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The Elderly Prognostic Index (EPI) is based on the integration of a simplified geriatric assessment, hemoglobin levels and International Prognostic Index and has been validated to predict overall survival in older patients with diffuse large B-cell lymphoma (DLBCL). In this study, we evaluated the ability of EPI to predict the risk of early mortality. This study included all patients registered in the Elderly Project for whom treatment details and a minimum follow-up of 3 months were available. Three main treatment groups were identified based on the anthracycline amount administered: cases receiving70% of the theoretical anthracyclines dose (Full Dose [FD] group), ≤70% (Reduced Dose [RD]) and palliative therapy (PT; no anthracyclines). The primary endpoint was early mortality rate, defined as death for any cause occurring within 90 days from diagnosis. We identified 1150 patients with a median age of 76 years (range 65-94). Overall, 69 early deaths were observed, accounting for 19% of all reported deaths. The cumulative rate of early mortality at 90 days was 6.0%. Comparing early with delayed deaths, we observed a lower frequency of deaths due to lymphoma progression (42% vs. 75%; p 0.001) and a higher frequency due to toxicity and infections (22% vs. 4%, p 0.001, and 22% vs. 3%, p 0.001, respectively) for early events. A multivariable logistic analysis on 931 patients (excluding PT) confirmed an independent association of high-risk EPI (odds ratio [OR] 3.60; 95% confidence interval [CI] 1.15-11.2) and bulky disease (OR 2.08; 95% CI 1.09-3.97) with the risk of early mortality. The cumulative incidence of early mortality for older patients with DLBCL is not negligible and is mainly associated with non-lymphoma related events. For patients receiving anthracyclines, high-risk EPI and bulky disease are associated with a higher probability of early mortality.

(1) Background: The purpose of this study is to retrospectively compare CT, MRI, and PET/CT in detecting lymphadenopathies and extra-nodal lesions in lymphoma and in disease staging. (2) Methods: Inclusion criteria were the availability of TB (Total Body) CT and/or PET/CT performed before treatment, MRI performed no later than 2 weeks after TBCT, histological confirmation of lymphoma, clinical-diagnostic follow-up. Using these criteria, we included 64/353 patients with TBCT and MRI performed at our hospital, 20/64 had PET/CT performed in other hospitals. Histology and follow-up were gold standard. (3) Results: The sensitivity, specificity, and accuracy in lymph nodes detection was 84.5%, 94.4%, and 91% for CT and 95%, 98.9%, and 95.6% for MRI. High agreement was observed between CT and MRI regarding the number and size of positive lymph nodes and for disease staging. MRI identified eight more extra-nodal lesions than CT. In the subgroup of 20 patients, PET/CT did not show a significant superiority in sensitivity, specificity, accuracy, and staging ability than CT and MRI. (4) Conclusions: Our study demonstrates a mild superiority of MRI over CT in lymphoma staging. Although PET/CT remains the reference standard, MRI demonstrated a similar diagnostic accuracy, with the added value of being radiation-free.

Background Primary effusion lymphoma (PEL) is a very rare non-Hodgkin lymphoma caused by human herpesvirus-8 (HHV8) that grows in liquid phase within body cavities. The diagnosis of PEL is based on cytology but requires confirmatory ancillary tests. PEL occurs mainly in association with HIV infection. This study describes 9 cases of PEL in HIV-negative patients and compares their characteristics with 10 HIV-associated cases of PEL diagnosed at a single institution in Italy between 1995 and 2019. Methods Clinical records were reviewed for demographic data, comorbidities, laboratory abnormalities, and outcome. PEL samples were evaluated for cytomorphology, immunophenotype, immunoglobulin (IG)/T cell receptor (TR) rearrangements, and HHV8 and Epstein-Barr virus (EBV) viral loads in effusion supernatants. Results HIV-unrelated PEL occurred in 8 elderly patients (7 men, 1 woman) and 1 young adult with primary antibody deficiency. Cytology revealed HHV8-positive lymphoma cells lacking B/T cell antigens and exhibiting 2 cell patterns (polymorphous or monotonous). IG was clonally rearranged in all cases; aberrant TRG occurred in 2 cases. Effusion supernatants had more than 106 HHV8 DNA copies per mL and variable loads of EBV DNA. Compared with HIV-associated PEL, the HIV-negative cohort was characterized by older age, less frequent association with Kaposi sarcoma and/or multicentric Castleman disease, comparable but less abnormal laboratory parameters, and a nonsignificant survival benefit. PEL cases with low apoptosis were associated with better prognosis. Conclusion To the best of our knowledge, our case series of HIV-unrelated PEL is the largest thus far, expands the spectrum of cytological findings, and supports the need for a multidisciplinary approach in the diagnostic workup.

PURPOUSE: to assess the clinicopathologic features of a poorly defined subset of diffuse large b-cell lymphoma, which is characterized by the secretion of an IgM paraprotein (IgMs-DLBCL). EXPERIMENTAL DESIGN: multicentre, retrospective, and comparative study to analyse with an integrated diagnostic approach the IgMs-DLBCL subset.RESULTS: Overall, 650 DLBCL were enrolled: 102 had an associated serum IgM and 56 other paraproteins (OP), the remaining 492 cases were the reference group (REF). IgMs-DLBCL were characterized by older age, advanced stage, dissemination to extra-nodal organs, elevated LDH and poor PS. As a result, the majority of IgMs had a high IPI, NCC-IPI and CNS-IPI score (p

Lymphoma represents a heterogeneous hematological malignancy (HM), which is characterized by severe immunosuppression. Patients diagnosed of coronavirus disease 2019 (COVID-19) during the course of HM have been described to have poor outcome, with only few reports specifically addressing lymphoma patients. Here, we investigated the clinical behavior and clinical parameters of a large multicenter cohort of adult patients with different lymphoma subtypes, with the aim of identifying predictors of death. The study included 856 patients, of whom 619 were enrolled prospectively in a 1-year frame and were followed-up for a median of 66 days (range 1-395). Patients were managed as outpatient (not-admitted cohort, n = 388) or required hospitalization (n = 468), and median age was 63 years (range 19-94). Overall, the 30- and 100-days mortality was 13% (95% confidence interval (CI), 11% to 15%) and 23% (95% CI, 20% to 27%), respectively. Antilymphoma treatment, including anti-CD20 containing regimens, did not impact survival. Patients with Hodgkin’s lymphoma had the more favorable survival, but this was partly related to significantly younger age. The time interval between lymphoma diagnosis and COVID-19 was inversely related to mortality. Multivariable analysis recognized 4 easy-to-use factors (age, gender, lymphocyte, and platelet count) that were associated with risk of death, both in the admitted and in the not-admitted cohort (HR 3.79 and 8.85 for the intermediate- and high-risk group, respectively). Overall, our study shows that patients should not be deprived of the best available treatment of their underlying disease and indicates which patients are at higher risk of death. This study was registered with ClinicalTrials.gov, NCT04352556.

COVID19 in patients affected by lymphoma represents an important challenge because of the higher mortality rate. Anti-SARS-CoV-2 monoclonal antibodies (anti-S MoAbs) appear promising in this setting. We report a monocentric retrospective study including 176 patients affected by lymphoma which developed SARS-CoV-2 infection since the start of COVID19 pandemic. Overall, mortality was 13.1%, with a decreasing trend between first waves to the last wave of pandemic (18.5% vs. 9.4%, p 0.076). Patients receiving anti-S MoAbs (41.3%) showed inferior mortality rate (overall survival, OS 93.2% vs. 82.7%, p 0.025) with no serious toxicity, reduced documented pneumonia (26% vs. 33%, p 0.005), and reduced need of oxygen support (14.5% vs. 35.7%, p 0.003). Among patients who received 3 doses of vaccine, the employment of anti-COVID MoAbs showed a trend of superior survival versus those who did not receive Anti-S MoAbs (OS rates 97.3% vs. 84.2%, p 0.064). On multivariate analysis, active haematological disease (OS 72% (HR 2.49 CI 1.00-6.41), bendamustine exposure (OS 60% HR 4.2 CI 1.69-10.45) and at least one comorbidity (HR 6.53 CI 1.88-22.60) were independent prognostic factors for death. Our study confirms the adverse prognostic role of COVID-19 in lymphoma patients in presence of active disease, comorbidities and previous exposure to bendamustine. In our experience, anti-S MoAbs represented a therapeutic option in vaccinated patients.

Introduction: Patients with cancer may be more susceptible to and have higher morbidity and mortality rates from COVID-19 than the general population, while epidemiologic data specifically addressed to hematologic patients are limited. To investigate whether patients with hematologic diseases undergoing therapy are at increased risk for acquiring SARS CoV-2 infection compared to the general population, a retrospective study was carried out at a referral hematologic center in Rome, Italy, during the period of the greatest epidemic spread (March 8 to May 14, 2020). Methods: All adult and pediatric patients with a diagnosis of a neoplastic or a nonneoplastic hematologic disease who underwent treatment (chemotherapy or immunosuppressive or supportive therapy) during the study period or in the previous 6 months were considered. The prevalence of COVID-19 in the overall outpatient and inpatient population undergoing hematologic treatment compared to that of the general population was analyzed. The measures taken to manage patients during the epidemic period are described. Results: Overall, 2,513 patients with hematological diseases were considered. Out of 243 (9.7%) patients who were screened for SARS CoV-2, three of 119 (2.5%) outpatients with fever or respiratory symptoms and none of 124 asymptomatic patients were diagnosed with COVID-19. Three further patients were diagnosed with COVID-19 and managed in other hospitals in Rome. As of May 14, 2020, the prevalence of COVID-19 in our hematologic population accounted for 0.24% (95% CI 0.23–0.25; 6 of 2,513 patients: 1 case in every 419 patients) as compared to 0.12% (7,280 of 5,879,082 residents; 1 case in every 807 residents) in the general population (p = 0.14). Three of 6 patients diagnosed with COVID-19 required critical care and 2 died while still positive for SARS CoV-2. Out of 225 healthcare providers on duty at our Institution during the study period, 2 (0.9%) symptomatic cases were diagnosed with COVID-19. Conclusion: In our experience, the prevalence of COVID-19 in hematologic patients, mainly affected by malignancies, was not significantly higher compared to that of the general population. Definition of adapted strategies for healthcare services, while continuing to administer the standard hematologic treatments, represents the crucial challenge for the management of hematologic diseases in the COVID-19 era.

Extranodal Marginal Zone Lymphoma (EMZL lymphoma) is an indolent B-cell lymphoma with a median age at diagnosis of about 60 years. It accounts for 7–8% of all B-cell lymphomas. It can occur in various extranodal sites, including stomach, lung, ocular adnexa, and skin; furthermore, the disseminated disease can be found in 25–50% of cases. Several infectious agents, such as Helicobacter pylori (H. Pylori) in the case of gastric Mucosa Associated Lymphoid Tissue (MALT) Lymphoma, can drive the pathogenesis of this cancer, through the autoantigenic stimulation of T cells, but there may also be other factors participating such autoimmune diseases. Initial staging should include total body computed tomography, bone marrow aspirate, and endoscopic investigation if indicated. Fluorescence in situ hybridization (FISH), should be performed to detect the presence of specific chromosomal translocations involving the MALT1 and BCL10 genes, which leads to the activation of the NF-κB signaling pathway. Depending on the location and dissemination of the disease, different therapeutic choices may include targeted therapy against the etiopathogenetic agent, radiotherapy, immunochemotherapy, and biological drugs. The purpose of this review is to illustrate the complex biology and the diagnosis of this disease and to better define new treatment strategies.

BACKGROUND: In 2014 we identified a new subset of DLBCL, defined as "IgM-secreting" (Cox MC & Di Napoli A , PLOS One 2014). This was characterised by poor prognostic features and outcome as well as frequent central nervous (CNS) system localizations. Furthermore, IgM-secretion, was an independent prognostic factor in multivariate analysis. Here we report on the largest series of IgM-secreting-DLBCL, from a multicentre Italian study. METHODS: The observational and biological study was approved by the Ethical Committee of the AUO Sant'Andrea, Italy. Enrolment criteria were: DLBCL with an associated IgM paraprotein diagnosed between 1st January 2010 and 31st December 2018 (IgM-secreting). Data were collected both prospectively and retrospectively from 17 Centres participating in the study. In addition, histopathology samples were centrally revised for immunohistochemistry (IHC) and FISH analyses. The control group (CTRL) consisted in a series of consecutive DLBCL, without an associated IgM-paraprotein (diagnosed between 01/01/2013 and 30/06/2016, enrolled in the Lymphoma Registry of the Lazio region (ReLLi Network). Last follow-up was carried out on 31st December 2019. RESULTS: 569 DLBCL cases were enrolled: 102 (17.9%) were IgM-secreting; 48 (8.4%) had a non-IgM paraprotein (IgA, IgG, or other), and 414 (72.7%) had no associated paraprotein (CTRL). IgM-secreting cases within the consecutive DLBCL patients enrolled in the ReLLi Registry were 41/466 (8.8%, 95CI 6.4-11.7%) while non IgM-paraprotein DLBCL cases were 11/466 (2.4%, 95CI 1.2-4.2%). The median level of IgM paraprotein was 17gr/L (range: 60 (p=.001); 2] advanced stage (pUNL (p=.008) ; 5] ≥2 Extra-nodal sites involved (p60, B-symptoms, bulky disease, IPI >low risk and IgM-secreting IgM showed a worse survival (all with p CONCLUSION: Our data confirm that IgM-secreting DLBCL: 1) represents a sizable proportion of non-DH DLBCL; 2) have poor prognostic features and 3) have mostly a non-GC phenotype. Furthermore, IgM secretion appears to be an independent prognostic factor for both PFS and OS. Studies to define the biological features of this new subset are ongoing. Disclosures Cantonetti: Mundipharma: Consultancy; Takeda: Consultancy; Vifor: Consultancy; Roche: Consultancy. Re:BerGenBio ASA: Research Funding. Abruzzese:Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bms: Honoraria.

Anti-CD19 chimeric antigen receptor (CAR) T cells represent the first approved third-line therapy associated with long-term remissions in patients with refractory/relapsed (R/R) diffuse large B-cell lymphoma (DLBCL). Eligibility criteria to identify patients who can successfully receive CAR-T are still debated. For this reason, the aim of this study was to identify factors influencing eligibility and define a realistic patient estimate. Of 1100 DLBCL patients, 137 were included. Based on the Juliet trial inclusion criteria, only 64 patients (46.7%) would be eligible. Median overall survival (OS) was 8.04 months in eligible

In solid tumors and lymphomas, the neutrophil/lymphocyte (N/L) ratio at diagnosis has been shown to be a prognostic factor. The aim of our study was to validate the originally reported N/L ratio cut-point of 3.5 in patients with diffuse large B-cell lymphoma (DLBCL) registered in an Italian real-life database. The prognostic role of the N/L ratio at diagnosis on event-free survival (EFS) and overall survival (OS) was assessed in 505 patients with DLBCL. Patients with an N/L ratio3.5 (

To evaluate follow-up after α-interferon (IFN) discontinuation, 23 patients with chronic myeloid leukemia (CML) in stable complete molecular response (CMolR) with IFN were revisited. After a median IFN treatment of 105.8 months (IR 56.1 - 127.3), all patients discontinued IFN for prolonged CMolR (12), intolerance (8) or planned ABMT (3). After 12.5 months, one patient developed an extramedullar blast crisis. Four patients needed to start imatinib, all achieving again molecular response. Eighteen patients are still off-therapy (median time from IFN discontinuation 125.5 months, IR 86.9-205.3); among these, five are BCR-ABL negative, six present with a sporadic positivity (BCR-ABL ratio < 0.1) and seven show a stable and long-lasting mild positivity (BCR-ABL ratio < 0.5). Patients in prolonged CMolR with IFN have low risk of recurrence after discontinuation; the reappearance of a BCR-ABL positivity < 0.5 did not always precede a relapse, suggesting mechanisms of immunological control induced by IFN.

Lymphomatoid granulomatosis (LYG) is a rare Epstein–Barr Virus (EBV)-associated B-cell chronic lymphoproliferative disorder [1]. In 1972, Liebow et al. [2] described LYG as a disease that was in a ...

INTRODUCTION MCL is an incurable disease and treatment approach should be adapted to patient's characteristics: age, PS, co-morbidities, social conditions, presence of caregiver, etc. In this study we describe the experience of RELLI in real life about old MCL pts followed in Latium region and diagnosed and registered in our database between January 2013 to December 2017. MATHERIALS and METHODS Data were collected in a regional data base. All new diagnosis of lymphoproliferative disease were considered medical history, clinical characteristics and lymphoma related characteristics were registered starting from an existing data base or medical records of single Institutions. RESULTS In the database were registered 91 pts with MCL (70M/21F) older than 65 years with a median age of 74 yrs (range 66-87). At diagnosis 11/91 (12.1%) were in stage I-II and 80/91 (87.9%) in stage III-IV; only 6 (6.6%) pts presented systemic symptoms. High levels of LDH were present in 45.1% of pts, at least one extranodal localization was reported in 4.4% and Ki67 > 30% in 48.5%. Prognostic score was evaluated at diagnosis: MIPI (LR 46.5%, IR 19.7%, HR 33.8%) and MIPI-c (LR 36.6%, ILR 22.5%, IHR 22.5%, HR 18.4%). Treatment was evaluated according to the age of pts: 65 -70 and >70 years; in the first group immuno-chemotherapy (ICT) was: Benda containing regimen 43.5% (R-BAC 17.4%, R-B 26.1%) and CHOP-like regimen 36.1% (R-CHOP21 17.4%, R-COMP21 8.7%). In contrast in older pts the choice of ICT was: Benda containing regimen 64% (R-BAC 14.8%, RB49.2%), and CHOP-like regimen 13.1% (R-CHOP21 8.2%, R-COMP 4.9%).The overall response rate (ORR), progression free-survival (PFS) and overall survival (OS) were calculated from the start of treatment and evaluated in the two groups of pts: ORR was 100% in younger (CR 69.6%, PR 30.4%) and 68.8% in older (CR 50.8%, PR 18%). According to the type of ICT, as expected, pts treated with bendamustine containing regimens (+/- Cytarabine) have better response and longer survival. With a median follow-up of 34.5 months, media OS of the entire population isn't reached and PFS is projected at 50% at 60 months. CONCLUSIONS In the era before new biologic drugs the approach to treatment of MCL was sufficiently homogeneous in the Lazio region. In real life Ky67 was principal factor influencing OS. MIPI and MIPI-c score divided the entire population into two groups at high and low risk. Age not change the OS but only the response rate to treatment (Figure 1). Disclosures Abruzzese: BMS: Consultancy; Incyte: Consultancy; Novartis: Consultancy; Pfizer: Consultancy. Di Rocco:Roche: Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Pfizer: Speakers Bureau; Sandoz: Consultancy. Martelli:F. Hoffman-La Roche, Celgene, Janssen, Sandoz, Novartis, Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; F. Hoffman-La Roche, Celgene, Janssen, Sandoz, Novartis, Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria; Servier: Honoraria.

BACKGROUND. Patients (pts) with diffuse large B-cell lymphoma (DLBCL) refractory to second-line therapy or relapsed after an autologous stem cell transplant (ASCT) have a very poor clinical outcome with a median overall survival (OS) of 5 and 8-10 months, respectively. Autologous anti-CD19 chimeric antigen receptor (CD19 CAR) T cells have been associated with sustained complete remissions and long-term survivals in a large proportion of pts with R/R DLBCL by the two pivotal clinical trials Zuma1 and Juliet. This has led to the rapid approval by FDA and then by EMA of CAR-T cells for the third-line treatment of R/R DLBCL. Despite being a potentially revolutionary treatment for pts with advanced disease, the costs are much greater than any previously approved cancer therapy and this may become a substantial economic challenge for the health care system. The definition of inclusion and exclusion criteria capable of identifying more precisely pts who can successfully undergo CAR-T cell therapy, minimizing the severity of the toxicity, still remains a matter of discussion. Moreover, some eligible pts run the risk of becoming ineligible because of poor disease control. Indeed, one of the major obstacles to the successful use of CAR-T cells is the 4-5 week period so far required for the manufacturing and transfer of CAR-T cells. To address this issue, we have examined data of R/R DLBCL pts managed between 2010 and 2018 at our Center in order to: 1) better identify the characteristics and outcome of a cohort of R/R DLBCL pts potentially eligible, according to the approval criteria, for CAR-T cell therapy; 2) define factors influencing CAR-T cell eligibility; 3) make a realistic estimate of pts eligible for CAR-T cells. METHODS. All DLBCL pts treated at our Center with R-CHOP were recorded and those who then subsequently underwent a second or subsequent line of therapy were included in our analysis. This cohort of R/R DLBCL was reviewed under IRB approval to determinate the potential eligibility to CAR-T cell therapy by applying the Juliet clinical trial inclusion/exclusion criteria. OS was defined as the time of interval from the second relapse until death from any cause or last follow-up. OS curves were estimated according to the Kaplan-Meier method and compared using the log-rank test. Univariate and multivariable analyses were performed using the Cox proportional hazard model. Model selection was performed in a stepwise fashion. Conditional survival at the threshold of 28 days was predicted using the final multivariate Cox regression model after estimation of the baseline hazard through a Nelson-Aalen estimator. OS curves were estimated with the Kaplan-Meier method and compared using the log-rank test. RESULTS. We have analyzed 116/480 (24%) pts with R/R DLBCL after R-CHOP managed between January 2010 and May 2018. Of these, 82/116 (71%) had received at least two lines of treatment and were further investigated. Median age was 64 years (21-87), 13 had relapsed after an ASCT, 7 within 1 year. Thirty of the 82 pts (37%) were defined as ineligible for CAR-T cell therapy by restrospective review, for reasons reported in Table 1. The median OS was 7 months in eligible vs 2 months in non-eligible pts (p=0.3). The 1-year OS was 27% in the overall pts population. In univariate analysis, OS was significantly reduced in pts with: B symptoms (p=.026), ECOG ≥2 (p= CONCLUSIONS. In this retrospective real-life cohort of R/R DLBCLs, 82/480 pts (17%) were R/R tosecond-line treatment including ASCT. Considering Juliet's inclusion/exclusion criteria for CAR-T cell therapy, only 50 pts (10.4%) would be eligible for CAR-T cells. Our analysis suggests that elevated LDH plus ECOG ≥2 have to be considered the two most significant features of very rapid disease progression. These variables should be taken in account in order to better select DLBCL pts potentially eligible to CAR-T therapy. Disclosures Di Rocco: Roche: Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Pfizer: Speakers Bureau; Sandoz: Consultancy. Martelli:Servier: Honoraria; F. Hoffman-La Roche, Celgene, Janssen, Sandoz, Novartis, Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; F. Hoffman-La Roche, Celgene, Janssen, Sandoz, Novartis, Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria. Foà:Roche: Consultancy, Speakers Bureau; Amgen Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Shire: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Janssen: Consultancy, 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, Speakers Bureau; Celltrion: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Shire: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau.

Introduction: Management of elderly patients with Diffuse Large B-Cell Lymphoma (DLBCL) is challenging. A simplified Comprehensive Geriatric Assessment (sCGA) based on ADL (Activity of Daily Living), IADL (Instrumental ADL) and CIRS-G (Comorbidity Index Rating Scale for Geriatrics) scales has demonstrated to be better than clinical judgement to stratify patients' outcome but has never been included in initial assessment. To further assess the impact of sCGA on patients' outcome, we conducted a prospective observational study on a large series of elderly patients with DLBCL. Methods: Patients were enrolled if 65 year old or older, with an untreated de novo DLBCL. sCGA was available at a web based platform that classified patients as FIT, UNFIT, and FRAIL, as shown in Table 1. Treatment choice was left at physician discretion. According to anthracycline dose, therapy was classified as curative (≥70% of full anthracycline dose), intermediate ( Results: From December 2013 to December 2017, 1353 patients have been registered by 37 centres and 1207 were eligible. Median age was 76 years (65-94), 68% had stage III-IV, and 55% had an International Prognostic Index(IPI) ≥3; 500 (42%), 304 (25%), and 403 (33%) were classified as FIT, UNFIT and FRAIL, respectively. Data on treatment were available in 1164 patients: rituximab was used in 96% of patients; treatment was curative in 89%, 53%, and 36% of FIT, UNFIT, and FRAIL patients, respectively; intermediate in 10%, 39%, and 31%, palliative in 0%, 8%, and 33% of patients. The OS was available in 1158 out 1164 cases. With a median follow up of 30 months (1-59) 3y-OS was 64% (95% CI 61% to 67%). According to sCGA the OS was significantly different among the 3 geriatric groups. Correlation with OS was improved when sCGA was integrated with age < or ≥ 80 years to define 3 groups of patients (Table 2): FIT and UNFIT younger than 80 years (sCGA Group 1; 55%, 3 yr OS 75%), UNFIT ≥ 80 years and FRAIL younger than 80 years (sCGA Group 2: 28%, 3yr OS 58%), FRAIL ≥ 80 years (sCGA Group 3: 17%; 3yr OS 43%). Univariable and multivariable analysis for OS was conducted using the 3 sCGA groups and other clinical and laboratory features. The 3 sCGA groups were shown as independent prognostic factors with IPI and with anemia (Hb < 12 g/dl). We used results of multivariable analysis to build a categorical prognostic index assigning different weights to prognostic features based on their Hazard Ratio (HR) (Table 3). The Elderly Prognostic Index (EPI) was defined as the score obtained from the sum of the weights and allowed to define 3 risk groups: Low Risk (LR: score 0-1; 23% of patients); Intermediate Risk (IR; score 2-4; 48%); High Risk (HiR; score 5-7; 29%). The 3 EPI risk groups had a different 3 year OS of 87%(95%CI 81-91), 69%(95%CI 63-73), and 42% (95%CI 36-49); HR for IR vs LR 2.57 (1.72, 3.84); HiR vs LR 6.21(4.17 -9.25), HiR vs IR 2.42 (1.91-3.05) (Figure1). Regarding treatment modality, curative, intermediate and palliative therapies were adopted in 89%, 10%, and 1% of the LR group; 70%, 24%, 7% of the IR group, and 37%, 35%, 28% of the HiR group. The model was internally validated by means of 1000 procedures confirming good performance (slope shrinkage 0.935 and c-Harrell 0.675 in validation sample compared with 0.682 in training sample). The EPI was also tested in an external validation data set that was identified from the pivotal study of sCGA in DLBCL (N=172 patients, Tucci A. et al, Leuk Lymph, 2015) (Figure 1). Conclusion: Using data from this large prospective observational study on elderly DLBCL patients we were able to build a new prognostic index that allows to identify 3 risk groups with significant differences in terms of 3 years OS. The EPI is the first index that integrates geriatric assessment with clinical features and contributes to improving management and clinical research in elderly patients with DLBCL. Disclosures Spina: Servier: Membership on an entity's Board of Directors or advisory committees, Other: lecture fee; Sandoz: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Mundipharma: Membership on an entity's Board of Directors or advisory committees, Other; Roche: Other: lecture fee; Teva: Membership on an entity's Board of Directors or advisory committees, Other: lecture fee; GILEAD: Membership on an entity's Board of Directors or advisory committees, Other: lecture fee; Celgene: Other: lecture fee; BMS: Other: lecture fee; Sanofi Genzyme: Other: lecture fee; CTI: Membership on an entity's Board of Directors or advisory committees, Other: lecture fee; Menarini: Membership on an entity's Board of Directors or advisory committees, Other: lecture fee, Research Funding; Takeda: Other: lecture fee; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees, Other: lecture fee; Pfizer: Membership on an entity's Board of Directors or advisory committees. Merli:Janssen: Honoraria; Takeda: Honoraria, Other: Travel Expenses; Gilead: Honoraria; Mundipharma: Honoraria; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Research Funding; Sandoz: Membership on an entity's Board of Directors or advisory committees; Teva: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses. Cavallo:Takeda: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Ladetto:Roche: Honoraria; AbbVie: Honoraria; J&J: Honoraria; Celgene: Honoraria; ADC Therapeutics: Honoraria; Acerta: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau. Chiappella:Celgene: Other: advisory board, Speakers Bureau; Janssen: Other: advisory board, Speakers Bureau; Servier: Other: advisory board, Speakers Bureau; Roche: Speakers Bureau; Teva: Speakers Bureau. Nassi:Takeda: Consultancy; Janssen: Consultancy; Merck: Consultancy. Ferrero:Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Speakers Bureau; Servier: Speakers Bureau; EUSA Pharma: Membership on an entity's Board of Directors or advisory committees. Luminari:ROCHE: Membership on an entity's Board of Directors or advisory committees; CELGENE: Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant; GILEAD: Other: Lecturer; TAKEDA: Other: Travel Grant.

The prognostic effect of hypogammaglobulinemia (HGG), clinical and biologic characteristics on the infection risk and outcome has been retrospectively analyzed in 899 patients with stage A chronic lymphocytic leukemia (CLL). Low levels of IgG were recorded in 19.9% of patients at presentation, low levels of IgM and/or IgA in 10.4% and an additional 20% of patients developed HGG during the course of the disease. Before the start of any treatment, 160 (12.9%) patients experienced at least one grade ≥3 infection requiring a systemic anti-infective treatment and/or hospitalization. While IgG levels at diagnosis were not associated with an increased risk of grade ≥3 infection or with an adverse outcome, a significantly increased rate of grade ≥3 infections was recorded in patients with unmutated IGHV (p = 0.011) and unfavorable FISH aberrations (p = 0.009). Late onset HGG, more frequently recorded in patients with Rai stage I–II (p = 0.001) and unmutated IGHV (p = 0.001), was also associated with a higher rate of severe infections (p = 0.002). These data indicate that, stage A patients with clinical and biologic characteristics of a more aggressive disease develop more frequently late onset HGG, grade ≥3 infections and require a closer clinical monitoring.

Fewer than 10% of patients with myelodysplastic syndromes (MDS) are younger than 50 years. A series of 91 younger patients (median age 44 years with female prevalence) are reported and compared with elderly patients. Frequent karyotypic changes were trisomy 8 (9.8%) and monosomy 7 (5%). Twenty-three patients had occupational exposure to potential mutagens (benzene and solvents), with a male predominance, higher frequency of refractory cytopenia with multilineage dysplasia (RCMD) (52%) and higher frequency of monosomy 7 (21.7%). At a median follow-up of 72 months, 22 patients (24%) evolved to acute leukemia, with higher frequency being observed among the exposed cohort (39% vs. 19% non-exposed). Unfavorable factors for overall survival were: age40 years,5% of blasts, trilinear bone marrow involvement and intermediate-high World Health Organization Prognostic Scoring System (WPSS) risk. The present results suggest that younger MDS could be identified as a distinct subset. For patients belonging to the low/intermediate-I risk group, due to a low transformation rate, aggressive approaches should rarely be recommended.

Background: Almost all PCNSL belong to the category of DLBCL. However, affected pts are treated with high-dose methotrexate-based combinations that are not currently used in other DLBCL and require hospitalization and extensive expertise to manage toxicity. The use of R-CHOP could overcome these difficulties, but CNS availability of related drugs is poor. TNF induces BBB permeabilization and enhances CNS access of anticancer drugs. Coupling TNF with NGR, a peptide that targets CD13+ tumor vessels, improves its biological effects and therapeutic index. Thus, we tested the hypothesis that this conjugate (called NGR-hTNF) can break the BBB, thereby improving CNS access and activity of R-CHOP in pts with r/rPCNSL enrolled in a phase II trial (NCT03536039). Herein, we report results of activity, safety and BBB permeabilization. Methods: HIV-neg adults with PCNSL failed after methotrexate-based chemo and measurable disease were enrolled and treated with 1 course of R-CHOP, followed by 5 courses of R-CHOP21 preceded by NGR-hTNF (0.8 μg/m², 1-h inf). Overall response rate (ORR) was the primary endpoint. The two-stage Simon Minimax design was used; sample size estimated to demonstrate an improvement from 30% ORR (P0) to 50% (P1) (one-sided test; α 10%; β 90%) was 28 pts. NGR-hTNF/RCHOP would be declared active if ≥12 responses were recorded. As secondary endpoints, changes in vessel permeability, CD13 expression and anticancer drugs pharmacokinetics were assessed in the first 10 pts. Changes in BBB permeability were assessed by Dynamic Contrast Enhanced MRI (DCE-MRI) and 99mTc-DTPA-SPECT in tumor lesions, perilesional areas and normal appearing brain. DCE-MRI findings recorded before/after the 1st course (RCHOP alone - baseline) and before/after the 2nd and 6th courses (NGR-hTNF/RCHOP) were compared to establish the effect of TNF, and results were expressed as Ktrans values normalized using contralateral white matter. SPECT was performed before and after the 3rd course, and results were expressed as changes in the volume of ≥30% 99mTc-DTPA uptake (cm3). CD13 expression was assessed by immunohistochemistry on diagnostic tissue samples. Rituximab, cyclophosphamide and doxorubicin concentrations on matched CSF/plasma samples collected before/after the 1st, 2nd and 6th courses were tested to exclude a non-specific effect of NGR-hTNF on pharmacokinetics. Results: 22 pts (median age: 58 yo, range 26-78; 11 males) were enrolled; 18 pts had intermediate-high IELSG score. Pts were heavily pretreated: 13 had received ASCT, WBRT or both; 13 had refractory disease. Twenty pts were evaluable for the primary endpoint. NGR-hTNF/RCHOP combination was active: the predetermined activity threshold (≥12 responses) was achieved, with confirmed tumor response in 13 pts (65%; 95%CI= 45-85%), which was complete in 9. At a median follow-up of 8 months (2-26), 9 pts remain relapse free and 12 pts are alive. Treatment was well tolerated; toxicities were quickly solved without dose reductions or interruptions. G4 toxicities were neutropenia (49% of courses) and thrombocytopenia (15%), anemia (1%), and FN (1%). Ten SAEs were recorded in 8 pts: g2 seizures (n= 2), g2 DVT (2), g3 infections (2), g3 syncope (2), g4 FN and g2 LVEF reduction. There were 3 cases of g1-2 TNF infusion reaction. DCE-MRI studies showed an increase of vascular permeability after NGR-hTNF infusion as median (range) Ktrans of tumor and perilesional areas raised from baseline values of 23.5 (6.8-98.8) and 2.5 (0.4-3.9) to 35.3 (23.9-887.7; p= 0.39) and 4.7 (2.2-37.7; p= 0.01), respectively. Likewise, SPECT studies showed a significant enlargement of the volume ≥30% 99mTc-DTPA uptake, with median (range) values before and after NGR-hTNF infusion of 26 cm3 (5 - 67) and 40 cm3 (10 - 92), respectively (p= 0.02), with a median volume increase of 45% (14-87%). As important features supporting the specificity of the effect of NGR-hTNF, CD13 was expressed in all diagnostic samples, and drug levels in CSF/plasma samples were not influenced by NGR-hTNF. Conclusions: NGR-hTNF/RCHOP is active and safe in pts with r/rPCNSL. NGR-hTNF enhances vascular permeability specifically in tumor lesions and perilesional areas, which was consistently demonstrated by DCE-MRI, SPECT and plasma/CSF pharmacokinetics studies and was in line with CD13 expression. Accrual completion is warranted. This innovative approach deserves to be addressed as first-line treatment in PCNSL pts. Disclosures Angelucci: Novartis: Honoraria, Other: Chair Steering Comiittee TELESTO Protocol; Vertex Pharmaceuticals Incorporated (MA) and CRISPR CAS9 Therapeutics AG (CH): Other: Chair DMC; Jazz Pharmaceuticals Italy: Other: Local ( national) advisory board; Roche Italy: Other: Local (national) advisory board; Celgene: Honoraria, Other: Chair DMC.

About 75% of patients with chronic lymphocytic leukemia (CLL) are more than 65 years at the time of diagnosis. Treatment of the elderly remains complicated due to multiple factors, such as comorbidities, decline in functional reserve and fitness. Since chronological age by itself cannot properly predict life expectancy and treatment tolerance, an accurate assessment of the fitness status is of crucial importance for an optimal treatment choice. Areas covered: This review will discuss the most relevant aspects concerning the issues experienced in the management of elderly/unfit patients with CLL. The most frequently observed age-related toxicities, fitness assessments, supportive care measures and treatment options for elderly patients and for patients who are deemed unfit will be discussed. Literature search methodology included examination of PubMed index. Expert commentary: During the last decade, different trials focusing on elderly/unfit patients have investigated more tolerable chemoimmunotherapy schedules and, more recently, the activity and safety of chemo-free regimens. Chlorambucil combined with an anti-CD20 monoclonal antibody has shown clinical activity with a relatively good profile of toxicity. The recent introduction of the B-cell receptor antagonists, ibrutinib and idelalisib, and other targeted drugs in development (e.g. venetoclax), is broadening the therapeutic armamentarium of elderly CLL patients.

An experimental investigation of solid-propellant, nonsteady (pulse durations of ∼1 ms), magnetoplasmadynamic (MPD) thruster operation as a function of thruster scale (size) is qualitatively discussed. Measurements include the electrical characteristics, impulse bit (thrust stand), exhaust velocity (time-of-flight Langmuir probe system), and ablated propellant mass for each scaled thruster. The same number of thruster shots is used to collect data at each operating point. The baseline thruster is found to operate in one of two electrical modes (high and low), in a random fashion, at a fixed energy. As the absolute energy level is increased, the probability of high-mode operation is found to increase. The scaled thrusters (33% smaller and 25% larger based on nozzle exit radius) operate in only one electrical mode. Furthermore, these tests show that the smaller thruster's operating characteristics at equal thruster energy exhibit higher currents, impulse bits, and propellant consumption, whereas the other two thrusters show the effective Maecker's law coefficient b e f f increasing as a function of the time integral of the MPD discharge squared current Ψ, as well as the thruster efficiency increasing with thruster energy. These data imply that the smaller thruster operates in a different regime than the larger thrusters. This operational regime difference is likely related to the smaller thruster's higher current densities at constant thruster energy.

The efficacy and safety of azacitidine in elderly patients (aged >65 years) with myelodysplastic syndromes (MDS) treated outside clinical trials are reported. Thirty-eight patients with MDS received azacitidine (75 mg/m(2), schedule 5+2 +2): seven patients were classified as having refractory cytopenia with multilineage dysplasia (RCMD), nine patients with refractory anemia with excess of blasts (RAEB) type 1, 18 patients with RAEB type 2 and four patients with chronic myelomonocytic leukemia type 2 (CMML-2). According to International Working Group (IWG) 2006 criteria, after the first four cycles we detected complete remission in seven patients (CR, 18%), improvement of bone marrow dysplasia and reduction of blast percentage in seven patients (partial response, 18%), stable disease in 20 patients (53%) and progression to acute leukemia in four patients (10%). Median overall survival for all patients treated was 16.4 months. Only mild non-hematologic toxicity was detected (grade 1-2 nausea and pruritus), whereas 55% of patients experienced hematologic side effects (25% grade 3-4 thrombocytopenia and 30% grade 3-4 neutropenia). Our results suggest that advanced age should not preclude effective treatment with azacitidine in non-selected elderly patients wih MDS.

Currently, chronic myelomonocytic leukemia (CMML) is considered by the recent World Health Organization (WHO) classification as a specific subtype of myelodysplastic syndrome/myeloproliferative neo...

We read with great interest the paper by Itzkynson et al. [1] hat reported the results of the combination of erythropoietin and zacitidine in myelodysplastic syndrome (MDS) patients. Overall, 2 out of 282 patients were treated concomitantly with azacitiine and erythropoietic stimulating agents (ESA) for a relatively hort period of time (median duration 5.8 months). The authors eported an overall response rate of 53% in patients treated with the ombination compared to 43% in patients treated with azacitidine lone, without statistically significant difference. No differences ere reported in terms of complete response (CR) and marrow esponse (mCR) between the two groups of subjects, whereas the ate of hematologic improvement-erythroid (HI-E) was superior in he combination group (44%) compared to azacitidine alone group 27%), with an increased rate of patients becoming transfusion ndependent in the former group. Again no difference in terms of rogression rate was observed, whereas ESA-treated patients had longer survival (OS), with a median of 19.6 months compared to 1.9 months for patients who did not receive ESA. With the aim to valuate the possible effect of the above described combination, 60 DS patients treated with azacitidine in our institute, 8 of whom eceived the drug in association with ESA, were retrospectively anaysed. There were 44 males and 16 females, median age 69 years range 44–83). According to WHO criteria [2], 35 patients were

We here describe a single-institution experience on 40 patients with myelodysplastic syndromes (MDS) consecutively treated with deferasirox at the dose of 10–30 mg/kg/day according to Consensus Guidelines on Iron Chelation Therapy, outside of clinical trials. Serum ferritin (SF) was measured monthly, and safety assessment included monitoring of adverse events during treatment and of liver and renal parameters. Median SF at baseline of the 40 patients was 2,878 ng/ml. Median dose of deferasirox was 1,125 mg/day. At a median follow-up of 12 months of treatment, there was a significant reduction in SF from baseline, the median value being 1,400 ng/ml (p = 0.001). Interruptions due to toxicity were recorded in 40 % of patients: most common adverse events were diarrhoea (five patients, 12.5 %) and skin rash (four patients, 10 %). Seven patients had increased serum creatinine values >33 % above baseline, but there were no progressive increases. Four patients (three refractory anaemia and one refractory anaemia with excess blasts type 1) had a reduction of transfusion requirement (from a median of 5 to 1 unit/month) according to International Working Group 2006 criteria, with mean Hb value increasing from 8.5 to 10.5 g/dl, and mean Hb improvement being 2 g/dl (p = 0.02). No increased toxicity was noted when deferasirox was used concomitantly with azacitidine (eight patients who were intermediate 2 International Prognostic Scoring System risk) or lenalidomide (two patients with del(5q)). In conclusion, the oral iron chelator deferasirox is effective and safe when used in MDS patients with transfusion requirement, also if administered concomitantly with other drugs.

Background: Imatinib has become first line therapy in chronic myeloid leukemia patients. Little is known about the infective consequences during the treatment with this drug in large series of chronic phase patients. Material and methods: From January 2001 to September 2006 we treated with imatinib 250 patients in first line (early CP) or after interferon failure (late CP), out of clinical trials and recorded all the bacterial and viral infections occurred. Results: We recorded a similar incidence of bacterial and viral infections both in first line and late CP patients (respectively, 16% and 13%) during 3.5 years of follow-up. Analysis of presenting features predisposing to infections revealed differences only in late CP patients, with elevated percentage of high Sokal risk patients and a more longer median time from diagnosis to start of imatinib. Conclusions: Opportunistic infections and reactivation of Herpes Zoster are observed during imatinib therapy at very low incidence.

This paper discusses an experimental investigation of solid propellant, quasi-steady (pulse durations of ~1 ms), magnetoplasmadynamic (MPD) thruster operation as a function of thruster scale (size). Measurements include the electrical characteristics, impulse bit (thrust stand), exhaust velocity (time-of-flight (TOP) Langmuir probe system), and ablated propellant mass for each scaled thruster. The same number of thruster shots is used to collect data at each operating point. The baseline thruster is found to operate in one of two electrical modes (high and low), hi a random fashion, at a fixed energy. As the absolute energy level is increased, the probability of high mode operation is found to increase. The scaled thrusters (33% smaller and 25% larger based on nozzle exit radius) operate in only one electrical mode. Furthermore, these tests show that the smaller sized thruster exhibits different behavior than the two larger thrusters. The smaller thruster's characteristic curves for impulse bit as a function of thruster energy, and effective Maecker's law coefficient (bg ~) as a function of the tune integral of the MPD discharge current OP) have different slopes than for the other two thrusters which show the same trends. These data imply that the smaller thruster operates in a different regime than the larger thrusters. This operational regime difference is likely related to the smaller thruster's higher current densities at constant thruster energy.