The IELSG38 trial was conducted to investigate the effects of subcutaneous (SC) rituximab on the complete remission (CR) rate and the benefits of SC rituximab maintenance in patients with extranodal marginal zone lymphoma (MZL) who received front-line treatment with chlorambucil plus rituximab. Study treatment was an induction phase with oral chlorambucil 6 mg/m2/day on weeks 1-6, 9-10, 13-14, 17-18, and 21-22, and intravenous rituximab 375 mg/m2 on day 1 of weeks 1-4, and 1,400 mg SC on weeks 9, 13, 17, and 21. Then, a maintenance phase followed with rituximab administered at 1,400 mg SC every two months for two years. Of the 112 patients enrolled, 109 were evaluated for efficacy. The CR rates increased from 52% at the end of the induction phase to 70% upon completion of the maintenance phase. With a median follow-up of 5.8 years, the 5-year event-free, progression-free, and overall survival rates were 87% (95% CI: 78-92), 84% (95% CI: 75-89), and 93% (95% CI: 86-96), respectively. The most common grade ≥3 toxicities were neutropenia (33%) and lymphocytopenia (16%). Six patients experienced treatment-related serious adverse events, including fever of unknown origin, sepsis, pneumonia, respiratory failure, severe cerebellar ataxia, and fatal acute myeloid leukemia. The trial showed that SC rituximab did not improve the CR rate at the conclusion of the induction phase, which was the main endpoint. Nevertheless, SC rituximab maintenance might have facilitated long-term disease control, potentially contributing to enhanced event-free and progression-free survival.

Background Parsaclisib, a potent and highly selective PI3K & delta; inhibitor, has shown clinical benefit in patients with relapsed or refractory (R/R) B-cell malignancies. This phase 2 study (CITADEL-203; NCT03126019, EudraCT 2017-001624-22) assessed efficacy and safety of parsaclisib monotherapy in patients with R/R follicular lymphoma (FL).Methods Patients & GE;18 years of age with histologically confirmed R/R FL (grade 1-3a) and prior treatment with & GE;2 systemic therapies received parsaclisib 20 mg once daily (QD) for 8 weeks then parsaclisib 20 mg once weekly (weekly dosing group [WG]) or parsaclisib 20 mg QD for 8 weeks then parsaclisib 2.5 mg QD (daily dosing group [DG]); DG was selected for further assessment. Primary endpoint was objective response rate (ORR).Findings At data cut-off (January 15, 2021), 126 patients had been treated (WG: n = 23; DG: n = 103). ORR (95% confidence interval [CI]) was 77.7% (68.4-85.3) with a complete response rate (95% CI) of 19.4% (12.3-28.4) in DG; median (95% CI) duration of response was 14.7 months (10.4-not estimable [NE]), median progression-free survival was 15.8 months (11.0-NE), and median overall survival was not reached. The most common any-grade treatment-emergent adverse events (TEAEs) among all treated patients included diarrhoea (n = 48, 38.1%), nausea (n = 31, 24.6%), and cough (n = 28, 22.2%); the most common grade & GE;3 TEAEs were diarrhoea (n = 15, 11.9%), neutropenia (n = 13, 10.3%), and colitis (n = 7, 5.6%). Dose interruption, reduction, and discontinuation from TEAEs occurred in 46.8% (n = 59), 17.5% (n = 22), and 23.8% (n = 30) of patients, respectively.Interpretation Treatment with parsaclisib demonstrated rapid and durable responses, and a manageable safety profile in patients with R/R FL.Funding Incyte Corporation.Copyright & COPY; 2023 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Introduction: Although in a phase III trial of extranodal MZL (EMZL) patients (pts) the combination of rituximab and chlorambucil had superior progression-free and event-free survival (PFS, EFS) compared to either drug given alone (Zucca et al. JCO 2016), there is no standard front-line therapy for MZL pts requiring systemic treatment, and no randomized trial specifically addressed initial treatment for the splenic (SMZL) and nodal (NMZL) MZL subtypes. BTK inhibitors have shown durable responses with a favorable benefit-risk profile for all MZL subtypes in the relapsed setting. The ongoing IELSG47/MALIBU phase II trial is exploring efficacy and safety of rituximab plus ibrutinib in untreated MZL, with a focus on EMZL. We report here a planned preliminary analysis of the response and toxicity in the exploratory cohort of SMZL and NMZL pts. Methods: Treatment was comprised of 8 rituximab doses (the first 4 weekly and the subsequent 4 monthly, all but the first given subcutaneously) in combination with ibrutinib (560 mg once daily) for 2 years. Response evaluation was planned at 6, 24 weeks, and 12, 18, and 24 months after treatment start and was performed using Matutes criteria in SMZL and Lugano Classification in NMZL. Results: Between October 2019 and June 2021, 45 pts (30 with SMZL and 15 with NMZL) were enrolled from 16 centers in France, Italy, and Switzerland. Median age was 68 years (range: 44–81), 17 pts were male (38%), 41 pts had stage IV (91%), and 17 had elevated LDH (38%). All SMZL and 9 (60%) NMZL pts had bone marrow involvement. The best objective response reached in the entire cohort at any time was complete response (CR) in 22 pts (49%) and partial response (PR) in 19 pts (42%). Of the 36 pts currently evaluable for response at 12 months, 18 (50%) had a CR and 15 (42%) had a PR, while 3 (8%) had disease progression. The median time to best response was 2 months (range: 1–20). At a median follow-up of 23 months, 7 pts relapsed (1 SMZL and 6 NMZL) with a median duration of response of 18 months (range: 1–28+); 3 pts died (due to SARS-CoV2 infection, ischemic stroke, and car accident, respectively). The 2-year overall survival (OS) rate was 92% (95% CI: 75–97), with no significant difference between SMZL and NMZL. Median PFS was 24 months in the NMZL subset and was not reached among SMZL pts (p = 0.0133). The 2-year PFS was 77% (95% CI: 59–88) in the whole cohort, 86% (95% CI: 62%–95%) in SMZL, and 59% (95% CI: 27–81) in NMZL. Treatment was generally well-tolerated, with the most frequent grade 3–4 adverse events being neutropenia (reported in nine pts [20%]) and cutaneous rash (reported in four pts [9%]). Grade 3 atrial fibrillation or hypertension were reported in one (2%) and two (4%) pts, respectively. Treatment was discontinued in 15 pts (33%) after a median of 8 months (range: 2–23): 3 due to progressive disease, 6 due to toxicities, 4 due to unrelated events (1 second primary tumor, 1 stroke, 1 car accident, 1 cold agglutinine disease) and 2 due to consent withdrawal. The research was funded by: The research was supported partially by Janssen (financial and drug supply) and Roche (drug supply) Keywords: extranodal non-Hodgkin lymphoma, indolent non-Hodgkin lymphoma, molecular targeted therapies Conflicts of interests pertinent to the abstract C. Thieblemont Honoraria: BMS, Gilead/Kyte, Novartis, Roche, Janssen, Incyte, Abbvie, Miltenyi A. Tedeschi Consultant or advisory role: Astrazeneca, Janssen, Beigene, Abbvie A. Stathis Consultant or advisory role: Janssen, Roche Research funding: Abbvie, ADC Therapeutics, Amgen, AstraZeneca, Bayer, Cellestia, Incyte, LoxoOncology, Merck, Novartis, Pfizer, Philogen, Roche Educational grants: AstraZeneca Other remuneration: Expert testimonies from Bayer, Eli/Lilly S. Luminari Consultant or advisory role: Jannsen, Novartis, Beigene, BMS, Gilead, Regeneron, Genmab, Incyte L. Arcaini Consultant or advisory role: Roche, Janssen-Cilag, Verastem, Incyte, EUSA Pharma, Celgene/Bristol Myers Squibb, Kite/Gilead, ADC Therapeutics Research funding: Gilead Sciences Other remuneration: Speakers’ Bureau of EUSA Pharma, Novartis O. Casasnovas Consultant or advisory role: Roche, Takeda, BMS, Merck, Gilead, Janssen, ADC therapeutics, Incyte, Astra Zeneca Honoraria: Roche, Takeda, BMS, Merck, Gilead, Janssen, ADC therapeutics, Incyte, Astra Zeneca Research funding: Roche, Takeda, Gilead, Abbvie Educational grants: Roche, Takeda, Janssen, Abbvie E. Zucca Consultant or advisory role: from BeiGene, BMS/Celgene, Celltion Healthcare, Curis, Eli/Lilly, Incyte, Ipsen, Janssen, Kyte (a Gilead Company), Merck, Roche Research funding: AstraZeneca, BMS/Celgene, Incyte, Janssen, Merck and Roche Educational grants: Abbvie, BeiGene, Janssen and Roche. A. Conconi Consultant or advisory role: Regeneron Other remuneration: speaker fees from Roche, Abbvie, Incyte, Takeda, AstraZeneca

Splenic marginal zone B-cell lymphoma (SMZL) is a heterogeneous clinico-biological entity. The clinical course is variable, multiple genes are mutated with no unifying mechanism, and essential regulatory pathways and surrounding microenvironments are diverse. We sought to clarify the heterogeneity of SMZL by resolving different subgroups and their underlying genomic abnormalities, pathway signatures, and microenvironment compositions to uncover biomarkers and therapeutic vulnerabilities. We studied 303 SMZL spleen samples collected through the IELSG46 multicenter international study (NCT02945319) by using a multiplatform approach. We carried out genetic and phenotypic analyses, defined self-organized signatures, validated the findings in independent primary tumor metadata and in genetically modified mouse models, and determined correlations with outcome data. We identified 2 prominent genetic clusters in SMZL, termed NNK (58% of cases, harboring NF-κB, NOTCH, and KLF2 modules) and DMT (32% of cases, with DNA-damage response, MAPK, and TLR modules). Genetic aberrations in multiple genes as well as cytogenetic and immunogenetic features distinguished NNK- from DMT-SMZLs. These genetic clusters not only have distinct underpinning biology, as judged by differences in gene-expression signatures, but also different outcomes, with inferior survival in NNK-SMZLs. Digital cytometry and in situ profiling segregated 2 basic types of SMZL immune microenvironments termed immune-suppressive SMZL (50% of cases, associated with inflammatory cells and immune checkpoint activation) and immune-silent SMZL (50% of cases, associated with an immune-excluded phenotype) with distinct mutational and clinical connotations. In summary, we propose a nosology of SMZL that can implement its classification and also aid in the development of rationally targeted treatments.

Background: Diffuse Large B-Cell Lymphoma (DLBCL) is a heterogeneous disease characterized by biological and clinical aspects conditioning different prognosis. Chemo-immunotherapy treatment with R-CHOP proved to be less effective in patients with double hit (DH)/triple hit (TH) or double expressor (DE) DLBCL who require more intensive regimens Aims: To investigate survival outcomes of DLBCL patients treated according to biological profile in the real-life clinical practice at Istituto Nazionale dei Tumori in Milano. Primary objective was to verify whether personalized treatment could overcome well known differences in Progression Free Survival (PFS) observed between DE, DH/TH and non DE/DH/TH patients when they are uniformly treated with R-CHOP Methods: We retrospectively collected clinical and survival data of all newly diagnosed DLBCL patients referred at our Hematology Division from January 2013 to August 2021. All DLBCL patients are evaluated for BCL2, BCL6 and MYC expression in immunohistochemistry and gene rearrangements by fluorescent in situ hybridization, and they are assigned to treatment based on the biologic profile: non DE/DH/TH patients receive 6 cycles R-CHOP-21 + 2R, DE patients receive 6 cycles R-DA-EPOCH and DH/TH receive R-CODOX-M/R-IVAC. Central Nervous System (CNS) prophylaxis with lumbar puncture and/or intravenous high dose methotrexate is reserved for DE or DH patients and for those with CNS-IPI 3-5 Results: Since 2013, 243 patients affected by DLBCL at diagnosis were consecutively treated according to biological risk: 139 non DE/DH/TH patients received R-CHOP, 80 DE patients received R-DA-EPOCH and 24 high risk patients received R-CODOX-M/R-IVAC (n= 13 DH/TH patients and n=11 DE patients with CNS IPI 3-5). Median age was 62 years (range, 21-86), 178 patients (73%) presented in stage 3-4 and 97 patients (40%) had an IPI score of 3-5. The three groups were not significantly different in terms of clinical characteristics, except for median age, which was higher in the R-CHOP group (66 years vs. 58 and 57 years in R-DA-EPOCH and R-CODOX-M/R-IVAC groups, respectively). Despite the toxicity expected with an intensified therapy, 95% of patients completed the treatment and no toxic deaths were registered. Febrile neutropenia was observed in 3%, 15% and 29% of patients in RCHOP, RDAEPOCH and RCODOX-M/R-IVAC, respectively. At a median follow-up of 42 months (range, 2-106 months), the estimated 3 years PFS and OS for the entire population were 80% and 89%, respectively. Patients with low IPI, limited stage and germinal center B cell of origin had significant better PFS as compared to the rest. Three years PFS and OS according to biological entity and relative treatment group were not significantly different, being 84%, 77% and 66%, (p=ns) and 93%, 85% and 74%, (p=ns) in non DE/DH/TH, DE and high risk patients, respectively. Similar PFS between non DE/DH/TH, DE and high risk patients were observed also in the subgroup of patients with IPI3-5 with PFS of 77%, 65% and 57%, respectively (p=ns). CNS prophylaxis was administered to 177 patients (73%) and 9 cases of CNS recurrence (4%) were observed Summary/Conclusion: In this study, we describe the feasibility of a personalized treatment according to biological risk in a real-life setting. This approach seems to overcome the poor outcome of DLBCL patients at high risk of relapse and ameliorate the prognosis of the overall DLBCL population. Biological characteristics should be carefully considered at diagnosis in order to give patients a personalized program and improve their outcome

Background: Follicular lymphoma (FL) is the second most common form of non-Hodgkin lymphoma (NHL) in Western countries, accounting for 20-30% of all NHLs (Hübel K. Hemasphere. 2020;4:e317). While most patients (pts) respond well to first-line therapy, they typically experience frequent relapses and progressively shorter duration of response with subsequent lines of therapy (Batlevi CL. Blood Cancer J. 2020;10:74; Rivas-Delgado A. Br J Haematol. 2019;184:753-9), and increasingly refractory disease with limited treatment options. Thus, there is an unmet need for effective treatment options for pts with relapsed or refractory (R/R) FL. Parsaclisib is a potent, highly selective, next-generation phosphatidylinositol 3-kinase (PI3K)δ inhibitor. Here we report results of the primary analysis of CITADEL-203 (NCT03126019, EudraCT 2017-001624-22), a phase 2, multicenter, open-label study of parsaclisib monotherapy in R/R FL.

Background: Follicular lymphoma (FL) is the most common subtype of indolent non-Hodgkin lymphoma (NHL). Although most patients with FL respond well to first-line therapy, they will inevitably relapse, and the subsequent course is often characterized by a pattern of recurrent relapses with progressively shorter intervals between treatment lines. Moreover, the use of multiple consecutive therapies often leads to refractory disease with severely limited treatment options, demonstrating the need for new therapies for this patient population. Currently approved phosphoinositide 3-kinase (PI3K) inhibitors are often poorly tolerated. Parsaclisib, a potent, highly-selective, next-generation PI3Kδ inhibitor, has shown promising activity in patients with previously treated B-cell malignancies. Here, we report preliminary results of CITADEL-203 (NCT03126019), a multicenter, open-label phase 2 study of parsaclisib in relapsed or refractory (R/R) FL. Methods: Key eligibility included, age ≥18 years, histologically confirmed R/R FL grade 1, 2, or 3a, ≥2 prior systemic therapies, Eastern Cooperative Oncology Group performance status (ECOG PS) ≤2, and ineligible for hematopoietic stem cell transplantation (HSCT). Patients were allocated to receive parsaclisib 20 mg once daily (QD) for 8 weeks followed by either 20 mg once weekly (weekly-dosing group [WG]) or 2.5 mg QD (daily-dosing group [DG]). Prophylaxis for Pneumocystis jirovecii pneumonia (PJP) was required. Objective response rate (ORR) was the primary endpoint; complete response rate (CRR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety and tolerability were secondary endpoints. All radiology-based endpoints were based on independent review. Results: From March 2018 to 17January 2020 (data cut-off), 106 patients (WG, n = 22; DG, n = 84) were treated. Enrollment is ongoing (target: 120 patients). At cut-off, 39 (37%) patients had discontinued treatment, including 25 (24%) for disease progression. The median exposure (range) was 5.3 months (0.5-18.1). The median age was 67 years, and 54% of the patients were men. The median time since initial diagnosis was 6 years. At enrollment, most patients (92%) had an ECOG PS ≤1, and 43% had a Follicular Lymphoma International Prognostic Index score ≥3 (high risk). The median (range) number of prior systemic therapies was 2 (1−8); 20% of the patients had prior HSCT; 47% were refractory to and 41% had relapsed from their most recent therapy. At the data cut-off, 96 patients were evaluable for response, including 74 in DG (Table). The ORR and CRR were 69.8% (95% confidence interval [CI]: 59.6−78.7) and 13.5% respectively, in all evaluable patients, and 71.6% (95% CI: 59.9% - 81.5%) and 13.5%, respectively, in DG. The median time to response was 8 weeks. The median DOR (95% CI) was not reached among responders overall (9.2 months−not estimable) and those in DG (7.4 months−not estimable). The median PFS (95% CI) was 15.8 months (11.3−15.8) overall and 15.8 months (11.0−15.8) in DG. The median follow-up (range) for this population was 10.2 months (1.9−22.2) overall and 9.5 months (1.9−21.1) in DG. Among the 106 patients evaluable for safety, the most common treatment-emergent adverse events (TEAE) were diarrhea (27.4% of patients), nausea (22.6%), cough (18.9%), and fatigue (15.1%). The most common TEAEs grade ≥3 were diarrhea (9.4% of patients), neutropenia (6.6%), and colitis (3.8%). TEAEs leading to dose interruption or dose reduction occurred in 39.6% and 9.4% of patients, respectively. TEAEs leading to treatment discontinuation occurred in 16% of patients. Serious TEAEs observed in ≥2 patients included diarrhea (5.7% of patients), colitis (3.8%), and pleural effusion (1.9%). There were no fatal TEAEs. TEAEs of clinical interest included rash (12.3% of patients), exfoliative dermatitis (1.9%), pneumonia (0.9%), and PJP (0.9%). New or worsening grade ≥3 laboratory test values of clinical interest included increase in alanine/aspartate amino transferase (0.9%/0% of patients), and decrease in neutrophil count (8.5%), platelet count (0%), and hemoglobin (1.9%). Conclusion: Parsaclisib demonstrated a high rate of rapid and durable response, and had an acceptable safety profile and was generally well tolerated. These results demonstrate a favorable benefit-risk profile in R/R FL. Updated data will be presented. Disclosures Lynch: Morphosys: Consultancy; Takeda: Research Funding; Incyte: Research Funding; TG therapeutics: Research Funding; Rhizen: Research Funding; Bayer: Research Funding; Juno: Research Funding; Cyteir: Research Funding; Genentech: Research Funding. Paneesha:Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Gilead: Honoraria; Janssen: Honoraria; AbbVie: Honoraria. Avigdor:Takeda, Gilead, Pfizer: Consultancy, Honoraria; Janssen, BMS: Research Funding. McKinney:Verastem: Consultancy; Pharmacyclics: Consultancy; Kite/Gilead: Honoraria, Speakers Bureau; Beigene: Research Funding; Celgene: Consultancy, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; Incyte: Research Funding; Molecular Templates: Consultancy, Research Funding; Nordic Nanovector: Research Funding; Novartis: Research Funding; BTG: Consultancy. Wahlin:Gilead Sciences: Research Funding; Roche: Consultancy, Research Funding. Belada:Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Research Funding; Celgene: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Research Funding. Canales:Celgene, Gilead, iQone, Janssen, Karyopharm, Novartis, F. Hoffmann-La Roche, Sandoz: Honoraria; Janssen, F. Hoffmann-La Roche, Sandoz, Takeda: Speakers Bureau. Cunningham:Bayer: Research Funding; OVIBIO: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Lilly: Research Funding; Janssen: Research Funding; Clovis Oncology: Research Funding; Celgene: Research Funding; MedImmune: Research Funding; Merck: Research Funding; Merrimack: Research Funding; Sanofi: Research Funding; AstraZeneca: Research Funding; 4SC: Research Funding. Morley:Kite: Honoraria; Janssen: Honoraria; Abbvie: Other: Conference Support; Takeda: Other: Conference Support; Roche: Other: Conference Support; Advisory board. Zheng:Incyte: Current Employment, Current equity holder in publicly-traded company. DeMarini:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Jiang:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Trněný:1st Faculty of Medicine, Charles University, General Hospital in Prague: Current Employment; Incyte: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company); MorphoSys: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Roche: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Bristol Meyers Squibb: Consultancy, Honoraria, Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company); Celgene: Consultancy.

We previously published the results of a pilot study showing that vaccination with tumor-loaded dendritic cells (DCs) induced both T and B cell response and produced clinical benefit in the absence of toxicity in patients with relapsed, indolent non-Hodgkin lymphoma (iNHL). The purpose of the present short report is to provide a 15-year follow-up of our study and to expand the biomarker analysis previously performed. The long-term follow-up highlighted the absence of particular or delayed toxicity and the benefit of active immunization with DCs loaded with autologous, heat-shocked and UV-C treated tumor cells in relapsed iNHL (5-year and 10-year progression-free survival (PFS) rates: 55.6% and 33.3%, respectively; 10-year overall survival (OS) rate: 83.3%). Female patients experienced a better PFS (p=0.016) and a trend towards a better OS (p=0.185) compared with male patients. Of note, we observed a non-negligible fraction of patients (22%) who experienced a long-lasting complete response. In a targeted gene expression profiling of pre-treatment tumor biopsies in 11 patients with available formalin-fixed, paraffin-embedded tissue, we observed that KIT , ATG12 , TNFRSF10C , PBK , ITGA2 , GATA3 , CLU , NCAM1 , SYT17 and LTK were differentially expressed in patients with responder versus non-responder tumors. The characterization of peripheral monocytic cells in a subgroup of 14 patients with available baseline blood samples showed a higher frequency of the subset of CD14 ++ CD16 + cells (intermediate monocytes) in patients with responding tumors. Since in patients with relapsed iNHL the available therapeutic options are often incapable of inducing a long-lasting complete remission and can be sometimes characterized by intolerable toxicity, we think that the encouraging results of our long-term follow-up analysis represent a stimulus to further investigate the role of active vaccination in this specific setting and in earlier lines of therapy and to explore novel combinatorial strategies encompassing other innovative immunotherapy agents, such as immune-checkpoint inhibitors.

Introduction: The International Extranodal Lymphoma Study Group (IELSG), in collaboration with the Italian Lymphoma Foundation (FIL) and the Lymphoma Study Association (LYSA), conducted the IELSG38 trial to evaluate the role of rituximab maintenance in mucosa associated lymphoid tissue (MALT) lymphoma patients (pts) after the administration of a front-line rituximab-chlorambucil regimen. In a prior study (IELSG19), this regimen, without maintenance, produced superior event-free (EFS) and progression-free survival (PFS) in comparison to either agent alone. Methods: Pts with MALT lymphoma arisen at any extranodal site, de novo, or relapsed following local therapy and/or antibiotics were eligible. Treatment consisted of an induction phase with chlorambucil (6 mg/m2/d orally on weeks 1 to 6, 9 to 10, 13 to 14, 17 to 18, and 21 to 22) and rituximab (375 mg/m2 intravenously on day 1 of week 1, 2, 3, 4 and 1400 mg subcutaneously on week 9, 13, 17, and 21). Pts with complete (CR), partial response (PR) or stable disease were eligible for maintenance with subcutaneous rituximab 1400 mg every two months for two years. Results: The study completed its planned accrual enrolling 112 patients, 53 women and 59 men (median age 65 years; range 32-86). Primary lymphoma localization was gastric in 32% and non-gastric in 68% of pts. Over half of pts (56%) had advanced disease (stage III-IV). MALT IPI showed low risk in 29%, intermediate risk in 40% and high risk in 30%. Twenty-four pts did not complete study treatment. Fifteen ceased before maintenance: 4 due to drug related (DR) adverse events (AEs), 3 to non-DR AEs, 2 to high grade transformation, 1 each for progressive disease (PD), second tumor, protocol deviation, investigator decision, patient decision, consent withdrawal. Nine discontinued during maintenance (3 DR AEs, 2 PD, 2 second tumors, 1 patient decision, 1 protocol deviation). The most common AEs of grade≥3 were hematologic (neutropenia in 33%, lymphocytopenia in 16%, leukopenia in 14%). Five pts experienced DR serious AEs (fever of unknown origin, sepsis, pneumonia, acute respiratory distress syndrome and progressive multifocal leukoencephalopathy). Best response was CR in 87% of pts. In the intention-to-treat population, CR rate increased over time from 53% at the end of induction to 65% at the end of maintenance. With a median follow-up of 65 months (IQR, 58-69), median EFS, PFS and OS were not reached. The 5-year EFS, PFS and OS were respectively 76% (95%CI, 67-83%), 87% (95%CI, 79-92%) and 93% (95%CI, 86-96%). The research was funded by: F. Hoffmann-La Roche Ltd, Basel provided the drug rituximab free of charge and partially supported the study financially. Keywords: Chemotherapy Combination, Therapies Immunotherapy Conflicts of interests pertinent to the abstract P. Feugier Consultant or advisory role: Roche Educational grants: Roche F. Merli Consultant or advisory role: Roche Educational grants: Roche E. Gyan Consultant or advisory role: Roche F. Morschhauser Consultant or advisory role: Roche A. Pulsoni Consultant or advisory role: Roche, Merck, Pfizer, Sandoz, Takeda, Gylead, Bristol Myers Squibb G. Cartron Consultant or advisory role: Roche, Celgene-BMS Honoraria: Sanofi, Celgene, Gilead, Novartis, Roche, Abbvie O. Casasnovas Consultant or advisory role: Roche, Takeda, MSD, BMS, Gilead Honoraria: Roche, Takeda, MSD, BMS, Gilead Research funding: Roche, Gilead Educational grants: Roche, Amgen C. Haioun Consultant or advisory role: Roche Honoraria: Roche A. M. Liberati Consultant or advisory role: Servier Research funding: Novartis, Janssen, Abbvie, Roche, Amgen, Celgene, BMS, Takeda, Incyte, Beigene, Oncopeptides AB, Verastem, Karyopharm, Archigen, Debiopharm International, Morphosys, Fibrogen, Onconova Therapeutics Inc D. Rossi Honoraria: Abbvie, Astra Zeneca, Janssen Research funding: Abbvie, Astra Zeneca, Janssen S. Luminari Consultant or advisory role: Rochem, Janssen, BMS, Regeneron, Genmab, Incyte Educational grants: Janssen, BMS A. Stathis Consultant or advisory role: Roche, Bayer, Eli LIlly Research funding: Merck, Bayer, Roche, Novartis, Pfizer, ADC Thearapeutics, MEW Pharma, Eli Lilly C. Thieblemont Consultant or advisory role: Roche, Incyte, Janssen, Gilead, Kyte, Novartis

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease, including one-third of cases overexpressing MYC and BCL2 proteins (double expressor lymphoma, DEL) and 5-10% of patients with chromosomal rearrangements of MYC, BCL2 and/or BCL-6 (double/triple-hit lymphomas, DH/TH). TP53 mutations are detected in 20- 25% of DEL. We report the efficacy of dose-adjusted EPOCH and rituximab (DA-EPOCH-R) in a series of 122 consecutive patients, including DEL (n=81, 66%), DEL-MYC (n=9, 7%), DEL-BCL2 (n=13, 11%), or high-grade lymphomas (DH/TH) (n=19, 16%). Central nervous system (CNS) prophylaxis included intravenous methotrexate (n=66), intrathecal chemotherapy (IT) (n=40) or no prophylaxis (n=16). Sixty-seven patients (55%) had highintermediate or high International Prognostic Index (IPI) and 30 (25%) had high CNS-IPI. The 2-year progression-free survival (PFS) and overall survival (OS) for the entire study population were 74% and 84%, respectively. There was a trend for inferior OS for DH/TH (2-year OS: 66%, P=0.058) as compared to all the others. The outcome was significantly better for the IPI 0-2 versus IPI 3-5 (OS: 98% vs. 72%, P=0.002). DA-EPOCH-R did not overcome the negative prognostic value of TP53 mutations: 2-year OS of 62% versus 88% (P=0.036) were observed for mutated as compared to wild-type cases, respectively. Systemic CNS prophylaxis conferred a better 2-year OS (94%) as compared to IT or no prophylaxis (76% and 65%, respectively; P=0.008). DA-EPOCH-R treatment resulted in a favorable outcome in patients with DEL and DEL with single rearrangement, whereas those with multiple genetic alterations such as DEL-DH/TH and TP53 mutated cases still have an inferior outcome.

Objectives: To compare cognition in a group of older long-term survivors from Non-Hodgkin Lymphoma (NHL) and in a corresponding group of non-cancer controls of the same age. Functional status, polypharmacy and multimorbidity were also evaluated. Methods: A cross-sectional study was performed in a population of 63 outpatient long-term survivors from NHL, aged 65 or more and 61 non-cancer controls. Socio-demographic, clinical and functional data were collected. Cognitive function was assessed through neuropsychological tests. Results: NHL survivors showed a slightly worse functional status than controls, they were affected by more chronic conditions (3.4 vs 2.3; p =.003) and were taking a higher number of medications (3.4 vs 2.3; p =.03). The Mini Mental State Examination (MMSE) was not significantly different between the groups. NHL survivors performed worse than controls in executive functioning (Trail Making Test B-A 47.9 vs 32.1 p =.04, OR for Stroop test time over 75th percentile in survivors: 2.66; CI 95% 1.04-6.61; OR for Multiple Features Target Cancellation time over 75th percentile in survivors: 2.84; CI 95% 1.10-7.31). A small, statistically significant difference was also observed in verbal memory scores between the two groups. Conclusions: The findings of this study suggest that, compared with non-cancer controls, older survivors from NHL may have a lower cognitive performance, especially in the executive functioning and attention domains, regardless of multimorbidity and polypharmacy. Further evidence from larger samples is needed to confirm such findings and better characterize cognitive decline in NHL survivors. (C) 2020 Elsevier Ltd. All rights reserved.

Poster: EANM 19 / EP-0381 / Prognostic value of baseline metabolic heterogeneity on 18F-FDG PET/CT in primary mediastinal large B-cell lymphoma (PMBCL) treated with R-DAEPOCH chemotherapy by: Alessi1, A. Guidetti2, L. Devizzi2, G. Argiroffi3, A. Lorenzoni3, G. Serafini3, B. Padovano3, A. Cicchetti4, F. SCALORBI3, V. Marasco2, L. Farina2, A. Dodero2, P. Corradini2, E. Seregni3; 1Fondazione I.R.C.S.S. Istituto Nazionale Tumori, Diagnostica per Immagini Radioterapia, MILAN, ITALY, 2Department of Oncology and Hematology; Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, ITALY, 3Nuclear Medicine Unit; Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, ITALY, 4Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, ITALY

Introduction: Diffuse Large B-Cell Lymphoma (DLBCL) is an heterogeneous disease: 30-40% of cases have high expression of MYC and BCL2 proteins (Dual Expressor, DE) and 5-10% have chromosomal rearrangements involving MYC, BCL2 and/or BCL6 (Double-/ Triple-Hit, DH/TH). Although the optimal treatment for those high-risk lymphomas remains undefined, DA-EPOCH-R produces durable remission with acceptable toxicity (Dunleauvy K, Lancet 2018). TP53 mutation is an independent marker of poor prognosis in patients (pts) with DLBCL treated with R-CHOP therapy. However, its prognostic value in poor prognosis lymphomas, receiving intensive therapy, has not been investigated yet. Methods: A series of consecutive pts (n=87) with biopsy proven diagnosis of DE DLBCL (MYC expression ≥40% and BCL2 expression ≥ 50% of tumor cells) or DE-Single Hit (DE-SH, i.e., DE-DLBCL with a single rearrangement of either MYC, BCL2 or BCL6 oncogenes) or DE-DH/TH (MYC, BCL2 and/or BCL6 rearrangements obtained by FISH) were treated with 6 cycles of DA-EPOCH-R and central nervous system (CNS) prophylaxis consisting of two courses of high-dose intravenous Methotrexate. Additional eligibility criteria included age ≥18 years and adequate organ functions. Cell of origin (COO) was defined according to Hans algorithm [germinal center B cell like (GCB) and non GCB)]. TP3 mutations were evaluated by next generation sequencing (NGS) based on AmpliseqTM technology or Sanger sequencing and considered positive when a variant allelic frequency ≥10% was detected. Results: Eighty-seven pts were included [n=36 DE only, n=32 DE-SH (n=8 MYC, n=10 BCL2, n=14 BCL6), n=19 DE-DH/TH] with 40 patients (46%) showing a non GCB COO. Pts had a median age of 59 years (range, 24-79 years). Seventy-three pts (84%) had advanced disease and 44 (50%) an high-intermediate/high-risk score as defined by International Prognostic Index (IPI). Only 8 of 87 pts (9%) were consolidated in first clinical remission with autologous stem cell transplantation following DA-EPOCH-R. After a median follow-up of 24 months, 73 are alive (84%) and 14 died [n=12 disease (n=2 CNS disease); n=1 pneumonia; n=1 suicide]. The 2-year PFS and OS were 71% (95%CI, 60-80%) and 76% (95%CI, 61%-85%) for the entire population. For those with IPI 3-5 the PFS and OS were not significant different for DE and DE-SH pts versus DE-DH/TH pts [64% vs 57% p=0.77); 78% vs 57% p=0.12)]. The COO did not influence the outcome for DE only and DE-SH [PFS: 78% vs 71% (p=0.71); 92% vs 86% (p=0.16) for GCB vs non -GCB, respectively]. Fourty-six pts (53%;n=18 DE only, n=18 DE-SH, n=10 DE-DH/TH ) were evaluated for TP53 mutations with 11 pts (24%) carrying a clonal mutation (n=6 in DE, n=3 in DE-SH, n=2 in DE-DH/TH). The 2-year PFS and OS did not significantly change for pts DE and DE-SH TP53 wild type as compared to DE and DE-SH mutated [PFS: 84 % vs 77%, (p=0.45); OS: 87% vs 88%, (p=0.92)]. The two pts DE-DH/TH with TP53 mutation are alive and in complete remission.Conclusions: High risk DLBCL pts treated with DA-EPOCH-R have a favourable outcome independently from high IPI score, DE-SH and DE-DH/TH. Also the presence of TP53 mutations does not negatively affect the outcome of pts treated with this intensive regimen. The efficacy of DA-EPOCH-R in overcoming poor prognostic genetic features in DLBCL should be confirmed in a larger prospective clinical trial. Disclosures Rossi: Daiichi-Sankyo: Consultancy; Roche: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Mundipharma: Honoraria; BMS: Honoraria; Sandoz: Honoraria. Carlo-Stella:Takeda: Other: Travel, accommodations; F. Hoffmann-La Roche Ltd: Honoraria, Other: Travel, accommodations, Research Funding; Rhizen Pharmaceuticals: Research Funding; Celgene: Research Funding; Amgen: Honoraria; AstraZeneca: Honoraria; Janssen Oncology: Honoraria; MSD: Honoraria; BMS: Honoraria; Genenta Science srl: Consultancy; Janssen: Other: Travel, accommodations; Servier: Consultancy, Honoraria, Other: Travel, accommodations; Sanofi: Consultancy, Research Funding; ADC Therapeutics: Consultancy, Other: Travel, accommodations, Research Funding; Novartis: Consultancy, Research Funding; Boehringer Ingelheim: Consultancy. Corradini:AbbVie: Consultancy, Honoraria, Other: Travel Costs; KiowaKirin: Honoraria; Gilead: Honoraria, Other: Travel Costs; Amgen: Honoraria; Celgene: Honoraria, Other: Travel Costs; Daiichi Sankyo: Honoraria; Janssen: Honoraria, Other: Travel Costs; Jazz Pharmaceutics: Honoraria; Kite: Honoraria; Novartis: Honoraria, Other: Travel Costs; Roche: Honoraria; Sanofi: Honoraria; Takeda: Honoraria, Other: Travel Costs; Servier: Honoraria; BMS: Other: Travel Costs.

A prospective trial conducted in the period 2000-2005 showed no survival advantage for high-dose chemotherapy with rituximab and autograft (R-HDS) versus conventional chemotherapy with rituximab (CHOP-R) as first-line therapy in 134 high-risk follicular lymphoma patients aged <60 years. The study has been updated at the 13-year median follow up. As of February 2017, 88 (66%) patients were alive, with overall survival of 66.4% at 13 years, without a significant difference between R-HDS (64.5%) and CHOP-R (68.5%). To date, 46 patients have died, mainly because of disease progression (47.8% of all deaths), secondary malignancies (3 solid tumor, 9 myelodysplasia/acute leukemia; 26.1% of all deaths), and other toxicities (21.7% of all deaths). Complete remission was documented in 98 (73.1%) patients and associated with overall survival, with 13-year estimates of 77.0% and 36.8% for complete remission versus no-complete remission, respectively. Molecular remission was documented in 39 (65%) out of 60 evaluable patients and associated with improved survival. In multivariate analysis, complete remission achievement had the strongest effect on survival (P<0.001), along with younger age (P=0.002) and female sex (P=0.013). Overall, 50 patients (37.3%) survived with no disease recurrence (18 CHOP-R, 32 R-HDS). This follow up is the longest reported on follicular lymphoma treated upfront with rituximab-chemotherapy and demonstrates an unprecedented improvement in survival compared to the pre-rituximab era, regardless of the use of intensified or conventional treatment. Complete remission was the most important factor for prolonged survival and a high proportion of patients had prolonged survival in their first remission, raising the issue of curability in follicular lymphoma. (Registered at clinicaltrials.gov identifier: 00435955)

Diffuse large B cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma (NHL) subtype in Europe.1 According to 2016 World Health Organization classification of lymphoid neoplasms, 2 molecular subtypes of DLBCL have been identified on the basis of gene expression profiling: germinal center B–cell-like, and activated B–cell-like, which differ in their molecular and cytogenetic patterns and have different clinical outcomes.2 First-line treatment for DLBCL is usually represented by an anthracycline-containing chemoimmunotherapy regimen, such as R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone).