Horwitz, Steven M.

Abstract Since the publication of the Revised European-American Classification of Lymphoid Neoplasms in 1994, subsequent updates of the classification of lymphoid neoplasms have been generated through iterative international efforts to achieve broad consensus among hematopathologists, geneticists, molecular scientists, and clinicians. Significant progress has recently been made in the characterization of malignancies of the immune system, with many new insights provided by genomic studies. They have led to this proposal. We have followed the same process that was successfully used for the third and fourth editions of the World Health Organization Classification of Hematologic Neoplasms. The definition, recommended studies, and criteria for the diagnosis of many entities have been extensively refined. Some categories considered provisional have now been upgraded to definite entities. Terminology for some diseases has been revised to adapt nomenclature to the current knowledge of their biology, but these modifications have been restricted to well-justified situations. Major findings from recent genomic studies have impacted the conceptual framework and diagnostic criteria for many disease entities. These changes will have an impact on optimal clinical management. The conclusions of this work are summarized in this report as the proposed International Consensus Classification of mature lymphoid, histiocytic, and dendritic cell tumors.

Peripheral T-cell lymphomas (PTCLs) are a heterogeneous group of lymphoproliferative disorders arising from mature T cells, accounting for about 10% of non-Hodgkin lymphomas. PTCL-not otherwise specified is the most common subtype, followed by angioimmunoblastic T-cell lymphoma, anaplastic large cell lymphoma, anaplastic lymphoma kinase–positive, anaplastic large cell lymphoma, anaplastic lymphoma kinase–negative, and enteropathy-associated T-cell lymphoma. This discussion section focuses on the diagnosis and treatment of PTCLs as outlined in the NCCN Guidelines for T-Cell Lymphomas.

Abstract Background: Despite many treatment options, multiple myeloma (MM) remains largely incurable with poor outcomes among patients who progress after treatment with a protease inhibitor, immunomodulatory imide drugs (IMiDs), and/or an anti-CD38 antibody. Multiple targeted therapies have been developed for different subtypes of non-Hodgkin lymphoma (NHL); however, these therapies are typically not curative for patients with relapsed/refractory (R/R) disease. IMiDs are a standard of care for treatment of MM and have shown activity in some NHL subtypes. However, given that many patients treated with these agents frequently develop disease progression, an unmet need remains. CFT7455 is a next-generation IKZF1/3 degrader, which is more potent and catalytically active than other approved agents targeting the cereblon E3 ligase complex that degrade IKZF1/3. CFT7455 is orally bioavailable and selective for IKZF1 (Ikaros) and IKZF3 (Aiolos). Depletion of these targets from malignant B cells result in tumor cell death, and depletion from the tumor microenvironment results in T-cell activation. In i n vitro and in vivo models of MM and NHL, including anaplastic large cell lymphoma, diffuse large B-cell lymphoma, and mantle cell lymphoma (MCL), CFT7455 demonstrated greater activity than other agents in similar classes. These results provided rationale for a first-in-human, phase 1 study to evaluate CFT7455. Study Design: This is an open-label, multicenter, phase 1 clinical trial with dose escalation and dose expansion phases. The dose escalation phase, beginning with a starting dose of 50 mcg daily, may include single-participant cohorts at initial dose levels, after which 3-6 patients are enrolled per cohort using a Bayesian logistic regression model. After initial exploration of single-agent CFT7455 in a mixed cohort of patients with R/R MM or select NHLs, dose escalation is split to perform dose determination in R/R MM separate NHL. Once a safe dose of CFT7455 in R/R MM is determined, the combination of CFT7455 with dexamethasone will be explored in R/R MM. CFT7455 is dosed orally in 28-day cycles, on a 21-day on, 7-day off schedule, until disease progression or intolerable toxicity. Expansion cohorts of single-agent CFT7455 and CFT7455 plus dexamethasone in R/R MM, and single-agent CFT7455 for peripheral T-cell lymphoma and MCL are planned. Primary objectives include: safety and tolerability, randomized phase 2 dose (RP2D)/maximum tolerated dose (MTD) of CFT7455, and estimation of antitumor activity of CFT7455. Secondary objectives include assessment of pharmacokinetics. Exploratory objectives include characterization of target engagement and IKZF1/3 degradation and assessing the immunomodulatory effects of CFT7455. For MM patients, key inclusion criteria include histologically/cytologically-confirmed MM that is R/R. Patients must not be candidates for regimens known to provide clinical benefit, defined as having received ≥3 prior anti-myeloma regimens including ≥2 consecutive cycles of lenalidomide, pomalidomide, a proteasome inhibitor, a glucocorticoid, and an anti-CD38 antibody. Key exclusion criteria include the presence of central nervous system malignancy, recent venous thromboembolism or inability to undergo its prophylaxis. Plasma cell leukemia is excluded. For NHL patients, key inclusion criteria include histologically/cytologically-confirmed NHL that is R/R. Patients mustn't be candidates for regimens known to provide clinical benefit, defined as the requisite prior lines of therapy according to an indication-specific basis. Key exclusion criteria include the presence of central nervous system malignancy, recent venous thromboembolism or inability to undergo its prophylaxis. Several lymphoma subtypes less likely to benefit are excluded (eg, Richter transformation, Burkitt lymphoma, Sezary syndrome, and lymphoblastic lymphoma). Approximately 164 patients at approximately 13 US sites will be enrolled. This trial is registered with clinicaltrials.gov as NCT04756726, enrollment is ongoing. Disclosures Berdeja: Legend Biotech: Consultancy; Incyte: Research Funding; Ichnos Sciences: Research Funding; Genentech: Research Funding; GlaxoSmithKline: Research Funding; Lilly: Research Funding; SecuraBio: Consultancy; EMD Serono: Research Funding; Janssen: Consultancy, Research Funding; Bluebird bio: Consultancy, Research Funding; Amgen: Research Funding; Astex Pharmaceuticals: Research Funding; Kite Pharma: Consultancy; CRISPR Therapeutics: Consultancy, Research Funding; Celularity: Research Funding; Celgene: Consultancy, Research Funding; Poseida: Research Funding; Acetylon: Research Funding; Teva: Research Funding; Novartis: Research Funding; BMS: Consultancy, Research Funding; Sanofi: Research Funding; Abbvie: Research Funding; Takeda: Consultancy. Ailawadhi: GSK: Consultancy, Research Funding; Sanofi: Consultancy; Cellectar: Research Funding; Janssen: Consultancy, Research Funding; Xencor: Research Funding; Beigene: Consultancy; Karyopharm: Consultancy; BMS: Consultancy, Research Funding; Ascentage: Research Funding; Pharmacyclics: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; AbbVie: Consultancy; Takeda: Consultancy; Genentech: Consultancy; Medimmune: Research Funding. Horwitz: Millennium /Takeda: Consultancy, Research Funding; Kura Oncology: Consultancy; Janssen: Consultancy; Tubulis: Consultancy; Myeloid Therapeutics: Consultancy; Affimed: Research Funding; Aileron: Research Funding; Vividion Therapeutics: Consultancy; ONO Pharmaceuticals: Consultancy; Celgene: Research Funding; Acrotech Biopharma: Consultancy; Daiichi Sankyo: Research Funding; Forty Seven, Inc.: Research Funding; Trillium Therapeutics: Consultancy, Research Funding; C4 Therapeutics: Consultancy; Kyowa Hakko Kirin: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; SecuraBio: Consultancy, Research Funding; Shoreline Biosciences, Inc.: Consultancy; ADC Therapeutics: Consultancy, Research Funding; Verastem: Research Funding. Matous: Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Mehta-Shah: C4 Therapeutics: Consultancy; Kiowa Hakko Kirin: Consultancy; Karyopharm: Consultancy; Ono Pharmaceuticals: Consultancy; Secura Bio: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; AstraZeneca: Research Funding; Bristol Myers Squibb: Research Funding; Celgene: Research Funding; Innate Pharmaceuticals: Research Funding; Roche/Genentech: Research Funding; Corvus Pharmaceuticals: Research Funding; Verastem: Research Funding. Martin: GlaxoSmithKline: Consultancy; Sanofi: Research Funding; Oncopeptides: Consultancy; Amgen: Research Funding; Janssen: Research Funding. Richardson: Takeda: Consultancy, Research Funding; Sanofi: Consultancy; Secura Bio: Consultancy; Oncopeptides: Consultancy, Research Funding; GlaxoSmithKline: Consultancy; Regeneron: Consultancy; Protocol Intelligence: Consultancy; AstraZeneca: Consultancy; Karyopharm: Consultancy, Research Funding; Celgene/BMS: Consultancy, Research Funding; AbbVie: Consultancy; Janssen: Consultancy; Jazz Pharmaceuticals: Consultancy, Research Funding. Richard: Karyopharm, Janssen: Honoraria. Bhutani: Sanofi: Consultancy; Amgen, BMS, Takeda: Speakers Bureau; Janssen, MedImmune, Takeda, Celgene, BMS, Cerecor, Celularity: Research Funding. Yee: Takeda: Consultancy; Adaptive: Consultancy; Karyopharm: Consultancy; Bristol Myers Squibb: Consultancy; Oncopeptides: Consultancy; GSK: Consultancy; Amgen: Consultancy; Sanofi: Consultancy; Janssen: Consultancy. Palmer: C4 Therapeutics: Current Employment. Gorman: C4 Therapeutics: Current Employment. Schoenborn-Kellenberger: C4 Therapeutics: Current Employment. Bilic: C4 Therapeutics: Current Employment. Crystal: C4 Therapeutics: Current Employment, Current equity holder in publicly-traded company. Mahler: C4 Therapeutics: Current Employment, Current equity holder in publicly-traded company. Lonial: Merck: Honoraria; Abbvie: Consultancy, Honoraria; BMS/Celgene: Consultancy, Honoraria, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Research Funding; AMGEN: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Research Funding.

Abstract Introduction Central nervous system (CNS) relapse (CNSr) in patients with aggressive non-Hodgkin lymphoma (NHL) occurs uncommonly (estimated incidence 5%) but carries a high morbidity and mortality. Studies have identified risk factors for CNSr such as high tumor burden and extranodal (EN) disease. However, most focus on B-cell NHL with minimal data in T-cell lymphomas (TCL), which are significantly less common and more heterogenous. The few small series of CNSr in TCL report a median overall survival (OS) less than 3 months (mo) with incidence ranging from 2.6-9%. To better define CNSr in TCL, we performed a multi-institutional retrospective analysis of TCL patients with CNSr and herein describe clinicopathologic characteristics and treatment of CNSr. Methods We performed a retrospective observational study using data from 9 US academic centers with IRB approval at individual sites. We included adult patients diagnosed with a mature T-cell neoplasm as per the 2016 WHO classification between 1/1/2009-1/1/2019, who were found to have CNSr at any time after initial diagnosis, and collected patient, disease, and treatment characteristics at time of initial diagnosis as well as at CNSr. Patients with a diagnosis of a precursor T-cell malignancy or with CNS disease identified at initial TCL diagnosis (TCLd) and/or prior to first-line systemic treatment were excluded. Results In this analysis, we report the outcomes of 75 patients (male n=45, female n=30). At TCLd, the median age was 59 years (range 20-81), and 61% of patients (n=46) had an IPI score of at least 3, 92% (n=69) had EN involvement with 37% (n=28) involving at least 2 EN sites, and 59% (n=44) had BM involvement. The most common pathologic diagnoses were peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS; 24%, n=18), angioimmunoblastic T-cell lymphoma (AITL; 17%, n=13), adult T-cell leukemia/lymphoma (ATLL; 17%, n=13), and mycosis fungoides (MF; 12%, n=9) (Figure 1A). First-line systemic therapy for TCL included anthracyclines for 72% (n=54). Autologous and allogenic transplants were performed prior to CNSr in 12% (n=9) and 8% (n=6) of patients, respectively. Prior to CNSr, 48% (n=36) had non-CNS relapse. Some form of CNS prophylaxis was used during initial systemic lymphoma therapy in 24% of patients (n=18), predominantly intrathecal methotrexate (IT MTX; n=16). Median time from TCLd to CNSr was 8.5mo, though this was significantly longer in MF (46.8mo [range 17.5-187.7]) versus PTCL, NOS (7.6mo [range 1.1-58.4], P=0.0002), AITL (21.2mo [range 2.0-61.6, P=0.008), and ATLL (7.3mo [range 0.7-46.4], P=0.0005) (Figure 1B). CNSr developed within 6mo of TCLd in 31% of patients (n=23) and within 12mo in 57% (n=43). Symptoms related to CNSr occurred in 71% of patients (n=53). CNSr patterns were 61% leptomeningeal (n=46), 21% parenchymal (n=16), and 17% both (n=13) with no significant survival difference between leptomeningeal or parenchymal disease alone (HR 1.45, 95% CI 0.78-2.70, P=0.28). Concomitant systemic relapse was observed in 59% of patients (n=44). The most common CNS-directed therapy for CNSr was IT MTX (56%; n=42), though multiple different IT and/or systemic regimens were used. Patients received a median of 1 line of CNS-directed treatment (range 0-5). The overall response rate to initial CNS directed treatment was 32% (16% CR, 16% PR). Median follow up after CNSr was 40.7mo. At last follow up, 83% had died (n=62). Median OS after CNSr was 4.6mo (range 0.1-68.7) (Figure 1C). Those with ATLL had the shortest median OS after CNSr (2.7mo) versus 6.3mo in MF (HR 3.69, 95% CI 1.44-9.42, P=0.005), 6.5mo in AITL (HR 2.16, 95% CI 0.92-5.06, P=0.054), and 4.8mo in PTCL, NOS (HR 1.49, 95% CI 0.70-3.19, P=0.27) (Figure 1D). The most common cause of death was progressive lymphoma (77%; n=48). Conclusions This is to our knowledge the largest series of CNSr in TCL to date. Most CNSr occurred within 12mo, though CNSr occurred later in patients with MF. Although the prognosis after CNSr was generally poor, we found that median OS in CNSr was longer than previously reported, perhaps reflecting more effective treatments for CNS and systemic relapse, inclusion of MF, or lead time bias. Further analysis of the impact of different treatment strategies and outcomes in CNSr was limited by the small sample size and heterogeneity within our cohort, and future analyses in a larger cohort should focus on factors associated with outcomes. Figure 1 Figure 1. Disclosures Horwitz: 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; Affimed: 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. Bennani: Purdue Pharma: Other: Advisory Board; Daichii Sankyo Inc: Other: Advisory Board; Kyowa Kirin: Other: Advisory Board; Vividion: Other: Advisory Board; Kymera: Other: Advisory Board; Verastem: Other: Advisory Board. Chavez: AstraZeneca: Research Funding; ADC Therapeutics: Consultancy, Research Funding; Merk: Research Funding; MorphoSys, AstraZeneca, BeiGene, Genentech, Kite, a Gilead Company, and Epizyme: Speakers Bureau; MorphoSys, Bayer, Karyopharm, Kite, a Gilead Company, Novartis, Janssen, AbbVie, TeneoBio, and Pfizer: Consultancy; BMS: Speakers Bureau. Sokol: Dren Bio: Membership on an entity's Board of Directors or advisory committees; Kyowa-Kirin: Membership on an entity's Board of Directors or advisory committees. Saeed: Nektar Therapeutics: Consultancy, Other: research investigator; MEI Pharma Inc: Consultancy, Other: investigator; Celgene Corporation: Consultancy, Other: investigator; MorphoSys AG: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb Company: Consultancy; sano-aventis U.S.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen Pharmaceutica Products, LP: Consultancy, Other: investigator; Kite Pharma: Consultancy, Other: investigator; Other-TG therapeutics: Consultancy, Other: investigator; Other-Epizyme, Inc.: Consultancy; Other-Secura Bio, Inc.: Consultancy; Seattle Genetics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees. Mehta-Shah: Kiowa Hakko Kirin: Consultancy; C4 Therapeutics: Consultancy; Verastem: Research Funding; Karyopharm: Consultancy; Ono Pharmaceuticals: Consultancy; Secura Bio: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; AstraZeneca: Research Funding; Bristol Myers Squibb: Research Funding; Celgene: Research Funding; Innate Pharmaceuticals: Research Funding; Roche/Genentech: Research Funding; Corvus Pharmaceuticals: Research Funding. Olszewski: TG Therapeutics: Research Funding; PrecisionBio: Research Funding; Celldex Therapeutics: Research Funding; Acrotech Pharma: Research Funding; Genentech, Inc.: Research Funding; Genmab: Research Funding. Allen: Epizyme: Consultancy; MorphoSys: Consultancy; ADC Therapeutics: Consultancy; Secure Bio: Consultancy; Kyowa Kirin: Consultancy. Gerson: Abbvie: Consultancy; Kite: Consultancy; TG Therapeutics: Consultancy; Pharmacyclics: Consultancy. Landsburg: Triphase: Research Funding; Takeda: Research Funding; Curis: Research Funding; ADCT: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Other: DSMB member; Incyte: Membership on an entity's Board of Directors or advisory committees; Morphosys: Membership on an entity's Board of Directors or advisory committees. Schuster: Adaptive Biotechnologies: Research Funding; Pharmacyclics: Research Funding; Merck: Research Funding; Genentech/Roche: Consultancy, Research Funding; Tessa Theraputics: Consultancy; Juno Theraputics: Consultancy, Research Funding; Loxo Oncology: Consultancy; BeiGene: Consultancy; Alimera Sciences: Consultancy; Acerta Pharma/AstraZeneca: Consultancy; Abbvie: Consultancy, Research Funding; Nordic Nanovector: Consultancy; Novartis: Consultancy, Honoraria, Patents & Royalties, Research Funding; Incyte: Research Funding; TG Theraputics: Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Svoboda: Atara: Consultancy; Adaptive: Consultancy, Research Funding; Astra Zeneca: Consultancy, Research Funding; Imbrium: Consultancy; Pharmacyclics: Consultancy, Research Funding; Genmab: Consultancy; Merck: Research Funding; Incyte: Research Funding; BMS: Consultancy, Research Funding; TG: Research Funding; Seattle Genetics: Consultancy, Research Funding. Barta: Kyowa Kirin: Honoraria; Acrotech: Honoraria; Daiichi Sankyo: Honoraria; Seagen: Honoraria.

Abstract Purpose: TTI-621 (SIRPα-IgG1 Fc) is a novel checkpoint inhibitor that activates antitumor activity by blocking the CD47 “don't eat me” signal. This first-in-human phase I study (NCT02663518) evaluated the safety and activity of TTI-621 in relapsed/refractory (R/R) hematologic malignancies. Patients and Methods: Patients with R/R lymphoma received escalating weekly intravenous TTI-621 to determine the maximum tolerated dose (MTD). During expansion, patients with various malignancies received weekly single-agent TTI-621 at the MTD; TTI-621 was combined with rituximab in patients with B-cell non-Hodgkin lymphoma (B-NHL) or with nivolumab in patients with Hodgkin lymphoma. The primary endpoint was the incidence/severity of adverse events (AEs). Secondary endpoint included overall response rate (ORR). Results: Overall, 164 patients received TTI-621: 18 in escalation and 146 in expansion (rituximab combination, n = 35 and nivolumab combination, n = 4). On the basis of transient grade 4 thrombocytopenia, the MTD was determined as 0.2 mg/kg; 0.1 mg/kg was evaluated in combination cohorts. AEs included infusion-related reactions, thrombocytopenia, chills, and fatigue. Thrombocytopenia (20%, grade ≥3) was reversible between doses and not associated with bleeding. Transient thrombocytopenia that determined the initial MTD may not have been dose limiting. The ORR for all patients was 13%. The ORR was 29% (2/7) for diffuse large B-cell lymphoma (DLBCL) and 25% (8/32) for T-cell NHL (T-NHL) with TTI-621 monotherapy and was 21% (5/24) for DLBCL with TTI-621 plus rituximab. Further dose optimization is ongoing. Conclusions: TTI-621 was well-tolerated and demonstrated activity as monotherapy in patients with R/R B-NHL and T-NHL and combined with rituximab in patients with R/R B-NHL.

Hepatosplenic T-cell lymphoma (HSTCL) is a rare subtype of T-cell lymphoma associated with an aggressive clinical course and a worse prognosis. HSTCL develops in the setting of chronic immune suppression or immune dysregulation in up to 20% of cases and is most often characterized by spleen, liver, and bone marrow involvement. Diagnosis and management of HSTCL pose significant challenges given the rarity of the disease along with the absence of lymphadenopathy and poor outcome with conventional chemotherapy regimens. These Guidelines Insights focus on the diagnosis and treatment of HSTCL as outlined in the NCCN Guidelines for T-Cell Lymphomas.

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.

Abstract Background: MDX-060 is a fully human anti-CD30 IgG1k monoclonal antibody that induces Fc-receptor mediated killing of CD30 expressing cell lines and inhibits the growth of CD30-expressing tumor cells in a murine xenograft model. We previously reported data from the first 31 patients in a Phase I/II open-label, dose escalation study of MDX-060 in patients with relapsed or refractory CD30+ lymphomas. The purpose of the study is to determine the safety and tolerability profile of the drug, and to preliminarily evaluate efficacy. We now update the findings of this study, including reporting the results of a new higher dose cohort. Methods: In the Phase I portion of the study, MDX-060 was administered intravenously at dose levels of 0.1, 1, 5, or 10 mg/kg weekly for 4 weeks to cohorts of 3–6 patients. In the Phase II portion of the study additional patients were administered MDX-060 intravenously at 10 (n=10) or 15 (n=17) mg/kg weekly for 4 weeks. Responses were assessed at month 2. Results: To date, MDX-060 has been administered to 48 patients; 40 with Hodgkin’s disease (HD), 6 with anaplastic large cell lymphoma (ALCL) and 2 with other CD30 positive lymphomas. MDX-060 has been well tolerated, and a maximum tolerated dose has not been identified. There were 2 drug-related serious adverse events, 1 patient in the 1 mg/kg dosing cohort had Grade 3 elevated liver transaminase, and 1 patient in the 15 mg/kg cohort had Grade 3 pneumonia/Grade 4 ARDS. Objective clinical responses have been observed in 5 patients. Two patients had complete responses; 1 patient with ALCL in the 1 mg/kg cohort lasting 100 days, and 1 patient with HD in the 15 mg/kg cohort lasting 117 days. Retreatment of the ALCL patient with MDX-060 resulted in a second complete response. Three patients had partial responses; 1 patient with HD in the 5 mg/kg cohort lasting 92 days, and 1 patient with HD in the 15 mg/kg cohort, which is continuing at 176 days. In addition, 1 patient with ALCL in the 15 mg/kg cohort had a partial response. Stable disease was observed in 17 patients following MDX-060 administration with a median duration of 132 days (range:15–387 days). Baseline soluble CD30 levels in the plasma were evaluated, but did not appear to correlate with clinical outcome. Conclusions: Preliminary evidence indicates MDX-060 to be well tolerated in heavily pre-treated patients with CD30+ lymphomas, with minimal toxicity, and with clinical activity observed at 1 mg/kg, 5 mg/kg and 15 mg/kg. Additional patients are being accrued at 1 mg/kg and 5 mg/kg to more accurately assess efficacy at these dose levels.

8060 Background: ENKL is a rare and aggressive subtype of peripheral T-cell lymphoma. Due to its geographic predilection there is a paucity of data on clinical experiences from non-Asian countries. The purpose of this study was to analyze characteristics and outcomes of patients (pts) with ENKL identified from major academic centers in NA. Methods: Pts with newly diagnosed CD56+ ENKL were retrospectively identified. Analyses included disease characteristics, ethnicity, therapy, and outcomes. Results: 115 pts (63.5% Caucasian, 20% Asian, 16.5% other) were identified across 10 centers diagnosed between 5/1990-5/2011 (Era 1: pre-2000, n=16; Era 2: 2000-2005, n=45; Era 3: post-2005, n=54). Median age was 52 years (19-88). 75 (65%) had stage I/II disease and were treated with combined modality therapy (CMT) n=48, chemotherapy (CT) n=14 or radiotherapy (RT) n=14. 40 pts had stage III/IV disease and were treated with CT (n=23), CMT (n=12) or RT (n=5). CT regimens used alone or in CMT were either anthracycline-based (n=68) or other (n=29). 63% of stage I/II pts and 40% with stage III/IV achieved complete remission (CR). 30 pts underwent a stem cell transplant (SCT); 14 in first CR and 16 at progression/relapse (autologous, n=21; allogeneic, n=9). Pts with stage I/II disease had a better progression-free survival (PFS) and overall survival (OS) compared with stage III/IV (12 vs 5.2 months (p=0.003) and 41.5 vs 8.9 months (p<0.0001), respectively). For all stages, treatment with CMT compared with CT or RT alone was also associated with better PFS and OS, 18.0 vs 3.9 months (p<0.0001), and 41.5 vs 10.2 months (p=0.002) respectively. Non-anthracycline-based regimens were associated with better PFS (p=0.001) and OS (p=0.045). No survival differences were seen between Asian and non-Asian pts. Conclusions: This series represents one of the largest experiences of ENKL in NA. Our data are consistent with Asian studies in: 1) majority of pts present with early stage disease; 2) overall poor outcome; 3) superiority of CMT and non-anthracycline regimens. Advances in understanding biology and international collaborative efforts are required to improve outcome in this rare entity.

Abstract Introduction: Lenalidomide (len) is an immunomodulatory agent with single agent activity in relapsed and refractory peripheral T-cell lymphoma (PTCL). CHOEP (cyclophosphamide, doxorubicin, vincristine, etoposide, and prednisone) is a common initial regimen. Herein, we report the completed phase II results of the combination of len-CHOEP. Methods: Eligible patients (pts) had newly diagnosed PTCL, ANC ≥1000 cells/mm3, platelets ≥100 K/mm3, and adequate organ function. Based on phase I results [Lunning et al. T-cell Forum 2018] 10 mg of len was chosen for phase II. CHOEP was administered at standard doses with len given on days 1-10 of 21-day cycle for six planned cycles. Mandatory prophylaxis included aspirin (ASA) or alternative thromboprophylaxis and growth factor support per institutional guidelines with each cycle. A PET/CT after two cycles (PET-2) for interim response assessment was required per protocol. The primary endpoint was complete response (CR) by PET/CT after 6 cycles (PET-6) of len-CHOEP utilizing the revised Cheson 2007 criteria with secondary endpoints to include toxicity, overall response rate (ORR), progression free survival (PFS), 2-year PFS, and overall survival (OS). Pts who had CR or partial response (PR) at the end of therapy had the option of len maintenance (10 mg/day for 21 out of 28 days) for 1-year or consolidative autologous stem cell transplant (ASCT) without len maintenance. Per protocol pts dosed at 10 mg in phase I (N=8) were included in the phase II analysis. Results: Forty pts with PTCL-NOS (23), ALK negative ALCL (5) and AITL (12) enrolled into the phase II portion. Median age was 62 years (range 24-79) and 21 were male. Thirty (75%) pts completed all 6 cycles. Reasons for discontinuing len-CHOEP early were toxicity (n=6) and progressive disease (PD; n=4). PET-2 was not done in 4/40 pts (n=2 each either not performed or PD). In an intent to treat (ITT) analysis the CR rate at the end of treatment was 48% (19/40; 95CI-32-64%) with an ORR of 68%. In pts who completed 6 cycles (n=30) the CR/ORR rate was 63%/87% respectively. Seven pts (18%) experienced primary treatment failure. Of the 19 pts in CR at end of initial therapy, 14 were in a CR at PET-2 assessment. Two pts in a PET-2 CR discontinued prior to cycle 6 due to toxicity and have not progressed. Five pts converted from a PR to CR after PET-2, but 7 of 13 PRs remained PRs. Responding pts (CR/PR; n=30) proceeded either to an ASCT (n=18), len maintenance (n=10) or neither (investigator/pts preference; n=2). At a median follow up of 13 months (range: 4-23 months), the 1-year estimated PFS and OS is 68% [95% CI--50-80%] and 89% [95%CI--73-96%] respectively. There were five grade (G) 5 events including PD (n=1), secondary malignancy (n=1; AML), sepsis (n=2), and cardiac arrest (n=1). Serious or recurrent adverse events (SAEs or AEs) of interest occurring during any cycle included 38% G 3-4 febrile neutropenia despite mandated GCSF use, 43% G 3-4 anemia, 43% G 3-4 thrombocytopenia (without report of G 3-4 bleeding or bruising despite ASA use), 3% G3-4 rash (all G 23%), and 8% G 3-4 diarrhea (all G 43%). Conclusions: The phase II portion of the study in an ITT population noted an unexpectedly modest 48% CR rate and a high discontinuation rate (15%) due to AEs or SAE. The utility of response at PET-2 and post initial therapy strategy (len maintenance vs ASCT) continue to be monitored for PFS and OS in this limited cohort. Improving frontline outcomes for pts with PTCL remains an unmet need. Disclosures Lunning: Celgene: Consultancy; TG Therapeutics: Consultancy; Genentech: Consultancy; Bayer: Consultancy; AbbVie: Consultancy; Spectrum: Consultancy; Kite: Consultancy; Janssen: Consultancy; Gilead: Consultancy; Portola: Consultancy; Seattle Genetics: Consultancy; Astra-Zeneca: Consultancy; Genzyme: Consultancy; Juno: Consultancy; Genentech: Consultancy; Verastem: Consultancy. Horwitz:Millennium/Takeda: Consultancy, Research Funding; Trillium: Consultancy; Mundipharma: Consultancy; Kyowa-Hakka-Kirin: Consultancy, Research Funding; Portola: Consultancy; Aileron Therapeutics: Consultancy, Research Funding; Innate Pharma: Consultancy; Corvus: Consultancy; Spectrum: Research Funding; Seattle Genetics: Consultancy, Research Funding; Infinity/Verastem: Consultancy, Research Funding; ADC Therapeutics: Consultancy, Research Funding; Forty Seven: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. Advani:Janssen Pharmaceutical: Other: Institutional Research Support; Cell Medica: Other: Consultancy/Advisory Role; Bayer Healthcare Pharmaceuticals: Other: Consultancy/Advisory Role; Merck: Other: Institutional Research Support; Forty Seven, Inc: Other: Institutional Research Support; Millenium: Other: Institutional Research Support; Roche/Genentech: Other: Consultancy/Advisory Role, Institutional Research Support; Pharmacyclics: Other: Institutional Research Support; Celgene: Other: Institutional Research Support; Regeneron Pharmaceuticals, Inc.: Other: Institutional Research Support; Kura: Other: Institutional Research Support; Infinity: Other: Institutional Research Support; Autolus: Other: Consultancy/Advisory Role; Kyowa: Other: Consulting/Advisory Role; Takeda: Other: Consultancy/Advisory Role; Bristol Myers Squibb: Other: Consultancy/Advisory role and Institutional Research Support; Agensys: Other: Institutional Research Support; Gilead/Kite: Other: Consultancy/Advisory Role; Seattle Genetics: Other: Consultancy/Advisory role, Institutional Research Support; AstraZeneca: Other: Consultancy/Advisory Role. Vose:Epizyme: Honoraria; Roche: Honoraria; Novartis: Honoraria, Research Funding; Celgene: Research Funding; Incyte Corp.: Research Funding; Legend Pharmaceuticals: Honoraria; Bristol Myers Squibb: Research Funding; Seattle Genetics, Inc.: Research Funding; Abbvie: Honoraria; Acerta Pharma: Research Funding; Kite Pharma: Research Funding; Merck Sharp & Dohme Corp.: Research Funding. Mehta-Shah:Verastem: Research Funding; Genetech: Research Funding; Celgene: Research Funding; Bristol-Myers Squibb: Research Funding; Spectrum: Consultancy. Haverkos:Viracta Therapeutics: Membership on an entity's Board of Directors or advisory committees. Moskowitz:ADC Therapeutics: Research Funding; Bristol Myers-Squibb: Consultancy, Research Funding; Merck: Research Funding; Incyte: Research Funding; Takeda: Honoraria; Seattle Genetics: Consultancy, Honoraria, Research Funding. Ansell:Merck & Co: Research Funding; Pfizer: Research Funding; Bristol-Myers Squibb: Research Funding; Seattle Genetics: Research Funding; Trillium: Research Funding; Takeda: Research Funding; LAM Therapeutics: Research Funding; Affimed: Research Funding; Celldex: Research Funding; Regeneron: Research Funding.