Witzig, Thomas E.

Background: Central nervous system (CNS) involvement by peripheral T cell lymphoma (PTCL) is a rare condition. Among primary CNS lymphomas, only 2% are secondary to PTCL, while the risk of CNS relapse in all cases of PTCL is estimated at 2% to 6%. Little is known about the presentation and outcomes of PTCL patients with CNS involvement given the rarity of this entity. In this study, we describe patient characteristics, histology, and clinical course of patients with CNS involvement by PTCL. Methods: The Mayo Clinic Lymphoma Database was used to identify PTCL patients with primary or secondary CNS involvement seen at our institution between 2000 and 2018. A total of 12 patients were identified and their medical records were reviewed for patient and disease characteristics, CNS-directed treatment modality, and outcomes. The Kaplan-Meier method was used for time-to-event analysis. Results: The median age at CNS diagnosis was 63 years (range 41 to 76) and 11 (93%) patients were male. The histological diagnoses were PTCL, NOS in 9 (75%) patients, enteropathy-associated T-cell lymphoma in 2 (17%) patients, and angioimmunoblastic T-cell lymphoma in 1 (8%) patient. Five patients presented with primary T-cell CNS lymphoma (all with a PTCL, NOS histology), while the remaining 7 (58%) patients also had systemic involvement. All patients presented with neurologic symptoms at the time of CNS involvement diagnosis including: focal motor deficits in 6 patients (unilateral upper extremity weakness, gait impairments, and hemiparesis), cognitive decline in 5 patients (memory impairments, reduced attention, and confusion), headache in 4 patients, and seizure in 3 patients. The CNS disease location included the brain parenchyma in 9 (75%) patients, leptomeninges in 1 (8%) patient, and lumbar plexus in 1 (8%) patient. One patient (8%) had positive CSF finding only without radiologic evidence of involvement. CSF analysis was performed in 11 patients. Elevated protein levels were noted in 3 (27%) patients, malignant cells in 2 (18%), and no clear abnormalities in the remaining 6 (55%) patients. Concomitant bone marrow involvement was seen in only 1 patient. Elevated LDH was seen in 2 patients. The a median LDH was 195 U/L (range 139 to 4,360) The most common CNS-directed therapies were: high-dose methotrexate (MTX)-based regimens in 8 (67%) patients, including high-dose MTX in combination with temozolomide (n=2), or cytarabine and thiotepa (n=2). Intrathecal MTX, temozolomide and dexamethasone, lenalidomide, high-dose steroids, and surgical resection were the treatment modality used for one patient each. At a median follow up of 18 months, eight (75%) out of 12 patients were not alive at the time of last follow up. The median overall survival (OS) from diagnosis was 16 months (95% CI: 2.8-173). The median progression free survival (PFS) from initiation of CNS-directed therapy was 9 months (95% CI: 1.6-33) (figure). Four patients had a PFS longer than 12 months. These 4 patients were treated with: temozolomide/dexamethasone, high-dose MTX, lenalidomide, and high-dose MTX followed by cytarabine/thiothepa. Conclusion: CNS involvement by T-cell lymphoma is a rare complication that carries a poor prognosis. Early onset of neurologic symptoms should trigger prompt investigation of CNS involvement. Despite the short OS and PFS, some patients may achieve a relatively longer disease free interval. Disclosures Bennani: Adicet Bio: Other: Advisory board; Seattle Genetics: Other: Advisory board; Purdue Pharma: Other: Advisory board; Seattle Genetics: Other: Advisory board; Seattle Genetics: Other: Advisory board; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Kite Pharma: Other: Advisory board; Kite Pharma: Other: Advisory board; Bristol-Myers Squibb: Research Funding; Adicet Bio: Other: Advisory board; Purdue Pharma: Other: Advisory board; Purdue Pharma: Other: Advisory board; Adicet Bio: Other: Advisory board; Kite Pharma: Other: Advisory board. Cerhan:Celgene: Research Funding; NanoString: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees. Nowakowski:Celgene: Consultancy, Research Funding; Bayer: Consultancy, Research Funding; Curis: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; Genentech, Inc.: Research Funding; MorphoSys: Consultancy, Research Funding; NanoString: Research Funding; Selvita: Membership on an entity's Board of Directors or advisory committees. Ansell:Mayo Clinic Rochester: Employment; Affimed: Research Funding; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Regeneron: Research Funding; Trillium: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding; LAM Therapeutics: Research Funding; Trillium: Research Funding; Mayo Clinic Rochester: Employment; Affimed: Research Funding; LAM Therapeutics: Research Funding; Seattle Genetics: Research Funding. Paludo:Celgene: Research Funding; Verily Life Sciences: Research Funding; Verily Life Sciences: Research Funding; Celgene: Research Funding.

Introduction: The phase 3 international, randomized, double-blind ROBUST clinical trial (NCT02285062) compared progression-free survival between patients with previously untreated ABC-type DLBCL treated with placebo plus rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (placebo-R-CHOP) versus lenalidomide + R-CHOP (R2-CHOP) for 6 21-day cycles. HRQoL, as measured by the Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) and the EuroQoL 5-dimension 3-level (EQ-5D-3L) patient-reported questionnaires, was evaluated as a secondary endpoint for the 2 treatment arms. Methods: For each treatment group, FACT-Lym and EQ-5D-3L scores were measured at baseline (BL), mid-, end-of-treatment (EOT), and post-treatment, in 12-week intervals from Week 34 onward. Patients were evaluated if they had completed BL and ≥ 1 post-BL calculable FACT-Lym subscale measurements. Non-inferiority (NI) of R2-CHOP versus placebo-R-CHOP was measured for 4 key FACT-Lym subscales: Physical Well-Being (PWB), Additional Concerns (AC), Functional Well-Being (FWB), and Trial Outcome Index (TOI). NI was assessed at EOT (typically 3-4 weeks after completing Cycle 6) and at post-treatment follow-up at Week 34 by analysis of covariance (ANCOVA). The NI margins were prespecified as 1 less than the higher published minimal important difference (MID) for each subscale. Since a range of MIDs have been published, a more conservative value was also used as a sensitivity analysis. Time to improvement (TTI), using published responder definitions, was also assessed for the FACT-Lym subscales. EQ-5D-3L scores were summarized descriptively. Results: Demographic and baseline disease characteristics were balanced across the 2 treatment arms (N = 285 per arm). The percentage of patients who completed the FACT-Lym out of the expected population remained > 85% at all time points with > 50 patients still on the study in each treatment arm up to Week 142. Completion rates and reasons for missing assessments were balanced across the 2 treatment arms. FACT-Lym subscale scores were generally higher after EOT, similar for both treatment groups, and mean changes from BL were close to or above MID (where defined), except for the Social/Family Well-Being subscale. Mean differences in FACT-Lym TOI between treatment arms are shown in Table 1. As positive treatment differences favor R2-CHOP and -10 was the predefined NI margin, NI was demonstrated for the FACT-Lym TOI subscale at both EOT and Week 34 assessments. Superiority of R2-CHOP was demonstrated at EOT as the confidence interval (CI) lies completely above 0 (P < 0.04); however, this difference was not clinically meaningful. Furthermore, NI was also demonstrated when using the sensitivity analysis margin of -4.5. ANCOVA models were also fitted for the other key subscales of PWB, AC and FWB (Table 2). NI was demonstrated for all NI margins at both time points for the PWB and AC subscales. The FACT-Lym FWB subscale demonstrated NI for both margins at EOT and Week 34 for the primary NI margin of -2 based on the MID minus 1, but did not demonstrate NI when an NI margin of -1, based on an alternative published MID, was used. The TTI curves and associated summary statistics were similar for the 2 treatment arms, with a median TTI for the FACT-Lym TOI of 21 weeks (95% CI 15-22) for patients treated with R2-CHOP and 18 weeks (95% CI 15-22) for patients treated with placebo-R-CHOP. Mean EQ-5D-3L visual analogue scale (VAS) and Utility Index (UK weights) change from baseline scores were higher in both treatment arms and the mean changes were above, or close to, the published MID (7 for VAS, 0.1 for Utility Index) at EOT assessments. Prespecified sensitivity and subgroup analyses supported the conclusions from the primary HRQoL analyses. Conclusions: The predefined NI levels were met for the 4 key FACT-Lym subscales. Similar results were observed across the other HRQoL assessments, sensitivity, and subgroup analyses. Adding lenalidomide to the R-CHOP regimen did not adversely affect the HRQoL of patients with DLBCL as measured by FACT-Lym and EQ-5D-3L. These data serve as a benchmark for future clinical trials combining next-generation immunomodulatory drugs with standard R-CHOP to improve clinical efficacy while maintaining HRQoL in patients with DLBCL. HRQoL analyses should become an integral part of future clinical trials of novel combination regimens in DLBCL. Disclosures Chiappella: Roche: Speakers Bureau; Teva: Speakers Bureau; Servier: Other: advisory board, Speakers Bureau; Janssen: Other: advisory board, Speakers Bureau; Celgene: Other: advisory board, Speakers Bureau. Cocks:Adelphi Values: Employment; Amgen: Consultancy; BMS: Consultancy; Celgene Corporation: Consultancy; Endomag Ltd.: Consultancy. Greenwood:Adelphi Values: Employment. Williams:Adelphi Values: Employment. Scott:Celgene: Consultancy; Roche/Genentech: Research Funding; NanoString: Patents & Royalties: Named inventor on a patent licensed to NanoSting [Institution], Research Funding; Janssen: Consultancy, Research Funding. Yamamoto:SymBio: Research Funding; Ono: Consultancy, Honoraria, Research Funding; Otsuka: Honoraria; Sanofi: Honoraria; Astra-Zeneca: Consultancy, Research Funding; Sumitomo Dainippon: Honoraria; Chugai: Consultancy, Honoraria, Research Funding; Eisai: Consultancy, Honoraria, Research Funding; Janssen: Honoraria; Gilead Sciences: Research Funding; Solasia Pharma: Research Funding; Bayer: Research Funding; Celgene Corporation: Consultancy, Honoraria, Research Funding; ARIAD: Research Funding; Pfizer: Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Kyowa Kirin: Honoraria; MSD: Consultancy, Honoraria; Mundipharma: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Research Funding; Meiji Seika Pharma: Consultancy, Honoraria; HUYA/IQVIA Services Japan: Consultancy, Honoraria; Novartis: Honoraria, Research Funding; Incyte: Research Funding; Takeda: Consultancy, Honoraria, Research Funding. Jurczak:Bayer: Research Funding; Takeda: Research Funding; Gilead: Research Funding; Sandoz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Morphosys: Research Funding; Incyte: Research Funding; Celgene Corporation: Research Funding; Loxo: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celtrion: Research Funding; Novo Nordisk: Research Funding; Servier: Research Funding; TG Therapeutics: Research Funding. Özcan:Sanofi: Other: Travel support; Abdi Ibrahim: Other: Travel support; BMS: Other: Travel support; Takeda: Honoraria, Other: Travel support, Research Funding; Archigen: Research Funding; Roche: Other: Travel support, Research Funding; Bayer: Research Funding; Janssen: Other: Travel support, Research Funding; Celgene Corporation: Research Funding, Travel support; AbbVie: Other: Travel support, Research Funding; MSD: Research Funding; Novartis: Research Funding; Jazz: Other: Travel support; Amgen: Honoraria, Other: Travel support. Belada:Roche: Consultancy; Gilead Sciences: Consultancy; Takeda: Consultancy. Margunato-Debay:Celgene Corporation: Employment, Equity Ownership. Czuczman:Celgene Corporation: Employment, Equity Ownership. Zhai:Celgene Corporation: Employment, Equity Ownership. Braverman:Celgene Corporation: Employment. Vitolo:Juno Therapeutics: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kite: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; F. Hoffmann-La Roche: Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Nowakowski:Selvita: Membership on an entity's Board of Directors or advisory committees; NanoString: Research Funding; MorphoSys: Consultancy, Research Funding; Curis: Research Funding; Bayer: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Genentech, Inc.: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding.

Background: The 2018 iwCLL guidelines recommend close observation of early stage CLL pts who do not meet indications for therapy ("watch and wait" strategy). Prior attempts at early therapeutic intervention in unselected early-stage CLL pts using alkylating agents such as chlorambucil and chemoimmunotherapy failed to show a significant benefit; and these therapies were associated with substantial toxicities. The introduction of Bruton tyrosine kinase (BTK) inhibitors has revolutionized the treatment landscape of CLL. The German CLL Study group recently presented results of the CLL12 study which demonstrated a significant improvement in event-free survival (EFS) among untreated early stage high risk CLL pts who received ibrutinib compared to placebo (median EFS not reached vs. 47.8 months, respectively; Langerbeins, EHA, 2019). Acalabrutinib is a more selective second-generation BTK inhibitor that has fewer adverse events in pts with CLL, and has shown equally impressive clinical activity for CLL pts. We are conducting an investigator initiated randomized phase 2 study to compare acalabrutinib with or without obinutuzumab (a glycoengineered anti-CD20 monoclonal antibody approved in the treatment of CLL) among high risk early stage CLL pts. Study Design: All pts with newly diagnosed (<2 years from registration) previously untreated early stage CLL who do not meet the 2018 iwCLL guidelines for initiation of therapy are eligible for enrollment in this study. Pts undergo risk stratification according to the CLL-International prognostic index (CLL-IPI) which consists of the following 5 variables: age >65 years (1 point), Rai stage I-IV (1 point), del17p and/or TP53 mutation (4 points), unmutated immunoglobulin heavy chain (IGHV) genes (2 points), and serum β2-microglobulin >3.5 g/dL (2 points). Pts with high (4-6) and very high (7-10) risk CLL-IPI are randomly (1:1) assigned to acalabrutinib 100 mg orally twice daily (Arm A) or acalabrutinib with obinutuzumab at a standard approved schedule (Arm B). Treatment with acalabrutinib is continued for a minimum of 2 years unless the patient has unacceptable side effects or withdraws consent. Pts with low (0-1) and intermediate (2-3) risk CLL-IPI score are assigned to an observation arm with follow-up once every 6 months for 2 years, and then according to routine clinical practice (Arm C). Endpoints: The primary endpoint of the intervention arms (Arms A and B) is the achievement of minimal residual disease (MRD)-negative complete remission in the bone marrow after 2 years of therapy. MRD is assessed using an 8-color flow cytometry with a detection limit of 0.01%. The primary endpoint of the observation arm (Arm C) is time to first therapy. Secondary endpoints for all arms are: progression-free survival, overall survival, and safety. Statistical design: A randomized trial comparing the experimental arm (acalabrutinib plus obinutuzumab) against the control arm (acalabrutinib alone) will be conducted as described by Rubinstein. A sample size of 36 pts per arm provides 80% power to detect an improvement in MRD-negative complete response rate from 10% to 30%, using a one-sided test at a significance level of 0.10 (EAST 6.4). We anticipate accruing an additional 8 high/very high risk pts (4 in each arm) to account for ineligibility, cancellation, or major treatment violation. The total enrollment for Arms A and B will be 80 pts. We will enroll 40 pts to Arm C; for a total enrollment of 120 pts. Key correlatives: Comprehensive profiling to assess the innate and adaptive immune system in paired peripheral blood and bone marrow will be conducted in all pts registered to Arms A and B at baseline, 12 and 24 months after enrollment. In addition, bone marrow hematopoietic function will be assessed in all pts at these time points. We will employ a CLL focused custom 61-gene panel to estimate tumor mutational burden as well as mutational profiles for each patient at baseline, 12, and 24 month time points, as well at the time of disease progression. Preliminary results: The trial is registered at clinicaltrials.gov NCT03516617. The trial opened to accrual at all three Mayo Clinic sites (Rochester, MN; Jacksonville, FL; and Scottsdale, AZ) in September 2018. Twenty-eight pts have been registered; the baseline characteristics are shown in Table 1. The trial is expected to complete enrollment in September 2020; and the primary analysis will be available in September 2022. Disclosures Parikh: Janssen: Research Funding; AstraZeneca: Honoraria, Research Funding; Pharmacyclics: Honoraria, Research Funding; MorphoSys: Research Funding; AbbVie: Honoraria, Research Funding; Acerta Pharma: Research Funding; Ascentage Pharma: Research Funding; Genentech: Honoraria. Ding:DTRM Biopharma: Research Funding; Merck: Research Funding. Ailawadhi:Pharmacyclics: Research Funding; Cellectar: Research Funding; Takeda: Consultancy; Amgen: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Celgene: Consultancy. Kenderian:Novartis: Patents & Royalties, Research Funding; Tolero: Research Funding; Humanigen: Other: Scientific advisory board , Patents & Royalties, Research Funding; Lentigen: Research Funding; Morphosys: Research Funding; Kite/Gilead: Research Funding. Chanan-Khan:Mayo Clinic: Employment; Ascentage: Research Funding; Millennium: Research Funding; Jansen: Research Funding; AbbVie: Research Funding; Xencor: Research Funding; Pharmacyclics: Research Funding; Merck: Research Funding. Kay:Infinity Pharmaceuticals: Other: DSMB; Celgene: Other: Data Safety Monitoring Board; Agios: Other: DSMB; MorphoSys: Other: Data Safety Monitoring Board. OffLabel Disclosure: Drug: Acalabrutinib Purpose: treatment of CLL

Background: Standard first-line treatment for patients diagnosed with diffuse large B-cell lymphoma (DLBCL) is the R-CHOP regimen. Despite numerous efforts to improve on this regimen, in all comers and specifically in those with activated B-cell (ABC)-type DLBCL, results from large randomized studies have failed to show a significant clinical advantage above this standard. Recently, 2 large clinical trials in previously untreated DLBCL evaluated the combination of lenalidomide/R-CHOP (R2-CHOP) vs standard R-CHOP and demonstrated discordant results. We analyzed data from these trials to identify differences that may have impacted the disparate trial outcomes while identifying patient characteristics associated with benefit from the addition of lenalidomide across the trials. Methods: The 2 trials included in this evaluation are ROBUST, an international, randomized, double-blinded, placebo-controlled, phase III study of R2-CHOP vs placebo/R-CHOP, and the Intergroup ECOG-ACRIN 1412 (E1412) trial, a US-only, randomized, open-label, phase II study of R2-CHOP vs R-CHOP. Additional key study design differences included dosing, and subtype timing and inclusion (both studies used gene expression profiling [GEP] by NanoString). R-CHOP dosing differed only for prednisone, which was a flat 100 mg dose, d1-5 in ROBUST and 100 mg/m2, d1-5 in E1412. The lenalidomide dose and schedule varied between studies: 15 mg/d, d1-14/21 for ROBUST (210 mg/cycle) and 25 mg/d, d1-10/21 (250 mg/cycle) for E1412. ROBUST enrolled only patients prospectively identified with the ABC subtype, whereas E1412 enrolled all otherwise eligible patients and retrospectively evaluated for ABC-type with prespecified ABC-type accrual and power parameters. Both studies enrolled patients with IPI status ≥ 2, ECOG PS 0-2, and Ann Arbor stage II-IV (E1412 stage II with mass > 10 cm). The primary endpoint in both was progression-free survival (PFS; central review for ROBUST and investigator-assessed for E1412). Secondary endpoints included event-free survival (EFS; key for ROBUST), overall and complete response rates, overall survival (OS), and safety. Results: ROBUST enrolled 570 ABC patients and E1412 enrolled 280 GCB, ABC, and unclassified DLBCL patients. Patient profiles in both studies (ROBUST [ABC]/E1412 [all COO]) were similar in terms of median ages (65 y/66 y), male sex (58%/61%), and ECOG PS 1-2 (55%/63%). Patients in E1412 were more high risk: IPI 2 (42% ROBUST/34% E1412), IPI ≥ 3 (58%/66%), and Ann Arbor stage III/IV disease (87%/97%). Importantly, there was a notable difference in the time from patient diagnosis to treatment: median 31 days for ROBUST and 21 days (22% > 31 d) for E1412. Only 6% of patients in ROBUST were treated within 2 weeks of diagnosis vs 30% in E1412. At a median follow-up of ~2.5 y for both studies, E1412 met its primary endpoint of improvement in PFS with 34% reduction in the risk of PD/death (2-y PFS: 76% vs 70%) for all patients, but did not reach statistical significance in ABC-DLBCL patients for 2-y PFS (71% vs 61%) or 2-y OS (88% vs 76%). ROBUST showed no significant improvement in the primary PFS endpoint (2-y PFS: 67% vs 64%) or 2-y OS (79% vs 80%) in ABC patients. Subgroup analyses of PFS comparing R2-CHOP vs R-CHOP control within each study suggested that certain baseline factors favor the R2-CHOP arm, including: female sex, high IPI score (≥ 3), non-bulky disease (< 7 cm), and high Ann Arbor stage IV disease. Conclusion: While the ROBUST study design integrated state-of-the-art, real-time GEP to prospectively identify ABC-DLBCL patients with rapid lab turnaround time, cases of logistical delays in tissue submission for central analysis and staging procedures may have resulted in accrual of patients with lower-risk DLBCL and prolonged time from diagnosis to treatment. In contrast, E1412 retrospectively stratified patients by COO through GEP and was able to accrue higher-risk patients irrespective of COO within a shorter time from diagnosis to treatment, which among other differences (eg, smaller population size, study phase), could contribute to the improvement over R-CHOP control. Our comparative findings have significant implications for the design of future biomarker-driven trials and provide momentum for studies of novel combinations with R-CHOP in DLBCL. Further investigation into other factors, including dose intensity and their correlation with outcomes, will be presented. Disclosures Nowakowski: Celgene: Consultancy, Research Funding; NanoString: Research Funding; MorphoSys: Consultancy, Research Funding; Genentech, Inc.: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; Selvita: Membership on an entity's Board of Directors or advisory committees; Curis: Research Funding; Bayer: Consultancy, Research Funding. Chiappella:Servier: Other: advisory board, Speakers Bureau; Roche: Speakers Bureau; Teva: Speakers Bureau; Celgene: Other: advisory board, Speakers Bureau; Janssen: Other: advisory board, Speakers Bureau. Hong:Dana Farber Cancer Institute: Employment; Merck: Consultancy. Scott:Roche/Genentech: Research Funding; Celgene: Consultancy; Janssen: Consultancy, Research Funding; NanoString: Patents & Royalties: Named inventor on a patent licensed to NanoSting [Institution], Research Funding. Amengual:Appia Pharmaceuticals: Research Funding; Epizyme: Speakers Bureau. Leonard:BeiGene: Consultancy; Miltenyi: Consultancy; Sandoz: Consultancy; Gilead: Consultancy; Celgene: Consultancy; ADC Therapeutics: Consultancy; MorphoSys: Consultancy; ADC Therapeutics: Consultancy; Epizyme, Inc: Consultancy; Miltenyi: Consultancy; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy; Karyopharm Therapeutics: Consultancy; Akcea Therapeutics: Consultancy; Merck: Consultancy; Nordic Nanovector: Consultancy; Akcea Therapeutics: Consultancy; Bayer Corporation: Consultancy; Sandoz: Consultancy; MorphoSys: Consultancy; Gilead: Consultancy; BeiGene: Consultancy; AstraZeneca: Consultancy; Nordic Nanovector: Consultancy; Sutro Biopharma: Consultancy; Merck: Consultancy. Friedberg:Bayer: Honoraria, Other: Data & Safety Monitoring Committee; Acerta: Other: Data & Safety Monitoring Committee. Kostakoglu:F. Hoffman-La Roche: Consultancy; Genentech: Consultancy. Jurczak:Morphosys: Research Funding; Bayer: Research Funding; Roche: Research Funding; Incyte: Research Funding; Gilead: Research Funding; Celgene Corporation: Research Funding; Sandoz: Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Research Funding; Servier: Research Funding; Takeda: Research Funding; TG Therapeutics: Research Funding; Celtrion: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Loxo: Membership on an entity's Board of Directors or advisory committees, Research Funding. Yamamoto:Bristol-Myers Squibb: Consultancy, Honoraria; Bayer: Research Funding; Celgene Corporation: Consultancy, Honoraria, Research Funding; Mundipharma: Consultancy, Honoraria, Research Funding; Astra-Zeneca: Consultancy, Research Funding; Eisai: Consultancy, Honoraria, Research Funding; Meiji Seika Pharma: Consultancy, Honoraria; ARIAD: Research Funding; MSD: Consultancy, Honoraria; Gilead Sciences: Research Funding; Ono: Consultancy, Honoraria, Research Funding; SymBio: Research Funding; HUYA/IQVIA Services Japan: Consultancy, Honoraria; AbbVie: Consultancy, Research Funding; Chugai: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria; Sumitomo Dainippon: Honoraria; Incyte: Research Funding; Janssen: Honoraria; Kyowa Kirin: Honoraria; Novartis: Honoraria, Research Funding; Otsuka: Honoraria; Sanofi: Honoraria; Solasia Pharma: Research Funding; Takeda: Consultancy, Honoraria, Research Funding. Czuczman:Celgene Corporation: Employment, Equity Ownership. Russo:Celgene Corporation: Employment, Equity Ownership. Hudak:Celgene Corporation: Employment, Equity Ownership; Novartis: Employment, Equity Ownership. Zhang:Celgene Corporation: Employment, Equity Ownership. Wade:Celgene: Employment, Equity Ownership. Kahl:ADC Therapeutics: Consultancy, Research Funding; BeiGene: Consultancy; TG Therapeutics: Consultancy; Seattle Genetics: Consultancy. Vitolo:Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; F. Hoffmann-La Roche: Speakers Bureau; Juno Therapeutics: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kite: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. OffLabel Disclosure: Yes, these trials discuss off-label clinical trial investigation of lenalidomide plus R-CHOP in patients with newly diagnosed diffuse large B-cell lymphoma.

Introduction: Chronic myelomonocytic leukemia (CMML), an aggressive myeloid malignancy, can be categorized into two subtypes, proliferative CMML (pCMML) and dysplastic (dCMML), based on a white blood cell (WBC) count of ≥ 13 x 109/L for the former (Arber et al. Blood 2016). While this WBC cut off is somewhat arbitrary, patients with pCMML have unique phenotypic features and a shorter survival. We carried out this study to assess the genomic, transcriptomic and epigenetic landscapes of these two CMML subtypes. Methods: Peripheral blood (PB) and bone marrow (BM) mononuclear cells (MNC) were obtained from WHO-defined CMML patients. Next generation sequencing (NGS) using a 36-gene panel was performed on 350 patients with Illumina HiSeq4000 platform with median read depth of 400X. RNA sequencing (RNA-seq) was performed on 25 patients by bulk whole transcriptome sequencing using Illumina TruSeq. DNA immunoprecipitation sequencing (DIP-seq) was performed on 18 patients using 5-methylcystocine (5mC), 5-hydroxymethylcytosine (5hmC) and bridging monoclonal antibodies with subsequent paired-end sequencing using HiSeq4000. Chromatin immunoprecipitation sequencing (ChIP-seq) was performed on 30 patients with Illumina HiSeq2500 to a depth of 25 million for histone 3 lysine 4 monomethylation (H3K4me1) and histone 3 lysine 4 trimethylation (H3K4me3) and 50 million reads for histone 3 lysine 27 trimethylation (H3K27me3) and Input per sample. Results: Five hundred and seventy-three patients with WHO defined CMML were included; median age 71 years (range 18-95 years), 67% males. 282 patients had pCMML (49%), while 291 (51%) had dCMML. As pre-defined, patients with pCMML were more likely to have higher absolute monocyte counts (p<0.0001), circulating immature myeloid cells (p<0.0001), PB blasts (p<0.0001), and higher lactate dehydrogenase levels (p=0.03). At last follow up 234 (41%) deaths and 70 (20%) leukemic transformations were documented. The median OS for pCMML vs dCMML in this cohort was 19 months vs 30 months (p<0.0001, Figure 1A) and validated in an independent Austrian cohort (p=0.02). Genomic profiling: NGS performed on 350 patients (BM MNC) revealed a higher frequency of NRAS (35 vs 17%, p=0.004), cumulative RAS pathway (NRAS, KRAS, CBL and PTPN11) (73 vs 47%, p=0.001), ASXL1 (p=0.003) and JAK2V617F (p=0.04) mutations in pCMML relative to dCMML (Figure 1B); while dCMML had a higher frequency of SF3B1 mutations (p=0.02). There were no differences in distribution of TET2 and SRSF2Transcriptomic analysis: RNA-seq was performed on PB MNC from RAS pathway mutant pCMML patients (n=12) and RAS pathway wildtype dCMML patients (n=13). Unsupervised clustering analysis resulted in appropriate segregation revealing distinct expression profiles between disease subtypes (Figure 1C). Compared to dCMML, 3729 genes were significantly differentially upregulated and 2658 genes were differentially downregulated in pCMML. Among genes most highly upregulated were mitotic checkpoint kinases including AURBK, PLK1, PLK2, PLK4 andEpigenetic profiling: ChIP-seq of PB and BM MNC from pCMML (n=18) and dCMML (n=12) patients and healthy, age-matched controls (n=10) revealed a global increase in H3K4me1, without significant differences in H3K4me3 or H3K27me3 occupancies (regardless of stratification by ASXL1 mutational status; 40% ASXL1mt in pCMML, 30% dCMML) in pCMML vs dCMML (Figure 1D). H3K4me1 occupancy was also increased in a sequence-specific manner at the transcription start sites of the aforementioned mitotic kinases (PLK1 and WEE1). DIP-seq was performed on PB MNC to assess global differences in 5-mC and 5-hmC levels, between pCMML (n=9) and dCMML (n=9), with no differences seen between the two subtypes (regardless of TET2 mutational status, 40% TET2mt in each subtype) (Figure 1E). Conclusions: Despite the somewhat arbitrary WBC distinction between pCMML and dCMML, clear phenotypic, genetic, transcriptomic, epigenetic and survival differences exist between the two subtypes, providing strong biological rationale for this distinction. pCMML patients have a higher frequency of oncogenic RAS pathway mutations, a unique transcriptomic profile enriched in mitotic check point kinases and a unique chromatin configuration with global and sequence specific enrichment in H3K4me1, with no significant global differences in 5mC, 5hmC, or H3K4me3 and H3K27me3 occupancy. Figure 1 Disclosures Geissler: AOP: Honoraria; Pfizer: Honoraria; AstraZeneca: Honoraria; Novartis: Honoraria; Celgene: Honoraria; Roche: Honoraria; Abbvie: Honoraria; Ratiopharm: Honoraria; Amgen: Honoraria. Al-Kali:Astex Pharmaceuticals, Inc.: Research Funding. Patnaik:Stem Line Pharmaceuticals.: Membership on an entity's Board of Directors or advisory committees.

Introduction: Additional Sex Combs-Like 1 (ASXL1) is a chromatin modifier frequently affected by truncating mutations in myeloid malignancies. These mutations are associated with poor survival outcomes and increased rates of acute leukemic transformation. In chronic myelomonocytic leukemia (CMML), ASXL1 mutations are thought to affect transcriptional activity mainly by modifying histone marks, however additional epigenomic mechanisms have not been fully explored. We interrogated the epigenome of patients with ASXL1-mutant (MT) and -wildtype (WT) CMML using a multiomics approach to define cis-regulatory elements (CREs) such as distal enhancers (DEs). Methods: Bone marrow mononuclear cells from patients with CMML were subjected to targeted NGS of DNA, whole transcriptome shotgun sequencing (RNA-seq), immunoprecipitation (IP) of DNA (hydroxy-)methyl residues (DIP-seq), IP of the histone modifications H3K4me1, H3K4me3, and H3K27me3 (ChIP-seq), and DNA transposase accessibility studies (ATAC-seq). After quality control all samples were sequenced on an Illumina HiSeq 4000 before further processing and data analysis. Global assessments of DNA (hydroxy-)methylation, DNA accessibility, and histone modifications between ASXL1 MT and WT CMML were performed. The samples in the two groups were treated as biological replicates and subjected to a consensus peak calling strategy requiring an overlap of at least 30% between samples and an adjusted p-value < 5x10-5 for a signal peak to be considered statistically significant. Differential gene expression was estimated to define the up-regulated genes in ASXL1 MT CMML. Potential CREs were defined as sites with statistically significant signal peaks overlapping in at least two of the three epigenomic marks: H3K4me1, 5hmC, and ATAC. Potential DEs were defined as CREs in non-coding regions outside promoter regions (defined as transcription start site ±3kb) that were annotated in GeneHancer. Annotated DEs only present in ASXL1 MT but not WT CMML (specific DEs) were intersected with the list of up-regulated genes and the ReMap atlas. Results: Sixteen WHO-defined CMML patients were included, median age 69 years (48 - 77), 63% male; of which 8 patients (50%, all truncating frame shift mutations) were ASXL1 MT and 8 (50%) WT. The burden and spectrum of co-mutations was similar between ASXL1 WT and MT CMML (21 versus 23 per group; p = 0.684; heatmap). There was a predominant up-regulation of gene expression in ASXL1 MT CMML: 707 genes up- and 124 down-regulated (volcano plot, FDR < 0.050 for all genes). There were 64336 potential CREs, the vast majority (97%) being present in both ASXL1 MT and WT CMML (left Venn diagram). These CREs were most commonly located in introns, promoter regions, and distal non-coding regions (bar graph and pie chart). There were 1303 CREs unique to ASXL1 MT CMML (specific DEs), 1161 (90%) of which were annotated in GeneHancer (left Euler diagram). Of these 1161 annotated specific DEs 859 (74%) were located outside promoter regions and 34 (4%) of them were known to be associated with genes up-regulated in ASXL1 MT CMML (Euler diagrams). These specific DEs were characterized by an increase in H3K4me1 occupancy and DNA accessibility (average signal tracks, purple bars indicating annotated DEs, thin bars below peaks indicating statistical significance). We previously observed epigenomic modification of promoter regions in 519 of the 707 up-regulated genes (73%) facilitating transcriptional activity in ASXL1 MT CMML. For 13 of the up-regulated genes (right Venn diagram, blue genes in volcano plot) the specific DEs were the sole identified mechanism, while for the other 21 genes there were additional mechanisms noted in the promoter region. The top five transcription factor candidates binding the 34 specific DEs included JMJD1C, MYC, KDM5B, RCOR1, and HDAC2 (-log10(E) > 40 for all candidates). Conclusions: Using a multiomics approach based on H3K4me1, 5hmC, and ATAC data we identified potential CREs in ASXL1 MT CMML and characterized potential DEs using publicly available annotation data. Specific DEs were associated with up-regulated genes serving as a possible explanation for the observed transcriptional activity, shedding further light on the adverse prognostic impact associated with ASXL1 mutations. Figure 1 Disclosures Patnaik: Stem Line Pharmaceuticals.: Membership on an entity's Board of Directors or advisory committees.

Background: While there is evidence in the literature of increased prevalence of hypogammaglobulinemia in chronic lymphocytic leukemia (CLL), there are no studies evaluating the prevalence of hypogammaglobulinemia in newly diagnosed diffuse large B cell lymphoma (DLBCL) or the relationship between hypogammaglobulinemia and presentation or outcomes. The objective of this study was to examine the prevalence of hypogammaglobulinemia in newly diagnosed DLBCL patients and to test the hypothesis that DLBCL patients with baseline hypogammaglobulinemia have a distinct clinical profile and outcome. Methods: We obtained banked frozen sera from 200 newly diagnosed, treatment-naïve, DLBCL patients from the Lymphoma SPORE Molecular Epidemiology Resource (MER), a prospective cohort study conducted at the Mayo Clinic and the University of Iowa. IgG/A/M levels were measured using immunoturbidimetric assay whereas IgE level was measured using electrochemiluminescence immunoassay; deficiency was defined using standard reference ranges. IgE levels were considered deficient if &lt;2 UI/ml. The associations between Ig deficiencies and clinical factors were evaluated with Wilcoxon rank sum and chi-squared (Fisher's exact, where appropriate) tests. Event-free survival (EFS) was defined as time from diagnosis to progression, relapse, retreatment, or death, and EFS24 was defined as EFS at 24 months after diagnosis (achieve or failure to achieve EFS24). The association of Ig levels with EFS24 was estimated using odds ratios (OR) and 95% confidence intervals (CI) from logistic regression, and with EFS, overall survival (OS), and lymphoma-specific survival (LSS) was estimated using Kaplan-Meier curves and hazard ratios (HR) and 95% CI from Cox regression. Results: The mean age (SD) of the cohort was 65.6 (13.4) years, 54% were males and 98% of the patients were white. Over a median follow-up of five years, there were 59 (29.5%) deaths. The prevalence of hypogammaglobulinemia, defined as any deficiency, in newly diagnosed, treatment-naïve DLBCL was 22.1% (44/199) in our cohort, and the most common Ig deficiency was for IgG (&lt;700 mg/dL, 13.5%), followed by IgM (&lt;40 mg/dL, 9.0%), IgE (&lt;2 UI/ml, 7.5%) and IgA (&lt;70 mg/dL, 4.0%) (Table1). There were no statistically significant differences between Ig deficient and non-deficient patients in terms of age at diagnosis, gender, stage, cell of origin, or MYC double hit status. However, median LDH levels were higher in Ig deficient patients (228 vs 194, p&lt;0.01). Any immunoglobulin deficiency was associated with inferior EFS (HR 1.94, 95% CI 1.16-3.24) (Figure 1) and OS (HR 2.02, 95% CI 1.17-3.49), and these associations were not attenuated after adjustment for the international prognostic index (IPI). Any Ig deficiency was also associated with failure to achieve EFS24 (OR=2.13, 95% CI 1.00-4.60) after adjusting for IPI. Conclusions: To the best of our knowledge, this is the first study to report the prevalence of hypogammaglobulinemia in treatment naïve DLBCL. We found that any Ig deficiency was not uncommon in our cohort and it was associated with an inferior EFS and OS in DLBCL patients. The prevalence of hypogammaglobulinemia in DLBCL patients seems to be lower than has been described in CLL patients. While the underlying relationship between these two immunologic disorders deserves further study, our findings highlight the interaction between global immune dysfunction and emergence of a clonal B cell process. Disclosures Nowakowski: Genentech, Inc.: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; Curis: Research Funding; Bayer: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Selvita: Membership on an entity's Board of Directors or advisory committees; NanoString: Research Funding; MorphoSys: Consultancy, Research Funding. Farooq:Celgene: Honoraria; Kite Pharma: Research Funding. Cerhan:NanoString: Research Funding; Celgene: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees.

Introduction: Waldenström macroglobulinemia (WM) is characterized by circulating monoclonal IgM and bone marrow infiltration with lymphoplasmacytic lymphoma (LPL) cells. Presently, there is limited data to guide prognosis or treatment options of WM based on the proportion of lymphocytes or plasma cells in the LPL population on the pathology. In this study, we aim to look at differing clinical features and outcomes of patients with WM based on the plasma cell (PC) percentage in the diagnostic bone marrow biopsy. Methods Patients with WM seen at Mayo Clinic, Rochester, MN between January 2001 and December 2017, with a bone marrow biopsy and a corresponding serum free light chain (FLC) examination at diagnosis of WM were included. The percentage of lymphocytes and PCs in the marrow biopsy was determined based on morphology ± immunohistochemistry. On immunohistochemistry, CD138 and/or MUM-1 positivity was used to quantify PCs, whereas CD20 and/or PAX5 were used to quantify lymphocytes. Patients with ≥10% PC component in the lymphoplasmacytic (LPL) cells on bone marrow biopsy were considered to have WM with excess plasma cells (WMEPC), while those with &lt;10% PCs were considered to have lymphocytic WM (LWM). Continuous variables were compared using Wilcoxon test and categorical variables were compared using Chi square test or Fisher's exact test. Time-to-next therapy (TTNT) was defined as the period from initiation of first line therapy to start of second line therapy or death due to any cause before second line therapy. Time-to-event analyses were conducted using Kaplan Meier method. Results: Of 228 evaluable patients, 147 (64%) had ≥ 10% PCs in the initial marrow biopsy. The median follow-up was 3.4 years (95% CI: 2.3-4.3 years) for LWM and 4.3 years (95% CI: 3.4-4.8 years) for WMEPC (p=0.33). The baseline characteristics of WMEPC versus LWM are depicted in Table 1. Patients with WMEPC had lower bone marrow involvement by LPL (30%) compared to LWM (60%; p&lt;0.001) at diagnosis, but the rate of symptomatic hyperviscosity was higher in WMEPC during the disease course (Table 1). The TTNT was shorter for WMEPC [2.6 years (95% CI: 1.8-4.5 years)] compared to LWM [4.5 years (95% CI 3.2-8.2)], although it did not reach statistical significance (p=0.09, Figure 1). There was a trend towards shorter OS for WMEPC [Not reached (95% CI 7.2- NR)] compared to LWM [10.7 years (95% CI 7.3 -12.1 years); p=0.28], Figure 2. Of the 228 patients, 79% (n=182) had data available for systemic therapy. The rate of PR or better with frontline therapy was higher in rates in LWM compared to WMEPC (61 % vs 42% p=0.02, Table 1). Among WMEPC cohort, patients receiving either a proteasome inhibitor (PI)-based or an immunomodulatory (IMiD)-based combination as frontline therapy (n=16) had higher rates of partial response or better (68%) compared to non-PI/non-IMiD based therapy (n=114), p=0.04. Conclusion: WM with excess plasma cells at diagnosis is associated with a trend towards shorter TTNT and OS compared to WM with &lt;10% plasma cells in the lymphoplasmacytic population at diagnosis. Our preliminary data shows higher rates of partial response or better with the use of PI/IMiD based therapy, but the small cohort size limits the strength of this finding which needs to be validated externally. Disclosures Ansell: Bristol-Myers Squibb: Research Funding; Trillium: Research Funding; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; LAM Therapeutics: Research Funding; Mayo Clinic Rochester: Employment; Regeneron: Research Funding; Trillium: Research Funding; Bristol-Myers Squibb: Research Funding; Affimed: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding; Bristol-Myers Squibb: Research Funding; Affimed: Research Funding; LAM Therapeutics: Research Funding; Trillium: Research Funding; Mayo Clinic Rochester: Employment; Seattle Genetics: Research Funding; Mayo Clinic Rochester: Employment; Bristol-Myers Squibb: Research Funding; Seattle Genetics: Research Funding; Mayo Clinic Rochester: Employment; Trillium: Research Funding; LAM Therapeutics: Research Funding; Affimed: Research Funding; Affimed: Research Funding; Bristol-Myers Squibb: Research Funding; Regeneron: Research Funding; Mayo Clinic Rochester: Employment; Trillium: Research Funding; Bristol-Myers Squibb: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding; LAM Therapeutics: Research Funding; LAM Therapeutics: Research Funding; Regeneron: Research Funding; Mayo Clinic Rochester: Employment; Affimed: Research Funding; Mayo Clinic Rochester: Employment; Trillium: Research Funding; Regeneron: Research Funding; Regeneron: Research Funding; Seattle Genetics: Research Funding; Affimed: Research Funding; Seattle Genetics: Research Funding; Mayo Clinic Rochester: Employment; Trillium: Research Funding; Trillium: Research Funding; Bristol-Myers Squibb: Research Funding; Trillium: Research Funding; LAM Therapeutics: Research Funding; LAM Therapeutics: Research Funding; Regeneron: Research Funding; Regeneron: Research Funding; Affimed: Research Funding; Seattle Genetics: Research Funding; LAM Therapeutics: Research Funding; Seattle Genetics: Research Funding; Seattle Genetics: Research Funding; Affimed: Research Funding; Mayo Clinic Rochester: Employment; LAM Therapeutics: Research Funding; Affimed: Research Funding. Gertz:Spectrum: Honoraria, Research Funding; Janssen: Honoraria; Celgene: Honoraria; Prothena: Honoraria; Alnylam: Honoraria; Ionis: Honoraria. Dingli:alexion: Consultancy; Janssen: Consultancy; Millenium: Consultancy; Rigel: Consultancy; Karyopharm: Research Funding. Nowakowski:Selvita: Membership on an entity's Board of Directors or advisory committees; NanoString: Research Funding; MorphoSys: Consultancy, Research Funding; Genentech, Inc.: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; Curis: Research Funding; Bayer: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. Dispenzieri:Alnylam: Research Funding; Celgene: Research Funding; Takeda: Research Funding; Pfizer: Research Funding; Janssen: Consultancy; Intellia: Consultancy; Akcea: Consultancy. Lacy:Celgene: Research Funding. Kumar:Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Takeda: Research Funding. Kapoor:Janssen: Research Funding; Cellectar: Consultancy; Glaxo Smith Kline: Research Funding; Amgen: Research Funding; Takeda: Honoraria, Research Funding; Sanofi: Consultancy, Research Funding; Celgene: Honoraria.

Background: FDG PET/CT and bone marrow biopsy (BMB) are considered standard procedures for the staging of patients with new, untreated FL. A key issue in FL is the early identification of patients who will fail early. We recently reported (Am J Hematology 2019) that the presence of ≥2 EN sites, spleen, bone or soft tissue involvement as detected by PET all predicted failure to achieve EFS24. In Hodgkin lymphoma and diffuse large B-cell NHL, PET has replaced the routine need for a staging BMB. However, there is no such evidence in FL. The goal of this study was to determine the value of FDG PET/CT in determining bone involvement in FL using BMB as the gold standard. Methods: Patients were identified using the Mayo Clinic Lymphoma Database. 548 patients with newly diagnosed FL grades 1-3A between years 2003-2016, available BMB results, and PET/CT imaging at diagnosis, were included in the analysis. The presence of bone and spleen involvement on PET/CT, SUVmax and SUVmean of the axial skeleton at L3, and BMB results were recorded and compared. Results: In all, 36% (197/548) of patients had a positive BMB, and 34% (189/548) had bone involvement detected on PET/CT. Compared to BMB, the sensitivity and specificity of PET/CT in detecting bone involvement as determined by BMB were 60% and 80%, respectively. We noted that 59 patients had focal bone involvement on PET/CT rather than a diffuse component, and found that 47% (28/59) of these patients had a negative BMB obtained in the posterior iliac crest. Excluding these patients, the sensitivity and specificity of PET/CT in detecting bone involvement were 53% and 88%, respectively (Table 1). With respect to the spleen, 29% (157/548) of patients had evidence of splenic FL involvement on PET/CT, and of these, 69% (109/157) also had a positive BMB. The sensitivity and specificity of spleen involvement on PET/CT in predicting bone involvement on BMB were 55% and 86%, respectively (Table 2). We recorded SUV data at L3 in the 439 patients who had either a diffuse pattern of bone involvement on PET/CT, or a PET/CT read as negative. We analyzed the positive and negative predictive values (PPV and NPV) of SUVmax and SUVmean at several cut-off points to determine whether axial bone SUV is reliable at determining patients with a positive or negative BMB. The NPV for an SUVmax of less than 2.0 was 96% (n=25 patients classified as negative). For SUVmean, the best cut-off point was at less than 1.4, where NPV was 100% (n=15 patients classified as negative). There was no logical cut-off point for a significant PPV > 95%. Conclusion: In newly diagnosed FL, the sensitivity and specificity of bone involvement on PET/CT are insufficient for PET/CT to routinely replace BMB. However, in patients where the need for BMB at staging is being debated, certain factors on PET/CT can help facilitate this decision. The detection of focal bone lesions, especially those that may be missed on posterior iliac crest BMB, can make BMB unnecessary. If both the spleen and bone appear involved on PET/CT, this confers a relatively high chance that BMB will be positive. If SUVmax at L3 is less than 2.0, or if SUVmean is less than 1.4, the BMB will likely be negative, with a NPV > 95%. This decision-making algorithm is outlined in Figure 1 and may serve as a useful guideline for clinical trials and routine practice. Disclosures No relevant conflicts of interest to declare.

Introduction: New Diffuse Large B-cell (DLBCL) treatments remain a clinical need despite the success of rituximab combined with CHOP chemotherapy (RCHOP), which results in durable responses in 60-70% of patients. Those refractory to, or who relapse following, first-line therapy have a very poor outcome, with only 20% surviving beyond 5 years. Rationally-targeted frontline strategies are needed, especially for those with high-risk disease. Significant advances have been made in the genomic classification of DLBCL, but none have impacted the design of phase III trials for untreated DLBCL patients. Building on new genetic profiling studies to personalize clinical treatment, an NCI initiative, could allow clinicians to add targeted therapies to the RCHOP backbone based on individual tumor signatures. The phase II ECOG-ACRIN1412 trial, which compared RCHOP combined with lenalidomide (R2CHOP) versus RCHOP showed significantly superior event free survival (EFS) and overall survival benefits for those treated with R2CHOP. Herein, we report the profile of a high-risk ABC/non-GCB subset of DLBCL driven by genomic alterations in inflammatory genes that are susceptible to front-line R2CHOP, but continue to experience poor outcome with RCHOP alone. Methods: We studied a total of 196 DLBCL patients. 47 were treated with R2CHOP from an investigator-initiated, open-label, single-arm phase II study (NCT00670358). 149 were newly diagnosed DLBCL cases treated with RCHOP, or R-immunochemotherapy (herein called RCHOP), and followed prospectively through the Molecular Epidemiology Resource (MER) of the University of Iowa/Mayo Clinic SPORE that served as a contemporary cohort. Patients from each treatment group were divided based on their event free survival at 24 months (EFS24). DNA alterations within these populations were identified through whole exome sequencing (WES). Variants were analyzed for their presence in EFS24 achievement or failure groups in both RCHOP and R2CHOP. Both tumor and germline sequencing was performed for 47/47 R2CHOP cases and 49/149 RCHOP cases. Gene expression data from the PanCan panel of 730 B-cell-related genes was analyzed to determine gene expression profiles characteristic of the high-risk/R2CHOP-profile on 59 available non-GCB DLBCL cases (45 RCHOP; 14 R2CHOP). A two-sided comparative marker analysis T statistic test was applied to assess what genes displayed differential expression based on achieving EFS24 in both R2CHOP and RCHOP populations. Positive values represented associations with achieving EFS24 and negative values were associated with cases of EFS24 failure. Results: Three genes were enriched in the RCHOP cases that failed EFS24 but achieved EFS24 with R2CHOP among non-GCB patients: PIM1, SPEN, and MYD88 (L265P), herein referred to as Responder Alterations. In R2CHOP cases, patients with a Responder Alteration had a better overall EFS (P = 0.051) compared to wild type patients. In contrast, RCHOP treated patients with a Responder Alteration in their tumor had a significantly worse overall EFS (P = 0.0004) compared to patients without a mutation. Together, PIM1, SPEN, or MYD88 (L265P) mutations were present in 38.0% (30/79) of all non-GCB cases. Collective R2CHOP and RCHOP EFS24 differential gene expression T values were significantly different for 18 previously-defined signatures. The R2CHOP cases that achieved EFS24 were enriched for genes involved in cell cycle, JAK-STAT, cytokine signaling, and NF-κB pathways based on these signatures and ontology analyses. Lastly, cases with WES and PanCan data were analyzed together to observe differential gene expression patterns between cases with and without signature mutations. These data suggest that R2CHOP disrupts tumors reliant on IRF4, NF-κB, and STAT transcription factors, leading to a loss of proliferative feedback systems. Conclusions: Our combined analysis of DNA and RNA across R2CHOP and RCHOP treatment cohorts identifies a high-risk non-GCB phenotype that encompasses approximately 38% of non-GCB patients, is capable of sustaining JAK-STAT and NF-κB signaling, and is sensitive to R2CHOP. Our study lays the groundwork for a precision therapy approach in DLBCL in which DNA or RNA profiles can be used to identify patients early in treatment who may not benefit from the current standard of care, RCHOP, and who would benefit from the addition of lenalidomide or other targeted agents. Disclosures Gandhi: Celgene Corporation: Employment, Equity Ownership, Patents & Royalties. Ansell:LAM Therapeutics: Research Funding; Seattle Genetics: Research Funding; LAM Therapeutics: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding; Bristol-Myers Squibb: Research Funding; Affimed: Research Funding; Trillium: Research Funding; Trillium: Research Funding; Regeneron: Research Funding; Bristol-Myers Squibb: Research Funding; LAM Therapeutics: Research Funding; Trillium: Research Funding; Affimed: Research Funding; LAM Therapeutics: Research Funding; Bristol-Myers Squibb: Research Funding; Trillium: Research Funding; Affimed: Research Funding; Bristol-Myers Squibb: Research Funding; Trillium: Research Funding; LAM Therapeutics: Research Funding; Bristol-Myers Squibb: Research Funding; Regeneron: Research Funding; Affimed: Research Funding; Seattle Genetics: Research Funding; Mayo Clinic Rochester: Employment; Regeneron: Research Funding; Seattle Genetics: Research Funding; Mayo Clinic Rochester: Employment; Seattle Genetics: Research Funding; LAM Therapeutics: Research Funding; LAM Therapeutics: Research Funding; LAM Therapeutics: Research Funding; Regeneron: Research Funding; Regeneron: Research Funding; Seattle Genetics: Research Funding; Seattle Genetics: Research Funding; Trillium: Research Funding; Trillium: Research Funding; Affimed: Research Funding; Affimed: Research Funding; Mayo Clinic Rochester: Employment; Mayo Clinic Rochester: Employment; Mayo Clinic Rochester: Employment; Seattle Genetics: Research Funding; Mayo Clinic Rochester: Employment; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Affimed: Research Funding; Regeneron: Research Funding; Regeneron: Research Funding; Bristol-Myers Squibb: Research Funding; Regeneron: Research Funding; Seattle Genetics: Research Funding; Trillium: Research Funding; Mayo Clinic Rochester: Employment; Mayo Clinic Rochester: Employment; Trillium: Research Funding; Affimed: Research Funding; Mayo Clinic Rochester: Employment; Bristol-Myers Squibb: Research Funding; Affimed: Research Funding; LAM Therapeutics: Research Funding. Cerhan:Celgene: Research Funding; NanoString: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees. Nowakowski:Curis: Research Funding; Bayer: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; Genentech, Inc.: Research Funding; MorphoSys: Consultancy, Research Funding; NanoString: Research Funding; Selvita: Membership on an entity's Board of Directors or advisory committees. Novak:Celgene Coorperation: Research Funding.