Friedberg, Jonathan W.

Abstract Introduction For patients with Stage III/IV Hodgkin lymphoma (HL), lack of response as assessed by PET scan following cycle 2 (PET2) of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) is predictive of poor clinical outcomes. SWOG Study S0816 utilized response-adapted therapy, where patients achieving a complete remission (CR) on PET2 (Deauville Score ≤ 3) continued 4 additional cycles of ABVD and those patients unable to achieve a complete remission (CR) on PET2 (Deauville Score > 3) were switched to therapy with escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (eBEACOPP) for 6 cycles. This study demonstrated a 2-year PFS of 64% in the PET2+ patients after switching to eBEACOPP, which was much higher than expected (Press 2016). Herein, we report the 5-year follow-up of survival and toxicities of the patients treated on S0816. Methods Patients with Stage III/IV HL were enrolled to S0816 from 7/1/09-12/2/12 (n=358). Eligible patients were age 18-60 years, had measurable disease, no prior lymphoma therapy, a Zubrod performance status of 0-2, and no serious medical comorbidities. Patients were treated with response-adapted therapy as above. A subset of 336 eligible and HIV-negative patients were analyzed. Of 336, 331 had central review of PET2. PFS and OS estimates were calculated using the Kaplan-Meier method. The two-sided Fisher's exact test was used to compare the rate of second cancer between patients switched to treatment eBEACOPP and those treated with continued ABVD after 2 initial cycles of ABVD. Results The median age of patients was 32 years (range, 18-60). All were Stage III/IV and 51% had an International Prognostic Score of ≥ 3. PET2 was negative in 271 patients (82%) and positive in 60 patients (18%). Of PET2+ patients, 49 (82%) switched to eBEACOPP as planned and 11 (18%) declined. Median follow-up is now 5.9 years (range, 0.2-8.3 years). Eighty-five (25%) patients have either progressed or died, for an estimated 5-year PFS of 74% (95% CI: 69%-79%; Figure 1). There were 64 (24%) events in those patients who were PET2- for a 5-year PFS of 76% (95% CI: 71-81%; Figure 2). There were 20 (33%) events in those patients who were PET2+ for a 5-year PFS of 65% (95% CI: 51-76%; Figure 2). One event occurred in a patient without central review of PET2. Nineteen patients have died for an estimated 5-year overall survival of 94% (95% CI: 91%-96%; Figure 1). Eleven (3%) patients died of HL including 6 (2%) that had PET2- and 5 (8%) that had PET2+. Other causes of death included: treatment-related toxicity [sepsis (eBEACOPP n=1), bleomycin lung injury (eBEACOPP n=1; ABVD n=1), and graft versus host disease (ABVD n=1)]; second primary cancers [(eBEACOPP n=2; cervical cancer and non-Hodgkin lymphoma (NHL)]; and unknown causes (ABVD n=2). Post-therapy grade 3 adverse events were uncommon but included 1 case each of heart failure, peripheral neuropathy, prolonged neutropenia, diarrhea, DVT (catheter-related) in patients who received continued ABVD and osteonecrosis of hips/shoulders in patients who received eBEACOPP. There were 13 (4%) cases of reported second cancers, including 7 (14%) in patients treated with eBEACOPP [1 each of myelodysplastic syndrome, kidney, melanoma, NHL, cervical, medullary thyroid, and basal cell carcinoma] and 6 (2%) in patients treated with ABVD (1 each of kidney, melanoma, NHL, bladder, prostate, and squamous cell carcinoma; 2-sided Fisher's exact P value = 0.001). Conclusions The long-term overall survival of the patients treated on S0816 remains high (94%) at 5 years. Despite historical data suggesting favorable clinical outcomes in patients with a negative PET2, nearly 25% of these patients experienced relapse events, demonstrating limitations of a PET-adapted approach and of standard frontline therapy with ABVD. In patients who were PET2+, PFS was favorable relative to historical series, but was associated with a high rate of secondary malignancies. Our results emphasize the importance of long-term follow-up in this disease, and the need for better biomarkers at diagnosis of HL and less toxic approaches for patients with a positive PET2. Acknowledgment In memory of Oliver W. Press, principal investigator of this trial, who died in 2017. Disclosures Straus: DAVA Oncology: Consultancy, Honoraria; Medical Crossfire: Speakers Bureau; Millenium (Takeda): Consultancy, Research Funding; JUNO: Consultancy; Bayer: Consultancy; Onco Tracker: Consultancy; Seattle Genetics: Consultancy; Roch China: Speakers Bureau; InPractice Elselvier: Consultancy; Memorial Sloan Kettering Cancer Center: Employment. Rimsza:NanoString: Other: Inventor on the patent for the Lymph2Cx assay. Bartlett:ImaginAB: Research Funding; Genentech: Research Funding; Forty Seven: Research Funding; Bristol-Meyers Squibb: Research Funding; Merck & Co: Research Funding; Novartis: Research Funding; Celgene: Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Immune Design: Research Funding; Acerta: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra Zeneca: Research Funding; Millennium: Research Funding; Janssen: Research Funding; Affimed: Research Funding; Novartis: Research Funding; Pharmacyclics: Research Funding. Evens:Janssen: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy; Seattle Genetics, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics International DMC: Membership on an entity's Board of Directors or advisory committees; Affimed: Consultancy; Abbvie: Consultancy; Novartis: Consultancy; Tesaro: Research Funding; Acerta: Consultancy. LaCasce:Seattle Genetics: Consultancy, Honoraria; Bristol-Myers Squibb: Other: Data safety and monitoring board; Research to Practice: Speakers Bureau; Humanigen: Consultancy, Honoraria. Barr:AbbVie, Gilead: Consultancy. Leonard:Gilead: Consultancy; Sutro: Consultancy; BMS: Consultancy; Juno: Consultancy; MEI Pharma: Consultancy; Celgene: Consultancy; Bayer: Consultancy; Pfizer: Consultancy; AstraZeneca: Consultancy; Biotest: Consultancy; Novartis: Consultancy; Karyopharm: Consultancy; Genentech/Roche: Consultancy; ADC Therapeutics: Consultancy; United Therapeutics: Consultancy. Kahl:Genentech: Consultancy; Celgene: Consultancy; Acerta: Consultancy; AstraZeneca: Consultancy; Juno: Consultancy; CTI: Consultancy; ADC Therapeutics: Consultancy; Abbvie: Consultancy; Gilead: Consultancy; Seattle Genetics: Consultancy. Smith:BMS: Consultancy; Portola: Honoraria. Friedberg:Bayer: Honoraria.

Abstract Introduction: The optimal initial management of mantle cell lymphoma (MCL) is unknown, but aggressive induction chemoimmunotherapy followed by autologous stem cell transplant confers long remission durations and is standard for younger patients. Cytarabine-based induction achieves higher rates of MRD-negativity compared to anthracycline-based induction regimens and correlates with improved outcomes. Whether a similar benefit exists after bendamustine-rituximab (RB) induction is unknown. S1106 compared induction R-HyperCVAD/MTX/ARAC (RH) or RB followed by autologous stem cell transplantation (ASCT). We previously reported similar 2-year (yr) progression-free survival (PFS) and overall survival (OS) with either regimen, and provocatively found that MRD negativity was similar with both regimens. RH was more toxic than RB and had higher stem cell mobilization failure rates. Methods: Inclusion criteria were untreated stage III, IV or bulky stage II MCL, Cyclin D1 +, age > 18-65, and adequate organ function. Randomization was stratified by MIPI. Patients (pts) received either 4 cycles of RH or 6 cycles of RB followed by ASCT. MRD was assessed at baseline and post induction. Extraction of genomic tumour DNA from paraffin embedded tissue or bone marrow aspirate and PCR amplification of IGH-VDJ, IGH-DJ, and IGK regions was performed followed by high-throughput sequencing to determine the tumor clonotype(s) (Adaptive Biotechnologies). DNA from peripheral blood mononuclear cells (PBMC) and plasma was amplified and sequenced to determine lymphoma molecules per million diploid genomes. Herein we report the results of the updated analysis at a median follow-up (mFU) of 5 yrs. Results: Fifty-two of 53 pts were evaluable. Baseline characteristics were similar between the two groups except for more female pts in the RH group. This study was closed based on prespecified criteria of stem cell mobilization failures in the RH arm. With mFU of 5 yrs (range, 29 days-6yrs), updated ORR (94.1% RH vs. 85.7% RB) and CR (41% RH vs. 43% RB) rates were similar. The 5-yr estimated PFS was 62% and 66% and the 5-yr estimated OS was 74% and 80% for RH and BR, respectively (Fig.1). Increased grade 3/4 toxicity and inadequate stem cell mobilization was seen in the RH arm thus challenging its use as an induction platform for future upfront MCL trials. 9/17 pts in RH and 23/35 pts in RB arm underwent ASCT. A landmark analysis was performed evaluating 5-yr PFS and 5-yr OS with and without ASCT in each arm. (Table 1) 27 patients consented to optional MRD assessment, with 12 paired serial samples (baseline and post induction). Overall, the estimated 5 yr PFS was 90% for all patients who achieved MRD negative status at the end of RB. Long-term toxicity included acute myeloid leukemia (N=1) in the RH arm at 5.4 yrs after diagnosis and lung cancer (n=1) in the RB arm at 2.9 yrs after diagnosis. Conclusion: The optimal induction regimen prior to ASCT in the initial management of MCL is a source of significant debate. Our initial findings supported RB as an effective platform with the ability to achieve MRD negativity. Long-term results of this study continue to demonstrate excellent response rates, 5-yr PFS and 5-yr OS with either RH or RB without any new toxicity signal. The 5-yr outcomes with RB compare favorably to more aggressive cytarabine-based induction regimens. Thus, R-Bendamustine could be an excellent backbone for induction therapy in transplant eligible patients and needs to be tested in larger phase III trials. Support: NIH/NCI grants CA180888, CA180819, CA180821, CA180820, and in part by Sequenta, Inc. (Adaptive Biotechnologies) Disclosures Kamdar: Seattle Genetics: Speakers Bureau; Genentech: Consultancy. Chen:Millennium Pharmaceuticals: Consultancy, Research Funding; Affimed: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Merck & Co., Inc.: Consultancy, Research Funding, Speakers Bureau; Genentech Inc.: Consultancy. Rimsza:NanoString: Other: Inventor on the patent for the Lymph2Cx assay. Barr:AbbVie, Gilead: Consultancy. Phillips:Genentech: Consultancy; Seattle Genetics: Consultancy; Bayer: Consultancy; Gilead: Consultancy; Pharmacyclics: Consultancy, Research Funding; Abbvie: Research Funding. Leonard:ADC Therapeutics: Consultancy; Karyopharm: Consultancy; Bayer: Consultancy; Pfizer: Consultancy; Genentech/Roche: Consultancy; Gilead: Consultancy; Juno: Consultancy; Sutro: Consultancy; AstraZeneca: Consultancy; BMS: Consultancy; Novartis: Consultancy; Celgene: Consultancy; MEI Pharma: Consultancy; United Therapeutics: Consultancy; Biotest: Consultancy. Kahl:Seattle Genetics: Consultancy; AstraZeneca: Consultancy; Gilead: Consultancy; Abbvie: Consultancy; Celgene: Consultancy; Acerta: Consultancy; CTI: Consultancy; Juno: Consultancy; ADC Therapeutics: Consultancy; Genentech: Consultancy. Friedberg:Bayer: Honoraria. Smith:Portola: Honoraria; BMS: Consultancy.

Abstract Background: To address the current and long-term unmet health needs of the growing population of patients diagnosed with non-Hodgkin lymphoma (NHL) and NHL survivors, we established the Lymphoma Epidemiology of Outcomes (LEO) cohort study (NCT02736357; https://leocohort.org/) with recruitment at eight centers (Cornell University, Emory University, Mayo Clinic, MD Anderson, University of Iowa, University of Miami, University of Rochester, and Washington University). Here we report on the first two years of enrollment. Methods: All patients ≥18 years with NHL (exclusive of chronic lymphocytic leukemia) newly diagnosed within 183 days of enrollment are eligible. LEO reviews all pathology diagnoses; annotates and harmonizes all cases with clinical, epidemiologic, pathology and treatment data; builds a NHL tumor bank that includes an H&E slide, a formalin-fixed, paraffin-embedded tissue sample and extracted tumor DNA and RNA; collects peripheral blood and banks DNA, serum, plasma and buffy coat in a central biorepository; and prospectively follows patients regularly to ascertain disease progression/relapse, retreatment, transformation, second cancers, survival, updated exposures, and patient-reported outcomes. We examined the demographics, clinical characteristics, and NHL subtypes for patients enrolled in the first two years (2015-2017) in LEO Cohort and compared these characteristics to population-based registry data from the United States Surveillance, Epidemiology, and End Results (SEER) Program for 2011-2015. We also examined baseline body mass index (BMI), comorbidities and quality of life (QOL) measured with the Functional Assessment of Cancer Therapy - General (FACT-G) scores (0-100 scale) overall and by NHL subtype that were collected in LEO but not available in SEER or any other large, prospective US NHL cohort. Results: From 2015-2017, LEO enrolled 3244 NHL patients across 47 states (Figure) with a median age at diagnosis of 62 years (range, 18-94 years) and 55.9% male. Based on self-identified race/ethnicity, 85% of the participants were White, 7.4% were Black/African American, 2.6% were Asian, and 3.5% other or more than one race; 9.9% were Hispanic (regardless of race). The most common subtypes were diffuse large B-cell (DLBCL, 33.9%), follicular (FL, 22.2%), mantle cell (MCL, 9.3%), marginal zone (MZL, 8.3%), T-cell (TCL, 10.9%), and all other NHL subtypes (other NHL, 15.3%). These distributions were all within 5% of SEER data, except that 6.8% of participant in LEO were in the age 80+ years group compared to 18.5% in SEER (Table). The overall prevalence of self-reported comorbidities at enrollment was 13.5% for heart disease (range, 12.1% for FL to 16.6% for MCL), 8.8% for diabetes (range, 7.1% for FL to 9.8% for DLBCL), 4.6% for osteoporosis (range, 3.0% for MCL to 6.3% for MZL), and 5.9% for autoimmune disease (range, 2.0% for MCL to 12.6% for MZL). The median BMI was 27.9 kg/m2 (range, 26.7 kg/m2 for TCL to 28.3 kg/m2 for MZL). A total of 2151 participants completed the FACT-G with a median score of 78.7 (range, 75.9 for TCL to 83.3 for MZL). Complete IPI data were available on 2296 participants: 40.4% IPI 0-1, 32.7% IPI 2, 18.3% IPI 3, 8.7% IPI 4-5. Overall, 73.7% of participants were initially treated with systemic therapy (range, 40.0% for MZL and 91.8% for DLBCL); 14.5% were initially managed with observation (range, 1.4% DLBCL and 31.8% for FL); and 2.0% were initially manage with radiotherapy (range, 0.2% for MCL and 3.8% for DLBCL). Outcomes are being prospectively collected. Conclusions: LEO is a large and diverse cohort of newly diagnosed NHL patients and the first two years of enrollment reflects the broader United States NHL population. Enrollment is ongoing. This unique resource will enable examination of the interactions among a broad array of clinical and molecular factors and their impact on multiple outcomes, to improve prognostication, identify new approaches to improve outcomes and survivorship, and facilitate clinical trials using this infrastructure. Disclosures Flowers: Acerta: Research Funding; Pharmacyclics/ Janssen: Consultancy; OptumRx: Consultancy; Janssen Pharmaceutical: Research Funding; V Foundation: Research Funding; Burroughs Wellcome Fund: Research Funding; Spectrum: Consultancy; Eastern Cooperative Oncology Group: Research Funding; Abbvie: Consultancy, Research Funding; Bayer: Consultancy; Millennium/Takeda: Research Funding; Abbvie: Research Funding; Celgene: Research Funding; Gilead: Consultancy; BeiGene: Research Funding; Karyopharm: Consultancy; Denovo Biopharma: Consultancy; Genentech/Roche: Consultancy; Gilead: Research Funding; Genentech/Roche: Research Funding; National Cancer Institute: Research Funding; TG Therapeutics: Research Funding; Pharmacyclics: Research Funding. Nastoupil:TG Therappeutics: Research Funding; Merck: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Janssen: Research Funding; Spectrum: Honoraria; Gilead: Honoraria; Genentech: Honoraria, Research Funding; Karus: Research Funding; Novartis: Honoraria; Juno: Honoraria. Kahl:Acerta: Consultancy; Genentech: Consultancy; Seattle Genetics: Consultancy; Juno: Consultancy; CTI: Consultancy; ADC Therapeutics: Consultancy; Gilead: Consultancy; Celgene: Consultancy; AstraZeneca: Consultancy; Abbvie: Consultancy. Casulo:Celgene: Research Funding; Gilead: Honoraria. Friedberg:Bayer: Honoraria. Lossos:Affimed: Research Funding. Martin:Seattle Genetics: Consultancy; Kite: Consultancy; Janssen: Consultancy; Gilead: Consultancy; Bayer: Consultancy; AstraZeneca: Consultancy. Leonard:Bayer: Consultancy; Celgene: Consultancy; Biotest: Consultancy; United Therapeutics: Consultancy; BMS: Consultancy; MEI Pharma: Consultancy; Juno: Consultancy; Sutro: Consultancy; Karyopharm: Consultancy; ADC Therapeutics: Consultancy; Pfizer: Consultancy; AstraZeneca: Consultancy; Gilead: Consultancy; Genentech/Roche: Consultancy; Novartis: Consultancy. Bernal-Mizrachi:Kodikaz Therapeutic Solutions: Consultancy, Equity Ownership; Takeda Pharmaceutical Company: Research Funding. Maurer:Morphosys: Research Funding; Nanostring: Research Funding; Celgene: Research Funding. Cerhan:Nanostring: Research Funding; Jannsen: Other: Scientific Advisory Board; Celgene: Research Funding.

Abstract Background:The role of radiation therapy (XRT) for advanced stage Hodgkin lymphoma (HL) is controversial. In the HD15 trial, the German Hodgkin Study Group (GHSG) administered XRT for PET-positive residual disease ≥2.5 cm at least 2 weeks after completion of chemotherapy and showed 91.5 % in-field control rate with a median follow-up of 102 months (Engert, A; personal communication). However, there is no comparison arm where patients with PET-positive residual disease ≥2.5 cm did not receive XRT. SWOG S0816 was a US intergroup trial utilizing ABVD-based therapy with response adaptation based on interim PET imaging; XRT was not allowed per protocol, and counted as an event. In this analysis, we identified patients in S0816 who would have met HD15 criteria for XRT, but did not receive XRT per design. We then modeled the potential impact of XRT on disease control. Patients and Methods:Of 336 eligible and evaluable HIV-negative patients enrolled in S0816, 49 had an end-of-treatment PET (termed "PET3," to be done 6-8 weeks after completion of chemotherapy) that was positive (i.e. Deauville 4-5) upon central review. We simulated the progression free survival (PFS) if XRT had been delivered per HD15 criteria (PET positive disease and ≥2.5 cm), evaluating by assumptions of 50, 80 and 90% control of the disease within the XRT fields. Receiver operating characteristics (ROC) analyses were performed with additional size cut-off points of 2.0 and 1.5 cm. Results:The median follow-up for the 49 PET3 positive patients was 71 months (range 9.7-92.6). For these 49 patients, the observed landmark PFS at 2 years after the date of PET3 was 30.6%. Twenty-four (49%), 33(67%), and 40 (82%) of the 49 patients had at least one site of disease that met the HD15 criteria for XRT with ≥2.5 cm, ≥2.0 cm, and ≥1.5 cm size cut-offs respectively. Sixteen, 19, and 25 patients had disease progression respectively from each group at median of 1.4-1.5 months. Twelve, 12, and 15 patients had relapses limited to the sites that would have been radiated following HD15 criteria with ≥2.5 cm, ≥2.0 cm, and ≥1.5 cm respectively. Estimated landmark PFS at 2 years for the 49 PET3 positive patients assuming 50, 80, and 90 % control of the disease within the radiated sites following HD15 guideline with ≥2.5 cm, ≥2.0 cm, and ≥1.5 cm cut-off are summarized in columns A, B, and C of the table respectively. For the entire group of 336 patients, the observed PFS at 2 years was 79%. Estimated 2-year PFS for the entire group of 336 patients assuming 50, 80, and 90 % control of the disease within the radiated sites following HD15 guideline with ≥2.5 cm, ≥2.0 cm, and ≥1.5 cm cut-off are in columns D, E, and F of the table respectively. Conclusion: Among the PET3 positive patients, consolidation XRT per HD15 criteria with cut-off points of 2.5, 2.0, and 1.5 cm could have raised the 2-year PFS by 12-28 % assuming 50-90% local control within radiated sites. However, the improvement in PFS is more moderate at 1.6-3.9 % if we consider the entire cohort of 336 patients. Although there may be some gain in PFS as the cut-off point is lowered by our ROC analysis, one needs to consider the trade-off against potentially increasing normal tissue toxicity as more sites are irradiated. Table. Table. Disclosures Brem: Pharamcyclics: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Genetech: Membership on an entity's Board of Directors or advisory committees; Celgene: Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees. Bartlett:Merck & Co: Research Funding; Forty Seven: Research Funding; Celgene: Research Funding; Immune Design: Research Funding; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; ImaginAB: Research Funding; Janssen: Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Millennium: Research Funding; Genentech: Research Funding; Astra Zeneca: Research Funding; Pharmacyclics: Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Meyers Squibb: Research Funding; Affimed: Research Funding; Novartis: Research Funding; Pharmacyclics: Research Funding. Evens:Seattle Genetics, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Affimed: Consultancy; Janssen: Consultancy; Tesaro: Research Funding; Bayer: Consultancy; Acerta: Consultancy; Pharmacyclics International DMC: Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy. Rimsza:NanoString: Other: Inventor on the patent for the Lymph2Cx assay. Leonard:Novartis: Consultancy; Celgene: Consultancy; MEI Pharma: Consultancy; AstraZeneca: Consultancy; ADC Therapeutics: Consultancy; United Therapeutics: Consultancy; BMS: Consultancy; Biotest: Consultancy; Sutro: Consultancy; Karyopharm: Consultancy; Juno: Consultancy; Gilead: Consultancy; Genentech/Roche: Consultancy; Pfizer: Consultancy; Bayer: Consultancy. Kahl:Seattle Genetics: Consultancy; Genentech: Consultancy; Acerta: Consultancy; AstraZeneca: Consultancy; Abbvie: Consultancy; ADC Therapeutics: Consultancy; CTI: Consultancy; Gilead: Consultancy; Juno: Consultancy; Celgene: Consultancy. Smith:BMS: Consultancy; Portola: Honoraria. Friedberg:Bayer: Honoraria.

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

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

Abstract Abstract 3708 Background: Rituximab maintenance (RM) following induction therapy has been demonstrated to increase PFS in randomized trials in both first-line and relapsed settings (ECOG 1496, EORTC 20981, and most recently, PRIMA), and RM has been frequently used in clinical practice in the U.S. and other countries. We examined the various RM approaches used by practicing physicians in the U.S., factors that predicted whether RM was used, and compared the “real-world” effectiveness of RM to the outcomes of observation (Obs) following front-line R-based induction in FL patients (pts). Methods: The National LymphoCare Study is a prospective, multi-center, longitudinal, observational study that collects data on treatment and outcomes for pts diagnosed with FL in the U.S. from 2004–2007. Pts who achieved complete response (CR), partial response (PR) or stable disease (SD) following initial treatment with R-based therapy and who did not initiate second line therapy during the 215-day period following the date of last dose of initial therapy were categorized as Obs. Pts meeting the same criteria who started maintenance R treatment in the 215-day period comprise the RM group. Multivariable logistic regression analyses were performed to identify characteristics related to receiving RM. We compared RM and Obs groups in progression-free survival (PFS), time to next treatment (TTNT), and overall survival (OS) using Cox proportional hazards models controlling for confounding factors of clinical interest (sex, FLIPI risk group, treatment setting [academic vs. community], and induction therapy). PFS was defined as the number of days from the 215 day period following induction that defined the Obs and RM groups up to and including the date of disease progression as assessed by the treating physician or death from any cause. Pts who had not yet experienced a PFS event at the time of analysis were censored at the date of the most recent response assessment. Results: Of the 2,732 pts enrolled in NLCS, 1,536 pts completed R-based induction therapy. Among these,1,236 pts achieved CR/PR/SD and met other criteria described above to be included in analysis. 557 pts started RM treatment in the 215-day post-induction work up period (128 following R and 429 following R-chemo), and 679 pts were observed (125 following R and 554 following R-chemo). The mean duration of RM was 528 days, and the mean number of RM doses received was 13. 23% received Rx4 every 6 months, 20% Rx1 every 2 or 3 months, and 57% received another schedule. 14% of pts discontinued RM early (n=79). The most common reasons for early discontinuations were disease progression (29%), toxicity (11%), or death (7%). Pts who received R induction were more likely to receive RM than those who received R-chemo as induction (51% vs. 44%). Pts treated in community practices were slightly more likely to receive RM compared with those who were treated in academic centers (46% vs. 40%). In multivariable models, the most significant predictors of receiving RM were grade (I/II), stage (III/IV), geographic region (other than West), community practice setting, and R induction treatment (all p<0.05). After adjusting for FLIPI risk group, induction treatment, and clinical factors, RM significantly improved PFS (HR= 0.72; p= 0.010) and TTNT (HR= 0.74; p= 0.03). At 4 years of follow-up, 11% of pts in the combined population have died and there was no significant difference in OS between RM and Obs groups. 22% (n=124) of RM pts had received 2nd line treatment at the time of analysis, of whom 36% received R alone and 31% received R-chemo. The response rate for 2nd treatment was similar between RM and Obs groups (60% CR/PR for both groups). Conclusions: RM following front-line R-based induction was common in this period. However, a large percentage of pts received a RM schedule that was not consistent with standard published schedules reflecting variation among community practices. Nevertheless, RM use in clinical practice produced significant differences in PFS and TTNT compared to Obs. Importantly, response to second-line treatment was similar between RM and Obs groups. Additional followup is needed to determine whether RM produces OS benefits in this context. Disclosures: Sinha: Celgene: Research Funding. Zhou:RTI-HS: Employment; Novartis: Research Funding. Friedberg:Genentech: Consultancy; astellas: ; Lilly: ; Abbott/Trubion: ; Seattle Genetics: Honoraria; Cephalon: Consultancy. Hirata:Genentech Inc/Roche: Employment; Roche: Equity Ownership. Flowers:Spectrum: Consultancy, Research Funding; Millennium/Takeda: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Genentech/Roche (unpaid): Consultancy; Novartis: Research Funding; Seattle Genetics: Consultancy.

Abstract Abstract 1603 Background: We have previously reported similar outcomes for patients with bulky stage I or II mediastinal HL treated with combined modality therapy either with ABVD + radiotherapy or the Stanford V regimen in the North American Intergroup trial E2496 (Advani et al, ASH 2010 abstract 416). In the current analysis, we compare the patterns of failure between the two groups. Methods: Patients with stage I/II bulky mediastinal HL (maximum mediastinal mass width > 1/3 of intrathoracic diameter) were randomized to receive chemotherapy (CT) on either Arm A (ABVD x 6–8 cycles administered q 28 days) or Arm B (12 weeks of Stanford V administered weekly). Two-3 weeks after completion of chemotherapy all patients received modified involved field radiotherapy (RT) (36 Gy) delivered to the mediastinum, hila, and supraclavicular regions. Patients on Stanford V arm also received involved field RT to any other sites ≥ 5 cm at diagnosis. Patients were assessed 3, 6 and 12 months after completing RT with computed tomography scanning and then every 6 months for 5 years. The primary end points were failure free survival (FFS) and overall survival (OS). Disease progression was defined as 'in-field', 'distant' or both relative to the radiation fields prescribed in the E2496 protocol. Distant sites of failure were further characterized as intra-thoracic, intra-abdominal or other (bone, bone marrow and axillae, if not previously irradiated). Results: Two hundred and sixty-seven patients were randomized: 136 on the ABVD arm and 131 on the Stanford V arm. Patient characteristics were well matched with no differences between two arms in overall response rates (ORR), FFS and OS. (Advani et al ASH 2010 abstract 416). At a median follow up of 5.5 years 40 patients have relapsed with no difference in ABVD (n=18, 13%) versus Stanford V (n=22, 17%) (p=0.49). Central review of RT fields available in 37/40 patients found major violations with under treatment of tumor noted in 7/37 (19%). Patterns of failure are shown in Table 1. There were no differences in patterns of relapse for the two study arms. In-field relapses occurred in <10% in both study arms. Conclusion: For patients with stage I/II bulky mediastinal HL, combined modality therapy with either ABVD +RT or the Stanford V regimen results in excellent disease control. In-field relapse was uncommon. These results set a benchmark for assessing ongoing trials omitting RT in patients with stage I/II bulky mediastinal HL. Future research efforts should focus on risk stratification to identify the small subset of patients who are likely to fail standard upfront therapy. US cooperative group efforts in this subset of patients are ongoing that use interim PET-CT imaging based risk-adapted strategies. Disclosures: Horning: Genentech: Employment, Equity Ownership.

Abstract Abstract 415 Background: The ability to cure patients (pts) with advanced Hodgkin's Lymphoma (HL) with combination chemotherapy (CC) (MOPP and variants, ABVD and variants) represented a major milestone in oncology research, and CC became a paradigm for other malignancies. Further, the rationale for combined modality therapy (CMT) (radiation (RT) and CC) in HL evolved based on the high frequency of relapse in initially involved sites. As response rates and survival improved, newer treatments such as the combined modality Stanford V regimen were developed to shorten the duration of chemotherapy, add RT to sites of disease and reduce toxicity while maintaining or improving the cure rate. Indeed, the Stanford V regimen was tested and validated in a Phase II co-operative group trial (E1492) (J Clin Oncol 2000; 18:972). In order to investigate this approach against “standard” therapy, we conducted a randomized Phase III Intergroup trial of ABVD vs. the Stanford V regimen for patients with locally extensive or advanced HL. Objectives: The trial was designed to detect a 33% reduction in the failure free survival (FFS) hazard rate with Stanford V compared with ABVD, which corresponds to a difference in five-year FFS of 64% vs. 74%. Method: Patients with locally extensive (defined as clinical Ann Arbor Stage I-IIA/B and bulky mediastinal disease (BMD) (mass > 1/3 maximum intrathoracic diameter on standing postero-anterior chest x-ray or >/−10 cm on computerized tomography) or advanced (Ann Arbor Stage III or IV) HL were randomized to receive either ABVD × 6–8 cycles (C) (51% had 6 C, 35% had 8 C, 14% had <6 C) + 36 Gy (only in pts with BMD) or Stanford V × 12 weeks (95% had 12 weeks) + 36 Gy (for sites >5cm or for macroscopic splenic disease). The log-rank test was used to compare FFS for all eligible patients stratified on extent of disease (locally extensive vs. advanced), and number of International Prognostic Factor Project (IPFP) risk factors (0–2 vs. 3–7). An extended Cox model was also used to address non-proportional hazard between the two arms. Results: 854 pts enrolled from April, 1999 to June, 2006 and 812 were eligible for analysis. 404 pts were randomized to ABVD and 408 to Stanford V. Median age was 33 yrs in both arms (range 16–83). 53% were men and 47% women; 4% had Stage I, 31% had Stage II, 39% had Stage III and 25% had Stage IV disease by Ann Arbor criteria. 35% of pts on ABVD and 35% on Stanford V had BMD. Three % of pts had nodular lymphocyte predominant HL, 77% of pts had nodular sclerosis HL, 14% had mixed cell HL. Age, stage, pathology and risk factors (0–2 vs. 3–7) were similar in both arms. In total, 65% were IPFP score 0–2 and 33% were 3–6. Response rate. There was no difference in response rates (RR) between the two arms (ABVD=72% CR+ CCR, 7.7% PR, 7.9% SD; Stanford V= 69 % CR +CCR, 7% PR and 10 % SD. 8% were not evaluable for response on ABVD and 9% on Stanford V. Toxicity was similar in both groups. The most frequent Grade 3 + 4 toxicity was neutropenia, and was similar between the 2 groups (76% Grade 3 + 4 in ABVD and 70% Grade 3+ 4 in Stanford V). Grade 5 toxicity was <1% in both groups. There was, however, more Grade 3 lymphopenia in Stanford V (78% vs. 42%, p< 0.0001) and more Grade 3 +4 sensory neuropathy in Stanford V (10%) than in ABVD (3%) (p< 0.0001). A total of 26 second primary cancers developed, 12 after ABVD and 14 after Stanford V (p=NS). FFS and OS. For 812 eligible patients, with a median follow up of 5.25 years, 5-year FFS was 73% for ABVD and 71% for Stanford V (p=0.29 by log rank) (Figure left); 5-year OS was 88% for ABVD and 87% for Stanford V (p=0.87 by log-rank, HR=0.97, 95% CI: 0.65 to 1.44) (Figure right) indicating no significant difference in either FFS or OS between the 2 arms. Conclusion: In the largest Phase III intergroup trial of HL in North America, there was no significant difference in RR, FFS, OS, and 5-year toxicity when ABVD (+ RT for BMD) is compared with Stanford V (+RT for nodal sites >5 cm and macroscopic splenic disease). There was more Grade 3 lymphopenia (p< 0.0001) and more Grade 3 + 4 sensory neuropathy (p< 0.0001) on Stanford V. Thus ABVD (plus RT for BMD) remains the standard of care because Stanford V did not meet the objective of 33% improvement in FFS. For some patients, Stanford V, when given as described with RT, remains an acceptable alternative. Disclosures: Friedberg: Genentech: Honoraria. Blum:Seattle Genetics: Research Funding; Novartis: Research Funding; Celgene: Research Funding. Horning:Genentech: Employment.

Abstract Abstract 416 Background: Standard therapy for locally extensive Hodgkin Lymphoma (HL) defined as stage I/II with bulky mediastinal disease [mediastinal mass ratio (MMR) > than 1/3 of the chest diameter on standing postero-anterior chest x-ray or 10 cm on computerized tomography] is combined modality therapy (CMT). E2496 was a North American intergroup, randomized phase III study comparing ABVD versus the Stanford V regimen for patients with locally extensive and advanced stage HL. In this subgroup analysis we compare two CMT approaches, ABVD + radiotherapy (RT) and the Stanford V regimen, in patients with stage I/II bulky mediastinal HL. Methods: Patients with stage I/II HL bulky mediastinal disease were randomized to receive chemotherapy (CT) on either Arm A (ABVD × 6–8 cycles administered q 28 days) or Arm B (12 weeks of Stanford V, administered weekly). Two-3 weeks after completion of chemotherapy, modified involved field RT was delivered at 36 Gy to the mediastinum to patients on ABVD as well as Stanford V. Patients on Stanford V also received involved field RT to any other sites >5 cm at diagnosis. The primary endpoint was failure free survival (FFS) defined as the time to either progression/relapse or death. The log-rank test was used to compare FFS and OS (overall survival) for all eligible patients. Results: Of the 812 eligible patients with advanced HL enrolled on the study 267 had locally advanced bulky mediastinal disease: 136 on ABVD and 131 on Stanford V. Patient characteristics between the two randomized groups were well matched with a median age of 30 years and 86% had stage II disease. On ABVD 61% of patients received 6 cycles, 29% 8 cycles of CT and 77% required some dose modification. In Stanford V 97% completed the assigned 12 weeks of CT and 76% required some dose modification. 82% received RT per protocol in ABVD versus 88% in Stanford V. The overall response (CR+PR) was 82% in ABVD and 86% in Stanford V. At a median follow-up of 5.47 years, there are 19 failures and 6 deaths in the ABVD group and 25 failures with 9 deaths in the Stanford V group. We failed to detect statistically significant differences between ABVD +RT and Stanford V for FFS (5y 85% versus 77% p=0.13, HR=1.56 95% CI (0.87, 2.88) and OS (5y 95% versus 92% p=0.31, HR=1.69 95% CI (0.60, 4.75). No difference in hematologic toxicity was observed between the two arms. Evaluation of pulmonary function and patterns of failure are pending. Conclusions: For stage I/II patients with bulky mediastinal disease, CMT with either ABVD +RT or the Stanford V regimen results in high cure rates and is highly effective. ABVD for 6–8 cycles plus 36 Gy RT remains the US standard of care. Longer follow up is required to assess RT related late effects. Future research efforts should focus on risk stratification to identify; a) the 15–20% of patients destined to relapse after standard therapy and evaluate treatment intensification strategies and b) the 80–85% of patients who are cured with standard therapy and determine whether a subset can achieve the same excellent outcomes with a reduction or elimination of radiation. Planned US cooperative group trials will address these questions, using ABVD as the chemotherapy backbone in conjunction with interim PET imaging for risk stratification. Disclosures: Blum: Seattle Genetics: Research Funding; Novartis: Research Funding; Celgene: Research Funding. Horning:Genentech: Employment.