Abstract: Introduction In aggressive lymphoma, the prognostic value of FDG-PET/CT is well established to assess the response to therapy and predict long-term outcome. However, there are still many controversies for using PET/CT in indolent non-Hodgkin lymphomas because of the low FDG avidity. Therefore, this study was planned to evaluate the roles of PET/CT in marginal zone lymphoma, which is a representative of indolent lymphoma. Method We retrospectively analyzed the data of 136 patients with advanced stage marginal zone lymphoma from 13 independent institutions between January 2008 and January 2018. All of the enrolled patients had Ann Arbor stage III-IV except some patients with stage II with bulky mass or rapid progression. Patients were treated with 6th or 8th cycles of immunochemotherapy which consisted of R-CVP (Rituximab, cyclophosphamide, vincristine, prednisolone) (90.4%), R-CHOP (Rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone) (5.9%), R-B (Rituximab, bendamustine) (3.7%). PET/CT scan was performed at diagnosis, after 2~3 cycles of immunochemotherapy (interim), and at the end of the treatment. Interim PET/CT response was assessed according to Deauville 5-PS (DS) and semi-quantitative assessment based on the rate of reduction in the SUVmax (deltaSUVmax). Results The median age of the patients was 59.5 years (range;28.0~84.0), and 115 patients (84.6%) had stage III-IV. 119 patients (87.5%) had one or more extranodal site involvement, and gastrointestinal tract (25%) was the most commonly involved extranodal site. Fifty-one patients (37.5%) were classified into high risks and 85 patients (62.5%) were with low risks based on IPI. The median SUVmax of the lesion was 4.8 (range; 0.8-23.5) on initial PET/CT. According to Deauville 5-PS in interim PET/CT, 37 patients (27.2%) were defined in score 1, 34 patients (25.0%) in score 2, 31 (22.8%) patients in score 3, 27 patients (19.9%) in score 4, and 7 patients (5.1%) in score 5. The optimal cutoff value for the deltaSUVmax was 59.8 according to the ROC analysis. After median follow up of 35.9 months, performance status, LDH, IPI and interim PET/CT response were significant prognostic factors for progression free survival (PFS) in univariate analysis. Patients who achieved complete metabolic response (DS 1-2) showed significantly longer progression free survival (PFS) than patients with DS 3-5 grade (Figure 1A, 89.3 months vs. 43.9 months, P=0.046). However, the semi-quantitative method using deltaSUVmax did not predict the survival outcome. In regard to post-treatment PET/CT assessment, patients who achieved complete response showed long PFS (Figure 1B, P 〈 0.05). In multivariate analysis, complete metabolic response (DS 1-2) achievement in interim PET/CT was the strong prognostic factor in patients with advanced stage marginal zone lymphoma (HR 2.017, 95% CI 0.981-4.147, P 〈 0.05). Conclusion Deauville 5-PS based interim PET/CT response assessment is useful to predict the survival outcome of advanced stage marginal zone lymphoma in post-rituximab era. Whereas, the semi-quantitative assessment based on deltaSUVmax did not have the prognostic impact. Figure 1. Progression free survival of all patients according to Deauville 5-PS based interim PET/CT response (Figure A, B) and post-transplant PET/CT response (Figure C) Figure 1 Disclosures No relevant conflicts of interest to declare.

Abstract: Background: Primary breast diffuse large B-cell lymphoma (DLBCL) has poor outcomes with frequent extranodal failures, particularly in the central nervous system (CNS). To prevent CNS recurrence, we designed this phase II trial that addressed feasibility and activity of conventional immunochemotherapy and CNS prophylaxis. Methods: This prospective, multicenter, single-arm phase II study was conducted to evaluate efficacy and safety of 6 cycles of conventional rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone every 21 days (R-CHOP) with the addition of 4 doses of intrathecal methotrexate (IT MTX; 12mg) during the first 4 cycles of R-CHOP in patients with primary breast DLBCL. Primary breast lymphoma was defined as lymphoma involving one or both breasts as a sole extranodal site regardless of specific nodal involvement status. The primary end-point was 2-year progression-free survival (PFS). Secondary end-points included cumulative incidence of CNS recurrence, overall survival (OS), and safety. All patients provided written informed consents and the study was registered at www.clinicaltrials.gov as #NCT01448096. Results: Thirty-three patients with primary breast DLBCL were enrolled between Jan 2012 and Jul 2017 in the Consortium for Improving Survival of Lymphoma (CISL) member institutions. The median age was 50 years at diagnosis (range, 29-75) and all were female. Right breast involvement was more common than left (18 [55%] vs 14 [42%] ) and bilateral breast involvement was found in one patient (3%). Nodal involvement was present in 16 patients (49%), primarily in regional nodes (14 patients). Thus, the Ann Arbor stage was IE in 17 (52%), IIE in 13 (39%), IIIE in 2 (6.1%), and IV in 1 (3.0%). ECOG performance status was ≥2 in 1 patient (3%) and serum LDH level was elevated in 9 (27%). Therefore, the IPI and the CNS-IPI risk were mainly low (28 patients, 85%; respectively). No patients had CNS involvement at diagnosis. 32 (97%) of the 33 patients completed R-CHOP as planned, and the remaining patient withdraw a consent after four cycles of R-CHOP because of poor tolerance. CNS prophylaxis using IT MTX was completed as planned in 31 patients (94%), but it was discontinued in 2 patients because of patient's refusal. These 2 patients received two and three IT MTX doses, respectively. 32 patients (97%) were evaluable for treatment response and all these patients achieved a complete response. At the cutoff date of this analysis (10 Jul 2019), all patients who entered a follow-up phase had at least 24.0 months of follow-up. With a median follow-up duration of 46.1 months (IQR 31.1-66.8), 6 patients had experienced treatment failure and 3 of these died. The 2-year PFS and OS were 81.3% (95% CI, 67.7-94.8) and 93.5% (95% CI, 84.9-100.0), respectively (fig 1A and B). Of the 6 patients with treatment failure, diseases involved CNS with or without lymph nodes in 4 patients and breasts in 2 patients (1 ipsilateral and 1 contralateral breast recurrence). 3 of the four patients with CNS recurrence had isolated CNS recurrences (2 brain parenchymal and 1 meningeal disease) and one had a concurrent meningeal and lymph nodal recurrence. All 4 patients with CNS recurrence had received prophylactic IT MTX as planned by protocol. The 2-year cumulative incidence of CNS recurrence, taking into account the competing risk of death, was 12.5% (95% CI, 0.3-23.2, fig 1C). Although the number of patients with intermediate CNS-IPI risk was small (5 patients, 15%), the cumulative incidence of CNS recurrence did not differ significantly according to the CNS-IPI risk group. All CNS recurrences occurred within the first 2 years after enrolment. Toxicities were generally manageable during the R-CHOP and IT MTX treatment. No deaths as a result of toxicity occurred during treatment. Conclusion: Our study shows that conventional R-CHOP with prophylactic IT MTX is feasible in patients with primary breast DLBCL. However, given a substantially high rate of CNS recurrence, further studies to properly define the best strategy for CNS prophylaxis should be needed in patients with primary breast DLBCL. Figure 1 Disclosures Yoon: F. Hoffmann-La Roche Ltd: Research Funding. Kim:Celltrion: Research Funding; Novartis: Research Funding; Donga: Research Funding; Kyowa-Kirin: Research Funding; Novartis: Research Funding; J + J: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding.

Abstract: Introduction : CT-P10 is an approved biosimilar to the innovator rituximab by both US FDA and EMA based on a review of comprehensive data package inclusive of foundational and extensive analytical characterization, nonclinical and clinical data. In patients with newly diagnosed advanced stage follicular lymphoma (AFL), equivalence of pharmacokinetics and noninferiority of efficacy was demonstrated in the primary analysis (Kim WS et al. Lancet Hematol. 2017), and progression-free survival (PFS) and overall survival (OS) at a median follow-up of 22.6 months showed the therapeutic similarity between the CT-P10 and Rituxan (RTX) (Kim WS et al. Blood 2018;132:1616). Here, we report the updated data at a median follow-up of 40 months regarding time-to-event endpoints and safety in this CT-P10 3.3 study. Methods: This phase III, randomized, and double-blind study in patients with previously untreated AFL (NCT02162771) was completed within the planned study period. Patients received R-CVP induction therapy (every 3 weeks for 8 cycles) in the Core Study Period and rituximab monotherapy (every 2 months for 12 cycles) in the Maintenance Study Period. Computerized Tomography scans were performed at baseline, month 3 and 6 during the Core Study Period, and then every 6 months for 2 years during the Maintenance Study Period. After 2 years, patients were followed every 6 months for tumor evaluation up to 3 years from the last patient's first infusion date. Kaplan-Meier (KM) method was used to estimate the time-to-event endpoints. Results: In total, 140 patients with AFL were enrolled (CT-P10-CVP; N=70, R-CVP; N=70) with a median age of 58 years and 55.0% of female. The majority of patients completed the induction therapy (62 patients [88.6%] in each group, respectively). Among them, 122 patients (62 [88.6%] patients in CT-P10 and 60 [85.7%] patients in RTX) entered the Maintenance Period and 84 patients (46 [65.7%] patients in CT-P10 and 38 [54.3%] patients in RTX) completed the maintenance therapy. To date, investigator assessed PFS, time-to-progression (TTP) and OS, medians had not been reached in either group due to insufficient number of events. The median follow-up durations of each group were 40 months (25th-75th percentile, 37 to 44) in CT-P10 and 39 months (25th-75th percentile, 36 to 43) in RTX. A total of 42 patients (21 [30.0%] patients in each group, respectively) experienced disease progression and 12 patients reported death during the study. Of these 12 patients, 5 patients (3 [4.3%] patients in CT-P10 and 2 [2.9%] patients in RTX) died due to lymphoma and the other 7 patients (5 [7.1%] patients in CT-P10 and 2 [2.9%] patients in RTX) died due to adverse events or other reasons. There were no significant differences between the 2 groups in PFS (Cox proportional Hazard Ratio [HR]: 1.33; 95% Confidence Interval [CI] : 0.67-2.63; 4-year PFS: CT-P10 60.9% [95% CI: 46.5%-72.5%], RTX 54.7% [95% CI: 36.1%-70.0%] ; Figure 1). The TTP revealed the trends similar to PFS. The KM curves showed no significant differences between the 2 groups in TTP (Cox proportional HR: 1.17; 95% CI: 0.58-2.37; 4-year TTP: CT-P10 64.2% [95% CI: 49.4%-75.7%] , RTX 55.8% [95% CI: 36.8%-71.1%]; Figure 2). Even with a limited number of events, OS was comparable between the 2 groups (Log rank p-value: 0.287; 4-year OS: CT-P10 88.0% [95% CI: 77.5%-93.8%], RTX 93.3% [95% CI: 83.2%-97.4%] ). Overall safety profiles of CT-P10 were consistent with those of RTX (Table 1). No new safety signals were identified during the study and a similar number of patients in each group experienced at least 1 treatment-emergent adverse event, infusion-related reaction, or infection considered to be related to the study drug. One patient from each group reported hepatitis B virus activation related to the study drug. The proportion of patients with positive anti-drug antibody was also similar in both groups (4.3% [3/70] vs 5.7% [4/70] in CT-P10 and RTX) and 2 patients (2.9%) in each group showed the positive neutralizing antibody results. Conclusion: Long-term efficacy results in patients with AFL showed comparable PFS, TTP and OS between the 2 groups, indicating therapeutic similarity of CT-P10 to originator RTX. In addition, CT-P10 was consistently well tolerated and showed comparable safety profiles, including immunogenicity, over the entire study period without any unexpected toxicities compared to RTX. Disclosures Buske: Amgen: Research Funding; Hexal: Honoraria, Speakers Bureau; Bayer: Research Funding; Roche: Honoraria, Research Funding, Speakers Bureau; Janssen: Honoraria, Research Funding, Speakers Bureau; Pfizer: Honoraria; Celltrion: Honoraria, Speakers Bureau. Kwak:Pepromene Bio: Consultancy, Equity Ownership, Research Funding; InnoLifes: Consultancy, Equity Ownership; Xeme BioPharma, Inc: Consultancy, Equity Ownership; Enzychem LifeSciences: Consultancy; Celltrion Healthcare: Consultancy; Celltrion, Inc.: Consultancy. Jurczak:Celtrion: Research Funding; Sandoz: Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca/Acerta: Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Research Funding; Loxo: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Research Funding; Takeda: Research Funding; Servier: Research Funding; Roche: Research Funding; Novo Nordisk: Research Funding; Incyte: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Morphosys: Research Funding; Celgene: Research Funding; Bayer: Research Funding. Sancho:ROCHE: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GILEAD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; JANSSEN: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; CELGENE: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria; SANOFI: Honoraria; SERVIER: Honoraria; CELLTRION: Consultancy; Kern-Pharma: Honoraria; Sandoz: Consultancy. Kim:Novartis: Research Funding; Donga: Research Funding; Celltrion: Research Funding; J & J: Research Funding; Kyowa-Kirin: Research Funding; Mundipharma: Research Funding; Roche: Research Funding. Ogura:Celltrion: Honoraria; Celgene: Honoraria; MeijiSeika Pharma: Honoraria; Mundi Pharma: Honoraria; Teva Takeda: Honoraria; Verastem: Honoraria. Lee:Celltrion: Employment. Kim:Celltrion: Employment. Ahn:Celltrion: Employment.

Abstract: INTRODUCTION: Fibroblastic reticular cells (FRCs) are essential for adaptive immune response and maintaining lymph node (LN) homeostasis. FRCs regulate immune cell entry into the LN and confer compartmentalization of lymphocytes by secretion of essential chemokines. Indeed, FRCs are activated and display an undifferentiated phenotype in LN of patients with follicular lymphoma, but their meaning and mode action are unclear. The mammalian Hippo signaling pathway is an essential regulator of cell fate, differentiation, and homeostasis. Its final downstream effectors YAP and TAZ (YAP/TAZ) are inhibited by LATS1 and LATS2 (LATS1/2) in a phosphorylation-dependent manner. The roles of YAP/TAZ in hematopoiesis are considered to be dispensable under healthy physiological condition, but their significance appears to be context dependent in pathologies including hematologic malignancies. OBJECTIVES: We hypothesized that the Hippo pathway plays important roles in regulating FRCs by interacting with lymphocytes, with relevance to structural and functional properties of LNs. Using FRC-specific YAP/TAZ depletion or hyperactivation mouse models, we sought to investigate the roles of YAP/TAZ in orchestrating lymphocyte homeostasis by FRCs. METHODS: Animal care and experimental procedures were performed under the approval of the Institutional Animal Care and Use Committee (KA2016-12) of KAIST. Yap/Taz∆FRC or Lats1/2∆FRC mouse were generated by crossing FRC-specific Ccl19-Cre or inducible Pdgfrb-Cre-ERT2 mouse with Yapfl/fl/Tazfl/fl or Lats1fl/fl/Lats2fl/fl mouse, respectively. Cre-ERT2-negative but flox/flox-positive littermates were defined as wild-type mice (WT). In order to induce Cre activity, 2 mg of tamoxifen (Sigma-Aldrich) was dissolved in corn oil and intra-peritoneally injected for four consecutive days. Skin-draining LNs were analyzed with immunofluorescence staining, flow cytometry, or fluorescence activated cell sorting. Chemokine expression was measured from sorted FRCs with qRT-PCR, immunoblotting, or ELISA. APC BrdU flow kit (BD Biosciences) was used for cell cycle analysis. Blood count in mice was measured with hemocytometer (pocH-100iV DiFF, Sysmex). RESULTS: Both YAP/TAZ were highly and equally distributed in nucleus and cytoplasm of mouse LN FRCs, in addition to blood and lymphatic endothelial cells. LNs of Yap/Taz∆FRC mice compared with WT revealed a slight reduction in LN weight and reduced total cell number (~64.9%), decreased proportion (~42.9%), and number (~61.1 %) of FRCs among CD45- stromal cells, which were less proliferative (~65.2%) but had no difference in apoptosis. However, neither proliferation nor apoptosis of immune cells was altered. Analysis of isolated FRCs revealed that mRNA levels of lymphoid chemokines for immune cell trafficking and function were significantly attenuated in Yap/TazΔFRC mice compared with WT. Intriguingly, Lats1/2∆FRC mice looked pale from 1 week after birth. We found lower red blood cell (RBC) count (~16.1%) with decreased concentration of hemoglobin (~25.8%) in Lats1/2∆FRC mice compared with WT, suggesting hypochromic anemia. Moreover, although whole body length and overall organ size were small in Lats1/2∆FRC mice compared with WT at 2 weeks after birth, we could not observe any gross or microscopic abnormalities in major organs including brain, heart, lung, liver, and kidney in Lats1/2∆FRC mice. We further analyzed the primary lymphoid organ thymus and the secondary lymphoid organ spleen, as they are both supported by CCL19+ FRCs. Similar to major organs, the overall size of thymus and spleen was smaller in Lats1/2∆FRC mice compared with WT at 2 weeks after birth. However, microscopic analysis of thymus revealed that the border between the cortex and medulla was disrupted by the expanded medulla at the periphery that blends into the surrounding cortex in Lats1/2∆FRC mice, and analysis of spleen also revealed unclear lymphoid follicles with significantly reduced number of immune cells within the expanded white pulp in Lats1/2∆FRC mice compared with WT. CONCLUSIONS: Our findings present YAP/TAZ as essential governors of FRCs by supporting hematopoiesis and lymphocyte homeostasis. Considering that YAP/TAZ are enriched in bone marrow stromal cells, additional work to elucidate their role in promoting bone marrow microenvironment will improve our understanding on hematopoietic stem cell niche. Disclosures No relevant conflicts of interest to declare.