Abstract: T cell therapy for the treatment of malignant diseases is based on the lenti- or retroviral introduction of an exogenous receptor in peripheral blood T cells. The exogenous receptor is either antibody based or T cell receptor (TCR) based. Chimeric antigen receptors (CAR) are antibody based receptors that can redirect T cells against membrane antigens expressed by malignant cells. CD19-specific CARs were reported to be very effective in the treatment of CD19+ acute leukemias. To redirect T cells based on cytoplasmic antigens, transduction of a TCR is required. However, this approach still faces technical problems, esp. interference of the endogenous TCR chains may cause loss of avidity and possibly induction of autoimmunity. We here present an alternative strategy, in which, not mature T cells but CD34+ hematopoietic precursor cells are transduced and subsequently differentiated to mature T cells after introduction of a wild type TCR or of a fusion TCR:CD3ζ with or without costimulator signal. When Wilms tumor 1 (WT1)/HLA-A2-specific T cell receptor α and β chain is introduced in CD34+ cells derived from human thymus, cord blood or adult mobilized precursor cells and subsequently induced to differentiate to T cells on OP9 stromal cells expressing Delta-like ligand 1(OP9-DL1) in the presence of stem cell factor, flt3 ligand and interleukin 7, massive proliferation is observed while the cells differentiate to CD4+CD8+double positive (DP) transduced TCR+ immature cells. Few mature T cells are generated in these cultures, but after addition of the specific peptide to HLA-A2+ cultures, DP cells rapidly differentiate to phenotypically mature naïve CD8 single positive T cells. Upon activation, these T cells specifically lyse WT1/HLA-A2 cell lines and produce interferon-γ. Microarray expression analysis revealed these culture-generated T cells to be similar to TCR-transduced peripheral blood T cells, except for 1) the expression of only one TCR α and β chain by the in vitro generated T cells and 2) the underexpression of costimulatory/inhibitory molecules such as CD28, CTLA-4 and PD-L1. The absence of CD28 on the cell membrane was confirmed by flow cytometry. Since it was shown that CD28 signaling is essential for in vivo functionality using CARs, we next generated fusion TCR constructs of a gp100/HLA-A2-specific TCR and the signaling cassettes of CD3ζ and CD28.The following constructs were introduced in CD34+ cells: wild type TCR, TCR:ζ or TCR:CD28ζ α and β chains. The α and β chain double-transduced cells were subsequently cultured on OP9-DL1 in the absence of the specific antigen. It was observed that TCR:ζ transduced precursors proliferated significantly less than wild type TCR transduced cells, but the majority of the cells differentiated towards DP TCR:ζ+ cells, which upon addition of the specific antigen differentiated to phenotypically mature T cells. TCR:CD28ζ transduced cells proliferated least of all and spontaneously matured to functional double negative T cells without passing through the DP stage. These observations are compatible with data obtained in mice showing that strong TCR activation during thymocyte differentiation inhibits the generation of DP cells. In all of these cultures, endogenous TCR rearrangements were suppressed, which resulted in single receptor tumoricidal cells. Functional analysis of these various cell populations showed similar proliferation on T cell growth factors and specific cytolytic activity of gp100+ HLA-A2+ tumor lines. However, the TCR:CD28ζ transduced cells produced significantly higher levels of TNFα and interferon-γ and were the only ones that produced interleukin-2 upon specific stimulation. In conclusion, we have shown that high numbers of polyfunctional single receptor TCR:CD28ζ+ cells can be generated in vitro from clinically relevant stem cell sources. These cells produce interleukin-2, TNFα and interferon-γ and specifically kill gp100/HLA-A2+ tumor cell lines. Disclosures No relevant conflicts of interest to declare.

Abstract: Background Peripheral T-cell lymphoma (PTCL) is a heterogeneous and accounts for approximately 10% of all lymphomas. Outcome of relapse/refractory (R/R) PTCL is poor with median progression-free survival (PFS) and overall survival (OS) of 3 and 6 months in the absence of stem-cell transplantation (SCT). [Mak, JCO, 2013]. Brentuximab vedotin (BV) monotherapy is approved for R/R systemic anaplastic large cell-lymphoma (ALCL) based on 86% overall response rate (ORR) and 57% complete remission (CR). [Pro, JCO, 2012] . In other CD30-positive (CD30+) R/R PTCL, the ORR of BV is 41%. Gemcitabine (G) used as monotherapy in control arm in the randomized phase 3 LUMIERE trial, provided ORR and CR rates of 35 and 22% respectively. [O'Connor, JCO, 2019]. Considering these results we designed a phase 2 study for R/R CD30+ PTCL combining G and BV with the primary end point to increase the ORR by 15%, compared to G monotherapy. Patients (pts) and Methods: Pts with histologically confirmed CD30+ (≥5%) PTCL who failed or were refractory to 1-3 prior lines of systemic therapy, with measurable disease and ECOG performance status & lt; 3 were eligible. Pts received an induction of 4 cycles of G-BV (28-days cycles; G: 1000 mg/m² at D1 and D15 plus BV: 1.8 mg/kg at D8). Pts with CR or partial remission (PR) and non-eligible for SCT, received BV maintenance 1.8 mg/kg at D1 (21-days cycles) up to 12 cycles. The primary endpoint was the ORR (CR + PR) according to Lugano criteria based on CT-scan. Secondary objectives included tolerance and safety, DOR, PFS, OS and impact of BV maintenance. Eligible pts were censored at time of SCT. (NCT03496779). Results: From April 2018 to October 2019, 71 pts were included. Pathology central review according to WHO 2017 criteria, so far available for 50 patients, confirmed angioimmunoblastic T-cell lymphoma (AITL) (22 ; 31%); nodal PTCL-TFH (5 ; 7%); PTCL-NOS (5 ; 7%); ALK- ALCL (10 ; 14.1%) ; ALK+ ALCL (4 ; 5.6%), Enteropathy associated T-cell lymphoma (EATL) (2 ; 2.8%); unclassified PTCL (2 ; 2.8%). There were 47 male and 24 female with a median age of 66 years (20-79) and 17 pts were & gt; 75 years. Median time from diagnosis to enrolment was 9.4 months (range, 6-21). Sixty-five pts (91.6%) presented with stage III-IV. The number of prior lines of therapy were 1 (57 pts), 2 (11 pts) or 3 (3 pts), all pts had received previous CHOP-like chemotherapy, 11 pts previous autologous SCT, 5 pts epigenetic modifiers and 39.4% were refractory to their last line of treatment prior to inclusion. The cut-off date of this analysis was 01/31/2020. The 4 cycles of G-BV induction were completed in 45 pts (63%). The reasons for early discontinuation were progression (21 pts), death (3 pts) or adverse event (2 pts). In intention-to-treat analysis, the ORR at the end of induction (EOI) was 47.9% including CR (14 pts; 19.7%), PR (20 pts; 28.2%). PET performed in all patients reaching EOI showed overall and complete metabolic responses in 45.1 and 23.9%, respectively. During G-BV induction 58 pts (81.7%) had at least one G & gt; 3 adverse event (AE) including neutropenia (67.2%), thrombopenia (17.2%), infections (15.5%), peripheral neuropathy (PN) (5.2%) and cardiac event (5.2%). Overall PN of any grade was recorded in 8/71 patients (11%) during G-BV induction and caused BV withdrawal in one case. Among the 34 responding pts after EOI, 27 pts began BV maintenance and 7 pts remain on maintenance at cut-off date. Eight pts were removed from the study due to SCT eligibility, either after the 4 GBV induction (4 pts) or after 1 or 2 maintenance BV cycles (4 pts). With a median follow-up (FU) of 9.5 (0.5-19.4) months, median PFS is 4.5 months (95%CI [3.5 - 10]) and median OS is 12 months (95%CI [8.6 - NR] ). Among the 34 patients in PR/CR after induction, the duration of response (DOR) is 12.8 months (95%CI [10.3 - NR]). At last FU were recorded 32 deaths. Disease status at time of death was PD (25 pts), CR (1 pt) NE or missing (6 pts). Conclusion: The addition of BV to G increases the overall response rate by 15% in the treatment of R/R CD30+ PTCL. OS data are encouraging for this overall R/R patient population but PFS is overall short and a longer FU is mandatory. Especially the DOR of pts achieving CR or PR after 4 cycles of G-BV exceeds 1 year on BV maintenance. This combination is generally well tolerated and this study suggests that G-BV combination could be an interesting alternative for R/R CD30+ PTCL. Disclosures Tournilhac: Janssen: Consultancy, Honoraria, Other: Travel grant; INNATE Pharma: Consultancy, Honoraria; GILEAD: Consultancy, Honoraria, Other: Travel Grant; ABBVIE: Consultancy, Honoraria, Other: Travle grant; Takeda: Consultancy, Honoraria, Other: Travel grant. Laribi:novartis: Honoraria, Research Funding; amgen: Research Funding; abbvie: Honoraria, Research Funding; takeda: Research Funding. Ysebaert:AbbVie: Consultancy; Roche: Consultancy; Janssen: Consultancy. Guidez:BMS: Honoraria; TAKEDA: Honoraria; Service Hématologie et Thérapie cellulaire CHU POITIERS: Current Employment; AMGEN: Honoraria; CELGENE: Honoraria; JANSEN: Honoraria. Le Gouill:Loxo Oncology at Lilly: Consultancy; Roche Genentech, Janssen-Cilag and Abbvie, Celgene, Jazz pharmaceutical, Gilead-kite, Loxo, Daiichi-Sankyo and Servier: Honoraria. André:Celgene: Other, Research Funding; Takeda: Consultancy; Bristol-Myers-Squibb: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Karyopharm: Consultancy; Gilead: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Novartis: Consultancy, Research Funding; Amgen: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Johnson & Johnson: Research Funding; CHU UCL Namur, site Godinne, Yvoir, Belgium: Current Employment; Roche: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Abbvie: Consultancy; Seattle Genetics: Consultancy. Dupuis:Henri Mondor University Hospital Creteil France: Current Employment. Thieblemont:Roche, Amgen, Kyte Gilead, Celgene, Abbvie, Novartis, Cellectis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Roche, Hospita: Research Funding; Cellectis: Speakers Bureau. Bachy:Beigene: Membership on an entity's Board of Directors or advisory committees; Roche, Gilead: Consultancy; Amgen: Research Funding; Roche, Celgene, Amgen, Janssen, Gilead, Novartis, Sanofi: Honoraria. Morschhauser:Celgene: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; F. Hoffmann-La Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Epizyme: Membership on an entity's Board of Directors or advisory committees; Genentech, Inc.: Consultancy; Servier: Consultancy; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Feugier:janssen: Consultancy, Honoraria, Research Funding; gilead: Consultancy, Honoraria, Research Funding; roche: Consultancy, Honoraria, Research Funding; astrazeneca: Consultancy, Honoraria, Research Funding; abbvie: Consultancy, Honoraria, Research Funding. Cartron:F. Hoffmann-La Roche: Consultancy, Honoraria; Abbvie: Honoraria; Jansen: Honoraria; Celgene: Consultancy, Honoraria; Sanofi: Honoraria; Gilead: Honoraria. Camus:ROCHE: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); JANSSEN: Honoraria; AMGEN: Honoraria; PFIZER: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Sibon:takeda france: Consultancy. Snauwaert:roche: Other: travel; janssen: Other: travel; abbvie: Other. Delarue:BMS: Other: stock options ; Celgene/BMS: Current Employment. De Leval:Abbvie: Honoraria; Lausanne University Hospital & Lausanne University Institute of Pathology: Current Employment; Roche Diagnostics: Honoraria; Lunaphore Technologies SA: Consultancy, Honoraria. Gaulard:CHU Henri Mondor, Assistance Publique-Hôpitaux de Paris: Current Employment; TAKEDA: Consultancy, Honoraria, Research Funding; INNATE PHARMA: Research Funding; Roche: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company).

Abstract: BACKGROUND: Obinutuzumab is a type II anti-CD20 monoclonal antibody that induces antibody-dependent cellular cytotoxicity, antibody-dependent cell-mediated phagocytosis, and direct cell death better than rituximab. Given promising results with lenalidomide and rituximab (R2), we assessed the safety and efficacy of lenalidomide combined with obinutuzumab (GALEN)in a large phase Ib/II study in separate patient populations (NCT01582776). In relapsed/refractory follicular B-cell lymphoma (FL), we found the GALEN regimen might be even more efficient than R2 while retaining a similarly manageable safety profile. Here, we report the results for the phase II part assessing efficacy and safety of GALEN in advanced untreated FL patients (pts) in need of systemic therapy. METHODS: Eligible pts had grade 1-3a FL and required systemic therapy per GELF criteria. Induction treatment consisted of lenalidomide (LEN) 20 mg on day (d) 1-21 of a 28-d cycle for the first cycle and on d2-22 of a 28-d cycle from cycles 2 to 6. Obinutuzumab (GA) 1000 mg was given IV on d8, 15, and 22 of cycle 1 and d1 of cycles 2 to 6. Responding pts then received maintenance with LEN at 10 mg on d2-22 every 28d for 12 cycles and GA 1000 mg every 8 wk for 12 cycles until progression or unacceptable toxicity. The primary study endpoint was complete response (CR)/CR unconfirmed (CRu) rate by investigator assessment at the end of induction according to 1999 IWG criteria. Secondary endpoints included overall response rate (ORR) and CR according to IWG 2007, progression-free survival (PFS), duration of response (DOR), overall survival (OS) and safety. RESULTS: 100 pts with WHO FL gr 1-2 (91%) and 3a (9%) according to local pathology reports were enrolled between October 2015 and February 2017. Median age was 60.5 years (range, 32-89), 43% had FLIPI score ≥3, 89% stage III/IV, and 31% bulky disease ( 〉 7 cm). All 100 pts were evaluable for safety and efficacy. At a median follow-up of 2.1 years, 96 pts (96%) completed induction, 41 completed maintenance, 36 were ongoing in maintenance, and 23 prematurely discontinued treatment due to disease progression (n=12, including 2 during induction), toxicity (n=6, including 2 during induction), concurrent illness (n=3), consent withdrawal (n=1), or other cause (n=1). At the end of induction, 61 pts had regression by more than 75% of sum of the product of the greatest diameters (SPD) of target lesions and 83/97 (85.6%) with PET assessment were PET negative (Juweid criteria) including 79/93 (84.9%) with a 5PS (Deauville scale) score of 1-3. Sixteen pts with SPD regression 〉 75% and 25 pts with negative PET were conservatively downgraded to PR due to missing bone marrow evaluation, leading to 47% CR/CRu rate and 59% CR rate at the end of induction per IWG1999 and 2007 criteria, respectively. Response rates at the end of induction, PFS, DOR and OS are summarized in the Table and Figure. Most common AEs ( 〉 10% of pts) during induction (% all gr/% gr 3/4) were neutropenia (43/42), asthenia (35/2), constipation (32/0), infusion-related reactions (23/3), diarrhea (21/2), rash (21/2), cough (18/0), nausea (13/0), pruritus (12/1), weight decrease (12/0), bronchitis (11/0), muscle spasms (11/1), and pyrexia (11/0). Febrile neutropenia occurred in 2% of pts. Eight second primary malignancies were reported in 8 pts, including 2 deemed unrelated since they were misdiagnosed at baseline. Three (3%) pts had died, 1 each due to lymphoma, toxicity of additional treatment, and intestinal adenocarcinoma. CONCLUSION: The immunomodulatory GALEN regimen is highly effective with no unexpected toxicity in advanced, untreated FL pts in need of systemic therapy and has the potential to challenge immunochemotherapy in this setting. Disclosures Morschhauser: BMS: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Epizyme: Consultancy; Janssen: Other: Scientific Lectures. Salles:Celgene: Honoraria, Research Funding; AbbVie: Honoraria; Acerta: Honoraria; Janssen: Honoraria; Gilead: Honoraria; Amgen: Honoraria; Epizyme: Honoraria; Merck: Honoraria; Morphosys: Honoraria; Takeda: Honoraria; Servier: Honoraria; Pfizer: Honoraria; Roche: Honoraria, Research Funding; Novartis: Consultancy, Honoraria. Feugier:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Cartron:Celgene: Consultancy, Honoraria; Janssen: Honoraria; Roche: Consultancy, Honoraria; Sanofi: Honoraria; Gilead Sciences: Honoraria. Maerevoet:abbvie: Membership on an entity's Board of Directors or advisory committees, Other: travel grant; roche: Other: travel grant; takeda: Membership on an entity's Board of Directors or advisory committees, Other: travel grant; Karyopharm: Membership on an entity's Board of Directors or advisory committees. Tilly:Roche: Membership on an entity's Board of Directors or advisory committees; Astra-Zeneca: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria. Haioun:Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Sciences: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria; Roche: Consultancy, Honoraria. Houot:BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Janssen: Honoraria; Novartis: Honoraria.

Abstract: Introduction : High total metabolic tumor volume (TMTV) measured on 18F-FDG PET/CT before R-CHOP has been shown to be significantly associated with worse progression-free survival (PFS) and overall survival (OS) in patients with diffuse large B-cell lymphoma (DLBCL; Cottereau et al. Clin Cancer Res. 2016;22:3801-9) . The REMARC study (NCT01122472) is an international, multicenter, double-blind, randomized phase III trial that assessed lenalidomide (LEN) maintenance therapy versus placebo (PBO) in 650 patients responding to R-CHOP. With a median follow-up of ~40 months, independent review demonstrated that 2 years of LEN maintenance therapy significantly improved progression-free survival (PFS); median was not reached in the LEN arm vs 58.9 months in the PBO arm (HR=0.71 [95% CI, 0.54-0.93]; p=0.0135; Thieblemont et al. J Clin Oncol. 2017;35:2473-81). Methods: For these analyses, patients enrolled in the REMARC trial who had baseline PET/CT before R-CHOP (not mandatory per study protocol) with available fused images and end of treatment PET/CT were included. Total metabolic tumor volume (TMTV, defined as the sum of the regions of the local tumors with FDG uptake) was measured on baseline PET/CT with the 41% SUVmax thresholding method using the free semiautomatic software Beth Israel Fiji20 (http://petctviewer.org). The optimal TMTV cut-off to PFS (per FDA censoring rule) and overall survival (OS) was determined by Receiver Operating Curve (ROC) curves and X-tile analyses. Survival was estimated using Kaplan Meier (KM) curves. Multivariable analysis were performed with descending Cox model including TMTV, IPIaa, treatment arm and PET/CT response evaluated by Deauville criteria. Analyses were performed on the evaluable population and separate arms Results: 228 of 650 REMARC patients had TMTV data available for analysis, including n=108 in the PBO arm and n=120 in the LEN arm. Clinical characteristics were similar to the overall population. The median baseline TMTV was 295 cm3 (Q1-Q3, 99-702). After a median follow-up of 51.6 mo, 4y-PFS was 73% and 4y-OS was 85%. The optimal TMTV cut-off determined by ROC was 300 cm3 for PFS and OS. Patients with TMTV 〉 300 vs ≤300 cm3 presented with worse ECOG performance status (ECOG ≥2: 19% vs 9%, p=0.034), higher Ann Arbor stage (stage III-IV: 95% vs 86%, p=0.042), more extra-nodal sites ( 〉 1: 65% vs 38%, p 〈 0.001), more frequently elevated LDH (76% vs 43%, p 〈 0.001), higher IPI (IPI 3-5: 87% vs 51%, p 〈 0.001), and higher aaIPI (aaIPI 2-3: 76% vs 34%, p 〈 0.001). In all evaluated patients, a significant impact of TMTV for cut-offs of 〉 300 vs ≤300 cm3 was observed for PFS (HR=2.09; 95% CI, 1.22-3.69) and OS (HR=2.99; 95% CI, 1.44-6.18). Patients with high TMTV 〉 300 cm3 vs low TMTV ≤300 cm3, respectively, had a 4-year PFS of 57% vs 73% and OS of 70% vs 88%. These results were more disparate when a higher TMTV cut-off of 〉 1000 was applied. In multivariate analysis, only TMTV maintained an independent prognostic value. The prognostic impact of TMTV 〉 300 vs ≤300 cm3 on PFS (HR=2.4; 95% CI, 1.1-5.22) and OS (HR=5.0; 95% CI, 1.4-17.) was maintained in the PBO arm (Figure 1A). In contrast, when the analysis was focused on patients in LEN arm, TMTV 〉 300 vs ≤300 cm3 lost its prognostic impact on PFS and OS. In the LEN arm, 4-year PFS and OS did not differ significantly between patients with high and low TMTV (Figure 1B). Conclusion: TMTV measured on baseline PET/CT is a strong prognosticator of outcome in DLBCL, even in patients in response after R-CHOP. High TMTV at baseline was significantly associated with worse PFS and OS in patients receiving PBO following a response to R-CHOP in the REMARC study. Interestingly, LEN maintenance reduces the negative impact of high baseline TMTV on survival in patients with DLBCL Disclosures Casasnovas: takeda: Consultancy; merck: Consultancy; MSD: Consultancy; Roche: Consultancy; Gilead Sciences: Research Funding; Roche: Honoraria; Takeda: Honoraria; Merck: Honoraria; Gilead Sciences: Honoraria; Janssen: Honoraria; Celgene: Honoraria; MSD: Honoraria; Roche: Research Funding; Gilead Sciences: Consultancy; Janssen: Consultancy. Tilly:Celgene: Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Astra-Zeneca: Membership on an entity's Board of Directors or advisory committees. Feugier:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Ribrag:Infinity: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Amgen: Research Funding; Roche: Honoraria, Other: travel; MSD: Honoraria; BMS: Consultancy, Honoraria, Other: travel; epizyme: Consultancy, Honoraria; NanoString Technologies: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; argenX: Research Funding; pharmamar: Other: travel; Incyte Corporation: Consultancy. Macro:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Financial support for congress; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Financial support for congress; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Financial support for congress; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Financial support for congress. Morschhauser:Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Epizyme: Consultancy; Janssen: Other: Scientific Lectures; Roche: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Trotman:Janssen: Other: Unremunerated member of Ad Board, Research Funding; F. Hoffman-La Roche: Other: Travel to meeting, Unremunerated member of Ad Board, Research Funding; Takeda: Other: Unremunerated member of Ad Board; Celgene: Other: Unremunerated member of Ad Board, Research Funding; PCYC: Research Funding; Beigene: Research Funding. Godmer:CELGENE: Other: Invitation to congress. Salles:Servier: Honoraria; Novartis: Consultancy, Honoraria; Morphosys: Honoraria; Servier: Honoraria, Other: Advisory Board; Celgene: Honoraria, Other: Advisory Board, Research Funding; Acerta: Honoraria; Merck: Honoraria; Janssen: Honoraria, Other: Advisory Board; Pfizer: Honoraria; Epizyme: Honoraria; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Gilead: Honoraria, Other: Advisory Board; BMS: Honoraria, Other: Advisory Board; Takeda: Honoraria; Amgen: Honoraria; Abbvie: Honoraria. Coiffier:CELGENE: Consultancy, Membership on an entity's Board of Directors or advisory committees; MUNDIPHARMA: Membership on an entity's Board of Directors or advisory committees; CELLTRION: Membership on an entity's Board of Directors or advisory committees; MORPHOSYS: Membership on an entity's Board of Directors or advisory committees; NOVARTIS: Membership on an entity's Board of Directors or advisory committees. Meignan:F. Hoffman-La Roche Ltd: Honoraria.

Abstract: Early identification of ultra-risk diffuse large B-cell lymphoma (DLBCL) patients is needed to aid stratification to innovative treatment. Previous studies suggested high baseline total metabolic tumor volume (TMTV) negatively impacts survival of DLBCL patients. We analyzed the prognostic impact of TMTV and prognostic indices in DLBCL patients, aged 60 to 80 years, from the phase 3 REMARC study that randomized responding patients to R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) into maintenance lenalidomide or placebo. TMTV was computed on baseline positron emission tomography/computed tomography using the 41% maximum standardized uptake value method; the optimal TMTV cutoff for progression-free (PFS) and overall survival (OS) was determined and confirmed by a training validation method. There were 301 out of 650 evaluable patients, including 192 patients classified as germinal center B-cell–like (GCB)/non-GCB and MYC/BCL2 expressor. Median baseline TMTV was 238 cm3; optimal TMTV cutoff was 220 cm3. Patients with high vs low TMTV showed worse/higher Eastern Cooperative Oncology Group performance status (ECOG PS) ≥2, stage III or IV disease, & gt;1 extranodal site, elevated lactate dehydrogenase, International Prognostic Index (IPI) 3-5, and age-adjusted IPI 2-3. High vs low TMTV significantly impacted PFS and OS, independent of maintenance treatment. Although the GCB/non-GCB profile and MYC expression did not correlate with TMTV/survival, BCL2 & gt;70% impacted PFS and could be stratified by TMTV. Multivariate analysis identified baseline TMTV and ECOG PS as independently associated with PFS and OS. Even in responding patients, after R-CHOP, high baseline TMTV was a strong prognosticator of inferior PFS and OS. Moreover, TMTV combined with ECOG PS may identify an ultra-risk DLBCL population. This trial was registered at www.clinicaltrials.gov as #NCT01122472.

Abstract: 7523 Background: Outcomes of pts with newly diagnosed DLBCL with high/poor risk according to the revised International Prognostic Index (IPI) treated with immunochemotherapy (IC) remain suboptimal, with a 4-year survival rate of 55% (Sehn et al, Blood 2007). SC epco is a well-tolerated bispecific antibody with single-agent activity in the relapsed/refractory (R/R) aggressive B-cell NHL setting. The mechanism of action and safety profile of epco are distinct from IC, and epco is well suited for use in combinations and in earlier lines of therapy. Addition of a novel agent to standard of care IC may overcome the adverse prognosis of high-risk pts. Presented here are updated results of epco + rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in previously untreated DLBCL pts with IPI 3–5 (EPCORE NHL-2 arm 1; NCT04663347). Methods: Adults with previously untreated CD20 + DLBCL and IPI ≥3 received SC epco (every week, cycle [C] 1–4; every 3 weeks, C5–6) + R-CHOP for 6 cycles (21 d) followed by single-agent epco every 4 weeks up to 1 y (in cycles of 28 d). To mitigate CRS, epco step-up dosing and corticosteroid prophylaxis were required. Response was assessed by PET-CT with contrast per Lugano 2014 criteria. Results: As of Dec 1, 2021, 33 pts (median age, 66 y; range, 19–82) received epco + R-CHOP (epco 24 mg, n = 4; 48 mg, n = 29). Median time from diagnosis to first dose was 25 d (range, 5–70). All pts had IPI ≥3 and ≥24% had double- or triple-hit DLBCL. Median follow-up was 3 mo (range, 0–9.7); median number of total cycles initiated was 5 (1–13). Overall, 94% of pts (31/33) remained on Tx. Tx-emergent adverse events (TEAEs) in ≥30% of pts were neutropenia (48%; febrile neutropenia in 9% of all pts), CRS (45%), infections (42%), anemia (39%), injection -site reactions (36%), nausea (33%), constipation (30%), and pyrexia (30%). No TEAEs led to epco discontinuation. AEs of special interest included CRS (42% grade [G] 1/2, 3% G3) and ICANS (3% G2); 1 pt had tumor lysis syndrome (3% G3). Most CRS events occurred in C1 and resolved after a median of 2 days (1–11); 4 pts with CRS received tocilizumab. No fatal TEAEs were reported. In efficacy-evaluable pts, the overall response rate (ORR) was 96% (24/25); 68% (17/25) had complete metabolic response (CMR). For the 10 pts who received 6 cycles of R-CHOP and had a subsequent response assessment, the ORR and CMR rate were 100% and 90%, respectively. As of the data cutoff, all of these 10 pts remained in response, with the longest duration of response 7.1+ mo and ongoing. Updated data will be presented. Conclusions: Epco is the first SC bispecific antibody assessed in combination with standard of care in previously untreated DLBCL. The safety profile of epco + R-CHOP is manageable. CRS events were mostly of low grade and did not lead to Tx discontinuation. ORR and CMR rate were high with no relapses as of the data cutoff date. Clinical trial information: NCT04663347.

Abstract: In humans, high Notch activation promotes γδ T cell development, whereas lower levels promote αβ-lineage differentiation. How these different Notch signals are generated has remained unclear. We show that differential Notch receptor–ligand interactions mediate this process. Whereas Delta-like 4 supports both TCR-αβ and -γδ development, Jagged1 induces mainly αβ-lineage differentiation. In contrast, Jagged2-mediated Notch activation primarily results in γδ T cell development and represses αβ-lineage differentiation by inhibiting TCR-β formation. Consistently, TCR-αβ T cell development is rescued through transduction of a TCR-β transgene. Jagged2 induces the strongest Notch signal through interactions with both Notch1 and Notch3, whereas Delta-like 4 primarily binds Notch1. In agreement, Notch3 is a stronger Notch activator and only supports γδ T cell development, whereas Notch1 is a weaker activator supporting both TCR-αβ and -γδ development. Fetal thymus organ cultures in JAG2-deficient thymic lobes or with Notch3-blocking antibodies confirm the importance of Jagged2/Notch3 signaling in human TCR-γδ differentiation. Our findings reveal that differential Notch receptor–ligand interactions mediate human TCR-αβ and -γδ T cell differentiation and provide a mechanistic insight into the high Notch dependency of human γδ T cell development.