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Several clinical risk models have been proposed to predict the outcome of follicular lymphoma (FL). The development of next-generation sequencing technologies has allowed the integration of somatic gene mutations into clinical scores to build genotyped-based risk models, such as the m7–Follicular Lymphoma International Prognostic Index (FLIPI). We explored 4 clinical or clinicogenetic-risk models in patients with symptomatic FL who received frontline immunochemotherapy. Of 191 patients with FL grades 1 to 3a, 109 were successfully genotyped. The treatment consisted of rituximab (R) plus cyclophosphamide, vincristine, and prednisone (R-CVP)/cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) (72.5%) or R-bendamustine (R-B) (27.5%). The proportion of cases classified as high risk for FLIPI, FLIPI-2, PRIMA–prognostic index, or m7-FLIPI were 39.3%, 14%, 30.3%, and 22%, respectively. No case with low-intermediate FLIPI was upgraded in the m7-FLIPI, but 18 of the 42 high-risk patients with FLIPI were downgraded to low-risk m7-FLIPI. The sensitivity and specificity for the prediction of POD24 were highest for FLIPI. The discrimination between progression-free survival (PFS) and overall survival (OS) was the best for FLIPI (c-index: 0.644 and 0.727, respectively). When analyzed only in patients treated with R-B, m7-FLIPI showed a higher discrimination between PFS and OS. Thus, the FLIPI remains the clinical risk score with higher discrimination in patients with advanced FL treated with immunochemotherapy; however, the performance of the m7-FLIPI should be further investigated in patients treated with R-B., Instituto de Salud Carlos III (ISCIII, European Union (FIS-FEDER PI15/0459, FIS-FEDER PI19/00034, GILEAD GLD18/00117, 2017SGR205, and PT20/00023), Xarxa de Banc de Tumors de Catalunya, Pla Director d’Oncologia de Catalunya, The biobank of the Fundación

Background Patients with chronic lymphocytic leukemia (CLL) may be more susceptible to COVID-19 related poor outcomes, including thrombosis and death, due to the advanced age, the presence of comorbidities, and the disease and treatment-related immune deficiency. The aim of this study was to assess the risk of thrombosis and bleeding in patients with CLL affected by severe COVID-19. Methods This is a retrospective multicenter study conducted by ERIC, the European Research Initiative on CLL, including patients from 79 centers across 22 countries. Data collection was conducted between April and May 2021. The COVID-19 diagnosis was confirmed by the real-time polymerase chain reaction (RT-PCR) assay for SARS-CoV-2 on nasal or pharyngeal swabs. Severe cases of COVID-19 were defined by hospitalization and the need of oxygen or admission into ICU. Development and type of thrombotic events, presence and severity of bleeding complications were reported during treatment for COVID-19. Bleeding events were classified using ISTH definition. STROBE recommendations were used in order to enhance reporting. Results A total of 793 patients from 79 centers were included in the study with 593 being hospitalized (74.8%). Among these, 511 were defined as having severe COVID: 162 were admitted to the ICU while 349 received oxygen supplementation outside the ICU. Most patients (90.5%) were receiving thromboprophylaxis. During COVID-19 treatment, 11.1% developed a thromboembolic event, while 5.0% experienced bleeding. Thrombosis developed in 21.6% of patients who were not receiving thromboprophylaxis, in contrast to 10.6% of patients who were on thromboprophylaxis. Bleeding episodes were more frequent in patients receiving intermediate/therapeutic versus prophylactic doses of low-molecular-weight heparin (LWMH) (8.1% vs. 3.8%, respectively) and in elderly. In multivariate analysis, peak D-dimer level and C-reactive protein to albumin ratio were poor prognostic factors for thrombosis occurrence (OR = 1.022, 95%CI 1.007‒1.038 and OR = 1.025, 95%CI 1.001‒1.051, respectively), while thromboprophylaxis use was protective (OR = 0.199, 95%CI 0.061‒0.645). Age and LMWH intermediate/therapeutic dose administration were prognostic factors in multivariate model for bleeding (OR = 1.062, 95%CI 1.017–1.109 and OR = 2.438, 95%CI 1.023–5.813, respectively). Conclusions Patients with CLL affected by severe COVID-19 are at a high risk of thrombosis if thromboprophylaxis is not used, but also at increased risk of bleeding under the LMWH intermediate/therapeutic dose administration.

Current therapeutic approaches for Sézary syndrome (SS) do not achieve a significant improvement in long-term survival of patients, and they are mainly focused on reducing blood tumor burden to improve quality of life. Eradication of SS is hindered by its genetic and molecular heterogeneity. Determining effective and personalized treatments for SS is urgently needed. The present work compiles the current methods for SS patient–derived xenograft (PDX) generation and management to provide new perspectives on treatment for patients with SS. Mononuclear cells were recovered by Ficoll gradient separation from fresh peripheral blood of patients with SS (N = 11). A selected panel of 26 compounds that are inhibitors of the main signaling pathways driving SS pathogenesis, including NF-kB, MAPK, histone deacetylase, mammalian target of rapamycin, or JAK/STAT, was used for in vitro drug sensitivity testing. SS cell viability was evaluated by using the CellTiter-Glo_3D Cell Viability Assay and flow cytometry analysis. We validated one positive hit using SS patient–derived Sézary cells xenotransplanted (PDX) into NOD-SCID-γ mice. In vitro data indicated that primary malignant SS cells all display different sensitivities against specific pathway inhibitors. In vivo validation using SS PDX mostly reproduced the responses to the histone deacetylase inhibitor panobinostat that were observed in vitro. Our investigations revealed the possibility of using high-throughput in vitro testing followed by PDX in vivo validation for selective targeting of SS tumor cells in a patient-specific manner.

Long-term safety and efficacy of eltrombopag in adults with persitent/chronic primary immune thrombocytopenia (ITP) evaluated in EXTEND study, showed a high response rate (80%) but, in the clinical safety study, it was observed that 6% of the patients presented venous and arterial thrombotic events. In addition, in the course of the disease, autoimmune hemolytic anemia (Evans syndrome, ES) may occur and could increase the risk of thrombosis. We report an interesting case of splenic rupture due to massive intrasplenic arterial thrombosis in the course of ES in a patient with chronic ITP treated with eltrombopag. The purpose of this case report is to highlight the potential increase in thrombotic risk that may involve the use of eltrombopag in hemolysis situations in patients with ITP.

Genome complexity has been associated with poor outcome in patients with chronic lymphocytic leukemia (CLL). Previous cooperative studies established five abnormalities as the cut-off that best predicts an adverse evolution by chromosome banding analysis (CBA) and genomic microarrays (GM). However, data comparing risk stratification by both methods are scarce. Herein, we assessed a cohort of 340 untreated CLL patients highly enriched in cases with complex karyotype (CK) (46.5%) with parallel CBA and GM studies. Abnormalities found by both techniques were compared. Prognostic stratification in three risk groups based on genomic complexity (0-2, 3-4 >= 5 and abnormalities) was also analyzed. No significant differences in the percentage of patients in each group were detected, but only a moderate agreement was observed between methods when focusing on individual cases (kappa=0.507; P

Introduction: Patients (pts) with CLL may be at particular risk of severe COVID-19 given advanced age and immune dysregulation. Two large series with limited follow-up have reported outcomes for pts with CLL and COVID-19 (Scarfò, et al. Leukemia 2020; Mato, et al. Blood 2020). To provide maximal clarity on outcomes for pts with CLL and COVID-19, we partnered in a worldwide effort to describe the clinical experience and validate predictors of survival, including potential treatment effects. Methods: This international collaboration represents a partnership between investigators at 141 centers. Data are presented in two cohorts. Cohort 1 (Co1) includes pts captured through efforts by European Research Initiative on CLL (ERIC), Italian CAMPUS CLL Program, and Grupo Español de Leucemia Linfática Crónica. The validation cohort, Cohort 2 (Co2), includes pts from US (66%), UK (23%), EU (7%), and other countries (4%). There is no overlap in cases between cohorts. CLL pts were included if COVID-19 was diagnosed by PCR detection of SARS-CoV-2 and they required inpatient hospitalization. Data were collected retrospectively 2/2020 - 5/2020 using standardized case report forms. Baseline characteristics, preexisting comorbidities (including cumulative illness rating scale (CIRS) score ≥6 vs. The primary endpoint of this study was to estimate the case fatality rate (CFR), defined as the proportion of pts who died among all pts hospitalized with COVID-19. Chi-squared test was used to compare frequencies; univariable and multivariable analyses utilized Cox regression. Predictors of inferior OS in both Co1 and Co2 were included in multivariable analyses. Kaplan-Meier method was used to estimate overall survival (OS) from time of COVID-19 diagnosis (dx). Results: 411 hospitalized, COVID-19 positive CLL pts were analyzed (Co1 n=281, Co2 n=130). Table 1 describes baseline characteristics. At COVID-19 dx, median age was 72 in Co1 (range 37-94) and 68 in Co2 (range 41-98); 31% (Co1) and 45% (Co2) had CIRS ≥6. In Co1, 48% were treatment-naïve and 26% were receiving CLL-directed therapy at COVID-19 dx (66% BTKi ± anti-CD20, 19% Venetoclax ± anti-CD20, 9.6% chemo/chemoimmunotherapy (CIT), 1.4% PI3Ki, 4% other). In Co2, 36% were never treated and 49% were receiving CLL-directed therapy (65% BTKi ± anti-CD20, 19% Venetoclax ± anti-CD20, 9.4% multi-novel agent combinations, 1.6% CIT, 1.6% PI3Ki, 1.6% anti-CD20 monotherapy, 1.6% other). Most pts receiving CLL-directed therapy had it held at COVID-19 diagnosis (93% in Co1 and 81% in Co2). Frequency of most COVID-19 symptoms/laboratory abnormalities were similar in the two cohorts including fever (88% in both), lymphocytosis (ALC ≥30 x 109/L; 27% vs. 21%), and lymphocytopenia (ALC < 1.0 x 109/L; 18% vs. 28%), while others varied between Co1 and Co2 (p Median follow-up was 24 days (range 2-86) in Co1 and 17 days (1-43) in Co2. CFRs were similar in Co1 and Co2, 30% and 34% (p=0.45). 54% and 43% were discharged while 16% and 23% remained admitted at last follow-up in Co1 and Co2, respectively. The proportion of pts requiring supplemental oxygen was similar (89% vs. 92%) while rate of ICU admission was higher in Co2 (20% vs. 48%, p Conclusions : In the largest cancer dx-specific cohort reported, pts with CLL hospitalized for COVID-19 had a CFR of 30-34%. Advanced patient age at COVID-19 diagnosis was an independent predictor of OS in two large cohorts. This CFR will serve as a benchmark for mortality for future outcomes studies, including therapeutic interventions for COVID-19 in this population. The effect of CLL treatment on OS was inconsistent across cohorts; COVID-19 may be severe regardless of treatment status. While there were no significant differences in distribution of current lines of therapy between cohorts, prior chemo exposure was more common in Co1 vs. Co2, which may account for difference in OS. Extended follow-up will be presented. Disclosures Roeker: American Society of Hematology: Research Funding; Abbott Laboratories: Other: spouse with minority ownership interest ; AbbVie: Other: spouse with minority ownership interest . Scarfo:Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AstraZeneca: Honoraria; Gilead: Membership on an entity's Board of Directors or advisory committees. Abrisqueta:Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Speakers Bureau; AbbVie: Consultancy, Honoraria, Speakers Bureau. Eyre:AbbVie: Consultancy, Honoraria, Other: travel support; Gilead: Consultancy, Honoraria, Other: travel support; Janssen: Consultancy, Honoraria, Other: travel support; KITE, AZ, Loxo Oncology at Lilly: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Muntañola Prat:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grants; participated in advisory boards; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grants; participated in advisory boards; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grants; participated in advisory boards. Villacampa:AstraZeneca: Other: advisory role; Merck Sharp & Dohme: Honoraria. Leslie:AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; BeiGene: Speakers Bureau; KitePharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene/BMS: Speakers Bureau; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pharmacyclics/Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Epizyme: Speakers Bureau; Karyopharm: Speakers Bureau; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Allan:Acerta, Genentech, Abbvie, Sunesis, Ascentage, Pharmacyclics, Janssen, AstraZeneca, BeiGene: Consultancy; Celgene, Genentech, Janssen, TG Therapeutics: Research Funding; Abbvie, Janssen, AstraZeneca, Pharmacyclics: Honoraria. Furman:Incyte: Consultancy; Genentech: Consultancy; Sunesis: Consultancy; Pharmacyclics: Consultancy; Loxo Oncology: Consultancy; Oncotarget: Consultancy; Janssen: Consultancy, Speakers Bureau; TG Therapeutics: Consultancy, Research Funding; Abbvie: Consultancy; Beigene: Consultancy; AstraZeneca: Consultancy, Research Funding; Acerta: Consultancy; Verastem: Consultancy. Pagel:BeiGene, Astrazeneca, Loxo Oncology, Gilead: Consultancy. Hernandez-Rivas:Gilead: Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Rovi: Membership on an entity's Board of Directors or advisory committees. Patel:Genentech: Consultancy, Speakers Bureau; Adaptive Biotechnologies: Consultancy; Janssen: Consultancy, Speakers Bureau; Celgene/BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; BeiGene: Consultancy; Kite: Consultancy; Pharmacyclics: Consultancy, Speakers Bureau; AstraZeneca: Consultancy, Research Funding, Speakers Bureau. Motta:Roche: Honoraria; Janssen: Honoraria. Lamanna:AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; Verastem: Research Funding; Bei-Gene: Research Funding; TG Therapeutics: Research Funding; Acerta: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche-Genentech: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Vitale:Janssen: Honoraria. Kamdar:Roche: Research Funding. Österborg:BeiGene: Research Funding; Kancera: Current equity holder in publicly-traded company, Research Funding; Sanofi: Consultancy; Karolinska Univeristy Hospital, Stockholm, Sweden: Current Employment. Hanson:Janssen-Cilag: Research Funding; Gilead: Research Funding; AbbVie: Honoraria. Eichhorst:ArQule: Consultancy, Honoraria, Other: travel support, Research Funding; BeiGene: Consultancy, Honoraria, Other: travel support, Research Funding; Gilead: Consultancy, Honoraria, Other: travel support, Research Funding; AstraZeneca: Consultancy, Honoraria, Other: travel support, Research Funding; Oxford Biomedica: Consultancy, Honoraria, Other: travel support, Research Funding; AbbVie: Consultancy, Honoraria, Other: travel support, Research Funding; F. Hoffmann-LaRoche: Consultancy, Honoraria, Other: travel support, Research Funding; Janssen-Cilag: Consultancy, Honoraria, Other: travel support, Research Funding; Celgene: Consultancy, Honoraria, Other: travel support, Research Funding; Novartis: Consultancy, Honoraria, Other: travel support, Research Funding. Reda:Gilead: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees. Varettoni:Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel/accommodations/expenses; AbbVie: Other: Travel/accommodations/expenses; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees. Marchetti:Gilead: Consultancy; Novartis: Speakers Bureau; Amgen: Speakers Bureau; AbbVie: Other: Sponsored meetings; Takeda: Other: Sponsored meetings; Pfeizer: Other: Sponsored meetings. Munir:F. Hoffmann-La Roche: Consultancy, Other: Medical writing support, furnished by Scott Battle, PhD, of Health Interactions, was funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland; Alexion: Honoraria. Zabalza:Janssen: Honoraria, Other: travel grants; Roche: Other: travel grants; Novartis: Other: travel grants. Janssens:Amgen: Consultancy, Other: travel grants; speaker fees; Abbvie: Consultancy, Other: travel grants; speaker fees; Celgene: Consultancy, Other: travel grants; speaker fees; Janssen: Consultancy, Other: travel grants; speaker fees; Gilead: Consultancy, Other: travel grants; speaker fees; Novartis: Consultancy, Other: travel grants; speaker fees; Sanofi-Genzyme: Consultancy, Other: travel grants; speaker fees; Roche: Consultancy, Other: travel grants; speaker fees. Niemann:AstraZeneca: Honoraria, Research Funding; CSL Behring: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Sunesis: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Danish Cancer Society: Honoraria, Research Funding; Novo Nordisk Foundation: Honoraria, Research Funding. Perini:Takeda: Honoraria; Janssen: Honoraria, Speakers Bureau; Abbvie: Speakers Bureau. Patten:AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra Zeneca: Honoraria. Marasca:Roche: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Shire: Honoraria. Iyengar:Janssen: Honoraria; Gilead: Honoraria. Ferrari:Abbvie: Honoraria. El-Sharkawi:Roche: Other: Conference fees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Itchaki:Abbvie Inc: Consultancy, Research Funding. Ma:Novartis: Research Funding; Juno: Research Funding; Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding, Speakers Bureau; Kite: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; Bioverativ: Consultancy, Honoraria; BeiGene: Honoraria, Research Funding, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Research Funding; TG Therapeutics: Research Funding. Van Der Spek:AMGEN: Other: Teaching activities. Seymour:Seattle Genetics: Research Funding; Merck: Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen/Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; Genentech: Research Funding; Bristol-Myers Squibb: Research Funding. Rigolin:Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Mauro:Roche: Other; Octopharma: Other; Takeda-Shire: Other; Gilead: Other; Janssen: Other; Abbvie: Other. Laurenti:Janssen: Honoraria; Gilead: Honoraria; AbbVie: Honoraria; Roche: Honoraria. Levin:Janssen: Membership on an entity's Board of Directors or advisory committees, Other: travel compensation; Abbvie: Membership on an entity's Board of Directors or advisory committees, Other: travel compensation; Roche: Membership on an entity's Board of Directors or advisory committees, Other: travel compensation. Špaček:Gilead: Honoraria; Abbvie: Honoraria; Janssen: Honoraria. Walewska:AbbVie: Other: sponsored for educational meetings, Speakers Bureau; Janssen: Other: sponsored for educational meetings, Speakers Bureau; Gilead: Speakers Bureau; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees. Wiestner:Pharmacyclics LLC, an AbbVie Company; Acerta, Merck, Nurix, Verastem, and Genmab: Research Funding; National Institutes of Health: Patents & Royalties: and other intellectual property. Broom:Gilead: Other: Travel support, Speakers Bureau. Kater:Abbvie: Research Funding; Roche: Research Funding; Janssen: Research Funding; Celgene: Research Funding; Genentech: Research Funding. Ujjani:AstraZeneca: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Verastem Oncology: Consultancy, Honoraria; Gilead/Kite: Consultancy, Research Funding; Atara: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; MorphoSys: Consultancy. Vandenberghe:Celgene: Other: sponsorship to attend Lugano lymphoma meeting in 2019; Gilead: Other: travel grants, Research Funding; Abbvie: Other: travel grants, Research Funding; Janssen: Other: travel grants; Roche: Other: travel grants, Research Funding. Chong:Novartis: Membership on an entity's Board of Directors or advisory committees; Tessa: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; KITE Pharma: Membership on an entity's Board of Directors or advisory committees. Pu:Takeda Pharmaceuticals: Consultancy. Brown:Janssen, Teva: Speakers Bureau; Gilead, Loxo, Sun, Verastem: Research Funding; Abbvie, Acerta, AstraZeneca, Beigene, Invectys, Juno/Celgene, Kite, Morphosys, Novartis, Octapharma, Pharmacyclics, Sunesis, TG Therapeutics, Verastem: Consultancy. Trentin:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Octapharma: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Shire: Honoraria. Farina:Abbvie: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Sanchez:Abbvie: Other: travel grants; Amgem: Other: travel grants; Janssen: Other: travel grants; Celgene: Other: travel grants; Roche: Other: travel grants. Shadman:Abbvie, Genentech, Astra Zeneca, Sound Biologics , Pharmacyclics, Verastem, ADC therapeutics, Beigene, Cellectar, BMS, Morphosys and Atara Biotherapeutics: Consultancy; Mustang Bio, Celgene, Pharmacyclics, Gilead, Genentech, Abbvie, TG therapeutics, Beigene, Astra Zeneca, Sunesis, Beigene: Research Funding. Foglietta:Janssen: Honoraria; Gilead: Honoraria. Jaksic:Roche: Honoraria; Janssen: Honoraria; Abbvie: Honoraria. Sportoletti:AbbVie: Honoraria; Janssen: Honoraria. Barr:Morphosys: Consultancy; Gilead: Consultancy; AstraZeneca: Consultancy, Research Funding; Verastem: Consultancy; Seattle Genetics: Consultancy; TG therapeutics: Consultancy, Research Funding; Abbvie/Pharmacyclics: Consultancy, Research Funding; Celgene: Consultancy; Merck: Consultancy; Genentech: Consultancy; Janssen: Consultancy. Ruchlemer:Abbvie Inc: Consultancy, Research Funding. Kersting:Celgene: Other: travel grant; Janssen: Research Funding; Abbvie: Research Funding. Huntington:Pharmacyclics: Honoraria; AbbVie: Consultancy; Novartis: Consultancy; Genentech: Consultancy; DTRM: Research Funding; Celgene: Consultancy, Research Funding; Bayer: Consultancy, Honoraria; Astrazeneca: Honoraria; TG Therapeutics: Research Funding. Herishanu:Roche: Honoraria; Sanofi: Honoraria; Medison: Honoraria; Janssen: Honoraria; Abbvie: Honoraria; AstraZeneca: Honoraria. Jacobs:TG Therapeutics, Inc.: Research Funding; Astra Zeneca: Consultancy, Speakers Bureau; AbbVie: Consultancy, Speakers Bureau; Pharmacyclics: Research Funding, Speakers Bureau; Seattle Genetics: Consultancy; Verastem: Consultancy; Janssen: Consultancy, Speakers Bureau; Genentech: Speakers Bureau; Sanofi Genzyme: Speakers Bureau. Portell:BeiGene: Consultancy, Research Funding; Pharmacyclics: Consultancy; TG Therapeutics: Research Funding; Infinity: Research Funding; Roche/Genentech: Consultancy, Research Funding; Xencor: Research Funding; Bayer: Consultancy; Amgen: Consultancy; Janssen: Consultancy; Kite: Consultancy, Research Funding; Acerta/AstraZeneca: Research Funding; AbbVie: Research Funding. Rambaldi:Sanofi: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Astellas: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); BMS/Celgene: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); University of Milan: Current Employment; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support of parent study and funding of editorial support. Received travel support., Research Funding; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support from Gilead.; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Research grant from Amgen Inc.; Omeros: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Advisory board and speaker fees from Pfizer.. Brander:Verastem: Consultancy, Honoraria, Other, Research Funding; NCCN: Other; Novartis: Consultancy, Other; Teva: Consultancy, Honoraria; Tolero: Research Funding; NCCN: Other; Novartis: Consultancy, Other; Teva: Consultancy, Honoraria; Tolero: Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; ArQule: Consultancy, Other, Research Funding; Ascentage: Other, Research Funding; AstraZeneca: Consultancy, Honoraria, Other, Research Funding; BeiGene: Other, Research Funding; DTRM: Other, Research Funding; Genentech: Consultancy, Honoraria, Other, Research Funding; Juno/Celgene/BMS: Other, Research Funding; MEI Pharma: Other, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Other, Research Funding; Pfizer: Consultancy, Other; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding. Rossi:Abbvie: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Novartis: Other: Advisory board; Astellas: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Pfizer: Membership on an entity's Board of Directors or advisory committees; Alexion: Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Coscia:Karyopharm Therapeutics: Research Funding; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Coombs:Abbvie: Consultancy, Honoraria; Genentech: Honoraria; AstraZeneca: Honoraria; MEI Pharma: Honoraria; LOXO Oncology: Honoraria; Octapharma: Honoraria; Novartis: Honoraria. Schuster:Novartis, Genentech, Inc./ F. Hoffmann-La Roche: Research Funding; AlloGene, AstraZeneca, BeiGene, Genentech, Inc./ F. Hoffmann-La Roche, Juno/Celgene, Loxo Oncology, Nordic Nanovector, Novartis, Tessa Therapeutics: Consultancy, Honoraria. Foà:Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees; Novartis: Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees; Incyte: Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Cuneo:Astra Zeneca: Honoraria; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Bosch:Jansen: Honoraria; Abbvie: Honoraria; Novartis: Honoraria; Astra Zeneca: Honoraria; Takeda: Honoraria; Celgene: Honoraria; Roche: Honoraria. Stamatopoulos:AstraZeneca: Honoraria; Janssen, Gilead, Abbvie: Honoraria, Research Funding. Ghia:Adaptive, Dynamo: Consultancy, Honoraria; Novartis: Research Funding; BeiGene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Celgene/Juno: Consultancy, Honoraria; Lilly: Consultancy, Honoraria; MEI: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Gilead: Consultancy, Honoraria, Research Funding; ArQule: Consultancy, Honoraria; Acerta/AstraZeneca: Consultancy, Honoraria. Mato:Adaptive: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; BeiGene: Consultancy; LOXO: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; TG Therapeutics: Consultancy, Other: DSMB, Research Funding.

Key Points Patients with FL anti-HBc+ present with worse 10-year PFS and OS.Patients with anti-HBc+ present with a higher frequency of ARID1A mutations and lack of EP300 mutations., Epidemiological studies have demonstrated the association between hepatitis B virus (HBV) infection and B-cell non–Hodgkin lymphoma (NHL), mainly for diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL). We studied a cohort of 121 patients with FL for HBV infection status, clinical features, and gene mutational profile. Anti-HBc was detectable in 16 patients (13.2%), although all had undetectable HBV DNA. Anti-HBcore+ (anti-HBc+) cases presented with older age at diagnosis than anti-HBc− cases (68.1 vs 57.2 years; P = .007) and higher β2-microglobulin (56.3% vs 28.9%; P = .04). All patients included in the study fulfilled criteria for treatment and received therapy with rituximab or rituximab-containing chemotherapy. There were no episodes of HBV reactivation or HBV hepatitis during treatment and/or maintenance. Remarkably, anti-HBc+ patients had significantly lower 10-year progression-free survival (PFS; 12.9% vs 58.3%; P < .0001) and overall survival (OS; 22.0% vs 86.2%; P < .0001), that remained at multivariate analysis. Gene mutational profiling of all cases showed that anti-HBc+ cases had higher incidence of ARID1A mutations and absence of EP300 mutations, 2 key epigenetic regulators in FL. Overall, our study shows that FL patients with resolved HBV infection have a worse outcome independently of other well-known clinical risk factors and a distinct gene mutational profile.

Patients with chronic lymphocytic leukemia (CLL) may be more susceptible to Coronavirus disease 2019 (COVID-19) due to age, disease, and treatment-related immunosuppression. We aimed to assess risk factors of outcome and elucidate the impact of CLL-directed treatments on the course of COVID-19. We conducted a retrospective, international study, collectively including 941 patients with CLL and confirmed COVID-19. Data from the beginning of the pandemic until March 16, 2021, were collected from 91 centers. The risk factors of case fatality rate (CFR), disease severity, and overall survival (OS) were investigated. OS analysis was restricted to patients with severe COVID-19 (definition: hospitalization with need of oxygen or admission into an intensive care unit). CFR in patients with severe COVID-19 was 38.4%. OS was inferior for patients in all treatment categories compared to untreated (p

Objective Our aim was to retrospectively assess the role of routine CT scans within the first year of follow-up with a limited surveillance policy prior to Lugano recommendations in diffuse large B-cell lymphomas (DLBCL) achieving complete metabolic remission (CMR). We also evaluated the type of relapse detection and exposure to CT scans within the first five years. Methods Patients diagnosed with DLBCL who achieved CMR after first-line immunochemotherapy were included. Imaging studies and medical records were thoroughly reviewed. Results Among 101 DLBCL patients in the first CMR, a total of 19 relapses were identified in the study period (18.8% of DLBCL patients included). Nine patients relapsed within the first year (47.4% of all relapses) but only 3 of them were detected by the 202 surveillance CT scans performed during this first year of follow-up. Conclusions Our real-world data provide clinically applicable results which are in agreement with the Lugano recommendations based on trial data, highlighting the lack of utility of routine CTs in DLBCL patients achieving CMR.

Insulin‐like growth factor levels and chronic lymphocytic leukaemia Spanish Ministry of Economy and Competitiveness–CarlosIII Institute of Health cofunded by FEDER funds/European Regional Develpment Fund (ERDF)–a way to build Europe (PI17/01280, PI11/01810, PI14/01219, PI11/02213, PI15/00966, RCESP C03/09, RTICESP C03/10, RTIC RD06/0020/0095, RD12/0036/0056, Rio Hortega CM13/00232, SV-09-CLINIC-1, CIBERESP and SAF2016-79347-R) and the Agència de Gestió d’Ajuts Universitaris i de Recerca AGAUR(2017SGR1085, 2014SGR756). The ICGC CLL-Genome Project was funded by Spanish Ministerio de Economía y Competitividad (MINECO) through the Instituto de Salud CarlosIII (ISCIII), PMP15/00007 and CIBERONC

Introduction: Dysregulated NK cell-mediated immune responses contribute to tumor evasion in chronic lymphocytic leukemia (CLL), although the NK cell compartment in CLL-like monoclonal B-cell lymphocytosis (MBL) is poorly understood. In healthy individuals, human cytomegalovirus (HCMV) induces the expansion of NK cells expressing high levels of CD94/NKG2C NK cell receptor (NKR) specific for HLA-E. Methods: We analyzed the expression of NKG2A, NKG2C, ILT2, KIR, CD161, and CD57 in 24 MBL and 37 CLL. NKG2C was genotyped in these patients and in 81 additional MBL/CLL, while NKG2C gene expression was assessed in 26 cases. In 8 CLL patients with increased lymphocytosis (≥20 × 109 /L), tumor HLA-E and HLA-G expression was evaluated. Results: NKR distribution did not significantly differ between MBL and CLL patients, although they exhibited reduced NKG2C+ NK cells compared with a non-CLL group (4.6% vs 12.2%, P = .012). HCMV+ patients showed increased percentages of NKG2C+ NK cells compared with HCMV- (7.3% vs 2.9%, P = .176). Frequencies of NKG2C deletions in MBL/CLL were similar to those of the general population. Low/undetectable NKG2C expression was found among NKG2C+/- (45%) and NKG2C+/+ (12%) patients. CLL cases with increased lymphocytosis displayed especially reduced NKG2C expression (1.8% vs 8.1%, P = .029) and tumor cells with high HLA-E (>98%) and variable HLA-G expression (12.4%, range: 0.5-56.4). CLL patients with low NKG2C expression (

Several studies in chronic lymphocytic leukemia (CLL) patients have reported impaired immune cell functions, which contribute to tumor evasion and disease progression. However, studies on CLL-like monoclonal B-cell lymphocytosis (MBL) are scarce. In the study described here, we characterized the immune environment in 62 individuals with clinical MBL, 56 patients with early-stage CLL, and 31 healthy controls. Gene expression arrays and quantitative reverse transcription polymerase chain reaction were performed on RNA from CD4+ peripheral blood cells; serum cytokines were measured with immunoassays; and HLA-DR expression on circulating monocytes, as well as the percentages of Th1, cytotoxic, exhausted, and effector CD4+ T cells, were evaluated by flow cytometry. In addition, cell cultures of clonal B cells and CD14-enriched or -depleted cell fractions were performed. Strikingly, MBL and early-stage CLL differed in pro-inflammatory signatures. An increased inflammatory drive orchestrated mainly by monocytes was identified in MBL, which exhibited enhanced phagocytosis, pattern recognition receptors, interleukin-8 (IL8), HMGB1, and acute response signaling pathways and increased pro-inflammatory cytokines (in particular IL8, interferon γ [IFNγ], and tumor necrosis factor α). This inflammatory signature was diminished in early-stage CLL (reduced IL8 and IFNγ levels, IL8 signaling pathway, and monocytic HLA-DR expression compared with MBL), especially in those patients with mutations in IGHV genes. Additionally, CD4+ T cells of MBL and early-stage CLL exhibited a similar upregulation of Th1 and cytotoxic genes and expanded CXCR3+ and perforin+ CD4+ T cells, as well as PD1+ CD4+ T cells, compared with controls. Cell culture assays disclosed tumor-supporting effects of monocytes similarly observed in MBL and early-stage CLL. These novel findings reveal differences in the inflammatory environment between MBL and CLL, highlighting an active role for antigen stimulation in the very early stages of the disease, potentially related to malignant B-cell transformation.

Chronic lymphocytic leukemia (CLL) is a disease of the elderly, characterized by immunodeficiency. Hence, patients with CLL might be considered more susceptible to severe complications from COVID-19. We undertook this retrospective international multicenter study to characterize the course of COVID-19 in patients with CLL and identify potential predictors of outcome. Of 190 patients with CLL and confirmed COVID-19 diagnosed between 28/03/2020 and 22/05/2020, 151 (79%) presented with severe COVID-19 (need of oxygen and/or intensive care admission). Severe COVID-19 was associated with more advanced age (≥65 years) (odds ratio 3.72 [95% CI 1.79–7.71]). Only 60 patients (39.7%) with severe COVID-19 were receiving or had recent (≤12 months) treatment for CLL at the time of COVID-19 versus 30/39 (76.9%) patients with mild disease. Hospitalization rate for severe COVID-19 was lower (p < 0.05) for patients on ibrutinib versus those on other regimens or off treatment. Of 151 patients with severe disease, 55 (36.4%) succumbed versus only 1/38 (2.6%) with mild disease; age and comorbidities did not impact on mortality. In CLL, (1) COVID-19 severity increases with age; (2) antileukemic treatment (particularly BTK inhibitors) appears to exert a protective effect; (3) age and comorbidities did not impact on mortality, alluding to a relevant role of CLL and immunodeficiency.

In recent years, considerable progress has been made in frontline therapy for elderly/physically unfit patients with CLL. The combination of obinutuzumab and chlorambucil (O-Clb) has been shown to prolong progression free survival (PFS, median PFS-31.5 months) and overall survival (OS) compared to chlorambucil alone. More recently, obinutuzumab given in combination with either ibrutinib or venetoclax improved PFS but not OS when compared to O-Clb. In this retrospective multinational, multicenter co-operative study, we evaluated the efficacy and safety of frontline treatment with O ± Clb in unfit patients with CLL, in a “real-world” setting. Patients with documented del (17p13.1)/TP53 mutation were excluded. A total of 437 patients (median age, 75.9 years; median CIRS score, 8; median creatinine clearance, 61.1 mL/min) were included. The clinical overall response rate was 80.3% (clinical complete and partial responses in 38.7% and 41.6% of patients, respectively). Median observation time was 14.1 months and estimated median PFS was 27.6 months (95% CI, 24.2-31.0). In a multivariate analysis, high-risk disease [del (11q22.3) and/or IGHV-unmutated], lymph nodes of diameter > 5 cm, obinutuzumab monotherapy and reduced cumulative dose of obinutuzumab, were all independently associated with shorter PFS. The median OS has not yet been reached and estimated 2-year OS is 88%. In conclusion, in a “real-world” setting, frontline treatment with O-Clb achieves PFS comparable to that reported in clinical trials. Inferior outcomes were noted in patients with del (11q22.3) and/or unmutated IGHV and those treated with obinutuzumab-monotherapy. Thus, O-Clb can be still considered as legitimate frontline therapy for unfit CLL patients with low-risk disease.

Background. CLL-like monoclonal B-ceII lymphocytosis (MBL) is considered a requisite precursor of CLL, with 1-2% of subjects annually progressing to CLL requiring therapy. The role of immune alterations leading to and operating in MBL and controlling progression to CLL is not well characterized. Since an increased frequency of immune-related conditions associated with immune dysfunction exists prior to CLL diagnosis (Landgren et al, Br J Haematol 2007 and Blood 2007; Andersen et al, Leukemia 2020), immune alterations likely exist in MBL. We have examined the serum protein profiles of MBL and CLL in search of clues linking immune dysfunction with malignant transformation. Objectives. 1. Characterize the serum proteomic profiles of MBL individuals, IGHV-mutated CLL (M-CLL) and IGHV-unmutated CLL (U-CLL) patients, and age-matched healthy controls (HC). 2. Compare the serum proteomic profiles between the groups. 3. Assess the effect of IGHV mutation status on serum proteomic profiles in CLL. Methods. A total of 12 MBL, 12 M-CLL, 12 U-CLL and 12 age-matched HC were studied. Patients were cared for at Northwell Health, New York (n=25) and Hospital del Mar, Barcelona (n=11). All patients were treatment naive except for one U-CLL patient who was treated one year beforehand. Serum samples were collected, and their protein levels measured employing SOMAmers (modified single-stranded DNA aptamers; SomaLogic) to quantify relative levels of 1,310 proteins. P-values Results. Overall, the levels of 862 proteins differed significantly between groups: MBL vs. HC: 10 downregulated (d) and 24 upregulated (u); M-CLL vs. HC: 206d and 6u; U-CLL vs. HC: 54d and 40u; M-CLL vs. MBL: 384d and 5u; U-CLL vs. MBL: 74d and 24u; and M-CLL vs. U-CLL: 35d and 0u. IPA highlighted a role for the pro-inflammatory HMGB1 pathway in several comparisons. First, an activated HMGB1 pathway was predicted in MBL compared to HC, together with activation of phagocytes, and an inhibition of the systemic immune suppressor TGF-β. Second and consistent with the former, U-CLL patients displayed an activated HMGB1 pathway compared to HC, along with other signs of immune stimulation (activated NFkB and Th1 pathways, maturation of dendritic cells, and inhibition of TGF-β) and leukemic progression (activated progression of tumor, and leukocyte extravasation). Third and contrary to the above, the HMGB1 pathway was inhibited when comparing M-CLL to HC, in line with a global immune suppression signature (inhibited PRR, GM-CSF, FcεRI, IL1, IL8, TNF, Th1, STAT3 and NFkB pathways, in addition to inhibited cell movement, viability and activation). Notably, inhibition of immune pathways was predicted for both M-CLL and U-CLL compared to MBL (diminished TNF and IL6 signaling, and reduced cell movement), although the greatest differences were seen for M-CLL vs. MBL comparison, including blockade of the HMGB1 pathway in M-CLL. Finally, the M-CLL vs. U-CLL comparison suggested inhibited INFγ, IL2, IL3, IL4, NFkB, and decreased T lymphocyte stimulation and movement of tumor cells in M-CLL patients. Conclusions. An increased pro-inflammatory signature with involvement of the HMGB1 pathway was identified in MBL and U-CLL compared with HC, whereas the opposite was seen for M-CLL. Since MBL most often exhibit mutated IGHV (91% of cases in our cohort), these findings suggest immune stimulation as a characteristic feature in the pre-leukemic and U-CLL leukemic stage that surprisingly is not operative in M-CLL. Consistent with this, M-CLL displayed a global immune suppression (HMGB1 pathway inhibition), whereas U-CLL exhibited signs of immune stimulation (HMGB1 pathway activation) compared to HC which may relate to distinct capabilities of the two subtypes to interact with the microenvironment. Lastly, the increased inflammatory signature identified in MBL, which are mainly IGHV-mutated, was lessened in CLL, mainly in M-CLL patients. This is consistent with a decreased influence of immune imbalance and the HMGB1 pathway associated with IGHV-mutated clonal expansions. Acknowledgments. GB is supported by a grant from Fundación Alfonso Martín Escudero. Disclosures Allen: Alexon: Research Funding; Bristol Myers Squibb: Other: Equity Ownership; C4 Therapeutics: Other: Equity Ownership; Sanofi Genzyme: Membership on an entity's Board of Directors or advisory committees. Rhodes: Conquer Cancer Foundation Young Investigator Award: Other: Grant/Research Support; AbbVie, Genentech, Pharmacyclics, TG Therapeutics: Other: Consultant.

OBJECTIVE: To evaluate the role of N-terminal pro-brain-type natriuretic peptide (NT-proBNP) and a cardiovascular (CV) risk score named FRESCO for predicting anthracycline-induced cardiotoxicity (AIC) in diffuse large B-cell lymphoma (DLBCL). METHODS: A total of 130 consecutive DLBCL patients treated in first-line with anthracycline-containing immunochemotherapy. Competitive risk between NT-proBNP, FRESCO, and time to AIC was considered. RESULTS: Cumulative incidence of AIC was 12.2% and 17.5% at 1 and 5 years, respectively. Median time to development cardiotoxicity was 6.4 months, with half of the cases showing heart failure and the other half silent AIC. Both NT-proBNP levels and FRESCO score were independently associated with higher risk of AIC (P = 0.001 and P = 0.03, respectively). Patients with NT-proBNP ≥600 pg/mL or those with FRESCO ≥4.5% had 3.97 or 2.54 times higher risk of AIC than those with lower values (P = 0.001 and P = 0.048, respectively). According to the previous cutoffs, three groups of patients with a significantly different risk of AIC could be identified (P < 0.0001). CONCLUSIONS: Doxorubicin-containing chemotherapy is associated with increased risk of silent and overt AIC. Baseline NT-proBNP levels and FRESCO CV risk score are accurate predictors of AIC and can identify groups of patients at different risk, in which personalized cardiologic evaluation should be offered.

INTRODUCTION. Chromosome banding analysis (CBA) is the gold standard to identify complex karyotypes (CK; ≥3 chromosomal aberrations in the same clone). CK are predictors of poor prognosis and treatment refractoriness in patients with chronic lymphocytic leukemia (CLL). Patients with CK (15% at diagnosis) constitute a heterogeneous subgroup with highly variable clinical course. Recent studies that aim to refine CK definition in CLL suggest that ≥5 is the number of anomalies detected by CBA that better predicts an impaired outcome (Baliakas et al, 2019). Molecular techniques as genomic microarrays also detect genomic complexity (GC). A recent multicentric ERIC study (Leeksma et al, ASH 2017) identified that patients with ≥5 copy number alterations (CNA) detected by microarrays are associated with an adverse outcome. However, risk stratification regarding genomic complexity assessed by CBA and microarrays has not been compared. OBJECTIVES. 1. To compare genomic complexity in CLL defined by CBA vs microarrays; 2. To compare risk stratification based on genomic complexity measured by both techniques. METHODS. The study cohort included 293 CLL patients from 16 European institutions (67% males) with available CBA result at diagnosis or prior to first treatment. The cohort was enriched in patients with CK (n=153, 52%). Tumor DNA extracted from peripheral blood (n=254) or bone marrow samples (n=39) obtained at the time of CBA was hybridized to CGH-arrays (n=12) and SNP-arrays (n=281) platforms. Clinically relevant aberrations [11q-, +12, 13q-, 17p-] and CNA ≥5Mb were considered for the anomaly count. Three risk groups were defined using previously suggested cut-off points for CBA and microarrays [non-CK/low-GC: 0-2; low/intermediate-CK/GC: 3-4; high-CK/GC: ≥5 (Baliakas et al, Leeksma et al)]. Groups obtained by both methods were compared and correlated with other clinical and biological data. Time to first treatment (TTT) of patients categorized according to the number of alterations detected by CBA and microarrays was analyzed. RESULTS. Median number of abnormalities detected was 3 (range: 0-19) by CBA and 2 (range: 0-18) by microarrays. When stratified according to previously defined criteria, a moderate agreement was observed between both techniques (κ=0.483, p Regarding the prognostic value of genomic complexity and considering the number of abnormalities detected as a continuous variable, CBA and microarrays showed a similar concordance index (C-index) for TTT (0.615 vs 0.609, respectively). When considering all the abnormalities independently of their size or when lowering the cutoff to 1Mb for those non-CLL abnormalities, similar impact on TTT was observed (C-index=0.593 vs 0.616). The three risk groups defined by each method showed significant differences on TTT (Figure 1, p CONCLUSIONS. 1. CBA and microarrays are helpful techniques for assessing genomic complexity in CLL patients; 2. Risk categories established by both methods have a significant impact on TTT although they show a moderate agreement; 3. Discordant cases are being investigated to refine genomic complexity criteria equivalent by both techniques. ACKNOWLEDGEMENTS. 17SGR437, GLD17/00282, FPU17/00361 Disclosures Rigolin: AbbVie: Speakers Bureau; Gilead: Speakers Bureau; Gilead: Research Funding. Gimeno:JANSSEN: Consultancy, Speakers Bureau; Abbvie: Speakers Bureau. Bosch:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AstraZeneca: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; F. Hoffmann-La Roche Ltd/Genentech, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Acerta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Kyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Honoraria, Research Funding. Cuneo:Amgen: Honoraria; Abbvie: Honoraria, Speakers Bureau; Gilead: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Roche: Honoraria, Speakers Bureau. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership.

Background. Dysregulated NK-cell responses have been reported in chronic lymphocytic leukemia (CLL) patients, but little is known about the NK cell compartment in CLL-like monoclonal B cell lymphocytosis (MBL). Human cytomegalovirus (HCMV) infection induces an adaptive reconfiguration of the NK cell compartment characterized by the differentiation and persistent expansion of a subset displaying the CD94/NKG2C NK receptor (NKR). Moreover, a deletion of the NKG2C (KLRC2) gene has been reported to modulate the magnitude of the NK cell repertoire redistribution. Little is known about the expression of NKG2C in CLL and MBL patients. Aims. To analyse the distribution of NKR, with special attention to NKG2C, in MBL and CLL patients, assessing the relation of the NK cell immunophenotype with clinical features. Methods. The study cohort included 61 patients, 24 were diagnosed with clinical MBL and 37 were treatment-naïve CLL (32/37 Binet A). The expression of NKG2C, NKG2A, ILT2 (LIR1, LILRB1), CD161, CD57 and KIRs (identified with a cocktail of monoclonal antibodies) was assessed by flow cytometry in peripheral blood NK cells. The NKG2C (KLRC2) genotype was analysed in a larger representative MBL/CLL cohort (n=135). Results. The proportions of NK cells were reduced in CLL patients compared to MBL (median 5.5% vs. 10%; P=0.003), whereas their absolute numbers were increased (median 0.85x109/L vs. 0.57x109/L; P=0.002). No significant differences between MBL and CLL were detected regarding the distribution of the different NKR: NKG2C (median: 2.7 vs. 5.9%, respectively), NKG2A (31.4 vs. 30.8%), ILT2 (18.0 vs.15.8%), KIRs (54.4 vs. 52.7%), CD161 (16.1 vs. 16.4%) and CD57 (40.4 vs. 38.9%). Though a reduced NKG2C expression was noticed in both entities, it was specially marked in patients with a greater (>30x109 cells/L) lymphocytosis (1.4 vs. 7.7%, P=0.016). The proportions of NKG2C+ NK cells in HCMV+ patients (85%, 47/55) as compared to HCMV- individuals were not significantly different (6.3% vs. 2.9%, respectively). HCMV+ patients showed a significantly lower NKG2C expression when compared with two independent age-matched cohorts of HCMV+ non-CLL/-MBL individuals, including 43 non-metastatic breast cancer patients (4.2% vs. 15.3% , P Conclusions. 1. MBL and CLL exhibited low proportions of NKG2C+ NK cells. This immunophenotype was particularly evident in CLL patients with increased lymphocytosis and could not be explained by differences in HCMV seropositivity, NKG2C zygosity nor age. 2. Additional studies are required to define the mechanism(s) and putative implications of the reduced NKG2C expression in these lymphoproliferative disorders. Acknowledgements. PI11/1621; PI15/437; 2017/SGR437; Fundació La Caixa; Fundación Española de Hematología y Hemoterapia (FEHH). Disclosures Gimeno: JANSSEN: Consultancy, Speakers Bureau; Abbvie: Speakers Bureau. Abrisqueta:Celgene: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Other: Travel, Accommodations, expenses, Speakers Bureau; Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, expenses, Speakers Bureau; Roche: Consultancy, Honoraria, Other: Travel, Accommodations, expenses, Speakers Bureau. Bosch:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Kyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Acerta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; F. Hoffmann-La Roche Ltd/Genentech, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding.

Background and objective. Specific immunochemotherapy is the standard treatment of patients with Burkitt leukemia or lymphoma (BL/L). The BURKIMAB08 trial showed 3-yr overall survival (OS) probability of 72% (Ribera JM et al, Cancer. 2013; 119:1660-8). However, the toxicity was high, and 11% of patients died in complete response (CR). In the BURKIMAB14 trial, dose-intensity of chemotherapy blocks was reduced in patients ≤55 years who achieved CR, with the aim to decrease the death rate without impact on efficacy. We present the results of this trial in 80 patients with BL/L and compare them with those of the BURKIMAB08 trial. Patients and method. All patients received a pre-phase with cyclophosphamide, prednisone and rituximab. Patients in localized stages (I-II non-bulky) received 4 blocks of immunochemotherapy (A1, B1, C1, A2), with 33% reduction of doses of iphosphamide, methotrexate and ARA-C in patients ≤55 years in CR (assessed by PET-CT) after B1 cycle. Patients in stages III-IV and mature B-ALL received 6 immunochemotherapy blocks (A1, B1, C1, A2, B2, C2), with the same dose reduction in cycles C1, A2, B2, C2 in patients ≤55 years in CR after B1 cycle. Patients >55 years received reduced intensity chemotherapy (as in BURKIMAB08) in both induction and post-induction cycles. The CR rate, cumulated incidence of relapse (CIR) and OS were analyzed and compared with those from the BURKIMAB08 trial. Results. From 2014-2019, 80 patients with BL/L were enrolled. Median age (range): 48 (17-80) years, 57 (71%) ≤55 years, 61 males (76%), 15 (19%) patients in stages I-II non-bulky and 65 (81%) in stages III-IV, 25 of whom (38%) had mature B-ALL. 18 patients (23%) were HIV positive, 13 (17%) showed CNS involvement at diagnosis and 23 (31%) bulky mass (>10 cm). 45 patients (60%) had intermediate-high or high IPI. All patients in stages I-II non-bulky showed CR. 4/65 patients in stages III-IV or mature B-ALL are receiving induction therapy, 1/65 withdrew the trial, 7/60 (12%) died in induction, 2/60 (3%) were resistant and 51/60 (85%) achieved CR. Of them, 6 relapsed, 3 withdrew the trial and 3 died in CR (one in the group of localized stage). OS probability at 3 years was 74% (95%CI: 64%-84%) (localized stages 100% [NE], advanced stages 68% [56%-80%], p=0.047, without difference in patients in stages III-IV vs. mature B-ALL, Figure 1). Patients >55 years showed a significantly lower probability of OS (61% [41%-81%] vs. 80% [68%-92%], p=0.022, Figure 2). A lower but non-statistically significant OS probability was observed in HIV-infected vs. non-HIV-positive patients (61% [36%-86%] vs. 78% [67%-89%], p=0.310). The CIR for patients in advanced stage/mature B-ALL was 13% (3%-28%)A trend for lower death rate in CR was observed in BURKIMAB14 vs. BURKIMAB 08 trial (3/62 vs. 16/151, p=0.180), without differences in CIR (9% [3%-21%] vs. 12% [6%-20%]) or in OS (74% [64%-84%] vs. 72% [65%-79%], respectively). Conclusions. The results of the BURKIMAB14 trial are promising, especially for patients in localized stages and for those Supported in part with the grants PI14/01971 FIS, Instituto Carlos III, SGR 288 (GRC) y Fundación "La Caixa". Figure 1. OS according to stage (I-II, vs. III-IV vs. mature B ALL) Figure 2. OS according to age (≤55 y vs >55 y) Figure 1 Disclosures Abrisqueta: Abbvie: Consultancy, Honoraria, Other: Travel, Accommodations, expenses, Speakers Bureau; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, expenses, Speakers Bureau; Roche: Consultancy, Honoraria, Other: Travel, Accommodations, expenses, Speakers Bureau. Fernandez:Teva: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding. Terol:Roche: Consultancy; Abbvie: Consultancy; Astra Zeneca: Consultancy; Janssen: Consultancy, Research Funding; Gilead: Research Funding. Gimeno Vázquez:JANSSEN: Consultancy, Speakers Bureau; Abbvie: Speakers Bureau. Sancho:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Other: Advisory board; Novartis: Honoraria; Kern Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria; Celltrion: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squib: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sandoz: Consultancy; F. Hoffmann-La Roche Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Background:The isolation of cell-free DNA (cfDNA) evolved the concept of liquid biopsy. Several works have analyzed the presence of cfDNA in lymphomas, especially in diffuse large B-cell lymphoma (DLBCL) and Hodgkin lymphoma (HL), however there is limited information regarding the detection of cfDNA in other types of lymphomas or the role of cfDNA detection to monitor disease outcome. Objectives:1.- To analyze the presence of cfDNA at diagnosis of patients with lymphoproliferative malignancies. 2.- To evaluate the change in concentration of cfDNA ([cfDNA]) after treatment in DLBCL patients. Material and Methods:A retrospective study in a single center was performed including 221 adult patients since January 2015 to February 2019 with: DLBCL, HL, marginal zone lymphoma (MZL), follicular lymphoma (FL), chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), lymphoplasmacytic lymphoma (LPL) and peripheral T-cell lymphomas (TCL). All patients had plasma samples collected at diagnosis that were stored in the institutional biobank (MarBiobank). The cfDNA were obtained from 1 mL of -80°C frozen stored plasma using the MagMax Cell Free DNA isolation kit (Thermo Fisher Scientific). The cfDNA quantification was performed using the Qubit system with the dsDNA high sensitivitykit (Thermo Fisher) and is expressed as ng/mL of plasma. In addition, patients with DLBCL who were treated with rituximab-CHOP/CHOP-like regimens were evaluated for [cfDNA] analysis, pre and post-treatment, and results were compared with PET-CT scan findings. Results: Stored plasma samples at diagnosis were available in 221 patients: DLBCL 82, HL 22, CLL/LPL 13, FL 36, MZL 37, MCL: 11, TCL 10 and others 10 (B-cell lymphoma unclassified, hairy cell leukemia, Burkitt lymphoma). Successful identification of cfDNA was obtained in 95.9% (212/221) of samples. DLBCL patients showed higher [cfDNA] globally and, DLBCL, HL and FL patients showed a higher concentration than MZL who exhibited the lower concentration of all groups (p=0.009; p=0.013 and p=0.002); see table 1. 50 DLBCL patients with a median follow-up since diagnosis of 25.5 (5-51) months were analyzed. Median age was 67 (19-79) years, males 56% (28). IPI distribution: low-risk 28% (14), low-intermediate 26% (13), high-intermediate 24% (12) and high risk 22% (11) cases. Detection of cfDNA was successful in 100% at diagnosis and in 98% (49) cases post-therapy. The mean [cfDNA] at diagnosis was 2.21 (standard deviation- SD: 1.60) ng/mL with a correlation with LDH concentration (p After therapy 86% (43) of patients achieved at least PR (41 complete response), and the mean [cfDNA] for these patients was 1.58 (SD 1.96); patients who showed no response or progressive disease after therapy exhibited higher [cfDNA] 21.25 ng/mL (SD 41.91)(p Conclusions:Isolation of cfDNA was feasible in >95% of lymphoma patients independently of histology or disease stage. Patients with DLBCL exhibited the higher cfDNA concentration which were also correlated with LDH concentrations and high-risk IPI. Kinetics of [cfDNA] is related to response to therapy in DLBCL and also might detect relapse. Even though additional studies are necessary, monitoring of cfDNA may help in management of patients with DLBCL. Disclosures Salar: Roche: Research Funding, Speakers Bureau; Janssen Pharmaceuticals: Consultancy, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; Celgene: Consultancy. Sanchez-Gonzalez:Takeda: Consultancy, Speakers Bureau; Alexion: Speakers Bureau; Gilead: Speakers Bureau; Shire: Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau. Gimeno:JANSSEN: Consultancy, Speakers Bureau; Abbvie: Speakers Bureau. Bellosillo:Qiagen: Consultancy, Speakers Bureau; TermoFisher Scientific: Consultancy, Speakers Bureau.

Chronic lymphocytic leukemia (CLL) occurs in older individuals with a median age at diagnosis of 72 years. In recent years, there has been considerable progress in the frontline therapy of elderly/physically unfit patients with CLL. The German CLL11 trial showed that addition of obinutuzumab to chlorambucil (G-Clb) prolongs progression free survival (PFS) and overall survival (OS) compared to chlorambucil alone or in combination with rituximab. More recently, obinutuzumab together with ibrutinib or venetoclax were shown to be superior to G-Clb with regard to PFS, but there was no advantage in terms of OS. In this retrospective, multinational and multicenter co-operative study the European Research Initiative on CLL (ERIC) and the Israeli CLL Study Group (ICLLSG) evaluated the efficacy of frontline treatment with G-Clb in patients with CLL, in a "real-world" setting. Our analysis excluded CLL patients with documented del(17p) or TP53 mutations since they are no longer treated with chemotherapy. Results: A total of 437 treatment-naïve patients with CLL from 51 medical centers located in 13 countries were included. The median age of this patient population was 75.9 years; 59.7% were men, median CIRS total score was 8 and estimated creatinine clearance 61.1 mL/min. Seventy four patients had Binet stage A (17.2%), 167 (38.8%) stage B and 190 (44.1%) stage C. Results of FISH and IGHV mutational status were available for 332 and 115 patients, respectively. High-risk cytogenetics, del(11q) was documented in 18.7% patients and IGHV-unmutated gene in 64.4%. The vast majority of patients were treated with G-Clb (N=408) and the rest with obinutuzumab monotherapy (G-monotherapy, N=29). The clinical overall response was 86.5%, including clinical complete and partial responses in 41.6% and 45.8% of cases, respectively. The median observation time was 14.1 months (m) and the median PFS of the entire cohort was 27.6m (95% CI, 24.2-31.0). The PFS for G-Clb was significantly better than G-monotherapy (P=0.001; HR=0.38, 95% CI: 0.22-0.67), being the 2-year PFS estimates 61.8% and 52.8%, respectively. The median PFS was significantly shorter for patients with del(11q) (19.2m) compared to those with normal FISH (not reached, P5cm, G-monotherapy, reduced cumulative dose of obinutuzumab and status less than CR, were independently associated with shorter PFS. Seventy patients (16%) received a second-line treatment. The median OS for the entire cohort has not been reached yet and 2-year OS estimate is 88%. In conclusion, in a "real-world" setting, frontline treatment with G-Clb achieves PFS comparable to that reported in clinical trials. Inferior outcomes were observed in patients with high-risk disease [del(11q) and/or IGHV-unmutated] and those treated with G-monotherapy. Thus, even today in the era of novel drugs, G-Clb can be considered a legitimate frontline treatment in unfit CLL patients with low-risk disease [non-del(11q) and IGHV-mutated]. Disclosures Herishanu: Roche: Honoraria; AbbVie: Honoraria; Janssen: Honoraria. Simkovic:Roche: Honoraria; University Hospital Hradec Kralove: Employment; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Acerta: Consultancy, Honoraria. Mauro:Gilead: Consultancy, Research Funding; Shire: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Jannsen: Consultancy, Research Funding; Roche: Consultancy, Research Funding. Coscia:Abbvie: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm Therapeutics: Research Funding. Scarfo:AstraZeneca: Honoraria; Janssen: Honoraria; AbbVie: Honoraria. Tedeschi:AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen spa: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; SUNESIS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BeiGene: Honoraria. Gimeno Vázquez:JANSSEN: Consultancy, Speakers Bureau; Abbvie: Speakers Bureau. Assouline:F. Hoffmann-La Roche Ltd: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau. Levato:Novartis: Honoraria; Pfizer: Honoraria; Incyte: Honoraria; BMS: Honoraria. Rigolin:Gilead: Speakers Bureau; Gilead: Research Funding; AbbVie: Speakers Bureau. Loscertales:Janssen: Honoraria; Roche: Honoraria; AstraZeneca: Honoraria; AbbVie: Honoraria; Gilead: Honoraria. Ghia:Dynamo: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Acerta/AstraZeneca: Consultancy, Honoraria; ArQule: Consultancy, Honoraria; BeiGene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Juno/Celgene: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria, Research Funding; Novartis: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy; Gilead: Consultancy, Honoraria, Research Funding.

INTRODUCTION: Chronic lymphocytic leukemia (CLL)-like monoclonal B cell lymphocytosis (MBL) is considered a precursor of CLL. It is found in 5-10% of elderly healthy individuals and shows a progression rate to CLL requiring therapy of 1.1% per year. A balance between microenvironmental factors and intrinsic properties of the emerging B cell clone may be decisive for the transition from MBL to CLL, although biomarkers of progression remain unknown. The objective is to describe biological markers (B cell gene expression profiles and serum cytokine levels) that predict progression from MBL to CLL. METHODS: Gene expression profiles of clonal B cells from 14 MBL subjects (median age: 76 years, clonal B cells: 0.5-4.3 x109/L) were evaluated. With a median follow-up from analysis of 59 months (range: 10-77), 3 cases (21.4%) had progressed to CLL Binet stage A at last follow-up (clonal lymphocytosis >5x109/L, range: 6.2-7.9). Clonal B cells (CD19+CD5+) were isolated from peripheral blood by immunomagnetic methods (Miltenyi Biotec). Extracted RNA (RIN>7) was hybridized to GeneChip Human Gene 2.0 ST arrays (Affymetrix). Gene expression profiles were compared between MBL cases that progressed to CLL (P-MBL, n=3) and non-progressive MBL cases (NP-MBL, n=11). Differential gene expression was evaluated employing linear models for microarrays in R, and genes with P1.5 or 5x109/L, range: 6.4-17.3). Clonal B cells and cytokine levels were compared between P-MBL (n=5) and NP-MBL (N=36). For cytokine levels, the optimal cut-off values to stratify MBL cases according to their progression risk were assessed using the maxstat R package, whereas for clonal B cells a cut-off value of 3.9 x109/L was considered according to the results obtained by Kostopoulos et al (Blood Cancer J, 2017). The effect of different covariates on progression-free survival was evaluated using log-rank test. Cox proportional hazards regression models were performed to assess their independent prognostic value. P RESULTS: A total of 455 genes were differentially expressed (250 upregulated and 205 downregulated in P-MBL). IPA predicted an inhibition of apoptosis as well as proteins with tumor suppressor activity (SMARCA4) in P-MBL, besides enhanced bioenergetic processes (transmembrane potential of mitochondria) and anti-inflammatory features (activation of IL13 pathway and decreased chemotaxis of phagocytes and granulocytes) (Table 1). P-MBL displayed increased clonal B cells (4.2 vs. 1.7 x109/L, P=0.003) and levels of IL10 (1.15 vs. 0.9 pg/mL, P=0.087) as well as diminished levels of IL6 (2.04 vs. 3.75 pg/mL, P=0.041). MBL cases with ≥3.9 x109/L clonal B cells, ≥1.08 pg/mL of IL10 and ≤2.04 pg/mL of IL6 had an increased risk of progression to CLL (P CONCLUSIONS: 1. P-MBL cases showed an inhibition of the apoptotic pathway and an activation of bioenergetic processes, which may account for the increased clonal B cells observed in this group. 2. P-MBL exhibited enhanced anti-inflammatory features, including augmented levels of the anti-inflammatory cytokine IL10. 3. Increased clonal B cells and IL10 levels predicted a higher risk of progression to CLL, suggesting that an augmented proliferative rate of clonal B cells together with a supporting tumor microenvironment are required for progression from MBL to CLL. ACKNOWLEDGEMENTS. PI11/01621, PI15/00437, 2017/SGR437, Fundació La Caixa, Fundación Española de Hematología y Hemoterapia (FEHH). Disclosures Gimeno: JANSSEN: Consultancy, Speakers Bureau; Abbvie: Speakers Bureau. Rai:Cellectis: Membership on an entity's Board of Directors or advisory committees; Genentech/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; Pharmacyctics: Membership on an entity's Board of Directors or advisory committees. Abrisqueta:Roche: Consultancy, Honoraria, Other: Travel, Accommodations, expenses, Speakers Bureau; Abbvie: Consultancy, Honoraria, Other: Travel, Accommodations, expenses, Speakers Bureau; Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, expenses, Speakers Bureau; Celgene: Consultancy, Honoraria. Bosch:AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Kyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; F. Hoffmann-La Roche Ltd/Genentech, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Honoraria, Research Funding; Acerta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AstraZeneca: Honoraria, Research Funding; Takeda: Honoraria, Research Funding.

INTRODUCTION: CXCL9, CXCL10 and CXCL11 (CXCL9-10-11) are closely related cytokines that specifically bind to their receptor CXCR3. They act inducing chemotaxis, proliferation and/or cytotoxicity of CD4+ Th1 and cytotoxic T cells, which express CXCR3. Although the CXCL9-10-11/CXCR3 axis promotes immune activation, their pro- or anti-tumor effects in chronic lymphocytic leukemia (CLL) remain controversial. The aims of this study are: 1. To investigate serum levels of CXCL9-10-11 and the protein expression of their receptor CXCR3, as well as Th1 and cytotoxic gene expression signatures and protein expression of the cytotoxic molecules granzyme B and perforin in peripheral blood (PB) CD4+ T cells of controls, CLL-like monoclonal B-cell lymphocytosis (MBL) and CLL Binet stage A patients. 2. To assess the correlations between all previous parameters. 3. To evaluate Th1, cytotoxic and PD1+ T cell populations during disease progression. METHODS: Samples from 52 MBL subjects, 61 untreated CLL patients (Binet stage A/B [CLL-A/CLL-B]: 53/8) and 31 age-matched controls were employed. Serum levels (pg/mL) of CXCL9-10-11 were measured in 24 controls, 41 MBL and 44 CLL-A patients using Human CXCL9/MIG Quantikine ELISA Kit (R&D Systems) and U-PLEX Platform (Meso Scale Discovery). In addition, cryopreserved PB mononuclear cells from 8 controls, 11 MBL, 10 CLL-A and 8 CLL-B were studied by flow cytometry. Anti-CD3, anti-CD4, anti-granzyme B, anti-perforin, anti-CXCR3 and anti-PD1 antibodies, FVS510 and Fixation/Permeabilization Kit were used for cell staining (BD Biosciences). Protein expression of CXCR3, granzyme B, perforin and PD1 (measured as percentage of positive cells in PB CD4+ T cells) was assessed using FACSCanto II cytometer (BD Biosciences). In addition, purified CD4+ cells from PB (purity≥90%) were isolated by immunomagnetic methods (Miltenyi Biotec) to analyze gene expression in 9 controls, 13 MBL and 14 CLL-A patients. Extracted RNA (RIN>7) was hybridized to GeneChip Human Gene 2.0 ST arrays (Affymetrix). Differential gene expression was evaluated with linear models in R, and genes with P-value1.5 were considered differentially expressed. Linear regression and Pearson correlations were calculated to evaluate the relationship between the different components of the CXCL9-10-11/CXCR3 axis (Figure 1). P-values RESULTS: MBL subjects showed significantly increased CXCL9-10-11 serum levels as well as CXCR3 protein expression, Th1 and cytotoxic gene expression and perforin protein expression in CD4+ T cells compared to controls. A similar trend was obtained for CLL-A versus controls, although the differences for CXCL10 and cytotoxic proteins did not achieve statistical significance despite their increased levels (Table 1). CXCL9 and CXCL10 serum levels were significantly and strongly correlated with CXCR3 protein expression in CD4+ T cells (r=0.746, P-value=0.001 and r=0.716, P-value=0.002, respectively). Very strong positive and significant correlations were also detected between CXCR3 protein expression and Th1 gene expression in CD4+ T cells (correlation coefficients >0.8 for 6/7 genes). Significant positive correlations were also observed between CXCR3 protein expression and cytotoxic genes as well as granzyme B protein (Table 2). Protein expression of CXCR3 and cytotoxic molecules were similarly increased in the different stages of the disease. However, CLL-B patients displayed an increased percentage of CD4+ T cells expressing PD1 (around 7% in MBL and CLL-A versus 16% in CLL-B), although significance was not achieved (Table 1). CONCLUSIONS: 1. The increased levels of the different components of the CXCL9-10-11/CXCR3 axis in MBL and CLL-A, together with the strong correlations observed, point to an important activation of this molecular pathway in the first stages of the disease. 2. Correlations between CXCR3 and Th1/cytotoxic genes/proteins suggest that the increased Th1/cytotoxic features of CD4+ T cells in MBL and CLL-A are triggered by CXCL9-10-11/CXCR3 stimulation, and might be considered as a potential target for CLL immunotherapy. 3. The lower percentage of PD1+ CD4+ T cells in MBL/CLL-A may allow efficient effector Th1/cytotoxic responses at these stages of the disease. ACKNOWLEDGEMENTS. PI11/01621, PI15/00437, 2017/SGR437, Fundació La Caixa, Fundación Española de Hematología y Hemoterapia (FEHH). Disclosures Gimeno: Abbvie: Speakers Bureau; JANSSEN: Consultancy, Speakers Bureau. Rai:Genentech/Roche: Membership on an entity's Board of Directors or advisory committees; Pharmacyctics: Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees; Cellectis: Membership on an entity's Board of Directors or advisory committees. Abrisqueta:Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, expenses, Speakers Bureau; Abbvie: Consultancy, Honoraria, Other: Travel, Accommodations, expenses, Speakers Bureau; Roche: Consultancy, Honoraria, Other: Travel, Accommodations, expenses, Speakers Bureau. Bosch:Acerta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Kyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AstraZeneca: Honoraria, Research Funding; F. Hoffmann-La Roche Ltd/Genentech, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

On behalf of Grupo Español de Leucemia Linfática Crónica (GELLC) and Grupo Cooperativo Español de Citogenética Hematológica (GCECGH)., We analyzed the features of chronic lymphocytic leukemia (CLL) with multiple abnormalities (MA) detected by FISH. A local database including 2095 CLL cases was used and 323 with MA (15.4%) were selected. MA was defined by the presence of two or more alterations (deletions of 13q14 (13q-), 11q22 (11q-), 17p13 (17p-) or trisomy 12 (+12)). The combination of 13q- with 11q- and 13q- with 17p-, accounted for 58.2% of the series, in contrast to 11q- with 17p- (3.7%). Patients carrying MA since diagnosis presented a short time to first therapy(TTFT) (27 months) and overall survival (OS) (76 months). The combinations including 17p- had a shorter OS (58 months) than the ones without 17p- (not reached, p =.002). Patients with a complex-FISH were the ones with worse OS (34 months). MA imply poor prognosis when they emerge at diagnosis, probably due to the high incidence of bad prognosis markers, which may be a reflection of a more complex karyotype.

Predoctoral contract to MS (CIBERESP), Spanish Ministry of Economy and Competitiveness Juan de la Cierva de Incorporación grant IJCI-2014-20900. Spanish Ministry of Economy and Competitiveness - Carlos III Institute of Health cofunded by FEDER funds/European Regional Develpment Fund (ERDF) - a way to build Europe [(grants PI17/01280, PI11/01810, PI14/01219, PI11/02213, PI09/1662, PI15/00966, RCESP C03/09, RTICESP C03/10, RTIC RD06/0020/0095, RD12/0036/0056, Rio Hortega CM13/00232, SV-09-CLINIC-1 and Centro de Investigación Biomédica en Red: Epidemiología y Salud Pública (CIBERESP))] and the Agència de Gestió d'Ajuts Universitaris i de Recerca AGAUR (2017SGR1085, 2014SGR756). The ICGC CLL-Genome Project was funded by Spanish Ministerio de Economía y Competitividad (MINECO) through the Instituto de Salud Carlos III (ISCIII), PMP15/00007 and Centro de Investigación Biomédica en Red: Oncología (CIBERONC)., Solans, M., Castelló, A., Benavente, Y., Marcos-Gragera, R., Amiano, P., Gracia-Lavedan, E., Costas, L., Robles, C., Gonzalez-Barca, E., Banda, E.L., Alonso, E., Aymerich, M., Campo, E., Dierssen-Sotos, T., Fernández-Tardón, G., Olmedo-Requena, R., Gimeno, E., Castaño-Vinyals, G., Aragonés, N., Kogevinas, M., Sanjose, S., Pollán, M., Casabonne, D.

Rituximab is a chimeric monoclonal antibody targeting the CD20 antigen which is present on the surface on B-lymphocytes [1]. Rituximab has become part of the standard therapy for B-cell non-Hodgkin...

Doxorubicin-containing chemotherapy is the standard regimen for elderly patients with aggressive lymphoma. However, many of them cannot receive it due to severe associated comorbidities. Toxicity and efficacy of intermediate doses of nonpegylated liposomal doxorubicin (NPLD) in modified-CHOP regimen ± Rituximab were prospectively analyzed in 35 frail elderly patients (median age: 76 years) with previously untreated aggressive lymphoma with one or more severe comorbidities. NPLD at intermediate doses (30 mg/m 2 ) is effective and well tolerated in these patients. In addition, NT-proBNP levels > 900 ng/ml at diagnosis have demonstrated to be a good predictor for OS and PFS in this cohort of patients.

MYD88 (L265P) mutation is an independent prognostic factor for outcome in patients with diffuse large B-cell lymphoma

Introduction: Anthracyclines are cytotoxic antibiotics used in the treatment of lymphomas. Myocardiopathy is a well-known toxicity of anthracyclines, and both acute/subacute and late-onset presentations have been described. Early detection of asymptomatic cardiac dysfunction and identification of biomarkers for anthracycline cardiotoxicity risk may be important to prevent irreversible heart damage. Objective: To prospectively evaluate the incidence, time of appearance and clinico-biological variables associated with the development of myocardiotoxicity in patients with diffuse large B-cell lymphoma (DLBCL) treated with R-CHOP/R-CHOP-like regimens. Patients and Methods: one hundred and sixty six patients with DLBCL from 05/2004 to 05/2014. Excluded: HIV infection (10), treatment without anthracyclines (21) and other causes (5) (Table 1). Left ventricular ejection fraction (LVEF) determined by high resolution echocardiography and the N-terminal brain natriuretic peptide (NT-proBNP) fragment were done prior initiation of treatment, at the end and every 6-12 months thereafter. Myocardiotoxicity was defined as: LVEF 15% if prior LVEF Results: median age 68 years (IQR: 54-75), 51% male, median NT-proBNP 251.8 pg/mL (IQR: 76.2-560.1), median LVEF 64% (IQR: 60-69%) and median FRESCO scale 4.5 (IQR 2.1-7.2). NT-proBNP was correlated with FRESCO scale, but not with LVEF. With a median follow-up of 64.7 months (95% CI 56.4-73.6) 24 cardiac events were observed (5 clinical CHF + normal LVEF, 7 clinical CHF + LVEF low and 12 low LVEF without clinical CHF). Cumulative incidence of myocardiotoxicity was 8.8% at 6 months (95% CI 5.0 to 15.3), 12.3% at 12 months (95% CI 7.6 to 19.6), 14.2% at 24 months (95% CI 9.1 to 21.9) and 17.6% at 5 years (95% CI 11.6 to 26.1). C statistic for myocardiotoxicity was: FRESCO scale 0.7192 (95%CI: 0.6284- 0.8099) and FRESCO scale+NT-proBNP 0.807 (95%CI: 0.7309-0.8832). Competing risks analysis showed a significantly increased cumulative incidence of myocardiotoxicity in patients with NT-proBNP >600 +/- FRESCO >4.5 (Figure 1). Finally, we performed a computational modeling using 12 Bayesian networks to analyze the connections between demographic characteristics, cardiovascular risk factors, treatment, occurrence of cardiotoxicity and death (Figure 2 illustrates one of the networks). Conclusions: myocardiotoxicity induced by anthracyclines remains an important problem in the daily practice. The FRESCO cardiovascular risk function is useful for predictingmyocardiotoxicity and levels of NT-proBNP improved accuracy myocardiotoxicity risk. We propose that patients with NT-proBNP >600 pg/mL or FRESCO > 4.5 should have a specific cardiologic surveillance and follow-up in cardio-oncology units from the start of their anthracyclin-containing chemotherapy. Disclosures No relevant conflicts of interest to declare.

INTRODUCTION Chemotherapy-induced hepatitis B virus (HBV) reactivation is a well-recognized complication and is a potentially life-threatening condition in cancer patients with chronic HBV (hepatitis B surface antigen [HBsAg]-positive). Rituximab has been associated with an increase in HBV reactivation in chronic HBV patients (45%) and even in patients with resolved infection (HBsAg negative and hepatitis B core antibody [anti-HBc]-positive (22%); however, the reported frequency varies among different studies. Current guidelines for management of chronic HBV recommend routine antiviral HBV prophylaxis with lymphoma before starting chemotherapy. In contrast, there is little evidence-based consensus regarding patients with resolved HBV infection. Aim: To analyze the incidence of HBV reactivation and the role of antiviral HBV prophylaxis in lymphoma patients with chronic HBV or resolved HBV treated with chemotherapy, immunotherapy or immunochemotherapy managed according to our institutional HBV guidelines. Secondary endpoints were to analyze the incidence of HBV in this population and HBV guidelines adherence. PATIENTS AND METHODS Lymphoma patients with chronic HBV or resolved HBV in a single center. HBV viral status definitions: Active Chronic HBV infection: HBsAg positive, anti-HBc positive and HBV DNA >2000 IU/mL; Inactive Carriers: HBsAg positive, Anti-HBc positive, HBV DNA undetectable or HBV reactivation was defined as increased serum HBV DNA (≥1 log10), regardless of liver biochemistry or HBsAg status. Institutional HBV guidelines: serum samples were collected at baseline for HBsAg and anti-HBc testing in all lymphoma patients. Patients were evaluated by a hepatologist if any of them fulfilled HBV viral status definition. Baseline at screening and monitoring every 3 months during therapy and up to 24 months after completing therapy (assessment of liver biochemistry, serum HBV DNA, HBsAg and anti-HBs levels). Specific prophylaxis strategies according to HBV status: Group A (Active chronic HBV): treatment for HBV; Group B (Inactive carriers): antiviral HBV prophylaxis; Group C (Resolved HBV): antiviral HBV prophylaxis if rituximab containing-therapy or follow-up only if rituximab-free therapy. HBV antiviral prophylaxis was started before therapy and finished 12 months after completing therapy. RESULTS From January 2012 to January 2015, 227 lymphoma patients received chemotherapy or immunochemotherapy. 142 (63%) patients received rituximab-containing therapy. 43 (19%) patients were anti-HBc positive. Group A: 2 (1%) patients; Group B: 2 (1%) patients; Group C: 39 (17%) patients. 14 (6%) patients have coinfection with hepatitis C virus and 12 (5%) patients co-infection with human immunodeficiency virus (HIV). Adherence to HBV guidelines was 90%. Patients in Group A (n=2) and B (n=2) received antiviral treatment/prophylaxis before starting therapy. In the Group C, 16 (41%) patients underwent only follow-up and 23 (59%) patients received HBV antiviral prophylaxis (lamivudine in 4, entecavir in 8 and tenofovir in 11). Median duration of HBV prophylaxis was 18 months (95% CI: 16-19 months). After a median follow-up of 21 months, 2 patients developed HBV reactivation during lymphoma treatment: 1 from group B (reactivation rate of 50%) and 1 from group C (reactivation rate of 3%). Both patients had received rituximab-containing treatment and both developed HBV reactivation (without hepatitis flare) within the first 6 months after finishing antiviral HBV prophylaxis (delayed HBV reactivation). Outcome was favorable in both patients. Characteristics of HBV reactivation patients are shown in table I. Cumulative incidence of HBV reactivation at 12 and 24 months were 0% and 8%, respectively. CONCLUSION Our strategy of close monitoring patients with chronic HBV or resolved HBV that receive chemotherapy and adding antiviral HBV prophylaxis only in selected patients clearly decrease HBV reactivation. Nevertheless, this strategy may not fully protect patients from late HBV reactivations. Larger validation studies are needed to confirm our data and to establish the best cost-effective strategy in this lymphoma population, especially in the new era of inmunomodulatory drugs of their real involvement in HBV reactivation is unknown. Table 1 Table 1. Disclosures No relevant conflicts of interest to declare.

Gastrointestinal involvement is a rare event in patients with B-cell chronic lymphocytic leukemia (B-CLL) and is usually associated to lymphomatous transformation. However, in autopsy studies the reported incidence of microscopic infiltration can reach up to 50% of cases. Seven B-CLL patients in advanced stage/progressive disease were evaluated by colonoscopy because of continuous diarrhea. Five out of seven patients (71%) presented histological evidence of colonic infiltration. Persistent diarrhea in patients with progressive/advanced B-CLL can be a clinical sign of intestinal infiltration and justifies endoscopic examinations.

Current standard-of-care therapy for diffuse large B-cell lymphoma (DLBCL) results in up to 40% of patients who either relapse or develop refractory disease. In this setting, further therapeutic improvements are needed. This study analyzed the in vitro effects of the combination of bendamustine with the histone deacetylase inhibitor vorinostat in DLBCL cells. This combination enhanced histone acetylation and double strand DNA breaks resulting in an additive to synergistic cytotoxic effect in both ABC- and GCB-type DLBCL cells, independently of their TP53 mutational status. These results support the rationale for considering bendamustine and vorinostat combination as a novel approach in DLBCL treatment. Th is work was supported by grants from AECC Cataluña 2009, 2014 SGR 567, Instituto de Salud Carlos III FEDER (PT13/0010/0005) and the “ Xarxa de Bancs de tumors ” sponsored by Pla Director d ’ Oncologia de Catalunya (XBTC). Concepci ó n Fern á ndez-Rodr í guez received a fellowship from the Ministry of Economy and Competitiveness of Spain (PFIS grant FI11/00353).

Chronic lymphocytic leukemia (CLL) is characterized by a highly variable clinical course. Del(11q) and del(17p), routinely studied by conventional G-banding cytogenetics (CGC) and fluorescence in situ hybridization (FISH), have been related to progression and shorter overall survival. Recently, array-based karyotyping has gained acceptance as a high-resolution new tool for detecting genomic imbalances. The aim of the present study was to compare genomic arrays with CGC and FISH to ascertain whether the current techniques could be substituted in routine procedures. We analyzed 70 patients with CLL using the Cytogenetics Whole-Genome 2.7M Array and CytoScan HD Array (Affymetrix), CGC and FISH with the classical CLL panel. Whereas 31.4% and 68.6% of patients presented abnormalities when studied by CGC and FISH, respectively, these rates increased when arrays were also analyzed (78.6% and 80%). Although abnormality detection is higher when arrays are applied, one case with del(11q) and three with del(17p) were missed by genomic arrays due to their limited sensitivity. We consider that the complete substitution of CGC and FISH by genomic arrays in routine laboratories could negatively affect the management of some patients harboring 11q or 17p deletions. In conclusion, genomic arrays are valid to detect known and novel genomic imbalances in CLL, but should be maintained as a complementary tool to the current techniques.

NT-proBNP provides diagnostic and prognostic information in heart syndromes but its role in cancer has not yet been established. The prognostic value of NT-proBNP was prospectively studied in 104 non-Hodgkin lymphoma (NHL) patients treated with chemotherapy. Echocardiography and NT-proBNP were determined prior to treatment. In multivariate analysis, NT-proBNP ≥ 900 pg/ml was the variable with higher risk of death (adjusted hazard ratio 11.1; 95% CI 3.8-32.9; P0.001). The C statistic for NT-proBNP ≥ 900 pg/ml was significantly better than IPI score for prediction of survival. These findings suggest that NT-proBNP ≥ 900 pg/ml could be considered a useful marker for risk assessment in NHL patients treated with chemotherapy.

Background Follicular lymphomas are currently subdivided into grades I, II, IIIa and IIIb. This distinction is, however, questioned.Design and Methods We studied the gene expression profile of 43 follicular lymphomas, 50 B-cell non-Hodgkin’s lymphomas of different histotype, and 20 samples of normal B-lymphocytes in order to assess: (i) the relationship of follicular lymphoma with normal B cells and other B-cell non-Hodgkin’s lymphomas; (ii) whether follicular lymphoma is a unique disease; and (iii) whether follicular lymphoma grade IIIb is closer to follicular lymphoma or diffuse large B-cell lymphoma of the germinal center B-cell type.Results First, we found that the molecular profile of follicular lymphoma is intimately related to that of normal germinal center B cells, irrespectively of the histological grade. Secondly, we observed that follicular lymphoma has a relatively homogeneous gene expresion profile that is distinct from that of other B-cell non-Hodgkin’s lymphoma and does not include discrete molecular subgroups. However, by further clustering samples according to signatures differentially expressed among follicular lymphomas or in follicular lymphomas versus diffuse large B-cell lymphoma, we showed that grade I–IIIa tumors tend to cluster together, while grade IIIb follicular lymphoma constitutes a distinct subgroup, whose molecular signature is closer to that of the remaining follicular lymphomas than to that of diffuse large B-cell lymphoma of the germinal center B-cell type.Conclusions These data support the hypothesis that grade IIIb follicular lymphoma does indeed belong to the group of follicular lymphomas rather than diffuse large B-cell lymphomas, and also suggests a possible revision of the histological grading of follicular lymphomas, with their simple distinction into follicular lymphoma (grade I–IIIa) and follicular lymphoma/large cell (grade IIIb).

Introduction: DLBCL is the more common non Hodgkin lymphoma. This is an aggressive lymphoma that is treated with a standard chemotherapy regimen: R-CHOP. In the last years attempts have been done to improve the outcome both increasing dose-density (CHOP14) or intensity (CHOEP, ACVBP, autologous stem cell transplantation) without obtaining benefit in terms of survival. This has allowed setting R-CHOP administered every 21 days (R-CHOP21) as the standard treatment for DLBCL patients. RDI is an important issue to consider when treating malignancies. Although this a well-known prognostic factor in Hodgkin lymphoma, scarce information has been published in DLBCL. Objective: The purpose of this study is further analyzing the prognostic impact of RDI in two cohorts of DLBCL patients treated with R-CHOP21 or R-CHOP14, to evaluate its differential impact when increasing dose density. Material and methods: All patients diagnosed of DLBCL from January-1999 to June-2013 at University Hospital Son Espases were retrospectively identified from Pathology Department registry to avoid selection bias. Only patients treated with R-CHOP21 or R-CHOP14 +/- radiotherapy were included (N=115). To increase the R-CHOP14 cohort we added also all patients treated with R-CHOP14 in the same time period in two additional hospitals (Hospital Son Llatzer of Palma and Hospital del Mar of Barcelona) identified from their Pharmacy registries to avoid selection bias (N=42). Other regimes, consolidations or maintenance were excluded. Table 1 shows main characteristics of the global series (N=157). RDI represents the ratio of the amount of a drug actually administered to the amount planned for a fixed time period. RDI was calculated as previously described. Briefly, RDI of each drug was obtained followed by an average of RDI in CHOP consisting in the sume of RDI of the 3 drugs divided by 3. Main prognostic factors at diagnosis in DLBCL were obtained, including international prognostic index (IPI) factors. Evaluations were carried out following standard guidelines. Results: Overall response and complete response rates were similar in both groups:86% and 76% for R-CHOP21 and 94% and 74% for R-CHOP14(p=0.17 and p=0.85, respectively). Median follow-up for alive patients was 68 months (4-156). There were no differences between the two cohorts in terms of either OS or PFS (Figure 1). In the R-CHOP21, both a reduction higher than 15% in RDI [RR 7.41 (2.51-21.83); (p Conclusions: Overall in our series there were no differences in terms of response or survival between patients treated with R-CHOP21 or R-CHOP14. A higher rate of RDI reduction was observed in the R-CHOP14 group. However, the impact of RDI reductions on response and survival was only observed in the R-CHOP21 group but not in patients treated with R-CHOP14. We can conclude that R-CHOP21 and R-CHOP14 are equivalent regimens in terms of response and survival only if RDI reductions are avoided. For patients receiving R-CHOP21 we recommend using clinical and support measures in order to avoid RDI reductions. Table 1. Main clinical characteristics of the patients. R-CHOP21 group(n=74) R-CHOP14 group(n=83) P Age (median & range) 65 (25-88) 55 (15-79) 0.005 Sex (M/F) 34 (46%) / 40 (54%) 51 (61%) / 32 (39%) 0.056 ECOG PS > 1 17 (23%) 18 (22%) 0.85 Ann Arbor stage III-IV 40 (54%) 48 (58%) 0.75 B-symptoms 25 (34%) 26 (31%) 0.86 Elevated LDH 33 (46%) 40 (49%) 0.75 > 1 extranodal site 8 (11%) 19 (23%) 0.057 Bulky disease 23 (31%) 34 (41%) 0.24 R-IPI unfavorable 24 (32%) 26 (32%) 1 NCCN-IPI: - Low - Low-intermediate - High-intermediate - High 9 (13%) 27 (39%) 26 (38%) 7 (10%) 17 (21%) 35 (44%) 24 (30%) 4 (5%) 0.31 Elevated Beta-2-microglobulin 32 (49%) 31 (39%) 0.24 Radiotherapy 27 (36%) 27 (32%) 0.62 Figure 1. Figure 1. Figure 2. Figure 2. Disclosures No relevant conflicts of interest to declare.

BACKGROUND Somatic mutations in the myeloid differentiation primary response gene 88 (MYD88) have been described in B-cell lymphomas, including DLBCL. Our group has confirmed the remarkable site-specific occurrence of MYD88 mutations at some immune-privileged locations and, in addition, has described that DLBCL patients are at high risk of progression and death after first-line treatment, with independence of other well-known clinical prognostic factors (Leukemia 2014). AIMS To further analyze the clinical responsiveness and outcome after second-line treatment in DLBCL patients carrying MYD88 L265P. METHODS A series of 175 patients with DLBCL diagnosed at our institution between 2000 and 2013 were included. Inclusion criteria were: full clinical data available, treatment with remission intention, enough material for DNA extraction and absence of HIV infection. The presence of MYD88 L265P mutation was assessed by allele-specific oligonucleotides (ASO)-PCR in DNA samples extracted from FFPE tissue. RESULTS In 129 patients (74%) treatment consisted on rituximab plus CHOP or CHOP-like schedules, while the remaining cases received other treatments depending on their clinical requirements. With a median follow-up time of 57 months, progression free survival (PFS) at 5 years after first-line treatment was 57%. Twelve of these patients (9.3%) had MYD88 L265P mutation, and these patients had a significantly worse PFS that patients who did not (18% vs 59%, p=0.018). Overall survival (OS) at 5 years after first line treatment was 65% (17% vs 72%, with vs without MYD88 mutation, respectively; p=0.001). We further analyzed the outcome after second-line treatment in 32 cases: 6 patients had refractory disease (0 with MYD88 mutation) and 26 patients were in first relapse. Three out of 5 patients carrying MYD88 mutation and 25 out of 27 patients without MYD88 mutation were treated with chemotherapy. Only one out of 5 cases (20%) with MYD88 mutation responded to second-line therapy whereas response was observed in 16 out of 27 cases (59%) without MYD88 mutation(p=0.106). PFS at 4 years from starting second-line therapy was 0 % in cases with MYD88 DLBCL and 34% in those without MYD88 mutation (p=0.092). Moreover, OS at 4 years from starting second-line therapy was 0 % in cases with MYD88 DLBCL and 37% in those without MYD88 mutation (p=0.019)(Figure 1). CONCLUSION Our study shows that MYD88 L265P in DLBCL patients is not only associated to worse respond after first -line therapy, but also to a very poor response to second-line therapy, and consequently to a dismal outcome. New treatments are urgently needed for these patients. Acknowledgments: This study was supported in part by 2014SGR567 Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Dear Editor, A 27-year-old man was admitted for evaluation of peripheral lymph nodes with no other systemic symptoms. Initial laboratory tests, peripheral blood smears and bone marrow examinations were unremarkable. The thoracoabdominal computed tomography (CT) scan showed thoracic lymph nodes and a bulky retroperitoneal adenopathic mass. After the lymph node biopsy, the patient was diagnosed with follicular lymphoma grade 3 (World Health Organization) stage 4-A, IPI 1/5, FLIPI 2/5. He received chemotherapy with CHOP–rituximab and local radiotherapy to the abdominal mass. The patient achieved criteria of complete remission uncertain (gallium scintigraphy negative), and he initiated maintenance therapy with rituximab. Three and a half years after, the patient noticed a progressive pain in the left area of the scalp, and he asked for evaluation. On physical examination, he presented a swelling on the left parieto-temporal area of the head that was painful at palpation. A cranial radiography showed an isolated radiolucent lesion on the left parietal zone of the skull. A cranial CT scan described a lytic lesion of 12 mm in diameter in the same area, with edema of subcutaneous tissue. Thoraco-abdominal CT scan and bone marrow biopsy were normal. Bone scintigraphy and 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) showed a locally increased uptake of 2×2 cm along the left parietal bone with extension to soft tissue. A surgical biopsy was decided, but a complete resection of the lesion was finally performed. The pathologic appearance of the lesion was a diffuse infiltration by cells with histiocytic appearance, vesicular nuclei, folded and grooved nuclear membranes, inconspicuous nucleoli, and abundant pale eosinophilic cytoplasm. This cluster of cells surrounded a large aggregation of eosinophils with central necrosis. Immunostaining showed cell positivity for CD1a and S-100 antibodies and negativity for CD79a, CD20, CD3, and CD5, and Ki67

A higher JAK2 V617F-mutated clone is observed in platelets than in granulocytes from essential thrombocythemia patients, but not in patients with polycythemia vera and primary myelofibrosis

Abstract 2003 Background: Tumor microenvironment has been shown to play a critical role in the biology and treatment response of some types of non Hodgkin's lymphomas. The significance of the presence of Treg cells (FOXP3+) in MALT lymphomas of the stomach remains unknown. The main aim of this study was to analyze by immunohistochemistry the presence of Treg cells in the microenviroment of gastric MALT (gMALT) lymphomas at the time of diagnosis and during follow-up after treatment, and to evaluate their possible impact in outcome. Methods: Patients were included in the study if they had gMALT lymphoma diagnosed according to the 2008 WHO criteria and diagnostic paraffin-embedded blocks were available for review. Thirty-three patients met the criteria for inclusion in the study. Sections were immunostained for CD20, CD3, CD4, CD8, CD68, FOXP3, PD-1, bcl-10 and Ki67. t(11;18) was studied by FISH and/or PCR and t(1;14) by FISH. Clonality study of the B cell receptor was done according to the BIOMED-2 protocol. The number of CD20+ tumor cells and FOXP3+ infiltrating cells was quantified using a micrometric ocular (WPK 10 × mn) that has a 10 mm linear scale divided to 100 parts. Results: The median age was 63 y (range 32–83) with 52% being male. Stage: I in 66%, II in 25% and IV in 9%; B-symptoms in 6%. Translocation t(11;18) was present in 9 (27%) pts and 2 additional cases had strong nuclear expression of BCL-10 without t(11;18) or t(1;14). At diagnosis, the mean (± standard deviation) number of CD20+ tumor cells and FOXP3+ infiltrating cells was 680±232 cells/cm2 and 30±29 cells/cm2, respectively. The mean number of CD20+ tumor cells and FOXP3+ infiltrating cells was similar between gMALT with or without t(11;18). Number of treatments analyzed was 37 (treatment not available in 2 pts and 5 pts received more than 1 treatment). Treatment regimens included: eradication therapy (n=11); interferon+ribavirin (n=1); single or combined agent chemotherapy without rituximab (n=5); rituximab alone or CHOP-like with rituximab (n=4); fludarabine (n=8); fludarabine or bendamustine with rituximab (n=8). The first response evaluation showed an overall clinical response rate of 84% (CR 76%) with persistence of residual disease by histology or molecular (IGHV) studies in 31% and 56%, respectively. Overall, the mean (±SD) CD20+ tumor cells and FOXP3+ infiltrating cells was significantly reduced after treatment (730±208 vs 285±343, p Conclusion: Based on these preliminary findings, there is a significant change of CD20+ cells and moderate reduction of Treg cells in responding patients after treatment for gastric MALT lymphoma. Interestingly, regimens with fludarabine or bendamustine with or without rituximab result in quicker and deeper reduction of CD20+ tumor cells while infiltrating FOXP3+ cells are only moderately reduced. Disclosures: No relevant conflicts of interest to declare.