Advanced Stage Follicular Lymphoma Research Articles

18-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography in the Management of Aggressive Non-Hodgkin's B-Cell Lymphoma

18-Fluorodeoxyglucose (FDG-PET/CT) is an established imaging modality that has been proven to be of benefit in the management of aggressive B-cell non-Hodgkin's lymphoma, such as diffuse large B-cell lymphoma and advanced stage follicular lymphoma. The combination of anatomic and functional imaging afforded by FDG-PET/CT has led to superior sensitivity and specificity in the primary staging, restaging, and assessment of response to treatment of hematological malignancies when compared to FDG-PET and CT alone. The use of FDG-PET/CT for posttreatment surveillance imaging remains controversial, and further study is needed to ascertain whether this modality is cost effective and appropriate for use in this setting.

Follicular Lymphoma: To Treat or Not to Treat Is No Longer the Question

Follicular lymphoma arises from germinal center B cells and is the most common indolent non-Hodgkin lymphoma (1). It has a widely variable clinical course but nearly always presents as advanced disease with asymptomatic lymphadenopathy and has a long median overall survival of 8-10 years or more (2). Treatment before the onset of symptoms or organ dysfunction related to disease progression has not been proven to improve disease-specific survival or overall survival (OS), although early treatment may result in higher complete response rates and may prevent prognos- tically significant histological progression (3,4). However, the introduction of rituximab as a therapy for this disease has changed the landscape of this debate (5). When treatment is indicated, a variety of combination chemotherapeutic regimens have proven efficacy, and although some result in improvements in progression- free (PFS) and event-free survival (EFS), none are superior with respect to OS. The addition of rituximab to these regimens, how- ever, has resulted in a statistically significant improvement in OS in this disease (6-9). Response rates to chemoimmunotherapy are high, but this disease remains, for the most part, incurable and will, with rare exception, relapse. Further attempts to improve PFS and OS have included maintenance therapy with rituximab or con- solidation high-dose chemotherapy with autologous stem cell transplant (HDC-ASCT) (10-15). In this issue of the Journal, Al Khabori et al. (16) report the results of a meta-analysis exploring the efficacy and toxicity of HDC-ASCT compared with conventional-dose chemotherapy or chemoimmunotherapy in patients with untreated, advanced-stage follicular lymphoma. Four studies, including 941 patients with a median follow-up of 5-9 years, were identified that met the eligibility criteria; and data regarding OS, EFS, treatment-related mortality, myelodysplastic syndrome (MDS)/acute myelogenous leukemia (AML), and secondary malignancies were abstracted (12-15). Only one of these studies included rituximab in both arms (15). There was no difference in OS between HDC-ASCT and con- ventionally treated patients, but EFS was statistically significantly improved following HDC-ASCT compared with conventional treatment. Treatment-related mortality and the rates of sec- ondary solid tumor malignancies were not different between the two arms. The rate of MDS/AML was somewhat higher following HDC-ASCT, although the difference was not statisti- cally significant. In these prospective randomized controlled trials, the 4- to 7-year EFS and OS ranged from 38% to 61% and 76% to 84%, respectively, and were similar whether or not rituximab was part of the therapy in each arm. An EFS benefit despite the absence of an improvement in OS is not insignificant in a disease with a long clinical course, as time off therapy may have an important impact on personal productivity and quality of life. However, the lack of OS benefit seen following HDC-ASCT in untreated patients has often been attributed, in part, to an increased rate of sec- ondary MDS/AML and solid tumors, which have been reported to be as high as 16%-21% at 10 years following total body irradiation-containing regimens (17,18). The lower rate of both secondary MDS/AML (4%) and solid tumors (5%) following HDC-ASCT observed in this meta-analysis may be a reflection of conditioning regimens, as two of the four studies did not include total body irradiation, or it may reflect abbreviated follow-up. An investigation into the efficacy of HDC-ASCT in untreated follicular lymphoma is timely in light of the recent data showing the efficacy of maintenance rituximab in the ECOG1496 and PRIMA trials (10,11). The results of the studies included in this meta-analysis are similar to the 3-year PFS of 68%-75% seen in these two trials of maintenance rituximab. Given the risk of sec- ondary MDS/AML and solid tumors following HDC-ASCT and

Examining the Outcomes of Watchful Waiting (WW) Among US Patients with Advanced Stage Follicular Lymphoma (FL)

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.

Brief Chemoimmunotherapy R-FND with Rituximab Consolidation Followed by Randomization Between Rituximab Maintenance Vs. Observation As First Line Treatment in Elderly Patients with Advanced Follicular Lymphoma (FL): Final Results of a Prospective Randomized Trial by Italian Lymphoma Foundation (FIL)

Abstract 777Introduction. Fludarabine containing regimens are effective in FL; the role of Rituximab (R) maintenance has been established recently. Aim of the study was to investigate efficacy and safety of R-maintenance vs. observation in elderly FL patients who respond to a brief chemo-immunotherapy with four courses of R-FND + four doses of Rituximab as consolidation. Methods. From January 2004 to December 2007, elderly patients (age 60–75) with untreated advanced stage FL who required treatment, were enrolled by 33 FIL centers. Treatment plan was: four courses of R-FND (standard doses of Rituximab, Fludarabine, Mitoxantrone, Dexamethasone) every 28 days followed by four weekly Rituximab infusions as consolidation; responding (Complete Response, CR + CRu + Partial Response, PR) patients were randomized between a short Rituximab maintenance with a single dose every two months for a total of four doses (Arm A) or observation (Arm B). Qualitative and quantitative PCR monitoring for IgH/Bcl-2 rearrangement on bone marrow (BM) was performed at diagnosis, after R-FND and R consolidation and during maintenance/observation. Results. 242 patients were enrolled at diagnosis in the study and 234 were eligible for treatment: median age was 66 yrs; advanced stage II 14%, stage III 21% and stage IV 65%; BM involvement and B symptoms were documented in 55% and 18% respectively. According to FLIPI risk patients were: Low 11%, Intermediate 34%, High 55%. According to Comprehensive Geriatric Assessment (CGA), concomitant illness were: one in 38% and greater than or equal to two in 23% of patients. Qualitative PCR analysis for IgH/Bcl-2, performed in 223 patients at diagnosis, was positive in 49%. Two hundred and two (86%) patients completed the induction treatment and were randomized between maintenance or observation; 32 were not because of stable/progressive disease (15), adverse events (nine) or other causes (eight). At the end of chemoimmunoterapy and consolidation overall response rate was 86% with 68% CR and 18% PR. After four courses of chemo-immunotherapy, 90 patients were in PR of whom 37 (41%) were converted to CR with the addition of Rituximab consolidation. As regard to Bcl2 analysis, PCR negativity was detected in 61% after R-FND and increased to 73% after R consolidation. With a median follow-up of 33 months, two-years Overall Survival and Progression Free Survival (PFS) were 93% (95% CI 92%–97%) and 77% (95% CI 71%–93%), respectively. Two-years PFS according to maintenance/observation phase was: 80% vs 68% (p.225), Figure 1. Two-years PFS rates according to FLIPI score were 87% for low/intermediate risk and 70% for high risk (p < 0.0001). A total of 1119 courses were delivered; the most frequent CTC grade 3–4 toxicity was neutropenia in 25% of the courses, with only 13 events of serious infections. Two toxic deaths during treatment (0.8%) occurred: 1 HBV reactivation and 1 Steven Johnson syndrome. In the maintenance/observation phase the following severe (WHO grade 3–4) toxicities were recorded: 15 patients experienced neutropenia, 8 cardiac events, 4 infections; no other relevant toxicities were recorded. Second malignancy were recorded in 11 patients. Conclusions. a short term chemo-immunotherapy R-FND + Rituximab consolidation is able to achieve high CR rate and a good two-years PFS in elderly FL patients. Good results were also observed in higk-risk FLIPI score. Two-years PFS of 80% in patients randomized to R maintenance was promising although there was no statistical difference compared to observation. This finding may be attributed to the relatively short follow-up or to the choice of a short course of Rituximab maintenance (only four doses) or both. [Display omitted] Disclosures:Vitolo:Jannsen-Cilag: Speakers Bureau; Celgene: Speakers Bureau; Roche Italy: Speakers Bureau. Off Label Use: The study includes use of Rituximab as maintenance in responding patients after first line chemoimmunotherapy. Gamba:Roche Italia: Employment. Supekar:Roche Italia: Employment.

A Phase III Randomized Intergroup Trial (SWOG S0016) of CHOP Chemotherapy Plus Rituximab Vs. CHOP Chemotherapy Plus Iodine-131-Tositumomab for the Treatment of Newly Diagnosed Follicular Non-Hodgkin's Lymphoma

Abstract 98▪▪This icon denotes a clinically relevant abstract Background:Advanced follicular lymphomas (FL) are incurable with conventional chemotherapy and there is no consensus on the best treatment approach. The SWOG cancer research cooperative group and Cancer and Leukemia Group B (CALGB) compared the safety and efficacy of two immunochemotherapy regimens for FL in a Phase III randomized intergroup protocol (S0016) that enrolled 554 patients with previously untreated, advanced stage FL between 3/1/2001 and 9/15/2008. Methods:Pts were eligible if they had advanced stage (bulky stage II, III or IV) evaluable FL of any grade (1, 2, or 3) and had not received any prior therapy. In one arm (CHOP-R), patients received 6 cycles of CHOP chemotherapy (750 mg/m2 cyclophosphamide, 50 mg/m2 doxorubicin, 1.4 mg/m2 vincristine, and 100 mg prednisone daily for 5 days) at 3 week intervals with 6 doses of rituximab anti-CD20 antibody (375 mg/m2 on days 1, 6, 48, 90, 134 and 141 according to the schedule described by Czuczman et al.[J.Clin.Oncol 17:268, 1999]). In the second arm of the protocol, patients received 6 cycles of CHOP, followed by a dosimetric infusion of tositumomab/iodine I-131 tositumomab and then 1–2 weeks later a therapeutic infusion of I-131-tositumomab labeled with sufficient I-131 (median 85 mCi) to deliver a total body dose of 75 cGy (CHOP-RIT). The study was designed to have 86% power to detect a hazard ratio (HR) of CHOP-RIT to CHOP-R of 0.67 for 2 yr PFS based on a one-sided.021 level test (accounting for 3 interim analyses). Results:Of the 554 enrolled pts, 532 were eligible and 526 were evaluable for toxicity (263 on each arm of the protocol). Pt characteristics (age, sex, race, stage, beta 2 microglobulin level, tumor bulk, B symptoms) were well-balanced in the two arms of the protocol. In general, both regimens were well-tolerated (Table I). Median follow-up time among patients still alive is 4.9 years. One hundred and six of 267 eligible pts on the CHOP-R arm have progressed or died compared to 86 of 265 eligible pts on the CHOP-RIT arm. The 2 year estimate of PFS was 76% on the CHOP-R arm and 80% on the CHOP-RIT arm (Figure 1). In multivariate Cox regression adjusting for the stratification factor (serum beta-2 microglobulin level), the hazard ratio for CHOP-RIT vs. CHOP-R was 0.79 (95% CI: 0.60–1.05, p=.11 [2-sided] or p=.06 [1-sided]). Twenty-six of 267 pts on the CHOP-R arm have died compared to 40 of 265 eligible pts on the CHOP-RIT arm. The 2-year estimate of overall survival was 97% on the CHOP-R arm and 93% on the CHOP-RIT arm. In multivariate Cox regression adjusting for the stratification factor serum beta-2 microglobulin, the hazard ratio for CHOP-RIT vs. CHOP-R was 1.55 (95% CI: 0.95–2.54, p=.08 [2-sided]). [Display omitted] Table I:Toxicity and Efficacy of Treatment Arms on Protocol S0016CHOP-RCHOP-RITP ValuesEvaluable for toxicityN = 263N = 263Grade 4 HematologicToxicity94 (36%)79 (30%).19Grade 4 Non-Hematologic Toxicity4 (1.5%)5 (1.9%)1.0Treatment Related Mortality1 (0.4%)4 (1.5%).37Second Malignancies23 (8.7%)22 (8.3%)1.0AML/MDS3 (1.1%)7 (2.7%).34Evaluable for responseN=263N=260Overall Response Rate (CR + PR)224 (85%)223 (86%).90Complete Response Rate (including unconfirmed CR)108 (41%)120 (46%).25Response Assessment not possible (missing data)27 (10%)22 (8%).55Assessed for SurvivalN=267N=2652 Yr Progression Free Survival (PFS)76%80%p = 0.11 (2-sided)HR=0.79 (95% CI: 0.60–1.05)2 Yr Overall Survival (OS)97%93%p =0.08 (2-sided)HR=1.55 (95% CI: 0.95–2.54) Conclusion:No statistically significant differences in PFS, OS, or serious toxicities are yet demonstrable with either regimen administered in this trial. However, PFS and OS are outstanding with either of the two regimens with median times to progression not yet reached for either treatment. Future studies will be needed to assess whether combining CHOP-R with RIT consolidation and with maintenance rituximab will confer additive benefit, as being evaluated in a follow-up trial (SWOG protocol S0801) that has recently completed accrual. Disclosures:Press:Spectrum: Consultancy, Honoraria; Roche/Genentech: Consultancy, Honoraria, Research Funding. Off Label Use: Front-line use of I-131-tositumomab for consolidation therapy in 1st remission of follicular lymphoma. Friedberg:Genentech: Consultancy, Honoraria. Czuczman:Glaxo Smith Kline: Consultancy, Research Funding; Genentech: Consultancy, Honoraria. Kaminski:Glaxo Smith Kline: Patents & Royalties. Maloney:Genentech/Roche: Consultancy, Honoraria, Speakers Bureau; Glaxo Smith Kline: Consultancy, Honoraria, Speakers Bureau. Cheson:Glaxo Smith Kline: Research Funding. Fisher:Roche: Consultancy, Honoraria.

Maximum Standard Uptake Value (SUVmax) on FDG-PET Imaging Predicts Time to First Treatment in Patients with Low Grade Follicular Lymphoma,

Abstract 4204 Introduction:Most patients with asymptomatic advanced-stage low grade follicular lymphoma (FL) are managed by a ”watch and wait” strategy until they develop disease related symptoms or significant progression in tumor volume. The median time to first treatment (TFT) has been reported to be about 30 months from initial diagnosis (Ardeshna et al., Lancet 2003; 362: 516–22). Various prognostic factors such as FLIPI have been developed to estimate progression free survival and overall survival, but predictors for TFT from diagnosis have not been well defined in this population. The optimal frequency of follow-up and surveillance imaging remains unclear. Methods:We reviewed our institutional database of FL patients who underwent [18F]-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) or FDG-PET imaging at diagnosis or as part of follow-up imaging during the ”watch and wait” period. Only patients with FL with low grade histologies (grade 1 or 2) on tissue biopsy who were untreated prior to FDG-PET imaging and with a minimum of 6 months of follow-up after the imaging were included in the analysis. SUVmax was defined as the highest lesional SUV on each scan and was determined by a nuclear medicine physician. ROC curve analysis was used to identify SUVmax cutoff values which would best predict short (≤ 6 months) vs. long (> 6 months) TFT with clinically relevant sensitivity and specificity for a training set of patients. The SUVmax cutoff value was then tested in another set of patients for the ability to categorize patients by TFT ≤ 6 months vs. > 6 months from imaging. Comparison between the two groups was performed using the Fisher’s exact test. STATA 10.1 software was utilized for data analysis. Results:78 FL patients followed in our institution from 2001 until 2011 were included in the study. In the training set of 27 patients (median age 52 years, range 19–67), the ROC curve analysis revealed that an SUVmax cutoff at 10 could distinguish between those with TFT ≤ 6 months vs. > 6 months. When applied to the test set of 51 patients (median age 53, range 18–82), an SUVmax ≥ 10 was able to predict short TFT correctly in 14 out of 16 patients who required treatment ≤ 6 months from the FDG-PET or FDG-PET/CT scan (positive predictive value of 88%). SUVmax ≥ 10 had a high specificity in the test set (90%), but limited sensitivity (47%). A Fisher’s exact test (two sided) confirmed that the association between SUVmax ≥ 10 and short vs. long TFT groups was statistically significant (p=0.006). Conclusion:SUVmax ≥ 10 on FDG-PET or FDG-PET/CT imaging in patients with low grade FL can be used to identify those who will have a short TFT. An SUVmax cutoff at 10 could be an important factor in determining the frequency of clinical and imaging follow-up in asymptomatic, advanced-stage low grade FL patients who are managed by a ”watch and wait” strategy. Disclosures:No relevant conflicts of interest to declare.

Fractionated 90y Ibritumomab Tiuxetan (Zevalin™) Radioimmunotherapy As An Initial Therapy of Follicular Lymphoma – First Results From a Phase II Study in Patients Requiring Treatment According to GELF/BNLI Criteria

Abstract 102 Background:Radioimmunotherapy (RIT) has proven to be highly active in relapsed follicular lymphoma (FL) and the best single agent efficacy results in frontline therapy of FL were obtained with Iodine-131 Tositumomab (Bexxar™) (Kaminski et al NEJM 2005); albeit half of the patients had low tumor burden. In patients with higher tumor burden, using more than one fraction of RIT increases the overall radiation dose over that of a single fraction of treatment, thereby potentially improving both the response rates and survival (Illidge et al, Blood 2009). Methods:We conducted an international, multicenter phase 2 trial to evaluate the efficacy and toxicity of Fractionated 90Y Ibritumomab tiuxetan (Zevalin™) RIT as an initial therapy of Follicular Lymphoma. Eligible patients had untreated follicular lymphoma (grade 1, 2, or 3a) and at least one criterion of high tumour burden - one lymphoma lesion greater than 7 cm or three separate nodes of 3 cm or more; symptomatic splenic enlargement; raised serum concentrations of either lactate dehydrogenase or β2-microglobulin; compressive syndrome; or the presence of B symptoms. Treatment consisted of two doses of 90Y-ibritumomab tiuxetan (11.1 MBq/kg) given 8–12 weeks apart. Patients with greater than 20% bone marrow involvement (BM) with lymphoma received 4 weekly infusions Rituximab (375 mg/m2) and proceeded to fractionated RIT only if a repeat BM biopsy demonstrated clearing of lymphoma with less than or equal to 20% involvement. The primary endpoint was end of treatment response (EOR) of the intent-to-treat (ITT) population according to IWC 1999, assessed 12 weeks after last 90Y Ibritumomab tiuxetan infusion (21 weeks after treatment start). Secondary objectives were safety and progression free survival (PFS). Results:74 patients with a median age of 61 years (28−80), including 58 (78%) with stage III–IV stage, 23 (31%) intermediate risk FLIPI 2 and 34 (46%) with high risk FLIPI 3–5; were included between June 2007 and June 2010 in 7 centres. Thirteen (18%) patients with >20% BM involvement required rituximab pre-treatment, 2/74 did not qualify for RIT, meaning 72 received the first 90Y Ibritumomab tiuxetan infusion and 55 (76%) completed the full treatment schedule. The 2nd infusion of RIT was withheld secondary to hematologic toxicity with 1st infusion (n=12, 17%) or human anti murine antibodies positive testing (n = 4; 5.6%) or other (n = 1, 1.4%). Two out of 72 patients did not have recorded response data and the EOR was 95.7% (67/70) with CR/CRu of 57.1% (40/71). Six patients subsequently improved response making an ORR of 97.1% (68/70) (95% CI 90.0% – 99.7%), and CR/CRu of 64.3%% (45/70) (95% CI 51.9% – 75.4%). For the subset of 17 patients who only received a single 90Y Ibritumomab tiuxetan infusion, ORR (CR/CRu) was 100% (76,5%). At a median follow-up of 1.52 years (range 0.13 – 3.69 years) the PFS is 67 %, 20 patients have progressed and 12 of these have required further treatment (8 chemotherapy, 2 radiotherapy, 2 other). Updated data with median follow-up of more than 2 years will be presented.Ten patients experienced at least one SAE during the treatment period, with 3 related to study treatment (one case of rigors associated with the first infusion of rituximab and 2 cases of neutropenic sepsis both associated with the second RIT dose. The most common toxicity was hematologic: after the first 90Y Ibritumomab tiuxetan dose, related G3-4 hematological AEs were transient neutropenia (20.8%, 18 days median duration) and thrombocytopenia (20.8%; 20 days median duration). After the second 90Y Ibritumomab tiuxetan dose, related G3-4 hematological AEs increased to 36.4% for neutropenia (31days median duration), 14% for anemia (8/55 required transfusion) and 56.4% for thrombocytopenia (40 days median duration). There has been one case of MDS diagnosed 26 months after treatment and one death due to metastatic breast cancer diagnosed 9 months post last dose of 90Y Ibritumomab tiuxetan Conclusion:Fractionated RIT using 90Y-ibritumomab tiuxetan is an effective frontline treatment of advanced-stage follicular lymphoma in patients with high tumor burden requiring treatment and delivers high response rates. The treatment was well tolerated by patients with few infectious episodes and AE's and manageable hematologic toxicity. Disclosures:Illidge:Bayer Schering Pharma: Honoraria, Research Funding, Speakers Bureau. Morschhauser:Roche: Consultancy, Honoraria.

Denileukin diftitox in combination with rituximab for previously untreated follicular B-cell non-Hodgkin's lymphoma

Follicular lymphoma exhibits intratumoral infiltration by non-malignant T lymphocytes inluding CD4+CD25+ regulatory T (Treg) cells. We combined denileukin diftitox with rituximab in previously untreated, advanced-stage follicular lymphoma patients anticipating that denileukin diftitox would deplete CD25+ Treg cells while rituximab would deplete malignant B-cells. Patients received rituximab 375 mg/m2 weekly for 4 weeks and denileukin diftitox 18 mcg/kg/day for 5 days every 3 weeks for 4 cycles; neither agent was given as maintenance therapy. Between August 2008 and March 2010, 24 patients were enrolled. One patient died before treatment was given and was not included in the analysis. Eleven of 23 patients (48%; 95% CI: 27–69%) responded; 2 (9%) had complete responses and 9 (39%) had partial responses. The progression-free rate at 2 years was 55% (95%CI: 37–82%). Thirteen patients (57%) experienced grade ≥3 adverse events and 1 patient (4%) died. In correlative studies, soluble CD25 and the number of CD25+ T-cells decreased after treatment, however there was a compensatory increase in IL-15 and IP-10. We conclude that while the addition of denileukin diftitox to rituximab decreased the number of CD25+ T-cells, denileukin diftitox contributed to the toxicity of the combination without an improvement in response rate or time to progression.

Newly diagnosed and relapsed follicular lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Newly diagnosed and relapsed follicular lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Bortezomib Added to R-CVP Is Safe and Effective for Previously Untreated Advanced-Stage Follicular Lymphoma: A Phase II Study by the National Cancer Institute of Canada Clinical Trials Group

Bortezomib has demonstrated promising activity in patients with follicular lymphoma (FL). This is the first study to evaluate the safety and efficacy of bortezomib added to rituximab, cyclophosphamide, vincristine, and prednisone (R-CVP) in previously untreated advanced-stage FL. This is a phase II multicenter trial adding bortezomib (1.3 mg/m(2) days 1 and 8) to standard-dose R-CVP (BR-CVP) for up to eight cycles in patients with newly diagnosed stage III/IV FL requiring therapy. Two co-primary end points, complete response rate (complete response [CR]/CR unconfirmed [CRu]) and incidence of grade 3 or 4 neurotoxicity, were assessed. Between December 2006 and March 2009, 94 patients were treated with BR-CVP. Median patient age was 57 years (range, 29 to 84 years), and the majority had a high (47%) or intermediate (43%) Follicular Lymphoma International Prognostic Index score. BR-CVP was extremely well tolerated, with 90% of patients completing the intended eight cycles. No patients developed grade 4 neurotoxicity, and only five of 94 patients (5%; 95% CI, 0.8% to 9.9%) developed grade 3 neurotoxicity, which was largely reversible. On the basis of an intention-to-treat analysis, 46 of 94 patients (49%; 95% CI, 38.8% to 59.0%) achieved a CR/CRu, and 32 of 94 patients (34%) achieved a partial response, for an overall response rate of 83% (95% CI, 75.4% to 90.6%). The addition of bortezomib to standard-dose R-CVP for advanced-stage FL is feasible and well tolerated with minimal additional toxicity. The complete response rate in this high-risk population compares favorably to historical results of patients receiving R-CVP. Given these results, a phase III trial comparing BR-CVP with R-CVP is planned.

Vaccination With Patient-Specific Tumor-Derived Antigen in First Remission Improves Disease-Free Survival in Follicular Lymphoma

Vaccination with hybridoma-derived autologous tumor immunoglobulin (Ig) idiotype (Id) conjugated to keyhole limpet hemocyanin (KLH) and administered with granulocyte-monocyte colony-stimulating factor (GM-CSF) induces follicular lymphoma (FL) -specific immune responses. To determine the clinical benefit of this vaccine, we conducted a double-blind multicenter controlled phase III trial. Treatment-naive patients with advanced stage FL achieving complete response (CR) or CR unconfirmed (CRu) after chemotherapy were randomly assigned two to one to receive either Id vaccine (Id-KLH + GM-CSF) or control (KLH + GM-CSF). Primary efficacy end points were disease-free survival (DFS) for all randomly assigned patients and DFS for randomly assigned patients receiving at least one dose of Id vaccine or control. Of 234 patients enrolled, 177 (81%) achieved CR/CRu after chemotherapy and were randomly assigned. For 177 randomly assigned patients, including 60 patients not vaccinated because of relapse (n = 55) or other reasons (n = 5), median DFS between Id-vaccine and control arms was 23.0 versus 20.6 months, respectively (hazard ratio [HR], 0.81; 95% CI, 0.56 to 1.16; P = .256). For 117 patients who received Id vaccine (n = 76) or control (n = 41), median DFS after randomization was 44.2 months for Id-vaccine arm versus 30.6 months for control arm (HR, 0.62; 95% CI, 0.39 to 0.99; P = .047) at median follow-up of 56.6 months (range, 12.6 to 89.3 months). In an unplanned subgroup analysis, median DFS was significantly prolonged for patients receiving IgM-Id (52.9 v 28.7 months; P = .001) but not IgG-Id vaccine (35.1 v 32.4 months; P = .807) compared with isotype-matched control-treated patients. Vaccination with patient-specific hybridoma-derived Id vaccine after chemotherapy-induced CR/CRu may prolong DFS in patients with FL. Vaccine isotype may affect clinical outcome and explain differing results between this and other controlled Id-vaccine trials.

Management Options for Follicular Lymphoma: Observe; R-CHOP; B-R; Others?

Treatment results are improving for patients who have advanced-stage follicular lymphoma; this progress is in large part related to the inclusion of anti-CD20 monoclonal antibody therapy in front-line therapy programs. Rituximab has been combined successfully in chemo-immunotherapy regimens with several standard chemotherapy combinations, and with bendamustine. Post-remission treatment strategies, including radioimmuotherapy consolidation and rituximab maintenance, have had a favorable impact on duration of remission. Thus, although traditional palliative strategies can still have a role in many situations, such approaches must now be placed in perspective with options that have the potential to achieve durable disease control. Recent therapeutic advances have renewed the hope that potentially curative treatment options may be forthcoming for these patients.

Improving the treatment outcome in follicular lymphoma using rituximab maintenance

Follicular lymphoma (FL) is the second most frequent lymphoma, representing approximately 70% of all indolent lymphomas and approximately 20% of all nonHodgkin’s lymphomas (NHLs) in adults [1]. Patients with FL usually have a long overall survival (OS) time, but disease progression typically occurs 3–5 years after initiation of treatment. There is no commonly accepted standard frontline therapy for FL patients. For several years a broad range of therapeutic options were available; however, historical studies did not show a survival benefit of one particular regimen. The real progress in FL treatment has been made after the introduction of immunochemotherapy with rituximab, an anti-CD20 monoclonal antibody. The CD20 antigen is expressed on the surface of both normal and NHL B-cells, although it is in especially high density on FL tumor cells [2]. The addition of rituximab to standard polychemotherapy regimens such as cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) or cyclophosphamide, vincristine and prednisone (CVP), resulted in a significant increase in overall response (OR), complete response (CR) and time-to-progression (TTP) rates in FL [3–6]. In a study conducted by Hiddemann et al., 428 patients with untreated, advanced-stage FL were randomly assigned to therapy with CHOP alone or CHOP combined with rituximab (R-CHOP) [7]. R-CHOP reduced the relative risk for treatment failure by 60% and significantly prolonged TTP (p < 0.001). In addition, patients treated with R-CHOP had a significantly higher OR rate (96 vs 90%; p = 0.011) and prolonged time of remission (p = 0.001), as well as superior OS (p = 0.016). In a large, randomized, multicenter study, the combination of rituximab with a CVP regimen (R-CVP) resulted in a significant increase in both OR and CR rates compared with patients treated with CVP alone (81 and 41 vs 57 and 10%, respectively; p < 0.0001) [8]. According to the current recommendations, immunochemotherapy with rituximab used in combination with CVP or CHOP regimens, but also with purine nucleoside analog-based schemes or bendamustine, should be applied in FL patients with progressive, symptomatic disease [9]. However, despite distinct progress in FL treatment, the disease still remains incurable. Different maintenance regimens were assessed to provide means for improving progression-free survival (PFS) and OS of indolent NHL patients. Numerous randomized trials examined the benefit of IFN-a consolidation or maintenance therapies for indolent NHL, including FL [10,11]. In the Southwest Oncology Group (SWOG) study, 279 indolent lymphoma patients in advanced clinical stage III and IV, who responded to the induction treatment with prednisone, methotrexate, doxorubicin, cyclophosphamide, etoposide, mechlorethamine, vincristine and procarbazine (ProMACE-MOPP), were randomly assigned either to consolidation with IFN-a or to the observation “...maintenance treatment with rituximab should be considered for all [follicular lymphoma] patients responding to first-line therapy, as a new standard of care in previously untreated [follicular lymphoma] patients.”

90Y-Ibritumomab Tiuxetan (Zevalin®) Consolidation of First Remission In Advanced-Stage Follicular Non-Hodgkin's Lymphoma: Updated Results After a Median Follow-up of 66.2 Months From the International, Randomized, Phase III First-Line Indolent Trial (FIT) In 414 Patients

AbstractAbstract 594The FIT trial was conducted to evaluate the safety and efficacy of 90Y-ibritumomab tiuxetan (0.4 mCi/kg; maximum dose 32 mCi) when used as consolidation of first complete or partial remission in patients with previously untreated, advanced-stage follicular lymphoma (FL). Patients were randomly assigned to either 90Y-ibritumomab treatment (n = 207) or observation (n = 202) within 3 months (mo) of completing initial induction therapy (chemotherapy only: 86%; rituximab in combination with chemotherapy: 14%). Response status prior to randomization did not differ between the groups: 52% complete response (CR)/CR unconfirmed (CRu) to induction therapy and 48% partial response (PR) in the 90Y-ibritumomab arm vs 53% CR/CRu and 44% PR in the control arm. The primary endpoint was progression-free survival (PFS) of the intent-to-treat (ITT) population. Results from the first extended follow-up after a median of 3.5 years revealed a significant improvement in PFS from the time of randomization with 90Y-ibritumomab consolidation compared with control (36.5 vs 13.3 mo, respectively; P < 0.0001; Morschhauser et al. JCO. 2008; 26:5156-5164). Here we report a median follow-up of 66.2 mo (5.5 years). Five-year PFS was 47% in the 90Y-ibritumomab group and 29% in the control group (hazard ratio (HR) = 0.51, 95% CI 0.39–0.65; P < 0.0001). Median PFS in the 90Y-ibritumomab group was 49 mo vs 14 mo in the control group. In patients achieving a CR/CRu after induction, 5-year PFS was 57% in the 90Y-ibritumomab group, and the median had not yet been reached at 92 months, compared with a 43% 5-year PFS in the control group and a median of 31 mo (HR = 0.61, 95% CI 0.42–0.89). For patients in PR after induction, the 5-year PFS was 38% in the 90Y-ibritumomab group with a median PFS of 30 mo vs 14% in the control group with a median PFS of 6 mo (HR = 0.38, 95% CI 0.27–0.53). Patients who had received rituximab as part of induction treatment had a 5-year PFS of 64% in the 90Y-ibritumomab group and 48% in the control group (HR = 0.66, 95% CI 0.30–1.47). For all patients, time to next treatment (as calculated from the date of randomization) differed significantly between both groups; median not reached at 99 mo in the 90Y-ibritumomab group vs 35 mo in the control group (P < 0.0001). The majority of patients received rituximab-containing regimens when treated after progression (63/82 [77%] in the 90Y-ibritumomab group and 102/122 [84%] in the control group). Overall response rate to second-line treatment was 79% in the 90Y-ibritumomab group (57% CR/CRu and 22% PR) vs 78% in the control arm (59% CR/CRu, 19% PR). Five-year overall survival was not significantly different between the groups; 93% and 89% in the 90Y-ibritumomab and control groups, respectively (P = 0.561). To date, 40 patients have died; 18 in the 90Y-ibritumomab group and 22 in the control group. Secondary malignancies were diagnosed in 16 patients in the 90Y-ibritumomab arm vs 9 patients in the control arm (P = 0.19). There were 6 (3%) cases of myelodysplastic syndrome (MDS)/acute myelogenous leukemia (AML) in the 90Y-ibritumomab arm vs 1 MDS in the control arm (P = 0.063). In conclusion, this extended follow-up of the FIT trial confirms the benefit of 90Y-ibritumomab consolidation with a nearly 3 year advantage in median PFS. A significant 5-year PFS improvement was confirmed for patients with a CR/CRu or a PR after induction. Effective rescue treatment with rituximab-containing regimens may explain the observed no difference in overall survival between both patient groups who were – for the greater part – rituximab-naïve. Disclosures:Hagenbeek:Roche Global Advisory Board: Consultancy. Radford:Schering (May 2009): Honoraria, Membership on an entity's Board of Directors or advisory committees. Vitolo:Roche Italy: Membership on an entity's Board of Directors or advisory committees; Celgene Italy: Membership on an entity's Board of Directors or advisory committees. Soubeyran:Roche: Honoraria, Research Funding; Cephalon: Research Funding. Bischof Delaloye:Expert Statement (questions of reimbursement in Switzerland): Honoraria. Morschhauser:Roche: Honoraria, Paid expert testimony within the past 2 years; Bayer: Honoraria.

90Yttrium Ibritumomab Tiuxetan as First Line Treatment for Follicular Lymphoma. First Results from an International Phase II Clinical Trial

AbstractAbstract 593 Background:The international FIT Trial (ASH 2007) had shown that Radioimmunotherapy (RIT) with 90Yttrium Ibritumomab Tiuxetan (Zevalin®) significantly improves the remission rate in follicular lymphoma (FL) if given as consolidation after chemotherapy. Since high remission rates are achieved in combination with both mild and aggressive chemotherapy regimens we asked whether chemotherapy is needed at all before applying RIT. Methods:Previously untreated patients with follicular lymphoma Grade I-IIIA from 7 centers in Austria, Germany, Italy, and Sweden have entered a prospective phase II clinical trial. Patients received 90Yttrium Ibritumomab Tiuxetan at the standard single dose of 15 MBq/kg (0.4 mCi/kg). Only stage III and IV FL patients older than 50 y (as required by radiation safety agency) and with clinical need for treatment (tumor lesions increasing at least 50% in the last 6 months, B-Symptoms, bulky disease up to 10cm) were allowed to enter the protocol. The primary end point was the clinical and molecular remission rate six months after primary treatment with 90Yttrium Ibritumomab Tiuxetan. Secondary end points were time to progression as well as safety and tolerability of 90Yttrium Ibritumomab Tiuxetan. Results:59 of 60 planned patients have been recruited between July 2007 and June 2010. Treatment was well tolerated without severe acute toxicity and with only grade I-II adverse events. Hematological toxicity was modest: 24 patients exhibit Thrombocytopenia (in one case Grade 4, in 13 cases Grade 3) and Neutropenia, (Grade 3 in 13 cases, no grade 4), Anemia (only grade 1–2) was noticed in 5 patients, other side effects were grade 1 or 2. Febrile episodes were not observed after RIT.At the first follow-up 6 months after RIT 25 patients were in complete remission (45%) and 22 patients were in partial remission (40%) adding up to an ORR of 85%. One year after therapy, the response rate is 72% with 52% CR and 20% PR. Among the 33 patients who have reached a follow up of more than 18 months, 52% continue to stay in complete remission, 9% are still in partial remission while 36% of the patients progressed and are off study, either in observation or with a new treatment. At a median follow-up of 23 months the PFS is 17.9 months.2 Deaths occurred during observation time, both patients had been off study because of progressive disease: one patient died of progressive lymphoma after several lines of salvage chemotherapy, pancreas carcinoma was the cause of death in a further patient about 10 months after lymphoma progression. While 3 more cases of non-hematological cancers (colon adenocarcinoma, oral cavity squamous carcinoma, renal cancer) were recorded during the study, reevaluation of the CT scans done before RIT revealed in 2 of these patients lesions that were preexisting but missed or misinterpreted as lymphoma. In addition, the short latency between RIT and cancer diagnosis makes a causal relationship unlikely in the remaining two cases. Progression to high-grade lymphoma occurred in 3 patients so far.49% of the patients (n = 28/57) had evidence of BCL2-IgH translocation in peripheral blood and/or bone marrow by PCR analysis. Of 26 patients evaluated 6 months after treatment 19 have turned negative (molecular remission rate MR = 73%). 9 of these MR patients had only achieved partial remission at clinical evaluation, 3 of them achieved a complete remission later during observation while 3 progressed. Ancillary PET studies were performed in 2 centers including sequential evaluation after therapy. Preliminary evaluation suggests that positivity of PET predicts relapse before this becomes clinically evident. Conclusion:Radioimmunotherapy with 90Yttrium Ibritumomab Tiuxetan was very safe and well accepted by patients, it induces high percentages of both clinical and molecular responses when given as first line treatment to patients with advanced stage follicular lymphoma. Remission rates are similar to those achieved by standard chemoimmunotherapy protocols, but absence of infectious episodes and the limited severity of side effects compares extremely well with the toxicity of chemotherapy regimens. Duration of remission will be a crucial issue for final comparison. Our study suggests first line RIT as a valuable option, particularly for older and/or frail patients with FL in need of therapy. Disclosures:No relevant conflicts of interest to declare.

A Novel Cancer Vaccine Strategy In Previously Untreated Patients with Stage III/IV Follicular Lymphoma Generates Tumor-Reactive T Cells and Clinical Response

AbstractAbstract 1804 Introduction:Advanced stage follicular lymphoma (FL) cannot be cured by current conventional therapies. Treatment with idiotype cancer vaccines has thus far been disappointing, and is expensive and labor intensive. Hence, simpler principles for vaccinations that do not require production of patient-specific tumor antigens are warranted. We designed a novel strategy involving intratumoral injections of low-dose anti-CD20 antibody (Rituximab) and autologous dendritic cells (DC) in irradiated lymph nodes. The aim was to facilitate antigen up-take and presentation by DCs to T cells to achieve systemic anti-tumor responses in patients with FL. Method:Ten untreated patients with stage III/IV follicular lymphoma not in need of conventional therapy underwent standard work-up, including CT-scans, FDG PET/CT and bone marrow samples. Single tumor cells were frozen for later immunoassays. Apheresis was performed for isolation of monocytes subsequently cultured with IL-4 and GM-CSF for 5 days to generate immature dendritic cells (DC). The first 6 patients received a single 8 Gy dose of radiotherapy against an enlarged node on day 1, followed by intratumoral injections of DCs (1 × 108) and GM-CSF (50 μg) on days 3 and 4. The treatment was repeated against a different enlarged node after 6 weeks. Thereafter, the protocol was changed, and patients received intratumoral injections of a small dose of rituximab (5 mg) on days 1 and 3 in order to enhance ADCC, radiotherapy (8 Gy) on day 2 and intratumoral injections of DCs and GM-CSF sc on days 4 and 5. This therapy was then repeated after 2 and 4 weeks, targeting other lymph nodes. Follow-up included repeated PET/CT-scans, bone marrow sampling and preparation of peripheral blood mononuclear cells (PBMC) for later immune studies. Tumor-specific helper and cytotoxic T cell responses were monitored by flow cytometry after a 5-day co-culture of single tumor cells with autologous PBMC sampled before, and 2 and 4 months after, treatment. Proliferation was studied by incorporation of CFSE, whereas degranulation (CD107a/b) and interferon gamma release was measured following re-stimulation with tumor cells for 5h. Result:Ten patients with FL of a total of 20 planned for this study were treated so far. No adverse events were observed. Among the first 6 patients treated by the original strategy, two showed a systemic metabolic response by PET/CT and one of these had a good response by regular CT not qualifying for PR. The protocol was then modified as described above. The first patient treated by the new strategy that included intratumoral rituximab, had a systemic metabolic response by PET/CT after 2 and 4 months and was PET negative with a normal CT by 8 months (Figure 1). Another patient showed a systemic PET response at 2 and 4 months. Analysis of T cell responses against autologous tumor cells has been initiated and we have so far demonstrated a vigorous CD8 dominated T cell response, as assayed by proliferation, degranulation and cytokine production, in the patient who achieved a negative PET-scan at 8 months (Figure 2). In parallel with the metabolic response, the immune response became stronger during follow-up after treatment. One patient without clinical response was also analysed, and no immune response was demonstrated. Further analysis of immune responses in the other patients is on-going. Conclusion:The present strategy is a novel principle to generate T cell responses and clinical anti-tumor responses detected by PET/CT in FL. [Display omitted] [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Update on a Prospective Study Evaluating the Safety and Efficacy of Combination Therapy with Fludarabine, Mitoxantrone and Rituximab Followed by Yttrium-90 Ibritumomab Tiuxetan and Maintenance Rituximab as Front Line Therapy for Patients with Indolent Lymphomas

AbstractAbstract 3946 Background:The First Line Indolent Trial (FIT) recently reported the superiority of consolidation therapy with 90Y-ibritumomab tiuxetan (Zevalin) versus observation in patients with advanced stage follicular lymphoma (FL) after induction with chemotherapy. The benefit of rituximab maintenance has also been shown in indolent lymphomas. We report the updated results of a single institution phase II clinical trial using a combination of the above in indolent lymphomas, namely chemo-immunotherapy followed by radioimmunotherapy and rituximab maintenance. Patients and Method:Patients with previously untreated indolent lymphomas including FL and marginal zone lymphomas (MZL), age ≥ 18, PS 0–2, measurable disease, with adequate bone marrow, liver and kidney function were eligible. Previous treatment with rituximab alone was allowed. Initial treatment consisted of 4–6 cycles of FM (fludarabine 25 mg/m2 on days 1–3, mitoxantrone 12 mg/m2 on day 1 of each 28-day cycle). The protocol was amended after enrolling the first four patients to include rituximab 375 mg/m2 on day 1 of each cycle. After 6 to 8 weeks, responding patients received Zevalin followed by maintenance rituximab (375 mg/m2 weekly × 4, repeated every 6 months for 2 years). Results:22 patients were enrolled between July 2003 and May 2007. The median age was 55 years (range 32–79 years). 11 patients were men. One patient had stage II, 7 had stage III, and 14 had stage IV disease. 20 patients had FL and 2 had MZL. In the FL group, 18 (90%) patients were intermediate or high risk. All but one patient had 4 or more cycles of chemotherapy with an ORR of 100%, a CR of 45% (n=10), a PR of 50% (n=11) and stable disease in one patient. 19 patients underwent therapy with Zevalin. With Zevalin, 6 patients with PR post chemotherapy converted to CR, resulting in an improved CR of 79% (n=15) and a PR of 21% (n=4). Of the 19 patients that underwent Zevalin, 16 proceeded to rituximab maintenance. Of those excluded from rituximab maintenance, one patient refused maintenance, one had prolonged cytopenias after Zevalin and one transformed to DLBCL just prior to rituximab maintenance, requiring alternative treatment. The decision was made to give rituximab maintenance on a different schedule at 375 mg/m2, 1 dose every 3 months, to 2 patients for mild cytopenias. With rituximab maintenance, 2 patients in PR converted to CR. All patients who received chemotherapy and Zevalin were included in the survival analysis (n=19). At a median follow up of 47.7 months, median PFS was 47.2 months and median OS was not reached. 7 patients relapsed and 1 patient transformed to DLBCL, with 6 patients requiring alternative treatment. 3 of these relapses occurred while on rituximab maintenance and one occurred 2 months after receiving Zevalin prior to the initiation of immunotherapy maintenance. Of all relapses/transformations, 2 patients are deceased. In the remainder of patients, 4 (24%) are in stable relapse and 13 (76%) in CR. The most common adverse effects of this regimen were hematological. With chemotherapy, 7 patients had grade 3/4 neutropenia and 4 patients had grade 3/4 thrombocytopenia. Post Zevalin, 11 patients experienced one or more grade 3/4 cytopenias: 8 patients had neutropenia, 8 had thrombocytopenia, and 4 had anemia with time to recovery of counts ranging between 2–4 weeks. 8 of these patients had bone marrow involvement at the start of treatment. One patient developed treatment related MDS that evolved to AML 4 years after the start of therapy. This patient died. Other grade 3/4 adverse effects included: grade 3 hypoxia and pneumonia post chemotherapy in a patient with grade 1 neutropenia and grade 2 cellulitis after Zevalin in a patient with grade 3/4 neutropenia. Conclusion:Chemoimmunotherapy followed by consolidation with radioimmunotherapy and rituximab maintenance is well tolerated and able to improve complete remission rates and maintain durable responses in patients with untreated indolent lymphomas. The use of this approach in indolent NHL patients may become a new standard of care. Disclosures:Off Label Use: Both radioimmunotherapy consolidation with zevalin and rituximab (immunotherapy) maintenance have been used in indolent lymphomas first line post chemo-immunotherapy. However, in this study, we looked at the combination of chemo-immunotherapy followed by zevalin consolidation and rituximab maintenance. This combination is off-label. Kassar:Alexion: Honoraria. Gregory:Amgen: Consultancy; Astellas: Research Funding; Celgene: Research Funding; Cephalon: Research Funding, Speakers Bureau; Genentech (Roche): Consultancy, Research Funding, Speakers Bureau; Glaxo-Smith-Kline: Research Funding; Immunomedics: Research Funding; NCIC CTG: Research Funding; Novartis: Consultancy, Research Funding; Onyx (Proteolix): Research Funding; Spectrum Pharmaceuticals: Consultancy.

Tolerance and Response to Initial Systemic Therapy In Older Patients with Follicular Lymphoma (FL): Observations From 186 Unselected Recent Cases In the Practices of US-Based Medical Oncologists (MOs).

AbstractAbstract 3842 Background:Advanced-stage FL is generally considered incurable, but the disease often responds to systemic anticancer treatment (SAT). A number of factors influence the selection of a specific SAT, which must be administered judiciously to older patients, particularly those with known comorbidities. A paucity of information exists to document which SATs are chosen for this population in clinical practice and the resultant clinical outcomes. We attempted to address this issue by aggregating and examining clinical information on individual patients receiving initial treatment for FL. Methods:US community-based MOs were recruited from a database of past participants in our CME activities to provide anonymous information on the presenting symptoms, diagnostic workup, treatment selection, side effects and clinical antitumor responses for all patients in their practices with a new diagnosis of FL since January 1, 2008. Modest, per-patient honoraria were provided to each MO for this work. Results:From April 14 to July 9, 2010, 38 MOs entered a total of 186 cases of FL into a web-based data bank (minimum 1 case, maximum 15, median 4.5). The median age was 66, with 45% under age 65, 26% from 65 to 74 and 29% age 75 and older. 53% of the patients were women.42% of patients were minimally symptomatic or asymptomatic at diagnosis (Table 1), and across each of the three age groups the presence of various symptomology was similar. A number of SATs were initiated, including R-CHOP (26%), RCVP (25%), and rituximab monotherapy (13%). 15% of patients were observed without SAT. For patients first treated in 2010, an increase in the use of bendamustine/rituximab was observed, representing 8 of 26 patients (31%) versus 3 out of 80 patients (4%) in 2009. The choice of regimen differed by age, with, for example, more R-CHOP (37%) used for patients under age 65 and more R-CVP (38%) and rituximab monotherapy (28%) selected for patients age 75 and older. Overall, these treatments resulted in complete clinical responses in 57% of patients and “things went very well with expected or fewer toxicities” in 58%. These outcomes are similar to what has been reported in published data from randomized Phase III trials of these regimens. No major differences were observed in the levels of efficacy and side effects between the three age groups (Table 1). Conclusions:This unselected case series produced, in a rapid manner, information addressing a variety of clinical issues in newly diagnosed FL, including the impact of age on treatment selection and resultant outcomes. These data suggest that MOs are able to individualize SATs for older patients and match the short-term outcomes and tolerability of the therapies selected for younger patients. This risk-benefit differential is of particular palliative importance as this dataset demonstrates a majority of patients present with clinically significant tumor-related symptoms at diagnosis. Additional work of this kind is needed to better understand how physicians adjust the dose and schedule of SATs to prevent and ameliorate toxicity, particularly in older patients. Disclosures:Gregory:Cephalon Inc: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen Inc: Consultancy; Genentech BioOncology: Consultancy, Speakers Bureau; Novartis Pharmaceuticals: Consultancy; Spectrum Pharmaceuticals: Consultancy. Cheson:Celgene Corporation: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Cephalon Inc: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Millenium Pharmaceuticals Inc: Membership on an entity's Board of Directors or advisory committees; Pfizer Inc: Membership on an entity's Board of Directors or advisory committees. Czuczman:Amgen Inc: Membership on an entity's Board of Directors or advisory committees; Biogen Idec: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Cephalon Inc: Membership on an entity's Board of Directors or advisory committees; Genentech BioOncology: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Lilly USA LLC: Membership on an entity's Board of Directors or advisory committees; Millenium Pharmaceuticals Inc: Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees.

Interferon Maintenance Prolongs Remission Duration After Rituximab-Containing Induction In First-Line Advanced Stage Follicular Lymphoma Patients – a Retrospective Analysis of the German Low-Grade Lymphoma Study Group (GLSG)

AbstractAbstract 2864 Background:Rituximab (R) maintenance in first remission of follicular lymphoma (FL) has recently been shown to improve remission duration as compared to observation only (Salles et al., ASCO 2010). During the nineties of the last century, maintenance using interferon alpha (IFN) had been shown to be effective in indolent lymphoma (Solal-Celigny et al., NEJM 1993, Hagenbeek et al., JCO 1998). Therefore IFN-maintenance became a standard in GLSG trials after 1995. However, data on the impact of IFN after R-containing chemotherapy are rare. We performed a retrospective analysis of GLSG trials in which we compared the outcome of patients who received IFN-maintenance and patients who did not start any form of consolidation or maintenance therapy after achieving a partial or complete remission. We adjusted the analysis for potential confounders that might have influenced the decision not to start IFN-maintenance. Methods:In the GLSG first-line trials “CHOP vs. MCP” and “CHOP vs. R-CHOP” patients younger than 60 years had been randomized between consolidating high-dose radiochemotherapy followed by autologous stem cell transplantation (ASCT) and IFN-maintenance. For all responding patients older than 60 years, IFN-maintenance was intended. All patients with FL achieving a partial or complete remission after MCP, CHOP, or R-CHOP who did not start ASCT were included in the current analysis. Patients intended for IFN who did not start IFN-maintenance were compared to patients who started IFN-maintenance. We compared patient and treatment characteristics between these groups in order to detect possible reasons why IFN-maintenance was not started. Remission duration (RD) was calculated from the end of induction to relapse or death. RD was censored at the latest follow-up date in patients without event, but also when a new antilymphoma therapy was initiated without any sign of progression. No censoring was done for any form of dose reduction or stopping of IFN, which was recommended in the trials if inacceptable side effects were observed. We compared RD with IFN-maintenance to observation only by Kaplan-Meier-curves and log rank test and we adjusted for the potential confounders FLIPI, performance status, R-containing induction and remission status in multiple Cox-Regression. In order to assess the impact of IFN-maintenance after R-containing induction, we performed a subgroup analysis of R-CHOP treated patients. Results:Of 1306 FL patients with clinical remission, ASCT was started in 306 patients and documentation concerning postremission therapy was missing in 21 patients. In 719 (73%) of the remaining 979 patients IFN-maintenance was started, whereas 260 patients did not receive IFN-maintenance. Patients in which IFN-maintenance was started were not more frequently younger than 60 years (59% vs. 55%, p=0.24), and not more frequently in a better performance status (ECOG 0–1: 93% vs. 91%, p=0.33). There was only a trend to better FLIPI (LR/IR/HR 13%/41%/46% vs. 15%/34%/52%, p=0.10) as compared to patients with observation only. Patients with IFN-maintenance had not more frequently achieved a CR (19% vs. 21%, p=0.65), but more patients had been treated without Rituximab during induction (57% vs. 37%, p<0.0001). According to our analysis patients with IFN-maintenance had a significantly prolonged RD (hazard ratio 0.73, 95% CI 0.59 to 0.91, p=0.0045) which was even more pronounced after adjustment for FLIPI factors, performance status, Rituximab containing induction, and remission status (adjusted hazard ratio 0.59, 95% CI 0.47 to 0.74, p<0.0001). In 309 (65%) of 473 patients treated with R-CHOP IFN-maintenance was started. RD after 3 years was 78% vs. 64% (p=0.0007) and the adjusted hazard ratio for IFN-maintenance was 0.57 (95% CI 0.39 to 0.84 p=0.0042). Conclusions:Although this is not a randomized comparison, our analysis shows that the impact of IFN, which was observed before using R-containing therapy may still be valid in the era of immunochemotherapy. Since R-maintenance seems more effective and has less side effects, IFN-maintenance will no longer be the first choice for maintenance therapy in FL. However, it seems relevant to keep in mind that IFN is still an active substance in lymphoma therapy and may be a therapeutic option when rituximab maintenance is not possible. It may also be relevant for future investigations in lymphoma therapy. Disclosures:Dreyling:Johnson & Johnson:.Hiddemann:Roche: Honoraria, Research Funding.

An Intergroup Randomised Trial of Rituximab Versus a Watch and Wait Strategy In Patients with Stage II, III, IV, Asymptomatic, Non-Bulky Follicular Lymphoma (Grades 1, 2 and 3a). A Preliminary Analysis

Abstract 6 Patients with asymptomatic, advanced stage, follicular lymphoma have shown no benefit of immediate chemotherapy when compared with a watchful-waiting approach, whereby chemotherapy is deferred until disease progression. Deferring chemotherapy may spare the patient the side effects of the chemotherapy in the short term and historically this has been the preferred approach. With the advent of rituximab and its relatively favourable side effect profile we designed this study to compare a watchful waiting approach with immediate treatment with rituximab. Adult patients with asymptomatic stage 2, 3 or 4 follicular lymphoma (grades 1–2 & 3a) and adequate bone marrow reserve were randomly assigned with a ratio 1:1:1 to watchful waiting (arm A) or rituximab 375mg/m2 weekly for 4 weeks (arm B) or rituximab 375mg/m2 weekly for 4 weeks followed by rituximab maintenance every 2 months for 2 years (starting at month 3 until month 25)(arm C). The primary endpoints were a) time to initiation of new therapy (chemotherapy or radiotherapy) and b) effect on quality of life. The study was designed to detect an improvement in the median time to initiation of therapy in each of the rituximab arms of 18 months (from 30 months to 48 months) with 2.5% significance level and 90% power. A total of 230 events were required and 600 patients were planned. In September 2007, a decision was made to discontinue arm B as evidence of the efficacy of maintenance rituximab became clear. With the two arms comparison, using a significance level of 5%, a total of 360 patients in Arm A and Arm C were planned. Between September 2004 and May 2009 462 patients were randomised (186 Arm A, 84 Arm B, and 192 Arm C). 95% of patients had low tumour burden (GELF criteria) the other 5% had raised LDH but fulfilled the remaining GELF criteria. 98% were entered into the study within 4 months of diagnostic biopsy. Median age 60yr (range27-87). 54% female. ECOG performance status 0=91% & 1=9%. Grade 1–2=89%. Stage 2(21%), stage 3(40%), stage 4 (39%). 42% had bone marrow involvement. FLIPI score: 0=9%, 1=26%, 2=41%, 3=22%, 4=2%. In March 2010 the Data Monitoring committee concluded that the data regarding time to initiation of new therapy was mature and recommended full analysis of data to be performed and presented in the knowledge that rituximab maintenance was still ongoing in 20 patients. To date 45 SAEs have been reported (Arms A=14, B=6, C=25), 14 SAE were considered possibly, probably or definitely related to the study drug (Arm B=4, C=10). 5 allergic reactions (two grade 3), 6 infections, 3 episodes of grade 4 neutropenia. Responses were assessed at month 7, 13 and 25. CT was compulsory at months 7 and 25. Bone marrow was only required if CR on clinical and CT criteria. An interim analysis was performed on 9 Feb 2010. At month 7: Arm A: spontaneous remission was seen in 3%, PR=6%, NC (no change) =74%, PD=17%. Arm B: CR+CRu=45%, PR=33%, NC=19%, PD=3%. Arm C: CR+CRu=49%, PR=36%, NC=11%, PD=3%. At the time of the interim analysis 93 (20%) patients had initiated new treatment. Of these 93 patients 84 (90%) had clinically reported progression. New treatment was chemotherapy in 78 (84%), radiotherapy in 10 (11%), rituximab monotherapy in 2 (2%), surgery in 1(1%),currently not known in 2 (2%). The estimated median time to initiation of new therapy in arm A was 33 months, similar to our previous trial of watchful waiting (Ardeshna et al Lancet 2003). The time to initiation of new therapy was significantly longer in the rituximab arms (fig 1, p value of log-rank test 0.5). These data indicate that initial treatment with rituximab significantly delays the need for new therapy and this finding may change the management of patients with newly diagnosed asymptomatic follicular lymphoma. Disclosures: Ardeshna:Roche: Funding data manager, Honoraria, Membership on an entity9s Board of Directors or advisory committees. Off Label Use: Rituximab is currently not licensed for use as a single agent in previously untreated patients with with asymptomatic advanced stage follicular lymphoma. Pocock:Roche: Honoraria, Membership on an entity9s Board of Directors or advisory committees. Cunningham:Roche: Research Funding. Davies:Roche: Honoraria, Membership on an entity9s Board of Directors or advisory committees; chugai: Honoraria, Research Funding. Walewski:Roche: Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau. Linch:Roche: Honoraria, Membership on an entity9s Board of Directors or advisory committees.