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A non-invasive myelodysplastic syndromes (MDS) diagnostic model would allow for care while avoiding invasive bone marrow examinations (BME). BME-established MDS patients were compared to non-MDS (BME-excluded) patients. Variables (gender, age, hemoglobin (Hb), mean red blood cell corpuscular volume (MCV), platelet (PLT), and white blood cell (WBC)) were combined with multivariate logistic regression; a probability score (Y) was calculated. MDS (n = 48) and non-MDS (n = 63) patients were used to establish the model. The ROC was drawn, giving an AUC of 0.748 (95% CI: 0.656-0.84). Two cutoff values were used for Y. Y ≥ 0.633: high likelihood (positive predictive value (PPV) = 85%); Y ≤ 0.288: low likelihood (negative predictive value (NPV) = 81%) of MDS. The first group is defined as probable MDS (pMDS); the second, probably not MDS (pnMDS). The model was validated with 40 additional patients (20 with and 20 without MDS). Using clinical and lab data, we could diagnose or exclude MDS in about half of the patients, avoiding BME. Future work will use larger cohorts of patients to improve and further validate the model.

Background Several therapies are recommended by NCCN/ESMO guidelines for autologous stem cell transplant (ASCT)-ineligible patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL). In the single-arm, Phase II L-MIND study (NCT02399085), the chemotherapy-free regimen tafasitamab + lenalidomide (LEN) demonstrated efficacy for this patient population. In the absence of randomized clinical trial data, RE-MIND2 (NCT04697160), an observational, retrospective cohort study, compared patient outcomes from L-MIND with matched patient populations treated with NCCN/ESMO recommended therapies for ASCT-ineligible patients with R/R DLBCL. Methods Data were retrospectively collected between 1 April and 13 November 2020 from academic and public hospitals, as well as private practices in North America, Europe and Asia Pacific. To ensure consistency with L-MIND I/E criteria, patients aged ≥18 years with histologically confirmed DLBCL and who had received ≥2 systemic therapies for DLBCL (including ≥1 anti-CD20 therapy) were enrolled. For the main analysis, patients from the L-MIND tafasitamab + LEN cohort were matched with patients from the RE-MIND2 observational cohort using estimated propensity score-based 1:1 nearest neighbor matching, balanced for six baseline characteristics: age ( A sensitivity analysis was performed using an inverse probability of treatment weighting method calculating the average effect of the treatment on the treated, to generate balanced cohorts based on nine baseline characteristics: age, refractoriness to last line of therapy, number of previous lines of therapy, history of primary refractoriness, prior ASCT, Ann Arbor Stage (I/II vs III/IV), elevated LDH (yes vs no), neutropenia (yes vs no), and anemia (yes vs no). Additional sensitivity analyses accounting for missing baseline characteristics using multiple imputation technique were performed. Data are presented for tafasitamab + LEN versus polatuzumab vedotin + bendamustine + rituximab (pola-BR), rituximab + LEN (R2), and CD19 CAR-T therapies (CAR-T). The primary endpoint was overall survival (OS). Secondary endpoints included objective response rate (ORR), complete response rate, progression-free survival and duration of response. Results Of 3,454 patients enrolled from 200 sites, 106, 106, and 149 patients were treated with pola-BR, R2, and CAR-T, respectively. For the comparative analysis, matched patient pairs were created using 1:1 nearest neighbor matching with a caliper. Matched pairs consisted of: tafasitamab + LEN vs pola-BR, n=24 pairs; vs R2, n=33 pairs; and vs CAR-T, n=37 pairs. A significant OS benefit was associated with tafasitamab + LEN compared to pola-BR (HR: 0.44, 95% confidence interval [CI]: 0.20-0.96; p=0.038) and R2 (HR=0.44, 95% CI: 0.22-0.84; p=0.014) (Figure 1A-B). There was no significant difference in OS benefit between tafasitamab + LEN and CAR-T (HR=0.95, 95% CI: 0.47-1.91; p=0.891) (Figure 1C). ORR was 62.5% (15/24) for tafasitamab + LEN vs 58.3% (14/24) for pola-BR (p=1.000), 63.6% (21/33) vs 30.3% (10/33) for R2 (p=0.013), and 59.5% (22/37) vs 75.7% (28/37) for CAR-T (p=0.214). Improved outcomes were also observed with tafasitamab + LEN for other secondary endpoints (Table 1). Results are consistent with those obtained in the sensitivity analyses. Conclusions The results of this retrospective cohort analysis suggest that the novel tafasitamab + LEN combination may significantly improve health outcomes, with a prolonged survival benefit for ASCT-ineligible R/R DLBCL patients, relative to NCCN/ESMO recommended therapies. Tafasitamab + LEN improved survival outcomes compared with pola-BR and R2 in closely matched patient populations. Comparable outcomes were observed for tafasitamab + LEN vs CAR-T. Although based on limited patient numbers, these data may be clinically relevant in the context of emerging therapies for R/R DLBCL. While this study design does not replace randomized data, it remains more rigorous than inter-trial comparison. The limitations of comparing clinical trial and matched retrospective real-world data will be discussed. Funding: MorphoSys AG. Figure 1 Figure 1. Disclosures Nowakowski: Celgene, MorphoSys, Genentech, Selvita, Debiopharm Group, Kite/Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene, NanoString Technologies, MorphoSys: Research Funding. Joffe: AstraZeneca. Epizyme: Consultancy. Fleury: Abbvie, Astrazeneca, BMS, Celgene, Janssen, Kite-Gilead, Merck, Novartis, Roche, Seattle Genetics: Other: conference and advisory role. Peters: AbbVie, Incyte: Consultancy, Honoraria. Greil: Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Daiichi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Sandoz: Honoraria, Research Funding. Ku: Roche: Consultancy; Antegene: Consultancy; Genor Biopharma: Consultancy. Marks: Kite/Gilead: Membership on an entity's Board of Directors or advisory committees; AbbVie: Other: Meeting attendance; Kite/Gilead: Honoraria; Merck: Consultancy. Kim: AstraZeneca: Research Funding. Zinzani: BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; EUSA Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ADC Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck Sharp & Dohme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kyowa Kirin: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Therapeutics Inc: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ImmuneDesign: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Trotman: Beigene: Research Funding; Celgene: Research Funding; Bristol Myers Squibb: Research Funding; Roche: Research Funding; Janssen: Research Funding; PCYC Pharmacyclics: Research Funding. Sabatelli: Incyte: Current Employment, Current equity holder in publicly-traded company. Huang: MorphoSys: Current Employment. Waltl: MorphoSys: Current Employment. Winderlich: MorphoSys: Current Employment, Current equity holder in publicly-traded company. Ambarkhane: MorphoSys: Current Employment, Other: Support for attending meetings/travel. Kurukulasuriya: MorphoSys: Current Employment, Current equity holder in publicly-traded company, Other: Support for attending meetings/travel. Cordoba: Pfizer: Research Funding; Kyowa-Kirin: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ADCTherapeutics: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees; Takeda: 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; Kite: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Hess: Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead/Kite: Research Funding; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genmab: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; EUSA: Honoraria, Membership on an entity's Board of Directors or advisory committees. Salles: Miltneiy: Consultancy; Novartis: Consultancy; Morphosys: Consultancy, Honoraria; Janssen: Consultancy; Genentech/Roche: Consultancy; Kite/Gilead: Consultancy; Regeneron: Consultancy, Honoraria; Velosbio: Consultancy; Takeda: Consultancy; Allogene: Consultancy; Ipsen: Consultancy; Loxo: Consultancy; Rapt: Consultancy; Genmab: Consultancy; Incyte: Consultancy; Epizyme: Consultancy, Honoraria; Debiopharm: Consultancy; BMS/Celgene: Consultancy; Beigene: Consultancy; Abbvie: Consultancy, Honoraria; Bayer: Honoraria.

Introduction: EBV can be associated with several types of lymphomas, with reported frequencies of up to 8-10% in diffuse large B cell lymphoma (DLBCL), 30-100% in peripheral T cell lymphoma (PTCL) subtypes, 80% in post-transplant lymphoproliferative disease (PTLD), and 15-30% in classical Hodgkin lymphoma (HL), with adverse impact on outcomes. Nanatinostat (Nstat) is a Class-I selective oral HDAC inhibitor that induces the expression of the lytic BGLF4 EBV protein kinase in EBV + tumor cells, activating ganciclovir (GCV) via phosphorylation. This results in GCV-induced inhibition of viral and cellular DNA synthesis and apoptosis. Herein we report the final results from this exploratory study for patients with R/R EBV + lymphomas (NCT03397706). Methods: Patients aged ≥18 with histologically confirmed EBV + lymphomas (defined as any degree of EBER-ISH positivity), R/R to ≥1 prior systemic therapies with an absolute neutrophil count ≥1.0×10 9/L, platelet count ≥50×10 9/L, and no curative treatment options per investigator were enrolled into 5 dose escalation cohorts to determine the recommended phase 2 doses (RP2D) of Nstat + VGCV for phase 2 expansion. Phase 2 patients received the RP2D (Nstat 20 mg daily, 4 days per week + VGCV 900 mg orally daily) in 28-day cycles until disease progression or withdrawal. Primary endpoints were safety/RP2D (phase 1b) and overall response rate (ORR) (phase 2); secondary endpoints were pharmacokinetics, duration of response (DoR), time to response, progression free survival and overall survival. Responses were assessed using Lugano 2014 response criteria beginning at week 8. Results: As of 18 June 2021, 55 patients were enrolled (phase 1b: 25; phase 2: 30). Lymphoma subtypes were DLBCL (n=7), extranodal NK/T-cell (ENKTL) (n=9), PTCL, not otherwise specified (PTCL-NOS) (n=5), angioimmunoblastic T cell lymphoma (n=6), cutaneous T cell (n=1), HL (n=11), other B cell (n=3), and immunodeficiency-associated lymphoproliferative disorders (IA-LPD) (n=13), including PTLD (n=4), HIV-associated (n=5), and other [n=4: systemic lupus erythematosus (SLE) (n=2), common variable/primary immunodeficiency (n=2)]. Median age was 60 years (range 19-84), M/F 35/20, median number of prior therapies was 2 (range 1-11), 76% had ≥2 prior therapies, 78% were refractory to their most recent prior therapy, and 84% had exhausted standard therapies. EBER positivity ranged from 10% of patients included neutropenia (27%), thrombocytopenia (20%), anemia (20%), and lymphopenia (14%). Dose reductions and interruptions due to treatment-related AEs were reported in 14 (25%) and 16 (29%) patients, respectively. Only 1 patient had to discontinue therapy. There were no cases of CMV reactivation. For 43 evaluable patients (EBER-ISH + with ≥ 1 post-treatment response assessment) across all histologies, the investigator-assessed ORR and complete response (CR) rates were 40% (17/43) and 19% (8/43) respectively. Patients with T/NK-NHL (n=15; all refractory to their last therapy) had an ORR of 60% (n=9) with 27% (n=4) CRs. Two patients (ENKTL and PTCL-NOS) in PR and CR respectively were withdrawn at 6.7 and 6.6 months (m) respectively for autologous stem cell transplantation. For DLBCL (n=6), ORR/CR was 67%/33% (both CRs were in patients refractory to first-line R-CHOP). For IA-LPD (n=13), ORR/CR was 30%/20% (PTLD: 1 CR, other: 1 CR, 1 PR). For HL (n=10), there was 1 PR (4 SD). The median DoR for all responders was 10.4 m, with a median follow-up from response of 5.7 m (range 1.9-34.1 m). For the 17 responders, 8 lasted ≥ 6 months. Conclusions: The combination of Nstat and VGCV was well-tolerated with a manageable toxicity profile and shows promising efficacy in patients with R/R EBV + lymphomas, particularly in refractory T/NK-NHL, a heterogeneous group of aggressive lymphomas with dismal outcomes, with multiple durable responses. Further evaluation of this novel combination therapy for the treatment of recurrent EBV + lymphomas is ongoing in the phase 2 VT3996-202 trial. Disclosures Haverkos: Viracta Therapeutics, Inc.: Honoraria, Research Funding. Baiocchi: Prelude Therapeutics: Consultancy; viracta: Consultancy, Current holder of stock options in a privately-held company; Codiak Biosciences: Research Funding; Atara Biotherapeutics: Consultancy. Brammer: Seattle Genetics: Speakers Bureau; Celgene: Research Funding; Kymera Therapeutics: Consultancy. Feldman: Alexion, AstraZeneca Rare Disease: Honoraria, Other: Study investigator. Brem: Karyopharm: Membership on an entity's Board of Directors or advisory committees; SeaGen: Speakers Bureau; BeiGene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees; KiTE Pharma: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Consultancy; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics/Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Morphosys/Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Scheinberg: Roche: Consultancy; Abbvie: Consultancy; BioCryst Pharmaceuticals: Consultancy; Alexion pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau. Joffe: AstraZeneca: Consultancy; Epizyme: Consultancy. Katkov: Viracta Therapeutics, Inc.: Current Employment. McRae: Viracta Therapeutics, Inc.: Current Employment. Royston: Viracta Therapeutics, Inc.: Current Employment. Rojkjaer: Viracta Therapeutics, Inc.: Current Employment. Porcu: Viracta: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Innate Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BeiGene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; Daiichi: Honoraria, Research Funding; Kiowa: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Spectrum: Consultancy; DrenBio: Consultancy.

Background: Venetoclax (Ven; BH3 mimetic) and Obinutuzumab (O; CD20 antibody) is an approved, fixed-duration regimen (one year) that induces undetectable minimum residual disease (uMRD) and durable remissions in treatment naïve patients (pts) with chronic lymphocytic leukemia (CLL; Fischer NEJM 2019). In the CLARITY trial of venetoclax-ibrutinib (BTK inhibitor; BTKi) in relapsed or refractory CLL, peripheral blood (PB) MRD response kinetics predicted bone marrow (BM) uMRD and were associated with progression-free survival (Rawstron EHA 2020). We explored MRD as a biomarker to direct treatment duration in an investigator-initiated phase 2 trial of Zanubrutinib (BTKi) and O-Ven (BOVen). We hypothesize that early MRD kinetics will identify a defined cohort of pts with delayed BM MRD clearance, and early recurrent detectable MRD after discontinuation of treatment in pts attaining uMRD. Methods: In this multicenter, phase 2 trial (NCT03824483), eligible pts had previously untreated CLL requiring treatment (iwCLL), ECOG PS ≤2, absolute neutrophil count (ANC) ≥1,000/ul, platelets (PLT) ≥75,000/ul (ANC ≥0/ul, PLT ≥20,000/ul if due to CLL). Informed consent was obtained from all pts. BOVen was administered in 28-day (D) cycles (C): Zanubrutinib 160 mg by mouth (PO) twice daily starting D1; Obinutuzumab 1000 mg IV D1 (split D1-2 if lymphocyte count ≥25,000/ul or lymph node ≥5cm), D8, D15 of C1, and D1 of C2-8; Venetoclax ramp up initiated C3D1 (target 400 mg PO daily). MRD was evaluated by flow cytometry (MRD-FC) and immunosequencing (MRD-IS; Adaptive ClonoSEQ) with uMRD defined as ≤10 -4 for flow and ≤10 -5 for IS. Treatment consisted of 8-24 cycles with duration determined by prespecified MRD criteria. Beginning on C7D1 then every 2 cycles, pts with PB uMRD-FC had BM within 14 days. If BM uMRD, PB MRD was repeated after two additional cycles. Pts with confirmed uMRD-FC in PB and BM discontinued therapy and entered posttreatment surveillance. Response was assessed per iwCLL. Adverse events (AE) were assessed per CTCAE v5. MRD-IS failure free survival (FFS) was calculated from end-of-treatment (EOT) to the date of detectable MRD-IS (≥10 -5) using the Kaplan-Meier method. Results: The study accrued 39 pts (03/19-10/19): median age 59 years (23-73), 3:1 male predominance, 28/39 (72%) IGHV unmutated, 5/39 (12.8%) del(17p)/TP53M. All pts were evaluable for toxicity with 37 evaluable for efficacy. At a median follow up of 26+ months (mo; 4.5-30.5+), 95% (35/37) pts achieved uMRD-FC in PB, among whom 33 (94%) also achieved uMRD-IS. BM uMRD-FC was seen in 89% (33/37) at a median time of 8 mo (6-16), all of whom met prespecified MRD criteria and discontinued therapy after a median of 10 mo (8-18). Three pts discontinued therapy with persistent detectable BM MRD after 24 cycles. The most common AEs were neutropenia (51%), thrombocytopenia (44%), diarrhea (44%), infusion related reaction (41%) and bruising (41%). The most common grade ≥3 AE was neutropenia (15%). No laboratory or clinical TLS occurred (Howard definition). A ≥400-fold reduction in PB MRD-IS after 4 cycles (ΔMRD400) was selected using the Youden Index and was highly predictive of attaining BM uMRD in ≤8mo (sensitivity 88% [21/24], specificity 100% [11/11], PPV 100% [21/21], NPV 79% [11/14]. As a result, the median duration of therapy was shorter among patients who achieved ΔMRD400 (8 vs 13 mo). Of 33 pts who met prespecified uMRD criteria and stopped therapy, 31 (94%) remain uMRD-FC following a median 15 mo (0-20) from EOT, and 2 pts had recurrent MRD (1 with PD recaptured PB uMRD with retreatment). Of 33 pts who discontinued therapy after achieving the prespecified MRD endpoint, MRD-IS was evaluated every 3 months in 31 pts for a median of 12 mo (range, 3-18) from EOT. MRD-IS FFS was longer in pts who achieved ΔMRD400 (log rank p Conclusion: BOVen achieved frequent, durable uMRD. All pts completed therapy (median 10 mo treatment), including 89% (33/37) who met the prespecified PB/BM uMRD endpoint. With a median posttreatment follow-up of 15 mo, 31 (94%) remain uMRD-FC. ΔMRD400 identified a cohort of pts (40%) with delayed BM MRD clearance and earlier MRD recurrence, despite longer treatment duration. ΔMRD400 warrants further study as a predictive biomarker for treatment duration. Figure 1 Figure 1. Disclosures Soumerai: Seattle Genetics: Consultancy; AstraZeneca: Consultancy; BeiGene: Consultancy, Research Funding; BMS: Consultancy; Adaptive Biotechnologies: Consultancy, Research Funding; AbbVie: Consultancy; TG Therapeutics: Consultancy, Research Funding; BostonGene: Research Funding; GlaxoSmithKline: Research Funding. Mato: Janssen: Consultancy, Research Funding; LOXO: Consultancy, Research Funding; Johnson and Johnson: Consultancy, Research Funding; Acerta/AstraZeneca: Consultancy, Research Funding; DTRM BioPharma: Consultancy, Research Funding; Genmab: Research Funding; AstraZeneca: Consultancy; MSKCC: Current Employment; Genentech: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Nurix: Research Funding; AbbVie: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; TG Therapeutics: Consultancy, Other: DSMB, Research Funding; BeiGene: Consultancy, Research Funding. Dogan: Seattle Genetics: Consultancy; Peer View: Honoraria; Takeda: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Physicians' Education Resource: Honoraria; EUSA Pharma: Consultancy. Joffe: Epizyme: Consultancy; AstraZeneca: Consultancy. Hochberg: Leuko: Consultancy; Intervention Insights: Consultancy. Abramson: Bluebird Bio: Consultancy; Morphosys: Consultancy; Bristol-Myers Squibb Company: Consultancy, Research Funding; Kymera: Consultancy; BeiGene: Consultancy; Novartis: Consultancy; C4 Therapeutics: Consultancy; Genmab: Consultancy; EMD Serono: Consultancy; Kite Pharma: Consultancy; Incyte Corporation: Consultancy; Astra-Zeneca: Consultancy; Allogene Therapeutics: Consultancy; Seagen Inc.: Research Funding; AbbVie: Consultancy; Karyopharm: Consultancy; Genentech: Consultancy. Batlevi: TouchIME: Honoraria; BMS: Current holder of individual stocks in a privately-held company; Medscape: Honoraria; GLG Pharma: Consultancy; Dava Oncology: Honoraria; Kite Pharma: Consultancy; Juno/Celgene: Consultancy; ADC Therapeutics: Consultancy; Life Sciences: Consultancy; Moderna: Current holder of individual stocks in a privately-held company; Regeneron: Current holder of individual stocks in a privately-held company; Viatris: Current holder of individual stocks in a privately-held company; Pfizer: Current holder of individual stocks in a privately-held company; Karyopharm: Consultancy; TG Therapeutics: Consultancy; Memorial Sloan Kettering Cancer Center: Current Employment; Seattle Genetics: Consultancy; Bayer: Research Funding; Xynomic: Research Funding; Roche/Genentech: Research Funding; Novartis: Research Funding; Epizyme: Research Funding; Janssen: Research Funding; Autolus: Research Funding. Matasar: Rocket Medical: Consultancy, Research Funding; Merck Sharp & Dohme: Current holder of individual stocks in a privately-held company; Juno Therapeutics: Consultancy; Merck: Consultancy; Genentech, Inc.: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; IGM Biosciences: Research Funding; GlaxoSmithKline: Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Memorial Sloan Kettering Cancer Center: Current Employment; Teva: Consultancy; TG Therapeutics: Consultancy, Honoraria; Pharmacyclics: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria, Research Funding; ImmunoVaccine Technologies: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy. Noy: Rafael Parhma: Research Funding; Morphosys: Consultancy; Targeted Oncology: Consultancy; Medscape: Consultancy; Pharmacyclics: Consultancy, Research Funding; Janssen: Consultancy, Honoraria; Epizyme: Consultancy. Palomba: Ceramedix: Honoraria; Seres: Honoraria, Other: Stock, Patents & Royalties, Research Funding; Notch: Honoraria, Other: Stock; Novartis: Consultancy; Kite: Consultancy; PCYC: Consultancy; BeiGene: Consultancy; Lygenesis: Honoraria; Nektar: Honoraria; Juno: Patents & Royalties; Wolters Kluwer: Patents & Royalties; Rheos: Honoraria; Magenta: Honoraria; Pluto: Honoraria; WindMIL: Honoraria; Priothera: Honoraria. Kumar: Abbvie Pharmaceuticals: Research Funding; Pharmacyclics: Research Funding; Kite Pharmaceuticals: Other: advisory board , Research Funding; Celgene: Honoraria, Other: advisory board, Research Funding; Astra Zeneca: Honoraria, Other: Advisory Board, Research Funding; Adaptive Biotechnologies, Celgene, Abbvie Pharmaceticals, Pharmacyclics, Seattle Genetics: Research Funding; Seattle Genetics: Research Funding. Roeker: AbbVie, AstraZeneca, Janssen, LOXO, Pharmacyclics, TG Therapeutics, Vaniam Group, Verastem: Consultancy; Pfizer: Consultancy, Research Funding; Pharmacyclics: Consultancy; TG Therapeutics: Consultancy; Loxo Oncology: Consultancy; Abbot Laboratories: Current equity holder in publicly-traded company. Thompson: VJHemOnc: Honoraria; MJH Life Sciences: Honoraria; Curio Science: Honoraria. Roshal: Physicians' Education Resource: Other: Provision of services; Auron Therapeutics: Other: Ownership / Equity interests; Provision of services; Celgene: Other: Provision of services. Huang: BeiGene: Current Employment, Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company, Divested equity in a private or publicly-traded company in the past 24 months, Other: Travel, Accommodations, Expenses; Protara Therapeutics: Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Biondo: Roche: Current holder of individual stocks in a privately-held company; Genentech, Inc.: Current Employment. Wu: Genentech, Inc.: Current Employment; Roche/GNE: Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Jacob: Adaptive Biotechnologies: Current Employment. Abdel-Wahab: H3B Biomedicine: Consultancy, Research Funding; Foundation Medicine Inc: Consultancy; Merck: Consultancy; Prelude Therapeutics: Consultancy; LOXO Oncology: Consultancy, Research Funding; Lilly: Consultancy; AIChemy: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Envisagenics Inc.: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees. Zelenetz: Novartis: Honoraria; Genentech/Roche: Honoraria, Research Funding; BMS/Celgene/JUNO: Honoraria, Other; AstraZeneca: Honoraria; MethylGene: Research Funding; Pharmacyclics: Honoraria; Amgen: Honoraria; MEI Pharma: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Verastem: Honoraria; Beigene: Honoraria, Other, Research Funding; Abbvie: Honoraria, Research Funding; SecuraBio: Honoraria; Janssen: Honoraria; Gilead: Honoraria; MorphoSys: Honoraria; NCCN: Other; LFR: Other. OffLabel Disclosure: Zanubrutinib is administered off-label in combination with venetoclax and obinutuzumab for patients with CLL/SLL.

Introduction Histone deacetylase (HDAC) inhibitors have single agent activity in various types of lymphoma. They restore antigen-specific immune recognition in B-cell lymphoma cells and modulate programmed cell death (PD)-1 expression on circulating T-lymphocytes. Pembrolizumab (PEM) is highly active in Hodgkin Lymphoma (HL) and demonstrates a 12-month PFS of 46% in patients with R/R HL. Preclinical studies have shown synergism of this combination in mouse models of various tumors. We present the interim efficacy analysis from the first stage of our phase II trial investigating the combination of the HDAC inhibitor Entinostat (ENT) and the PD-1-blocking antibody PEM in patients with R/R HL. Methods Patients with R/R HL received ENT 5-7 mg orally once weekly and PEM 200 mg intravenously once every three weeks. Prior use of anti-PD-1 or HDAC inhibitor was allowed if there had been clinical benefit. Tumor assessment was evaluated using the RECIL criteria. The primary endpoint is the 12-month progression-free survival (PFS). Using a Simon two-stage minimax design to power the study, 21 patients were to be enrolled in the first stage with a 12-month PFS rate of 40% considered undesirable and 60% desirable. Results At time of data censoring on 7/24/21, 22 patients with HL have been enrolled. The median number of prior therapies was 5 (2-17). 7 (32%) were refractory to the most recent therapy, 13 (59%) had received autologous stem cell transplant (ASCT), 12 (55%) prior anti-PD1 antibody therapy, and 3 (14%) prior HDAC inhibitor therapy. Out of 22 evaluable patients, the overall response rate (ORR) was 86% and the complete response (CR) rate was 45%. Responding patients included 9 with prior anti-PD-1 antibody and 3 with prior HDAC inhibitor therapy. With median duration of follow-up among survivors of 8.4 months (2-26), the 12-month PFS was 72% (44%-87%). Reasons for treatment discontinuation included: progression (n=6), toxicities (n=5) consolidation with transplant or radiation (n=3), withdrawal of consent (n=3), and completion of study protocol (n=2). Severe toxicities resulting in study discontinuation were pleural effusions, pericarditis, pneumonitis and peripheral neuropathy. Out of the 22 total patients with HL enrolled in this study, 50% of patients had grade ≥3 (41%) and thrombocytopenia (32%). 41% exhibited grade ≥3 non-hematologic AEs, which included pericardial or pleural effusions (n=2, 9%), as well as fatigue, musculoskeletal pain, abdominal pain, pneumonitis, elevated lipase, hyperglycemia, and peripheral neuropathy. AEs that were potentially immune-related included hypothyroidism (n=2, 9%), elevated transaminases (n=4, 18%), diarrhea (n=3, 14%) and pneumonitis (n=2, 8%). Conclusions Interim results following stage I of this phase 2 trial demonstrates a 12-month PFS rate of 74%, meeting the primary endpoint of the study and justifying continued investigation of the combination of PEM and ENT. In this heavily pretreated patient population, responses were seen in the majority of patients despite prior exposure to anti-PD-1 agents. Figure 1 Figure 1. Disclosures Vardhana: Immunai: Membership on an entity's Board of Directors or advisory committees. Moskowitz: Bristol-Myers Squibb: Research Funding; Seattle Genetics: Consultancy, Research Funding; ADC Therapeutics: Research Funding; Beigene: Research Funding; Miragen: Research Funding; Janpix Ltd.: Consultancy; Merck: Consultancy, Research Funding; Imbrium Therapeutics L.P./Purdue: Consultancy; Takeda: Consultancy; Incyte: Research Funding. Joffe: AstraZeneca. Epizyme: Consultancy. Khan: Seattle Genetics: Research Funding. Kumar: Seattle Genetics: Research Funding; Astra Zeneca: Honoraria, Other: Advisory Board, Research Funding; Kite Pharmaceuticals: Other: advisory board , Research Funding; Pharmacyclics: Research Funding; Abbvie Pharmaceuticals: Research Funding; Celgene: Honoraria, Other: advisory board, Research Funding; Adaptive Biotechnologies, Celgene, Abbvie Pharmaceticals, Pharmacyclics, Seattle Genetics: Research Funding. Zelenetz: Gilead: Honoraria; Genentech/Roche: Honoraria, Research Funding; AstraZeneca: Honoraria; MorphoSys: Honoraria; Novartis: Honoraria; Pharmacyclics: Honoraria; Verastem: Honoraria; SecuraBio: Honoraria; BMS/Celgene/JUNO: Honoraria, Other; MethylGene: Research Funding; Abbvie: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; MEI Pharma: Honoraria, Research Funding; Janssen: Honoraria; Beigene: Honoraria, Other, Research Funding; Amgen: Honoraria; NCCN: Other; LFR: Other. Horwitz: Affimed: Research Funding; ADC Therapeutics, Affimed, Aileron, Celgene, Daiichi Sankyo, Forty Seven, Inc., Kyowa Hakko Kirin, Millennium /Takeda, Seattle Genetics, Trillium Therapeutics, and Verastem/SecuraBio.: Consultancy, Research Funding; Aileron: Research Funding; Acrotech Biopharma, Affimed, ADC Therapeutics, Astex, Merck, Portola Pharma, C4 Therapeutics, Celgene, Janssen, Kura Oncology, Kyowa Hakko Kirin, Myeloid Therapeutics, ONO Pharmaceuticals, Seattle Genetics, Shoreline Biosciences, Inc, Takeda, Trillium Th: Consultancy; Celgene: Research Funding; C4 Therapeutics: Consultancy; Crispr Therapeutics: Research Funding; Daiichi Sankyo: Research Funding; Forty Seven, Inc.: Research Funding; Kura Oncology: Consultancy; Kyowa Hakko Kirin: Consultancy, Research Funding; Millennium/Takeda: Research Funding; Myeloid Therapeutics: Consultancy; ONO Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy, Research Funding; Secura Bio: Consultancy; Shoreline Biosciences, Inc.: Consultancy; Takeda: Consultancy; Trillium Therapeutics: Consultancy, Research Funding; Tubulis: Consultancy; Verastem/Securabio: Research Funding. Noy: Janssen: Consultancy, Honoraria; Epizyme: Consultancy; Morphosys: Consultancy; Rafael Parhma: Research Funding; Medscape: Consultancy; Targeted Oncology: Consultancy; Pharmacyclics: Consultancy, Research Funding. Batlevi: Memorial Sloan Kettering Cancer Center: Current Employment; Moderna: Current holder of individual stocks in a privately-held company; Viatris: Current holder of individual stocks in a privately-held company; BMS: Current holder of individual stocks in a privately-held company; Autolus: Research Funding; Pfizer: Current holder of individual stocks in a privately-held company; Dava Oncology: Honoraria; Bayer: Research Funding; Medscape: Honoraria; ADC Therapeutics: Consultancy; Regeneron: Current holder of individual stocks in a privately-held company; TouchIME: Honoraria; TG Therapeutics: Consultancy; Karyopharm: Consultancy; Seattle Genetics: Consultancy; Life Sciences: Consultancy; Kite Pharma: Consultancy; Juno/Celgene: Consultancy; GLG Pharma: Consultancy; Xynomic: Research Funding; Roche/Genentech: Research Funding; Novartis: Research Funding; Janssen: Research Funding; Epizyme: Research Funding. Matasar: Pharmacyclics: Honoraria, Research Funding; Juno Therapeutics: Consultancy; TG Therapeutics: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Rocket Medical: Consultancy, Research Funding; Genentech, Inc.: Consultancy, Honoraria, Research Funding; Merck: Consultancy; Merck Sharp & Dohme: Current holder of individual stocks in a privately-held company; GlaxoSmithKline: Honoraria, Research Funding; ImmunoVaccine Technologies: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Memorial Sloan Kettering Cancer Center: Current Employment; IGM Biosciences: Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Teva: Consultancy; Janssen: Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy. Palomba: Nektar: Honoraria; Notch: Honoraria, Other: Stock; PCYC: Consultancy; Kite: Consultancy; Ceramedix: Honoraria; Novartis: Consultancy; Priothera: Honoraria; Juno: Patents & Royalties; Wolters Kluwer: Patents & Royalties; Lygenesis: Honoraria; Pluto: Honoraria; Rheos: Honoraria; BeiGene: Consultancy; Seres: Honoraria, Other: Stock, Patents & Royalties, Research Funding; WindMIL: Honoraria; Magenta: Honoraria. Lee: Intellisphere, LLC: Consultancy. Dogan: EUSA Pharma: Consultancy; Takeda: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Peer View: Honoraria; Seattle Genetics: Consultancy; Physicians' Education Resource: Honoraria. Salles: Abbvie: Consultancy, Honoraria; BMS/Celgene: Consultancy; Kite/Gilead: Consultancy; Ipsen: Consultancy; Janssen: Consultancy; Genmab: Consultancy; Takeda: Consultancy; Morphosys: Consultancy, Honoraria; Rapt: Consultancy; Genentech/Roche: Consultancy; Epizyme: Consultancy, Honoraria; Beigene: Consultancy; Debiopharm: Consultancy; Regeneron: Consultancy, Honoraria; Loxo: Consultancy; Miltneiy: Consultancy; Novartis: Consultancy; Incyte: Consultancy; Bayer: Honoraria; Velosbio: Consultancy; Allogene: Consultancy. Younes: AZ: Current Employment, Other: Senior Vice President, Global Head of Haematology (Early and Late Stage) Oncology R&D at AstraZeneca. von Keudell: Pharmacyclics: Consultancy, Honoraria; AbbVie: Research Funding; Janssen: Research Funding; Merck: Consultancy, Honoraria; Merck: Research Funding; Incyte: Consultancy, Honoraria; BMS: Research Funding.

Introduction: Primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL,LT) is a rare subtype of lymphoma that has been reported to have aggressive clinical behavior and carry a poor prognosis. However, due to the extreme scarcity of data, optimal management of this entity remains poorly defined, particularly with respect to optimal induction therapy and the role for central nervous system (CNS) prophylaxis. We therefore reviewed our institutional experience with patients with PCDLBCL,LT to better delineate their clinical course and risk of CNS relapse. Methods: We searched our electronic database and individual electronic medical records for cases of skin-only PCDLBCL,LT and analyzed the presenting characteristics, treatment approaches, use of CNS prophylaxis, and clinical outcomes, including skin, systemic, and CNS relapse. Primary cutaneous follicle center lymphoma, primary cutaneous marginal zone lymphoma, and skin-only DLBCL arising in patients with a concurrent or antecedent indolent B-cell lymphoma were excluded. Additionally, cases with DLBCL involving both skin and nodal and/or extranodal sites at diagnosis were excluded. All patients underwent staging with positron emission tomography-computerized tomography (PET-CT). Diagnostic specimens were independently reviewed by hematopathologists with expertise in cutaneous lymphoma. Results: We identified 38 patients with PCDLBCL,LT followed at Memorial Sloan Kettering Cancer Center between July 2002 and October 2020. Fifteen (39%) were female and the median age was 76 years (range, 40-96). The disease was localized to the lower extremity in 15 cases (39%) and consisted of multiple lesions in 11 cases (29%). All but one patient had IPI 0-2. By Hans algorithm 79% of the samples had a non-GCB phenotype, 79% expressed MUM-1, 3% expressed CD10, and 82% exhibited Bcl2 expression. The median Ki-67 was 85% (range, 20%-100%). According to the CNS-IPI score, 25 out of 36 evaluable patients (69%) had low-risk disease and 11 (31%) intermediate-risk disease; no patient had high-risk disease. Induction therapy consisted of R-CHOP immunochemotherapy in 13 patients (33%), R-CHOP followed by radiation therapy (RT), at doses of 30-40 Gy, in 12 (31%), and RT alone, at doses of 30-45 Gy, in 10 (26%). One patient underwent excision alone, one received rituximab after excisional biopsy, and one best supportive care. Three patients (2 treated with chemotherapy + RT and one with chemotherapy only) received CNS prophylaxis with intrathecal methotrexate. Among 35 patients evaluable for response, the objective response rate was 86%, all of which were complete responses. One patient treated with rituximab had stable disease and 4 (2 treated with chemotherapy only, one RT, and one best supportive care) progressed. At a median follow-up of 8.9 years [range, 2.9-14.7], the 5-year progression-free survival for the cohort is 42% (Figure panel A). CNS relapse occurred in 5 patients (13%) involving leptomeninges in 1 case, parenchyma in 2, and both in 2. None of these patients received CNS prophylaxis. Of note, none of the three who did receive prophylaxis experienced CNS relapse. The 2-year and 5-year cumulative risk of CNS relapse are 7% and 19%, respectively (Figure panel B). At the time of this analysis, the 5-year overall survival rate is 66% (Figure Panel A), and in all, 16 patients (42%) have died. Among the 7 patients with known cause of death, 5 succumbed to progressive disease (including 3 with CNS disease), one to sepsis, and one to secondary acute myelogenous leukemia. Conclusions: To the best of our knowledge, this is the largest study analyzing the risk of CNS relapse in PCLBCL,LT patients treated with rituximab-containing immunochemotherapy. Our findings indicate that PCLBCL,LT is a highly aggressive disease associated with poor prognosis and high risk of CNS relapse. The 13% rate of CNS relapse in a population of patients with limited-stage disease, none of whom had high-risk CNS-IPI, suggests that alternate models of risk prediction are needed for patients with PCLBCL,LT and that clinical trials aimed at improving rates of cure and reducing the risk of CNS relapse for patients with PCLBCL,LT are needed. Figure 1 Figure 1. Disclosures Falchi: Abbvie: Consultancy, Research Funding; Genmab: Consultancy, Research Funding; Roche: Research Funding; Genetech: Research Funding. Ewalt: Loxo Oncology at Lilly: Membership on an entity's Board of Directors or advisory committees; Acceleron Pharma: Membership on an entity's Board of Directors or advisory committees. Batlevi: Memorial Sloan Kettering Cancer Center: Current Employment; Pfizer: Current holder of individual stocks in a privately-held company; Viatris: Current holder of individual stocks in a privately-held company; Life Sciences: Consultancy; Bayer: Research Funding; BMS: Current holder of individual stocks in a privately-held company; Seattle Genetics: Consultancy; Kite Pharma: Consultancy; Karyopharm: Consultancy; ADC Therapeutics: Consultancy; Dava Oncology: Honoraria; TouchIME: Honoraria; Moderna: Current holder of individual stocks in a privately-held company; TG Therapeutics: Consultancy; Medscape: Honoraria; Regeneron: Current holder of individual stocks in a privately-held company; Juno/Celgene: Consultancy; GLG Pharma: Consultancy; Xynomic: Research Funding; Roche/Genentech: Research Funding; Novartis: Research Funding; Epizyme: Research Funding; Janssen: Research Funding; Autolus: Research Funding. Caron: Astra-Zeneca: Current holder of individual stocks in a privately-held company; bristol myers: Current holder of individual stocks in a privately-held company; GlaxoSmithKlein: Current holder of individual stocks in a privately-held company; Johnson and Johnson: Current holder of individual stocks in a privately-held company; Novartis: Current holder of individual stocks in a privately-held company; pfizer: Current holder of individual stocks in a privately-held company; Teva: Current holder of individual stocks in a privately-held company. Hamlin: Alexion, AstraZeneca Rare Disease (formerly Portola Pharmaceuticals): Other: Study investigator, Research Funding; Incyte, Janssen, Molecular Templates: Research Funding; Kite, Karyopharm, Celgene: Membership on an entity's Board of Directors or advisory committees. Horwitz: ADC Therapeutics: Consultancy, Research Funding; Kyowa Hakko Kirin: Consultancy, Research Funding; Myeloid Therapeutics: Consultancy; Affimed: Research Funding; Vividion Therapeutics: Consultancy; Aileron: Research Funding; Verastem: Research Funding; C4 Therapeutics: Consultancy; Janssen: Consultancy; Seattle Genetics: Consultancy, Research Funding; Millennium /Takeda: Consultancy, Research Funding; Daiichi Sankyo: Research Funding; Forty Seven, Inc.: Research Funding; Trillium Therapeutics: Consultancy, Research Funding; Acrotech Biopharma: Consultancy; ONO Pharmaceuticals: Consultancy; Shoreline Biosciences, Inc.: Consultancy; Celgene: Research Funding; Tubulis: Consultancy; SecuraBio: Consultancy, Research Funding; Kura Oncology: Consultancy. Joffe: Epizyme: Consultancy; AstraZeneca: Consultancy. Khan: Seattle Genetics: Research Funding. Kumar: Seattle Genetics: Research Funding; Kite Pharmaceuticals: Other: advisory board , Research Funding; Pharmacyclics: Research Funding; Astra Zeneca: Honoraria, Other: Advisory Board, Research Funding; Celgene: Honoraria, Other: advisory board, Research Funding; Adaptive Biotechnologies, Celgene, Abbvie Pharmaceticals, Pharmacyclics, Seattle Genetics: Research Funding; Abbvie Pharmaceuticals: Research Funding. Moskowitz: Merck: Consultancy, Research Funding; Miragen: Research Funding; Janpix Ltd.: Consultancy; Bristol-Myers Squibb: Research Funding; Incyte: Research Funding; Beigene: Research Funding; ADC Therapeutics: Research Funding; Imbrium Therapeutics L.P./Purdue: Consultancy; Takeda: Consultancy; Seattle Genetics: Consultancy, Research Funding. Noy: Pharmacyclics: Consultancy, Research Funding; Medscape: Consultancy; Targeted Oncology: Consultancy; Morphosys: Consultancy; Rafael Parhma: Research Funding; Epizyme: Consultancy; Janssen: Consultancy, Honoraria. Palomba: Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Kite Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. von Keudell: Pharmacyclics: Consultancy, Honoraria; Merck: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; AbbVie: Research Funding; Merck: Research Funding; BMS: Research Funding; Janssen: Research Funding. Zelenetz: MEI Pharma: Honoraria, Research Funding; Pharmacyclics: Honoraria; BMS/Celgene/JUNO: Honoraria, Other; Gilead: Honoraria, Research Funding; Gilead: Honoraria; Novartis: Honoraria; Verastem: Honoraria; AstraZeneca: Honoraria; MethylGene: Research Funding; MorphoSys: Honoraria; Genentech/Roche: Honoraria, Research Funding; NCCN: Other; SecuraBio: Honoraria; Amgen: Honoraria; Janssen: Honoraria; Beigene: Honoraria, Other, Research Funding; Abbvie: Honoraria, Research Funding; LFR: Other. Dogan: Takeda: Consultancy, Research Funding; Peer View: Honoraria; Physicians' Education Resource: Honoraria; Seattle Genetics: Consultancy; Roche: Consultancy, Research Funding; EUSA Pharma: Consultancy. Salles: Allogene: Consultancy; Miltneiy: Consultancy; Loxo: Consultancy; Velosbio: Consultancy; Takeda: Consultancy; Novartis: Consultancy; Rapt: Consultancy; Regeneron: Consultancy, Honoraria; Epizyme: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria; Genmab: Consultancy; Incyte: Consultancy; Genentech/Roche: Consultancy; Ipsen: Consultancy; Janssen: Consultancy; Kite/Gilead: Consultancy; Debiopharm: Consultancy; BMS/Celgene: Consultancy; Beigene: Consultancy; Abbvie: Consultancy, Honoraria; Bayer: Honoraria. Matasar: Janssen: Honoraria, Research Funding; TG Therapeutics: Consultancy, Honoraria; Teva: Consultancy; Daiichi Sankyo: Consultancy; Merck Sharp & Dohme: Current holder of individual stocks in a privately-held company; Genentech, Inc.: Consultancy, Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; IGM Biosciences: Research Funding; Rocket Medical: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; ImmunoVaccine Technologies: Consultancy, Honoraria, Research Funding; Juno Therapeutics: Consultancy; Memorial Sloan Kettering Cancer Center: Current Employment; Pharmacyclics: Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Merck: Consultancy.

Introduction Diffuse large B-cell lymphoma of the ocular adnexa (OA-DLBCL) is extremely rare and historically was associated with poor prognosis and higher risk of central nervous system (CNS) relapse. In the rituximab era its prognosis may be more favorable, particularly in individuals with limited-stage disease. However, published series of patients with extranodal limited-stage DLBCL, including a study from our group (Bobillo et al. Blood 2021), rarely included OA-DLBCL. Studies specifically looking at OA-DLBCL reported diverse treatment approaches, including some that are no longer current, such as chemotherapy without rituximab or radiation alone. Thus, the optimal management of limited-stage OA-DLBCL remains poorly defined. To address this knowledge gap, we reviewed treatments and outcomes of OA-DLBCL patients treated at Memorial Sloan Kettering Cancer Center (MKSCC). Methods We retrospectively reviewed electronic medical records of consecutive patients with DLBCL managed at MSKCC who had ocular adnexal involvement and stage IE or IIE disease, and complete clinical information. Patients with stage III-IV disease, or evidence of intraocular or CNS involvement were excluded. Results Between 2000 and 2020 we identified 17 patients with limited-stage OA-DLBCL. The median age at diagnosis was 66 years [range: 24-84], all had ECOG PS 0-1, 94% had IPI 0-1 and 94% CNS-IPI 0-1. Primary sites of ocular adnexal involvement included: extraconal orbit (9), intraconal orbit (2), lacrimal gland (4), and eyelid (2). Median greatest diameter of lesions was 3.0 cm [range: 0-4.8 cm]. Among 11 evaluable patients, the cell of origin by Hans algorithm was GCB in 64%, non-GCB in 36% (Table). Staging procedures included brain and/or orbit imaging in 100% (MRI in 88%, CT in 12%), PET-CT in 94%, bone marrow evaluation in 69% (negative in all cases), and CSF evaluation in 47% (negative in all cases). Sixteen patients were treated with R-CHOP and one with CHOP. Eleven patients received short-course chemotherapy (3 cycles in 7 patients, 4 cycles in 4), and 6 received full-course therapy (i.e., 6 cycles). Thirteen patients (76%) received radiation therapy (RT) to the ocular adnexa, including 9/11 patients treated with short-course treatment and 3/6 receiving 6 cycles. One patient with stage IIE disease received RT to the left neck after 3 cycles R-CHOP, but did not receive RT to ocular adnexum. Six patients received CNS prophylaxis, all with intrathecal methotrexate (Table). First-line systemic therapy resulted in complete response (CR) in all patients. At a median follow-up of 64 months [range: 11-147], the 2- and 5-year PFS are 93% (95% CI 79-100%), and 84% (95% CI 64-100%), respectively, and 2- and 5-year OS are 100% and 91.7% (95% CI 76-100%), respectively (Figure). One of 17 patients had systemic relapse 18 months after first-line therapy and underwent salvage therapy followed by high-dose therapy and autologous stem cell transplantation, and remains in CR. There were no CNS relapses. Due to the paucity of events, we found no statistically significant associations between the number of chemotherapy cycles or the use of RT and PFS or OS. At the time of this analysis, four patients have died, none from lymphoma; one of the four died from acute myeloid leukemia 3 years after treatment. Discussion Our study demonstrates high response rates and highly favorable long-term outcomes in patients with limited stage OA-DLBCL treated with R-CHOP and RT. Our results are in line with those reported by Bobillo et al. in patients with stage 1 DLBCL involving other extranodal sites. With the limitation of a small sample size, short course R-CHOP was not associated with significantly worse response rates or increased risk of recurrence. Whether consolidation radiation therapy improves the results of chemotherapy alone remains to be determined in larger studies. Figure 1 Figure 1. Disclosures Batlevi: Dava Oncology: Honoraria; TG Therapeutics: Consultancy; Seattle Genetics: Consultancy; Epizyme: Research Funding; Novartis: Research Funding; Medscape: Honoraria; Viatris: Current holder of individual stocks in a privately-held company; Roche/Genentech: Research Funding; Regeneron: Current holder of individual stocks in a privately-held company; Pfizer: Current holder of individual stocks in a privately-held company; Memorial Sloan Kettering Cancer Center: Current Employment; Bayer: Research Funding; Kite Pharma: Consultancy; Karyopharm: Consultancy; ADC Therapeutics: Consultancy; TouchIME: Honoraria; Life Sciences: Consultancy; BMS: Current holder of individual stocks in a privately-held company; Janssen: Research Funding; Autolus: Research Funding; Moderna: Current holder of individual stocks in a privately-held company; Xynomic: Research Funding; GLG Pharma: Consultancy; Juno/Celgene: Consultancy. Caron: Astra-Zeneca: Current holder of individual stocks in a privately-held company; bristol myers: Current holder of individual stocks in a privately-held company; GlaxoSmithKlein: Current holder of individual stocks in a privately-held company; Johnson and Johnson: Current holder of individual stocks in a privately-held company; Novartis: Current holder of individual stocks in a privately-held company; pfizer: Current holder of individual stocks in a privately-held company; Teva: Current holder of individual stocks in a privately-held company. Hamlin: Kite, Karyopharm, Celgene: Membership on an entity's Board of Directors or advisory committees; Incyte, Janssen, Molecular Templates: Research Funding; Alexion, AstraZeneca Rare Disease (formerly Portola Pharmaceuticals): Other: Study investigator, Research Funding. Horwitz: Tubulis: Consultancy; Affimed: Research Funding; ONO Pharmaceuticals: Consultancy; Trillium Therapeutics: Consultancy, Research Funding; Acrotech Biopharma: Consultancy; Aileron: Research Funding; Shoreline Biosciences, Inc.: Consultancy; Celgene: Research Funding; Forty Seven, Inc.: Research Funding; Kyowa Hakko Kirin: Consultancy, Research Funding; SecuraBio: Consultancy, Research Funding; Verastem: Research Funding; C4 Therapeutics: Consultancy; Janssen: Consultancy; Kura Oncology: Consultancy; Millennium /Takeda: Consultancy, Research Funding; Myeloid Therapeutics: Consultancy; Daiichi Sankyo: Research Funding; Seattle Genetics: Consultancy, Research Funding; Vividion Therapeutics: Consultancy; ADC Therapeutics: Consultancy, Research Funding. Joffe: AstraZeneca. Epizyme: Consultancy. Khan: Seattle Genetics: Research Funding. Kumar: Celgene: Honoraria, Other: advisory board, Research Funding; Kite Pharmaceuticals: Other: advisory board , Research Funding; Astra Zeneca: Honoraria, Other: Advisory Board, Research Funding; Abbvie Pharmaceuticals: Research Funding; Seattle Genetics: Research Funding; Adaptive Biotechnologies, Celgene, Abbvie Pharmaceticals, Pharmacyclics, Seattle Genetics: Research Funding; Pharmacyclics: Research Funding. Matasar: Janssen: Honoraria, Research Funding; Teva: Consultancy; Juno Therapeutics: Consultancy; Merck: Consultancy; IGM Biosciences: Research Funding; Genentech, Inc.: Consultancy, Honoraria, Research Funding; Merck Sharp & Dohme: Current holder of individual stocks in a privately-held company; TG Therapeutics: Consultancy, Honoraria; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Memorial Sloan Kettering Cancer Center: Current Employment; Rocket Medical: Consultancy, Research Funding; Pharmacyclics: Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy; Takeda: Consultancy, Honoraria; ImmunoVaccine Technologies: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Honoraria, Research Funding. Moskowitz: Miragen: Research Funding; Merck: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Janpix Ltd.: Consultancy; Imbrium Therapeutics L.P./Purdue: Consultancy; Bristol-Myers Squibb: Research Funding; Takeda: Consultancy; Incyte: Research Funding; Beigene: Research Funding; ADC Therapeutics: Research Funding. Noy: Medscape: Consultancy; Targeted Oncology: Consultancy; Morphosys: Consultancy; Rafael Parhma: Research Funding; Pharmacyclics: Consultancy, Research Funding; Janssen: Consultancy, Honoraria; Epizyme: Consultancy. Palomba: Wolters Kluwer: Patents & Royalties; BeiGene: Consultancy; Rheos: Honoraria; PCYC: Consultancy; Juno: Patents & Royalties; Kite: Consultancy; Pluto: Honoraria; Novartis: Consultancy; Notch: Honoraria, Other: Stock; Seres: Honoraria, Other: Stock, Patents & Royalties, Research Funding; Magenta: Honoraria; WindMIL: Honoraria; Lygenesis: Honoraria; Nektar: Honoraria; Ceramedix: Honoraria; Priothera: Honoraria. von Keudell: Merck: Consultancy, Honoraria; AbbVie: Research Funding; Pharmacyclics: Consultancy, Honoraria; BMS: Research Funding; Merck: Research Funding; Incyte: Consultancy, Honoraria; Janssen: Research Funding. Zelenetz: SecuraBio: Honoraria; Pharmacyclics: Honoraria; AstraZeneca: Honoraria; MEI Pharma: Honoraria, Research Funding; Verastem: Honoraria; NCCN: Other; Janssen: Honoraria; BMS/Celgene/JUNO: Honoraria, Other; Amgen: Honoraria; Gilead: Honoraria; Gilead: Honoraria, Research Funding; Genentech/Roche: Honoraria, Research Funding; MethylGene: Research Funding; MorphoSys: Honoraria; Abbvie: Honoraria, Research Funding; LFR: Other; Beigene: Honoraria, Other, Research Funding; Novartis: Honoraria. Dogan: Roche: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Peer View: Honoraria; EUSA Pharma: Consultancy; Seattle Genetics: Consultancy; Physicians' Education Resource: Honoraria. Salles: Debiopharm: Consultancy; Takeda: Consultancy; Allogene: Consultancy; Velosbio: Consultancy; Genmab: Consultancy; Loxo: Consultancy; Miltneiy: Consultancy; Ipsen: Consultancy; Janssen: Consultancy; Kite/Gilead: Consultancy; Incyte: Consultancy; Morphosys: Consultancy, Honoraria; Novartis: Consultancy; Rapt: Consultancy; Regeneron: Consultancy, Honoraria; Genentech/Roche: Consultancy; Epizyme: Consultancy, Honoraria; BMS/Celgene: Consultancy; Beigene: Consultancy; Abbvie: Consultancy, Honoraria; Bayer: Honoraria.

Background: In untreated Hodgkin lymphoma (HL), metabolic tumor volume (MTV) significantly declined following pembrolizumab monotherapy, regardless of baseline MTV, and may serve as a better measure of treatment response to PD-1 blockade than the Lugano Classification (Allen, et al. Blood 2021). Furthermore, standard PET evaluation can fail to differentiate between malignancy, pseudoprogression and physiological background in patients (pts) receiving PD-1 blockade. The predictive power and prognostic significance of MTV in patients with relapsed or refractory (RR) HL receiving PD-1 blockade is unknown. We sought to examine the role of MTV in HL pts treated with PD-1 blockade. Methods: We identified 30 pts who received pembrolizumab or nivolumab-based therapy off-study for RR HL between July 2015 and May 2021. In the PET/CT analysis, all lesions were visually identified, and all measurable lesions were selected for the analysis. Responses were assessed by Lugano Classification. Indeterminant response (IR) was defined as evidence of progression on PET without clinical deterioration as per the Lyric Criteria. MTV was obtained by summing the metabolic volumes of all measurable lesions, using the 41% SUVmax threshold to measure each lesion MTV using Beth Israel plugin. MTV was evaluated at baseline (MTV0) and at first reassessment (MTV1) after initiation of PD-1 blockade. Δ (delta) MTV was calculated as % change in MTV from MTV0 to MTV1. Receiver operating characteristic (ROC) curve was performed for ΔMTV and best overall response rate (BOR) to determine the optimal cut-off value. Overall survival (OS) was measured from PD-1 blockade initiation to death or last follow-up. We examined the association between MTV and clinical factors, PET-1 response, and overall survival using Cox proportional hazards model and Fisher exact test, respectively. Results: 25 patients had complete clinical data and PET/CT analysis (Table 1). The median age at first relapse was 39 years (range: 18-81); 64% were male. 6 pts previously received PD-1 blockade on clinical trials and discontinued treatment due to study completion or toxicity. The median time between PET0 and PET1 was 3.4 months (range 2.0-7.3). Median MTV0 and MTV1 values were 39.8 ml and 17.1 ml, respectively. With a median follow up from initiation of PD-1 blockade among survivors of 38.7 months, 5 pts (19%) died. The median OS of the entire cohort was not reached (95%CI: 76.4-NR) (Figure 1). The best response to PD-1 blockade included 15 (60%) with complete metabolic response (CMR), 5 (20%) with partial metabolic response (PMR), and 5 (20%) with progression of disease (POD). Median ΔMTV was -70% (range -100 to +909%). MTV0 was not predictive of OS, PET1 response, or BOR. However, ΔMTV predicted for PET1 response (p=0.004) and BOR (p=0.004). 18 (72%) pts had a reduction in ΔMTV (range: -100, -22), while 7 (28%) pts had an increase in ΔMTV (range: 33-909). The optimal ΔMTV threshold for prediction of BOR was 120% (Figure 1). ΔMTV Among pts with IR on PET-1, ΔMTV Conclusions: Quantitative change in MTV from baseline to first reassessment may aid in predicting treatment response and long-term outcomes in patients with RR HL receiving PD-1 blockade, particularly those initially characterized as achieving indeterminate response. Further prospective clinical trials are needed to validate the role of ΔMTV in predicting response and long-term outcomes for RR HL pts receiving PD-1 blockade. Figure 1 Figure 1. Disclosures Moskowitz: Merck & Co., Inc.: Research Funding. Matasar: Seattle Genetics: Consultancy, Honoraria, Research Funding; TG Therapeutics: Consultancy, Honoraria; Bayer: Consultancy, Honoraria, Research Funding; Genentech, Inc.: Consultancy, Honoraria, Research Funding; Memorial Sloan Kettering Cancer Center: Current Employment; Juno Therapeutics: Consultancy; Merck: Consultancy; Pharmacyclics: Honoraria, Research Funding; Rocket Medical: Consultancy, Research Funding; Daiichi Sankyo: Consultancy; GlaxoSmithKline: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; ImmunoVaccine Technologies: Consultancy, Honoraria, Research Funding; Merck Sharp & Dohme: Current holder of individual stocks in a privately-held company; Teva: Consultancy; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; IGM Biosciences: Research Funding; Takeda: Consultancy, Honoraria. Zelenetz: Amgen: Honoraria; MorphoSys: Honoraria; Novartis: Honoraria; MEI Pharma: Honoraria, Research Funding; Beigene: Honoraria, Other, Research Funding; Gilead: Honoraria, Research Funding; Pharmacyclics: Honoraria; SecuraBio: Honoraria; Genentech/Roche: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Verastem: Honoraria; BMS/Celgene/JUNO: Honoraria, Other; MethylGene: Research Funding; AstraZeneca: Honoraria; Janssen: Honoraria; NCCN: Other; LFR: Other; Gilead: Honoraria. Joffe: AstraZeneca. Epizyme: Consultancy. von Keudell: Merck: Research Funding; Janssen: Research Funding; BMS: Research Funding; Incyte: Consultancy, Honoraria; AbbVie: Research Funding; Merck: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria. Batlevi: Medscape: Honoraria; Memorial Sloan Kettering Cancer Center: Current Employment; Moderna: Current holder of individual stocks in a privately-held company; Pfizer: Current holder of individual stocks in a privately-held company; ADC Therapeutics: Consultancy; Regeneron: Current holder of individual stocks in a privately-held company; TG Therapeutics: Consultancy; Kite Pharma: Consultancy; Seattle Genetics: Consultancy; TouchIME: Honoraria; BMS: Current holder of individual stocks in a privately-held company; Bayer: Research Funding; Viatris: Current holder of individual stocks in a privately-held company; Karyopharm: Consultancy; Juno/Celgene: Consultancy; Life Sciences: Consultancy; Dava Oncology: Honoraria; GLG Pharma: Consultancy; Xynomic: Research Funding; Roche/Genentech: Research Funding; Novartis: Research Funding; Epizyme: Research Funding; Janssen: Research Funding; Autolus: Research Funding. Caron: Astra-Zeneca: Current holder of individual stocks in a privately-held company; bristol myers: Current holder of individual stocks in a privately-held company; GlaxoSmithKlein: Current holder of individual stocks in a privately-held company; Johnson and Johnson: Current holder of individual stocks in a privately-held company; Novartis: Current holder of individual stocks in a privately-held company; pfizer: Current holder of individual stocks in a privately-held company; Teva: Current holder of individual stocks in a privately-held company. Noy: Rafael Parhma: Research Funding; Morphosys: Consultancy; Medscape: Consultancy; Pharmacyclics: Consultancy, Research Funding; Targeted Oncology: Consultancy; Epizyme: Consultancy; Janssen: Consultancy, Honoraria. Salles: Velosbio: Consultancy; Morphosys: Consultancy, Honoraria; Regeneron: Consultancy, Honoraria; Novartis: Consultancy; Epizyme: Consultancy, Honoraria; Allogene: Consultancy; Rapt: Consultancy; Genentech/Roche: Consultancy; Takeda: Consultancy; Miltneiy: Consultancy; Loxo: Consultancy; Kite/Gilead: Consultancy; Genmab: Consultancy; Incyte: Consultancy; Ipsen: Consultancy; Janssen: Consultancy; Debiopharm: Consultancy; BMS/Celgene: Consultancy; Beigene: Consultancy; Abbvie: Consultancy, Honoraria; Bayer: Honoraria. Moskowitz: ADC Therapeutics: Research Funding; Takeda: Consultancy; Incyte: Research Funding; Merck: Consultancy, Research Funding; Beigene: Research Funding; Seattle Genetics: Consultancy, Research Funding; Bristol-Myers Squibb: Research Funding; Miragen: Research Funding; Janpix Ltd.: Consultancy; Imbrium Therapeutics L.P./Purdue: Consultancy.

Introduction: The prognostic significance of immunoglobulin heavy-chain variable region gene (IGHV) mutational status in chronic lymphocytic leukemia (CLL) is well established. Previous studies have shown that CLL patients with mutated IGHV (M-IGHV) have a better prognosis, manifested in a longer time-to first treatment (TTFT) and overall survival (OS). Here we present an analysis on the impact of IGHV mutational status in an Israeli cohort of patients with CLL. Methods: A total of 254 patients with CLL (diagnosed from 1991 to 2020), followed at the Tel-Aviv Sourasky Medical Center were included. The IGHV mutational status has been determined by next-generation sequencing (NGS) or cDNA Sanger. The sequences with a germline homology 98% or higher were considered unmutated, and those with a homology less than 98% as mutated CLL. IGHV subsets were analyzed using the ARResT/AssignSubsets website. All data were statistically analyzed by IBM SPSS Statistics 27 (IBM Corporation, Armonk, NY, USA), P-values were two-sided, and the significance level was determined at a Results: Out of 254 patients, 132 (52.0%) had an unmutated IGHV gene (UM-IGHV), and 122 (48.0%) were mutated (M-IGHV). At diagnosis, most patients (Table 1) were ≤65 years of age (n=157, 61.8%), males (n=160, 63.0%) and had an absolute lymphocytic count equal to or less than (≤)15.0 x10 9/L (n=115, 52.5%). Advanced Binet stage was more commonly associated with UM-IGHV (n=44, 57.9%) (P=0.033). Among 240 patients (94.1%), the most frequently used VH gene segments (Figure 1) included; VH1-69 (n=35, 14.6%), VH4-34 (n=24, 10.0%), VH1-2 (n=17, 7.1%), and VH3-23 (n=16, 6.7%). Six major B-cell receptors (BCR) subsets (Figure 2) were identified in 21/180 of patients (11.7%), which most commonly included: CLL#1 (n=6, 28.6%), CLL#4 (n=5, 23.8%), and CLL#2(n=3, 14.3%). Patients with M-IGHV had a longer time to first treatment (TTFT) (P In multivariate analyses of the entire cohort; for TTFT (Table 2A), males (P=0.002, HR=1.9, [1.3-2.9]), >65 years of age at diagnosis (P=0.008, HR=1.8, [1.2-2.7]), advanced Binet stage (P65 years of age at diagnosis (P=0.010, HR=2.6, [1.3-5.5]) and UM-IGHV mutational status (P=0.004, HR=2.9, [1.4-5.9]) were found to be significant factors for shorter OS. In multivariate analyses performed separately for each IGHV mutational status group; males (P=0.021, HR=2.1, [1.1-4.0]), age >65 years (P=0.002, HR=3.2, [1.5-6.4]) and advanced Binet stage (P65 years at diagnosis (P=0.039, HR=4.3, [1.1-17.0]) was the only independent predictor in M-IGHV patients, while no variable maintained its statistical significance in UM-IGHV cases. Conclusion: As previously studied, our cohort demonstrates that M-IGHV CLL patients have better TTFT and OS. However, the rate of BCR subsets in Israel appears to be lower than expected. A separated multivariate analysis for M-IGHV and UM-IGHV patients revealed different independent predictors for TTFT and OS to each of the IGHV mutational status groups. Further studies with larger cohorts are required to deeply study these differences and provide further clinical insight into the pathophysiology of CLL. Figure 1 Figure 1. Disclosures Joffe: AstraZeneca: Consultancy; Epizyme: Consultancy. Herishanu: AbbVie: Honoraria, Research Funding; Janssen: Honoraria; Roche: Honoraria; Medison: Honoraria.

Introduction Central nervous system relapse (secondary central nervous system lymphoma -SCNS) is an uncommon but devastating complication of aggressive B-cell lymphoma. Patients (Pts) with CNS-IPI 4-6 are at greatest risk (10.2% at 2 years). Intravenous high-dose methotrexate (HD-MTX) is widely used to mitigate SCNS risk but data supporting this practice are limited. Methods We performed a multicentre, retrospective study at 21 sites in Australia, Asia, North America and Europe. Chart or registry review was performed for consecutively diagnosed pts with diffuse large B-cell lymphoma (DLBCL) and CNS-IPI 4-6, high grade B-cell lymphoma (HGBL) with rearrangements of MYC+BCL2 and/or BCL6 and primary breast/testicular DLBCL irrespective of CNS-IPI. Pts were diagnosed between 2000-2020, 18-80 years at diagnosis, and treated with curative intent anti-CD20 based chemo-immunotherapy. Pts with CNS involvement at diagnosis were excluded. HD-MTX was defined as at least one cycle of intravenous MTX at any dose. Time to SCNS was calculated from date of diagnosis (all-pts), and from the end of frontline systemic lymphoma therapy, defined as 6x21 days from diagnosis (complete response (CR-pts)), until SCNS, systemic relapse, death, or censoring, whichever came first. Cumulative risk of SCNS was computed using the Aalen-Johansen estimator treating death and systemic relapses as competing events. Adjusted cumulative risks were obtained by using an inverse probability of treatment weighting approach. The average treatment effect was computed as the difference in adjusted 5-year risk of SCNS. Results - 2300 and 1455 pts were included in the all-pts and CR-pts analyses, respectively. Baseline demographics and details of therapy are summarised in Table 1. Except for a predominance of males, pts ≤60 years and pts with ECOG 0-1 in the HD-MTX vs no HD-MTX groups, the demographics and treatments were well balanced. At a median follow up of 5.9 years (range 0.0-19.1) and 5.5 years from diagnosis (range 0.0-18.7), 201/2300 and 84/1455 pts experienced CNS events in the all-pts and CR-pts analyses respectively. For all-pts(n=2300), CNS-IPI was 4-6 in 2052(89.2%), with R-CHOP-like therapy given to 93.8%. 410 pts (17.8%) received HD-MTX (265 HD-MTX alone, 145 in combination with intrathecal methotrexate (IT-MTX);435 received IT-MTX alone;1455 received neither. There were 32/410 and 169/1890 SCNS events, with median time from diagnosis to SCNS of 8.8 and 6.7 months in the HD-MTX and no HD-MTX groups respectively. 5-year OS was 70% (95% CI, 65-76%) and 55% (95% CI 53-57%) in HD-MTX and no HD-MTX groups respectively. There was no difference in the adjusted 5-year risk of SCNS between the HD-MTX and no HD-MTX groups (8.4% vs 9.1%, adjusted hazard ratio [HR] 0.71, p=0.100) (Figure 1). For CR-pts(n=1455), CNS-IPI was 4-6 in 1267(87.0%), with R-CHOP-like therapy given to 93.3%. 284 pts (19.5%) received HD-MTX (170 HD-MTX alone, 114 with IT-MTX);298 received IT-MTX alone;873 received neither. There were 16/284 and 68/1171 SCNS events, with median time from diagnosis to SCNS of 11.0 and 10.3 months in the HD-MTX and no HD-MTX groups respectively. 5-year OS was 74%(95% CI 67-81%) and 75%(95% CI 72-78%) in the HD-MTX groups and no HD-MTX groups respectively (adjusted HR 1.08, p=0.622). There was no difference in the 5-year risk of CNS relapse between the HD-MTX and no HD-MTX groups 5.0% vs 6.0% (adjusted HR 1.03, p=0.903) (Figure 2). Exploratory analysis of the impact of HD-MTX among the highest risk groups CNS IPI 5 (n=368), CNS-IPI 6 (n=59) and CNS-IPI 6 plus all pts with testicular, renal or adrenal involvement (n=349) did not reveal differences in SCNS rates in HD-MTX treated pts. Additional subgroup analyses will be presented at the meeting. Conclusions To our knowledge, this is the largest study of the efficacy of HD-MTX in reducing SCNS events focusing exclusively on high-risk pts. The overall incidence of CNS relapse observed was consistent with previous reports in similar patient cohorts at 9%. The use of HD-MTX did not lower SCNS rates overall or when analysis was confined to CR pts at completion of curative intent therapy to compensate for potential immortal bias associated with HD-MTX therapy. Despite the limitations of the non-randomized and retrospective design, it appears unlikely that HD-MTX is associated with a clinically meaningful reduction in SCNS rates in pts with high risk for SCNS. Figure 1 Figure 1. Disclosures Lewis: AstraZeneca: Consultancy, Honoraria; Novartis: Patents & Royalties: Conference attendance; Janssen: Honoraria, Patents & Royalties: Conference attendance; Roche: Consultancy, Honoraria. Villa: Janssen: Honoraria; Gilead: Honoraria; AstraZeneca: Honoraria; AbbVie: Honoraria; Seattle Genetics: Honoraria; Celgene: Honoraria; Lundbeck: Honoraria; Roche: Honoraria; NanoString Technologies: Honoraria. Bobillo: F. Hoffmann-La Roche Ltd: Consultancy, Speakers Bureau; Gilead: Speakers Bureau. Ekstroem Smedby: Takeda: Consultancy; Janssen Cilag: Research Funding. Savage: Merck: Consultancy, Honoraria, Other: Institutional clinical trial funding; BMS: Consultancy, Honoraria, Other: Institutional clinical trial funding; AbbVie: Consultancy, Honoraria; Roche: Research Funding; Takeda: Other: Institutional clinical trial funding; Servier: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Astra-Zeneca: Consultancy, Honoraria; Beigene: Other: Institutional clinical trial funding; Genentech: Research Funding. Eyre: Beigene: Honoraria, Research Funding; Incyte: Consultancy; Secura Bio: Consultancy, Honoraria; Janssen: Honoraria; Gilead/KITE: Honoraria, Other: Travel support for conferences, Research Funding, Speakers Bureau; Loxo Oncology: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria, Other: Travel to conferences; AstraZeneca: Honoraria, Research Funding; Roche: Consultancy, Honoraria. Cwynarski: Incyte: Consultancy, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; Atara: Consultancy; Celgene: Consultancy; Takeda: Consultancy, Other: travel to scientific conferences, Speakers Bureau; Kite, a Gilead Company: Consultancy, Other: travel to scientific conferences, Speakers Bureau; Janssen: Consultancy, Other: travel to scientific conferences; Roche: Consultancy, Other: travel to scientific conferences, Speakers Bureau; BMS/Celgene: Other: travel to scientific conferences. Stewart: Teva: Honoraria; Sandoz: Honoraria; Amgen: Honoraria; AstraZeneca: Honoraria; Novartis: Honoraria; Celgene: Honoraria; Gilead: Honoraria; Abbvie: Honoraria; Janssen: Honoraria; Roche: Honoraria. Bishton: Gilead: Honoraria, Other: Travel grants; AbbVie: Honoraria, Other: Travel grants; Celgene/BMS: Honoraria, Other: travel grants; Celltrion: Honoraria, Other: Travel grants; Takeda.: Honoraria, Other: Travel grants . Fox: F. Hoffmann-La Roche Ltd: Consultancy, Membership on an entity's Board of Directors or advisory committees. Joffe: Epizyme: Consultancy; AstraZeneca: Consultancy. Eloranta: Janssen Pharmaceutical NV: Other: NV. Sehn: Genmab: Consultancy; Novartis: Consultancy; Debiopharm: Consultancy. Manos: Bristol-Myers Squibb: Other: Travel and meetings. Hawkes: Specialised Therapeutics: Consultancy; Gilead: Membership on an entity's Board of Directors or advisory committees; Merck Sharpe Dohme: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Antigene: Membership on an entity's Board of Directors or advisory committees; Regeneron: Speakers Bureau; Bristol Myers Squib/Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck KgA: Research Funding; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel and accommodation expenses, Research Funding, Speakers Bureau; Janssen: Speakers Bureau. Minson: Novartis: Research Funding; Hoffman La Roche: Research Funding. Dickinson: Celgene: Research Funding; Amgen: Honoraria; Takeda: Research Funding; Gilead Sciences: Consultancy, Honoraria, Speakers Bureau; MSD: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Other: travel, accommodation, expenses, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau. Øvlisen: Abbvie: Other: Travel expenses. Gregory: Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel fees, Speakers Bureau; Janssen: Consultancy; Novartis: Consultancy. Ku: Roche: Consultancy; Antegene: Consultancy; Genor Biopharma: Consultancy. Talaulikar: Roche: Honoraria, Research Funding; Jansenn: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; EUSA Pharma: Honoraria, Research Funding. Maurer: Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Genentech: Research Funding; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Morphosys: Membership on an entity's Board of Directors or advisory committees, Research Funding; Nanostring: Research Funding. El-Galaly: Abbvie: Other: Speakers fee; ROCHE Ltd: Ended employment in the past 24 months. Cheah: Roche: Consultancy, Honoraria, Other: advisory and travel expenses, Research Funding; Janssen: Consultancy, Honoraria, Other: advisory; MSD: Consultancy, Honoraria, Other: advisory, Research Funding; Gilead: Consultancy, Honoraria, Other: advisory; Ascentage pharma: Consultancy, Honoraria, Other: advisory; Beigene: Consultancy, Honoraria, Other: advisory; AbbVie: Research Funding; Celgene: Research Funding; AstraZeneca: Consultancy, Honoraria, Other: advisory; Loxo/Lilly: Consultancy, Honoraria, Other: advisory; TG Therapeutics: Consultancy, Honoraria, Other: advisory.

Purpose/Objective(s) Indolent non-Hodgkin lymphomas (iNHL), such as follicular lymphoma (FL) and marginal zone lymphoma (MZL) are highly radiosensitive. Previously untreated patients with localized disease are potentially curable (PC) with RT. While standard of care remains 24Gy, de-escalation to very low dose radiotherapy (VLDRT) of 4Gy reduces toxicities and treatment duration. Use of VLDRT outside of palliation remains controversial, however, we hypothesize it may be sufficient for most lesions. Materials/Methods We present the largest single institution VLDRT experience of adults with FL/MZL treated between 2005-2018 with modern principles including PET staging and involved site radiotherapy (ISRT). Outcomes include best clinical/radiographic response using Lugano criteria between 1.5-6 months post-VLDRT, and cumulative incidence of local progression (LP), distant progression and overall progression, all using death as competing risk. Outcomes were stratified by VLDRT intent; lesions considered PC were localized sites without prior treatment. All other sites were considered non-curable. Competing risk regression was used to identify potential histologic/clinical predictors of LP. Results In total, 250 patients were treated to 299 lesions including 52 potentially curative (PC) sites (Table 1). Post-VLDRT, overall response rate was 90% for all treated sites with 68% achieving complete response (CR). With median follow-up of 2.4y, the 2y cumulative incidence of LP was 25% for the entire cohort. PC patients had considerably lower 2y-LP of 9% (95% CI 3-19%) compared to 29% (95% CI 23-34%) for the non-curable. Lesion size > 6cm was associated with lower odds of CR and greater risk of LP relative to lesions 0-2cm. There was no suggestion of inferior outcomes for PC patients relative to non-curable. The probability of receiving additional RT to the same site 2y post VLDRT is 15% (95% CI 11-19%), and subsequent response after additional RT was 68% CR (n = 30/45), 18% partial response (n = 8), and 14% non-response (n = 6). Conclusion We demonstrate that modern VLDRT approaches utilizing PET staging and ISRT result in excellent ORR with nearly 70% CR. Importantly, the cumulative incidence of LP at 2 years post VLDRT is low at 25%, highlighting the possibility of durable remissions. Given clinical versatility and apparent efficacy for PC patients, we support an adaptive ISRT stepwise strategy where patients will be treated initially with VLDRT, reserving full dose treatment for those with suboptimal response. A prospective, multicenter study by ILROG has been developed to compare PC patients randomized to standard 24 Gy versus this proposed response-adapted approach.

Decreased absolute lymphocyte counts (ALCs) following frontline therapy for chronic lymphocytic leukemia may be associated with disease control, even in patients without evidence of minimal residual disease. We studied the prognostic significance of ALCs during the first year following treatment with fludarabine, cyclophosphamide, and rituximab (FCR). We evaluated 99 patients who achieved a partial response without lymphocytosis ( 1.8 vs not reached for ALC ≤ 0.7 at 9 months, P

Introduction: The standard approach for relapsed or refractory (RR) classical Hodgkin lymphoma (cHL) following front-line treatment failure is second line therapy (SLT) aimed to achieve complete response (CR), followed by consolidation with high dose therapy and autologous hematopoietic cell transplantation (HDT/AHCT). No one standard SLT exists and options include regimens containing platinum, gemcitabine, and more recently brentuximab vedotin (BV). Complete response rates associated with these regimens range from 50-70%. Due to the increasing use of BV in the front-line setting, development of SLT regimens that are both highly effective and BV-sparing are needed. Programmed death-1 (PD-1) inhibitors are highly active in RR cHL and have the potential to enhance the efficacy of standard chemotherapy. Here we report the results of our phase II study evaluating a novel anti-PD-1-based regimen, pembrolizumab plus gemcitabine, vinorelbine, and liposomal doxorubicin (pembrolizumab-GVD), as SLT for RR cHL. Methods: Transplant eligible patients (pts) with RR cHL following failure of 1-line of therapy were eligible. Treatment consisted of 2 to 4 cycles of pembrolizumab (200mg IV, day 1), gemcitabine (1000mg/m2 IV, days 1 and 8), vinorelbine (20mg/m2 IV, days 1 and 8) and liposomal doxorubicin (15mg/m2, days 1 and 8), given on 21-day cycles. Pts who achieved CR by PET (Deauville ≤3) after 2 or 4 cycles proceeded to HDT/AHCT. HDT/AHCT was carried out according to institutional standards and BV maintenance was allowed following HDT/AHCT. The primary endpoint was CR rate after 2 or 4 cycles of pembrolizumab-GVD. Enrollment occurred according to a Simon 2-stage design with sample size based upon a projected CR rate of 70%. In stage 1, 23 pts enrolled and 12 or more CRs were required to proceed to stage II; in stage II, an additional 16 pts enrolled. Out of a total of 39 pts, 24 CRs were required to declare this regimen promising. Results: Among 39 patients enrolled, 37 are evaluable for toxicity (2 pts have not yet started treatment) and 34 are evaluable for response (4 pts too early, 1 pt found to have composite lymphoma after enrollment). Of 37 treated pts, median age is 36 (range 21-71), 43% are male, 23 (62%) had advanced stage disease, and 15 (41%) had primary refractory disease. With regard to RR cHL risk factors (B-symptoms, extranodal disease, and relapse/refractory disease within 1 year of initial treatment), 4(11%) had no risk factors (RFs), 21 (57%) had 1 RF, 9 (24%) had 2 RFs, and 3 (8%) had all 3 RFs. Treatment was well tolerated with most adverse events being grade 1 or 2 (see figure 1). Grade 3 AEs included rash (n=1), elevated AST/ALT (n=3), oral mucositis (n=2), and neutropenia (n=3). Figure 2 shows the outcome for all 37 treated pts. Among 34 evaluable pts, 31 (91%) achieved CR after 2 cycles and 3 achieved partial response. An additional 1 pt achieved CR after 4 cycles of pembrolizumab-GVD, therefore in total, 32 of 34 (94%) achieved CR following pembrolizumab-GVD. 4 pts with CR after 2 cycles received an additional 2 cycles of pembrolizumab-GVD in order to delay HDT/AHCT during the height of the COVID-19 pandemic (n=3) or due to refusing HDT/ASCT (n=1). To date, 32 have undergone HDT/AHCT following 2 (n=27) or 4 (n=5) cycles of treatment. 1 pt is awaiting HDT/AHCT; 1 pt refused HDT/ASCT and received pembrolizumab maintenance instead. 2 pts received involved site radiation therapy to initial area of relapsed disease prior to planned HDT/AHCT and 10 pts received post-HDT/ASCT maintenance with BV. Median follow-up post-HDT/AHCT is 9 mos (range 0.03-20.9 mos) and all pts remain in remission to date. Conclusion: Second-line therapy with pembrolizumab-GVD is a highly effective and well-tolerated regimen that can efficiently bridge pts with RR cHL to HDT/AHCT. Updated results including all 39 enrolled pts will be presented at the meeting. Given the high CR rate observed with pembrolizumab-GVD, an expansion cohort evaluating 8 cycles of pembrolizumab maintenance (instead of HDT/AHCT) for patients who achieve CR after 4 cycles of pembrolizumab-GVD is planned. Disclosures Moskowitz: Merck: Consultancy; Incyte: Research Funding; Miragen Therapeutics: Consultancy; Seattle Genetics: Consultancy; Imbrium Therapeutics, L.P.: Consultancy; Merck: Research Funding; Seattle Genetics: Research Funding; Bristol-Myers Squibb: Research Funding. Shah:Amgen Inc.: Research Funding; Janssen: Research Funding. Kumar:AbbVie: Research Funding; Celgene: Honoraria, Other: Honoraria for Advisory Board; Seattle Genetics: Research Funding; Astra Zeneca: Honoraria, Other: Honoraria for Advisory Board; Celgene: Research Funding; Kite Pharmaceuticals: Honoraria, Other: Honoraria for Advisory Board; Adaptive Biotechnologies,: Research Funding; Pharmacyclics: Research Funding. Lahoud:MorphoSys: Other: Advisory Board. Batlevi:Life Sci, GLG, Juno/Celgene, Seattle Genetics, Kite: Consultancy; Janssen, Novartis, Epizyme, Xynomics, Bayer, Autolus, Roche/Genentech: Research Funding. Hamlin:J&J Pharmaceuticals: Research Funding; Portola: Research Funding; Incyte: Research Funding; Portola Pharmaceutics: Consultancy; Juno Therapeutics: Consultancy; Karyopharm: Consultancy; Celgene: Consultancy; Molecular Templates: Research Funding. Straus:Karyopharm Therapeutics: Membership on an entity's Board of Directors or advisory committees; Imedex, Inc.: Speakers Bureau; Targeted Oncology: Consultancy, Speakers Bureau; NY Lymphoma Rounds: Consultancy; Takeda Pharmaceuticals: Research Funding, Speakers Bureau; OncLive: Speakers Bureau; Elsevier: Membership on an entity's Board of Directors or advisory committees, Other: CME writer; ASH: Other: Conference in December 2019 on HL to other physicians during ASH; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Horwitz:ASTEX: Consultancy; Verastem: Consultancy, Research Funding; Myeloid Therapeutics: Consultancy; Miragen: Consultancy; Kura Oncology: Consultancy; Janssen: Consultancy; GlaxoSmithKline: Consultancy; Daiichi Sankyo: Research Funding; C4 Therapeutics: Consultancy; Affirmed: Consultancy; Vividion Therapeutics: Consultancy; Beigene: Consultancy; Portola: Consultancy, Research Funding; Mundipharma: Consultancy; Innate Pharma: Consultancy; Corvus: Consultancy; Trillium: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Millenium/Takeda: Consultancy, Research Funding; Kyowa Hakka Kirin: Consultancy, Research Funding; Infinity/Verastem: Research Funding; Forty Seven: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Aileron: Consultancy, Research Funding; ADCT Therapeutics: Consultancy, Research Funding. Falchi:Genmab: Research Funding; Roche: Research Funding. Joffe:Epizyme: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees. Noy:Pharmacyclics: Research Funding; Pharmacyclics: Consultancy; Janssen: Consultancy; Rafael Pharma: Research Funding; NIH: Research Funding; Morphosys: Consultancy; Medscape: Consultancy; Targeted Oncology: Consultancy. Matasar:Teva: Consultancy; Genentech, Inc.: Consultancy, Honoraria, Research Funding; Merck: Consultancy; Bayer: Consultancy, Honoraria, Research Funding; Juno Therapeutics: Consultancy; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Honoraria, Research Funding; IGM Biosciences: Research Funding; Janssen: Honoraria, Research Funding; Pharmacyclics: Honoraria, Research Funding; Immunovaccine Technologies: Honoraria, Research Funding; Rocket Medical: Consultancy, Research Funding; Takeda: Consultancy, Honoraria; Daiichi Sankyo: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding. Vardhana:Other: Other: SAV has received honoraria from Agios Pharmaceuticals and Rheos Pharmaceuticals, is an advisor for Immunai and has consulted for ADC Therapeutics. von Keudell:Genentech: Research Funding; Bayer: Research Funding; Pharmacyclics: Research Funding. Zelenetz:Novartis: Consultancy; Janssen: Consultancy; Celgene: Consultancy; Amgen: Consultancy; Adaptive Biotechnology: Consultancy; BeiGene: Membership on an entity's Board of Directors or advisory committees; Roche: Research Funding; Gilead: Research Funding; Genentech/Roche: Consultancy; Gilead: Consultancy; Sandoz: Research Funding; Celgene: Research Funding; MEI Pharma: Research Funding; MorphoSys: Research Funding. OffLabel Disclosure: Pembrolizumab as second-line therapy for Hodgkin lymphoma

Background: With the incorporation of positron emission tomography (PET) imaging as part of the standard staging evaluation of follicular lymphoma (FL), it is generally recommended to obtain the diagnostic biopsy from a lesion with the highest standardized uptake value (SUV) to rule out de novo histologic transformation (HT). In some cases such an approach might be impractical, while in other cases a biopsy from a diseased area with a high SUV may still demonstrate an indolent histology. To date, there is no data to guide treatment choices in patients (pts) with FL with high SUVmax but with no documented evidence of HT. Specifically, it remains unclear whether anthracycline-containing regimens, such as R-CHOP, provide a better outcome than R-Bendamustine (BR). Furthermore, it is unknown whether rituximab (R) maintenance is beneficial in this setting. Therefore, we aimed to compare the efficacy of R-CHOP vs BR in newly diagnosed FL pts with high SUVmax at baseline PET and to clarify the role of maintenance. Patients and Methods: We retrospectively identified 261 consecutive pts with newly diagnosed biopsy-proven FL1-3A and a SUVmax≥13 on baseline PET, who were treated with frontline R-CHOP (n=183) or BR (n=78) at 7 US cancer centers based on the physician's choice. Progression-free survival (PFS) was calculated from starting treatment until progression, relapse or death. Cut-offs of SUVmax ≥13≤18 and SUVmax>18 were used for sub-analysis (Haematologica;2020;105:1907-1913). Results: Median age was 59 years. The baseline characteristics of the two groups differed significantly for a younger age (58 vs 62 years, p=0.009), a higher rate of B-symptoms (26% vs 10%, p=0.005) and baseline SUVmax>18 (49% vs 36%, p=0.04) in the R-CHOP group. A diagnostic biopsy was obtained from the site at the highest SUV in 129 (71%) and 43 (55%) pts, respectively (p=0.01). These suggest a potential selection of R-CHOP in pts with adverse features. At the end of therapy (EoT), R-CHOP treated pts achieved higher PET-CT complete response rates (CR 82% vs 69%, p=0.02). This superiority held in pts with diagnostic biopsy at the highest SUV site (CR 83% vs 67%, p=0.03), but not in the others (CR 80% vs 71%, p=0.37). Progression occurred at EoT in 11 and 14 pts receiving R-CHOP and BR (6% vs 18%, p=0.02), with a higher rate of HT in the BR group (13% vs 4%, p=0.006). After a median follow-up of 76 months (range, 4-208 months), there was no significant difference in PFS between R-CHOP and BR treated pts (hazard ratio [HR] 1.22, p=0.34). PFS was strongly associated with FLIPI 2 (HR 2.32, p=0.01) and 3-5 (HR 2.69, p=0.003) in the univariate as well as in the multivariate analysis (FLIPI 2 HR 2.19, p=0.02; FLIPI 3-5 HR 2.51, p=0.01). There was a trend toward overall survival (OS) benefit in the R-CHOP group (Fig.1A). In the univariate analysis for OS, BR regimen (HR 2.12, p=0.03), age >60 (HR 2.54, p=0.006), FLIPI 3-5 (HR 5.13, p=0.03) and biopsy at the highest SUV site (HR 0.44, p=0.01) were prognostic, however none of those remained significant in the multivariate analysis (BR regimen HR 1.84, p=0.09; age >60 HR 1.92, p=0.08; FLIPI 3-5 HR 3.11, p=0.14; biopsy at the highest SUV site HR 0.60, p=0.13; SUVmax>18 HR 1.87, p=0.055). Among pts with EoT response after R-CHOP or BR (n=170 and n=64, respectively), one third in each group (36% vs 41%, respectively) received R-maintenance for a median of 8 administrations (range, 2-12). A significant PFS advantage (landmark analysis) was observed with R-maintenance (Fig.1B; HR 0.53, p=0.02); however, this did not translate in survival benefit (HR 0.67, p=0.49). In a multivariable model, R-maintenance (HR 0.53, p=0.02), FLIPI 2 (HR 2.47, p=0.03) and 3-5 (HR 2.79, p=0.01) remained independent prognosticators of PFS, while no parameters significantly affected OS. The 2-year HT rate (10% vs 17%) and cumulative incidence did not statistically differ between R-CHOP and BR groups (Fig.1C, p=0.159). Early progression (POD24) occurred in 43 and 22 pts who received R-CHOP and BR, respectively (24% vs 28%) and resulted in a significantly higher risk of death (HR 4.12, p=0.006). Conclusion: In newly diagnosed FL pts with SUVmax≥13 at baseline PET, R-CHOP was more effective in achieving CR and reducing the risk of early HT compared with BR, and it was associated with a trend toward survival advantage. Rituximab maintenance significantly prolonged PFS. A prospective evaluation with a larger population will be needed to confirm our findings. Disclosures Joffe: Epizyme: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees. Ruella:Abclon, BMS, NanoString: Consultancy; Abclon: Consultancy, Research Funding; UPenn/Novartis: Patents & Royalties. Svoboda:Adaptive: Consultancy; Astra-Zeneca: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Imbrium: Consultancy; Incyte: Research Funding; Pharmacyclics: Consultancy, Research Funding; Merck: Research Funding; Seattle Genetics: Consultancy, Research Funding; TG: Research Funding; Genmab: Consultancy; Atara: Consultancy. Witzig:Immune Design: Research Funding; Spectrum: Consultancy; Karyopharm Therapeutics: Research Funding; Acerta: Research Funding; Celgene: Consultancy, Research Funding; AbbVie: Consultancy; MorphSys: Consultancy; Incyte: Consultancy. Smith:TG Therapeutics: Consultancy, Research Funding; Janssen: Consultancy; BMS: Consultancy; Celgene: Consultancy, Research Funding; Pharmacyclics: Research Funding; Karyopharm: Consultancy, Research Funding; FortySeven: Research Funding; Acerta: Research Funding; Genentech/Roche: Consultancy, Other: Support of parent study and funding of editorial support, Research Funding. Armand:Affimed: Consultancy, Research Funding; Otsuka: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; IGM: Research Funding; Infinity: Consultancy; Genentech: Research Funding; Sigma Tau: Research Funding; Celgene: Consultancy; Adaptive: Consultancy, Research Funding; Tensha: Research Funding; Roche: Research Funding; Merck & Co., Inc.: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy; ADC Therapeutics: Consultancy. Nastoupil:Janssen: Honoraria, Research Funding; LAM Therapeutics: Research Funding; Gilead/KITE: Honoraria; Gamida Cell: Honoraria; TG Therapeutics: Honoraria, Research Funding; Merck: Research Funding; Novartis: Honoraria, Research Funding; Genentech, Inc.: Honoraria, Research Funding; Karus Therapeutics: Research Funding; Bayer: Honoraria; Celgene: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding. Ansell:Takeda: Research Funding; Regeneron: Research Funding; Bristol Myers Squibb: Research Funding; Seattle Genetics: Research Funding; Trillium: Research Funding; Affimed: Research Funding; AI Therapeutics: Research Funding; ADC Therapeutics: Research Funding. Zelenetz:Novartis: Consultancy; Adaptive Biotechnology: Consultancy; Genentech/Roche: Consultancy; Gilead: Consultancy; Gilead: Research Funding; Celgene: Consultancy; Roche: Research Funding; Amgen: Consultancy; BeiGene: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy; Sandoz: Research Funding; Celgene: Research Funding; MorphoSys: Research Funding; MEI Pharma: Research Funding. Younes:BioPath, Xynomic, Epizyme, and F. Hoffmann-La Roche: Consultancy; Janssen, Curis, Merck, Bristol-Myers Squibb, Syndax Pharmaceuticals, F. Hoffmann-La Roche, Curis (Inst), Johnson & Johnson (Inst), Novartis (Inst): Research Funding; Janssen, AbbVie, Merck, Curis, Epizyme, F. Hoffmann-La Roche, Takeda, Bristol-Myers Squibb, Bayer HealthCare Pharmaceuticals, Celgene, Incyte, Janssen Pharmaceuticals, Merck, Sanofi, Seattle Genetics, Takeda Millennium: Honoraria; AstraZeneca: Current Employment; MSKCC: Ended employment in the past 24 months.

Introduction Marginal Zone Lymphoma (MZL) includes three subtypes of indolent lymphoma: splenic MZL, extranodal MZL of mucosa-associated lymphoid tissue (MALT) and nodal MZL. The diagnosis of MZL is often made by exclusion of other lymphoma subtypes based on phenotype. One of the markers that are often involved in this discernment is CD5. The CD5 is not expressed in most of the cases of MZL, probably independently of the subtype, while it is usually expressed in different diseases such as Mantle Cell Lymphoma and Small Lymphocytic Lymphoma/Chronic Lymphocytic Leukemia. A subgroup of MZL, however, unequivocally expresses CD5, and very little is known about the characteristics and outcomes of these patients compared to their CD5 negative counterparts. Methods From our pathology database, we collected all the reports of indolent lymphoma containing the words "marginal zone" and/or "MALT" diagnosed or reviewed at MSKCC. We reviewed the text of the selected pathology reports to identify all cases that were unequivocally MZL and reported positivity or negativity of the CD5 marker in the lymphoma cells. From the electronic medical records, we collected all the relevant clinical information for all CD5+ MZL cases, and for a subset of CD5- MZL cases with a 1:2 match for age at diagnosis and sex. The survival and baseline characteristics analyses only included patients that were followed by our lymphoma group. We report differences between groups with the chi-squared test. Overall survival (OS) was estimated using the cumulative incidence method, and time to treatment (TTT) was estimated using the subdistribution function to adjust for semi-competing risk of death on treatment initiation. A modified proportional hazards model was used to compare the subdistribution hazard between groups, and a standard Cox proportional hazards model was used to compare the hazard of death between groups. Results From 03/1998 to 09/2019, 64 patients were diagnosed with CD5+ MZL and followed by the Lymphoma Service at MSKCC. The control group of CD5- MZL included 137 patients that matched the CD5+ positive patients for age at diagnosis and sex. 20.3% of the CD5+ vs 14.6% of the CD5- MZL were nodal (p=0.30); Extra-nodal (EN) localizations included: GI tract - other than stomach (5.9% CD5+, 9.4% CD5-), stomach (17.7% CD5+, 17.1% CD5-), skin (7.8% CD5+, 12.0% CD5-), lung (9.8% CD5+, 12.0% CD5-), eye (9.8% CD5+, 7.7% CD5-), spleen (25.5% CD5+, 18% CD5-), multiple sites (13.7% CD5+, 10.3% CD5-), other single EN sites (9.8% CD5+, 13.7% CD5-). IPI score was low in 52% CD5+ vs 61% CD5-; low intermediate in 28% CD5+ vs 19% CD5-; high intermediate in 21% CD5+ vs 13% CD5-; no CD5+ had high IPI, while 7% of CD5- did (chi-square p=0.04). Transformation to DLBCL was similar in the 2 groups with 7% events in CD5+ and 4% in CD5- (p=0.42). Bone marrow involvement seemed to be more prevalent in the CD5+ MZL (67.5% vs 47.2% of the CD5-; p=0.04). IGHV was mutated in 80% of the CD5+ and 64% of the CD5- (p=0.24). OS analysis was performed first considering death by any cause: median OS was not reached for CD5+ MZL (95% C.I. 8.8 years - NE) and it was 27 years for CD5- (95% C.I. 14.3 years - NE). No difference was observed between CD5+ vs CD5- (p=0.9, Figure 1A). We also calculated MZL related survival, including deaths related to transformation to high grade lymphoma. No difference was observed between CD5+ vs CD5-, (p=0.3, Figure 1B). Median time to 1st treatment (including topical treatment and radiation therapy) was 1.4 years (95% C.I. 0.4 - 2.3) for CD5+ and 0.4 years (95% C.I. 0.3 - 0.9). No difference was observed between CD5+ vs CD5- (p=0.2, Figure 1C). Median time to first systemic treatment was 4.3 years (95% C.I. 1.6 - 12.9) for CD5+ and 7 years (95% C.I. 3.1 - 15.4) for CD5- MZL. No difference was observed between CD5+ vs CD5- (p=0.6, Figure 1D). Conclusions In this retrospective case-control analysis assessing the differences between CD5+ and CD5- MZL in terms of clinical presentation, survival, transformation occurrence and time to first topical or systemic treatment, we demonstrate that the two subgroups might have some differences in terms of bone marrow involvement but probably no difference in terms of outcome. Our sample size is small, and larger studies on a population with more events might clarify, with multivariate analysis, if these differences are real. Figure Disclosures Joffe: Epizyme: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees. Palomba:Pharmacyclics: Honoraria; Celgene: Honoraria; Merck: Honoraria; Novartis: Honoraria; Regeneron: Research Funding; Juno Therapeutics, a Bristol-Meyers Squibb Company: Honoraria, Research Funding; Genentech: Research Funding. Noy:Rafael Pharma: Research Funding; Janssen: Consultancy; Pharmacyclics: Consultancy; Medscape: Consultancy; Targeted Oncology: Consultancy; Morphosys: Consultancy; Pharmacyclics: Research Funding; NIH: Research Funding. Matasar:Daiichi Sankyo: Consultancy; Immunovaccine Technologies: Honoraria, Research Funding; Pharmacyclics: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; IGM Biosciences: Research Funding; GlaxoSmithKline: Honoraria, Research Funding; Rocket Medical: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Genentech, Inc.: Consultancy, Honoraria, Research Funding; Merck: Consultancy; Bayer: Consultancy, Honoraria, Research Funding; Teva: Consultancy; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Juno Therapeutics: Consultancy; Takeda: Consultancy, Honoraria. Hamlin:J&J Pharmaceuticals: Research Funding; Portola Pharmaceutics: Consultancy; Portola: Research Funding; Molecular Templates: Research Funding; Incyte: Research Funding; Celgene: Consultancy; Karyopharm: Consultancy; Juno Therapeutics: Consultancy. Kumar:Kite Pharmaceuticals: Honoraria, Other: Honoraria for Advisory Board; Astra Zeneca: Honoraria, Other: Honoraria for Advisory Board; Celgene: Honoraria, Other: Honoraria for Advisory Board; Seattle Genetics: Research Funding; Pharmacyclics: Research Funding; Celgene: Research Funding; Adaptive Biotechnologies,: Research Funding; AbbVie: Research Funding. Moskowitz:Seattle Genetics: Consultancy; Miragen Therapeutics: Consultancy; Imbrium Therapeutics, L.P.: Consultancy; Merck: Research Funding; Bristol-Myers Squibb: Research Funding; Incyte: Research Funding; Seattle Genetics: Research Funding; Merck: Consultancy. Falchi:Genmab: Research Funding; Roche: Research Funding. von Keudell:Merck: Consultancy, Honoraria. Straus:Targeted Oncology: Consultancy, Speakers Bureau; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees; ASH: Other: Conference in December 2019 on HL to other physicians during ASH; Elsevier: Membership on an entity's Board of Directors or advisory committees, Other: CME writer; OncLive: Speakers Bureau; Takeda Pharmaceuticals: Research Funding, Speakers Bureau; NY Lymphoma Rounds: Consultancy; Imedex, Inc.: Speakers Bureau; Karyopharm Therapeutics: Membership on an entity's Board of Directors or advisory committees. Horwitz:Aileron: Consultancy, Research Funding; ADCT Therapeutics: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Forty Seven: Consultancy, Research Funding; Infinity/Verastem: Research Funding; Kyowa Hakka Kirin: Consultancy, Research Funding; Millenium/Takeda: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Trillium: Consultancy, Research Funding; Corvus: Consultancy; Innate Pharma: Consultancy; Mundipharma: Consultancy; Portola: Consultancy, Research Funding; Beigene: Consultancy; C4 Therapeutics: Consultancy; Daiichi Sankyo: Research Funding; GlaxoSmithKline: Consultancy; Janssen: Consultancy; Kura Oncology: Consultancy; Miragen: Consultancy; Myeloid Therapeutics: Consultancy; Verastem: Consultancy, Research Funding; Vividion Therapeutics: Consultancy; Affirmed: Consultancy; ASTEX: Consultancy. Dogan:Takeda: Consultancy; Roche: Consultancy, Research Funding; Physicians Education Resource: Consultancy; Corvus Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy; EUSA Pharma: Consultancy; AbbVie: Consultancy; National Cancer Institute: Research Funding. Zelenetz:BeiGene: Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnology: Consultancy; Novartis: Consultancy; Amgen: Consultancy; Janssen: Consultancy; Celgene: Consultancy; Gilead: Consultancy; Genentech/Roche: Consultancy; Gilead: Research Funding; Roche: Research Funding; Celgene: Research Funding; Sandoz: Research Funding; MorphoSys: Research Funding; MEI Pharma: Research Funding.

Background: Diffuse large B-cell lymphoma (DLBCL) is frequently curable after frontline therapy, however, relapses can occur after achievement of a PET-negative complete remission (CR). Early detection of relapse may be associated with improved outcomes with second-line curative intent therapy or novel therapies. Controversy exists regarding the utility of post-therapy surveillance imaging which is associated with patient (pt) anxiety, radiation exposure, false-positive results, and cost. A retrospective study found that serial minimal residual disease (MRD) monitoring during DLBCL surveillance could identify pts at risk of relapse before clinical evidence of disease (Roschewski, Lancet Oncol, 2015). In this multicenter prospective study, we assessed whether a next-generation sequencing (NGS)-based MRD assay could be used for early detection of molecular relapse in DLBCL. Methods: Eligible pts with DLBCL or high-grade B-cell lymphoma (HGBCL) who received anthracycline-containing chemotherapy were enrolled across five cancer centers. In pts who achieved a PET-negative CR, serial peripheral blood samples were obtained every 3 months (mos) and CT scans every 6 mos for 2 years (yrs) post-treatment. The clonoSEQ® next generation sequencing (NGS) MRD assay (Adaptive Biotechnologies, Seattle, WA) that leverages multiplex PCR followed by NGS to identify and track rearrangements of IgH, V-J, D-J and IgK/L loci and translocations in Bcl1/2-IgH was used. MRD positive was defined as any detectable rearrangement and MRD negative as no evidence of rearrangement. We also reported MRD positivity above the limit of detection (LOD) (observations required to have 95% reproducibility). Interim futility analysis was performed after approximately 50% of anticipated relapses occurred to assess the preliminary sensitivity of the assay. Progression-free survival (PFS) was defined as time from treatment start date to relapse or death. Results: 501 pts were enrolled and 401 were evaluable (pre-treatment tumor pathology available, completed frontline treatment, and achieved PET-negative CR at end-of-treatment). Baseline characteristics were median age of 62 yrs (range 19-95), male sex 58%, advanced stage 61%, and poor-risk by R-IPI 40% (Table 1). Histologies included DLBCL, NOS (86%), primary mediastinal B-cell lymphoma (6%), HGBCL (5%), T-cell rich B-cell lymphoma (1%), and other (1%). Pts received regimens including RCHOP x 6 cycles (36%), REPOCH x 6 cycles (20%), clinical trial (15%), combined modality therapy (RCHOP+RT) (10%), and other RCHOP variations (19%). Among the 401 evaluable pts, 44 relapses have occurred as of June 1, 2020. In 47% of pts (18/38), clinical relapse was detected using surveillance imaging alone (typically CT CAP with IV contrast) in an otherwise asymptomatic pt with a normal physical exam and laboratory evaluation. Clinical relapse was detected by clinical symptoms alone in 11% (4/28), by the evaluation of an oncologist alone in 0%, and by imaging and clinical symptoms and/or evaluation by an oncologist in 42% (16/38) (missing data in 6 pts). With a median follow-up of 2.2 yrs, the 2-yr PFS was 88.1% (84.8, 91.4) (Figure 1). Advanced age, advanced stage, and poor-risk R-IPI were associated with inferior PFS. Of the 44 relapses, 43 pts were included in the interim analysis and tumor-specific clonotypes were identified in 39 pts (91%). In 56% (22/39), the MRD assay was positive at or before clinical relapse. In 38% (15/39), the MRD assay was positive above the limit of detection at or prior to clinical relapse, with only 10 relapses detected more than 3 mos prior to relapse, reflecting the poor clinical sensitivity of the assay. The NGS-MRD assay was more sensitive in the acellular (plasma cell-free DNA) than in the cellular (circulating leukocytes) compartment. Results: Overall outcomes are excellent for DLBCL and HGBCL pts who achieve PET-negative complete remission. In interim analysis, surveillance MRD assessment using the clonoSEQ® assay fails to consistently identify pts at risk of recurrence before clinical evidence of relapse in DLBCL. In a prospective analysis, a substantial proportion (47%) of clinical relapses are detected by imaging in asymptomatic pts, supporting the value of CT surveillance imaging in DLBCL, particularly for pts with advanced stage or high-risk disease. Additional analyses are forthcoming for MRD assessment in all pts, including those in remission. Disclosures Kumar: Celgene: Research Funding; Pharmacyclics: Research Funding; Adaptive Biotechnologies,: Research Funding; AbbVie: Research Funding; Seattle Genetics: Research Funding; Celgene: Honoraria, Other: Honoraria for Advisory Board; Astra Zeneca: Honoraria, Other: Honoraria for Advisory Board; Kite Pharmaceuticals: Honoraria, Other: Honoraria for Advisory Board. Westin:Kite: Consultancy, Research Funding; Curis: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Amgen: Consultancy; Astra Zeneca: Consultancy, Research Funding; Morphosys: Consultancy, Research Funding; 47: Research Funding; Janssen: Consultancy, Research Funding; BMS: Consultancy, Research Funding. Nowakowski:Curis: Consultancy; Seattle Genetics: Consultancy; Nanostrings: Research Funding; MorphoSys: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Celgene/BMS: Consultancy, Research Funding; Kite: Consultancy; Denovo: Consultancy; Kymera: Consultancy; Ryvu: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other. Lossos:Verastem: Consultancy, Honoraria; Seattle Genetics: Consultancy, Other; NCI: Research Funding; Stanford University: Patents & Royalties; Janssen Biotech: Honoraria; Janssen Scientific: Consultancy, Other. Batlevi:Life Sci, GLG, Juno/Celgene, Seattle Genetics, Kite: Consultancy; Janssen, Novartis, Epizyme, Xynomics, Bayer, Autolus, Roche/Genentech: Research Funding. Drullinsky:Roche: Research Funding; Novartis: Research Funding. Gerecitano:Janssen: Current Employment. Hamlin:Celgene: Consultancy; Karyopharm: Consultancy; Juno Therapeutics: Consultancy; Portola: Research Funding; Molecular Templates: Research Funding; Incyte: Research Funding; J&J Pharmaceuticals: Research Funding; Portola Pharmaceutics: Consultancy. Horwitz:ASTEX: Consultancy; Affirmed: Consultancy; Vividion Therapeutics: Consultancy; Verastem: Consultancy, Research Funding; Myeloid Therapeutics: Consultancy; Miragen: Consultancy; Kura Oncology: Consultancy; Janssen: Consultancy; GlaxoSmithKline: Consultancy; Daiichi Sankyo: Research Funding; C4 Therapeutics: Consultancy; Beigene: Consultancy; Portola: Consultancy, Research Funding; Mundipharma: Consultancy; Innate Pharma: Consultancy; Corvus: Consultancy; Trillium: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Millenium/Takeda: Consultancy, Research Funding; Kyowa Hakka Kirin: Consultancy, Research Funding; Infinity/Verastem: Research Funding; Forty Seven: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Aileron: Consultancy, Research Funding; ADCT Therapeutics: Consultancy, Research Funding. Jacob:Adaptive Biotechnologies: Current Employment, Current equity holder in publicly-traded company. Joffe:AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Epizyme: Membership on an entity's Board of Directors or advisory committees. von Keudell:Bayer: Research Funding; Pharmacyclics: Research Funding; Genentech: Research Funding. Lahoud:MorphoSys: Other: Advisory Board. Matasar:Bayer: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Rocket Medical: Consultancy, Research Funding; Teva: Consultancy; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Daiichi Sankyo: Consultancy; IGM Biosciences: Research Funding; Janssen: Honoraria, Research Funding; Pharmacyclics: Honoraria, Research Funding; Immunovaccine Technologies: Honoraria, Research Funding; Merck: Consultancy; Juno Therapeutics: Consultancy; Genentech, Inc.: Consultancy, Honoraria, Research Funding. Mullins:Adaptive Biotechnologies: Current Employment, Other: shareholder. Noy:Pharmacyclics: Research Funding; NIH: Research Funding; Rafael Pharma: Research Funding; Janssen: Consultancy; Pharmacyclics: Consultancy; Medscape: Consultancy; Targeted Oncology: Consultancy; Morphosys: Consultancy. Straus:Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees; ASH: Other: Conference in December 2019 on HL to other physicians during ASH; Elsevier: Membership on an entity's Board of Directors or advisory committees, Other: CME writer; OncLive: Speakers Bureau; Takeda Pharmaceuticals: Research Funding, Speakers Bureau; NY Lymphoma Rounds: Consultancy; Targeted Oncology: Consultancy, Speakers Bureau; Imedex, Inc.: Speakers Bureau; Karyopharm Therapeutics: Membership on an entity's Board of Directors or advisory committees. Younes:Takeda: Consultancy; HCM: Consultancy; AstraZeneca: Current Employment; Novartis: Consultancy; Daiichi Sankyo: Consultancy; Janssen: Consultancy; Epizyme: Consultancy; BMS: Consultancy; BioPath: Consultancy; Curis: Consultancy. Zelenetz:MEI Pharma: Research Funding; MorphoSys: Research Funding; Sandoz: Research Funding; Celgene: Research Funding; Roche: Research Funding; Gilead: Research Funding; Genentech/Roche: Consultancy; Gilead: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Amgen: Consultancy; Novartis: Consultancy; Adaptive Biotechnology: Consultancy; BeiGene: Membership on an entity's Board of Directors or advisory committees.

Introduction: Interleukin-1 receptor-associated kinase 4 (IRAK4) is essential for toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) signaling in immune cells including B lymphocytes. It forms the Myddosome complex with the MYD88 adaptor protein, with IRAK4 being essential for downstream signaling, maximal activation of NFkB with inflammatory and immune response and tumor promotion [Treon 2012; Rhyasen 2015]. CA-4948 is a novel small molecule, oral inhibitor of IRAK4, first-in-class and only suppressor of the TLR pathway currently tested in hematological malignancies. When combined with the BTK inhibitor ibrutinib that blocks parallel BCR signaling and NF-kB activating pathway, it has shown synergy in in-vivo B-cell NHL models, providing strong rationale for clinical evaluation [Booher 2018]. Recent preclinical studies demonstrated the role of IRAK4 activation as a driver of secondary, adaptive tumor resistance and survival mechanisms of hematological and solid tumor malignancies [Melgar 2019] that could be blocked by CA-4948 to delay or reverse resistance. Study Design and Methods: This is a multicenter, open-label trial of oral CA-4948 combined with ibrutinib in adult patients with relapsed or refractory hematologic malignancies. (NCT03328078). It has 2 parts: a dose escalation (Part A2), and expansion basket of 4 cohorts (Part B). Part A2: Is a truncated 3+3 design: CA-4948 starting is 200 mg BID with subsequent escalation to 300 mg BID. Both dose are safe and active against NHL as seen in the nearly completed monotherapy Part A1 of this trial Patients will receive CA-4948 with ibrutinib at the labeled dose for the respective NHL subtype (560 mg or 420 mg) until toxicity or progression. Primary objectives are safety/tolerance (MTD, RP2D); 2nd objectives are pharmacokinetics and preliminary efficacy; exploratory objectives include biomarker correlations (e.g., MYD88-L265P mut, IRAK4 pathway, NFκB inhibition). Part B basket has four cohorts: 1 -MZL, 2 - ABC-DLBCL, 3 - PCNSL, and 4 - NHL with adaptive ibrutinib resistance. Cohorts 1-3 must be BTK-inhibitor naïve. Cohort 4 includes ibrutinib treated NHLs after developing adaptive, secondary resistance. All will receive the combination of ibrutinib and CA-4948. Cohort 4 patients will be allowed a Samples sizes, statistical considerations: Approx. 18 patients in Part A2. In Part B, a Simon 2-Step design will be applied to each cohort. Early stopping rule for futility after approx. 20 patients in Stage 1: full accrual with Stage 2 will add about 25 patients. Successful signal efficacy identification in a cohort may support further expansion or a subsequent controlled trial. The safety population will include all patients in the study who received any test dose. The efficacy population will have a valid baseline and post-baseline disease assessment. Safety assessments include TEAEs, safety labs, vitals, physical exams, PK, and ECGs; efficacy assessments: tumor imaging, para-protein determination, and histo/cyto-morphologic examinations. Part A2 inclusion: Histopathologically confirmed B-cell NHL as per the WHO 2016 classification. Eligible NHL subtypes: FL, MZL, MCL, DLBCL (including extranodal lymphomas of leg, testicle, or other sites, excluding mediastinal lymphoma), CLL/SLL, primary or secondary CNS lymphoma, and WM/LPL. Patients with FL, MCL, MZL, WM/LPL, or CLL/SLL should meet clinical treatment criteria. Part B inclusion: Cohorts 1-3 include patients with MZL, ABC-DLBCL, or PCNSL who are BTK-inhibitor naïve. Cohort 4 will include ibrutinib pre-treated MCL, MZL, CLL/SLL, WM/LPL, ABC-DLBCL, or PCNSL with adaptive resistance. Exclusions for both Parts A2 and B: Significant acute or chronic toxicity from prior anti-cancer therapy that has not resolved to Grade ≤ 1, as determined by NCI CTCAE v 4.03 within 7 days prior to start of study or serious co-morbidities. Disclosures Nowakowski: NanoString: Research Funding; Seattle Genetics: Consultancy; Curis: Consultancy; Kymera: Consultancy; Kite: Consultancy; Celgene/BMS: Consultancy, Research Funding; MorphoSys: Consultancy, Research Funding; Ryvu: Consultancy, Membership on an entity's Board of Directors or advisory committees. Leslie:TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Speakers Bureau; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; KitePharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BeiGene: Speakers Bureau; Pharmacyclics/Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Epizyme: Speakers Bureau; Karyopharm: Speakers Bureau; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees. Joffe:AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Epizyme: Membership on an entity's Board of Directors or advisory committees. Lunning:Kite: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; TG Therapeutics: Research Funding; Verastem: Consultancy, Honoraria; Acrotech: Consultancy; ADC Therapeutics: Consultancy; Legend: Consultancy; Janssen: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Curis: Research Funding; Gilead: Consultancy, Honoraria; Beigene: Consultancy, Honoraria; Aeratech: Consultancy, Honoraria; Bristol Meyers Squibb: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria. Patel:Adaptive Biotechnologies: Consultancy; Kite: Consultancy; BeiGene: Consultancy; AstraZeneca: Consultancy, Research Funding, Speakers Bureau; Pharmacyclics: Consultancy, Speakers Bureau; Celgene/BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Speakers Bureau; Genentech: Consultancy, Speakers Bureau. Landsburg:Takeda: Research Funding; Triphase: Research Funding; Seattle Genetics: Speakers Bureau; Morphosys: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Curis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees. Fenske:Medical College of Wisconsin: Current Employment. Ramchandren:Merck, Seattle Genetics, Janssen, Genentech: Research Funding; Seattle Genetics, Sandoz-Novartis, Pharmacyclics, an AbbVie Company, Janssen, Bristol-Myers Squibb: Consultancy. Skarbnik:Alexion: Consultancy; Beigene: Speakers Bureau; Verastem: Speakers Bureau; CLL Society: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, 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; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Tun:Bristol-Myers Squibb: Research Funding; Celgene: Research Funding; Mundipharma: Research Funding; Curis: Research Funding; TG Therapeutics: Research Funding; Acrotech: Research Funding; DTRM Biopharma: Research Funding.

Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare subtype of lymphoma that, like other Hodgkin lymphomas, has historically been treated aggressively. However, in most cases, NLPHL has an indolent course, which raises the question of to what extent these patients require aggressive upfront treatment. We describe the management and outcomes of consecutive NLPHL patients diagnosed at Memorial Sloan Kettering Cancer Center (MSK), with a focus on evaluating active surveillance. All patients aged 16 years or older diagnosed and followed at MSK between 1974 and 2016 were included. Treatment outcomes were compared between management with active surveillance and other strategies. We identified 163 consecutive patients who were treated with radiotherapy alone (46%), active surveillance (23%), chemotherapy (16%), combined modality (12%), or rituximab monotherapy (4%). Median follow-up was 69 months. Five-year progression-free survival (PFS), second PFS (PFS2), and overall survival (OS) estimates were 85% (95% confidence interval [CI], 78-90), 97% (95% CI, 92-99), and 99% (95% CI, 95-100), respectively. Only 1 of 7 deaths was lymphoma related. Patients managed with active surveillance had slightly shorter PFS than those receiving any active treatment, with 5-year PFS of 77% (95% CI, 56-89) vs 87% (95% CI, 79-92; P = .017). This difference did not translate into better PFS2 or OS. Only 10 patients managed with active surveillance (27%) eventually required treatment, after a median of 61 months, and none died. NLPHL has an excellent prognosis. Within the limitations of a retrospective analysis, active surveillance is a viable initial management strategy for selected NLPHL patients.

Background: Previous studies reported that early progression of disease (POD) after initial therapy predicted poor overall survival (OS) in patients with follicular lymphoma (FL). Here, we investigated whether pre-treatment imaging modality had an impact on prognostic significance of POD. Methods: In this retrospective study, we identified 1,088 patients with grade 1-3A FL of whom 238 patients with stage II-IV disease were initially treated with R-CHOP and 346 patients treated with R-chemotherapy. Patients (N=484) from the FOLL05 study served as an independent validation cohort. We risk-stratified patients based on pre-treatment radiographic imaging (PET, vs. CT) and early POD status using event defining and landmark analyses. A competing risk analysis evaluated the association between early POD and histologic transformation. Findings: In the discovery cohort, patients with POD within 24 months (PFS24) of initiating R-CHOP therapy had 5-year OS of 57·6% for CT-staged patients compared with 70·6% for PET-staged patients. In the validation cohort, the 5-year OS for patients with early POD was 53·9% and 100% in CT- and PET-staged patients, respectively. The risk of histologic transformation in patients whose disease progressed within one year of initiating therapy was higher in CT-staged patients compared with PET-staged patients (16·7% vs. 6·3%), which was associated with a 9.7 fold higher risk for death. Interpretation: In FL, pre-treatment PET-staging reduced the prognostic impact of early POD compared with CT-staging. Patients with early POD and no histologic transformation have an extended OS with standard therapy. Funding: NCI Cancer Center Support Grant (P30 CA008748). Declaration of Interest: 1) Connie L. Batlevi: Research Support: Janssen, Novartis, Epizyme, Xynomics; Honorarium: Dava Oncology. 2) Fushen Sha: None 3) Anna Alperovich: None. 4) Andy Ni: None. 5) Katy Smith: None 6) Zhitao Ying: None. 7) John F. Gerecitano: Currently employed by Janssen. Honoraria: Bayer, Epizyme, Roche, Genentech, Abbvie. 8) Paul A. Hamlin: consultancy at Portola Pharmaceutics, Celgene, Karyopharm, Juno Therapeutics; research funding from Portola, Molecular Templates, Incyte, JJ research funding from ADCT therapeutics, Aileron,Celgene, Forty-Seven, Infinity/Verastem, Kyowa-Hakka-Kirin, Millenium/Takeda, Seattle Genetics, Trillium. 10) Anita Kumar: Research Support: Abbvie, Adaptive Biotechnologies, Celgene, Pharmacyclics, Seattle Genetics; Scientific Advisory Board: Celgene. 11) Matthew J. Matasar: Honoraria: Genentech, Roche, Bayer, Pharmacyclics, Janssen, Seattle Genetics, GlaxoSmithKline. Consulting: Genentech, Bayer, Merck, Juno, Roche, Teva, Rocket Medical, Seattle Genetics. Research: Genentech, Roche, GlaxoSmithKline, Bayer, Pharmacyclics, Janssen, Rocket Medical, Seattle Genetics. Travel: Genentech, Roche, Seattle Genetics, Bayer. 12) Alison J. Moskowitz: consultancy at Kyowa Hakko Kirin Pharma, Miragen Therapeutics, Takeda Pharmaceuticals, ADC therapeutics, Seattle Genetics, Cell Medica, Bristol-Myers Squibb, Erytech Pharma; research funding from Incyte, Seattle Genetics, BMS, and Merck. 13) Craig H. Moskowitz: Consulting: Astra Zeneca, BMS, Karyopharm Therapeutics, Merck, Seatle Genetics, Takeda, Vaniam Group; Scientific Advisory Board: Astra-Zeneca, Karyopharm Therapeutics, Merck, Seattle Genetics, Takeda, Vaniam Group; Research support: BMS, Merck, Seattle Genetics. 14) Ariela Noy: Research funding from Pharmacyclics, NIH, Raphael Pharma; consulting for: Janssen, Pharmacyclics, Medscape, Targeted Oncology. 15) Maria Lia M. Palomba: Honoraria from Merck, Celgene, Juno and Pharmacyclics. 16) Carol Portlock: None 17) David Straus: Advisory Board and research support: Seattle Genetics. 18) Andrew D. Zelenetz: consultancy at Genentech/Roche, Gilead, Celgene, Janssen, Amgen, Novartis, Adaptive Biotechnology; research funding MEI Pharma, MorphoSys, Sandoz, Celgene, Roche, Gilead; Board of Directors (DMC Chair) Beigene. 19) Venkatraman E Seshan: None. 20) Stefano Luminari: Consulting/Advisory boards: Roche, Celgene, Sandoz, Gilead 21) Luigi Marcheselli: None. 22) Massimo Federico: Research support: Mundipharma s.r.l., Chephalon/Teva, Celgene, Millennium/Takeda, and Roche. Consulting/Advisory boards: Takeda, Roche, Celgene, Sandoz, and Spectrum. 23) Anas Younes: Research Support: Janssen, Curis, Merck, BMS, Syndax, and Roche; Honorarium: Janssen, AbbVie, Merck, Curis, Epizyme, Roche, Takeda; Consulting: Biopath, Xynomics, Epizyme, Roche. Ethical Approval: This is a retrospective study of adult patients (≥18 years old) diagnosed between the years of 1998 to 2009 with FL managed at Memorial Sloan Kettering Cancer Center (MSKCC). The institutional review board approved this study.

Multiple myeloma (MM) is a multi–subclonal malignancy with relatively high heterogeneity. Patients who initially presented with both monoclonal-protein (MP) and free light chain (FLC) secretion but then relapsed with a light chain escape pattern have been shown to reflect disease clonal evolution and to bare a worse prognosis. We hypothesized that a discordant MP/FLC pattern at diagnosis may reflect a similar clonal evolution that had occurred prior to diagnosis of active myeloma, conferring a worse outcome. We analyzed 255 consecutive newly diagnosed MM patients who received first line bortezomib-based therapy between 2007 and 2014, hypothesizing that their MP/FLC fingerprint at diagnosis reflects clonal heterogeneity and, therefore, affects outcome. An involved FLC level ≥ 700 mg/L and MP ≥ 2.5 g/L were used as cutoffs for low vs high FLC and MP levels, respectively. Patients were divided into 4 subgroups according to their involved FLC and MP blood levels at diagnosis: HiLC and HiMP for patients with either a predominant FLC or a predominant MP, respectively, and HiLC-MP and LoLC-MP when both FLC and MP were increased or decreased, respectively. There were 68 (27%) patients with HiLC, which presented more often with International Staging System-3 stage (P

e19201 Background: Automated extraction of key clinical features from imaging reports, such as the site, size and FDG avidity of lesions would allow for automatic determination of disease stage, response to treatment and relapse. Since the language used in clinical notes is domain and often task-specific, generic Natural Language Processing (NLP) tools are of limited utility. We describe a strategy for a rapid construction of task-specific NLP algorithms. As a test case, we aimed to identify bone involvement with lymphoma from PET/CT reports. Methods: We use an adaptive-learning approach to facilitate the generation of task-specific lexicons by a domain expert. In the case of identifying bone lymphoma, these include words describing the primary aspect (PA: e.g., “ uptake”, “SUV”); the secondary aspect, in this case, osseous sites (SA: e.g., “skeleton”, “T5”); modifiers such as context-specific affirmation/ negation/ uncertainty (e.g., “increased”/ “likely reactive”/ “possibly disease”) and generic negation (e.g., “no evidence of”). Presented with sentences containing seed PA terms, an expert is tasked with an exhaustive identification of terms for the other lexicons. In an iterative process, unseen sentences that do not include terms previously identified are presented for lexicon expansion. The process is repeated until no further expansion is possible. An explicit rule-based algorithm is built based on the lexicons to classify sentences as supporting, negating or inconclusive (i.e., requiring manual review) for the feature of interest. We used 500 reports to develop the algorithm, evaluated performance against 516 unseen reports that were independently classified by a blinded annotator, and measured the amount of effort (number of iterations) required to complete the PA and SA lexicon expansion. Results: Of 44 reports with bone involvement identified by the algorithm, 43 had an actual involvement and 1 was a negative case (PPV: 98%). Of 380 reports flagged as negative, 379 were truly negative and 1 was positive (NPV: 99.7%). Sensitivity was 64% (43/67); specificity 84% (379/449); 18% (93) reports were flagged for manual review. It took 13 and 5 iterations to build the PA and SA lexicons, each involving the review of up to 10 sentences. Conclusions: With minimal effort, we were able to construct a high-accuracy NLP system specific for identifying bone lymphoma. This approach can be extended to other contexts (e.g., lung involvement), domains (e.g., pathology reports), or to be utilized in machine learning.

e20017 Background: FDG avidity above liver on interim PET (PET2) during frontline ABVD is considered a marker of impending treatment failure and an indication to switch to an intensified regimen. However, in clinical practice the utility of PET2 for treatment decisions is less clear. We describe outcomes of patients with positive PET2 who continued treatment with ABVD in the clinical setting. Methods: A retrospective study of all patients with newly diagnosed advanced-stage Hodgkin lymphoma treated with frontline ABVD at Memorial Sloan Kettering Cancer Center between 2008-2017. Eligibility criteria were set to correspond with the RATHL inclusion criteria (stage IIB - IV, or IIA bulky or ≥ 3 involved sites). We identified all PET2 reports indicating suspected residual uptake. All positive PET2 images were then reviewed by a single study radiologist. To increase reproducibility and avoid selection of borderline cases, we defined as PET2 positive only those cases with a lesion-to-liver (mean) SUV ratio ≥ 1.3. We also used a recently published stringent criterion of lesion-to-liver (max) ratio ≥ 1.4 (mPET2+). Progression-free and overall survival (PFS, OS) were calculated from the date of initial treatment until progression or death of any cause. Consolidative radiation was not considered a PFS event, and all progressions were verified by biopsy. Results: We identified 227 patients fitting RATHL inclusion criteria treated with ABVD. Median age was 34, with 25% (58) ≥ 45 years, 12% (26) had an IPS ≥ 4; 28% (64) stage II (5% II-X) and 38% (87) with extranodal involvement. 57 (25%) patients had a PET2 report indicating suspected residual lymphoma (PET2+), however, only 32 (14%) met the more stringent mPET2+ criterion. Most patients with PET2+ continued ABVD (84%, 48), and 9 switched to escBEACOPP (this subset of patients had substantially worse disease and are not the focus of this analysis). 21 (9%) patients received consolidative radiation. With a median follow-up of 47 months (42-54m), PET2+ patients who continued ABVD had a 3yPFS of 70% (58-85%, n = 48); mPET+ had a 3yPFS of 71% (55-92%, n = 24). Overall survival was excellent regardless of PET2 status (5yOS 97%). Conclusions: The outcome of PET2+ patients in this analysis was better than previously reported and the continuation of ABVD was appropriate for most patients. Use of a confirmatory biopsy is important for identifying true progressions. Patients with PET2+ had an excellent OS. Evaluation of the superiority of alternative regimens in PET2+ patients requires an ABVD comparator arm.

8062 Background: Immunotherapy with anti CD20 is often associated with mild easily manageable infusion reactions. In rare cases, patients experience severe drug hypersensitivity reactions (DHR) serum sickness or anaphylaxis. These in turn may lead to discontinuation of the drug. In our experience, switching to a different anti-CD20 agent is a feasible alternative to discontinuation or desensitization protocols. Methods: From our pharmacology database we identified all the patients that received rituximab and/or obinutuzumab, and/or ofatumumab, and/or all the patients who received a flat dose of less than 50 mL of the same drugs and were followed at our institution. From the medical record, we identified all the cases where the anti-CD20 antibody was changed due to allergy, serum sickness or other types of DHR, and all those who received minimal doses of anti-CD20 in the context of a desensitization protocol. DHRs were evaluated either by an allergist, or by retrospective review following the World Allergy Organization guidelines. Our primary comparison, was to assess the proportion of pts able to completed planned infusion of abs using either approach (Fisher’s exact Test). Results: Among 343 patients receiving at least two different anti-CD20 antibodies or a flat dose of < 50 mL, we identified 44 patients experiencing severe DHRs needing intervention. At the time of the reaction, 16 (36%) received the anti-CD20 as single agent, 24 (54%) in combination with chemotherapy, 4 (9%) in combination with ibrutinib or lenalidomide. In 9 (20%) patients the reaction was defined as anaphylactoid (8 rituximab; 1 obinutuzumab) and in 8 (18%) patients, all receiving rituximab, as serum sickness. Episodes of DHR were addressed with either desensitization (n = 29) or change of anti-CD20 agent (n = 25), 9 patients received both of these approaches, one patient switched anti-CD20 antibodies twice. Overall, 21 desensitizations were successful (72.4%), 8 failed; 23 changes of anti-CD20 were successful (92%) and 2 failed (p = 0.09). Conclusions: In patients with DHR use of an alternative anti-CD20 antibody is safe and is an alternative or complementary approach to anti-CD20 desensitization.

TPS8072 Background: Diffuse large B-cell lymphoma (DLBCL) escapes host immune responses via inhibition of the B2M and CD58 pathways and upregulation of PD-1 ligands. However, treatment results with PD-1 blockade have been disappointing. One potential mechanism is the recruitment of intra-tumoral regulatory T-cells (Tregs) which suppress anti-tumor immunity and inhibit NK cell cytotoxicity. Targeting regulatory T cells with the CCR4 antibody mogamulizumab (KW-0761) represents a molecularly informed strategy to overcome this resistance. Mogamulizumab has been safely administered in combination with pembrolizumab (MK-3475) in patients with solid malignancies and may promote CD8 T-cell dependent effector and NK cell-dependent cytotoxicity in lymphomas. Methods: This is a multi-center NIH-ETCTN phase Ib/randomized phase II study. The phase I will evaluate the safety and tolerability of mogamulizumab in combination with pembrolizumab in patients with R/R DLBCL and determine the recommended phase II dose (RP2D). A traditional 3+3 design with a starting dose of pembrolizumab 200mg IV on day 1 of a 21-day cycle and mogamulizumab 1mg/kg IV on days 1, 8, 15 and then 1.5 mg/kg IV every 21 days. The phase II will evaluate the efficacy of the combination by PFS (primary endpoint) ORR and CR (secondary endpoints). This will be a randomized 1:1 study with allowed crossover, comparing the combination to single agent pembrolizumab Correlative studies will evaluate the association of tumor infiltrating CD8 and NK cells with response to treatment, somatic mutations in B2M and CD58 and with MHC-I expression on DLBCL cells. Functional characterization of circulating immune cells in the peripheral blood and measurement of pro and anti-inflammatory cytokines will be used to assess the levels, activation status and effector function of Tregs and circulating T cells. Inclusion criteria include measurable disease, ≥2 prior lines of therapy including or ineligible for autologous stem cell transplant, ECOG ≤ 2 and normal organ function. Prior or planned allogeneic stem cell transplant, as well as prior treatment with an anti PD-1/PD-L1/CTLA4 antibody, preexisting autoimmune disease or CNS involvement by lymphoma are exclusion criteria. The study aims to enroll up to 12 patients on the phase I and up to 58 patients on the phase II and can be opened at any ETCTN participating site. To date it has been opened at two sites and is accruing the first patients for the phase I portion. Clinical trial information: NCT03309878 .

8006 Background: Venetoclax (Ven)-Obinutuzumab (O) is approved for chronic lymphocytic leukemia (CLL) achieving frequent undetectable minimum residual disease (uMRD; Fischer NEJM 2019). Ven-Ibrutinib is synergistic with frequent uMRD but with grade >3 neutropenia in 33-48% patients (pts; Tam ASH 2019; Jain NEJM 2019). Zanubrutinib (B) is a highly specific BTK inhibitor that demonstrated 100% occupancy in lymphoid tissues, so may be preferred to combine with OVen. We hypothesize that treatment (tx) with BOVen using an MRD driven discontinuation strategy will achieve frequent uMRD and durable responses. Methods: In this multicenter, investigator initiated phase 2 trial (NCT03824483), eligible pts had previously untreated CLL requiring tx per iwCLL, ECOG PS 1, PLT >75 (ANC >0, PLT >20 if due to CLL). BOVen was administered in 28D cycles: B 160 mg PO BID starting D1; O 1000 mg IV D1 or split D1-2, 8, 15 of C1, D1 of C2-8; Ven ramp up initiated C3D1 (target 400 mg QD). Tx duration was determined by a prespecified uMRD endpoint (min 8 cycles). MRD was assessed in peripheral blood (PB; flow cytometry, sensitivity >10−4) starting C7D1 then every 2 cycles. Once PB uMRD was determined and confirmed in bone marrow (BM), tx continued 2 additional cycles. Adverse events (AE) were assessed per CTCAE v5. Median (med) time to uMRD (primary endpoint) was estimated using the Kaplan-Meier method. Results: The study accrued 39 pts (3-10/19): med age 59 years (23-73), 3:1 male, CLL IPI >4 26/39 (67%), unmutated IGHV 28/39 (72%), 17p del/ TP53 mutated 4/39 (10%), all pts were evaluable for toxicity with 37 evaluable for efficacy. At a med follow up of 8 months (mo; 3-10), 25/37 (68%) pts achieved PB uMRD. Med time to PB uMRD is 6 mo (4-8+). Another 8/37 (22%) had PB MRD < 0.1%. Of 25 with PB uMRD, 19 had BM uMRD with 10/19 completing 2 additional cycles and discontinued; 3 had BM MRD (all

We sought to define the genomic landscape of diffuse large B-cell lymphoma (DLBCL) by using formalin-fixed paraffin-embedded (FFPE) biopsy specimens. We used targeted sequencing of genes altered in hematologic malignancies, including DNA coding sequence for 405 genes, noncoding sequence for 31 genes, and RNA coding sequence for 265 genes (FoundationOne-Heme). Short variants, rearrangements, and copy number alterations were determined. We studied 198 samples (114 de novo, 58 previously treated, and 26 large-cell transformation from follicular lymphoma). Median number of GAs per case was 6, with 97% of patients harboring at least one alteration. Recurrent GAs were detected in genes with established roles in DLBCL pathogenesis (e.g. MYD88, CREBBP, CD79B, EZH2), as well as notable differences compared to prior studies such as inactivating mutations in TET2 (5%). Less common GAs identified potential targets for approved or investigational therapies, including BRAF, CD274 (PD-L1), IDH2, and JAK1/2. TP53 mutations were more frequently observed in relapsed/refractory DLBCL, and predicted for lack of response to first-line chemotherapy, identifying a subset of patients that could be prioritized for novel therapies. Overall, 90% (n = 169) of the patients harbored a GA which could be explored for therapeutic intervention, with 54% (n = 107) harboring more than one putative target., Key points This study demonstrates the applicability of CLIA-compliant targeted FFPE sequencing for large-scale clinical trials.TP53mut is the main predictor of refractoriness or early relapse.

The risk of developing non-Hodgkin lymphoma increases with age, yet elderly patients are under-represented in clinical trials. Here, we evaluate a combination regimen including ifosfamide, carboplatin and etoposide with or without rituximab (ICE ± R) in 32 fit elderly patients (median age 75.6 years) with relapsed or refractory diffuse large B-cell lymphoma. ICE ± R was generally administered in reduced doses and was well tolerated. The overall response rate (ORR) was 53.1% with a complete response (CR) rate of 40.6%. The median progression free survival (PFS) and overall survival (OS) were 3.9 and 17.0 months, respectively. Patients who responded to ICE ± R achieved median PFS of 47.2 months and OS of 78.9 months. Patients ineligible for autologous transplantation who responded to ICE ± R were treated with additional cycles, and achieved a median PFS of 18.9 months and OS of 21.7 months. Previous response to first-line therapy was the strongest predictor of response, PFS and OS to second-line treatment.

This study aimed to evaluate the efficacy and safety of the fludarabine-cyclophosphamide-rituximab regimen for young physically fit patients with chronic lymphocytic leukemia in the "real-life" setting. We specifically focused on the impact of dose reduction on patient outcomes. The patient cohort consisted of 128 patients with chronic lymphocytic leukemia (≤ 70 years) treated at 10 Israeli centers with front-line fludarabine-cyclophosphamide-rituximab. We defined reduced chemotherapy as two-thirds or less of the total indicated dose. Patients treated with rituximab were divided into two groups and compared: those who received full dosages of 375 mg/m(2) or 500 mg/m(2), and patients given less than six cycles with either dose. Overall and clinical complete response rates (92.8% and 70.4%), as well as toxicities and overall survival (median not reached at 6 years), were similar to other reported clinical trials, but progression-free survival was shorter (42.5 months). Almost 50% of patients had some dose reduction of chemotherapy, 21% receiving less than two-thirds of the indicated dose, while close to 30% did not complete six cycles of rituximab. Reduced doses of chemotherapy and rituximab were independently associated with shorter progression-free survival (hazard ratio 3.6, P0.0001 for reduced chemotherapy; hazard ratio 2.5, P=0.003 for incomplete-treatment with rituximab). Achieving a complete response was associated with longer overall survival but was not linked to the given dose of chemoimmunotherapy. In younger physically fit patients, front-line fludarabine-cyclophosphamide-rituximab therapy in the "real-life" setting achieves long remissions (albeit shorter than in clinical trials) and prolonged overall survival. However, dose reductions are commonly administered and may impact outcome.

This study aimed to compare the real-life results of TECAM, a thiotepa-based conditioning regimen consisting of thiotepa (40 mg/m2 days −5 to −2), etoposide (200 mg/m2 days −6 to −3), cytarabine (200 mg/m2 days −4 to −1), cyclophosphamide (60 mg/kg day −3), and melphalan (60 mg/m2 days −2 to −1) with that of the conventional carmustine-based regimen BEAM. We reviewed 125 consecutive patients who underwent a first autologous transplantation (ASCT) for B-cell lymphomas at a large tertiary transplantation center between 1999 and 2014. TECAM (n=65) and BEAM (n=60) had comparable results (3yPFS 49 vs 62%, P=0.16; 3yOS 64 vs 71%, P=0.44; TRM 1.6 vs 5%, P=0.35) without a difference in toxicity or time to engraftment. Notably, comparable outcomes were observed even though patients treated with TECAM were older (55 vs 44) and had a trend towards more prior lines of therapy (>2 prior lines: 43 vs 27%, P=0.08). In this regard, 23% of TECAM patients were over the age of 65 yet could withstand therapy with similar results to younger patients. We conclude that, replacing carmustine by thiotepa and cyclophosphamide for ASCT conditioning, has comparable efficacy and safety profiles with a possible advantage in older patients.

Little is known about the prognosis associated with statin therapy and its gender differences in older adults aged ≥80 years. To study the mortality and survival associated with statin therapy and their gender differences in older adults aged ≥80 years. This was a historical prospective study conducted at a tertiary medical center. The medical charts of all older adults aged ≥80 years who had been admitted to a single internal medicine department during 1 year were reviewed. All-cause 3‑year mortality and survival rates following hospital admission in men and in women using statins were investigated. The final cohort included 216 patients: 122 (56.5%) women, mean age 85.3 ± 3.9 years. Overall, 66 (53.2%) women and 58 (46.8%) men used statins for 3 years or more following hospital admission. During this time 48 (39.3%) women and 48 (51.1%) men died. The all-cause 3‑year mortality rates were significantly lower only in women who had used statins compared with women who had not used statins (24.2% vs. 57.1%; relative risk = 0.2; 95% confidence interval 0.1–0.5; p < 0.0001). The 3‑year cumulative survival rates were significantly higher in women who had used statins as part of primary as well as secondary cardiovascular prevention (p < 0.0001 and p = 0.014, respectively). A Cox regression analysis showed that statin therapy was independently associated with low 3‑year cumulative mortality rates in women (hazard ratio=0.3; 95% confidence interval=0.1–0.6; p = 0.001). In older adults aged ≥80 years, statin therapy is associated with high 3‑year cumulative survival rates only in women.

Personalization of therapy to target specific molecular pathways has been placed in the forefront of cancer research. Initial reports from clinical trials designed to select patients for appropriate treatment on the basis of tumor characteristics not only have generated considerable excitement but also have identified several challenges. These challenges include the overcoming of regulatory and logistic difficulties, identification of the best selection biomarkers and diagnostic platforms that can be applied in the clinical setting, definition of relevant outcomes in small preselected patient populations, and the design of methods that facilitate rapid enrollment and interpretation of clinical trials by aggregating data across histologically diverse malignancies with common genetic alterations. Furthermore, because our knowledge of the functional consequences of many genetic alterations lags, investigators and sponsors struggle with choosing between ideal clinical trial designs and more practical ones. These challenges are amplified when more than one biomarker is used to select patients for a combination of targeted agents. This review summarizes the current status and challenges of clinical trials in the genomic era and proposes ways to address these challenges.

Recurrent hospitalizations with hyponatremia are commonly encountered in older adults admitted to Internal Medicine wards. However, the incidence and the prognostic implication of this phenomenon have never been studied.Medical charts of all older adults (≥75 years) admitted to Internal Medicine wards at a tertiary medical center during 2009-2010 with symptomatic moderate to severe hyponatremia (blood sodium ≤130 meq/l) upon admission were reviewed. The study group included patients with one or more hospitalizations with hyponatremia in the year following the first hospitalization with hyponatremia. The control group included patients with a single hospitalization with hyponatremia. Mortality rates were studied one year following the second hospitalization with hyponatremia in the study group and one year following the single hospitalization with hyponatremia in the control group. Regression analysis was used to study the association between recurrent hospitalizations with hyponatremia and 1-year mortality while controlling for demographics, chronic co-morbidities, albumin serum levels, and the number of hospitalizations.The cohort included 431 older adults: 301 (69.8%) women; mean age of 84.6±5.6 years. Overall, 120 (27.8%) patients had recurrent hospitalizations with hyponatremia and 125 (29.0%) patients died within a year. 1-Year mortality rates were higher in patients with recurrent hospitalizations with hyponatremia than in patients with a single hospitalization with hyponatremia (42.5% vs. 23.8%; p0.0001). Regression analysis showed that recurrent hospitalizations with hyponatremia were independently associated with 1-year mortality (odds ratio 1.9; 95% confidence interval 1.1-3.2; p=0.018).Recurrent hospitalizations with hyponatremia in older adults are common and associated with 1-year mortality.

Automated morphological assessment of peripheral blood slides has become an important modality facilitating characterization and quantification of cells in a uniform, fast and robust manner. In this study, we evaluated the morphological diversity in peripheral blood films of 94 chronic lymphocytic leukemia (CLL) patients using the DM1200 CellaVision automated microscopy system. Aberrant lymphocytes and smudge cells were enumerated and correlated with CLL immunophenotype, chromosomal aberrations and prognostic parameters. Herein, we show that the percentages of aberrant and smudge cells was highly variable between patients and did not correlate with each other. Increased aberrant lymphocytes and fewer smudge cells were associated with an atypical immunophenotype including low expression of CD23, higher levels of FMC7 and bright surface levels of CD20. High fraction of aberrant lymphocytes also was associated with trisomy 12. These cells were predominantly of small/medium size, sometimes with cleft nuclei. No correlation was noted between aberrant or smudge cells and clinical stage, CD38, ZA70 or time to first treatment. Taken together, automated morphological analysis of peripheral blood leukocytes emerged as a powerful and robust tool for the quantitative morphological stratification of CLL. Integration of the automated morphological features discriminates between different CLL phenotypes and distinct chromosomal aberrations.

INTRODUCTION Despite major clinical advancements, mantle cell lymphoma (MCL) remains a therapeutic challenge with a considerable number of patients experiencing a dismal course. We sought to map the genomic landscape of MCL at diagnosis and at disease progression. We aimed to identify genomic drivers of aggressive phenotype, resistance and relapse and to characterize the genomic evolution of this disease. METHODS We evaluated the genetic landscape of 210 MCL patients, comparing patients sequenced pretreatment (pre-Tx) to those sequenced at disease progression (POD), including 23 patients with sequential samples. We used CLIA certified targeted sequencing platforms covering 151 genes recognized in lymphoma, including single nucleotide variants (SNV) and copy number alterations (CNA). We compared clinical characteristics, histologic features, IGHV mutational status and genomic profiles between pre-Tx and POD samples. We evaluated the association between genomic features and overall survival (OS) in pre-Tx cases. RESULTS Median age was 65 (range 31-92) with a male predominance (75%, n=172). Patients sequenced at POD were characterized by a higher rate of blastoid histology (31% n=20 vs. 10% n=16, p The most prevalent genomic abnormalities (mut) seen in the entire cohort were ATM (49%, n=111); TP53 (30%, n=69); KMT2D (22%, n=51); CCND1 (16%, n=37); WHSC1 (14%, n=33); and BIRC3 (14%, n=32). Compared to pre-Tx, POD cases had higher rates of TP53mut (49% n=33 vs. 22% n=36, p There were 110 cases with IGHV data (27% n=30 mutated and 73% n=80 unmutated). Mutated IGHV was associated with a higher rate of CCND1mut (37% n=11 vs. 8% n=6, p We evaluated pathological characteristics of the sequenced tumor biopsy. Blastoid histology (219 evaluable) observed in 16% (n=36) was associated with TP53mut (61% n=22 vs. 22% n=41, p=30% (171 evaluable) was associated with TP53mut (38% n=63 vs. 9% n=6, p=60% enriched for CCND1mut (28% n=11 vs. 15% n=10 30%>= Ki67 < 60% and 9% n=6 Ki67= Ki67 < 60% and no cases with Ki67 There were 23 patients with sequential biopsies with a median time difference of 37m (IQR 18-57) between samples. pre-Tx and POD sequential samples had strikingly similar genomic alterations (figure 2). Furthermore, the mutation landscape of these pre-Tx samples was highly similar to that seen in the overall POD samples. For example, TP53mut were observed in 48% of sequential pre-Tx samples, similar to 49% seen in overall POD samples and not to the 22% seen in overall pre-Tx samples. Genomic clustering identified four distinct clusters of patients with ATMmut (BIRC3mut; KMT2Dmut; NOTCH1/CCND1 and None) a cluster of WHSC1mut and a cluster of TP53mut associated with SMARCA4mut (figure 3). Survival analysis was limited to 151 pre-Tx patients and who had completed treatment or managed expectantly (20%, n=30). With a median follow-up of 49m, TP53mut was associated with shorter OS (HR 4.15; 1.9-9.0) corresponding to a 4yOS of 63% vs. 92% in TP53wt (figure 4). In 22 patients (15%) with BIRC3mut, no deaths were observed (p=0.03). Notably, however, the rate of BIRC3mut at POD was similar to pre-Tx and not associated with superior outcomes. CONCLUSIONS Our data suggests that the ultimate outcome of MCL is driven by clones present at diagnosis and in most cases is not the result of clonal evolution. As with former studies TP53mut is the strongest driver of poor outcome. Still a considerable subset of patients fares well. BIRC3mut seemed to confer a good prognosis, however this observation needs to be validated in a dedicated study as the rate of BIRC3mut was similar between pre-Tx and POD and not associated with a better prognosis in the latter. We identify several genomic clusters associated with targetable mutations. Figure Disclosures Kumar: Seattle Genetics: Research Funding. Straus:Hope Funds for Cancer Research: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Honoraria; Elsevier (PracticeUpdate): Consultancy, Honoraria. Palomba:Hemedicus: Other: Immediate Family Member, Speakers Bureau ; Merck & Co Inc.: Other: Immediate Family Member, Consultancy (includes expert testimony); Seres Therapeutics: Other: Immediate Family Member, Equity Ownership and Membership on an entity's Board of Directors or advisory committees; STRAXIMM: Other: Immediate Family Member, Membership on an entity's Board of Directors or advisory committees; Kite Pharmaceuticals: Other: Immediate Family Member, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Noble Insights: Consultancy; Evelo: Other: Immediate family member, Equity Ownership; MSK (IP for Juno and Seres): Other: Immediate Family Member, Patents & Royalties - describe: intellectual property rights . Noy:Janssen: Consultancy; Medscape: Honoraria; Prime Oncology: Honoraria; NIH: Research Funding; Pharamcyclics: Research Funding; Raphael Pharma: Research Funding. Horwitz:Forty-Seven: Research Funding; Kura: Consultancy; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Infinity/Verastem: Consultancy, Research Funding; Astex: Consultancy; Innate Pharma: Consultancy; Celgene: Consultancy, Research Funding; Infinity/Verastem: Consultancy, Research Funding; Kyowa Hakko Kirin: Consultancy; Mundipharma: Consultancy; Aileron: Research Funding; Millennium/Takeda: Consultancy, Research Funding; Astex: Consultancy; Astex: Consultancy; Trillium: Research Funding; Trillium: Research Funding; Infinity/Verastem: Consultancy, Research Funding; Innate Pharma: Consultancy; Kura: Consultancy; Millennium/Takeda: Consultancy, Research Funding; Millennium/Takeda: Consultancy, Research Funding; Innate Pharma: Consultancy; Seattle Genetics: Consultancy, Research Funding; Mundipharma: Consultancy; Aileron: Research Funding; ADCT Therapeutics: Research Funding; Forty-Seven: Research Funding; Affimed: Consultancy; Miragen: Consultancy; Celgene: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Aileron: Research Funding; ADCT Therapeutics: Research Funding; ADCT Therapeutics: Research Funding; Kura: Consultancy; Celgene: Consultancy, Research Funding; Miragen: Consultancy; Seattle Genetics: Consultancy, Research Funding; Aileron: Research Funding; Infinity/Verastem: Consultancy, Research Funding; Mundipharma: Consultancy; Miragen: Consultancy; Affimed: Consultancy; Affimed: Consultancy; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astex: Consultancy; Kura: Consultancy; Kyowa Hakko Kirin: Consultancy; Kyowa Hakko Kirin: Consultancy; Miragen: Consultancy; Innate Pharma: Consultancy; Forty-Seven: Research Funding; ADCT Therapeutics: Research Funding; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Mundipharma: Consultancy; Forty-Seven: Research Funding; Affimed: Consultancy; Trillium: Research Funding; Portola: Consultancy; Trillium: Research Funding; Portola: Consultancy; Kyowa Hakko Kirin: Consultancy; Millennium/Takeda: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Portola: Consultancy; Portola: Consultancy; Seattle Genetics: Consultancy, Research Funding; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Moskowitz:miRagen Therapeutics Inc: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Cell Medica: Consultancy; Merck: Research Funding; Cell Medica: Consultancy; ADC Therapeutics: Consultancy; Erytech Pharma: Consultancy; ADC Therapeutics: Consultancy; Erytech Pharma: Consultancy; ADC Therapeutics: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Incyte: Research Funding; Cell Medica: Consultancy; Cell Medica: Consultancy; Cell Medica: Consultancy; Cell Medica: Consultancy; Cell Medica: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; ADC Therapeutics: Consultancy; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Cell Medica: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Takeda Pharmaceuticals: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; Merck: Research Funding; Takeda Pharmaceuticals: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Incyte: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Incyte: Research Funding; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; ADC Therapeutics: Consultancy; Takeda Pharmaceuticals: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Merck: Research Funding; Incyte: Research Funding; Cell Medica: Consultancy; ADC Therapeutics: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Cell Medica: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Incyte: Research Funding; Incyte: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Incyte: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; Incyte: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Cell Medica: Consultancy; Cell Medica: Consultancy; Cell Medica: Consultancy; Incyte: Research Funding; Incyte: Research Funding; Takeda Pharmaceuticals: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; Cell Medica: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Erytech Pharma: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Incyte: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Merck: Research Funding; Merck: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Merck: Research Funding; Merck: Research Funding; Erytech Pharma: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Merck: Research Funding; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Erytech Pharma: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Erytech Pharma: Consultancy; Takeda Pharmaceuticals: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Incyte: Research Funding; Erytech Pharma: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; ADC Therapeutics: Consultancy; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Cell Medica: Consultancy; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; Takeda Pharmaceuticals: Consultancy. Matasar:Bayer: Other: Travel, accommodation, expenses; Janssen: Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Honoraria, Research Funding; Daiichi Sankyo: Consultancy; Seattle Genetics: Consultancy, Honoraria, Other: Travel, accomodation, expenses, Research Funding; Rocket Medical: Consultancy, Research Funding; Teva: Consultancy; Merck: Consultancy, Equity Ownership; Juno Therapeutics: Consultancy; Roche: Consultancy, Honoraria, Other: Travel, accommodation, expenses , Research Funding; Bayer: Consultancy, Honoraria, Other; Genentech, Inc.: Consultancy, Honoraria, Other: Travel, accommodation, expenses , Research Funding. Batlevi:Juno Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees. von Keudell:Genentech: Consultancy; Bayer: Consultancy; Pharmacyclics: Consultancy; Pharmacyclics: Consultancy; Genentech: Consultancy; Bayer: Consultancy. Dogan:Takeda: Consultancy; Novartis: Consultancy; Celgene: Consultancy; Seattle Genetics: Consultancy; Corvus Pharmaceuticals: Consultancy; Roche: Consultancy, Research Funding. Younes:Janssen: Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Abbvie: Honoraria; Takeda: Honoraria; Pharmacyclics: Research Funding; AstraZeneca: Research Funding; Genentech: Research Funding; HCM: Consultancy; BMS: Research Funding; Syndax: Research Funding; Merck: Honoraria, Research Funding; Curis: Honoraria, Research Funding; Epizyme: Consultancy, Honoraria; Xynomics: Consultancy; Celgene: Consultancy, Honoraria; Biopath: Consultancy. Zelenetz:Genentech/Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees; DAVA Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics/AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics/AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Beigene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees; Beigene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; DAVA Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech/Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Introduction: Gemcitabine/oxaliplatin (GemOx), with or without rituximab, is a frequently used treatment of relapsed or refractory (r/r) aggressive B-cell non-Hodgkin lymphoma (B-NHL), and is NCCN compendium-listed for both transplant-eligible and ineligible patients based upon results in small phase II clinical trials. Increasingly, GemOx is being accepted as a comparator arm for clinical trials in these populations. However, there is a paucity of observational data describing the effectiveness of R-GemOx in the treatment of r/r aggressive B-cell lymphoma. Methods: We conducted a retrospective analysis of the use of the GemOx regimen (with or without rituximab) in patients with r/r aggressive B-NHL at Memorial Sloan Kettering Cancer Center between January 2007 and January 2018, with a data cutoff of July 1, 2019. Data were extracted from the electronic medical record. Eligible diagnoses included diffuse large B-cell lymphoma and its subtypes (DLBCL); high-grade B-cell lymphomas (HGBL); transformed indolent B-cell lymphoma (tNHL) and grade 3B follicular lymphoma (FL3B). The primary objective of the study was to evaluate the activity of GemOx-based treatment in this patient population, as measured by overall response rate (ORR), complete response (CR) rate, progression-free survival (PFS), and overall survival (OS). CR was defined by a qualitatively negative 18-FDG-PET scan following completion of GemOx. PFS was defined as the time from start of therapy to disease progression or death, censoring patients at the time of initiation of any consolidative treatment. Similarly, OS was defined as the time from the start of GemOx until death or loss to follow-up. Results: Data were collected for 140 consecutive patients that received GemOx with (n=81) or without (n=59) rituximab in the treatment of a qualifying diagnosis (Table 1). Those treated had a median age at initiation of therapy of 69 (range, 30-92) and were predominantly male (58%). The median number of prior lines of therapy was 1 (range, 1-7), and the majority (97%) had received prior rituximab; few had received either prior autotransplant (11%) or allotransplant (1%). Regarding treatment delivered, the median number of cycles of therapy was 2 (range 1-12) with a mode of 2 (n=44, 31%). The ORR was 26% (n=37) with a CR rate of 15% (n=21). When evaluated by diagnosis, the ORR was 22% (n=19/88) in DLBCL, 40% (n=4/10) in HGBL, 35% (n=14/40) in tNHL, and 0% (n=0/2) in FL3B. Of the patients that responded to GemOx, 11 were successfully bridged to transplant (7 auto; 4 allo); two of those who went on to allotransplant had previously undergone autotransplant. Additionally, 3 patients went on to subsequently receive CAR-T therapy. Assessing the cohort overall, with a median follow-up of 48.1 months, PFS was only 1.4 months (95% CI: 1.3, 1.8), and median OS was 7.8 months (95% CI: 5.5, 12.0) (Figure 1). OS was longest for patients with tNHL at 10.2 months followed by DLBCL (7.5), HGBL (6.8) and FL3B (4.1) (Figure 2). Patients that received GemOx without rituximab in the setting of rituximab-refractory disease had a median OS of 4.1 months, less than that of 10.7 months for those receiving rituximab (p=0.052). However, there was no difference observed in PFS by inclusion of rituximab (1.6 months vs. 1.3 months, p=0.166). Patients with disease that was primary refractory following first-line therapy had a median OS of 4.5 months from initiation of GemOx, less than that of 10.8 months for patients that had achieved complete remission with first-line therapy (p=0.024). Patients that received GemOx as second-line therapy did not have a statistically significantly higher ORR (31% vs. 19%), OS (10.8 vs. 6.0 months), or PFS (1.7 vs, 1.4 months; all p=NS). In the subset of patients with DLBCL, there was again no significant difference in ORR (21% vs. 22%, p=NS), OS (8.5 vs. 6.1 months), or PFS (1.6 vs. 1.4 months; all p=NS). Conclusion: Despite compendium listing for both transplant-eligible and ineligible patients, and despite its adoption as a comparator arm in current and planned trials in r/r DLBCL, the real-world activity of GemOx with or without rituximab in the treatment of relapsed or refractory aggressive B-cell lymphoma is poor. Ongoing analysis is being conducted to seek clinical and histopathologic features associated with improved outcomes with GemOx. Disclosures Batlevi: Juno Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Colbourn:GILD: Other: Stock; LLY: Other: Stock; JNJ: Other: Stock; SGEN: Other: Stock; MRK: Other: Stock; SNY: Other: Stock; BIIB: Other: Stock; ABBV: Other: Stock; CELG: Other: Stock. Horwitz:Infinity/Verastem: Consultancy, Research Funding; Trillium: Research Funding; Infinity/Verastem: Consultancy, Research Funding; Kyowa Hakko Kirin: Consultancy; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium/Takeda: Consultancy, Research Funding; Mundipharma: Consultancy; Portola: Consultancy; Celgene: Consultancy, Research Funding; Portola: Consultancy; Innate Pharma: Consultancy; Seattle Genetics: Consultancy, Research Funding; Infinity/Verastem: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Kura: Consultancy; Aileron: Research Funding; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Forty-Seven: Research Funding; Celgene: Consultancy, Research Funding; ADCT Therapeutics: Research Funding; Kyowa Hakko Kirin: Consultancy; ADCT Therapeutics: Research Funding; Astex: Consultancy; Mundipharma: Consultancy; Miragen: Consultancy; Portola: Consultancy; Mundipharma: Consultancy; Seattle Genetics: Consultancy, Research Funding; Innate Pharma: Consultancy; Innate Pharma: Consultancy; Affimed: Consultancy; Affimed: Consultancy; Innate Pharma: Consultancy; Aileron: Research Funding; Kyowa Hakko Kirin: Consultancy; Forty-Seven: Research Funding; Kura: Consultancy; Millennium/Takeda: Consultancy, Research Funding; Forty-Seven: Research Funding; ADCT Therapeutics: Research Funding; Seattle Genetics: Consultancy, Research Funding; Astex: Consultancy; Aileron: Research Funding; Portola: Consultancy; Astex: Consultancy; Celgene: Consultancy, Research Funding; Trillium: Research Funding; Miragen: Consultancy; Trillium: Research Funding; Kyowa Hakko Kirin: Consultancy; Mundipharma: Consultancy; Millennium/Takeda: Consultancy, Research Funding; Trillium: Research Funding; Aileron: Research Funding; Affimed: Consultancy; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium/Takeda: Consultancy, Research Funding; Astex: Consultancy; Miragen: Consultancy; Miragen: Consultancy; Affimed: Consultancy; Celgene: Consultancy, Research Funding; Kura: Consultancy; Kura: Consultancy; ADCT Therapeutics: Research Funding; Forty-Seven: Research Funding; Infinity/Verastem: Consultancy, Research Funding. von Keudell:Bayer: Consultancy; Genentech: Consultancy; Pharmacyclics: Consultancy; Pharmacyclics: Consultancy; Bayer: Consultancy; Genentech: Consultancy. Kumar:Seattle Genetics: Research Funding. Noy:Medscape: Honoraria; Prime Oncology: Honoraria; NIH: Research Funding; Janssen: Consultancy; Pharamcyclics: Research Funding; Raphael Pharma: Research Funding. Palomba:Merck & Co Inc.: Other: Immediate Family Member, Consultancy (includes expert testimony); Seres Therapeutics: Other: Immediate Family Member, Equity Ownership and Membership on an entity's Board of Directors or advisory committees; Hemedicus: Other: Immediate Family Member, Speakers Bureau ; Kite Pharmaceuticals: Other: Immediate Family Member, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; STRAXIMM: Other: Immediate Family Member, Membership on an entity's Board of Directors or advisory committees; Noble Insights: Consultancy; Evelo: Other: Immediate family member, Equity Ownership; MSK (IP for Juno and Seres): Other: Immediate Family Member, Patents & Royalties - describe: intellectual property rights . Rodriguez-Rivera:Memorial Sloan Kettering Cancer Center: Employment. Sauter:Juno Therapeutics: Consultancy, Research Funding; Sanofi-Genzyme: Consultancy, Research Funding; Spectrum Pharmaceuticals: Consultancy; GSK: Consultancy; Novartis: Consultancy; Genmab: Consultancy; Precision Biosciences: Consultancy; Kite/Gilead: Consultancy; Celgene: Consultancy. Straus:Seattle Genetics: Consultancy, Honoraria; Hope Funds for Cancer Research: Membership on an entity's Board of Directors or advisory committees; Elsevier (PracticeUpdate): Consultancy, Honoraria. Vardhana:ADC Therapeutics: Consultancy; Rheos Pharmaceuticals: Honoraria; Agios Pharmaceuticals: Honoraria. Younes:Roche: Consultancy, Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Curis: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Abbvie: Honoraria; Takeda: Honoraria; Pharmacyclics: Research Funding; AstraZeneca: Research Funding; Genentech: Research Funding; Biopath: Consultancy; Xynomics: Consultancy; Epizyme: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; HCM: Consultancy; BMS: Research Funding; Syndax: Research Funding. Zelenetz:Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Beigene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech/Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; DAVA Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; DAVA Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech/Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Beigene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics/AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics/AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees. Matasar:GlaxoSmithKline: Honoraria, Research Funding; Daiichi Sankyo: Consultancy; Juno Therapeutics: Consultancy; Teva: Consultancy; Rocket Medical: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Other: Travel, accomodation, expenses, Research Funding; Janssen: Honoraria, Research Funding; Bayer: Other: Travel, accommodation, expenses; Genentech, Inc.: Consultancy, Honoraria, Other: Travel, accommodation, expenses , Research Funding; Bayer: Consultancy, Honoraria, Other; Roche: Consultancy, Honoraria, Other: Travel, accommodation, expenses , Research Funding; Merck: Consultancy, Equity Ownership; Pharmacyclics: Consultancy, Honoraria, Research Funding.

Bronchial-associated lymphoid tissue lymphoma (BALT) is a rare subtype of extranodal marginal zone lymphoma that is often diagnosed incidentally, without symptoms or compromise of pulmonary function. It usually progresses slowly . However, in contrast to other subtypes, oncologists may feel compelled to initiate treatment at the time of diagnosis, because of concern for progression resulting in irreversible lung damage. It is unclear, in many cases, whether the morbidity of treatment would be greater than that of the lymphoma itself. To address this issue, we compared patients with BALT initially managed expectantly to those receiving front-line treatment. A retrospective single institutional review of newly diagnosed primary BALT treated at Memorial Sloan Kettering Cancer Center between 1995 and 2017 was performed. Patients with evidence of extra-thoracic disease (except for isolated bone marrow involvement) and those with concurrent malignancy were excluded. Expectant management (active surveillance) was defined as a management plan of observation rather than treatment at diagnosis and at least 3 months of follow-up from completion of all diagnostic workup until initiation of subsequent therapy if necessary. Surgical Resection referred to complete resection of all disease lesions for diagnosis. Overall (OS) and event-free survival (EFS) were determined from diagnosis as time to treatment or death of any cause, among patients with surgical resection, active surveillance, and time-to-next treatment among those treated at diagnosis with systemic immuno/chemo-immunotherapy (systemic treatment). Medical records of 200 consecutive patients with MZL involving the lung were reviewed, and 127 met the criteria for primary BALT. Of the remaining 73 patients, 25 had concurrent malignancy and 48 had extra-thoracic disease. Nearly half (48%; n=61) had initial active surveillance, 40% (n=51) surgical resection, and 12% (n=15) systemic treatment at diagnosis. Median age was 65 years (IQR 54-74). Females predominated (64%, n=81). Rates of current or prior smoking (61%; n=78) and of autoimmune/connective tissue disease (20%; n=26) were high. Nearly half of the cases with concurrent cancers were primary carcinomas of the lung (n=11). Most patients presented with a single lesion (76%; n=96) with median size 2.5 cm (IQR 1.6-3.6) and without lobar predominance. A minority (5.5%; n=7) presented with thoracic nodal involvement, while 25% (n=32) presented with pleural involvement or effusion. Overall, few patients had bone marrow involvement, B symptoms, cytopenia or elevated LDH. With a median follow-up of over 60 months (IQR 25 - 107), estimated 6-year OS for the entire cohort was 92% (0.86, 0.98). Notably, high survival rates were found in all 3 groups (Figure 1). Estimated 6-year survivals were 88% (0.77,1.00) for patients with disease remaining after biopsy managed by active surveillance, 100% with initial complete diagnostic excision (surgical resection) and 78% (0.59, 1.00) for those with initial systemic treatment who likely had extensive initial disease and/or symptoms. Active surveillance patients had a shorter EFS than surgical resection patients but not than systemic treatment patients (6yEFS 63% vs. 74% vs. 57%, respectively; p=0.006). Estimated 6-year EFS (survival without treatment) of patients initially managed by active surveillance was 63% (95% CI 0.5-0.8), and 12% required only a single line of therapy (6yEFS2 85%; 95% CI 0.7-1.0). In conclusion, BALT is an indolent disease in most patients that can be managed expectantly and may not require therapy for many years. Slightly better survival in patients with fully resected disease could represent a selection bias of earlier detection or biologically less active disease. Initial observation of the pace of the disease in asymptomatic patients may clarify the minority who require treatment and avoid or delay its potential risks in the majority. Figure 1 Disclosures Rajeeve: ASH-HONORS Grant: Research Funding. Zelenetz:Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees; DAVA Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; DAVA Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics/AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Beigene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Beigene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech/Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech/Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics/AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees. Palomba:STRAXIMM: Membership on an entity's Board of Directors or advisory committees; Evelo: Equity Ownership; Kite Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Seres Therapeutics: Equity Ownership; Noble Insights: Consultancy; Merck & Co Inc.: Consultancy; MSK (IP for Juno and Seres): Patents & Royalties; Hemedicus: Speakers Bureau; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees. Moskowitz:Pharmacyclics: Research Funding; Seattle Genetics, Inc.: Consultancy, Research Funding; Merck: Consultancy, Research Funding; ADC Therapeutics: Research Funding; Celgene: Consultancy; Genentech: Consultancy, Research Funding. Noy:Medscape: Honoraria; Prime Oncology: Honoraria; NIH: Research Funding; Janssen: Consultancy; Pharamcyclics: Research Funding; Raphael Pharma: Research Funding. Horwitz:Mundipharma: Consultancy; Celgene: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Innate Pharma: Consultancy; Portola: Consultancy; Celgene: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Affimed: Consultancy; Affimed: Consultancy; Kyowa Hakko Kirin: Consultancy; Millennium/Takeda: Consultancy, Research Funding; Millennium/Takeda: Consultancy, Research Funding; Infinity/Verastem: Consultancy, Research Funding; Kura: Consultancy; Forty-Seven: Research Funding; Trillium: Research Funding; Mundipharma: Consultancy; Affimed: Consultancy; Kyowa Hakko Kirin: Consultancy; ADCT Therapeutics: Research Funding; Miragen: Consultancy; Trillium: Research Funding; Forty-Seven: Research Funding; Infinity/Verastem: Consultancy, Research Funding; Astex: Consultancy; Portola: Consultancy; Mundipharma: Consultancy; Mundipharma: Consultancy; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astex: Consultancy; Kyowa Hakko Kirin: Consultancy; Seattle Genetics: Consultancy, Research Funding; ADCT Therapeutics: Research Funding; Millennium/Takeda: Consultancy, Research Funding; Astex: Consultancy; Portola: Consultancy; Kura: Consultancy; Innate Pharma: Consultancy; Kura: Consultancy; Miragen: Consultancy; Seattle Genetics: Consultancy, Research Funding; Aileron: Research Funding; ADCT Therapeutics: Research Funding; ADCT Therapeutics: Research Funding; Infinity/Verastem: Consultancy, Research Funding; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kyowa Hakko Kirin: Consultancy; Miragen: Consultancy; Portola: Consultancy; Trillium: Research Funding; Seattle Genetics: Consultancy, Research Funding; Aileron: Research Funding; Forty-Seven: Research Funding; Aileron: Research Funding; Kura: Consultancy; Aileron: Research Funding; Miragen: Consultancy; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Affimed: Consultancy; Innate Pharma: Consultancy; Astex: Consultancy; Forty-Seven: Research Funding; Innate Pharma: Consultancy; Millennium/Takeda: Consultancy, Research Funding; Infinity/Verastem: Consultancy, Research Funding; Trillium: Research Funding. Moskowitz:Incyte: Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Incyte: Research Funding; Merck: Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Incyte: Research Funding; Incyte: Research Funding; Cell Medica: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Incyte: Research Funding; Cell Medica: Consultancy; Cell Medica: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Erytech Pharma: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Cell Medica: Consultancy; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Erytech Pharma: Consultancy; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Merck: Research Funding; Merck: Research Funding; Erytech Pharma: Consultancy; ADC Therapeutics: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; Takeda Pharmaceuticals: Consultancy; Incyte: Research Funding; Cell Medica: Consultancy; Incyte: Research Funding; Cell Medica: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; Cell Medica: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Erytech Pharma: Consultancy; Incyte: Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Cell Medica: Consultancy; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; Incyte: Research Funding; Incyte: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Erytech Pharma: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Incyte: Research Funding; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; ADC Therapeutics: Consultancy; Cell Medica: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Merck: Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; ADC Therapeutics: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Erytech Pharma: Consultancy; ADC Therapeutics: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; Cell Medica: Consultancy; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Incyte: Research Funding; Takeda Pharmaceuticals: Consultancy; Cell Medica: Consultancy; Cell Medica: Consultancy; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Erytech Pharma: Consultancy; Takeda Pharmaceuticals: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Cell Medica: Consultancy; Cell Medica: Consultancy; Cell Medica: Consultancy; Takeda Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Merck: Research Funding; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding. Matasar:GlaxoSmithKline: Honoraria, Research Funding; Teva: Consultancy; Juno Therapeutics: Consultancy; Merck: Consultancy, Equity Ownership; Roche: Consultancy, Honoraria, Other: Travel, accommodation, expenses , Research Funding; Genentech, Inc.: Consultancy, Honoraria, Other: Travel, accommodation, expenses , Research Funding; Bayer: Consultancy, Honoraria, Other; Daiichi Sankyo: Consultancy; Seattle Genetics: Consultancy, Honoraria, Other: Travel, accomodation, expenses, Research Funding; Rocket Medical: Consultancy, Research Funding; Bayer: Other: Travel, accommodation, expenses; Janssen: Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding. Kumar:Seattle Genetics: Research Funding. von Keudell:Bayer: Consultancy; Bayer: Consultancy; Pharmacyclics: Consultancy; Pharmacyclics: Consultancy; Genentech: Consultancy; Genentech: Consultancy. Batlevi:Juno Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Younes:Syndax: Research Funding; BMS: Research Funding; Celgene: Consultancy, Honoraria; AstraZeneca: Research Funding; Pharmacyclics: Research Funding; Takeda: Honoraria; Abbvie: Honoraria; HCM: Consultancy; Biopath: Consultancy; Xynomics: Consultancy; Epizyme: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding; Merck: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Curis: Honoraria, Research Funding; Genentech: Research Funding. Straus:Seattle Genetics: Consultancy, Honoraria; Elsevier (PracticeUpdate): Consultancy, Honoraria; Hope Funds for Cancer Research: Membership on an entity's Board of Directors or advisory committees.

Introduction:Programmed death-1 (PD-1) inhibitors are highly active in relapsed and refractory (RR) classical Hodgkin lymphoma (cHL), however their role as part of second-line therapy (SLT) for cHL is largely unexplored. The standard approach following front-line treatment failure is SLT, aimed to achieve complete response (CR), followed by consolidation with high dose therapy and autologous stem cell transplant (HDT/ASCT). There is no one standard SLT and options include platinum-containing regimens, gemcitabine-containing regimens and more recently brentuximab vedotin (BV)-containing regimens. Due to the increasing use of BV in the front-line setting, development of SLT regimens that are both highly effective and BV-sparing are needed. In this phase II study, we aimed to establish the safety and efficacy of SLT with the PD-1 inhibitor, pembrolizumab, combined with the outpatient-administered salvage regimen, GVD (gemcitabine, vinorelbine, liposomal doxorubicin). Methods: Transplant eligible patients (pts) with RR cHL following failure of 1-line of therapy are eligible. Treatment consists of 2 to 4 cycles of pembrolizumab (200mg IV, day 1), gemcitabine (1000mg/m2 IV, days 1 and 8), vinorelbine (20mg/m2 IV, days 1 and 8) and liposomal doxorubicin (15mg/m2, days 1 and 8), given on 21-day cycles. Response is assessed by PET after 2 and 4 cycles. Pts who achieve CR by PET (Deauville ≤3) after 2 or 4 cycles proceed to HDT/ASCT. An initial safety assessment for the first 6 treated pts was completed before continuing further enrollment. We report here the results of the safety assessment and the first stage of a Simon 2-stage design. Results:To date, 18 out of a planned 39 pts enrolled; 14 completed the first 2 cycles of treatment and underwent the first response assessment. Characteristics for the 14 evaluable pts are shown in the table. In brief, median age is 36 (range 21-43), 4 (29%) have primary refractory disease and 9 (64%) relapsed within the first year of initial treatment. No dose limiting toxicities were observed during the safety assessment and no significant adverse events were observed to date. Of the 30 cycles administered, 5 (17%) cycles were delayed due to treatment related adverse events which included grade 3 rash (3%) and grade 3 liver function test abnormalities (13%). Among the 14 evaluable pts, 13 (93%) achieved CR after 2 cycles of treatment and 1 achieved partial response. To date, 3 pts are proceeding to HDT/ASCT and 11 pts completed HDT/ASCT following 2 (n=10) or 4 (n=1) cycles of treatment. Median follow-up post HDT/ASCT is 4 mos (range 0.3-8.8 mos) and all pts remain in remission to date. Conclusion:Early trial results suggest that pembrolizumab-GVD is a highly effective and well-tolerated regimen that can efficiently bridge pts with RR cHL to HDT/ASCT. Efficacy criteria for stage one of the Simon 2-stage design was met and enrollment continues to better characterize CR rate and tolerability. Disclosures Moskowitz: ADC Therapeutics: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Erytech Pharma: Consultancy; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Cell Medica: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Cell Medica: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; ADC Therapeutics: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Merck: Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; ADC Therapeutics: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Merck: Research Funding; Cell Medica: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Merck: Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; ADC Therapeutics: Consultancy; Erytech Pharma: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Erytech Pharma: Consultancy; ADC Therapeutics: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Erytech Pharma: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; ADC Therapeutics: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Takeda Pharmaceuticals: Consultancy; Cell Medica: Consultancy; Erytech Pharma: Consultancy; Cell Medica: Consultancy; Cell Medica: Consultancy; Incyte: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; Incyte: Research Funding; Cell Medica: Consultancy; Incyte: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Incyte: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; ADC Therapeutics: Consultancy; Takeda Pharmaceuticals: Consultancy; Merck: Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Erytech Pharma: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Erytech Pharma: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Incyte: Research Funding; Erytech Pharma: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; ADC Therapeutics: Consultancy; Cell Medica: Consultancy; Merck: Research Funding; Takeda Pharmaceuticals: Consultancy; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Incyte: Research Funding; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; Erytech Pharma: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Merck: Research Funding; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; Incyte: Research Funding; Cell Medica: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Cell Medica: Consultancy; Incyte: Research Funding; Cell Medica: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Cell Medica: Consultancy; Takeda Pharmaceuticals: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; ADC Therapeutics: Consultancy; Takeda Pharmaceuticals: Consultancy; Incyte: Research Funding; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; Cell Medica: Consultancy; Cell Medica: Consultancy; Cell Medica: Consultancy; Takeda Pharmaceuticals: Consultancy; Merck: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; ADC Therapeutics: Consultancy; Incyte: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Incyte: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Merck: Research Funding; Erytech Pharma: Consultancy; Incyte: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Merck: Research Funding; Takeda Pharmaceuticals: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; ADC Therapeutics: Consultancy; Erytech Pharma: Consultancy. Shah:Amgen: Research Funding; Janssen: Research Funding. Kumar:Seattle Genetics: Research Funding. Batlevi:Juno Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Straus:Seattle Genetics: Consultancy, Honoraria; Elsevier (PracticeUpdate): Consultancy, Honoraria; Hope Funds for Cancer Research: Membership on an entity's Board of Directors or advisory committees. Rodriguez-Rivera:Memorial Sloan Kettering Cancer Center: Employment. Colbourn:ABBV: Other: Stock; CELG: Other: Stock; BIIB: Other: Stock; SGEN: Other: Stock; JNJ: Other: Stock; LLY: Other: Stock; GILD: Other: Stock; MRK: Other: Stock; SNY: Other: Stock. Horwitz:Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kura: Consultancy; Celgene: Consultancy, Research Funding; Infinity/Verastem: Consultancy, Research Funding; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium/Takeda: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Affimed: Consultancy; Aileron: Research Funding; Trillium: Research Funding; ADCT Therapeutics: Research Funding; Affimed: Consultancy; Astex: Consultancy; Infinity/Verastem: Consultancy, Research Funding; Trillium: Research Funding; Astex: Consultancy; Aileron: Research Funding; Seattle Genetics: Consultancy, Research Funding; Millennium/Takeda: Consultancy, Research Funding; Kyowa Hakko Kirin: Consultancy; Infinity/Verastem: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Forty-Seven: Research Funding; Celgene: Consultancy, Research Funding; ADCT Therapeutics: Research Funding; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Consultancy, Research Funding; Portola: Consultancy; Forty-Seven: Research Funding; Aileron: Research Funding; Seattle Genetics: Consultancy, Research Funding; Aileron: Research Funding; Forty-Seven: Research Funding; Trillium: Research Funding; ADCT Therapeutics: Research Funding; Astex: Consultancy; Trillium: Research Funding; Forty-Seven: Research Funding; Affimed: Consultancy; ADCT Therapeutics: Research Funding; Affimed: Consultancy; Astex: Consultancy; Innate Pharma: Consultancy; Innate Pharma: Consultancy; Kyowa Hakko Kirin: Consultancy; Mundipharma: Consultancy; Innate Pharma: Consultancy; Infinity/Verastem: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Kura: Consultancy; Kyowa Hakko Kirin: Consultancy; Kura: Consultancy; Kyowa Hakko Kirin: Consultancy; Miragen: Consultancy; Millennium/Takeda: Consultancy, Research Funding; Millennium/Takeda: Consultancy, Research Funding; Mundipharma: Consultancy; Miragen: Consultancy; Miragen: Consultancy; Portola: Consultancy; Mundipharma: Consultancy; Miragen: Consultancy; Kura: Consultancy; Innate Pharma: Consultancy; Mundipharma: Consultancy; Portola: Consultancy; Portola: Consultancy. Palomba:Hemedicus: Other: Immediate Family Member, Speakers Bureau ; Merck & Co Inc.: Other: Immediate Family Member, Consultancy (includes expert testimony); Seres Therapeutics: Other: Immediate Family Member, Equity Ownership and Membership on an entity's Board of Directors or advisory committees; STRAXIMM: Other: Immediate Family Member, Membership on an entity's Board of Directors or advisory committees; Kite Pharmaceuticals: Other: Immediate Family Member, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Noble Insights: Consultancy; Evelo: Other: Immediate family member, Equity Ownership; MSK (IP for Juno and Seres): Other: Immediate Family Member, Patents & Royalties - describe: intellectual property rights . Noy:Prime Oncology: Honoraria; NIH: Research Funding; Janssen: Consultancy; Medscape: Honoraria; Pharamcyclics: Research Funding; Raphael Pharma: Research Funding. Matasar:Genentech, Inc.: Consultancy, Honoraria, Other: Travel, accommodation, expenses , Research Funding; Daiichi Sankyo: Consultancy; Bayer: Consultancy, Honoraria, Other; Roche: Consultancy, Honoraria, Other: Travel, accommodation, expenses , Research Funding; Merck: Consultancy, Equity Ownership; Juno Therapeutics: Consultancy; Teva: Consultancy; Rocket Medical: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Other: Travel, accomodation, expenses, Research Funding; GlaxoSmithKline: Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; Bayer: Other: Travel, accommodation, expenses; Janssen: Honoraria, Research Funding. Vardhana:Rheos Pharmaceuticals: Honoraria; ADC Therapeutics: Consultancy; Agios Pharmaceuticals: Honoraria. von Keudell:Bayer: Consultancy; Pharmacyclics: Consultancy; Pharmacyclics: Consultancy; Genentech: Consultancy; Genentech: Consultancy; Bayer: Consultancy. Younes:Roche: Consultancy, Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Curis: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Abbvie: Honoraria; Takeda: Honoraria; Pharmacyclics: Research Funding; AstraZeneca: Research Funding; Genentech: Research Funding; Biopath: Consultancy; Xynomics: Consultancy; Epizyme: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; HCM: Consultancy; BMS: Research Funding; Syndax: Research Funding. Zelenetz:Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics/AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; DAVA Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech/Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees; Beigene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees; Beigene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech/Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; DAVA Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics/AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees. Moskowitz:Genentech: Consultancy, Research Funding; Seattle Genetics, Inc.: Consultancy, Research Funding; Celgene: Consultancy; Pharmacyclics: Research Funding; ADC Therapeutics: Research Funding; Merck: Consultancy, Research Funding. OffLabel Disclosure: Pembrolizumab is not approved for second-line use for classical Hodgkin lymphoma.

Introduction: Central nervous system (CNS) relapse in patients with diffuse large B-cell lymphoma (DLBCL) is an uncommon yet often fatal complication with an overall survival (OS) of less than 6 months. According to the clinical risk model CNS-IPI, patients with 4-6 risk factors have a 2-year rate of CNS relapse of 10%. Involvement of certain extranodal sites such as testes or breast also confers increased risk, even with low-CNS-IPI. In high-risk patients, CNS prophylaxis is usually recommended, although the optimal regimen remains unclear. In this study, we examined the efficacy of different regimens on preventing CNS relapse in high-risk patients. Methods: We reviewed all newly diagnosed patients (pts) with DLBCL at Memorial Sloan Kettering Cancer Center from 2001 to 2017 treated with frontline rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone (RCHOP) or RCHOP-like regimens. Patients with primary mediastinal lymphoma, HIV-positive or known CNS disease at diagnosis were excluded. High risk for CNS (HR-CNS) relapse was defined by high-CNS IPI (4-6 risk factors) or low-CNS IPI with testicular, breast, kidney/adrenal and/or bone marrow (BM) involvement. CNS prophylaxis was administered per physician preference. Results: We identified 2002 pts treated with RCHOP or RCHOP-like regimens. Among them, 569 (28%) were classified as HR-CNS relapse and were included in the study. Median age was 68 years (range 21-91) and 290 (51%) were male. The high-risk extranodal sites were: BM, n=118 (20%); kidney/adrenal, n=106 (18%); testes, n=51 (9%) and breast, n=47 (8%). 158 pts (28%) had more than 2 extranodal sites. Cell or origin determined by Hans algorithm was non-germinal center (GCB) (non-GCB) in 40%, GCB in 39% and missing in 21%. 284 pts (50%) received CNS prophylaxis: intrathecal (IT) methotrexate (MTX) and/or IT cytarabine, n= 245 (86%); or high-dose intravenous MTX (HD-MTX), n=40 (14%). Pts's characteristics are shown in Table 1. After a median follow-up of 5.6 years, CNS relapse was observed in 36 out of 569 pts with HR-CNS relapse (5-year risk 6.4%), of whom 14 (39%) had received prophylaxis (IT, n=12; HD-MTX, n=2). The risk of CNS relapse at 5 years in pts who received IT prophylaxis was 5.6% compared with 5.2% in pts who received intravenous HD-MTX. Pts with HR-CNS relapse who did not receive prophylaxis had a 5-year risk for CNS relapse of 7.6% (p=0.34) (Figure 1). Pts with non-GCB phenotype had a higher risk of CNS relapse compared with patients with GCB subtype (5-year risk of 10% vs. 2%) (p=0.03). The median time to CNS relapse was 9 months (range 6-110 months). Pts who received prophylaxis, (either IT or HD-MTX), relapsed later than patients who did not receive prophylaxis, with a median time to relapse of 19 months (range 7-55) vs. 8 months (range 6 to 110), respectively. The risk of CNS relapse at 1 year was lower for pts who received prophylaxis (IT or HD-MTX) compared to pts who did not, 1% vs. 3.2%, risk ratio (RR) 0.30 (95% CI; 0.07,0.68). However, over time the risk of CNS relapse became similar between prophylaxis and non-prophylaxis groups, with a 5-year risk of 5.8% vs. 7.6% (RR 0.76, CI 95%; 0.37, 1.55), respectively (Figure 2). CNS relapses were confined to the CNS (n=26, 72%) or included systemic relapsed in addition to CNS (n=10, 28%). CNS sites of relapse are detailed in table 2. Overall survival (OS) in patients with CNS relapse was worse than in pts who relapsed outside the CNS, with a 2-year OS of 24% (95% CI, 12%-40%) vs. 40% (95% CI, 31%-48%), respectively (p=0.002). Conclusion: In the era of chemoimmunochemotherapy, CNS prophylaxis tended to delay relapse rather than effectively preventing it. Although we did not detect differences in the efficacy between intrathecal and intravenous HD-MTX, larger studies are needed to better compare the efficacy of these two preventive modalities. Disclosures Noy: Medscape: Honoraria; Janssen: Consultancy; Prime Oncology: Honoraria; NIH: Research Funding; Pharamcyclics: Research Funding; Raphael Pharma: Research Funding. Horwitz:Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Mundipharma: Consultancy; Affimed: Consultancy; ADCT Therapeutics: Research Funding; Astex: Consultancy; Innate Pharma: Consultancy; Seattle Genetics: Consultancy, Research Funding; Miragen: Consultancy; Miragen: Consultancy; Kura: Consultancy; Kura: Consultancy; Innate Pharma: Consultancy; Infinity/Verastem: Consultancy, Research Funding; Trillium: Research Funding; Celgene: Consultancy, Research Funding; Portola: Consultancy; Millennium/Takeda: Consultancy, Research Funding; Millennium/Takeda: Consultancy, Research Funding; Portola: Consultancy; Trillium: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy; Infinity/Verastem: Consultancy, Research Funding; Kura: Consultancy; Miragen: Consultancy; Affimed: Consultancy; Millennium/Takeda: Consultancy, Research Funding; Aileron: Research Funding; Seattle Genetics: Consultancy, Research Funding; Mundipharma: Consultancy; Celgene: Consultancy, Research Funding; Kyowa Hakko Kirin: Consultancy; Seattle Genetics: Consultancy, Research Funding; Innate Pharma: Consultancy; Trillium: Research Funding; Forty-Seven: Research Funding; Aileron: Research Funding; Aileron: Research Funding; Astex: Consultancy; Forty-Seven: Research Funding; Miragen: Consultancy; Infinity/Verastem: Consultancy, Research Funding; Forty-Seven: Research Funding; Infinity/Verastem: Consultancy, Research Funding; Kyowa Hakko Kirin: Consultancy; Mundipharma: Consultancy; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astex: Consultancy; Trillium: Research Funding; Celgene: Consultancy, Research Funding; ADCT Therapeutics: Research Funding; Kura: Consultancy; Millennium/Takeda: Consultancy, Research Funding; Affimed: Consultancy; Portola: Consultancy; Seattle Genetics: Consultancy, Research Funding; Aileron: Research Funding; Forty-Seven: Research Funding; Innate Pharma: Consultancy; Kyowa Hakko Kirin: Consultancy; Portola: Consultancy; Affimed: Consultancy; ADCT Therapeutics: Research Funding; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADCT Therapeutics: Research Funding; Mundipharma: Consultancy; Kyowa Hakko Kirin: Consultancy. Palomba:Hemedicus: Other: Immediate Family Member, Speakers Bureau ; Merck & Co Inc.: Other: Immediate Family Member, Consultancy (includes expert testimony); Seres Therapeutics: Other: Immediate Family Member, Equity Ownership and Membership on an entity's Board of Directors or advisory committees; STRAXIMM: Other: Immediate Family Member, Membership on an entity's Board of Directors or advisory committees; Kite Pharmaceuticals: Other: Immediate Family Member, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Noble Insights: Consultancy; Evelo: Other: Immediate family member, Equity Ownership; MSK (IP for Juno and Seres): Other: Immediate Family Member, Patents & Royalties - describe: intellectual property rights . Matasar:Juno Therapeutics: Consultancy; Merck: Consultancy, Equity Ownership; Genentech, Inc.: Consultancy, Honoraria, Other: Travel, accommodation, expenses , Research Funding; Bayer: Consultancy, Honoraria, Other; Roche: Consultancy, Honoraria, Other: Travel, accommodation, expenses , Research Funding; Bayer: Other: Travel, accommodation, expenses; Janssen: Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; Teva: Consultancy; Rocket Medical: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Other: Travel, accomodation, expenses, Research Funding; Daiichi Sankyo: Consultancy; GlaxoSmithKline: Honoraria, Research Funding. Straus:Hope Funds for Cancer Research: Membership on an entity's Board of Directors or advisory committees; Hope Funds for Cancer Research: Membership on an entity's Board of Directors or advisory committees; Elsevier (PracticeUpdate): Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Hope Funds for Cancer Research: Membership on an entity's Board of Directors or advisory committees. Batlevi:Juno Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Moskowitz:Incyte: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; ADC Therapeutics: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Erytech Pharma: Consultancy; ADC Therapeutics: Consultancy; Erytech Pharma: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Merck: Research Funding; Incyte: Research Funding; Incyte: Research Funding; Erytech Pharma: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Merck: Research Funding; Cell Medica: Consultancy; Erytech Pharma: Consultancy; Incyte: Research Funding; Takeda Pharmaceuticals: Consultancy; Cell Medica: Consultancy; Takeda Pharmaceuticals: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Incyte: Research Funding; Cell Medica: Consultancy; Cell Medica: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Cell Medica: Consultancy; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; Incyte: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; Takeda Pharmaceuticals: Consultancy; Incyte: Research Funding; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Cell Medica: Consultancy; Takeda Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Merck: Research Funding; Merck: Research Funding; Merck: Research Funding; Erytech Pharma: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Merck: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Cell Medica: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; ADC Therapeutics: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Merck: Research Funding; Cell Medica: Consultancy; Cell Medica: Consultancy; Cell Medica: Consultancy; Incyte: Research Funding; Incyte: Research Funding; ADC Therapeutics: Consultancy; Incyte: Research Funding; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Erytech Pharma: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Erytech Pharma: Consultancy; Cell Medica: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Takeda Pharmaceuticals: Consultancy; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Erytech Pharma: Consultancy; ADC Therapeutics: Consultancy; Cell Medica: Consultancy; ADC Therapeutics: Consultancy; Erytech Pharma: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; ADC Therapeutics: Consultancy; Erytech Pharma: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Erytech Pharma: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Incyte: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Merck: Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Cell Medica: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Merck: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; ADC Therapeutics: Consultancy; Erytech Pharma: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Incyte: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Erytech Pharma: Consultancy; Takeda Pharmaceuticals: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Incyte: Research Funding; Cell Medica: Consultancy; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Cell Medica: Consultancy; Takeda Pharmaceuticals: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Incyte: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding. von Keudell:Bayer: Consultancy; Genentech: Consultancy; Pharmacyclics: Consultancy; Pharmacyclics: Consultancy; Genentech: Consultancy; Bayer: Consultancy. Dogan:Roche: Consultancy, Research Funding; Corvus Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy; Celgene: Consultancy; Takeda: Consultancy; Novartis: Consultancy. Zelenetz:DAVA Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; DAVA Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics/AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics/AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; DAVA Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech/Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics/AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Beigene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech/Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech/Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics/AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics/AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics/AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; DAVA Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech/Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Beigene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech/Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees. Younes:BMS: Research Funding; AstraZeneca: Research Funding; Genentech: Research Funding; Roche: Consultancy, Honoraria, Research Funding; Xynomics: Consultancy; Syndax: Research Funding; Epizyme: Consultancy, Honoraria; HCM: Consultancy; Celgene: Consultancy, Honoraria; Takeda: Honoraria; Abbvie: Honoraria; Merck: Honoraria, Research Funding; Curis: Honoraria, Research Funding; Pharmacyclics: Research Funding; Janssen: Honoraria, Research Funding; Biopath: Consultancy.

Introduction Indolent lymphomas, such as follicular lymphoma (FL) and marginal zone lymphoma (MZL), are highly radiosensitive and often respond to very low dose radiation therapy (VLDRT). We investigated the outcomes of patients treated with 4 Gy from a large, contemporary, real world cohort, and a subset of potentially curable (PC) patients with early stage (Ann Arbor stage I-II) disease and no prior therapy to the targeted lesion(s) before VLDRT. Methods We analyzed 256 treated sites from 210 consecutive adult patients (Table 1) with FL or MZL who were treated with VLDRT of 2 Gy x 2 fractions between 2006 and 2019 at our comprehensive cancer center. Initial overall response rate (ORR) was defined as complete response (CR) or partial response (PR) using Lugano criteria at first follow-up post-RT (median: 2.1 months; Interquartile range: 1.6-2.5 months). Stable disease (SD) or progressive disease (PD) at 2 months post-RT were considered local failure (LF). Freedom from local failure (FFLF) was defined as time from VLDRT to LF. Patients were censored at the start of a subsequent line of therapy if the VLDRT-treated site had not progressed. Event-free survival (EFS) was calculated per patient from VLDRT to LF or distant PD. FFLF and EFS were estimated using Kaplan-Meier and compared using log-rank. Results Initial ORR for all sites was 88% (CR: 65%, PR: 23%); 12% (n=31) were initially nonresponding (SD: 7%, PD: 5%). Thirteen sites with initial PR/SD/PD received additional RT (median: 30 Gy) within 6 months of VLDRT and had subsequent CR (n=7), PR (n=5), and PD (n=1). With median follow-up of 21 months, 2-year FFLF was 70%. Initial response to VLDRT was prognostic with a significantly improved 2-year FFLF for sites with CR (n=166) compared to those with PR (n=58) (88% vs. 66%, p In the subset of PC patients (n=50), there were 52 lesions. The histology of these sites was split between FL (n=21, 41%), MZL (n=22, 42%) and indolent lymphoma not further classified (n=9, 17%). The majority of the lesions in the PC cohort were extranodal (n=42, 81%). Median follow-up was 1 year with a 1-year EFS of 82%. Of the 12 PC patients who progressed post VLDRT, two thirds developed a distant site of recurrence outside of the VLDRT field. In field recurrence alone was rare (n=4). Diffuse large B cell lymphoma transformation after VLDRT was rare in the PC (n=0) and overall (n=6, 3%) cohort; all cases of transformed DLBCL were diagnosed out of VLDRT field. Conclusions Overall, patients with FL and MZL treated with only 4 Gy have excellent initial ORR. Upfront CR is prognostic of improved disease control. Early evaluation following VLDRT identifies nonresponders who may benefit from additional RT and spares many patients from higher doses of RT with durable local control. Our analysis of PC patients suggests that VLDRT does not compromise the standard curative RT approach. Disclosures No relevant conflicts of interest to declare.

Background After-hours out-of-hospital phone consultations require physicians to make decisions based on information provided by a nurse over the phone. Methods We conducted a simulation study to evaluate physicians’ actions following communication of key information. 22 nurses were asked to call physicians with six cases based on the six most common reasons for after-hours phone calls. We evaluated physicians’ actions following the communication of key clinical information: A situation cue described a patient's problem (eg, confusion). A background cue described a specific clinical finding regarding the cause of the problem (eg, patient's sodium is low). For each cue we defined a list of indicators, based on the medical literature, to ascertain whether physicians acted upon the provided information (which was defined as addressing at least one of the indicators). Results A total of 108 phone consultations (containing 88 situation and 93 background cues) were analysed. Situation cues were communicated in 90% (79/88) of the calls and background cues in 33% (31/93). Physician acted upon the provided information in 57% (45/79) and 48% (15/31) of the communicated situation and background cues, respectively. When the background cues were not communicated, physicians asked questions expected to elicit the cue in 12% of the cases. Responding to the situation cue was associated with longer conversations and active inquiry by the physician. Conclusions After-hours phone calls are error prone. Both nurse communication and physician decision-making are problematic. Efforts to improve patient safety in this setting must address both communication and decision-making.

The purpose of this study was to evaluate electrophysiologic study (EPS) in risk stratification of relative indications for pacemaker implantation (PMI) after transcatheter aortic valve implantation (TAVI).We reviewed files of all patients who had a left bundle branch block (LBBB) and underwent EPS after TAVI between 3/2009 and 5/2015. The indications for EPS were new-onset LBBB and the presence of an old or a new-onset LBBB associated with either PR prolongation after TAVI (∆PR20 ms) or with "slow" atrial fibrillation (100/min). Pacemakers were implanted when significant infranodal disease was demonstrated. The control group comprised of 55 consecutive patients who underwent TAVI and had an indication for an EPS per our definitions. These patients were discharged without further intervention. All patients were followed during 1 year for the composite endpoint of mortality or PMI after hospital discharge.Indications for EPS were new LBBB (n = 8, 30.8%), new LBBB + ∆PR20 ms (n = 9, 34.6%), baseline LBBB + ∆PR20 ms (n = 7, 26.9%) and new LBBB + slow AF100 bpm (n = 2, 7.7%). Multilevel conduction disturbances involving the AV node (n = 19, 73.1%), the His (n = 3, 11.5%), and the infra-His system (n = 4, 15.4%) were found. Post discharge, there were 5 (9%) deaths and 3 (5.5%) PMI in the control group compared to none in the EPS group corresponding to event-free survival of 85 and 100%, respectively (p = 0.04).Patients with LBBB with or without ∆PR20 ms are at a higher risk of mortality and late PMI at 1-year follow-up. EPS can be used to safely identify patients in whom a PMI is needed.

Follicular lymphoma (FL) is the 2nd most common type of lymphoma diagnosed in the Western World. Bone marrow (BM) involvement is an adverse prognostic factor in FL, routinely assessed by an arbitrary biopsy of the iliac crest. This study was aimed to investigate the role of positron emission tomography/computed tomography (PET/CT) in identifying BM involvement by FL. In this retrospective, single-center study we reviewed the records of consecutive patients with FL at diagnosis or relapse who underwent staging/restaging workup visual assessment of BM uptake was categorized as either normal, diffusely increased, or focally increased. Quantitative BM fluorine-18-fluro-deoxyglucose (FDG) uptake was measured using mean standardized uptake value (BM-SUVmean). The diagnosis of BM involvement was based on either BM histological findings or disappearance of increased uptake at end-treatment PET/CT in patients who responded to treatment. Sixty eight cases with FL were included. Sixteen (23.5%) had BM involvement, 13 (19.1%) had a biopsy proven involvement, and 3 (4.4%) had a negative BM biopsy, but increased medullary uptake that normalized post-treatment. BM FDG uptake in these patients was diffuse in 8 (50%) and focal in 8 (50%). Focal increased uptake was indicative of BM involvement; however, diffuse uptake was associated with 17 false positive cases (32.7%). Overall, visual assessment of BM involvement had a negative predictive value (NPV) of 100% and a positive predictive value (PPV) of 48.5%. On a quantitative assessment, BM-SUVmean was significantly higher in patients with BM involvement (SUVmean of 3.7 [1.7–6] vs 1.4 [0.4–2.65], P 2.7 had a PPV of 100% for BM involvement (sensitivity of 68%), while BM-SUVmean

Botezomib-based induction is highly effective for the treatment of newly diagnosed multiple myeloma (NDMM). We investigated the outcomes of NDMM patients who failed to respond to bortezomib-based induction in a 'real-life' clinical setting. In a cohort of 295 consecutive NDMM patients in 3 medical centers, 74 (25%) failed to achieve at least partial response after 4 induction cycles, and were classified as non-responsive. Compared to induction responders, they were older, more frequently anemic, had a higher incidence of del17p and ISS-3, and a worse performance status. In multivariable analysis, bortezomib-based induction failure occurred in 25% of patients and was the strongest independent factor predicting mortality with a 5-fold hazard ratio (95% CI 1.44-8.68). Three-year overall survival in responsive vs. non-responsive patients were 76% vs. 53%, respectively (p

Objective To present a framework for combining implicit knowledge acquisition from multiple experts with machine learning and to evaluate this framework in the context of anemia alerts. Materials and Methods Five internal medicine residents reviewed 18 anemia alerts, while ‘talking aloud’. They identified features that were reviewed by two or more physicians to determine appropriate alert level, etiology and treatment recommendation. Based on these features, data were extracted from 100 randomly-selected anemia cases for a training set and an additional 82 cases for a test set. Two staff internists assigned an alert level, etiology and treatment recommendation before and after reviewing the entire electronic medical record. The training set of 118 cases (100 plus 18) and the test set of 82 cases were explored using RIDOR and JRip algorithms. Results The feature set was sufficient to assess 93% of anemia cases (intraclass correlation for alert level before and after review of the records by internists 1 and 2 were 0.92 and 0.95, respectively). High-precision classifiers were constructed to identify low-level alerts (precision p=0.87, recall R=0.4), iron deficiency (p=1.0, R=0.73), and anemia associated with kidney disease (p=0.87, R=0.77). Discussion It was possible to identify low-level alerts and several conditions commonly associated with chronic anemia. This approach may reduce the number of clinically unimportant alerts. The study was limited to anemia alerts. Furthermore, clinicians were aware of the study hypotheses potentially biasing their evaluation. Conclusion Implicit knowledge acquisition, collaborative filtering and machine learning were combined automatically to induce clinically meaningful and precise decision rules.