ALBERT

Description: Abstract 98 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]). 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.

Description: INTRODUCTION: The expression of valine (V/V or V/F) at position 158 of the FCγIIIA (CD16) in contrast to phenylalanine alone (F/F) has been associated with higher response rates and longer PFS to single agent Rituximab. A polymorphism in position 131 FCγ RIIA (CD32) encodes histidine (H) or arginine (R) and has also been associated with improved outcome. These polymorphisms have been associated with higher affinity binding of human IgG1 and greater in vitro ADCC using effector cells and Rituximab, and suggest that the major mechanism of Rituximab is through the interaction with FC receptors on cells capable of mediating ADCC. There is no data on the effect of these polymorphisms on the outcome of Rituximab following or combined with chemotherapy. METHODS: We evaluated these polymorhisms using DNA from blinded samples collected from patients on SWOG 9800, a phase II trial evaluating the sequential use of CHOP followed by single agent Rituximab (375 mg/m2 x 4 weekly doses). We developed a SSCP method to rapidly determine these polymorphisms from DNA samples and confirmed this method through DNA sequencing. Briefly, DNA was amplified using specifically designed PCR primers that amplified the relevant portions of CD16 and CD32. PCR products were then run on SSCP gels under controlled conditions that allowed identification of the patterns associated with each of the polymorphisms. These results were then analyzed with respect to outcome based on the hypothesis that the presence of high affinity FC receptors would be associated with an improved outcome to CHOP followed by Rituximab in newly diagnosed patients with advanced stage follicular NHL. RESULTS: DNA samples were successfully evaluated on 87/89 eligible patients (no DNA on 2 patients). The freqeuncy of CD16 V/V, V/F and F/F was 13%, 51%, and 37% and CD32 H/H, H/R and R/R was 36%, 44%, and 21% respectively. There was no significant association between any combination of phenotypes and the two year PFS following sequential treatment with CHOP followed by Rituximab. The two-year PFS for patients with V/V, V/F or F/F in CD16 was 55%, 80% and 75% and for patients with H/H, H/R and R/R was 71%, 76% and 78% respectively. For CD16 the presence of one V vs no V resulted in identical estimates of 2 year PFS of 75% (p=.56). Likewise the presence of one H vs no H in the CD32 polymorphism did not result in significantly different PFS (78% vs 74%. p=.88). We also determined the effect of the polymorphism’s on the clearance of PCR detectable disease by analysis for t(14:18). There was no impact on the clearance of molecular disease following CHOP alone. Twenty-two of 32 patients who were still PCR positive for t(14:18) after CHOP converted to PCR negative following Rituximab. There was a suggestion of a trend toward a higher rate of molecular remission following Rituximab for patients with CD16 with at least one V phenotype (V/V or V/F: 12/15 cleared vs 10/17 with F/F, p=.26). In conclusion, we found no evidence that the encouraging efficacy of CHOP followed by Rituximab antibody therapy for patients with advanced follicular NHL is dependent on the presence of high-affinity FC gamma receptor polymorphisms.

Description: S0515 was a phase 2 trial to determine whether the addition of bevacizumab to cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) plus rituximab (R-CHOP) would improve progression-free survival (PFS) without adding significant toxicity in patients with newly diagnosed advanced diffuse large B-cell lymphoma. A total of 73 patients were enrolled. For the 64 eligible patients, median age was 68 years, and 60% had International Prognostic Index scores more than or equal to 3. The observed 1- and 2-year PFS estimates were 77% and 69%, respectively. These PFS estimates were not statistically different from the expected PFS for this population if treated with R-CHOP alone. Grade 3 or higher toxicities were observed in 81% of patients, including 2 grade 5 events. The majority of serious toxicities were hematologic but also included 5 patients with gastrointestinal perforations, 4 patients with thrombotic events, and 11 patients who developed grade 2 or 3 left ventricular dysfunction. Higher baseline urine VEGF and plasma VCAM levels correlated with worse PFS and overall survival. In conclusion, the addition of bevacizumab to R-CHOP chemotherapy was not promising in terms of PFS and resulted in increased serious toxicities, especially cardiac and gastrointestinal perforations. This study is registered at www.clinicaltrials.gov as #NCT00121199.

Description: Abstract 590 Background: Although the majority of patients (pts) with DLBCL have durable remissions following R-CHOP chemotherapy, a substantial proportion of pts with advanced stage disease and other clinical risk factors are not cured. Low toxicity options are required for the majority of pts who are over age 60, or have medical comorbidities. Radioimmunotherapy, a low-toxicity option, is active in relapsed DLBCL (Blood 110:54), and improves PFS when used as consolidation after chemotherapy in follicular lymphoma (JCO 26:5156). We therefore evaluated consolidative radioimmunotherapy with iodine-131 tositumomab in pts with previously untreated DLBCL. Methods: Eligible pts had bulky stage II, or advanced stage DLBCL with measurable disease and adequate organ function. Treatment was 6 cycles of R-CHOP-21, followed by 2 cycles of CHOP-21 (no rituximab), followed by iodine-131 tositumomab (65 cGy if platelet count between 100 and 150/mm3 or 75 cGy if normal platelet count) 4–12 weeks after last dose of CHOP. Results: Eighty six pts (84 eligible; 45 females) were enrolled. Median age was 64 years; International Prognostic Index risks were low (n=20, 24%), low intermediate (n=27; 32%), high intermediate (n=27, 32%) and high (n=10, 12%). Five pts died of toxicities possibly related to therapy including one case each of febrile neutropenia, acute myeloid leukemia, and renal failure; there were two deaths from cardiac ischemia including one following a GI bleed in setting of thrombocytopenia after iodine-131 tositumomab. With a median follow-up of 12 months, 26 pts have progressed or died, with a 1-year progression-free survival (PFS) estimate of 75% (95%CI: 64%-85%), and 1-year overall survival (OS) estimate of 83% (95% CI:74%-93%). Based on prior studies, the estimated historical 1-year PFS rate with R-CHOP alone in this population is 74%. Complete data on iodine-131 tositumomab treatment is available for 73 of 84 eligible patients: 23 pts (32%) did not receive iodine-131 tositumomab due to early progression (n=3), other adverse event (n=6), refusal (n=6), death (n=3), or other reasons (n=5). Conclusions: A consolidation strategy utilizing iodine-131 tositumomab after 8 cycles of CHOP chemotherapy (6 with rituximab) for DLBCL does not appear to be promising in regard to 1 year PFS or OS. Unlike follicular lymphoma, in this population of DLBCL, early progressions, deaths, and declining performance status during CHOP chemotherapy limits the number of pts who ultimately can benefit from a planned consolidation approach. These current results suggest that the incorporation of novel agents earlier in therapy may ultimately have greater impact in DLBCL than consolidation or maintenance approaches. (Supported by 5U10CA32102-31, 5U10CA38926-25, and GlaxoSmithKline). Disclosures: Friedberg: Genentech: Honoraria. Off Label Use: Iodine-131 tositumomab for large cell lymphoma. Gopal:GlaxoSmithKline: Research Funding. Press:Trubion Pharmaceuticals: Consultancy, Equity Ownership; PhaseRx: Equity Ownership; Algeta: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Genentech: Honoraria; Spectrum: Honoraria.

Description: Purpose: To determine the effect of post-transplant immunotherapy with Interleukin-2 (IL-2) on the progression-free and overall survival of patients with non-Hodgkin’s lymphoma (NHL) after autologous stem cell transplantation and to assess the toxicity of post-transplant IL-2 therapy. Patients and Methods: Patients with previously treated low, intermediate, or high grade NHL (except Working Formulation Groups A and I) were treated with high-dose cyclophosphamide, etoposide, and total body irradiation (TBI) and an autologous peripheral blood stem cell transplant (PBSCT). Twenty-eight to 80 days after PBSCT, patients were randomized to treatment with IL-2 versus observation. Results: Between January 1995 and July 2004, three hundred ninety-four patients with low-grade (n=61) or intermediate-high grade NHL (n=315) were registered at one of 39 SWOG transplant centers. One hundred ninety patients did not proceed to randomization, because of patient refusal (44), grade V toxicity (30), disease progression (28), toxicity (28), or other reasons. Two hundred four patients were randomized to treatment with continuous infusion intravenous IL-2 (9 ×106 units/m2/day for four days followed five days later by 1.6 ×106 units/m2/day for 10 days) versus observation. The 4-year progression-free survival estimate for all eligible patients is 34%, and the 4-year overall survival estimate is 52%. There was no difference in progression-free survival (hazard ratio (HR) of IL-2 to observation = 0.90; p = 0.56) nor in overall survival (HR of IL-2 to observation = 0.88; p = 0.55). There were no deaths related to IL-2 treatment. Grade IV IL-2-related toxicities included hematologic (n=10), cardiovascular (4), renal/bladder (2), flu-like symptoms (1), lung (1), metabolic (1), and neurologic (1) and were reversible in all cases. Conclusions: These results confirm earlier SWOG findings that a regimen of cylophosphamide, etoposide and TBI followed by PBSCT can be administered to patients with relapsed or refractory NHL with acceptable toxicity and with encouraging progression-free and overall survival. Post-transplant therapy with IL-2 given at this dose and schedule of administration had no significant effect on post-transplant relapse, progression-free survival or overall survival.

Description: Introduction: Patients with limited stage aggressive B-cell non-Hodgkin lymphoma (LS-NHL) and at least one stage-modified adverse risk factor have an excessive relapse rate leading to a 5-year overall survival (OS) of 50-77% and 10-year OS of 0-50%. In SWOG S0014 we have shown that the addition of rituximab to 3 cycles of CHOP plus involved field radiation therapy (IFRT) resulted in an improved estimated 4-year progression-free survival (PFS) of 88% and OS of 92%. Relapses were largely systemic (5 of 6 evaluable) and continued to be seen with longer follow-up. Ibritumomab tiuxetan (Zevalin ®) is a radiolabeled anti-CD20 antibody that has excellent single agent activity in diffuse large B-cell lymphoma and could prevent systemic relapse of disease. We now report long term results of SWOG S0313, a phase II study of ibritumomab tiuxetan consolidation after 3 cycles of CHOP plus IFRT in patients with LS-NHL. Methods: Patients with LS-NHL and at least one stage-modified adverse risk factor (non-bulky stage II, age 〉 60 years, elevated LDH, or WHO performance status of 2) were treated with CHOP on days 1, 22, and 43, followed 3 weeks later by 40-50 Gy of IFRT. Ibritumomab tiuxetan regimen was initiated 3 – 6 weeks following IFRT. Results: Forty-six patients were registered and eligible, with median follow-up of 7.3 years. Median age was 61, 37% of patients had elevated LDH, and 20% had systemic symptoms. Grade 4 adverse events occurring more than once included neutropenia (8 patients), leukopenia (5), and lymphopenia (2). Febrile neutropenia was observed in 4 patients. No cases of treatment-related myeloid neoplasms were noted. Eleven patients progressed and 8 patients died. The PFS estimate is 89% at 2 years, 82% at 5 years, and 75% at 7 years. OS estimate is 91% at 2 years, 87% at 5 years, and 82% at 7 years. These outcomes compare favorably to matched cohorts on prior SWOG trials, with 7-year PFS estimate of 68% on S0014 and 65% on S8736 (original pre-Rituximab trial); and 7-year OS estimate of 80% on S0014 and 73% on S8736 cohorts. Conclusions: Patients with high-risk LS-NHL treated with 3 cycles of CHOP plus IFRT followed by ibritumomab tiuxetan consolidation had outcomes that compare favorably to our historical experience. A US cooperative group study of R-CHOP and response-adapted IFRT followed by consolidative ibritumomab tiuxetan is ongoing. Disclosures Off Label Use: ibritumomab tiuxetan in diffuse large B-cell lymphoma.

Description: Abstract 591 Introduction: VEGF and VEGF receptors (VEGFR) are frequently over-expressed in DLBCL. Elevated levels of circulating VEGF have also been associated with a worse prognosis and resistance to chemotherapy. This trial was initiated to determine if the addition of anti-VEGF targeted therapy to standard R-CHOP would improve PFS without adding significant toxicity in previously untreated patients with stage III, IV or bulky stage II DLBCL. Methods: 64 eligible patients were treated with standard dose R-CHOP plus bevacizumab administered at 15mg/kg on day1. Patients received therapy every 21 days for a maximum of 8 cycles. Both biologics were administered prior to chemotherapy. Pretreatment tumor biopsies from 40 patients were submitted for construction of tissue microarrays for VEGF/VEGFR immunohistochemical analysis. Two 1 mm tissue cores were assessed for each DLBCL specimen and expression of VEGF and VEGFR scored on a scale of 0 (no expression) to +3 (strong expression) by 2 pathologists. Both lymphoma and endothelial cell (blood vessel) staining was assessed with the higher score being recorded. Results: 73 patients were enrolled with 9 patients found ineligible, the majority (n = 7) secondary to incorrect histology. Patient characteristics for the 64 eligible patients included: median age 68 years with 77% of the patients over 60 years (age range: 22–85), 44 males, IPI scores: 3 low, 22 low-intermediate, 29 high-intermediate, and 8 high. Median follow-up is 2.0 years. Based on prior studies, and adjusted for the observed IPI factor frequencies seen in this study, the projected 1 year historical PFS rate in this population would be 71%, while the observed 1 year PFS estimate was 77% (95% CI: 66 – 87%). The PFS estimate at 2-years was 69% (95% CI: 57 – 80%). The 1 and 2 year overall survival estimates were 86% and 79%, respectively. Among all patients (including ineligibles), a total of 30 patients experienced 40 serious adverse events (SAE) while on study. The majority of SAE were hematologic, but also included 2 patients with sudden death, 5 patients with GI perforations (4 occurring after cycle 1), and 5 patients with grade 3 or 4 thrombotic events. Additional adverse events of interest included 7 patients who developed hypertension (4 patients with grade 3), and 13 patients who developed grade 2 or 3 left ventricular dysfunction. VEGF expression was observed in 98% (IHC scoring: +1 in 18%, +2 in 38%, and +3 in 43%) of lymphoma cells and VEGFR was expressed in 95% (IHC scoring:+1 in 28%, +2 in 40%, and +3 in 28%) of blood vessels by immunohistochemistry analysis. Conclusions: Despite high protein expression of VEGF and VEGFR in newly diagnosed DLBCL specimens, the addition of bevacizumab to standard R-CHOP chemotherapy did not significantly improve PFS from expected results with R-CHOP alone. Although the observed 1-year PFS estimate trended higher than the historical estimate, a target PFS of 81% was pre-specified as warranting further investigation. Significant toxicities were associated with the addition of bevacizumab, including an increased incidence of cardiac dysfunction and GI perforation. Our results do not support additional studies of this regimen in this patient population. Disclosures: Stopeck: Genentech: Consultancy, Honoraria, Speakers Bureau. Off Label Use: Bevacizumab therapy in NHL. Fisher:Roche: Consultancy.

Description: The 5-year survival rate of patients with limited disease (LD) and aggressive histologies of non-Hodgkin lymphoma (NHL) who have at least one adverse risk factor is about 70% after treatment with three cycles of CHOP followed by involved-field radiotherapy (CHOP(3) plus IFRT). We have previously reported the effect of adding four infusions of rituximab to CHOP(3) plus IFRT demonstrating an improved estimated overall 5-year survival (OS) of 82% (Persky et al. J Clin Oncol26:2258, 2008). In this study we test the effect of adding ibratumomab tiuxetan consolidation to CHOP(3) plus IFRT in 40 evaluable patients. Patients had a biopsy diagnosis (no FNA allowed) of diffuse aggressive B-cell NHL without any follicular component and high risk LD. High risk LD is defined, using the stage-modified International Prognostic Index, as stage I with at least one adverse risk factor (age 〉 60 years, elevated LDH and a performance status of 2) OR non-bulky stage II disease. Patients with stage I and no risk factors were excluded because their survival exceeds 90% at 10 years using standard therapy. Patients with bulky stage II disease were not eligible because their prognosis is similar to advanced disease. CHOP chemotherapy was given at standard doses on days 1, 22, and 43. IFRT was given as previously described (above) starting on day 64 to include 40 – 46 Gy. The rituximab plus ibritumomab tiuxetan regimen was given 3 – 6 weeks following completion of IFRT over a period of 7 – 9 days. Rituximab, 250 mg/m2 was given on day 1 followed within 4 hours by 5 mCi of In-111 ibritumomab tiuxetan followed by whole body gamma camera images to assess biodistribution of the ibritumomab tiuxetan. Scans were obtained at 2 – 24 hours and at 48 – 72 hours. Following acceptable biodistribution, rituximab is repeated on days 7, 8, or 9 followed within 4 hours by Y-90 ibritumomab tiuxetan, 0.4 mCi/kg, not to exceed 32 mCi total dose. Forty patients are eligible. Patients have been followed for a median of 24 months (range 1 – 50 months). During this time there have been only three events recorded (progression or death from any cause). Estimated 2-year progression-free survival is 91% (95% CI: 81%-100%) and 2-year OS is 95% (95% CI: 87%-100%). Toxicity has been reversible with no treatment related deaths. There were 9 grade 3 and 10 grade 4 hematologic events, but only 3 episodes of febrile neutropenia and only one patient requiring platelet support. Other grade 3 toxicities were mostly gastrointestinal symptoms including mucositis and nausea/vomiting or flu-like symptoms. We conclude that patients with aggressive histologies of NHL and high-risk LD treated with CHOP(3) plus IFRT followed by ibritumomab tiuxetan consolidation result in outcome that compares favorably to our historical experience in the short term. Longer follow-up will determine whether these patients exhibit a pattern of late recurrences as seen in our prior experiences.

Description: Key PointsLimited-stage diffuse large B-cell lymphoma has good outcomes with CHOP followed by radiotherapy but has a pattern of continuous relapses. Adding radioimmunotherapy consolidation results in outcomes that are at least as good as with rituximab added to CHOP and radiotherapy.

Description: Large studies using snap frozen tissue for gene expression profiling (GEP) have identified a limited number of genes predicting outcome in DLBCL treated with CHOP alone (17 genes from Rosenwald et al NEJM 2002, 13 from Shipp et al, Nat Med 2002, 6 from Lossos et al, NEJM 2004, 2 from Tome et al, Blood 2005). Our objective was to test the prognostic value of these genes (38 total, 36 different genes) using FFPE tissues and compare results from patients treated with CHOP or CHOP-like regimen alone (C) (N=93) to those treated with CHOP + rituximab (R) (N=101). We used a multiplexed quantitative nuclease protection assay, the ArrayPlate (High Throughput Genomics), to measure mRNA levels reliably in FFPE samples as recently described. (Roberts et al, Lab Invest, ePub, 13 Aug 2007). Of 194 cases attempted, there was only 1 that did not result in adequately detectable signal. Univariate associations between gene levels and patient OS were performed using Cox proportional hazard regression models. For C alone cases, gene expression levels were significantly correlated with overall survival (OS) at p 〈 0.05 for 15/36 prognostic genes including the MHCII genes HLA-DR and HLA-DP, as well as C-MYC, BCL-6, BCL-2 and ten other genes. These genes represented all 4 Rosenwald prognostic signatures, 3/6 of Lossos genes, and 4/13 Shipp genes. In the R-treated cases, 8/36 genes correlated with OS including HLA-DR and HLA-DQ, the germinal center B-cell (GCB) genes BCL-6, and SERPINA9 as well as C-MYC, PLAU, PDCD4, and MnSOD. Again, all 4 Rosenwald signatures were represented. In our assay, genes that represent key gene expression signatures previously identified as the most prognostically important in large discovery-oriented GEP experiments were significantly associated with patient OS using FFPE tissues and retained significance in the R-treated patients, suggesting that previous findings remain relevant in the R-CHOP era. For most genes in both treatment groups, the estimated hazard ratios tended in the direction originally predicted, suggesting these genes would be significantly related to survival in a larger, more powered study. Previous studies have relied on unfixed, snap-frozen tissues which are available only in a minority of patients for GEP or quantitative RT-PCR measurements of mRNA expression. The ArrayPlate assay can assess prognostic genes in patients for which only FFPE material is available, is highly correlated with discovery microarray results, and should be easily adaptable as more prognostic genes are identified. Importantly, previously identified prognostically important genes such as MHCII and GCB genes remain correlated with survival in the R-CHOP treatment era.