ALBERT

Description: Increased breast cancer risk has been reported in some night shift (NS) workers but underlying biological mechanisms are still unclear. We assessed the association between NS work and DNA methylation of tumor suppressor (TP53, CDKN2A, BRCA1, BRCA2) and estrogen receptor (ESR1, ESR2) genes, methylation of repetitive elements (LINE-1, Alu), and telomere length (TL). Forty six female nurses employed in NS for at least two years were matched by age (30–45 years) and length of service (≥1 year) with 51 female colleagues not working in NS. Each subject underwent a semi-structured interview and gave a blood sample. We applied linear regression and spline models adjusted for age, BMI, smoking habit, oral contraceptive use, parity and marital status/age at marriage. Currently working in NS was associated with ESR1 hypomethylation (β: −1.85 (95%CI: −3.03; −0.67), p = 0.003). In current and former NS workers we observed TP53 (−0.93 (−1.73; −0.12), p = 0.03) and BRCA1 (−1.14 (−1.71; −0.58), p 〈0.001) hypomethylation. We found an increase between TL and number of years in NS in subjects employed in NS 〈12 years (0.06 (0.03; 0.09), p 〈0.001), while a decrease if employed in NS ≥12 years (−0.07 −0.10; −0.04), p 〈0.001). Our findings show NS-associated markers potentially involved in cellular aging, genomic instability, and cancer development.

Description: Background There is an increasing amount of data showing that tumor microenvironment, host immunity and host inflammation response play an important role in determining the clinical course in patients with malignant lymphoma. Several investigators have considered the absolute monocytes count(AMC) as a surrogate biomarker of tumor associated macrophages, reflecting the tumor microenvironment, the absolute lymphocytes count (ALC) as a surrogate biomarker of tumor infiltrating lymphocyte, reflecting systemic host immunity, and absolute neutrophil count (ANC) as the host inflammatory response to cancer. Every of these parameters have been suggested to be a prognostic factor in diffuse large B-cell lymphoma (DLBCL). The aim of the present study was to verify whether neutrophil to lymphocyte ratio (NLR) is an independent prognostic factor in DLBCL. Patients and Method This retrospective analysis included data from 1050 patients diagnosed with diffuse large B-cell lymphoma according to the WHO criteria. We reviewed the clinical and laboratory data of consecutive "therapy-naïve" patients, treated in different centers in Italy and in Israel between 1993-2012, after approval by local institutional review boards. Patients had received treatment with combination chemotherapy: cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), CHOP-like, or third-generation anthracycline-containing regimens, with or without rituximab. The cut-off for NLR was determined from the analysis of the log(HR) as function of NLR, by means of Cox cubic spline regression. The importance of the covariate was checked using the bootstrap inclusion frequency (BIF) with log-likelihood ratio test, considering a cut-off of 0.05, over 1000 resample of hierarchical Cox PH model, where NLR was added to IPI. Overall survival (OS) was assessed by Kaplan-Meier estimates and compared by risk groups using the log-rank test .We also performed Cox proportional hazard analysis. The effect size of risk was reported as a hazard ratio (HR) with the associated 95% confidence interval (CI95). Results Out of 1050 patients, 931 (89%)were completed for IPI and NLR. The median age was 60 years (range 18-89), 53% were males and 46% received chemotherapies with rituximab as part of the regimen. The 5-yr OS% after a median follow-up of 62 months (range 1-157 months) was 65% (95CI 61-68) for the entire cohort. The log(HR) vary linearly with the log(NLR) and the cut-off was selected at 3.6. Patients with NLR 〉3.6 showed a worst OS compared to those NLR ≤3.6 (58% vs 69%) with HR 1.54 (CI95 1.24-1.93, p3.6 maintain the prognostic value (HR 1.35, CI95 1.08-1.68, p=0.009) with a BIF of 73%. Also NLR in continuous form, log(NLR), showed a prognostic value, either in univariate (HR 1.28, CI95 1.12-1.48, p3.6, in patients population treated with CHOP or CHOP like without R and in patients population treated with CHOP and CHOP like plus R Figure 1. OS by NLR 〈 3.6 or NLR 〉3.6, in patients population treated with CHOP or CHOP like without R and in patients population treated with CHOP and CHOP like plus R Disclosures No relevant conflicts of interest to declare.

Description: Introduction: Follicular lymphoma grade 3 is recognized as a distinct entity in the World Health Organization classification of lymphoma. It is further classified into grade 3a and 3b depending on percentage of centroblasts. There is no consensus about its clinical course because some studies indicate an indolent behavior but others describe a more aggressive. Large systematic studies are missing in particular for 3b follicular lymphoma which is often considered as a separate entity. Methods: We performed a retrospective multicentric study on a group of 3b FL patients diagnosed in nine Italian FIL centers between November 2002 and January 2015. Planned inclusion criteria at enrollment were first line Rituximab containing regimen treatment and diagnostic samples availability for central pathologic review. Aim of the study was to determine clinical response, OS and PFS. Tumor response was based on the International Working Group response criteria. Survival analysis was performed with Kaplan-Meier method. Results: We enrolled a total of 51 patients, 50 evaluable for response at the time of analysis; median age was 62 yrs (range 48-71), 29 (56%) in stage III-IV, 10 (20%) with B symptoms. First line treatment was R-CHOP in the majority of patients 47 (92%), R-Bendamustine and R-CVP in 2 (4%) respectively. Seven patients (14%) received Rituximab maintenance after first line, six (12%) underwent high dose chemotherapy and autologous stem cell transplant (ASCT) as consolidation therapy and 5 (10%) were treated with local radiotherapy on residual disease. We observed CR in 48 patients (96%), PR in 1 (2%), PD in 1(2%). Ten patients relapsed or progressed after first line treatment and four of them died, three for progressive disease and one due to senile dementia while in CR. No relapses were recorded in pts receiving Rituximab maintenance but the advantage was not statistically significant and the number of patients receiving maintenance was low. With a median follow up of 63 months from diagnosis (IQR 33-82), 3-yrs PFS and OS rates were 82% and 93% (fig 1 and 2) with the evidence of a plateau in both survival curves after 5 years observation. Central pathologic review is ongoing. Conclusion: With the limit of a retrospective analysis our study confirms the clinical benefit of a combined modality treatment with Rituximab plus antracycline-containing chemotherapy in patients with 3b FL. Our results compare favorably with those previously reported in studies without Rituximab, that failed to show a plateau with 3-yrs PFS ranging between 22% and 52%. This results need to be confirmed with a longer follow up and after the planned pathologic review. Figure 1. Progression-Free Survival. Median Follow-up 62 months (IQR 33-82). Figure 1. Progression-Free Survival. Median Follow-up 62 months (IQR 33-82). Figure 2. Overall Survival. Median Follow-up 63 months. Figure 2. Overall Survival. Median Follow-up 63 months. Disclosures No relevant conflicts of interest to declare.

Description: Background There is an increasing amount of data showing that tumor microenvironment, host immunity and inflammatory responses play an important role in determining the clinical course and outcome in patients with malignant lymphoma. Several investigators have considered the absolute monocyte count (AMC) as a surrogate biomarker of tumor associated macrophages within the tumor microenvironment, the absolute lymphocyte count (ALC) as an important biomarker of tumor infiltrating lymphocytes, reflecting host immunity status, and the absolute neutrophil count (ANC) as indicative of the systemic inflammatory response to malignancy. All the above parameters have been suggested as significant prognostic factors in Hodgkin lymphoma (HL). The aim of the present retrospective study was to verify in whether neutrophil : lymphocyte ratio (NLR) can be utilized as an independent prognostic factor in a large cohort of patients with nodular sclerosis (NS) subtype HL. Patients and Methods This retrospective analysis included data from 1017 patients diagnosed with NS HL according to the WHO criteria. We reviewed the clinical and laboratory data of consecutive "therapy-naïve" patients, treated in different centers in Italy and in Israel between 1993-2012, after approval by local institutional review boards. Patients had received different combination chemotherapy regimens : doxorubicin, bleomycin, vinblastine and darcarbacine (ABVD), mechlorethamine, vincristine, procarbazine, and prednisone (MOPP)/epidoxirubicin, bleomycin, and vinblastine (EBV)/lomustine (CCNU), doxorubicin, and vindesine (CAD), Vinblastine, bleomycin, and methotrexate (VBM), bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) and Stanford V. The cut-off for NLR was determined from the analysis of the log (HR) as a function of NLR, using Cox cubic spline regression. The importance of the covariate was examined using the bootstrap inclusion frequency (BIF) with log-likelihood ratio test, (cut-off of 0.05), over 1000 resample of hierarchical Cox PH model, where NLR was added to IPI. Progression free survival (PFS) and overall survival (OS) were determined by Kaplan-Meier estimates and risk groups compared using the log-rank test .We also performed Cox proportional hazard analysis. The effect size of risk was reported as a hazard ratio (HR) with the associated 95% confidence interval (CI95). Results Of the 1017 patients, 990 (97%) had data on both IPS and NLR. Median age was 31 years (range 17-69) and 49% were males. The 5-yr PFS and OS after median follow-up of 85 months (range 1-244 months) were 81% (95CI 78-84) and 91% (95CI 89-93), respectively, for all patients. The log(HR) for PFS and OS varied linearly for the function of NLR and the cut-off was selected at 6 for both outcomes. Patients with NLR 〉6 had a worse PFS and OS compared to NLR ≤6 (84% vs 75% and 92% vs 88% at 5-years, respectively). Figure 1). For PFS the HR for patients with NLR〉6 was 1.65 (CI95 1.25-2.18, p6 maintained it's prognostic value in both PFS (HR 1.49, CI95 1.12-1.98, p=0.006; with a BIF of 76%) and OS (HR 1.56, CI95 1.06-2.29, p=0.023; with a BIF of 64%). This was also evident in continuous form for NLR both s in PFS (HR adjusted by IPS 1.02, CI95 1.01-1.04, p=0.010) and OS (HR adjusted by IPS 1.02, CI95 1.01-1.05, p=0.039). Conclusion . Although the majority of patients with HL can be cured, about 1/3 of those with advanced stage disease relapse or progress after first line therapy. Several approaches have been employed to recognize high risk patients, including gene expression profiling and positron emission tomography. However these procedures are expensive and not always easy to perform and interpret. In conclusion, despite it is retrospective nature, our study shows that NLR can reliably identify high risk patients at the time of diagnosis. This easily obtainable simple prognostic parameter could well be utilized to improve the discriminating power of the IPS score in patients with NS HL. Figure 1. PFS and OS by NLR 〈 6 or NLR ≥ 6 Figure 1. PFS and OS by NLR 〈 6 or NLR ≥ 6 Disclosures No relevant conflicts of interest to declare.

Description: Background: Histologic transformation (HT) refers to a biologic event leading to the development of a high grade non-Hodgkin lymphoma, mostly diffuse large B cell lymphoma (DLBCL), in patients (pts) with an underlying follicular lymphoma (FL), whose recently reported risk is 2% to 3% per year. The prognosis of t-FL has been considered historically very poor, but several studies in the Rituximab (RTX) era suggest that survival may be more favorable than previously recognized. The treatment approach for t-FL is often individualized and pts are generally excluded from clinical trials, so there is a paucity of objective data on the optimal management of t-FL, which still represents an unmet need. The aim of our survey conducted in a large number of pts with histologically confirmed t-FL observed in 9 FIL Centers was to analyze the clinical factors and the different treatment strategies which can predict post-transformation outcome. Methods: One hundred seventy-seven t-FL were retrospectively selected from Institutional datasets; the inclusion time frame was from 2002 to 2014. All Histologic Transformations (HT) were biopsy confirmed. Response assessment was made as recommended by International Workshop criteria. Survival analysis were performed with Kaplan-Meier method and compared by Log-Rank test. Results: T-FL occurred at initial diagnosis (Group 1) in 93 cases (53%): 52 were DLBCL (29%) evolving from a prior FL, 31 (17%) composite lymphoma and 10 (6%) discordant lymphoma. HT occurred after a previous FL diagnosis (Group 2) in 84 pts (47%): 15 pts (8%) were treatment-naïve at HT (Group 2A), 38 pts (21%) transformed at first relapse or progression (Group 2B) and 31 (18%) experienced late HT (Group 2C). Median age at HT was 60 years (range: 20-83). No differences were found between Group 1 and 2 and between Group 2A, 2B and 2C in term of clinical features (age, disease stage, B-symptoms). Group 1 received CHOP/CHOP-like regimens in 75% of pts. RTX was used with chemotherapy (CT) in 92% of pts and in 22% as maintenance. Autologous Stem Cell Transplantation (ASCT) was delivered as consolidation in 14%. Group 2 received CHOP/CHOP-like regimens in 39% of pts, platinum-containing regimens in 14%, high dose sequential therapy in 32%. RTX was added to CT in 71% of cases; 12% received RTX maintenance and 23% ASCT consolidation. CHOP as CT and RTX maintenance were used more often in Group 1 pts. Overall Response Rate (ORR) for Group 1 was 94%, with 77 pts (83%) achieving Complete Response (CR) and 10 (11%) Partial Response (PR).With a median follow-up of 43 months, 5-yr Progression-Free Survival (PFS) and Overall Survival (OS) were 60% and 83%, respectively. ORR for Group 2 was 57%, with 43 pts (51%) obtaining CR and 5 (6%) PR; focusing on the subgroups 2A, 2B, 2C ORR was 80%, 63% and 39%, respectively (p 0.017). The 5-yr OS was 52%, statistically inferior to Group 1 (p

Description: Background: Marginal zone Lymphomas (MZL) are indolent B cell non hodgkin Lymphoma (NHL) and include splenic, nodal and extranodal subtypes (SMZL, NMZL, ENMZL). When therapy is needed in symptomatic patients, standard treatment usually requires systemic immunochemotherapy (ICT). Although the outcome of MZL is generally measured in decades a high heterogeneity of clinical behaviour exists that warrants the identification of accurate prognostic features to better estimate the risk of relapse, progression or death in the individual patient. Recently the analysis of progression free survival (PFS) was used to identify clinically useful endpoints in B-cell NHLs, with PFS at 24 (PFS24) months identified to stratify overall survival (OS) in follicular NHL. Here we examined the ability of PFS24 to predict subsequent OS in a large, multinational MZL cohort as part of the NF10 observational multicentric international study promoted by Fondazione Italiana Linfomi (FIL). Methods: The NF10 Project was started in 2010 as a prospective registry specifically conceived to investigate the prognosis of Indolent Non-Follicular B-Cell Lymphomas (INFL). The registration of clinical, laboratory data, treatment and outcome details of consecutive adult patients with newly diagnosed INFL was available at a dedicated website. All patients with a histologic confirmed diagnosis of INFL also including MZL were eligible with no exclusion criteria. Patients were followed based on local institution guidelines, and PFS was defined as time from the date of pathologic diagnosis to progression, re-treatment, or death due to any cause. PFS24 was calculated only for patients requiring immediate therapy and was defined as being alive and progression-free 24 months from diagnosis. Subsequent OS was defined as time from achieving PFS24 or time from progression in patients failing to achieve PFS24 (progression within 24 months of diagnosis). Results: Between July 2010 and July 2018, 1.253 INFL cases have been registered by 65 centres in Europe and South America. MZLs were 677 (54%): 283 ENMZL (43%), 221 SMZL (32%), 69 NMZL (10%); 104 cases were classified as disseminated MZL (Diss-MZL 15%) due to the lack of a clear pattern of organ involvement. Median age was 66 years (range 27-93); Ann Arbor stage was III-IV in 79%; 14% had B symptoms, 6% had ECOG performance status (PS) 〉1, lactate dehydrogenase (LDH) and β2-microglobulin were above upper normal limit (UNL) in 26% and 56% of cases respectively. Bone marrow involvement was present in 67%, positive HCV and HBV serology was found in 8% and 18% of cases respectively. For the current study we identified 400 patients with MZL for whom immediate therapy was planned right after lymphoma diagnosis. Patients with immediate therapy were 59% of all MZL. Rituximab (R) combined with chemotherapy was used in 332 (82%): R plus bendamustine (RB) in 142 (36%), R plus alkylating agents (R-alk) in 101 cases (25%) (mostly ENMZL), R plus CHOP in 50 (12%) (mainly NMZL and DissMZL); R monotherapy was used in 36 (9%). The median follow-up was 38 months (range 1-83). For treated pts 3y-PFS was 79% and 3y-OS was 90%; progressive disease was the cause of death in 47% of all cases. The percentage of patients who failed to achieve PFS24 was 20% with a lower frequency in the subtypes NMZL and ENMZL (13%) compared to the group of SMZL and DissMZL (24%, p=0.015). Three-year OS for patients with progression within the first 24 months was 46% (95%CI 28-63%) with a HR of 28.3 (95%CI 10.6 - 75.6) when compared with patients without early relapse (96%, 95%CI 91-98%). When PFS24 was adjusted by IPI in all cases and by HPLL (Montalbán et al, BJH 2012) in SMZL, the PFS24 retained its prognostic role (p

Description: Marginal zone lymphomas (MZLs) are indolent nonfollicular B-cell lymphomas (INFLs) and have heterogeneous clinical behavior. Recently, time to progression of disease at 24 months (POD24) was identified to stratify overall survival (OS) in follicular non-Hodgkin lymphoma and in INFL. Here, we examined the ability of POD24 to predict subsequent OS in a large, international cohort of MZL as part of the NF10 prospective international registry headed by Fondazione Italiana Linfomi (FIL). POD24 was only calculated for MZL patients requiring immediate therapy and was defined as experiencing lymphoma progression within 24 months from diagnosis. Among the 1325 patients enrolled in the NF10 study, we identified 321 patients with MZL for whom immediate therapy was planned right after lymphoma diagnosis. Overall, POD24 was confirmed in 59 patients (18%). Three-year OS for patients with POD24 was 53% with a hazard ratio of 19.5 (95% confidence interval, 8.4-45) compared with patients without POD24 (3-year OS, 95%). Association of POD24 with OS was confirmed for the subgroup of splenic and extranodal MZLs. Assessment of POD24 stratifies subsequent outcome in MZL and identifies a high-risk population. This trial was registered at www.clinicaltrials.gov as #NCT02904577.

Description: Background: Indolent non follicular B-Cell Lymphomas (INFL) are a heterogeneous group of lymphomas and include small lymphocytic lymphoma (SLL), lymphoplasmacytic lymphomas (LPL) and marginal zone lymphomas of splenic (SMZL), nodal (NMZL) and extranodal (ENMZL) subtypes. In 2010 the NF10 study was started by the Fondazione Italiana Linfomi as a prospective registry specifically devised for investigating the prognosis of this group of lymphomas. We provide a preliminary report describing registered cases with an emphasis on initial therapy. Methods: The registration of consecutive adult patients with newly diagnosed INFL and no exclusion criteria is ongoing at a dedicated website via secure HTTP protocols. For the purposes of the study in addition to the conventional INFL subtype, the category of disseminated MZL and CD5- low grade lymphoma were also considered. So far the study has been activated in 65 centers in Europe and South America. Results: Between July 2010 and July 2015, 665 cases have been registered. The current report is based on 395 cases that have been validated. Forty-seven (12%) cases were registered as SLL, 76 (19%) as LPL, 59 (15%) as CD5-low grade and 213 (54%) as MZL, including 73 (18%) SMZL, 18 (5%) NMZL, 81 (21%) ENMZL or 41 (10%) disseminated subtypes. Median age was 67 years (range 29-94), 53% of patients were males; Ann Arbor stage was III-IV in 79%; 14% had B symptoms, 7% had ECOG performance status 〉 1, lactate dehydrogenase and b2-microglobulin were elevated in 70% and 54% of cases, respectively. Six percent of cases were HCV positive (HCV+ rate was 7.5% among MZL cases). Regarding HBV infection, 21% of patients were HBcAb-positive and 3% of patients were HBsAg-positive. Immediate systemic therapy was planned in 50% of patients. SMZL, SLL and CD5-low grade were the subtypes with the lower rates of immediate therapy (44%, 46% and 24% respectively) whereas ENMZL were addressed to systemic therapy in 67% of cases. When systemic therapy was prescribed rituximab (R) was used in 88%. In 81% of patients R was combined to cytotoxic therapy including alkylating agents in 40%, CHOP-like in 18%, bendamustine in 17% and fludarabine in 6%. ENMZL and CD5-low grade had the highest rates of R-alkylating use (61% and 64%); SMZL and MZL were frequently treated with R-CHOP like regimens (35% and 40%). Young age at diagnosis (less than 60 years) and increased b2-microglobulin were more frequently associated with patients requiring immediate systemic therapy. With 22 months of median follow up, 2-year progression free survival and overall survival (OS) were 88% (95CI: 83-92) and 95% (95CI: 91-97) respectively; the initial choice of deferring immediate therapy did not impact on OS. Conclusions: We provide a complete report on the initial approach to patients with INFL showing that immediate therapy is required in half of the cases with a heterogeneous approach among INFL subtypes. The majority of patients requiring therapy was treated with the combination of R and alkylating agents. The NF10 study confirms that a web-based world-wide cooperation allows the collection of a relevant and complete data set, providing a platform for future prognostic and pathobiological studies in order to identify novel and more efficient therapeutic targets. Disclosures 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. Ferrero:Mundipharma: Other: Speakers Honoraria; Celgene: Other: Speakers Honoraria. Gaidano:Celgene: Research Funding; Morphosys, Roche, Novartis, GlaxoSmith Kline, Amgen, Janssen, Karyopharm: Honoraria, Other: Advisory boards.