol. The 3 cohorts included Id+R (N=30), Id+B (N=34), and Id+BR (N=14). Pts were 67% male, median age [range] of 62 [37E84] years, 41% with refractory disease, 88% stage III/IV, and 36% of FL with high FLIPI scores. The median [range] number of prior therapies was 3 [1E10]. The median [range] duration of treatment was 10.6 [0.5-29.2] months. Overall response rate (ORR) was 63/78 (81%), with 22/78 (28%) CR. The ORR/CR for Id+R was 77%/20%, Id+B was 85%/29%, and Id+BR was 79%/43%. At 20 months, the PFS was 66%. For responders, 73% were progression-free at 20 months. Most common adverse events included (total%/≥G3%) pyrexia (56/4), fatigue (45/4), nausea (41/0), rash (40/8), cough (37/0), diarrhea (36/8), chills (18/0), URI (18/1), and pneumonia (17/15). Lab abnormalities included (total%/≥G3%) ALT/AST elevations (56/17). Conclusions: Idelalisib-based combination therapy is highly active and well tolerated in patients with relapsed/refractory iNHL. These data support further clinical development. Phase III trials evaluating the efficacy of idelalisib in combination with R, or BR in iNHL are ongoing (NCT01732913, NCT01732926). Clinical trial information: NCT01732913, NCT01732929.

Changes in the tumor microenvironment associated with transformation in follicular lymphoma.

8538 Background: Follicular lymphoma (FL) is a heterogeneous disease with a variable prognosis. Transformation to an aggressive lymphoma is associated with a poor prognosis. Previous studies have identified tumor microenvironment cells such as CD68+ macrophages, PD-1+ and FOXP3+ cells as prognostic in FL. However, results have been conflicting and infrequently address the risk of transformation. In this study we analyzed various components of the microenvironment and their association with transformation. Methods: Patients with FL that later transformed were identified through Mayo Clinic lymphoma database. Tissue specimens at diagnosis were stained with CD68, CD11c, CD21, CXCL13, FOXP3, PD-1 and CD14 and characterized by pattern of location and semi-quantitative cell content. Time to transformation (TTT) and overall survival (OS) were assessed by Kaplan-Meir analysis. Significant variables were further analyzed by cox proportional hazards model. Results: 58 patients were included with a median TTT of 4.7 years (range, 0.4-20). Presence of CD14+ cells vs absence and their location (follicular vs non-follicular) were associated with shorter TTT (4.5 vs 6.2 yrs., p=0.037 and 3.8 vs 5.9 yrs. p= 0.027, respectively). The quantity of PD-1+ cell content was not associated with TTT or OS. However, localization of PD-1 to the follicle compared to diffuse was associated with a longer TTT (6.1 vs 3.6 yrs. p=0.033) and superior OS (9.7 vs 4.6 yrs. p=0.009). On multivariate analysis, the pattern of CD14 and PD-1 staining remained significantly associated with shorter TTT (Table). Conclusions: In follicular lymphoma, a diffuse pattern of PD-1+ cells is associated with inferior TTT and OS. CD14+ cells localized to the follicle is associated with a shorter TTT. After accounting for FLIPI score, both these factors remained significant. These results identify two independent predictors of the rate of transformation in follicular lymphoma and suggest it is location rather than quantity of CD14+ or PD-1+ cells that influence outcomes. [Table: see text]

Prognostic significance of programmed cell death‐1‐positive cells in follicular lymphoma patients may alter in the rituximab era

Programmed cell death-1 (PD-1) is involved in one of the inhibitory pathways of the B7-cluster of differentiation (CD) 28 family; this pathway is known to be involved in the attenuation of T-cell responses and promotion of T-cell tolerance. PD-1 is known to negatively regulate T-cell receptor-mediated proliferation and cytokine production, lead to alternation in the tumor microenvironment. Although several studies have shown that high levels of PD-1-positive cells in follicular lymphoma (FL) patients influence their prognosis, those studies included patients treated without rituximab, and the prognostic impact of PD-1 positivity in the rituximab era (R-era) has not yet been elucidated. We retrospectively studied 82 patients with FL uniformly treated with standard R-CHOP therapy at six institutions between 2001 and 2009 (median follow-up for survivors: 55months). We also collected and examined biopsy specimens for diagnosis with respect to PD-1 positivity. The PD-1 positivity was significantly higher in male patients and patients with high beta-2 microglobulin (B2M≥3.0) (P=0.03 and 0.003, respectively). Three-year progression free survival (PFS) and overall survival (OS) were 60% and 86%, respectively. By univariate analysis, elevated LDH (P=0.07) worsened PFS. Male gender (P=0.03), high FLIPI score (P=0.05), and high B2M levels (P=0.08) worsened OS. Multivariate analysis detected no significant prognostic factors, including PD-1 positivity. However, in male subgroup, high levels of PD-1-positive cells were found to be a prognostic factor for PFS. Addition of rituximab might have altered the prognostic impact of PD-1-positive cells.

Phase 1b Study of TRU-016, an Anti-CD37 SMIP™ Protein, in Combination with Rituximab and Bendamustine in Relapsed Indolent Lymphoma

AbstractAbstract 3678 Background:CD37 is a tetraspanin protein expressed on the surface of normal and transformed B-cells across a wide range of maturational stages and demonstrates death signaling via SHP1. TRU-016 is a novel humanized anti-CD37 SMIP™ (mono-specific protein therapeutic) that has shown significantly greater direct killing of CLL cells than rituximab and greater Fc mediated cellular cytotoxicity of CLL cells than either alemtuzumab or rituximab in pre-clinical models. In preclinical in vitro and in vivo models of NHL significant activity of TRU-016 against multiple cell lines was observed. In a phase 1 study, TRU-016 showed activity in patients (pts) with CLL and NHL was observed. Given the single-agent clinical activity of TRU-016 and synergistic or additive effect of TRU-016 with multiple agents in preclinical models, this trial of TRU-016 with rituximab and bendamustine was conducted to establish the maximum tolerated dose, overall safety, and clinical activity of TRU-016 in pts with relapsed indolent NHL. Methods:Pts with relapsed or refractory indolent B-cell NHL with adequate organ function, ECOG ≤2, absolute neutrophil count ≥1000/μL, platelets’100,000/μL who were not refractory to bendamustine were eligible. After premedication with acetaminophen, diphenhydramine, and hydrocortisone pts received TRU-016 (10 or 20 mg/kg on Days 1 and 15) over 2–3 hrs combined with rituximab 375 mg/m2 (Day 2) and bendamustine 90 mg/m2 (Days 1 and 2) by IV infusion for up to six 28-day cycles. Safety was evaluated using CTCAE 4.03 and response was determined using the Revised Response Criteria for Malignant Lymphoma (Cheson 2007) after every 2 cycles. Results:12 pts, (9 with follicular lymphoma (FL) and 3 with small lymphocytic lymphoma (SLL)) were treated (6 each dose level). Pt characteristics: median age 57 yrs (range, 51–79), median prior regimens 3 (1–4), 67% ≥ stage III at diagnosis, 4 pts had bulky disease > 5cm. All pts had relapsed after prior rituximab (R) including 3 refractory to their most recent previous treatment. In addition, prior treatments included: CHOP-R (8), RICE (5), single agent R (5), transplant (2). FLIPI scores at study entry (FL pts) were: 8 intermediate, 1 low.The most frequent (>2 pts) adverse events (AEs) were: neutropenia (8), fatigue, nausea, insomnia, and WBC decreased (7 each); anemia, diarrhea, headache, hypophosphatemia, thrombocytopenia, and vomiting (3 each). Grade 3/4 AEs that occurred in >1 pt were neutropenia (6), hypophosphatemia (3), WBC decreased (2). Serious AEs (SAE) included asymptomatic pulmonary thrombosis in 2 pts and febrile neutropenia, pneumonia, myelodysplastic syndrome (pt had prior transplant, CHOP, RICE), deep vein thrombosis, and retinal vein occlusion (last 2 events and pulmonary thrombosis occurred in same pt) in 1 pt each. There was no apparent dose relationship to the SAEs.The best overall response was 10/12 (83%) with 4 CRs (32%). Four responding pts (1 CR, 3 PR) discontinued treatment prior to cycle 6 due to undergoing consolidation with transplant (2), development of myelodysplastic syndrome (1), and delayed neutrophil recovery (1). The 4 discontinuations occurred in the 20 mg cohort and limit the response evaluation of the 20 mg dose. However, after Cycle 2 Day 15, the overall response rate was 67% at 10 mg/kg and 100% at 20 mg/kg. Three of the 4 pts with bulky disease responded to the regimen Conclusions:TRU-016 in combination with rituximab and bendamustine was well-tolerated, induces responses in the majority of patients with relapsed indolent B-NHL. A MTD was not defined. Future combination studies of TRU-016 in NHL are warranted.AgeGenderHistologyBulky Disease (≥5 cm)Rai Staging at dx.Prior Lines of Therapy# of cyclesBest Response (reason for discontinuation)Cohort 1: 10 mg/kg TRU-01656MSLLnoIV16CR55FFLnoIV36CR60MFLyesII16PR51MFLnoI16SD56MSLLyesND32PD65MFLnoIII46PRCohort 2: 20 mg/kg TRU-01655FFLnoIII44PR (transplant)57MFLnoIV32PR (MDS)54FFLnoIII42PR (transplant)74FFLyesIV46PR67MFLnoII12CR (neutropenia)78MSLLyesIV25PR Disclosures:Mato:Celgene, Milennium, Genentech, Seattle Genetics: Speakers Bureau. Stromatt:Emergent Product Development: Employment.

Lenalidomide and Rituximab for Untreated Indolent Lymphoma: Final Results of a Phase II Study

AbstractAbstract 901 Background:The optimal management of patients (pts) with untreated, advanced stage indolent non-Hodgkins lymphoma (NHL) is evolving. Although several traditional chemo-immunotherapy regimens achieve high overall response (OR) rates, toxicity is common and nearly all patients relapse. Lenalidomide has single-agent activity in relapsed indolent NHL, and rituximab is effective alone and in combination with chemotherapy in untreated pts. Preclinical studies suggest that lenalidomide may augment immune effector cell function and ADCC in the presence of rituximab. The aim of this phase II, single arm study is to evaluate the efficacy and safety of lenalidomide and rituximab in pts with untreated, advanced stage, indolent NHL. Methods:Pts with advanced stage untreated indolent NHL and measurable disease (>1.5cm) were eligible for study entry. Pts received 20 mg/day of lenalidomide on days 1–21 and rituximab 375 mg/m2 on day 1 of each 28 day cycle for 6 cycles. Patients with evidence of tumor response could continue up to 12 cycles. To reduce the incidence of tumor flare, pts with small lymphocytic lymphoma (SLL) started at 10mg, with monthly dose escalation. Pts were evaluable for response if they had at least 1 response assessment. Prophylactic growth factors were not used. Response was assessed every 3 cycles using the 1999 International Working Group Response Criteria. Results:The study enrolled 110 pts; all have completed treatment or are off-study, and 103 pts are evaluable for response. Histologies included: SLL n=30, follicular lymphoma (FL) n=50, and marginal zone lymphoma (MZL) n=30. The median age was 58 (34-84) years, and 53% were male. Of the 46 evaluable pts with FL,78% had a FLIPI score of ≥ 2, and 52% met GELF criteria for high tumor burden. The best response for the 103 evaluable pts is listed in Table 1.Table 1:Best ResponseHistology (#)PDSDPRCR/CruORRSLL n=307%13%53%27%80%MZL n=27011%22%67%89%FL n=4602%11%87%98%ALL Pts n=1032%8%26%64%90%Among the FL pts, responses were high regardless of FLIPI score, tumor bulk, or GELF criteria at study entry. At the completion of therapy nearly all FL pts demonstrated molecular response with the absence of detectable BCL-2 by PCR. Forty five evaluable pts with FL had a positive PET scan prior to therapy and 42 (93%) attained a complete metabolic response following treatment. At a median follow up of 22 months, the estimated 2 year progression free survival (PFS) is 83% for all pts and 89% in pts with FL. [Display omitted] Among all pts, grade ≥3 neutropenia occurred in 40% (13% of total cycles) and thrombocytopenia occurred in 4% of pts. The most common grade ≥ 3 non-hematologic toxicities included rash (8 pts), muscle pain (7 pts), fatigue (3 pts), thrombosis (3 pts). Two episodes of neutropenic fever occurred. Six pts stopped treatment due to adverse events. Conclusion:The combination of lenalidomide and rituximab is active and tolerable in pts with untreated indolent lymphoma. High complete response rates with durable remissions were observed in patients with follicular lymphoma. Randomized studies comparing this regimen versus traditional combination chemotherapy regimens are underway. Disclosures:Fowler:Celgene: Research Funding; Roche: Research Funding. Off Label Use: lenalidomide. Neelapu:Celgene: Research Funding. McLaughlin:Celgene: Data Monitoring Committee for another study Other. Fanale:Celgene: Honoraria, Research Funding. Wang:Pharmacyclic: Research Funding. Lacerte:Celgene: Honoraria. Samaniego:Celgene: Research Funding.

The Bruton's Tyrosine Kinase Inhibitor Ibrutinib (PCI-32765) Is Active and Tolerated in Relapsed Follicular Lymphoma

AbstractAbstract 156 BackgroundBruton's tyrosine kinase (BTK) is a central mediator of B-cell receptor (BCR) signaling and is essential for normal B-cell development. Subtypes of non-Hodgkins lymphoma (NHL) may be dependent on chronic activation of the BCR pathway and primary follicular lymphoma (FL) cells have been found to maintain enhanced signaling when compared to normal B-cells (Irish JM, et al. Blood 2006; 108: 3135). Ibrutinib is an orally administered, covalently-bound inhibitor of BTK which induces apoptosis and inhibits cellular migration and adhesion in malignant B-cells. Based on promising preclinical data in B-cell malignancies, a phase I study was conducted to test the safety, tolerability, pharmacokinetics, and pharmacodynamics of ibrutinib in relapsed NHL. We report the long-term tolerability and sustained activity of ibrutinib in FL patients in this study with extended follow-up. MethodsAdult patients with relapsed or refractory B-cell lymphoma were eligible for trial entry and 16 patients with FL were enrolled in this Phase I study. Ibrutinib was administered orally with dose escalation according to protocol-defined dose-limiting toxicities (DLT) to define a maximum tolerated dose (MTD) or until 3 dose levels above attainment of full BTK occupancy. A 28-day on/7-day off (intermittent) schedule was evaluated in 5 cohorts (1.25–12.5 mg/kg PO qd) and a once daily oral dose (without a drug holiday) in 2 cohorts (8.3 mg/kg and 560-mg fixed dose). Patients were evaluable for safety if they received study drug. Efficacy was evaluated in all patients who received 2.5 mg/kg or higher (which achieves full BTK occupancy) and had one on-study imaging assessment. Efficacy was also analyzed at higher doses to determine if there was improved efficacy. Responses were assessed every 2 months using the Revised Response Criteria for Malignant Lymphoma (Cheson 2007). ResultsMedian age 60 (41–71), equal numbers of males and females, median time from diagnosis 54 months (19–186), median number of prior therapies 3 (1–5) including: stem cell transplantation (6%), alkylators (88%), anthracyclines (56%), nucleoside analogs (19%), and rituximab (100%). FLIPI scores at baseline: low risk = 19%, intermediate risk = 37%, high risk = 44%.Treatment-emergent AEs occurring in ≥ 25% included: diarrhea (50%), fatigue (44%), nausea (38%), cough (31%) and myalgia (25%). Observed grade 3 AEs included: anemia, anxiety, hypersensitivity, hypokalemia, hypophosphatemia, decreased neutrophil count, non-cardiac chest pain, pancytopenia, pneumonia and vomiting (one event each). A Grade 4 hypokalemia occurred and was considered to be related to study drug by the investigator. One case of myelodysplastic syndrome occurred 29 days after the last dose of ibrutinib in a patient with pre-existing anemia and multiple lines of prior treatment and was considered to be unrelated by the investigator.One patient in the 2.5 mg/kg/day intermittent cohort experienced DLTs of grade 2 neutropenia resulting in the ibrutinib dose being held > 7 days and a grade 4 hypokalemia. One patient in the 8.3 mg/kg/day intermittent cohort experienced a Grade 3 hypersensitivity reaction. No DLTs were observed in the 12.5 mg/kg/day cohort and the MTD was not reached.In the 16 patients with FL, 11 patients received ibrutinib at 2.5 mg/kg or higher and were evaluable for efficacy (2 patients at 2.5 mg/kg, 1 at 5 mg/kg, 3 at 8.3 mg/kg intermittent, 3 at 12.5 mg/kg, 2 at 8.3 mg/kg continuous dosing). Median time on ibrutinib was 7 months (0–29). Overall response rate (ORR) 54.5% (3 CRs, 3 PRs), duration of response (DOR) 12.3 months, median PFS 13.4 months. In the 9 patients who received ibrutinib at 5 mg/kg or higher, the median time on ibrutinib, ORR and DOR were similar to the efficacy in the 11 patients. However, there was a slight trend toward improved PFS of 19.6 months; 2 patients are still responding to ibrutinib at 25 and 29 months. ConclusionsThe BTK inhibitor ibrutinib (PCI-32765) is well tolerated and active in patients with relapsed FL. Based upon drug occupancy and clinical responses, a dose of 5 mg/kg/day or above is recommended for phase II studies. Extended dosing did not appear to increase toxicity and response rates improved with continued treatment in some patients. Phase II studies with ibrutinib in FL are planned. Disclosures:Advani:Pharmacyclics, Inc: Research Funding. Sharman:Celgene: Consultancy; Pharmacyclics: Honoraria; Calistoga: Honoraria; Portola pharmaceuticals: Consultancy. McGreivy:pharmacyclics: Employment. Kunkel:Pharmacyclics: Employment, Equity Ownership. Troung:Pharmacyclics, Inc: Employment, Equity Ownership. Zhou:Pharmacyclics, Inc.: Employment, Equity Ownership.

Absence of Prognostic Impact Associated with the Use of Statins in Patients with Follicular Lymphoma in the Rituximab Era: An Exploratory Analysis From the PRIMA Study.

AbstractAbstract 2649▪▪This icon denotes a clinically relevant abstract Background.Conflicting results have been published to date concerning the impact of statin use on the prognosis of patients with non-Hodgkin lymphoma (NHL) treated with a rituximab-containing first-line regimen. By impairing protein prenylation and possibly lipid-raft formation, statins have been shown to exert an antitumoral activity both on solid and hematological malignancies in vitro as well as in animal models. However, in vitro experiments have demonstrated an unexpected impairment of anti-CD20 antibody binding due to changes in conformational epitopes of the molecule. As a result, statins were found to decrease anti-CD20 induced complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity. Several groups worldwide attempted to assess the outcome of patients on statins receiving rituximab for NHL. No detrimental effect was observed across studies for patients with diffuse large B-cell lymphoma treated upfront with R-CHOP or R-CHOP-like regimen but a surprising prolonged event-free survival (EFS) was observed for patients with follicular lymphoma (FL) in one study. However, several caveats of the study precluded definitive conclusions to be drawn such as treatment heterogeneity, the enrollment of patients who did not receive rituximab, the retrospective assessment of statin use through medical charts and the consideration of EFS as the primary endpoint without specific evaluation of overall survival (OS). The impact of statin use on the prognosis of patients with FL therefore requires further investigation. Patients and methods.The randomized, open-label PRIMA study enrolled 1217 patients with de novo FL from 223 centers in 25 countries. Patients achieving at least a partial response following frontline therapy with R-CHOP, R-CVP or R-FCM were randomized between 2-years rituximab maintenance (every 8 weeks) or observation. A significant improvement of progression-free survival (PFS) was observed in the rituximab maintenance arm (HR=0.55, 95% CI=0.44–0.68, p<0.0001). All concomitant treatments at enrollment, including the use of statins, were prospectively collected. 1140 patients with complete medication data available at registration were included in this analysis. Among them, 10.4% (n=119) were on statins. Baseline demographic characteristics between patients on statins and those not on statins were compared with the use of a Chi-square test. Various endpoints such as EFS, PFS, OS, time-to-next lymphoma treatment (TTNLT) and time-to-next chemotherapy (TTNCT) were examined in univariate and multivariate analysis. All time-to-event durations were calculated from the date of randomization (6 months after the start of induction therapy). Results.As expected, the use of statins was associated to an older age at registration (P<0.001) and, as a consequence, to a higher FLIPI risk score (P<0.001). Male sex was also overrepresented among statins users, although not significant (P=0.07). Unexpectedly, LDH was more frequently above the upper normal limit (P=0.03). No other difference was observed with regards to demographic data according to statin use.No difference in overall response rate to induction regimen as well as in the quality of the response (CR/Cru versus PR versus others) was noted (P=0.53). No further difference was found at the end of the maintenance period either for patients in the observation or in the rituximab treatment arm. Of note, no imbalance was detected concerning the rate of adverse events between the 2 groups of patients as a whole (grade 1–2 versus 3–4, P=0.18) or with regards to each particular toxicity.Finally, outcome in terms of EFS, PFS (see figure above), OS, TTNLT and TTNCT were similar regardless of the use of statins (P=0.76, P=0.43, P=0.21, P=0.83 and P=0.31 respectively). Importantly, further adjustment for potential confounding factors in multivariate Cox models such as age, FLIPI score or LDH (which were imbalanced between the 2 groups) did not reveal a potential beneficial effect. Conclusion.As for other subtypes of NHL, the use of statins in patients with FL in the rituximab era appeared safe and was not associated with an inferior outcome as suggested by in vitro experiments. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Rituximab +/− Bevacizumab for Patients with Previously Treated Follicular Non-Hodgkins Lymphoma: A Randomized Phase II Trial of the Sarah Cannon Research Institute.

AbstractAbstract 2749 Background:Single-agent rituximab produces an overall response rate of approximately 50% and a median PFS of 9 months in patients with previously treated follicular NHL. Since resistance to rituximab eventually develops in nearly all patients, a number of novel agents are currently being evaluated in combination with rituximab to improve treatment efficacy. Vascular endothelial growth factor (VEGF) promotes angiogenesis and is increased in many tumor types. In NHL, high levels of VEGF are correlated with disease progression. Bevacizumab, a monoclonal antibody inhibiting VEGF, has extended PFS in several solid tumor types when added to combination chemotherapy. In this randomized phase II trial, we compared the efficacy and toxicity of bevacizumab + rituximab versus single-agent rituximab, in patients with previously treated follicular NHL. Methods:Eligible patients had follicular NHL (grade 1 or 2); NHL progression after either 1 or 2 prior chemotherapy regimens; measurable or evaluable disease; and ECOG PS 0–2. Prior rituximab treatment was allowed as long as progression occurred > 6 months following completion of treatment. Patients were randomized to receive single-agent rituximab (Regimen A) or rituximab plus bevacizumab (Regimen B). All patients received 375 mg/m2IV of rituximab weekly for 4 weeks. Regimen B patients also received bevacizumab 10 mg/kg IV on days 3 and 15 during the 4-week course of rituximab. Response evaluations were performed at weeks 6 and 12 as well as 4 weeks after the completion of all therapy. Patients with objective response or stable disease at week 12 received 4 additional doses of rituximab administered at months 3 (week 12), 5, 7, and 9; in addition, regimen B patients received bevacizumab 10 mg/kg IV every 2 weeks for a total of 16 doses (also beginning week 12). Addition of bevacizumab was hypothesized to improve the median PFS from 15 months to 20 months. Accrual of 90 patients (45/arm) was initially planned; the study was stopped early due to slow accrual. Results:Between 8/2005 and 3/2012, 60 patients were enrolled (Regimen A, 30; Regimen B, 29). Key clinical characteristics including age, performance status, FLIPI score, and previous treatment were comparable in the 2 treatment groups. 95% of patients had received 2 previous regimens, and 78% had received previous rituximab. After a median followup of 36 months, 92% of patients have either completed (40%) or discontinued treatment (lymphoma progression 30%, toxicity 12%, patient/physician decision 8%). The overall response rates were 42% in Regimen A (CR rate 10%) and 45% in Regimen B (CR rate 17%). The median progression-free survivals for Regimens A and B were 10.4 and 18.4 months, respectively (HR 0.33, p=0.0090). Median OS has not been reached for either group; at 3 years, the estimated OS rates are 54% (Regimen A) and 81% (Regimen B) (p=0.12). Grade 3/4 hematologic toxicity was uncommon, with no grade 4 neutropenia or thrombycytopenia, and 1 episode of febrile neutropenia (Regimen B). No grade 4 non-hematologic toxicity occurred; grade 3 non-hematologic toxicity occurred in 3 patients (10%) on Regimen A (infusion reaction 1, hyperglycemia 1, pneumonia 1) and 7 patients (24%) on Regimen B (hypertension 3, epistaxis 1, abdominal wall hematoma 1, wound dehiscence 1, confusion 1). All 7 patients who discontinued treatment due to toxicity (3 during the first 12 weeks) were on regimen B; 5 had bevacizumab-related toxicity. There were no treatment-related deaths. Conclusion:The addition of bevacizumab to rituximab was feasible with a modest increase in toxicity in this group of patients with previously-treated follicular NHL. The toxicities observed were consistent with the known profiles of each agent. While response rates were similar between regimens, the addition of bevacizumab lengthened the progression-free survival when compared to rituximab alone (median 18.4 vs. 10.4 months). Although results of this study must be interpreted with caution due to its small size, further study of VEGF- targeted therapies in NHL may be warranted. Disclosures:Off Label Use: Off-label bevacizumab use for treatment of follicular non-Hodgkin's lymphoma. Reeves:Celgene: Equity Ownership.

Early Stage Follicular Lymphoma: Is There a Clinical Impact of First Line Treatment?

AbstractAbstract 2722 IntroductionFollicular lymphoma (FL) is the commonest type of indolent lymphomas and is considered as an incurable malignancy with a relapsing and remitting course. Most patients are diagnosed with FL when they have an advanced stage of disease, only less than 20% presenting with stage I or II. Initial management of early stage (Ann Arbor stage I or II) FL remains undefined. Numerous options exist but radiotherapy appeared to be the standard of care for early stage disease based on single institution or retrospective series. Our aim was to revisit the outcome of patients with localized FL in the era of rituximab. Patients and MethodsWe analyzed 145 patients treated in our institution with early stage (I or II) FL between January 01/1967 and 01/2011. Patients were retrospectively divided into six groups according to their initial treatment: watch and wait (WW), chemotherapy alone (CT), radiotherapy alone (RT), combination of radiotherapy and chemotherapy (RT-CT), Rituximab alone (Ri) and immuno-chemotherapy (Ri-CT). ResultsOf the 145 patients (79 females and 66 males), 84 (57.9%) patients had stage I disease and 61 (42.1%) a stage II. Median age was 55 years (20% of patients > 65 years). Only 22 (15.2%) of them had a bulky disease (> 7cm). FLIPI score was 0–1 in 116 pts, 2 in 29 pts and none had a score >2.The management of patients significantly varied over the different time (period I: <1990; period II: 1991–2000 and period III: 2001–2011) Use of RT decreased (43% for period I versus 24% for period III) whereas watchful waiting increased from 19.5% for period I up to 75% for the period III. Rituximab and Ri- CT use increased rapidly to 86% for the period III.Patients characteristics were similar in terms of age between the 6 groups but differed in term of stage and prognostic factors, essentially more stage II (61%) and bulky disease (42%) in the Ri-CT group compared to the others.The CR rate varied from 57% for the Ri group to 95% for the RT-CT group with 69% for CT, 75% for Ri-CT and 81% for RT alone. As expected, the proportion of PR was higher in the Ri group (43%). With a median follow-up of 7 years, the relapse rate was significantly lower in the Ri-CT group (40% versus 90.5% RT, 84% RT-CT, 69% CT and 58% WW respectively).According to the modifications of management over time, OS and PFS are analyzed according to two period of time: < year 2000 and ≥ 2000. OS at 7.5 years for the patients managed after >2000 was better (75%) than for those managed <2000 (59%) (not statistically significant, p= 0.29). OS according to the different treatments did not show any difference: 72% WW, 74% CT, 74% Ri-CT, 67% RT-CT, 66% RT, and 100% for Ri, respectively. By contrast, a significant difference was found for PFS at 7.5 years in favor of the combination of Ri-CT (60%) versus the others (19% RT, 26% RT-CT, 23% CT and 26% for the WW strategy, respectively) (p= 0.00135) as described in Figure 1. ConclusionWithin the inherent limits of this retrospective study, delayed start of therapy was associated with a similar OS than the one observed in patients receiving immediate intervention, and PFS was not different between WW versus RT or RT-CT. Thus, the “watch and wait” strategy could be proposed as first line therapy, like it is in stage III and IV follicular lymphoma patients with a low tumor burden. However, when a treatment is required, the combination of immunochemotherapy seems to be the best option. [Display omitted] Legends: R-CT: Ri CT or immunochemotherapyOthers regimens: WW, RT, RT+CT, CT Disclosures:No relevant conflicts of interest to declare.

Impact of Obesity and Genetic Variation in Energy Balance and Metabolism Genes On Prognosis in Diffuse Large B-Cell Lymphoma (DLBCL) and Follicular Lymphoma (FL)

AbstractAbstract 684 Background.Obesity has been associated with an increased risk of developing of lymphoma, particularly DLBCL. Genetic variation in several energy balance genes, including leptin (LEP), its receptor LEPR, ghrelin (GHRL) and neuropeptide Y (NPY) have been shown to modulate risk of lymphoma, although their impact on survival is not known. In contrast, recent studies suggest that patients either overweight (Body Mass Index (BMI), 25 to<30 kg/m2) or obese (≥30 kg/m2) may have a superior prognosis in DLBCL, although its impact in FL and in the current treatment era is not known. We evaluated the association of BMI at the time of diagnosis, 2 years prior to diagnosis and at ages 18, 35 and 50 years, along with germline genetic variation in selected energy balance genes with event-free (EFS) and overall (OS) survival in DLBCL and FL. Methods.We evaluated these associations in a prospective cohort of newly diagnosed DLBCL (N=764) and FL (N=649) patients enrolled at the Mayo Clinic and University of Iowa from 2002–2009 as part of the Molecular Epidemiology Resource. Peripheral blood DNA, clinical data and self-reported historical weights were collected at enrollment. Patients received standard disease treatment strategies, and were systematically followed for disease progression, re-treatment, and death. Single nucleotide polymorphisms (SNPs) were genotyped as part of a custom Illumina iSelect panel. The most prevalent homozygous genotype was used as the reference group, and each SNP was modeled as having a log-additive effect in the regression model. Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CI) for the association of the obesity measures and SNPs with outcome, adjusted for treatment class and subtype specific prognostic factors (IPI, FLIPI). Results.For DLBCL patients (median age 63 years, range 18–92) the median follow-up was 47 months (range 0–101); 58% had an IPI 0–1 risk disease; and 87% received immunochemotherapy. For FL patients (median age 60 years, range 25–94), the median follow-up was 60 months (range 11–110); 24% had FLIPI score 3–5; and main initial treatments were observation (32%), rituximab (R)-monotherapy (12%), CVP +/−R (19%), and anthracycline +/−R (22%). The main results for BMI and prognosis are reported in the Table. For DLBCL, obese patients at diagnosis had better EFS and OS; this association was weaker for BMI at age 50 and 35 years. In contrast, for FL, overweight and obese patients at diagnosis had a poorer EFS and OS, and this was also observed for BMIs two years before diagnosis and at ages 50 and 35 years. In FL, the LEP SNP rs2167270 was associated with inferior EFS (HR=1.25; 95%CI 1.05–1.49) and OS (HR=1.28; 95%CI 0.90–1.83). The NPYSNP rs16147 was associated with inferior FL OS (HR=1.50; 95%CI 1.03–2.17) but was not associated with EFS. None of the energy balance and metabolism SNPs were associated with DLBCL EFS or OS. Conclusions.Higher BMI prior to and at diagnosis, as well as SNPs in LEP and NPY,were significantly associated with FL prognosis, with inferior outcomes in overweight and obese patients. These novel findings in the modern treatment era suggest an important role of obesity pathways in FL prognosis. In DLBCL, we confirm the recent findings of improved survival in DLBCL in obese patients, and extend this to the modern treatment era and BMI earlier in life.TableDLBCL*FL*EFSOSEFSOSHR95%CIHR95%CIHR95%CIHR95%CIBMI @ diagnosis (WHO)Normal1.00ref1.00ref1.00ref1.00refOverweight0.830.50-1.360.600.35-1.021.641.01-2.681.730.64-4.67Obese0.560.31-1.020.530.28-0.991.711.05-2.792.701.06-6.90BMI @ 2 years before diagnosis (WHO)Normal1.00ref1.00ref1.00ref1.00refOverweight0.990.65-1.500.960.60-1.551.250.87-1.792.070.87-4.94Obese0.860.55-1.340.770.46-1.301.721.18-2.504.151.82-9.47BMI @ age 50 (quartile)11.00ref1.00ref1.00ref1.00ref21.240.76-2.031.160.67-2.011.280.80-2.031.060.40-2.8330.830.48-1.450.960.52-1.751.240.78-1.971.920.78-4.7340.820.49-1.360.880.49-1.561.881.20-2.932.491.03-6.02BMI @ age 35 (quartile)11.00ref1.00ref1.00ref1.00ref20.830.51-1.350.970.55-1.711.210.81-1.801.430.61-3.3830.770.49-1.240.910.53-1.571.210.77-1.891.170.43-3.2340.680.42-1.080.850.49-1.471.571.06-2.322.210.98-5.02*DLBCL adjusted for IPI and treatment; FL adjusted for FLIPI and treatment. Disclosures:No relevant conflicts of interest to declare.

Rates and Outcomes of Follicular Lymphoma Transformation in the Rituximab Era: A Report From the University of Iowa/Mayo Clinic SPORE Molecular Epidemiology Resource

AbstractAbstract 1546 Background:Follicular lymphoma (FL) is an incurable disease with an undefined optimal management strategy. Global priorities in goals of care are avoidance of death and transformation to aggressive subtypes. Retrospective series, – most including patients diagnosed before ubiquitous rituximab use, - describe diverse rates of transformation with a common consensus of 3% per year, and with a median survival post transformation of less than 2 years. This study sought to characterize transformation events in a prospective observational series begun after diffusion of early rituximab use in FL. Methods:Newly diagnosed FL patients were prospectively enrolled in the University of Iowa/Mayo Clinic SPORE Molecular Epidemiology Resource (MER) from 2002–2009. Clinical data were abstracted from medical records using a standard protocol. Patients were actively followed for retreatment, transformation, and death. Inclusion criteria for this analysis were initial diagnosis of grade I-IIIa FL. Exclusion criteria for this cohort include composite diffuse large B-cell lymphoma (DLBCL), FL grade IIIb, or evidence of clinical or pathological transformation at the time of FL diagnosis. Transformation was defined as refractory/recurrent disease with either a) biopsy confirmed subtype of FLIIIb, DLBCL or higher grade B-cell lymphoma; or b) clinical indication of transformation (sudden rise in LDH, rapid discordant localized nodal growth, new involvement of unusual extranodal sites, new B symptoms or hypercalcemia). Risk of transformation was analyzed via time to transformation using a death as a competing risk. Time to transformation was defined as the date of initial FL diagnosis to date of transformation. Overall survival was defined as the date of initial diagnosis to date of death or last known follow-up for patients still alive. Results:There were 631 newly diagnosed grade I-IIIa FL patients with a median age at enrollment of 60 years (range 23–93). 54% were male. The most common types of initial therapy were observation (33%), rituximab (R) monotherapy (12%), alkylator based chemotherapy +/− R (22%), and anthracycline based chemotherapy +/− R (20%). At a median follow-up of 60 months (range 11–110), 79 patients had died, 311 patients had an event (death, progression, or retreatment), and 60 patients (9.5%) had transformed. Transformation was biopsy proven in 48 of the 60 patients (80%). The overall transformation rate at 5 years (TX5) was 10.7% (95% CI: 8.3%–13.8%) (Figure 1). Time to transformation was associated with a FLIPI score of 3–5 (HR=2.37, 95% CI 1.28–4.39, p=0.006), but was not significantly associated with other standard clinical characteristics. Risk of transformation was different in the common initial treatment groups with the highest rate in patients who were initially observed (TX5=14.4%) and lowest rate in patients who initially received R monotherapy (TX5=3.2%)(p=0.058). Outcome after transformation was inferior to MER subjects with de-novo diagnosed DLBCL (p<0.0001). The median overall survival from date of transformation was 44 months (95% CI: 22-NA). Survival after transformation was superior in patients who transformed greater than 18 months after FL diagnosis compared to patients who transformed earlier (5 yr OS =70% vs 20%) (p=7 ×10−5), and for those initially observed (median unreached) versus those patients who were initially treated with alkylator or anthracycline based chemotherapy (median survival of 11 months)( p=0.016). Conclusions:Follicular transformation rates in this modern large prospective observational study are similar to risk of death without transformation and slightly lower at 5 years than most previous reports. Post-transformation prognosis is substantially better than described in older series. These observed differences may be a function of the prospective nature of the study design, modern management strategies, or patient selection factors. Initial management strategies may influence the risk of transformation. Marked survival differences following early vs. late transformation suggest that these may be different biologic events. [Display omitted] [Display omitted] Disclosures:Link:Genentech: Consultancy, Research Funding; Celgene: Consultancy; Millenium: Consultancy. Johnston:Novartis: Consultancy.

Germline Genetic Variation and Risk of Follicular Lymphoma Transformation in the Modern Treatment Era

AbstractAbstract 149 Background.There are few established factors that predict risk of follicular lymphoma (FL) transformation, and only two studies have evaluated the role of germline genetic variation and risk of transformation. One study reported an association of a BCL6 SNP (397C>G) with risk of transformation, and a second study reported an association with rs6457327, which is in the HLA region of 6p21. This study evaluated the risk of FL transformation in the modern treatment era with germline SNPs that were previously reported to be associated with FL transformation (BCL6SNPs and rs6457327), along with SNPs (N=45) previously associated with either risk of FL or FL prognosis. Methods.Newly diagnosed FL patients were prospectively enrolled from 2002–2009 into the Molecular Epidemiology Resource of the University of Iowa/Mayo Clinic Lymphoma SPORE. Peripheral blood for genotyping was collected at enrollment, and clinical and treatment data were abstracted from medical records. All patients were actively followed for disease progression, retreatment, transformation and death. For this analysis, only FL patients with grade I-IIIa were included. Patients with composite DLBCL, FL grade IIIb, or other evidence of transformation at diagnosis were excluded. Transformation was based on either 1) biopsy confirmation of FL grade IIIb, DLBCL, or higher grade B-cell lymphoma; or 2) clinical indicators of transformation based on the published literature, including sudden rise in LDH, rapid discordant localized nodal growth, new involvement of unusual extranodal sites, new B-symptoms, or hypercalcemia. Genotyping was conducted using a custom Illumina iSelect panel. Cox regression was used to estimate Hazard Ratios (HRs) and 95% confidence intervals (CI) for individual SNPs with time to transformation, with death modeled as a competing risk. Each SNP was modeled with the most prevalent homozygous genotype used as the reference group, and each SNP was modeled as having a log-additive (per minor allele) effect in the regression model. An ordinal test was used to assess the trend, and p<0.05 was considered statistically significant. Results.There were 631 newly diagnosed grade I-IIIa FL patients, of whom 532 had DNA and were successfully genotyped. The median age at diagnosis was 60 years (range 23–93) and 53% were male. FLIPI distribution was 42% 0–1, 34% 2 and 24% 3–5. Initial therapies included observation (32%), rituximab (R) monotherapy (13%), alkylator-based chemotherapy +/− R (20%), and anthracycline-based chemotherapy +/− R (19%). At a median of 59 months of follow-up (range, 11–110), 58 patients died, 254 had an event (death, progression or retreatment) and 54 patients (10%) transformed. Transformation was biopsy proven in 43 of the 54 patients (80%). The SNP rs6457327 on chromosome 6p that was previously reported to be associated with transformation was positively associated with risk of transformation in our data (HR=1.40; 95%CI 0.97–2.04; p=0.07), although this association was weaker but still consistent with the prior report. Further, we evaluated additional typed SNPs from the HLA region of 6p, and found additional associations (p<0.05) with HLA-DRA (3 SNPs), HLA-DQA2 (2 SNPs), HLA-DOA (2 SNPs) and HLA-DPB1/HLA-DPA2 (2 SNPs), of which rs10484569 from HLA-DPB1/HLA-DPA2 was the most strongly associated with risk of transformation (HR=3.01; 95%CI 1.48–6.09; p=0.002). None of the BCL6 or other previously reported risk SNPs were associated with transformation. Of the SNPs previously associated with FL prognosis, only the FCGR2A rs1801274 (HR=1.41; 95%CI 0.94–2.10; p=0.09) and CD46 (CD46 molecule, complement regulatory protein) rs2466571 (HR=1.72; 95%CI 1.16–2.55; p=0.007) were associated with risk of transformation. For CD46, one additional SNP (rs2796269) was also associated with transformation (HR=0.61; 95%CI 0.40–0.95; p=0.03). Further adjustment for FLIPI score and treatment (observation versus all other) did not alter these associations. Conclusions.The previously reported association of rs6457327 with risk of transformation in the modern treatment era was replicated. In addition, several HLA loci and two FL prognosis SNPs were linked to transformation risk. The remaining published FL risk or prognosis SNPs were not associated with transformation. Our results support a role for germline genetic variation in the HLA region, FCRGR2A and CD46 in transformation of FL. Disclosures:No relevant conflicts of interest to declare.

Clinical Features of Newly Diagnosed CD25-Positive Follicular Lymphoma

AbstractAbstract 1543 Background:CD25 (the alpha chain of the IL-2 receptor) has been shown to be expressed in hairy cell leukemia cells and a small subset of normal B cells. Recently, we reported that CD25 is expressed in a subset of diffuse large B-cell lymphoma (DLBCL) (ASH 2011 118:2666). However, its expression in follicular lymphoma (FL) has yet to be fully examined. The aim of this study was to clarify the clinical features of newly diagnosed CD25+ FL. Patients and Methods:Eighty-four patients with newly diagnosed CD25+ FL who were admitted to our hospital between 2002 and 2012 were retrospectively evaluated. Biopsy specimens from lymph nodes or related tissues were analyzed by flow cytometry (FCM) using a combined method of single- and two-color staining. CD25 expression was defined as positivity of >20% of clonal B cells with CD19 or 20 expression >70% in a gated region. Results were compared with patients with reactive lymphadenopathy (n=27), DLBCL at initial presentation (n=91), and FL at relapse (n=13). Results:CD25 expression in untreated patients with FL (mean±SD, 10.6±9.9%; n=84) was almost equivalent to that in patients with reactive lymphadenopathy (mean±SD, 9.1±4.4%; n=27, P =0.3), and lower than that in untreated patients with DLBCL (mean±SD, 28.5±31.1%; n=91, P <0.001). There was a trend of a higher CD25 expression in biopsy specimens from relapsed FL than in those from newly diagnosed FL (mean±SD, 18.6±16.3 vs. 10.6±9.9%, respectively, P=0.077). With the sum of treated and untreated CD25+ FL, two-color FCM showed that the mean±SD of CD25/CD19 and CD25/CD20 dual expression was 28.5±26.5% (n=4) and 28±24.3% (n=4), respectively. The patients with newly diagnosed CD25+ (more than 20%) FL (n=10) showed some clinical features such as B symptoms (P =0.09), soluble IL-2 receptor titers of more than 5,000 U/ml (P =0.013), and advanced ages over 60 (P =0.16), compared with CD25- FL patients (n=74). Besides, there were some differences between CD25+ and CD25- FL in terms of histology grade 3 (50 vs. 32%, respectively, P=0.29) and the presence of t(14;18) (33 vs. 56%, respectively, P=0.27).Patients with FL at the initial presentation underwent rituximab-containing chemotherapy (n=68), radiotherapy (n=4), and observation (n=12). Kaplan–Meier analysis showed poorer progression-free survival (PFS) and overall survival (OS) in patients with CD25+ FL than that in patients with CD25- FL (2-year PFS, 36 vs. 82%, respectively, P <0.001; 6-year OS, 47 vs. 88%, respectively, P <0.01). Multivariate analysis revealed that CD25 expression is a significant prognostic factor for PFS (HR 6.4, 95%CI 2.4–17.4, P <0.001) and OS (HR 6.6, 95%CI 1.2–36.9, P= 0.027), which is independent of FLIPI score variables. Conclusion:Newly diagnosed CD25+ FL may constitute a distinct subgroup associated with aggressive clinical features and an inferior prognosis. CD25 may be a new prognostic marker, and could be a therapeutic target in FL patients. Disclosures:No relevant conflicts of interest to declare.

Fc gamma receptor 3a genotype in follicular lymphoma: the end of the story? Reply to "Fc gamma receptor 3a genotype predicts overall survival in follicular lymphoma patients treated on SWOG trials with combined monoclonal antibody plus chemotherapy but not chemotherapy alone". Haematologica. 2012;97(6):937-942

We have read with great interest the results of the recently published retrospective analysis of the Southwest Oncology Group (SWOG) trials.1 This paper will have an extraordinary impact on decision-making in clinical practice worldwide. Persky and colleagues concluded that Fc gamma receptor 3A polymorphism (FCGR3A) status may be predictive of survival in follicular lymphoma patients receiving treatments containing an anti-CD20 antibody. We fully agree with the statement that the exact mechanism of rituximab activity is not completely understood and polymorphisms such as FCGR3A (CD16), expressed on NK cells and macrophages, may result in different ADCC activation and, therefore, obtain different benefits from rituximab. However, we are doubtful about the conclusion that the predictive role of an Fc gamma receptor 3A polymorphism could be applied to all patients treated with an anti-CD20 antibody. First, the authors analyzed patients with two different treatment strategies using monoclonal antibodies. Thirty of them received CHOP followed by four doses of rituximab and 42 patients were treated with CHOP followed by tositumomab and iodine I 131. Neither regimen is currently standard in the US or Europe2,3 and they probably have different treatment efficacy. Sequential application of an antibody leads to different pharmacokinetics of the antibody than that in standard concomitant use. Second, the results may be influenced by the risk of lymphoma. We have no data about FLIPI scores in the CHOP-rituximab arm patients. It would be interesting to confirm the prognostic power of the FCGR3A polymorphism in multivariate analysis with conventional prognostic factors. Finally, despite the conclusion of the study, some studies did not support the predictive value of the FCGR3A polymorphism in patients treated in the rituximab era. A large prospective trial conducted by the Swiss Group for Clinical Cancer Research (SAKK) showed no differences among FCGR3A in terms of response or survival.4 Similarly, our results suggested that in patients with advanced follicular lymphoma treated with risk-adapted immunochemotherapy this polymorphism has no prognostic impact.5 In conclusion, we believe that results obtained in a limited sample of patients treated with two different regimens are not sufficient to allow a conclusion about the prognostic impact of the FCGR3A polymorphism to be drawn.

High serum carbohydrate antigen-125 (CA-125) level predicts poor outcome in patients with follicular lymphoma independently of the FLIPI score

Carbohydrate antigen-125 (CA-125) was established as a prognostic marker in cancer, especially in ovarian carcinoma. Many recent studies have also reported on the prognostic significance of CA-125 in patients with different types of lymphoma, but only a few studies have been carried out in patients treated with rituximab or high-dose therapy. The prognostic impact of CA-125 on a large cohort of patients with follicular lymphoma (FL) has not been studied. This study analyzed the prognostic significance of CA-125 levels in 116 prospectively enrolled patients with previously untreated FL. It showed that the CA-125 level at the time of treatment initiation correlates with the clinical stage, number of involved nodal areas, bulky disease, hemoglobin level, beta-2 microglobulin level, and lactate dehydrogenase level. Patients with CA-125 >35U/mL had significantly shorter progression-free (p<0.001) and overall (p=0.025) survival rates. Cox regression analysis identified high CA-125 levels as a prognostic factor for overall (HR 3.04, p=0.05) and progression-free (HR 3.55, p<0.001) survival rates independent of FLIPI score variables. CA-125 levels may help to refine risk assessment in the modern immunotherapy era.

Effect of short-duration chemoimmunotherapy plus radioimmunotherapy on response rates in relapsed follicular lymphoma: A U.K. NCRI Lymphoma Group Study, CR UK/07/038.

8056 Background: Radioimmunotherapy (RIT) and rituximab (R) maintenance have been investigated after chemotherapy (CT) or R-CT in first line treatment of follicular lymphoma (FL), but less is known about the efficacy of RIT after R-CT in relapsed FL. This phase II study was conducted to examine efficacy and safety of abbreviated R-CT followed by 90Y Ibritumomab tiuxetan in patients with recurrent FL. Methods: Patients (pts) had FL, at 1st or 2nd relapse after response to R-CT or CT alone. All had WHO/ECOG performance status ≤2, and adequate bone marrow (BM), kidney, liver and cardiac function. BM involvement by lymphoma had to be &lt;25% prior to infusion of 90Y Ibritumomab tiuxetan, but could be higher at study entry. Pts received 3 cycles of either R-CHOP or R-CVP, followed by 90Y Ibritumomab tiuxetan (15MBq/Kg, maximum 1200 MBq). No maintenance R was given. Results: 52 pts were enrolled from 6/2008 to 7/2010. Median age was 62 years (range 31-87). 46% had high FLIPI score at entry, 31% intermediate. 80% were at 1st recurrence. Median duration of best prior remission was 27.7 months. 65% pts had previously received R and 25% doxorubicin. 71% pts had R-CHOP and 29% R-CVP, prior to RIT. Overall response rate (ORR) after 3 cycles R-CT was 94% (CR/CRu 10%) and after RIT ORR 96% (CR/CRu 28%). Grade 3/4 thrombocytopenia occurred in 58% pts (median duration 16 days): 3/52 pts after R-CT and 27/52 after RIT. Grade 3/4 neutropenia occurred in 62% pts: 15/52 pts after R-CT and 27/52 after RIT. 5 pts had a total 8 grade 3 infections, only 1 attributable to RIT. 6 pts required platelets and 4 red cell transfusions. 1 pt developed myelodysplasia 10 months after 90Y Ibritumomab tiuxetan, but no other second malignancy was recorded. PFS was 31.4 months (95% CI 15.8 - not reached). There was no difference in PFS according to FLIPI score at entry or reinduction CT (R-CHOP vs R-CVP). Pts with CR/CRu following RIT showed a trend to improved PFS compared to those with PR (12 month PFS 90% versus 63%, p=0.06). Conclusions: Abbreviated R-CT and consolidation with 90Y Ibritumomab tiuxetan is an option for pts with recurrent FL, with responses of comparable duration to those seen after a full course R-CHOP.

RIT with Y90-Ibritumomab Tiuxetan in Follicular Non-Hodgkin Lymphoma: Evaluation of Recent Outcomes in a Single Institution

Background. Based on historical data we reviewed our hospital clinical database to analyse our updated information and therapy outcomes of follicular non-Hodgkin lymphoma (F-NHL) patients treated with 90Y-Ibritumomab tiuxetan. Patients and Methods. Between 2005 and 2011, 56 F-NHL patients were included in a clinical protocol conducted by a multidisciplinary team and treated in the same centre. All patients received 0.3 or 0.4 mCi/kg IV (88%) of 90Y-IT; response evaluation was performed 12 weeks after. Results. M/F 44.6%/55.4%, mean age 61.45 years (30–85); ECOG 0-1 96.9%. According to FLIPI score, distribution were good: 58.5%, intermediate: 29.2%, and poor: 12.3%. Previous therapies: >2: 40% (26). ORR was 94.6% (53/56). CR: 85.7%; CR according to previous disease: relapsed disease: 90% (27/30), refractory disease: 42.85% (3/7), consolidation with CR: 92.85% (13/14), and consolidation with PR: 100% (5/5). Global PR and NR were 8.9% (5) and 5.3% (3), respectively. Mean OS 63.86 months with a mean follow-up time of 57 months (2–73). Mean TTP: 52.65 months (95% CI: 43.83–61.48). Median OS and TTP were not achieved. No hospital submissions or deaths were registered. Conclusions. This study confirms the safety and high efficacy of 90Y-IT in F-NHL patients, RIT in early stage of disease could improve outcomes.

Rituximab Resistant Follicular Lymphoma: Predictors of Rituximab Resistance, Incidence of Transformation and Prognosis

Abstract 4981Follicular lymphoma (FL) is an indolent lymphoma characterized by slow growth, initial response to treatment with inevitable relapse. Recent trials have demonstrated improved progression free survival (PFS) with rituximab-containing induction, maintenance rituximab (MR) or both. However, a small subset of patients (pts) will show disease progression during the induction or maintenance phase. We evaluated rituximab resistance (RR) including incidence, predictors, rate of transformation and prognosis for pts demonstrating RR. We defined RR as disease progression during induction, maintenance or within 6 months of last dose of rituximab.We retrospectively identified pts who received rituximab for symptomatic FL from July 2006 to April 2010 at 2 regional cancer centres. Those with a diagnosis of FL grades 1, 2 or 3a with first exposure to rituximab (induction, maintenance or both) were included. Exclusion criteria included FL grade 3b and previous rituximab exposure. Progression was ascertained from clinical notes or radiological investigation as per IWG Criteria (1999). Transformation was defined by confirmatory biopsy and clinical suspicion of transformation was also recorded (nodal growth, rapid rise in LDH or new B symptoms). PFS and overall survival (OS) were measured from initiation of rituximab induction. Log-rank statistics were used to identify univariate predictors for RR and Cox regression for multivariate analysis with outcome as time to early progression (RR).Of the pts screened, 132 met inclusion criteria (112 pts receiving primary therapy, 20 for ≥ 2nd line therapy); 22 pts (16.7%) demonstrated RR. Incidence of RR was similar for pts receiving primary therapy (17.0%). Pt characteristics for rituximab sensitive (RS) and RR groups are shown in Table 1. From induction, median follow-up was 33 months (range 9 to 61 months). In univariate analysis, high risk FLIPI score at induction was predictive of RR (p = 0.002). Partial response to induction (p = 0.082) trended to significance. Other factors not predictive of RR included: age, gender, high grade histology (grade 3a), previous chemotherapy received, time from diagnosis to induction therapy and anthracycline-based induction. A Cox regression model was constructed with FLIPI score and anthracycline-based induction as covariates. FLIPI score was independently and significantly predictive of RR (HR 2.43; 95% CI, 1.4 to 4.1; p = 0.001). Of the 22 pts who were RR, 18 (81.8%) required subsequent chemotherapy with only 9 achieving at least a partial response. Ten pts (45.5%) required more than 1 line of chemotherapy post-progression with a median time to next line of therapy of 9 months (95% CI, 2.9 to 15.1; see figure). Among the RR pts, 5 (22.7%) showed evidence of transformation on biopsy at initial resistance and an additional 3 (13.6%) were clinically suspected. Within 12 months of resistance, a further 3 pts in the RR group demonstrated biopsy-proven transformation. Overall, 10 pts (45.5%) transformed (biopsy-proven) with no transformation in the RS group. During follow-up, 9 deaths occurred, all in those with RR, 5 following biopsy-proven transformation. The median PFS and OS in the RR group were 17 months and 47 months, respectively.Table 1CharacteristicsRS (n = 110)RR (n = 22)Age (MEAN)58.958.9Gender (females)43.6%40.9%High histological grade (3a)8.4%9.1%Previous treatment (yes)15.5%13.6%Alkylator11.8%13.6%Number of lines of previous treatment >14.5%4.5%Mean time from diagnosis to induction (months)30.328.1Induction chemoR-CVP based78.2%86.4%R-CHOP based18.2%9.1%Other3.6%4.5%Response to inductionPR77.3%72.7%CRu12.7%0%CR10.0%4.5%SD/PD0%22.7%FLIPI score at inductionLow (0, 1, 2)57.8%18.2%Intermediate (3)26.6%40.9%High (4 or 5)15.6%40.9%Stage 3 or 488.2%100%High tumor burden at diagnosis (GELF criteria)43.6%40.9%We demonstrated that the incidence of rituximab resistance in FL on first exposure to rituximab in our population was 16.7%. FLIPI score was predictive for RR and was independent of anthracycline-based induction regimens. Pts with RR had a high rate of histologic transformation (36.3% within 12 months post RR) and a shorter PFS/OS with a poor response to next therapy. Biopsies to confirm transformation should be performed in all pts demonstrating RR, and new therapies are needed for this group of pts. [Display omitted] Disclosures:Crump:Ortho Johnson & Johnson: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Millennium Pharmaceuticals: Consultancy, Membership on an entity’s Board of Directors or advisory committees. Kukreti:Celgene: Honoraria; Ortho Biotech: Honoraria; Roche: Honoraria.