Tun, Han W.

e19543 Background: Langerhans cell sarcoma (LCS) is a very rare cancer with the reported incidence of 2 per 100,000,000. It originates from antigen presenting cells belonging to the dendritic cell/macrophage family. Methods: Following IRB approval, we identified LCS patients treated at the Mayo Clinic Cancer Center. Medical charts were reviewed to extract clinical data. Results: Our cohort consists of 5 patients with confirmed diagnosis of LCS. The median age at diagnosis was 34 years (range, 11-75) with 60% (3/5) females. One female was an African American and the rest were Caucasians. ECOG performance status at the time of diagnosis was 0 in 4 patients and 3 in 1 patient. Four patients had disseminated disease at diagnosis. 3/5 patients had moderate splenomegaly at diagnosis. 2/5 patients presented with a bulky mediastinal tumor and 1/5 patients presented with bulky intraabdominal disease. Predominant sites of disease are summarized in the table. BRAF mutation was negative in all 3 tested patients. The median follow up for the whole cohort was 25 months (range; 5, 41). Three patients relapsed after the initial treatment. Patient # 4 received allogeneic stem cell transplantation after the 4th relapse and is in CR 14 months later. Patient # 5 had PD-L1 expression > 95% and was started on pembrolizumab with sustained response for 1 year. Conclusions: LCS is extremely rare and is associated with unfavorable outcomes after currently available therapeutic interventions. More studies on the genetic and molecular basis of LCS are necessary to develop targeted therapies. [Table: see text]

Abstract Background: Previous studies have proposed combination of various factors that predict poor mobilization after GCSF stimulation. However, there is no single clinical or laboratory test that reliably correlates with bone marrow reserve and PBPC mobilization. Peripheral blood CD34+ cell count (pCD34) reliably correlates with PBPC mobilization and yield but only after GCSF administration. Methods: We have prospectively followed 36 autologous PBPC transplant candidates, from the time of initial evaluation to transplant, to evaluate factors the correlate with bone marrow reserve and autologous PBPC mobilization. Results: The patients median age was 63 (range 26 – 76). 21 of the 36 patients were diagnosed with dysproteinemia, primarily multiple myeloma, 10 patients had non-Hodgkin’s lymphoma while the remaining 5 had other form of hematological malignancies. Our evaluation shows baseline platelet count prior to growth factor administration significantly correlate with total CD34+ cell yield (spearman: r = 0.64, p <0.001, Figure 1). In addition, daily platelet count during PBPC harvest correlate with CD34+ cell yield for the day (spearman: r = 0.6, p <0.001). Using multiple linear regression model (F = 19.1, p <0.001, R2 = 0.64), we have determined patients’ age (p = 0.03) and type of disease (p <0.001), in addition to platelet count (p<0.001), significantly correlate with total CD34+ cell yield. Further analysis showed low baseline platelet count predicts poor PBPC mobilization. Using Receiver Operating Curve (ROC), we have determined that platelet count of 174,000/ul was the best cut-off for collecting at least 2 million/Kg CD34+ cells with sensitivity of 81% and specificity of 78% and estimated correct classification of 81%. Even though pCD34 counts were slightly more sensitive and were better at identifying poor mobilizers in our cohort (best cut-off 10/ul, sensitivity 96%, specificity 67%, correct classification 89%), their clinical utility were diminished since the values were only known after GCSF administration. Conclusion: Baseline platelet count is a sensitive predictor of bone marrow reserve and can be used prior to growth factor administration to predict poor mobilization. Figure 1: Correlation of baseline platelet count and total CD34+ cell yield Figure 1:. Correlation of baseline platelet count and total CD34+ cell yield

TPS7570 Background: The DIAL study is testing the efficacy of dual immunomodulation in patients with advanced B cell non-Hodgkin lymphoma (B-NHL). Developed by the Cancer Therapy Evaluation Program (CTEP), the trial combines the use of a programmed cell death protein 1 (PD-1) inhibitor (nivolumab) with an agonist of the CD27 receptor (varlilumab) in a randomized phase 2 design. CD27, a co-stimulatory receptor, regulates T cell activation through interaction with CD70. T cell exhaustion plays a major role in immune evasion in B-NHL. Varlilumab is an agonistic IgG1 monoclonal antibody that recognizes CD27 leading to prevention or reversal of exhaustion. Varlilumab also demonstrates direct anti-tumoral activity in xenograft models of human lymphoma cell lines via antibody-dependent cell-mediated cytotoxicity. Phase 1 data supports the safety and tolerability of single-agent varlilumab in advanced hematologic malignancies. We hypothesize that CD27 activation synergizes with PD-1 inhibition resulting in a superior anti-lymphoma effect compared to PD-1 blockade alone. The study will also evaluate the effect of these agents on tumor and immune cells using IHC, mass cytometry (CyTOF), multiplex ELISA, imaging mass cytometry, and whole exome sequencing. Methods: The trial is enrolling patients with advanced aggressive B-NHL. Standard inclusion criteria and prior treatment with at least 2 lines of standard therapy are required. Prior autologous stem cell transplant and/or chimeric antigen receptor (CAR) T cell therapy is allowed. Patients with active CNS disease are excluded. Eligible patients will be randomized to treatment with single-agent nivolumab (group 1) or dual immunotherapy with nivolumab and varlilumab. Group 1 is allowed to cross-over at the time of progression. Nivolumab will be administered intravenously (IV) every 2 weeks (240 mg) for 4 months followed by monthly dosing thereafter (480 mg). Varlilumab will be given IV every 4 weeks (3 mg/kg). Response assessment will be done by PET-CT scan every 12 weeks. Primary outcome is overall response rate (ORR) according to the LYRIC criteria. The trial will enroll 48 patients per arm, allowing 80% power to detect at least 20% increase in ORR in the experimental arm (group 2) assuming a 25% ORR in the control arm (group 1). The trial is registered and open to participation to members of ETCTN and EDDOP. Clinical trial information: NCT03038672.

e19055 Background: IRAK4 is a signaling modulator of Toll-like receptors (TLRs) and members of the IL-1R family. TLR/IL-1R activity is frequently dysregulated in NHL, including DLBCL and Waldenström macroglobulinemia (WM). CA-4948, an oral inhibitor of IRAK4, has demonstrated anti-tumor activity in preclinical models. Methods: Dose finding cohorts (3+3 design) will test QD or BID dosing schedule in pts with R/R NHL. Dose expansion will occur in 2 cohorts of R/R NHL with or without MYD88 mutation at the RP2D or MTD. Key eligibility criteria: age ≥ 18 years, ECOG ≤1, and adequate organ function. Objectives: safety, MTD and RP2D (primary); PK and anti-tumor activity (secondary); exploratory biomarkers and PD effects. Plasma cytokine levels are being evaluated post ex-vivo TLR stimulation in whole blood. Results: 13 pts have been treated (6 at 50 mg QD; 3 at 100 mg QD; 4 at 50 mg BID). Tumor types included DLBCL (7), FL (5), WM (1). The most frequent treatment-emergent AEs (≥10% of pts) were fatigue (23%), conjunctivitis, constipation, neutrophil count decrease, white blood cell count decrease (each 15%). One pt treated at 100 mg QD experienced Gr 3 rash which resolved following oral steroid treatment; dose reduction to 50 mg QD was tolerated without flare up. One SAE of disease progression occurred. 9 pts completed the DLT evaluation period thru Cycle 2 including 2 ongoing in Cycle 4 and 6. Preliminary PK showed that CA-4948 is rapidly absorbed with maximum plasma concentration observed 1.0 to 4.0 hrs post administration. T1/2 in plasma was about 6 hrs. Minimal to no accumulation was observed following multiple doses. Plasma exposures were dose proportional. Preliminary PD data showed, similar to murine studies, on target reduction of NF-kB-associated factors such as IL-6 post-treatment from pts with complete sample sets (N = 8). Conclusions: Current dose/schedule is well tolerated with preliminary PK and PD effects at the initial dose level. MTD has not been reached. Clinical trial information: NCT03328078.

Targeted agents have greatly improved outcomes for patients (pts) with chronic lymphocytic leukemia (CLL) and other B cell lymphomas; however, single agents have been limited by intolerance, resistance and depth/durability of responses. Current novel targeted agent combinations may improve depth of response, but such "full dose" strategies have been associated with significant AEs, dose reductions/interruptions and discontinuations. Our in vitro & in vivo screening/optimization studies identified that concurrent inhibition of BTK & mTOR targets plus IMiD at low doses of each inhibitor can synergistically kill B-cell malignancies and may address drug-resistance. DTRM-555 is an optimized oral triplet combination of a novel BTK inhibitor DTRMWXHS-12 (DTRM-12) with everolimus (EV) & pomalidomide (POM). This once daily therapy was tested in a stepwise, phase I, US multicenter study in patients with highest unmet medical needs including r/r CLL, Richter's transformation (RT) of CLL, DLBCL, transformed B-cell lymphomas. We conducted a 3+3 design phase I, first human trial exploring DTRM-555 in pts ≥18 years, ECOG PS ≤1 with CLL, B-cell NHL, or Hodgkin lymphoma (HL) with no available standard therapy (NCT02900716). Our goal was to determine optimal doses for triplet combination therapy through 3 escalating phases of study: DTRM-12 in escalating doses (50, 100, 200, & 300 mg/day) in Part Ia, DTRM-12 at 200 mg or 300 mg & EV at 5 mg (doublet or DTRM-505) in Part Ib Arm A while DTRM-12 at 200 mg or 300 mg, EV at 5 mg & POM at 2 mg in Part Ib Arm B. For all arms, treatment was administered for 21 consecutive days of a 28-day cycle, until disease progression or unacceptable toxicity. Safety was the primary endpoint, and the dose-limiting toxicity (DLT) period was cycle 1. Secondary endpoints included response (iwCLL 2018 or Cheson 2014), progression free survival, duration of response and pharmacokinetics. Intra-patient migration between arms (Mono to doublet to triplet) was permitted if subsequent doses were tolerated. The trial commenced 9/27/2016 and completed enrollment 7/25/2019. Thirty-three pts were enrolled, including 2 screen failures and 4 intra-cohort migrations, with r/r DLBCL (n=8), CLL/SLL (n=5), RT (n=6), FL (n=5), MCL (n=4), MZL/LPL (n=3), HL (n=2). 30 of 31 treated pts were evaluated: 8 pts participated in phase Ia (DTRM-12) while 23 pts were treated on phase Ib combinations (DTRM-505 & DTRM-555). Baseline characteristics: 70% male (n=23), median age 70 years (range 46-94) and 94% white. Median prior therapies were 3 (range 1-10), 53% had been treated with ≥1 prior targeted agent (i.e., CD19/CD3 bispecific antibody, obtinutuzumab, pembrolizumab, nivolumab, ibrutinib, venetoclax, PI3k-i), CAR-T or HSCT. 35% pts were previously treated with ibrutinib. Table 1 describes Grade (Gr) 3 and 4 AEs (all causality, stratified by treatment arm). Regarding safety, AEs were manageable, with a total of 5 DLTs were observed: 2 (Gr 3 febrile neutropenia, URI) in part Ib arm A, 3 (Gr 4 thrombocytopenia, Gr 3 diarrhea, G3 febrile neutropenia) in Part Ib arm B. No MTD was reached for the mono & doublet arms, with the MTD of the triplet determined to be DTRM-12 200 mg, EV 5 mg, & POM 2 mg. Spider plot (Figure 1a) shows the clinical response for individual CLL and lymphoma pts treated with mono, doublet and triplet therapies. Depth and durability of response improved with combination therapies (vs. mono). Of note, 48% of all patients had a ≥50% reduction in sum of the products of lymph node diameters. Representative PET-CT scans are in Figure 1b-c. Responses in multi-refractory pts are ongoing (including 15+ mos in a pt with r/r DLBCL and 5+ mos PR in a pt aged > 90 yrs with r/r DLBCL; 4+ & 13+ mos PRs in two pts with RT). DTRM-12 plasma concentrations were unaffected by EV & POM (Once Daily Oral Therapies) in Figure 1d. The clinical trial met its primary endpoint as the triple combination DTRM-555 had an acceptable safety profile. Dose dependent drug levels with minimal inter-pt variations were observed in all arms, supporting once daily oral administration of this low-dose combination therapy. Encouraging clinical activity was observed in several high-risk, multi-refractory CLL and lymphoma pts, including those previously treated with ibrutinib. Thus synthetic lethality is a viable treatment approach. A phase II US expansion study is underway targeting pts with transformed lymphomas (follicular or prior CLL) and r/r DLBCL cohorts. Table 1. Disclosures Mato: AbbVie: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Johnson & Johnson: Consultancy, Research Funding; Celgene: Consultancy; AstraZeneca: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Gilead: Research Funding; Acerta: Consultancy; Janssen: Consultancy; TG Therapeutics: Consultancy, Other: DSMB member , Research Funding; LOXO: Consultancy, Research Funding; DTRM Biopharma: Research Funding. Schuster:DTRM Biopharma: Research Funding. Foss:Mallinckrodt: Consultancy; Acrotech: Consultancy; miRagen: Consultancy; Seattle Genetics: Consultancy, Other: fees for non-CME/CE services ; Eisai: Consultancy; Spectrum: Other: fees for non-CME/CE services . Isufi:Novartis: Consultancy; Astra Zeneca: Consultancy; Celgene: Consultancy. Ding:Merck: Research Funding; DTRM Biopharma: Research Funding. Brander:Novartis: Consultancy; MEI: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy; BeiGene: Research Funding; AstraZeneca: Consultancy, Research Funding; Acerta: Research Funding; Tolero: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; Teva: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria, Research Funding; DTRM Biopharma: Research Funding. Tun:Mundi-pharma: Research Funding; TG Therapeutics: Research Funding; Curis: Research Funding; DTRM Biopharma: Research Funding; Celgene: Research Funding; BMS: Research Funding. He:DTRM Biopharma: Employment, Equity Ownership. Kearney:DTRM Biopharma: Employment, Equity Ownership. Gui:DTRM Biopharma: Employment, Equity Ownership. Anderson:Theradex: Employment. Roeker:AbbVie: Equity Ownership; Abbott Laboratories: Equity Ownership. Huntington:Bayer: Consultancy, Honoraria; AbbVie: Consultancy; Celgene: Consultancy, Research Funding; Genentech: Consultancy; Pharmacyclics: Honoraria; DTRM Biopharm: Research Funding. OffLabel Disclosure: Everolimus in B cell lymphomas and CLL Pomalidomide in B cell lymphomas and CLL

AbstractClear‐cell renal cell carcinoma (ccRCC) presents challenges to clinical management because of late‐stage detection, treatment resistance, and frequent disease recurrence. Metabolically, ccRCC has a well‐described Warburg effect utilization of glucose, but how this affects complex carbohydrate synthesis and alterations to protein and cell surface glycosylation is poorly defined. Using an imaging mass spectrometry approach, N‐glycosylation patterns and compositional differences were assessed between tumor and nontumor regions of formalin‐fixed clinical ccRCC specimens and tissue microarrays. Regions of normal kidney tissue samples were also evaluated for N‐linked glycan‐based distinctions between cortex, medullar, glomeruli, and proximal tubule features. Most notable was the proximal tubule localized detection of abundant multiantennary N‐glycans with bisecting N‐acetylglucosamine and multziple fucose residues. These glycans are absent in ccRCC tissues, while multiple tumor‐specific N‐glycans were detected with tri‐ and tetra‐antennary structures and varying levels of fucosylation and sialylation. A polycystic kidney disease tissue was also characterized for N‐glycan composition, with specific nonfucosylated glycans detected in the cyst fluid regions. Complementary to the imaging mass spectrometry analyses was an assessment of transcriptomic gene array data focused on the fucosyltransferase gene family and other glycosyltransferase genes. The transcript levels of the FUT3 and FUT6 genes responsible for the enzymes that add fucose to N‐glycan antennae were significantly decreased in all ccRCC tissues relative to matching nontumor tissues. These striking differences in glycosylation associated with ccRCC could lead to new mechanistic insight into the glycobiology underpinning kidney malignancies and suggest the potential for new therapeutic interventions and diagnostic markers.

Abstract Background: As of 2013, approximately 558,340 people are living with non-Hodgkin lymphoma (NHL). Outcome disparities have been reported in lymphoid malignancies but a comprehensive analysis, especially with expanding ethnic minorities is necessary. We undertook a large Surveillance Epidemiology and End Results (SEER) based analysis to describe outcome disparities in different subgroups of T-cell and B-cell NHL patients (pts), with a focus on various ethnicities. Methods: The SEER 18 Registry data (1973-2011) was utilized for pts with a confirmed diagnosis of T-cell or B-cell NHL. Cases that received a diagnosis at death certificate or autopsy, no follow-up records, no documented age at diagnosis, sex, or race/ethnicity were excluded. Cox proportional hazards models, adjusted for gender, age, race, year (yr) of diagnosis, and stratified by SEER registries were used to evaluate association between pt characteristics and survival. All statistical tests were two-sided and utilized the SAS software (v9.4) with a two-sided significance level of 0.05. Results: The final analysis included 7,662 pts with T-cell NHL and 84,910 pts with B-cell NHL. The pt demographics are shown in Table 1. Pts were stratified based on yr of diagnosis to study the impact of therapeutic developments on pt outcomes (Table 1). Pts were also divided by T-cell NHL subtype: mature T-cell (9702/3) 51%, angioimmunoblastic T-cell (9705/3) 16%, anaplastic large cell (ALCL) (9714/3) 32%, and hepatosplenic gamma-delta cell (HSϒd) (9716/3) 0.8%. Median age at diagnosis was youngest for AA pts (54 yrs) and oldest for Asian pts (65 yrs) (Figure 1 A). Survival analysis revealed that females had a better median OS than males (3.3 yrs vs. 2.3 yrs, HR 0.876; 95% CI 0.824, 0.932; p<0.001). Increasing age was an independent predictor of worse overall survival, with pts age 18-44 having a median OS 9.4 yrs (HR 0.345; 95% CI 0.312, 0.382) and pts age ≥75 having a median OS of 1.0 yr (p<0.001). There was no statistically significant difference seen in median OS for pts with respect to yr of diagnosis (p=0.081). Among the different T-cell NHL subtypes, pts with ALCL had the best (3.8 yrs, HR 0.766; 95% CI 0.714, 0.822) and pts with HSϒd had the worst median OS (0.7 yrs HR 1.959; 95% CI 1.424, 2.695) (p<0.001). AA pts (1.7 yrs, HR 1.292; 95% CI 1.176, 1.419) and Hispanic pts (1.9 yrs, HR 1.215; 95% CI 1.087, 1.357) had significantly worse OS compared to White pts who had the longest median OS (3.1 yrs) (p<0.001) (Figure 1 B). To compare and contrast with aggressive B-cell NHL, similar analyses were performed using diffuse large B-cell (DLBCL) NHL (9680/3). DLBCL showed similar trends regarding sex, age and race. Ethnic minorities had significantly worse median OS including Hispanic (2.8 yrs, HR 1.154; 95% CI 1.111, 1.198) and AA pts (3.3 yrs, HR 1.261; 95% CI 1.212, 1.312) compared to White pts with a median OS of 5.8 yrs (p<0.001). B-cell NHL pts had a significant improvement in median OS over time with pts diagnosed in 2007-2011 having more than 3 times the median OS of pts diagnosed in 1973-1991 (7 yrs vs. 2.4 yrs; p<0.001). Conclusions: Studies of outcome disparities are important for evaluating disease characteristics and their relationship to specific pt populations over time. We have performed the largest population-based analysis for T-cell and B-cell NHL including various ethnicities in the novel therapeutic agent era. We observed that males, older pts and ethnic minorities had worse median OS for both T-cell and B-cell NHL. Despite novel therapeutics targeting T cells there has been no statistically significant improvement in OS over time. In contrast, significant improvement in B-cell NHL OS has been noted, presumably due to the advent of monoclonal antibodies. These results underline the urgency for the development of novel therapeutics as well as aggressive studies of disease biology and healthcare utilization for better triage of healthcare resources, especially for ethnic minorities. Table 1. Table 1. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Background: The DIAL study is testing the efficacy of dual immunomodulation in patients with advanced aggressive B cell non-Hodgkin lymphoma (B-NHL). Sponsored by the Cancer Therapy Evaluation Program (CTEP), the trial combines the use of a programmed cell death protein 1 (PD-1) inhibitor (nivolumab) with an agonist of the CD27 receptor (varlilumab) in a randomized phase 2 design. CD27, a co-stimulatory receptor, regulates T cell activation in the context of T cell receptor (TCR) engagement through interaction with CD70. T cell exhaustion plays a major role in immune evasion in B-NHL. Varlilumab is an agonistic IgG1 monoclonal antibody that recognizes CD27 leading to prevention or reversal of exhaustion in pre-clinical models. Varlilumab also demonstrates direct anti-tumoral activity in xenograft models of human lymphoma cell lines via antibody-dependent cell-mediated cytotoxicity. Phase 1 data supports the safety and tolerability of single-agent varlilumab in advanced hematologic malignancies (NCT01460134). We hypothesize that CD27 activation synergizes with PD-1 inhibition resulting in a superior anti-lymphoma effect compared to PD-1 blockade alone. The study will also evaluate the effect of these agents on tumor and immune cells using immunohistochemistry (IHC), mass cytometry (CyTOF), multiplex ELISA, imaging mass cytometry (IMC), and whole exome sequencing. Methods: The trial is enrolling patients with advanced aggressive B-NHL. Standard inclusion criteria and prior treatment with at least 2 lines of standard therapy are required. Prior autologous stem cell transplant and/or chimeric antigen receptor (CAR) T cell therapy is allowed. Patients with active CNS disease are excluded. Eligible patients are randomized to treatment with single-agent nivolumab (group 1) or dual immunotherapy with nivolumab and varlilumab. Group 1 is allowed to cross-over at the time of progression. Nivolumab will be administered intravenously (IV) every 2 weeks (240 mg) for 4 months followed by monthly dosing thereafter (480 mg). Varlilumab will be given IV every 4 weeks (3 mg/kg). Response assessment will be done by PET-CT scan every 12 weeks. Primary outcome is overall response rate (ORR) according to the LYRIC criteria. The trial will enroll 48 patients per arm, allowing 80% power to detect at least 20% increase in ORR in the experimental arm (group 2) assuming a 25% ORR in the control arm (group 1). The trial is registered (NCT03038672) and open to participation to members of the Experimental Therapeutics Clinical Trials Network (ETCTN) and Early Drug Development Opportunity Program (EDDOP). Figure Disclosures Tun: BMS: Research Funding; Celgene: Research Funding; Curis: Research Funding; TG Therapeutics: Research Funding; Mundi-pharma: Research Funding; DTRM Biopharma: Research Funding. Bartlett:Pharmacyclics: Research Funding; Merck: Research Funding; Incyte: Research Funding; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Millennium: Research Funding; Kite Pharma: Research Funding; Janssen: Research Funding; Immune Design: Research Funding; Affimed: Research Funding; Autolus: Research Funding; Bristol-Myers Squibb: Research Funding; Celgene: Research Funding; Forty Seven: Research Funding; Genentech, Inc.: Research Funding; Gilead: Research Funding. Kline:Merck: Honoraria; Merck: Research Funding. Awan:Janssen: Consultancy; Gilead: Consultancy; Sunesis: Consultancy; Genentech: Consultancy; Abbvie: Consultancy, Speakers Bureau; Pharmacyclics: Consultancy, Research Funding; AstraZeneca: Consultancy, Speakers Bureau. Lazaryan:Kadmon: Consultancy. Ansell:Affimed: Research Funding; Affimed: Research Funding; Bristol-Myers Squibb: Research Funding; Mayo Clinic Rochester: Employment; Affimed: Research Funding; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Affimed: Research Funding; Affimed: Research Funding; Affimed: Research Funding; LAM Therapeutics: Research Funding; Mayo Clinic Rochester: Employment; LAM Therapeutics: Research Funding; LAM Therapeutics: Research Funding; Seattle Genetics: Research Funding; LAM Therapeutics: Research Funding; Affimed: Research Funding; Bristol-Myers Squibb: Research Funding; LAM Therapeutics: Research Funding; Trillium: Research Funding; Regeneron: Research Funding; Regeneron: Research Funding; Regeneron: Research Funding; Regeneron: Research Funding; Bristol-Myers Squibb: Research Funding; Mayo Clinic Rochester: Employment; Seattle Genetics: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding; Seattle Genetics: Research Funding; LAM Therapeutics: Research Funding; Seattle Genetics: Research Funding; Affimed: Research Funding; Trillium: Research Funding; Trillium: Research Funding; LAM Therapeutics: Research Funding; Trillium: Research Funding; Trillium: Research Funding; Seattle Genetics: Research Funding; Mayo Clinic Rochester: Employment; Regeneron: Research Funding; Mayo Clinic Rochester: Employment; Regeneron: Research Funding; Bristol-Myers Squibb: Research Funding; Mayo Clinic Rochester: Employment; Mayo Clinic Rochester: Employment; Trillium: Research Funding; Seattle Genetics: Research Funding; Seattle Genetics: Research Funding; Mayo Clinic Rochester: Employment; Trillium: Research Funding; Mayo Clinic Rochester: Employment; LAM Therapeutics: Research Funding; Trillium: Research Funding; Seattle Genetics: Research Funding; Bristol-Myers Squibb: Research Funding; Affimed: Research Funding; Bristol-Myers Squibb: Research Funding; Regeneron: Research Funding; Bristol-Myers Squibb: Research Funding; LAM Therapeutics: Research Funding; Regeneron: Research Funding; Trillium: Research Funding. Diefenbach:Bristol-Myers Squibb: Consultancy, Research Funding; Denovo: Research Funding; Genentech: Consultancy, Research Funding; Incyte: Research Funding; LAM Therapeutics: Research Funding; MEI: Research Funding; Merck: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Millenium/Takeda: Research Funding; Trillium: Research Funding.

Background MZL is a low-grade non-Hodgkin's lymphoma (NHL) which involves lymph nodes, extranodal sites, or spleen. It is sensitive to radiation therapy, which is used in localized disease with curative intent. Yttrium-90 ibritumomab tiuxetan [(90)Y-IT; Zevalin] is a radio-immunoconjugate (RIC) that targets CD20. It is approved for relapsed/refractory low grade and follicular NHL. The data on its use in MZL is limited. We present long-term outcome of the largest reported cohort of MZL patients who received (90)Y-IT. Methods Medical records of patients who received treatment with (90)Y-IT at Mayo Clinic Cancer Center between January 2004 and December 2018 were analyzed. We selected patients with MZL and reviewed clinical data including age, gender, MZL type, clinical stage (Ann Arbor Staging System), treatment response, (90)Y-IT related adverse effects (AEs), as well as lymphoma and treatment related events. All patients received (90)Y-IT according to the standard treatment guidelines. Overall response rate (ORR) and complete response rate (CR) were calculated. Progression-free survival (PFS), time to next therapy (TTNT), and overall survival (OS) were analyzed using the Kaplan-Meier method. Results Twenty-one patients were identified (Table 1). The median age at diagnosis was 60 years (range, 11-81) and 71% (15/21) were female. 52% (11/21) were previously-untreated (UMZL) while 48% (10/21) were relapsed (RMZL). The median number of pretreatments in RMZL patients was 2 (range, 1-3). ECOG performance status at the time of treatment was 0 in 90% (19/21) and 1 in 10% (2/21). 62% (13/21) were stage III/IV disease at the time of (90)Y-IT therapy. The median follow-up was 8.5 years (95% CI; 4.5, 12.4); 17 (81%) patients remain alive. The ORR was 91% (19/21) with the two non-responders being in the RMZL group. The CR rate was 81% (17/21) and 65% (11/17) remain in CR at a median follow-up of 5.7 years (95% CI; 1.4, 11). Nine (43%) patients had a relapse during the study period. More relapses occurred in the RMZL group (7/10; 70%) compared to (2/11; 18%) in the UMZL group. Median PFS (whole cohort) was 10 years (95% CI; 2.1, NR) and TTNT (whole cohort) was not reached (NR) (95% CI; 2.1 years, NR). Median PFS was significantly higher in UMZL group compared to RMZL group NR (95% CI; 2.5 years, NR) vs 2.1 years (95% CI; 0.17, 9.9), respectively (Figure 1-A).Median OS (whole cohort) was 19.3 years (95% CI; 8.9, 19.3) without statistical difference in between UMZL group and RMZL group NR (95% CI; NR, NR) vs 16.6 years (95% CI; 9, 19.4), respectively (Figure 1-B). None of the 11 UMZL patients died at median follow up of 4.7 years (95% CI; 1.6, 9.2). All 4 deaths were in the RMZL group with 3 dying of transformation to high-grade lymphoma at 8, 22, and 25 months post-(90)Y-IT treatment. One patient died of myelodysplastic syndrome 7.3 years post-(90)Y-IT treatment while in CR. Toxicities were primarily hematologic. Grade ³3 neutropenia was observed in 6/21 (29%) patients with median time to nadir of 48.5 days (range, 19-70) and median time to recovery to normal absolute neutrophil count of 39.5 days (range, 7-476). Grade ³3 thrombocytopenia was observed in 3 (14%) patients with median time to nadir of 35 days (range, 19-357) and median time to recovery of 21 days (range, 2-538). Grade ³3 anemia was observed in only one patient. Only two patients required transfusions and growth factor support. Non-hematologic AEs included mild to severe fatigue in 4 patients. Conclusion RIC with (90)Y-IT is efficacious and well-tolerated in patients with previously untreated as well as relapsed MZL. As expected it appears to be more efficacious in previously untreated patients. Long-term complete remission (&gt;5 years) was observed in 52% of the study population (43% of UMZL and 9% of RMZL). Combination of efficacy, tolerability, and treatment schedule most convenient for patients makes (90)Y-IT a reasonable alternative to systemic therapy with immunotherapy, chemotherapy, or chemo-immunotherapy in management of MZL. Figure 1: (A) Progression-free survival; comparing time to progression or death after (90)Y-IT treatment between previously untreated patients (UMZL) and patients with relapsed MZL (RMZL), (B) Overall survival; comparing time to death from all causes after (90)Y-IT treatment between UMZL patients and RMZL patients. Disclosures Tun: Curis: Research Funding; TG Therapeutics: Research Funding; BMS: Research Funding; DTRM Biopharma: Research Funding; Celgene: Research Funding; Mundi-pharma: Research Funding. OffLabel Disclosure: The use of Yttrium-90 ibritumomab tiuxetan as a first line treatment for marginal zone lymphoma

BACKGROUND: Axi-cel is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy that is approved for treatment of relapsed/refractory (R/R) large B-cell lymphoma and is associated with high response rates and durable remissions. Recent data show that axi-cel is effective across various adverse prognostic features, namely cell of origin, disease bulkiness, and extranodal disease, among others. Hypoalbuminemia is a known adverse prognostic factor in lymphomas. It is unknown if axi-cel overcomes the adverse prognostic feature of hypoalbuminemia in R/R large B-cell or transformed follicular lymphoma. METHODS: We conducted a retrospective analysis of patients treated with axi-cel across three Mayo Clinic campuses (Rochester, Jacksonville, and Phoenix) from 06/01/2018 until 04/01/2019. The primary objective of this analysis was to assess the impact of hypoalbuminemia (defined at day 0, prior to infusion) on outcome after axi-cel therapy. RESULTS: A total of 50 (male=37, 74%) patients (pts), median age of 53 (26-67) years received axi-cel. The median number of prior lines of therapy was 3 (2-8) (Table 1). Two pts had no available serum albumin levels at time of axi-cel infusion. Seven (15%) of 48 pts had serum albumin levels lower than 3.5 g/dL (median= 3.3 g/dL (range 2.6-3.4)) and the median follow up of survivors was 7.6 (1.9-14.3) months. The best overall response rate (ORR) and complete remission (CR) rates in these pts were 57% and 57%, respectively. One (14%) patient had stable disease and 2 (29%) had disease progression. The median overall survival (OS) for pts with hypoalbuminemia was not reached. On the other hand, 41 (85%) pts had a normal serum albumin level (median=4.0 (range 3.5-5.1) g/dL) and the median follow up for survivors was 6.3 months. The best objective response rate (ORR) and complete remission (CR) rates in these pts were 82% and 44%, respectively. The median OS for pts with normal serum albumin was 14 (95%CI=6.3-29.6) months. There was no significant difference at 6-months and 1-year OS between pts with hypoalbuminemia vs. those with normal baseline serum albumin levels [6-month=100% vs. 79%(95%CI=64-93%); 1-year (100% vs. 54% (95%CI=26-82%), p=0.17] (Figure 1). All grades cytokine release syndrome (CRS) was diagnosed in all 7 pts with hypoalbuminemia (100%) and in 38 of 41 (92%) pts without hypoalbuminemia. There was no difference in the median duration of CRS between pts with or without hypoalbuminemia [6 (range 1-11) days vs 5 (range 1-19) days, p=0.89]. Neurotoxicity (all grades) was observed in 5 (71%) pts with hypoalbuminemia compared 26 (63%) with normal albumin levels. There was no statistically significant difference in median duration of neurotoxicity between pts with hypoalbuminemia and those with normal baseline albumin levels [9 (range 1-10) days vs. 3 (range 0-25) days, p= 0.72]. CONCLUSIONS: Hypoalbuminemia does not have a significant impact on the outcomes of axi-cel therapy, including the incidence of CRS or neurotoxicity. These results need to be validated in a large collaborative multicenter study. Further investigation is needed to assess the prognostic impact of severe hypoalbuminemia (<3g/dL) on axi-cel therapy. Disclosures Ansell: Mayo Clinic Rochester: Employment; Seattle Genetics: Research Funding; Trillium: Research Funding; Trillium: Research Funding; Mayo Clinic Rochester: Employment; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Affimed: Research Funding; Regeneron: Research Funding; Affimed: Research Funding; Bristol-Myers Squibb: Research Funding; Mayo Clinic Rochester: Employment; LAM Therapeutics: Research Funding; Affimed: Research Funding; Bristol-Myers Squibb: Research Funding; Trillium: Research Funding; Regeneron: Research Funding; Trillium: Research Funding; Affimed: Research Funding; LAM Therapeutics: Research Funding; Mayo Clinic Rochester: Employment; LAM Therapeutics: Research Funding; LAM Therapeutics: Research Funding; Bristol-Myers Squibb: Research Funding; Mayo Clinic Rochester: Employment; Mayo Clinic Rochester: Employment; Affimed: Research Funding; Regeneron: Research Funding; LAM Therapeutics: Research Funding; Seattle Genetics: Research Funding; Trillium: Research Funding; Affimed: Research Funding; Trillium: Research Funding; Bristol-Myers Squibb: Research Funding; LAM Therapeutics: Research Funding; Mayo Clinic Rochester: Employment; Trillium: Research Funding; Regeneron: Research Funding; LAM Therapeutics: Research Funding; Bristol-Myers Squibb: Research Funding; Mayo Clinic Rochester: Employment; LAM Therapeutics: Research Funding; Seattle Genetics: Research Funding; Trillium: Research Funding; Trillium: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding; Bristol-Myers Squibb: Research Funding; Mayo Clinic Rochester: Employment; Bristol-Myers Squibb: Research Funding; Seattle Genetics: Research Funding; LAM Therapeutics: Research Funding; Regeneron: Research Funding; Affimed: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding; Seattle Genetics: Research Funding; Affimed: Research Funding; Affimed: Research Funding. Bennani:Seattle Genetics: Other: Advisory board; Kite Pharma: Other: Advisory board; Seattle Genetics: Other: Advisory board; Adicet Bio: Other: Advisory board; Seattle Genetics: Other: Advisory board; Purdue Pharma: Other: Advisory board; Adicet Bio: Other: Advisory board; Purdue Pharma: Other: Advisory board; Purdue Pharma: Other: Advisory board; Adicet Bio: Other: Advisory board; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Kite Pharma: Other: Advisory board; Bristol-Myers Squibb: Research Funding; Kite Pharma: Other: Advisory board. Paludo:Verily Life Sciences: Research Funding; Celgene: Research Funding; Verily Life Sciences: Research Funding; Celgene: Research Funding. Tun:DTRM Biopharma: Research Funding; Mundi-pharma: Research Funding; BMS: Research Funding; Celgene: Research Funding; Curis: Research Funding; TG Therapeutics: Research Funding. Foran:Agios: Honoraria, Research Funding. Kharfan-Dabaja:Daiichi Sankyo: Consultancy; Pharmacyclics: Consultancy.