Williams, Michael E.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical trial updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. In 2003, the Eastern Cooperative Oncology Group initiated a randomized phase III clinical trial (E4402) comparing two different rituximab dosing strategies for patients with previously untreated low–tumor burden follicular lymphoma. Rituximab-responsive patients (n = 299) were randomly assigned to either a retreatment rituximab (RR) strategy or a maintenance rituximab (MR) strategy. Each dosing strategy was continued until treatment failure. The primary end point of the study was time to treatment failure (TTF). In the original report, there was no difference in TTF between the two dosing strategies. Here, we report on the long-term outcomes for secondary end points of time to first cytotoxic therapy, duration of response, and overall survival (OS). At 7 years, 83% of MR patients had not required first chemotherapy compared with 63% of RR patients (hazard ratio, 2.37 [95% CI, 1.5 to 3.76]). At 7 years, 71% of MR remained in their first remission compared with 37% of RR patients. Despite the improved first remission length with MR, there was no difference in OS at 10 years (83% v 84%). With mature long-term data, we confirm that prolonged maintenance rituximab does not confer an OS advantage in low–tumor burden follicular lymphoma.

LBA8025 Background: We compared lenalidomide plus high (standard) dose Dex (R+HighD) versus lenalidomide plus low dose Dex (R+LowD) in newly diagnosed MM. Methods: Pts with untreated, symptomatic MM were eligible. Pts in both arms received lenalidomide 25 mg/day PO days 1–21 every 28 days. In addition, pts in the R+HighD arm received Dex 40 mg days 1–4, 9–12, and 17–20 PO every 28 days; pts in the R+LowD arm received Dex 40 mg days 1, 8, 15, and 22 PO every 28 days. The primary null hypothesis was that response rates at 4 months on the 2 arms are equivalent. Planned sample size was 196 eligible pts per arm with one-sided 0.10 Type I and 0.05 Type II error rate. Pre-planned interim analysis is performed by an independent DMC when full information is available on 25%, 50% and 75% of accrual. All analysis were intent to treat. Results: 445 pts (median age, 65 yrs) were accrued; 223 randomized to R+HighD, 222 to R+LowD. Arms were well balanced for age, gender, stage, bone lesions, hemoglobin, beta-2 microglobulin, performance status, bone marrow plasma cells, and M protein levels at baseline. Major grade 3 or higher toxicities included thromboembolism (22.1% with R+HighD vs 6.1% in R+LowD), infection/pneumonia (15.7% vs 7.5%) and hyperglycemia (9.7% vs 6.6%). Grade 3 or higher non-hematologic toxicities occurred in 65.9% (R+HighD) versus 54.9% (R+LowD) respectively; corresponding grade 4 or higher rates were 20.3% vs 13.1% respectively. Overall survival (OS) at first interim analysis was significantly superior with R+LowD, P<0.001; one year survival 96.5% (R+LowD) versus 86% (Rev+HighD). OS differences in favor of R+LowD were seen in pts <65 (P=0.015; one year rate 98% vs 90%) and pts 65 and older (P=0.004; one year rate 95% vs 83%), respectively. DMC recommended release of survival results, and recommended switching all pts to R+LowD. DMC also recommended closure of an expansion phase trial of R+HighD investigating optimal thromboprophylaxis. Conclusions: Lenalidomide plus low-dose dexamethasone is associated with superior OS compared to lenalidomide plus high-dose dexamethasone. This study has major implications for future use of high-dose dexamethasone in the treatment of MM. No significant financial relationships to disclose.

Abstract Abstract 4608 Background: FCR has been a preferred 1st line therapy approach in CLL for the past decade. However it is associated with substantial toxicity and not recommended in NCCN guidelines for patients over age 70. We studied the impact of age, co-morbidities, and tempo of disease on 1st line therapy prescribing preferences of American hematology-oncology physicians (AHOP) for patients with CLL. Methods: During Feb-March 2012, prescribing preferences of 325 individual AHOP were assessed using a proprietary, live, case-based market research tool (Challenging Cases™). A core case scenario was constructed with variations based on altered age, co-morbidities, and tempo of disease progression prior to initial therapy. Preference data were acquired using blinded audience response technology. Responses for each scenario were obtained prior to any display of participant selections. All sources of research support were blinded. Core scenario: 67y male; CD 38+, ZAP 70+, del 13q and del 11q CLL, adenopathy, lymphocytosis, splenomegaly, anemia (Hgb 9.5 gm) but no thrombocytopenia. Co-morbidities: medication-controlled hypertension, moderate restrictive airways disease, and type 2 diabetes managed with metformin. Modified scenario: same clinical presentation except the patient is 72 years of age. Slower tempo of disease scenario: age 68y, time frame of observation without treatment 3 years from diagnosis, now with disease progression, anemia 10.9 gms, FISH only del 13q. Results: A progressive decrease in preference for FCR and commensurate rise in preference for BR as first line therapy occurs as age increases and co-morbidities are present (p<0.001). See table 1 Conclusion: As age crosses the 70 year threshold and as co-morbidities complicate therapy, there is a statistically significant increase in preference among AHOPs for prescribing bendamustine-rituximab as initial management for patients with RAI stage III CLL. Disclosures: Green: Xcenda: Employment; Teva: Consultancy, ownes publically traded shares in Teva Pharmaceuticals through 3rd party investment advisors, ownes publically traded shares in Teva Pharmaceuticals through 3rd party investment advisors Other. Williams:Xcenda: Honoraria. Willey:Xcenda: Employment. Scharf:Xcenda: Employment. Neely:xcenda: Employment. Foran:Xcenda: Honoraria.

Abstract Aim: A phase III trial of lenalidomide plus high (standard) dose dex (RD) versus lenalidomide plus low dose dex (Rd) in newly diagnosed myeloma (MM). Methods: Pts with untreated, symptomatic MM were eligible. Pts in the RD arm (Arm A) received lenalidomide 25 mg/day PO days 1–21 every 28 days plus dex 40 mg days 1–4, 9–12, and 17–20 PO every 28 days; pts in the Rd arm (Arm B) received lenalidomide at the same dose plus dex 40 mg days 1, 8, 15, and 22 PO every 28 days. The primary endpoint was response rate at 4 months, with the null hypothesis being that the response rates in the two 2 arms are equivalent. Planned sample size was 196 eligible pts per arm with one-sided 0.10 Type I and 0.05 Type II error rate. All analysis were performed on an intent to treat basis. An independent DMC recommended release of study results. Results: 445 pts (median age, 65 yrs) were accrued; 223 randomized to RD, 222 to Rd. Median follow-up time is 17 months. Arms were well balanced for age, gender, stage, bone lesions, hemoglobin, beta-2 microglobulin, performance status, bone marrow plasma cells, and M protein levels at baseline. Major grade 3 or higher toxicities, including DVT/PE and infections, were significantly higher in the high dose dex arm (see Table). Overall survival (OS) at the second pre-planned interim analysis was significantly superior with lenalidomide plus low dose dex, P<0.001; one year survival 96% (Rd) versus 87% (RD). The 18 month survival rate is 91% versus 80%, respectively. OS differences in favor of the low dose dex arm were seen in pts <65 (P=0.022; one year rate 97% vs 92%) as well as pts 65 and older (P=0.002; one year rate 94% vs 83%), respectively. Sixty-one patients have died; 42 in the RD arm and 16 in Rd arm. The cause of death has been verified by detailed chart review in 38 patients. Of 29 verified deaths in the RD arm, 13 were due to disease progression, 6 thrombosis/embolism, 3 infection, 3 cardiac ischemia, 1 stroke, and 1 respiratory failure. Of 9 verified deaths in the Rd arm, 5 were due to disease progression, 2 infection, 1 thrombosis/embolism, and 1 cardiac arrest. Response rate data are expected to be available at the time of the meeting. Conclusions: Lenalidomide plus low-dose dexamethasone (Rd) is associated with superior OS compared to lenalidomide plus high-dose dexamethasone (RD) in newly diagnosed MM. The increased mortality in Arm A is due to disease progression (myeloma deaths) as well as increased toxicity. This study has major implications for the use of high-dose dexamethasone in the treatment of newly diagnosed MM. Major Grade 3 or Higher Adverse Events Toxicity Arm A % Arm B % P value Neutropenia 10 19 0.01 DVT/PE 25 9 <0.001 Infections 16 6 <0.001 Any grade 3 or higher non-hematologic 49 32 <0.001 Any grade 4 or higher non-hematologic 20 9 <0.001 Deaths in first 4 months 5 0.5 0.006

Abstract Background: Immunomodulatory agents and proteasome inhibitors have significantly improved outcomes in the management of patients with multiple myeloma (MM). As a consequence, the role of upfront autologous stem cell transplant (ASCT) has become more controversial. The ECOG-ACRIN Cancer Research Group trial E4A03 demonstrated the superiority of lenalidomide (LEN) and low-dose dexamethasone (DEX; Ld) over LEN and high dose DEX (LD) in newly diagnosed MM (Rajkumar SV, Lancet Oncol, 2010). This led to the universal acceptance of Ld as a standard induction regimen. More recently, the FIRST study demonstrated the superiority of Ld as continuous therapy vs Ld given x 18 cycles and melphalan-thalidomide-prednisone x 12 cycles proving continuous Ld should be considered standard of care (Benboubker L, NEJM, 2014). Upon completion of four cycles of therapy, patients enrolled in E4A03 had the option of proceeding to ASCT or continuing on their assigned Ld or LD. A prior post-hoc retrospective landmark analysis (Siegel DS, Abstract, Blood 2010) comparing outcomes of early ASCT vs. no early ASCT showed that in patients <65, 65-70, and >70, the survival with early ASCT at 3 years appeared higher, supporting the role of early consolidative ASCT in newly diagnosed patients. This analysis is the long-term follow-up of the aforementioned study. Methods: A post hoc, retrospective landmark analysis was performed evaluating overall survival (OS) by early ASCT vs. no early ASCT overall and within age subgroups. The Kaplan-Meier method was used to estimate survival distributions and Cox regression for hazard ratio (HR) estimates. The landmark analysis included only patients surviving the first four cycles of therapy. Results: 21% of patients opted for early ASCT (n=90). At baseline (four cycles prior), early ASCT patients were younger (median 57.5y vs 66y), more fit (ECOG PS 0 45% vs 56%) and with less aggressive disease (ISS Stage 3 12% vs 28%). Median treatment duration was 7.6m for no early ASCT patients. The 1, 2, 3, 4, and 5-year survival probability estimates were higher for early ASCT vs. no early ASCT at 99%, 93%, 91%, 85%, and 80% vs. 94%, 84%, 75%, 65%, and 57%. The median OS in the early ASCT vs. no early ASCT was not reached vs. 5.8 years, respectively (Table 1). The survival hazard ratio (HR) for early ASCT was 0.55 [95%CI (0.38-0.80)]. In a further subgroup analysis of patients </= 65, 5-yr survival probability of those who had early ASCT vs. no early ASCT was 79% [95%CI (67-87)] vs. 62% [95%CI (54-69)], respectively. In patients </= 65, median OS in the early ASCT vs. no early ASCT was not reached vs. 7.4 years and the survival HR was 0.74 [95%CI (0.48-1.15)]. For patients >65, 5-yr survival probability of those who had early ASCT vs. no early ASCT was 83% [95%CI (56-94)] vs. 52% [95%CI (45-59)], respectively. In patients >65, median OS in the early ASCT vs. no early ASCT was not reached versus 5.2 years and the survival HR was 0.38 [95%CI (0.17-0.87)]. In all age groups, overall response rate was similar prior to the decision of proceeding with ASCT vs. no early ASCT. In a multivariable model adjusting for baseline prognostic factors, early ASCT retained marginal significance. Conclusions: The landmark analysis demonstrated that patients opting for ASCT after induction Ld/LD had a higher 1, 2, 3, 4, and 5- year survival probability and improvement in median OS regardless of DEX dose density. Results were stronger within the older age cohort and upheld in adjusted models. Limitations include lack of randomization and data on salvage therapy. At a time when lenalidomide and dexamethasone as induction is gaining worldwide acceptance in all age groups, early ASCT is safe and efficacious and should remain a standard of care for newly diagnosed MM even in the era of novel therapies. Table 1. Survival Probabilities (Time from Registration) for all Patients Included in the Landmark Analysis Median 1 year 2-year 3-year 4-year 5-year N Events Median (Yrs)(95% CI) Events Survival Probability(95% CI) Events Survival Probability(95% CI) Events Survival Probability(95% CI) Events Survival Probability(95% CI) Events Survival Probability(95% CI) No Early ASCT All 341 195 5.78(5.11 - 6.59) 22 0.94 (0.90 - 0.96) 53 0.84 (0.80-0.88) 84 0.75 (0.70-0.79) 119 0.65 (0.59-0.69) 144 0.57 (0.51 - 0.62) Early ASCT All 90 34 NR 1 0.99 (0.92 - 1.00) 6 0.93 (0.86 - 0.97) 8 0.91 (0.83 - 0.95) 13 0.85 (0.76 - 0.91) 18 0.80 (0.69 - 0.87) NR = not reached Disclosures Biran: Celgene: Speakers Bureau. Siegel:Celgene Corporation: Consultancy, Speakers Bureau; Amgen: Speakers Bureau; Takeda: Speakers Bureau; Novartis: Speakers Bureau; Merck: Speakers Bureau. Fonseca:Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Applied Biosciences: Membership on an entity's Board of Directors or advisory committees; Onyx/Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Binding Site: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding. Vesole:Idera Pharmaceuticals: Research Funding; Celgene Corporation: Speakers Bureau. Williams:Celgene: Consultancy, Research Funding. Abonour:Celgene: Research Funding, Speakers Bureau.

SummaryThe rituximab extended schedule or retreatment trial (RESORT; E4402) was a phase 3 randomized prospective trial comparing maintenance rituximab (MR) versus a retreatment (RR) dosing strategy in asymptomatic, low tumour burden indolent lymphoma. A planned exploratory sub‐study compared the two strategies for small lymphocytic (SLL) and marginal zone lymphomas (MZL). Patients responding to rituximab weekly × 4 were randomized to MR (single dose rituximab every 3 months until treatment failure) or RR (rituximab weekly × 4) at the time of each progression until treatment failure. The primary endpoint was time to treatment failure (TTTF). Patients with SLL (n = 57), MZL (n = 71) and unclassifiable small B‐cell lymphoma (n = 3) received induction rituximab. The overall response rate (ORR) was 40% [95% confidence interval (CI) 31–49%; SLL ORR 22·8%; MZL ORR 52·1%]; all 52 responders were randomized. At a median of 4·3 years from randomization, treatment failure occurred in 18/23 RR and 15/29 MR. The median TTTF was 1·4 years for RR and 4·8 years for MR (P = 0·012); median time to first cytotoxic therapy was 6·3 years for RR and not reached for MR (P = 0·0002). Survival did not differ (P = 0·72). In low tumour burden SLL and MZL patients responding to rituximab induction, MR significantly improved TTTF as compared with RR.

Abstract Purpose: Preclinical studies suggest that SNPs in the Fc gamma receptor (FCGR) genes influence response to rituximab, but the clinical relevance of this is uncertain. Experimental Design: We prospectively obtained specimens for genotyping in the rituximab extended schedule or re-treatment trial (RESORT) study, in which 408 previously untreated, low tumor burden follicular lymphoma (FL) patients were treated with single agent rituximab. Patients received rituximab in 4 weekly doses and responders were randomized to rituximab re-treatment (RR) upon progression versus maintenance rituximab (MR). SNP genotyping was performed in 321 consenting patients. Results: Response rates to initial therapy and response duration were correlated with the FCGR3A SNP at position 158 (rs396991) and the FCGR2A SNP at position 131 (rs1801274). The response rate to initial rituximab was 71%. No FCGR genotypes or grouping of genotypes were predictive of initial response. A total of 289 patients were randomized to RR (n = 143) or to MR (n = 146). With a median follow-up of 5.5 years, the 3-year response duration in the RR arm and the MR arm was 50% and 78%, respectively. Genotyping was available in 235 of 289 randomized patients. In patients receiving RR (n = 115) or MR (n = 120), response duration was not associated with any FCGR genotypes or genotype combinations. Conclusions: Based on this analysis of treatment-naïve, low tumor burden FL, we conclude that the FCGR3A and FCGR2A SNPs do not confer differential responsiveness to rituximab. Clin Cancer Res; 22(4); 821–6. ©2015 AACR. See related commentary by Cartron et al., p. 787