LeBlanc, Michael

Introduction Limited stage disease accounts for 30-40% of Diffuse Large B-cell Lymphoma (DLBCL), with better overall survival than advanced stage disease, but with increased late relapses regardless of treatment strategy (Stephens 2016). Preferred treatment for these patients (pts) per NCCN guidelines is abbreviated R-CHOP followed by radiotherapy. Based on promising results of radioimmunotherapy consolidation in SWOG S0313 (Persky 2015), and of PET-directed experience by the BC Cancer Agency (Sehn 2011), we designed a National Clinical Trials Network (NCTN) PET-directed study to tailor therapy after 3 cycles of R-CHOP, to improve outcomes and decrease toxicities. Methods Pts had non-bulky (< 10 cm) stage I/II untreated DLBCL. Mediastinal, HIV-associated, testicular, central nervous system, and indolent lymphoma were excluded. Pts received standard R-CHOP therapy and had an interim PET scan on day 15-18 of cycle 3, which was centrally reviewed in real time. Pts with negative PET scan (Deauville 1-3, iPET-neg) proceeded with 1 additional cycle of R-CHOP. Pts with positive PET scan (Deauville 4-5, iPET-pos) initiated 36 Gy of involved field radiation therapy (IFRT), plus additional boost to FDG-avid area up to 9 Gy, within 5 weeks of 3rd cycle of R-CHOP. This was followed by ibritumomab tiuxetan (IFRT-Zevalin) 3-6 weeks after completing IFRT. Final PET scan was performed 12 weeks after treatment completion. Results The study completed accrual in June 2016. Safety, response, interim PET, and immunohistochemistry-based cell of origin (COO) and MYC/BCL2 analyses were presented previously (Persky 2017, Stephens 2017). Of 159 pts enrolled, 1 was upstaged by PET, and 26 pts were ineligible - due to incorrect histology (mostly concurrent indolent or follicular lymphoma grade 3B) (21), lack of diagnostic tissue submission for central pathology review (3), and bulky disease (2). In 132 eligible pts, median age was 62 years, 62% had stage I, 17% had B symptoms, 14% had elevated LDH, 43% had extranodal involvement, and 66% had exclusive involvement of the head and neck region. Stage modified IPI (smIPI, Miller 1998) was 0 in 27%, 1 in 42%, 2 in 28%, and 3 in 4% of the pts. COO by Lymph2Cx was assessable in 87 pts - 68% were GCB, 23% were ABC, and 9% were unclassifiable. Double protein expressers (MYC and BCL2, DPE) were 16%, while 4 (3%) pts had "double hit" lymphoma (DHL) - 2 with MYC/BCL2 and 2 with MYC/BCL6 rearrangements - none of which were DPE. Of 132 eligible pts, 128 had an interim PET scan centrally reviewed, of which 110 were iPET-neg. Only 18 were iPET-pos, 4 of them due to infection (Deauville X) which were treated as iPET-neg. Of 14 truly iPET-pos pts (11%), 2 refused radiation, and 12 pts received IFRT-Zevalin. Eight pts (67%) converted from PR to CR after IFRT-Zevalin and 4 (33%) had PR, for an overall CR of 92% and PR of 4% (with 4% unevaluable). With median follow up of 4.5 yrs (range 1.1 - 7.5 yrs), only 5 pts progressed and 2 died from lymphoma. Of 5 progressors, 3 received R-CHOP x 4, 1 was iPET-pos but declined radiation, and 1 went off treatment after 1 cycle of R-CHOP. Eleven pts died from non-lymphoma causes, including 1 pt from secondary AML (iPET-neg arm), and 1 of lung adenocarcinoma diagnosed upon iPET. S1001 5-yr PFS estimate is 87% and OS estimate is 90% (figure 1), with iPET-pos and iPET-neg pts having similar outcomes - PFS 86% vs. 88%, OS 93% vs. 91%, respectively. Five-yr PFS by smIPI was 97% for smIPI of 0, 86% for 1-2, and 30% for 3. GCB had 5-yr PFS of 95%, vs. 70% for ABC and 47% for unclassifiable. DPE pts had 5-yr PFS of 70, vs. 89% for non-DPE pts. All 4 DHL pts maintain remission. Conclusions S1001 is the largest US study of limited stage DLBCL in the rituximab era, with best NCTN results in this disease subset. Only 5 patients progressed and 2 died from lymphoma. Our study confirms the distinct biology of limited stage DLBCL, with predominance of GCB origin (68%), and head and neck location (66%). Due to small number of lymphoma events, no strong conclusions about prognostic ability of smIPI, COO, DPE, or DHL, could be made. S1001 demonstrated that 89% of pts maintained excellent outcomes after R-CHOP x 4 with PET-directed therapy. Only 11% of pts were iPET-pos and required radiation, but they also had excellent outcomes. Together with the FLYER trial in younger pts (Poeschel 2018), this NCTN trial establishes R-CHOP x 4 alone as the new standard approach to limited stage disease for majority of the pts. Disclosures Persky: Sandoz: Consultancy; Morphosys: Other: Member, Independent Data Monitoring Committee; Debiopharm: Other: Member, Independent Data Monitoring Committee; Bayer: Consultancy. Stephens:Acerta: Research Funding; Karyopharm: Research Funding; Gilead: Research Funding. Park:BMS: Consultancy, Research Funding; Rafael Pharma: Membership on an entity's Board of Directors or advisory committees; G1 Therapeutics: Consultancy; Teva: Consultancy, Research Funding; Gilead: Speakers Bureau; Seattle Genetics: Research Funding, Speakers Bureau. Bartlett:Seattle Genetics: Research Funding; ADC Therapeutics: Consultancy, Research Funding; Pfizer: Research Funding; Millenium: Research Funding; Bristol-Myers Squibb: Research Funding; Celgene: Research Funding; Genenetech: Research Funding; Immune Design: Research Funding; Gilead: Research Funding; Forty Seven: Research Funding; Janssen: Research Funding; Affimed: Research Funding; Merck: Research Funding; Pharmacyclics: Research Funding. Swinnen:Pharmacyclics: Consultancy; AbbVie: Consultancy. Barr:Celgene: Consultancy; Merck: Consultancy; Seattle Genetics: Consultancy; Genentech: Consultancy; Verastem: Consultancy; Gilead: Consultancy; Astra Zeneca: Consultancy, Research Funding; Janssen: Consultancy; AbbVie: Consultancy; Pharmacyclics LLC, an AbbVie company: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding. Leonard:Nordic Nanovector: Consultancy; Akcea Therapeutics: Consultancy; BeiGene: Consultancy; Gilead: Consultancy; Miltenyi: Consultancy; ADC Therapeutics: Consultancy; Nordic Nanovector: Consultancy; Akcea Therapeutics: Consultancy; Sandoz: Consultancy; ADC Therapeutics: Consultancy; Miltenyi: Consultancy; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy; Karyopharm Therapeutics: Consultancy; Epizyme, Inc: Consultancy; Sutro Biopharma: Consultancy; AstraZeneca: Consultancy; AstraZeneca: Consultancy; Bayer Corporation: Consultancy; Bayer Corporation: Consultancy; Celgene: Consultancy; Epizyme, Inc: Consultancy; Celgene: Consultancy; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy; Merck: Consultancy; MorphoSys: Consultancy; Karyopharm Therapeutics: Consultancy; Gilead: Consultancy; Sutro Biopharma: Consultancy; BeiGene: Consultancy; Merck: Consultancy; MorphoSys: Consultancy; Sandoz: Consultancy. Kahl:TG Therapeutics: Consultancy; ADC Therapeutics: Consultancy, Research Funding; Seattle Genetics: Consultancy; BeiGene: Consultancy. Fisher:Celgene: Consultancy; AstraZeneca: Consultancy; Barclays: Honoraria; prIME: Honoraria. Rimsza:NanoSting: Patents & Royalties: Named inventor on a patent licensed to NanoSting [Institution]. Smith:Portola Pharmaceuticals: Research Funding. Friedberg:Bayer: Honoraria, Other: Data & Safety Monitoring Committee; Acerta: Other: Data & Safety Monitoring Committee. OffLabel Disclosure: Ibritumomab tiuxetan in diffuse large B-cell lymphoma

Abstract Background: Southwest Oncology Group (SWOG) S0016 was a phase III randomized study that compared safety and efficacy of cyclophosphamide, doxorubicin, vincristine, prednisone and rituximab (CHOP-R) with CHOP followed by consolidation with (131) iodine-tositumomab radioimmunotherapy (CHOP-RIT) for previously untreated follicular lymphoma (FL) patients. As reported previously, the study demonstrated excellent outcomes in both arms with 2-year progression-free survival (PFS) of 76% and 80% and 2-year overall-survival (OS) of 97% and 93% in the CHOP-R and CHOP-RIT arms, respectively. (Press. et al. JCO, 2012) We now report the long term outcome of patients who were treated on the S0016 study. Methods: Between 2001 and 2008, 531 previously untreated advanced follicular lymphoma patients were randomized to receive either 6 cycles of CHOP every 3 weeks with 6 doses of rituximab (CHOP-R) or 6 cycles of CHOP every 3 weeks followed by RIT. Patients with advanced-stage disease (bulky stage II, III or IV) with any pathologic grade (1, 2 or 3) were eligible. Results: Patients on CHOP-R (n=264) and CHOP-RIT (n=267) arms had balanced baseline characteristics including age (median 54.5 vs. 53.4 years), presence of B symptoms (29% vs. 26%), pathologic grade 3 (8% vs. 9%), "high" FLIPI risk group (22% vs. 26%), stage IV disease (59% vs. 63%), elevated β2M (53% vs. 55%), bone marrow involvement (56% vs. 55%) and bulky disease (24% vs. 26%). Objective remissions were documented in 226 of 267 eligible patients treated with CHOP-R (85%) and in 226 of 264 patients with CHOP-RIT (86%). Complete remission (CR) rate was 40% in the CHOP-R and 45% in the CHOP-RIT arm. Neutropenia was the most common adverse event (AE) in both arms (48% vs. 51%). Rate of grade 3-5 AEs were not different except for thrombocytopenia which was more common in the CHOP-RIT group (18% vs. 2%). After a median follow-up of 9.6 years (range 0.1 - 14.4 years), the estimated 10-year PFS was 42% (95% CI: 35.6%, 48.5%) in the CHOP-R arm and 57% (95% CI: 50.5%, 63.2%) in the CHOP-RIT arm (p-value = 0.01). 51% of responders on the CHOP-R arm and 38% of responders on the CHOP-RIT arm have relapsed (p-value= 0.01). The estimated 2-year relapse-free survival was 76% for CHOP-R patients and 81% for CHOP-RIT patients (p-value=0.15). There were 48 deaths in the CHOP+R arm and 59 deaths in the CHOP-RIT arm with an estimated 10-year OS of 82% (95% CI: 76.3%, 86.4%) with CHOP-R and 77% (95% CI: 70.5%, 81.4%) with CHOP-RIT (p-value = 0.18). (Figure-1) During the follow-up, 41 patients (15.4%) in the CHOP-R arm and 37 patients (14%) in the CHOP-RIT arm developed secondary malignancies. MDS/AML were more common in the CHOP-RIT arm (11 patients; 4.2%) compared to CHOP-R arm (5 patients; 1.9%) with a relative risk of 2.2 (95% CI: 0.8-6.3) (P-value 0.12). Conclusion: With almost 10 years of follow-up, patients with FL treated on protocol S0016 show outstanding survival in both CHOP-R and CHOP-RIT arms, and represent the best published long-term outcomes to date in this disease. Indeed, almost half of patients enrolled still remain progression-free, confirming registry experiences. While CHOP-RIT provided significantly longer PFS and lower relapse rate compared to CHOP-R in our study, the OS rate was not different between 2 arms due in part to higher incidence of fatal MDS/AML in the CHOP-RIT group, emphasizing the importance of long-term follow-up, and calling into question the validity of PFS as a surrogate for OS in this setting. Given these outstanding outcomes, we believe chemoimmunotherapy should remain the standard induction approach for patients with high-risk FL until long-term follow-up of alternative approaches demonstrates superiority. Support: NIH/NCI grants CA180888, CA180819, CA180821 and in part by GlaxoSmithKline Disclosures Shadman: Emergent: Research Funding; Acerta: Research Funding; Gilead: Honoraria, Research Funding; Pharmacyclics: Honoraria, Research Funding. Rimsza:NCI/NIH: Patents & Royalties: L.M. Rimsza is a co-inventor on a provisional patent, owned by the NCI of the NIH, using Nanostring technology for determining cell of origin in DLBCL.. Gopal:Paid Consultancy- Gilead, Janssen, Seattle Genetics, Spectrum, Research funding- Gilead, Janssen, Pfizer, BMS, Merck, Teva, Takeda, Spectrum, Seattle Genetics: Consultancy, Honoraria, Research Funding. Maloney:Juno Therapeutics: Research Funding; Genentech/Roche: Honoraria. Cheson:Gilead: Research Funding; Pharmacyclics: 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, Research Funding. Smith:Amgen: Other: Educational lecture to sales force; TGTX: Consultancy; Celgene: Consultancy; Pharmacyclics: Consultancy; Genentech: Consultancy, Other: on a DSMB for two trials ; Portola: Consultancy; Juno: Consultancy; Gilead: Consultancy; AbbVie: Consultancy. Fisher:Seattle Genetics: Consultancy; Gilead: Consultancy; Johnson and Johnson: Consultancy. Friedberg:Bayer: Other: Data Safety Monitoring Committee. Press:Roche / Genentech: Consultancy, Research Funding.

Background: Activation induced cytidine deaminase (AICDA or AID) causes somatic hypermutation (SHM) of the immunoglobulin heavy chain variable genes (IGHV). It has been widely hypothesized that aberrant targeting of AICDA creates additional driver mutations and intra-clonal heterogeneity which enables clonal evolution and thus disease progression. This hypothesis predicts that greater AICDA-mediated intraclonal heterogeneity will be associated with shortened progression free survival (PFS). To definitively test this hypothesis that AICDA-mediated heterogeneity is linked to risk of progression, we evaluated available samples from the largest US-based phase 3 trial of untreated follicular lymphoma patients treated with CHOP-based therapies, SWOG trial S0016. Methods: We have previously shown that ultradeep sequencing of two genes, the expressed IGHV and the 5' UTR of the translocated BCL2 allele, provide unrelated measures of AICDA-mediated genetic heterogeneity (Spence, J Immunol. 2014). Furthermore, the number of AICDA-mediated mutations in the 5' UTR of BCL2, but not in IGHV, correlates with the number of AICDA-mediated mutations at other known AICDA sites throughout the genome (such as PIM1, BCL6, RHOA, etc). Genomic DNA was prepared from all available paraffin-embedded specimens. Ultra-deep, amplicon-based sequencing (~10,000x) with internal controls to establish specimen-specific signal-to-noise parameters allowed sensitive and specific detection of sequence variants at 0.2% (FDR 1%). Results: For subjects with (152) and without (419) available specimens, the median duration of follow-up (11.3 years), the number of patients who progressed (60%), and other patient characteristics (demographics, histology, stage, FLIPI) were indistinguishable. Sequencing data that fulfilled strict quality metrics for low frequency variants were obtained for >75% of the specimens (114 for BCL2; 120 for IGHV); further analysis was restricted to these subjects. The extent of intraclonal variation within both the IGHV and the 5' UTR of BCL2 was highly variable. For BCL2, a median of 7 mutations/case were detected (range 0-61); the mutations were highly skewed to the RCYW motif (p<0.001), the preferred target of AICDA. These mutations defined a median of 5 subclones/case (range 1-22). The clonal IGHV was somatically mutated (<0.98 germline identity) in 94% of samples (median 0.89). For IGHV, a median of 113 subclones/case were detected (range 0-1531). Consistent with our prior study, no correlation was seen between the number of mutations detected in the IGHV and BCL2 or the number of subclones defined by IGHV and BCL2. Neither the number of mutations in nor the number of subclones defined by BCL2 or IGHV were prognostic. Cox regression showed no relationship between PFS and mutation number or subclone count based on either IGHV or BCL2 (hazard ratios are indistinguishable from 1; parameters were treated both as a continuous variables and dichotomized as quartiles). Furthermore, receiver operator curves did not suggest a cut point for any of these measures that would predict disease progression at any time (areas under the curve are indistinguishable from 0.5). Conclusions: Several measures of AICDA-mediated mutation and resulting subclonal heterogeneity were not found to be prognostic in previously untreated, advanced stage FL treated with CHOP-based regimens. In contrast, AICDA-mediated mutations have been reported to accrue during transformation from low grade FL to large cell lymphoma. This paradox calls for a more refined model to explain the role of AICDA in the progression of FL. Support: NIH/NCI grants U10CA180888, U10CA180819, U10CA180821, R21CA198072(WRB); and in part by GlaxoSmithKline. Disclosures Rimsza: NanoSting: Patents & Royalties: Named inventor on a patent licensed to NanoSting [Institution]. Leonard:Bayer Corporation: Consultancy; AstraZeneca: Consultancy; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy; Sandoz: Consultancy; ADC Therapeutics: Consultancy; Miltenyi: Consultancy; BeiGene: Consultancy; Sutro Biopharma: Consultancy; Celgene: Consultancy; Nordic Nanovector: Consultancy; Gilead: Consultancy; Karyopharm Therapeutics: Consultancy; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy; Bayer Corporation: Consultancy; Celgene: Consultancy; Epizyme, Inc: Consultancy; Merck: Consultancy; MorphoSys: Consultancy; AstraZeneca: Consultancy; Epizyme, Inc: Consultancy; Akcea Therapeutics: Consultancy; Miltenyi: Consultancy; ADC Therapeutics: Consultancy; BeiGene: Consultancy; Karyopharm Therapeutics: Consultancy; Merck: Consultancy; Sandoz: Consultancy; Gilead: Consultancy; Akcea Therapeutics: Consultancy; MorphoSys: Consultancy; Nordic Nanovector: Consultancy; Sutro Biopharma: Consultancy. Fisher:Celgene: Consultancy; Barclays: Honoraria; AstraZeneca: Consultancy; prIME: Honoraria. Smith:Portola Pharmaceuticals: Research Funding. Friedberg:Bayer: Honoraria, Other: Data & Safety Monitoring Committee; Acerta: Other: Data & Safety Monitoring Committee.

Key Points Five-year follow-up of S1106 demonstrates similar efficacy, MRD negativity, and 5-year survival with RH or RB, but RH was more toxic than RB. RB showed excellent efficacy and survival and less toxicity compared with a cytarabine-based regimen in transplant-eligible MCL patients.

Abstract Background: TP53 is reported to be mutated in about 20% of transformed and/or relapsed follicular lymphoma (FL) specimens but in fewer than 5% of pre-treatment FL specimens. The disparity in the reported prevalence of TP53 mutations at diagnosis versus transformation/relapse suggests that TP53-mutated subpopulations, which are too small for detection, might be present at the time of diagnosis in tumors destined to relapse. To test this hypothesis, we developed a more sensitive assay for TP53 mutations and applied the assay to SWOG S0016, a phase III randomized intergroup trial of CHOP chemotherapy plus rituximab (R-CHOP) compared with CHOP chemotherapy plus 131-iodine tositumomab (radio-immunotherapy (RIT)-CHOP) for previously untreated follicular non-Hodgkin lymphoma. Methods: Formalin Fixed Paraffin Embedded (FFPE) biopsies were available for 213/571 enrollees. 147 samples fulfilled inclusion criteria: 1) sufficient DNA for 3 PCR-reactions each at 250 ng gDNA (~40,000 diploid equivalents; 5'UTR and all exons of TP53 were amplified in 3 multiplexed reactions to obtain consistently sized amplicons); 2) appropriate size distribution of DNA products after library preparation (~300 bp). To maintain specificity with high read-coverage, each PCR included an amplicon of eUCR41 (eukaryotic ultra-conserved region) to provide specimen-specific metrics of DNA-damage and sequencing noise. Sequence reads (Ilumina 300 nt paired end) were merged, mapped to reference (>10,000x coverage), and single nucleotide variants (SNV) were called using LoFreq based on case and base-change error thresholds (from the eUCR41 data). Pathogenicity of each TP53 sequence variant was based on a consensus of the Seshat and IARC databases. Variant Allele Frequencies (VAF) of passenger SNVs (5'UTR of BCl2) allowed normalization to the minimum tumor fraction. Results: A total of 73 SNVs within TP53 were detected in 147 FFPE specimens (80 RIT-CHOP; 67 R-CHOP); the SNVs in 34 patients (23%; 17-30% 95% CI) created missense or nonsense mutations which met criteria for pathogenicity. The VAF for these SNVs ranged from 0.008 to 0.7 (median 0.02) and 82% had a VAF of less than 0.1. Among the 34 patients with a pathogenic TP53 mutation, no relationship was observed between the VAF and time to progression. The group of 34 patients with a pathogenic TP53 mutation had a shortened Progression Free Survival (PFS) (HR=1.68; p=0.035) and Overall Survival (OS) (HR=2.02; p=0.045). However, the relationship between TP53 mutations and PFS depended on treatment: for the R-CHOP arm, the pathogenic TP53 mutations were not associated with PFS (10-year PFS 44% vs 42%); in contrast, for the RIT-CHOP arm, pathogenic TP53 mutations were associated with a shortened PFS (10 year PFS 27% vs 65%; HR=3.2; p=0.001) (see figure). Furthermore, among patients with no detectable pathogenic TP53 mutation, RIT-CHOP was associated with a longer PFS than R-CHOP (10 year PFS 65% vs 44%; HR=0.58; p=0.046). Conclusions: Using specimens from SWOG S0016, we find that pathogenic TP53 mutations are present in 23% of untreated, advanced stage FL specimens, a considerably higher fraction than reports based on less sensitive methods. Long term follow-up of S0016 has shown that the RIT-CHOP arm had a small but statistically significant improvement in the 10-year PFS compared to R-CHOP (Shadman 2018). We now show that the interaction of RIT and TP53-status substantially affects PFS. First, in the cohort without a detectable TP53 mutation, a longer PFS was observed with RIT-CHOP than R-CHOP. Second, in the cohort with a detectable TP53 mutation, a shorter PFS was observed with RIT-CHOP than R-CHOP. This observation is consistent with the well-defined role of TP53 as the mediator of the apoptotic response to ionizing radiation. Therefore, an assay which detects subclonal populations with TP53 mutations defines two cohorts for which the inclusion of radio-immunotherapy had substantial and opposite effects on the risk of progression. Finally, this identification of subclonal TP53 mutations as a predictive biomarker highlights that preserving specimens from clinical trials to mine with new technologies can be key to the advancement of precision medicine. We wish to recognize the late Dr. Oliver Press for his central role in S0016 and his many contributions to SWOG. Support: NIH/NCI grants U10CA180888, U10CA180819, U10CA180821, R21CA198072 (RB); and in part by GlaxoSmithKline. Figure. Figure. Disclosures Rimsza: NanoString: Other: Inventor on the patent for the Lymph2Cx assay. Leonard:Juno: Consultancy; ADC Therapeutics: Consultancy; Pfizer: Consultancy; Gilead: Consultancy; Sutro: Consultancy; Biotest: Consultancy; United Therapeutics: Consultancy; BMS: Consultancy; Bayer: Consultancy; Genentech/Roche: Consultancy; Celgene: Consultancy; MEI Pharma: Consultancy; AstraZeneca: Consultancy; Karyopharm: Consultancy; Novartis: Consultancy. Smith:BMS: Consultancy; Portola: Honoraria. Friedberg:Bayer: Honoraria.

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: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 87 Background: The International Prognostic Index (IPI) remains the most powerful predictor of clinical outcome in DLBCL in the R-CHOP era, serving as a useful surrogate for the biology we are just beginning to understand. With a follow-up of more than 9 years, its uniformly staged and treated patients and its prospectively collected unstained slides for correlative studies, the clinical data set from E4494, the US Intergroup trial comparing CHOP and RCHOP in patients >60 years with DLBCL, stands as a valuable resource for investigating prognosis in DLBCL. Based on immunohistochemistry, we previously showed that rituximab modulates the prognostic significance of some biomarkers in DLBCL. With these same specimens, the quantitative nuclease protection assay (qNPA), a methodology for measuring mRNA levels in FFPET, was used to develop separate prognostic signatures for the CHOP and RCHOP arms that can be simply applied using stored unstained slides. Methods: Five micron unstained FFPET sections from 183 eligible and evaluable cases enrolled on E4494 and submitted for prospective immunohistochemical correlative studies more than ten years ago were used for this analysis. Tissue was scraped from slides and a multiplexed qNPA was performed in triplicate using a customized Array Plate assay (HTG, Inc) for 43 genes of interest. TBP served as a housekeeping gene. Association between standardized log gene expression and patient failure-free survival (FFS) and overall survival (OS) was obtained using the Cox proportional hazards model. A weighted analysis was used to eliminate the confounding effect of maintenance rituximab. Genes that showed at least marginal significance in the univariate analysis were used to perform LASSO (penalized method to select best subset) to select a final list of genes in the multivariate analysis. Using the predictive model for either CHOP or R-CHOP induction, individual risk scores were calculated based on the multivariable model, and cases were dichotomized into low and high risk groups based on the median risk score. The model was then validated using the Lenz dataset (NEJM, 2008). Results: In six cases, tissue from slides prepared >10 years ago was compared to freshly cut sections from corresponding blocks, and showed excellent concordance (corr=0.86). On-study characteristics for the 176 cases with analyzable data were representative of the greater E4494 patient population. Six gene predictors were developed for each arm of the trial: RCHOP: FN1, LMO2, AKT1, HIF1a, AKT3, BCL2; and CHOP: PDCD4, HLADRB1, COL3A1, LMO2, ROBO4, TP53. Both signatures proved powerful predictors of FFS and OS among CHOP (FFS: p=0.0031; OS: p=0.0013) and RCHOP (FFS: p=0.001; OS=p=0.0015) treated patients. When adjusted for the clinically-based IPI, the gene-risk score retained its significance (CHOP: FFS p=0.0007; OS p=0.0011; RCHOP: FFS p=0.003; OS, p=0.001) while the IPI became only marginally significant (CHOP: FFS: p=0.06, OS p=0.06; R-CHOP: FFS p=0.09, OS p=0.02), suggesting that the gene predictor accounted for much of the predictive power of the IPI. The predictive model was then validated using the Lenz dataset for OS. The predictor models for CHOP and R-CHOP-treated patients effectively dichotomized patients into prognostic subgroups (CHOP: p<0.0001; RCHOP: p=0.0014; see figure below) and this difference was maintained when the subset over age 60 was analyzed (CHOP: p=0.0008; RCHOP: p=0.017). When adjusted for the IPI, the molecular predictor developed for CHOP treated patients remained robust (OS: P=.0001; HR 2.39), while the molecular predictor for RCHOP predicted OS marginally (p=.06; HR 1.82), with shorter followup than the CHOP cohort. Conclusions: Unstained slides from FFPET stored for many years may be used to investigate gene expression in lymphoma biopsy specimens for which there is mature followup. Gene risk scores based on the expression of a limited number of genes are powerful predictors of clinical outcome. Disclosures: Pollock: HTG, Inc.: Employment, Equity Ownership. Botros:HTG, Inc.: Employment, Equity Ownership. Horning:Genentech: Employment, Equity Ownership.

Abstract Background: We recently clarified the use of consolidative autologous stem cell transplantation (ASCT) as first remission consolidation therapy for high grade diffuse aggressive T and B non-Hodgkin's lymphoma (NHL)in patients with high-intermediate (HI) or High (H) age adjusted IPI disease (Stiff et al, NEJM 369:1681). After receiving CHOP or R-CHOP for 5 cycles responding patients were randomized to either 3 more induction cycles or 1 cycle followed by an ASCT using either a BCNU or TBI based preparative regimen. We found a PFS but not OS advantage for those randomized to transplant and no differential treatment effect for those with T-NHL patients as compared to B-NHL in the initial analysis of this study. In light of Phase II data suggesting a value of early ASCT for T-NHL, a lack of randomized ASCT trials for T-NHL and the inferior prognosis for T-NHL as compared to B cell disease, we further evaluated this sub group, since a post hoc analysis of the entire trial did find a survival advantage for those with H IPI disease. This then provided a unique opportunity to evaluate the role of ASCT consolidation for T-cell NHL in the setting of a prospective randomized trial. Method: Among the 370 eligible B-NHL and T-NHL patients with HI/H IPI disease treated on this trial, 40 had a T-NHL phenotype and were the subject of this analysis. Individual patient files were re-reviewed and those randomized after the first 5 cycles of CHOP were further analyzed for stage, IPI group, histology (centrally reviewed), and response to induction and consolidation and updated survival outcome. Results: Of the 40 T-NHL patients enrolled on study, 28 (70%) were randomized after induction therapy, a similar ratio to the entire trial (68%). Twelve were not randomized; 1 was ineligible for study, and of the eligible 11, 9 were HI IPI and 8 had peripheral T cell (PTCL-NOS). These 11 were not randomized due to patient choice in 2, and all of the remaining 9 pts progressed early: 2 after C1; 3 after C3, 1 after C4, and 3 after C5. For the 28 randomized, their median age was 50 and 19 were males. Of the group, 21/28 had B symptoms at diagnosis, 14 had stage IV disease, and 18 and 10 were in the HI and H IPI groups respectively. Histologies included 11 with PTCL-NOS, 7 angioimmunoblastic and 10 anaplastic large cell NHL. At randomization 13 were to continue CHOP and 15, ASCT. Of the 15 assigned to ASCT, 3 did not undergo transplant (2-refusals, 1- unable to mobilize); 7 received the BCNU-etoposide-cyclophosphamide and 5 the TBI-etoposide-cyclophosphamide preparative regimen. The 5 year estimates of PFS and OS for the randomized ASCT vs CHOP only groups (intent to treat) were 40% vs 38% (p=0.56) and 40% vs 45% (p=0.98) respectively. We found no difference in outcome based on IPI group, histology or stage of disease. Interestingly, only 1/7 patients who received BCV as the ASCT preparative regimen are long term survivors vs 4/5 receiving the TBI-based regimen. Conclusions: We did not observe a PFS/OS advantage for those with high-risk T-NHL in first remission randomized to ASCT following CHOP induction vs CHOP alone in this retrospective analysis. In addition, the 30% early drop out rate before randomization due primarily to early progression strongly suggests that more optimal induction regimens need to be developed for this disease. While the numbers are small the finding that TBI based preparative regimens might be associated with a higher PFS is of interest and deserves further study. Support: NIH/NCI grants CA180888 and CA180819; Bristol-Myers Squibb. Contributions of Dr. Raymond R Tubbs, deceased, are gratefully acknowledged. Figure 1 Figure 1. Disclosures Porcu: miRagen: Other: Investigator in a clinical trial; celgene: Other: Investigator in a clinical trial; Millenium: Other: investigator in a clinical trial; Innate Pharma: Other: Investigator in a clinical trial. Winter:Pharmacyclics: Research Funding; Medivation: Other: Provision of investigational agent for clinical trial; Seattle Genetics: Research Funding; GSK: Research Funding. Kahl:This study was coordinated by the ECOG-ACRIN Cancer Research Group (Robert L. Comis, MD and Mitchell D. Schnall, MD, PhD, Group Co-Chairs) and supported by the National Cancer Institute of the National Institutes of Health under the following award number: Research Funding. Smith:Juno: Consultancy; TGTX: Consultancy; AbbVie: Consultancy; Celgene: Consultancy; Genentech: Consultancy, Other: on a DSMB for two trials ; Gilead: Consultancy; Portola: Consultancy; Amgen: Other: Educational lecture to sales force; Pharmacyclics: Consultancy. Rimsza:NCI/NIH: Patents & Royalties: L.M. Rimsza is a co-inventor on a provisional patent, owned by the NCI of the NIH, using Nanostring technology for determining cell of origin in DLBCL.. Fisher:Gilead: Consultancy; Seattle Genetics: Consultancy; Johnson and Johnson: Consultancy. Friedberg:Bayer: Honoraria, Other: Data Safety Monitoring Board.