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Background: Clinical trials have demonstrated the effectiveness of the CD30-targeted antibody-drug conjugate brentuximab vedotin (BV) for the treatment of classical Hodgkin lymphoma (HL) and non-Hodgkin lymphoma(e.g. ALCL, PTCL-NOS, AITL, CTCL and etc.). While clinical trials are critical for establishing efficacy, collection of real-world data outside of the controlled trial setting is important to evaluate how interventions are applied and assess the effectiveness of new treatments in routine clinical practice. Inclusion criteria are often rather restrictive compared with the patient populations seen by physicians in daily practice. There are limited real-world data related to treatment with BV in China. Our study aims to obtain timely real-world knowledge in terms of safety and effectiveness of BV in CD30+ lymphoma patients in China. Study Design and Methods: The study (NCT04837222) is a real-world, prospective, multicenter study to evaluate the safety and effectiveness of BV in patients with CD30+ lymphoma in China. Consecutive CD30+ lymphoma patients treated with BV as a part of standard clinical practice will be enrolled. Key inclusion criteria includes adult patients undergoing treatment with BV or to be received with BV, patient/legal guardian must be able to read, understand, and sign the Informed Consent Form, CD30+ lymphoma by INV (any CD30 expression). Exclusion criteria includes patient who currently participates in or with plan to participate in any interventional clinical trial, any other reason that, in the investigator's opinion, makes the patient unsuitable to participate in this study. As CD30+ lymphoma is not a common disease and the affordability of novel treatment is limited, 1000 patients with CD30+ lymphoma will be recruited from almost 30 hematology centers. The physician will determine the treatment regimen, as well as the frequency of laboratory and clinical assessment according to her/his routine practice. All patients will be followed up per routine clinical practice and data will be documented at baseline/3/6/9/12/18/24 months unless withdrawal of Informed Consent, death or loss of follow-up, whichever comes first. Loss to follow-up will be minimized through active contact with participating patients thereafter to ensure almost all clinically relevant outcomes will be captured. The primary endpoint is serious adverse events. Secondary endpoints include adverse events, adverse drug reaction, dose adjustment, characteristics of patients receiving BV, use of BV, number of BV cycles administered, disease characteristics, time to next treatment, overall response rate, duration of response, progression free survival rate, overall survival rate, quality of life and cost-effectiveness ratio. Descriptive analysis will be performed for data analysis. Disclosures Zhang: Takeda Pharmaceuticals: Current Employment.

Backgrounds: Relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL) patients have limited treatment options and are associated with poor prognosis. Patients generally receive salvage therapy as rituximab, ifosfamide, carboplatin and etoposide (R-ICE), followed by consolidation with high-dose therapy (HDT) and autologous stem cell transplantation (ASCT). However, only approximately 50% of patients can proceed to ASCT and only half of these achieve durable remission post-transplant. New therapeutic strategies are needed to improve response rates and to prevent recurrence following ASCT. The immunomodulatory agent lenalidomide has demonstrated direct anti-tumor effects in lymphoma. Some studies found that the addition of lenalidomide to the widely used R-ICE salvage regimen is feasible and results in promising response rates in R/R DLBCL patients. Pomalidomide is a third-generation immunomodulatory drug that has shown excellent therapeutic activity against relapsed/refractory primary central nervous system lymphoma (PCNSL) and primary vitreoretinal lymphoma (PVRL) with an acceptable toxicity profile. We aim to determine the safety, tolerability and efficacy of pomalidomide in combination with R-ICE in R/R DLBCL patients. Study Design and Methods: PRIDE (ChiCTR2100049327) is a phase I/II trial of pomalidomide plus R-ICE (PR-ICE) as a salvage regimen for first-relapse or primary refractory DLBCL. In phase I of the study, patients receive escalating doses of pomalidomide (2mg, 3mg or 4mg daily on d1-10) along with R-ICE therapy every 21 days by standard 3+3 design until the MTD has been determined. In stage II, all subjects receive three cycles of R-ICE plus pomalidomide, dosing as RP2D. Patients with CR or PR but not eligible for ASCT receive continuous pomalidomide as maintenance therapy for 12 months. Key eligibility criteria are as follows: histologically confirmed DLBCL; relapsed or refractory after one prior treatment for DLBCL; age 18-75 years; absolute neutrophil count >1500 /mm 3; platelet count > 75,000/mm 3; calculated creatinine clearance of over 60 mL/min by Cockroft-Gault formula; total bilirubin < 1.5×ULN; AST and ALT < 3×ULN. The primary endpoint of phase II is the CR rate after PR-ICE induction treatment. The CR rate for R-ICE in R/R DLBCL was estimated to be approximately 35%. We hypothesize that the addition of POM to R-ICE could increase the CR rate by approximately 20%. For phase II, it requires a sample size of 44 evaluable patients (one-sided alpha = 0.05, power 80%, dropout rate of 15%). Eligible patients who receive at least one dose of PRICE will be included in the efficacy and safety analyses. The 95% CI of CR was calculated using Clopper-Pearson method. The Kaplan-Meier method was used to estimate PFS and OS. All these analyses were conducted using SAS 9.4 software. Enrollment for phase I will begin in Q4 of 2021. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare. OffLabel Disclosure: Pomalidomide is indicated for the treatment of adult patients: in combination with dexamethasone, for patients with multiple myeloma (MM) who have received at least two prior therapies including lenalidomide and a proteasome inhibitor and have demonstrated disease progression on or within 60 days of completion of the last therapy in China. The abstract presents the rationale for the use of generic pomalidomide in combination with R-ICE, a combination that is not approved in China at present.

Introduction:Mantle cell lymphoma is an uncommon subtype of B-cell non-Hodgkin lymphoma with variable initial treatment strategies defined by disease risk factors, patient preferences and access to medical care. There is a paucity of reported data on treatment patterns and clinical outcomes in Chinese patient populations managed in the rituximab era. The study aim was to evaluate and compare outcome in relation to prognostic factors and first-line treatment in patients with MCL managed in real-world academic medical centers in China. Methods:Retrospective data were collected from 5 major Chinese Hematology Centers in Beijing, Guangzhou, Nanjing, Shanghai and Suzhou from the period of 2007 to 2017. Diagnosis for MCL was based on characteristic immuno-phenotype and CyclinD1 immunohistochemistry staining. Overall Survival (OS) time was calculated from date of diagnosis to date of death or date of last follow-up, whichever comes first. Kaplan-Meier estimator was used to estimate survival probability. Median follow-up time was estimated on overall survival by reverse Kaplan-Meier method. Survival difference between groups was evaluated by log-rank test for statistical significance. Results:A total of 605 patients with newly diagnosed MCL were included in the analysis. The median follow-up time of the whole group was 38 months. The median age was 58 years (range 28-83) with 59% patients under age 60; the M:F ratio was 3.5:1; 76% presented with ECOG PS of 0-1. Eighty-three percent patients had stage 3-4 disease, 38% had intermediate and high risk MIPI scores, and 30% had IPI scores of 3-5. Ki-67 was 30 (p=0.003). OS correlated with MIPI and IPI scores. The 3-year OS rates were 39.7%, 67.7% and 86.7% respectively for high-, intermediate- and low-risk MIPI scores (p Conclusions:This large retrospective dataset of MCL patients who received contemporaneous real-world management in Chinese Hematology Centers confirmed the survival advantage afforded by rituximab-containing chemo-immunotherapy and consolidative autologous stem-cell transplant in first-line setting. The majority of patients seeking care at major medical centers were younger than 60 years of age with good performance status and lower risk MIPI/IPI scores, which correlated with more favorable survival. Incorporation of novel agents signaled infrastructural readiness to explore novel agents and combination in both first-line and relapsed settings. Disclosures Ruan: Celgene: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Pharmacyclics LLC, an AbbVie company: Research Funding; Juno: Consultancy; Kite: Consultancy.

A Phase II Study of Lenalidomide Plus Rituximab in Patients with Newly Diagnosed Follicular Lymphoma: An Interim Analysis Zhong Zheng1, Li Wang1,2, Shu Cheng1, Peng-Peng Xu1, Wei-Li Zhao1,2 1State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Shanghai Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China 2Pôle de Recherches Sino-Français en Science du Vivant et Génomique, Laboratory of Molecular Pathology, Shanghai, China Abstract Background: Follicular lymphoma (FL) is the most common subtype of indolent non-Hodgkin lymphoma (iNHL). Rituximab plus chemotherapy for FL significantly improves the outcome of the patients, nevertheless, most patients ultimately relapse. Therefore, novel agents along with Rituximab have been applied to increase treatment efficacy in this subset of iNHL patients. Tumor immune eascape plays a crucial role in lymphoma progression. Through modulating tumor microenvironment, lenalidomide, are emerging as effective therapeutic approaches to affect tumor immunity and inhibit lymphoma cells proliferation. However, its anti-tumor activity activity has not yet been assessed in de-novo chinese FL patients. This prospective phase II study is to evaluate the efficacy and safety of lenalidomide in combination with Rituximab (R2) in newly diagnosed FL patients (NCT 03715309). Methods: Patients with newly diagnosed FL (grade 1 to 3a), aged 16 to 75 years, Eastern Cooperative Oncology Group performance status of 0 to 2 are enrolled. The doses and administration schedule are as follows: rituximab 375 mg/m2 on day 0, lenalidomide 25mg from day 1 to day 10 every 3 weeks for 6 cycles. The primary endpoint is complete response (CR) rate assessed by PET-CT, and secondary endpoints include progression-free survival (PFS), overall survival (OS), overall response rate (ORR) and main adverse events (AEs). Results: To date, eighty-six patients have been enrolled, with median age of 48 years (range, 22-73). At diagnosis, Seventy-seven patients (89.5%) presented advanced Ann Arbor stage and 19 cases (22.0%) showed elevated serum LDH level. Twenty-nine patients (33.7%) had multiple extra-nodal sites involving bone marrow, bone, gastrointestinal, and spleen. Twenty-one patients (24.4%) had IPI scores ≥ 3. For Sixty-four patients available for response evaluation, the CR rate was 81.2% (52/64) and the ORR was 90.1% (58/64). Grade 3-4 neutropenia was found in 18 cases (20.9%). No grade 3-4 thrombocytopenia and grade 3-4 anemia were observed. For non-hematological AEs, cutaneous reactions and tumor flare reaction were observed in 12 cases (13.9%) and in 1 case (1.16%), respectively, while no grade 4 non-hematological AEs were presented. Conclusion: Lenalidomide Plus Rituximab as first-line therapy for de novo patients with FL showed encouraging response and good tolerability. Disclosures No relevant conflicts of interest to declare.

Background: JWCAR029 is a CD19-directed 4-1 BB CAR T cell product, of which CD4 and CD8 CAR T cells are produced together and transfused in non-fixed ratio. A phase I, single-arm, open label study was conducted to evaluate the safety and efficacy of JWCAR029 in patients (pts) with relapsed or refractory B-NHL. Previously, preliminary data in six pts (Yan et al, Blood 2018 132:4187) showed high response rates and favorable safety profiles of JWCAR029. Herein, we presented the data of the Phase I trial of JWCAR029 (NCT03344367 and NCT03355859) in 29 pts with pharmacokinetics (PK), pharmacodynamics (PD), and anti-therapeutic antibody (ATA) evaluations. Methods: Eligible pts received lymphodepletion, with 25mg/m2 flu and 250mg/m2 cy, followed by a single dose of JWCAR029 at one of four dose levels (DL1, 25×106 cells; DL2, 50×106 cells; DL3, 100×106 cells; DL4, 150×106 cells). Blood samples were collected and analyzed for PK, PD, and ATA at a central lab per protocol defined time points. The existence and duration of CAR T cells (PK) were measured by validated flow cytometry and qPCR assays. CD4 and CD8 subpopulation of CAR+ T cells were detected by cetuximab targeting EGFRt as a marker co-expressed with CAR transgene in fresh peripheral blood. In parallel, batched frozen blood samples collected from each pt were detected for integrated CAR transgene by qPCR at the same protocol defined time points. Plasma ATA against murine CD19 scFv (FMC63) was measured with a validated electrochemiluminescent (ECL) assay. Results: As of July 5, 2019, blood samples from 29 pts who received JWCAR029 treatment with a minimum follow-up of 6 M (median, 6 M) were evaluable in the analysis. From DL1 to DL4, median Cmax, Tmax and AUC0-28 for JWCAR029 transgene detected by qPCR did not differ among dose levels (Table 1). CD4/CD8 ratio (range, 0.23-5.50) at cryopreserved drug product of JWCAR029 was not associated with best response of CR/PR at 6 M. Greater in vivo expansion was detected by both qPCR and flow cytometry in pts with best response of CR/PR than those with SD/PD at 6 M (Table 1). Higher concentration of CD8+CAR+T cells than CD4+CAR+T cells were detected in PB by flow cytometry for all treated pts (Cmax median= 30.6 vs 5.64). At 3 M, 81.5% (22/27) and 48.2% (13/27) pts had detectable CD8+ and CD4+ CAR+ T cells, respectively. Of those pts with detectable CAR+ T cells at 3 M, 70% (14/20) and 35% (7/20) had detectable CD8+ and CD4+ CAR+ cells at 6 M, respectively. Significantly higher Cmax and AUC0-28 were observed in patients with ≥ Grade 1 CRS (Cmax median= 85004 vs 16328, P 27.5% of pts (8/29) had detectable ATA in plasma, of which 25% (2/8) pts had pre-existing antibodies before CAR T cell infusion. 6 pts developed antibodies without pre-existing antibodies and were considered treatment-induced. The median time for treatment-induced antibody development was 6 M (range, 3-12). Increasing level of antibodies were detected at median time of 6 M (range, 6-6) for pts who had pre-existing antibodies and were considered treatment-boosted. No significant differences in PK profiles of JWCAR029 transgene levels were found between ATA negative group and treatment-induced ATA positive group (Cmax median= 44497 vs 50032; AUC median= 420635 vs 313654; Fig.1). Although the sample size of the treatment-boosted subgroup was small, there was a trend for lower expansion of CAR T cells in pts who had pre-existing ATA than pts who did not develop ATA (Cmax median= 3051 vs 44497; AUC median = 16437 vs 420635;Fig.1). In ATA positive subgroup, 100% (8/8) pts responded with CR rate of 75% (6/8). 6 M-response rate was 65.5% (5/8) for ATA positive subgroup and 57.1% (12/21) for ATA negative subgroup. Incidence of ≥ Grade 1 CRS or NT was indistinguishable between ATA positive and negative subgroups, 50% (4/8) in ATA positive vs 57.1% (12/21) negative. Conclusion: Preliminary data from JWCAR029 Phase I study has demonstrated that pts with best response of CR/PR at 6 months had a relatively higher CAR T cell expansion. Current data suggested that the prevalence of pre-existing ATA may compromise CAR+T PK profile. No association of the presence or boost of ATA with efficacy or safety of JWCAR029 was observed. Further exploration of ATA and clinical outcomes will be studied in the ongoing pivotal Phase 2 study in 70 pts with B-NHL. Disclosures Hao: JW therapeutics (Shanghai) Co., Ltd: Employment, Equity Ownership. Wang:JW therapeutics (Shanghai) Co., Ltd: Employment, Equity Ownership. Zhou:JW therapeutics (Shanghai) Co., Ltd: Employment, Equity Ownership. Yang:JW therapeutics (Shanghai) Co., Ltd: Employment, Equity Ownership. Wang:JW therapeutics (Shanghai) Co., Ltd: Employment, Equity Ownership. Lam:JW therapeutics (Shanghai) Co., Ltd: Employment, Equity Ownership. Li:JW therapeutics (Shanghai) Co., Ltd: Employment, Equity Ownership. Zheng:JW therapeutics (Shanghai) Co., Ltd: Employment, Equity Ownership.

Background Cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) or CHOP-like chemotherapy is widely used for treatment of peripheral T-cell lymphoma (PTCL). Given the poor response to CHOP-based regimens and the potential anti-lymphoma activity by alternating chemotherapy in PTCL, we conducted a phase 2, multi-center, randomized, controlled trial, comparing the efficacy and safety of CEOP/IVE/GDP alternating regimen with CEOP in a Chinese cohort of newly diagnosed patients with PTCL. Methods The primary endpoint of the study was the complete response rate (CRR). Patients with newly diagnosed PTCL, except for anaplastic large cell lymphoma (ALCL)- anaplastic lymphoma kinase (ALK) positive, were 1:1 randomly assigned. Patients in the CEOP/IVE/GDP group received intravenous cyclophosphamide 750 mg/m², epirubicin 70 mg/m², and vincristine 1.4 mg/m² (up to a maximum of 2 mg) on day 1, and oral prednisone 60 mg/m2 (up to a maximum of 100 mg) on day 1-5 every 21 days, at the 1st and 4th cycle with CEOP. Intravenous ifosfamide 2000 mg/m2 on day 1-3, epirubicin 70 mg/m2 on day 1, and etoposide 100 mg/m2 on day 1-4 every 21 days, at the 2nd and 5th cycle with IVE. Intravenous gemcitabine 1000 mg/m² on day 1, and 8, cisplatin 25 mg/m² on day 1-3, and dexamethasone 40mg on day 1-4 every 21 days, at the 3rd and 6th cycle with GDP, for a total of 6 cycles. Patients in the CEOP group received standard CEOP regimen every 21 days for 6 cycles. Analysis of efficacy and safety was of the intent-to-treat population. The study was registered with ClinicalTrials.gov, number NCT02533700. Findings Between Sep 22, 2015 and Sep 23, 2018, 102 patients were randomly assigned to two treatment groups: 51 each to the CEOP/IVE/GDP and the CEOP group. One patient was excluded because of the change of diagnosis and 3 patients withdrew informed consent before treatment in both study groups. 49 patients in the CEOP/IVE/GDP group and 49 patients in the CEOP group were included into efficacy and safety analysis as intent-to-treatment population. CRR at the end of treatment (EOT) in the CEOP/IVE/GDP group was similar as the CEOP group (36.7% vs. 32.7%, OR 0.84, 95% CI 0.36-1.88; p=0.835), while overall response rate (ORR) at EOT was higher in the CEOP/IVE/GDP group (73.5% vs. 51.0%, OR 0.38, 95% CI 0.17-0.86; p=0.037). There was no difference in median progression-free survival (15.4 months [95% CI 9.8-21.1] vs 10.7 months [4.5-16.8]; HR 0.73, 95% CI 0.45-1.18; p=0.20) or overall survival (24.3 months [95% CI 17.0-31.6] vs 21.9 months [7.5-36.2]; HR 0.69, 95% CI 0.41-1.17; p=0.17) between the CEOP/IVE/GDP and the CEOP group. Grade 3-4 hematological and non-hematological adverse events were similar between two study groups. Interpretation CEOP/IVE/GDP regimen showed similar CRR at EOT as CEOP regimen in PTCL. Nevertheless, CEOP/IVE/GDP increased ORR at EOT and could potentially bridge more patients to hematopoietic stem cell transplantation. Disclosures No relevant conflicts of interest to declare.

Introduction JWCAR029 is a CD19-directed 4-1BB chimeric antigen receptor (CAR) T cell product with a 4-1BB costimulatory domain, of which CD4 and CD8 CAR T cells are produced together and transfused in non-fixed ratio. We conducted a single arm, open-label, dose escalation Phase I trial of JWCAR029 in relapsed and refractory B-cell non-Hodgkin lymphoma (NCT03344367 and NCT03355859). Methods Eligible pts had confirmed B-cell NHL with R/R disease after ≥2 prior lines of therapy. All subjects received lymphodepleting chemotherapy prior to receiving JWCAR029. After lymphodepleting chemotherapy, JWCAR029 was administrated as a single infusion in escalating dose levels, from 25×106 CAR T cells (dose level 1, DL1), 50×106 CAR T cells (dose level 2, DL2), 100×106 CAR T cells (dose level 3, DL3) to 150×106 CAR T cells (dose level 4, DL4) according to mTPI-2 algorithm. Circulating blood counts, serum biochemistry, coagulation status, and cytokines were followed up after infusion. Cytokines were assessed on a Luminex platform. Tumor evaluation was evaluated per the Lugano criteria by PET-CT (Cheson, 2014) and safety and disease status was followed at approximately 1, 3, 6, 9, 12, 18 and 24 months after receiving JWCAR029. PK was measured by flow cytometry and real-time quantitative polymerase chain reaction system. All the adverse events were recorded for 24 months after infusion. The study was approved by Beijing Cancer Hospital and Shanghai Rui Jin Hospital Review Board with informed consent obtained in accordance with the Declaration of Helsinki. Results As of July 5, 2019, 44 patients were screened and 32 patients were enrolled and received treatment in two study sites in China. Twenty nine patients are evaluable and have been followed for at least 6 months: 20 diffuse large B cell lymphoma (DLBCL) and 9 follicular lymphoma, mantle cell lymphoma and extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue lymphoma. Median age was 52 years (range 29 to 68 years). The demographic characteristics of the patients are shown in Table 1. All patients received immunochemotherapy as induction and a median of four lines of salvage treatment (range 2 to 7). Eleven (34%) patients received bridging chemotherapy after T cell collection due to rapid tumor progression, followed by re-evaluation before CAR T cell infusion. Lymphodepletion consisted of fludarabine 25mg/m2/d and cyclophosphamide 250mg/m2/d on Day -4 to Day -2, followed by CAR T cell infusion on Day 0. Median time to peak CAR+ T cell expansion was 11 (8-15) days. No DLTs were reported. There were no treatment-related deaths. Seventeen patients (53.1%) reported cytokine release syndrome (CRS) with 16 grade 1 or 2 (50%) and 1 (3.1%) grade 3. No grade 4 or 5 CRS was observed. Main symptoms were fever (>39.0 degrees), fatigue, and muscle soreness. The rate of CRS was similar across dose level groups. Grade 1 and 2 neurotoxicity was observed in 5 patients (15.6%). No grade ≥3 neurotoxicity was reported. Most common adverse events (frequency >20%) included leukopenia (Gr 3-4: 21.9%, Gr 1-2: 43.8%), lymphopenia (Gr 1-2: 21.9%, Gr 3-4: 21.9%), neutropenia (Gr 1-2: 37.5%, Gr 3-4: 28.2%), thrombocytopenia (Gr 1-2: 21.9%, Gr 3-4: 3.1%), pyrexia (Gr 1-2: 21.9%) and immunoglobulins decreased (Gr 1: 28.1%). Among all 29 efficacy-evaluable patients (6 of DL1, 6 of DL2, 8 of DL3 and 9 of DL4), the best ORR was 89.7%; 85% for DLBCL patients. ORR/CRR of all evaluable patients at 1, 3 and 6 months were 86.2%/65.5%, 69%/62.1% and 58.6%/55.2%, respectively, and for the 20 DLBCL patients the ORR/CRR was 80%/60%, 55%/55%, and 45%/45%, respectively (Table 2). Conclusion Although longer follow-up is needed, the data from 29 evaluable patients in this Phase I trial have demonstrated high response rates and a favorable safety profile of JWCAR029 in relapsed and refractory B-cell non-Hodgkin lymphoma. A Ph II trial that further assess safety and efficacy of JWCAR029 in DLBCL and FL patients has been initiated and is open for enrollment. Disclosures Wang: JW therapeutics (Shanghai) Co., Ltd: Employment, Equity Ownership. Hao:JW therapeutics (Shanghai) Co., Ltd: Employment, Equity Ownership. Yang:JW therapeutics (Shanghai) Co., Ltd: Employment, Equity Ownership. Lam:JW therapeutics (Shanghai) Co., Ltd: Employment, Equity Ownership. Li:JW therapeutics (Shanghai) Co., Ltd: Employment, Equity Ownership. Zheng:JW therapeutics (Shanghai) Co., Ltd: Employment, Equity Ownership.

Background: Diffuse large B-cell lymphoma (DLBCL) represents the most common subtype of non-Hodgkin's lymphoma and is heterogeneous in clinical, immunophenotypic and genetic features. More than 50% of patients with DLBCL are older than 60 years at diagnosis. Among them, up to 40% of patients relapse or develop refractory disease upon R-CHOP treatment. Dose-dense R-CHOP14 failed to show superior efficacy or survival compared with standard R-CHOP21 in elderly patients and intensive chemotherapy followed by autologous stem cell transplantation was difficult due to toxicity. Therefore, development of new first-line therapy remains great interests to improve disease outcome in elderly patients with DLBCL. Perturbation of the epigenome plays a crucial role in lymphoma progression. Several histone deacetylase inhibitors (HDACIs) have been investigated in relapsed or refractory DLBCL as mono- or combination treatment, showing promising activities to suppress lymphoma growth and overcome resistance to immune-chemotherapies. This prospective phase II study was to evaluate the efficacy and safety of chidamide in combination with R-CHOP21 in elderly patients with newly diagnosed DLBCL (NCT02753647). Methods: Patients with newly diagnosed DLBCL, aged 61 to 75 years, Eastern Cooperative Oncology Group performance status of 0 to 2, IPI>1 were enrolled. The dose and administration schedule were as follows: rituximab 375 mg/m2 on day 0, cyclophosphamide 750mg/m2 on day 1, doxorubicin 50mg/m2 on day 1, vincristine 1.4 mg/m2 on day 1, prednisone 60 mg/m2 from day 1 to day 5, chidamide 20mg/d on days 1, 4, 8 and 11, every 21 days for 6 cycles. The primary endpoint was complete response (CR) rate assessed by PET-CT, and secondary endpoints included progression-free survival (PFS), overall survival (OS), overall response rate (ORR) and main adverse events (AEs). Results: From March 2016 to April 2018, 49 patients were enrolled; 41 patients completed all treatment and 8 patients were still in the treatment cycles. Median age was 67 years (range, 61-75) and 28 patients (57.1%) were male. Thirty-eight patients (77.6%) presented advanced Ann Arbor stage, and 41 patients (83.7%) showed elevated serum LDH level. Thirty-one patients (63.3%) had multiple extra-nodal sites, mainly involving bone, gastrointestinal, liver, and bone marrow. Forty-one patients (83.7%) had IPI scores ≥3 at diagnosis. By immunohistochemistry, 12 (24.5%) patients were categorized as germinal center B-cell (GCB) subtype based on Hans algorithm, and 12 (25.5%) patients were defined as BCL-2 and MYC double expression. Among 41 patients available for evaluation, the CR rate was 85.4% (35/41), and the ORR was 90.3% (37/41). After a median follow-up of 18 months (range, 3-30), the 1-year PFS was 92.1% and 1-year OS was 94.7%. There were 2 deaths due to disease progression, of which 1 had triple-hit lymphoma. Regarding toxicity, grade 3-4 neutropenia was observed in 167 cycles (60.5%), grade 3-4 thrombocytopenia in 27 cycles (9.8%), and grade 3 anemia in 11 cycles (4.0%). However, febrile neutropenia was reported in significantly fewer cycles (6.1%) and was a maximum of grade 3. Grade 3 liver dysfunction was observed in 7 cycles (2.5%). No grade 4 non-hematological events were reported. Of note, 2 patients positive for EBER-ISH at diagnosis remained in EBV-DNA negative during treatment and follow-up. Conclusion: Chidamide with R-CHOP21 is effective and safe in elderly patients with newly diagnosed DLBCL. Disclosures No relevant conflicts of interest to declare.

MicroRNAs (miRs), a class of 19- to 23-nucleotide non-coding RNA molecules, are involved in tumorigenesis by regulating tumor cells and microenvironment. Our study revealed serum miR21 expression in a large cohort of B-cell lymphoma patients and the biological function of miR21 both in vitro and in vivo. Comparing with healthy volunteers, serum miR21 was significantly increased in patients with B-cell lymphoma (Figure 1A). As revealed by immunohistochemistry in 50 tumor samples of DLBCL, CD31-positive microvessels were more frequently observed in high miR21 group than in low miR21 group (Figure 1B). High miR21 expression patients displayed more peripheral blood Treg cells than low miR21 expression patients, instead of natural killer (NK) cells (Figure 1C). We futher study the biological function of miR21, B-lymphoma cell SU-DHL-4 were transfected with miR21 mimics and treated with chemotherapeutic agents. Under the monoculture condition, as compared to the control mimics, ectopic expression of miR21 significantly diminished the cytotoxic effect of doxorubicin and cisplatin, but sensitized lymphoma cells to ABT-199. Under the direct co-culture system, mimicking lymphoma microenvironment, miR21 overexpression resulted in lymphoma cell resistance to chemotherapeutic agents, but sensitivity to ABT-199 in the direct co-culture system. ABT-199 remarkably downregulated miR21 expression in both the monoculture system and the direct co-culture system, irrespective to Bcl-2 expression. To clarify the underlying mechanism of miR21-mediated sensitization of ABT-199 on B-cell lymphoma, we studied the effect of miR21 on HUVEC sorted from the direct co-culture system. Co-culturing with miR21-overexpressing lymphoma cells significantly stimulated HUVEC growth, which was retarded by ABT-199 (Figure 2A). As detected by ELISA, VEGFA was increased by miR21 transfection and reduced by ABT-199 in both control siRNA-transfected HUVEC and Bcl-2 siRNA-transfected HUVEC (Figure 2B). Accordingly, similar changes of tube formation and endothelial cell migration towards lymphoma cells were present (Figure 2C). We hereafter studied the effect of miR21 on Treg cells sorted from the direct co-culture system. Consistent with change of VEGFA, co-culturing with miR21-overexpressing lymphoma cells significantly increased VEGFR2 expression on Treg cells, which were decreased by ABT-199 (Figure 2D). ABT-199-induced downregulation of VEGFA/VEGFR2 signaling was associated with Treg cell growth inhibition, resulting in reduction of immunosuppressive cytokine TGF-¦Â and molecule IL-2 (Figure 2E and 2F). In the direct co-culture system, miR21 overexpression induced ICOS expression on Treg cells and ICOSL expression on HUVEC and, both of which were inhibited by ABT-199 (Figure 3A). To confirm the role of ICOS/ICOSL axis, antibody against ICOS was added to the direct co-culture system. Pharmacological inhibition of ICOS/ICOSL interaction significantly abrogated the sensitivity of miR21-overexpressing cells to ABT-199, as well as HUVEC and Treg cell growth (Figure 3B). Blockade of ICOS/ICOSL also interfered the action of ABT-199 on VEGFA/VEGFR2 signaling between Treg cells and endothelial cells (Figure 3C). Murine xenograft model was established with subcutaneous injection of B-lymphoma cells, ABT-199 particularly retarded the growth of miR21-overexpressing tumors, consistent with the inhibition of ICOS/ICOSL axis, VEGFA/VEGFR2 signaling, tumor angiogenesis and Treg cell growth. Collectively, these data demonstrated that miR21 plays an oncogenic role in B-cell lymphoma by modulating tumor microenvironment and supported clinical rationale for using miR21 as a biomarker to select chemoresistant B-lymphoma patients who may benefit from treatments containing ABT-199. Disclosures No relevant conflicts of interest to declare.

Introduction: Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous group of aggressive lymphomas with a relapse/refractory rate of 30-40% under the current standard Rituximab plus cyclophophamide, adrimycin, vincristine and prednisone (R-CHOP21) treatment. As mechanism of action, Rituximab can target the B-cell receptor (BCR) and NF-ĸB signaling pathways, of which activating gene mutations are most frequently identified in activated B-cell-like (ABC) subtype of DLBCL and associated with increased disease relapse of the patients. The aim of our study was to investigate the clinical efficacy of additional two cycles of Rituximab maintenance (RM) in DLBCL and its relation with mutational status involved in BCR/NF-ĸB cascade. Methods: We retrospectively analyzed a total of 534 de novo DLBCL patients after 6 cycles of R-CHOP21 regimen in our institution from December 1998 to December 2012. Among 413 patients achieved complete response (CR), 211 patients received additional 2 cycles of RM in a intent-to-treat manner and 202 patients underwent observation (OBS). The remaining 121 patients were primarly refractory to R-CHOP regimen. All the patients were classified according to IPI and NCCN-IPI as previously described. Immunohistochemistry for germinal center B-cell (GCB) or non-GCB subgroups were determined by Hans classification. The mutational status of BCR/NF-ĸB-associated genes (mainly as CD79A, CD79B, MYD88, and CARD11) were detected in tumor samples of 124 patients (48 cases, 43 cases and 33 cases in the RM, OBS and Refractory group, respectively). Results: No significant difference of clincial and biological characteristics were found between the RM and OBS group, including age, gender, Ann Arbor stage, ECOG score, number of extranodal involvements, serum lactic dehydrogenase level, B symptoms, IPI and NCCN-IPI risk group, and GCB/non-GCB ratio. With a median follow-up of 36.5 months, the 3-year progrssion free survival (PFS) was 79.9% and 73.6% (P=0.123), and the 3-year overall survival (OS) was 91.0% and 87.4% (P=0.149) in RM and OBS group, respectively. According to NCCN-IPI, remarkable improvement of 3-year PFS and OS was observed in low-risk patients of the RM group (100% and 100%), comparing with those of the OBS group (82.5% and 88.2%, P=0.003 and 0.027 respectively, Figure 1). Similarly, male patients with low-risk IPI could also benefit from additional 2 cycles of Rituximab with a 3-year PFS of 100% in RM vs 84.4% in OBS (P=0.006). Overall, BCR/NF-ĸB mutations were detected in 46/124 patients (37.1%), including 20/48 (41.7%), 13/43(30.2%) and 13/33 (39.4%) patients in RM, OBS and Refractory group, respectively. However, MYD88 mutations were more frequently observed in the Refractory group than in the RM/OBS group (18/33 vs 6/91, P Conclusion: Low-risk NCCI-IPI patients with DLBCL responded to R-CHOP regimen benefit from additional two cycles of RM. As a potential target of Rituximab, BCR/NF-ĸB-associated mutations reflected disease resistance to Rituximab. Whether prolonged administration of Rituximab could improve the prognosis of the patients with these mutations warrants further investigation. Table 1. The distribution of BCR/NF-κB-associated mutations in patients with DLBCL Mutated gene Refractory (N=33) CR (N=91) Additional 2R (N=48) Observation (N=43) P value CD79a 1 (3.0%) 0 (0%) 0 (0%) 0.595a CD79b 5 (15.1%) 10 (20.8%) 6 (13.9%) 0.750 a MYD88 18 (54.5%) 3 (6.0%) 3 (6.9%) Figure 1. Progression-free survival (A) and overall survival (B) curves of diffuse large B-cell lymphoma patients according to low-risk NCCN-IPI. Figure 1. Progression-free survival (A) and overall survival (B) curves of diffuse large B-cell lymphoma patients according to low-risk NCCN-IPI. Figure 2. Progression-free survival (A) and overall survival (B) curves of diffuse large B-cell lymphoma patients with BCR/NF-ĸB-associated mutations. Figure 2. Progression-free survival (A) and overall survival (B) curves of diffuse large B-cell lymphoma patients with BCR/NF-ĸB-associated mutations. Disclosures No relevant conflicts of interest to declare.