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

Abstract: Primary testicular diffuse large B-cell lymphoma (PTL) is characterized by high risk of contralateral testis and central nervous system (CNS) relapse. Chemoimmunotherapy with intrathecal (IT) CNS prophylaxis and contralateral testis irradiation eliminates contralateral recurrences and reduces CNS relapses. The IELSG30 phase 2 study investigated feasibility and activity of an intensified IT and IV CNS prophylaxis. Patients with stage I/II PTL who had not received treatment received 2 cycles of IV high-dose methotrexate (MTX) (1.5 g/m2) after 6 cycles of the R-CHOP regimen (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone, every 21 days). IT liposomal cytarabine was administered on day 0 of cycles 2 to 5 of 21-day R-CHOP regimen. Contralateral testis radiotherapy (25-30 Gy) was recommended. Fifty-four patients (median age: 66 years) with stage I (n = 32) or II (n = 22) disease were treated with R-CHOP, 53 received at least 3 doses of IT cytarabine, 48 received at least 1 dose of IV MTX, and 50 received prophylactic radiotherapy. No unexpected toxicity occurred. At a median follow-up of 6 years, there was no CNS relapse; 7 patients progressed, and 8 died, with 5-year progression-free and overall survival rates of 91% (95% confidence interval [CI], 79-96) and 92% (95% CI, 81-97), respectively. Extranodal recurrence was documented in 6 patients (in 2 without nodal involvement). In 4 cases, the relapse occurred >6 years after treatment. Causes of death were lymphoma (n = 4), second primary malignancy (n = 1), cerebral vasculopathy (n = 1), unknown (n = 2). Intensive prophylaxis was feasible and effective in preventing CNS relapses. Late relapses, mainly at extranodal sites, represented the most relevant pattern of failure. This trial was registered at www.clinicaltrials.gov as #NCT00945724., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background: Multicenter clinical trials are producing growing amounts of clinical data. Machine Learning (ML) might facilitate the discovery of novel tools for prognostication and disease-stratification. Taking advantage of a systematic collection of multiple variables, we developed a model derived from data collected on 300 patients with mantle cell lymphoma (MCL) from the Fondazione Italiana Linfomi-MCL0208 phase III trial (NCT02354313)., Methods: We developed a score with a clustering algorithm applied to clinical variables. The candidate score was correlated to overall survival (OS) and validated in two independent data series from the European MCL Network (NCT00209222, NCT00209209); Results: Three groups of patients were significantly discriminated: Low, Intermediate (Int), and High risk (High). Seven discriminants were identified by a feature reduction approach: albumin, Ki-67, lactate dehydrogenase, lymphocytes, platelets, bone marrow infiltration, and B-symptoms. Accordingly, patients in the Int and High groups had shorter OS rates than those in the Low and Int groups, respectively (Int→Low, HR: 3.1, 95% CI: 1.0-9.6; High→Int, HR: 2.3, 95% CI: 1.5-4.7). Based on the 7 markers, we defined the engineered MCL international prognostic index (eMIPI), which was validated and confirmed in two independent cohorts; Conclusions: We developed and validated a ML-based prognostic model for MCL. Even when currently limited to baseline predictors, our approach has high scalability potential.

Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Background: Secondary CNS lymphoma is a rare but potentially lethal event in patients with diffuse large B-cell lymphoma. We aimed to assess the activity and safety of an intensive, CNS-directed chemoimmunotherapy consolidated by autologous haematopoietic stem-cell transplantation (HSCT) in patients with secondary CNS lymphoma., Methods: This international, single-arm, phase 2 trial was done in 24 hospitals in Italy, the UK, the Netherlands, and Switzerland. Adults (aged 18-70 years) with histologically diagnosed diffuse large B-cell lymphoma and CNS involvement at the time of primary diagnosis or at relapse and Eastern Cooperative Oncology Group Performance Status of 3 or less were enrolled and received three courses of MATRix (rituximab 375 mg/m 2 , intravenous infusion, day 0; methotrexate 3·5 g/m 2 , the first 0·5 g/m 2 in 15 min followed by 3 g/m 2 in a 3 h intravenous infusion, day 1; cytarabine 2 g/m 2 every 12 h, in 1 h intravenous infusions, days 2 and 3; thiotepa 30 mg/m 2 , 30 min intravenous infusion, day 4) followed by three courses of RICE (rituximab 375 mg/m 2 , day 1; etoposide 100 mg/m 2 per day in 500-1000 mL over a 60 min intravenous infusion, days 1, 2, and 3; ifosfamide 5 g/m 2 in 1000 mL in a 24 h intravenous infusion with mesna support, day 2; carboplatin area under the curve of 5 in 500 mL in a 1 h intravenous infusion, day 2) and carmustine-thiotepa and autologous HSCT (carmustine 400 mg/m 2 in 500 mL glucose 5% solution in a 1-2 h infusion, day -6; thiotepa 5 mg/kg in saline solution in a 2 h infusion every 12 h, days -5 and -4). The primary endpoint was progression-free survival at 1 year. Overall and complete response rates before autologous HSCT, duration of response, overall survival, and safety were the secondary endpoints. Analyses were in the modified intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT02329080. The trial ended after accrual completion; the database lock was Dec 31, 2019., Findings: Between March 30, 2015, and Aug 3, 2018, 79 patients were enrolled. 75 patients were assessable. 319 (71%) of the 450 planned courses were delivered. At 1 year from enrolment the primary endpoint was met, 42 patients were progression free (progression-free survival 58%; 95% CI 55-61). 49 patients (65%; 95% CI 54-76) had an objective response after MATRix-RICE, 29 (39%) of whom had a complete response. 37 patients who responded had autologous HSCT. At the end of the programme, 46 patients (61%; 95% CI 51-71) had an objective response, with a median duration of objective response of 26 months (IQR 16-37). At a median follow-up of 29 months (IQR 20-40), 35 patients were progression-free and 33 were alive, with a 2-year overall survival of 46% (95% CI 39-53). Grade 3-4 toxicity was most commonly haematological: neutropenia in 46 (61%) of 75 patients, thrombocytopenia in 45 (60%), and anaemia in 26 (35%). 79 serious adverse events were recorded in 42 (56%) patients; four (5%) of those 79 were lethal due to sepsis caused by Gram-negative bacteria (treatment-related mortality 5%; 95% CI 0·07-9·93)., Interpretation: MATRix-RICE plus autologous HSCT was active in this population of patients with very poor prognosis, and had an acceptable toxicity profile., Funding: Stand Up To Cancer Campaign for Cancer Research UK, the Swiss Cancer Research foundation, and the Swiss Cancer League., (Copyright © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Splenic marginal zone lymphoma (SMZL) is a rare lymphoma belonging to the marginal zone lymphoproliferative disorders. Usually, SMZL occurs with indolent presentation and, when required, the standard of care is represented by rituximab-based regimens. No direct comparison of different rituximab-based combinations and polychemotherapy regimens has been conducted to date. In a monocentric cohort of 68 SMLZ patients, we showed that rituximab in monotherapy or in combination with bendamustine, compared with rituximab associated with the polychemotherapy cycle cyclophosphamide, hydroxydaunorubicin, vincristine and prednisolone (CHOP), resulted in a higher 5-year progression-free survival (91.3 ± 9% and 75 ± 15.7% vs. 30.8 ± 12.1%, p < 0.001). Platelets at diagnosis <100 ×109/L (p = 0.034, HR = 4.3) and transformation into diffuse large B-cell lymphoma (p = 0.031, HR = 4.3) were associated with a lower overall survival., (© 2020 S. Karger AG, Basel.)

Lymphoma defines a group of different diseases. This study examined pre-treatment plasma samples from 66 adult patients (aged 20-74) newly diagnosed with any lymphoma subtype, and 96 frequency matched population controls. We used gas chromatography-mass spectrometry (GC-MS) to compare the metabolic profile by case/control status and across the major lymphoma subtypes. We conducted univariate and multivariate analyses, and partial least square discriminant analysis (PLS-DA). When compared to the controls, statistically validated models were obtained for diffuse large B-cell lymphoma (DLBCL), chronic lymphocytic leukemia (CLL), multiple myeloma (MM), and Hodgkin lymphoma (HL), but not follicular lymphoma (FL). The metabolomic analysis highlighted interesting differences between lymphoma patients and population controls, allowing the discrimination between pathologic and healthy subjects: Important metabolites, such as hypoxanthine and elaidic acid, were more abundant in all lymphoma subtypes. The small sample size of the individual lymphoma subtypes prevented obtaining PLS-DA validated models, although specific peculiar features of each subtype were observed; for instance, fatty acids were most represented in MM and HL patients, while 2-aminoadipic acid, 2-aminoheptanedioic acid, erythritol, and threitol characterized DLBCL and CLL. Metabolomic analysis was able to highlight interesting differences between lymphoma patients and population controls, allowing the discrimination between pathologic and healthy subjects. Further studies are warranted to understand whether the peculiar metabolic patterns observed might serve as early biomarkers of lymphoma., Competing Interests: The authors declare no conflict of interest.

Splenectomy in addition to immunotherapy with rituximab can provide quick and sometimes durable disease control in patients with splenic marginal zone lymphoma (SMZL). However, systemic chemotherapy is ultimately required in many cases. The BRISMA (Bendamustine-rituximab as first-line treatment of splenic marginal zone lymphoma)/IELSG (International Extranodal Lymphoma Study Group)36 trial is an open-label, single arm phase II study designed by the IELSG in cooperation with the Fondazione Italiana Linfomi and the lymphoma Study Association according to Simon's two-stage method. The primary endpoint was complete response rate. Fifty-six patients with SMZL diagnosis confirmed on central revision were treated with bendamustine (90 mg/m 2  days 1, 2) and rituximab (375 mg/m 2  day 1) every 28 days for six cycles (B-R). The overall response and CR rates were 91% and 73%, respectively. Duration of response, progression-free survival and overall survival at 3 years were 93% (95% confidence interval [CI] 81-98), 90% (95% CI 77-96) and 96% (95% CI 84-98), respectively. Toxicity was mostly haematological. Neutropenia grade ≥3 was recorded in 43% of patients; infections and febrile neutropenia in 5·4% and 3·6%. Overall, 14 patients (25%) experienced serious adverse events. Five patients (9%) went off-study because of toxicity and one patient died from infection. In conclusion, B-R resulted in a very effective first-line regimen for SMZL. Based on the results achieved in the BRISMA trial, B-R should be considered when a chemotherapy combination with rituximab is deemed necessary for symptomatic SMZL patients., (© 2018 British Society for Haematology and John Wiley & Sons Ltd.)

The aryl hydrocarbon receptor (AhR) is a transcription factor implicated in several pathways known to be relevant in lymphomagenesis. Aim of our study was to explore the link between AhR activation and risk of lymphoma subtypes. We used a Dual-Luciferase Assay ® and a luminometer to detect the activation of the luciferase gene, in HepG2 cells transfected with a specific reporter systems, by a 50 ml serum aliquot of cases of diffuse large B cell lymphoma (N = 108), follicular lymphoma (N = 85), chronic lymphocytic leukemia (N = 72), multiple myeloma (N = 80), and Hodgkin lymphoma (N = 94) and 357 controls who participated in the multicentre Italian study on gene-environment interactions in lymphoma etiology (ItGxE). Risk of each lymphoma subtype associated with AhR activation was calculated with polytomous logistic regression adjusting by age, gender, and study centre. The overall prevalence of AhR activation ranged 13.9-23.6% by subtype, and it varied by study area (8-39%). Risk associated with AhR activation was moderately elevated for follicular lymphoma (OR = 1.56, 95% CI 0.86, 2.80) and chronic lymphocytic leukemia (OR = 1.56, 95% CI 0.83, 2.96). Despite our inconclusive findings about the association with risk of lymphoma subtypes, we showed that the Dual-Luciferase Assay can be reliably and easily applied in population-based studies to detect AhR activation., Competing Interests: None.

The International Extranodal Lymphoma Study Group-26 study evaluated the prognostic role of 18-fluorodeoxyglucose positron-emission tomography (PET) in primary mediastinal large B-cell lymphoma. We assessed quantitative PET parameters at diagnosis and post-treatment in 100 patients. The end-of-therapy total lesion glycolysis (TLG) was the best individual outcome predictor, but the combination of baseline TLG and end-of-therapy visual analysis with Deauville Score (DS) showed a better positive predictive value. A model in which baseline TLG is combined with interim DS might identify patients with shorter progression-free survival. PET metrics combined with interim DS may allow early risk assessment and warrants further studies., (© 2017 John Wiley & Sons Ltd.)

Background: The prognosis of young patients with diffuse large B-cell lymphoma at high risk (age-adjusted International Prognostic Index [aa-IPI] score 2 or 3) treated with R-CHOP (rituximab, cyclophosphamide, vincristine, doxorubicin, and prednisone) is poor. The aim of this study was to investigate the possible benefit of intensification with high-dose chemotherapy and autologous stem-cell transplantation as part of first-line treatment in these patients., Methods: We did a multicentre, open-label, randomised, controlled, phase 3 trial with a 2 × 2 factorial design to compare, at two different R-CHOP dose levels, a full course of rituximab-dose-dense chemotherapy (no transplantation group) versus an abbreviated course of rituximab-dose-dense chemotherapy followed by consolidation with R-MAD (rituximab plus high-dose cytarabine plus mitoxantrone plus dexamethasone) and high-dose BEAM chemotherapy (carmustine, etoposide, cytarabine, and melphalan) plus autologous stem-cell transplantation (transplantation group) in young patients (18-65 years) with untreated high-risk diffuse large B-cell lymphoma (aa-IPI score 2-3). At enrolment, patients were stratified according to aa-IPI score and randomly assigned (1:1:1:1) to receive R-CHOP (intravenous rituximab 375 mg/m 2 , cyclophosphamide 750 mg/m 2 , doxorubicin 50 mg/m 2 , and vincristine 1·4 mg/m 2 on day 1, plus oral prednisone 100 mg on days 1-5) delivered in a 14-day cycle (R-CHOP-14) for eight cycles; high-dose R-CHOP-14 (R-MegaCHOP-14; R-CHOP-14 except for cyclophosphamide 1200 mg/m 2 and doxorubicin 70 mg/m 2 ) for six cycles; R-CHOP-14 for four cycles followed by R-MAD (intravenous rituximab 375 mg/m 2 on day 1 or 4 plus intravenous cytarabine 2000 mg/m 2 and dexamethasone 4 mg/m 2 every 12 h on days 1-3 plus intravenous mitoxantrone 8 mg/m 2 on days 1-3) plus BEAM (intravenous carmustine 300 mg/m 2 on day -7, intravenous cytarabine 200 mg/m 2 twice a day on days -6 to -3, intravenous etoposide 100 mg/m 2 twice a day on days -6 to -3, plus intravenous melphalan 140 mg/m 2 on day -2) and autologous stem-cell transplantation (day 0); or R-MegaCHOP-14 for four cycles followed by R-MAD plus BEAM and autologous stem-cell transplantation. The primary endpoint was failure-free survival at 2 years in the intention-to-treat population. This study is registered with EudraCT (2005-002181-14; 2007-000275-42) and with ClinicalTrials.gov, number NCT00499018., Findings: Between Jan 10, 2006, and Sept 8, 2010, 399 patients were randomly assigned to receive transplantation (n=199) or no transplantation (n=200); 203 patients were assigned to receive R-CHOP-14 and 196 were assigned to receive R-MegaCHOP-14. With a median follow-up of 72 months (IQR 57-88), 2-year failure-free survival was 71% (95% CI 64-77) in the transplantation group versus 62% (95% CI 55-68) in the no transplantation group (hazard ratio [HR] 0·65 [95% CI 0·47-0·91]; stratified log-rank test p=0·012). No difference in 5-year overall survival was observed between these groups (78% [95% CI 71-83] versus 77% [71-83]; HR 0·98 [0·65-1·48]; stratified log-rank test p=0·91). Grade 3 or worse haematological adverse events were reported in 183 (92%) of 199 patients in the transplantation group versus 135 (68%) of 200 patients in the no transplantation group. Grade 3 or worse non-haematological adverse events were reported in 90 (45%) versus 31 (16%); the most common grade 3 or worse non-haematological adverse event was gastrointestinal (49 [25%] vs 19 [10%]). Treatment-related deaths occurred in 13 (3%) patients; eight in the transplantation group and five in the no transplantation group., Interpretation: Abbreviated rituximab-dose-dense chemotherapy plus R-MAD plus BEAM and autologous stem-cell transplantation reduced the risk of treatment failure compared with full course rituximab-dose-dense chemotherapy in young patients with diffuse large B-cell lymphoma at high risk. However, these results might not be clinically meaningful, since this improvement did not reflect an improvement in overall survival. These results do not support further consideration of the use of intensification of R-CHOP as an upfront strategy in patients with diffuse large B-cell lymphoma with poor prognosis., Funding: Fondazione Italiana Linfomi., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Current data suggests that the risk of venous thromboembolism (VTE) in patients with non-Hodgkin lymphoma (NHL) is comparable to that observed in patients with solid tumours, although more robust confirmatory analyses are required. With that in mind, we investigated the occurrence of VTE in a pooled analysis of 12 "Fondazione Italiana Linfomi" (FIL) prospective clinical studies. Specifically, we wished to assess the cumulative incidence of VTE in NHL patients, evaluate the predictive value of the Khorana Score (KS), and identify other potential risk factors for VTEs. Data for VTE occurrence were retrieved from study databases and pharmacovigilance reports. Our analysis includes 1717 patients from 12 prospective phase II and III trials, including newly diagnosed NHL. We observed 53 VTEs (any grade) in 46 patients, with 20 severe VTEs in 17 patients. The cumulative incidences for "all-grade" or grade ≥3 VTEs were 2.9 % (95 % CI: 2.1-3.8) and 1.1 % (95 % CI: 0.6-1.6), respectively. KS categories were positively associated with the risk of VTE of any grade, and with severe events (i. e. grade ≥3; Gray's test p-values = 0.048 and 0.012, respectively). Among NHL patients, those with diffuse large B-cell lymphoma (DLBCL) showed a greater risk of (any grade) VTE (HR: 3.42, 95 % CI: 1.32-8.84, p-value = 0.011). Our study indicates that 1) VTE is a relevant complication for NHL patients, 2) KS is predictive of VTE events and 3) DLBCL histotype is an independent risk factor for VTE incidence, for which preventative interventions could be considered.

Categorization of primary cutaneous B-cell lymphomas (PCBCL) other than marginal zone (MZL) represents a diagnostic challenge with relevant prognostic implications. The 2008 WHO lymphoma classification recognizes only primary cutaneous follicular center cell lymphoma (PCFCCL) and primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL-LT), whereas the previous 2005 WHO/EORTC classification also included an intermediate form, namely PCDLBCL, other. We conducted a retrospective, multicentric, consensus-based revision of the clinicopathologic characteristics of 161 cases of PCBCL other than MZL. Upon the histologic features that are listed in the WHO classification, 96 cases were classified as PCFCCL and 25 as PCDLBCL-LT; 40 further cases did not fit in the former subgroups in terms of cytology and/or architecture, thus were classified as PCDLBCL, not otherwise specified (PCDLBCL-NOS). We assigned all the cases a histogenetic profile, based on the immunohistochemical detection of CD10, BCL6, and MUM1, and a "double hit score" upon positivity for BCL2 and MYC. PCDLBCL-NOS had a clinical presentation more similar to PCFCCL, whereas the histology was more consistent with the picture of a diffuse large B-cell lymphoma, as predominantly composed of centroblasts but with intermixed a reactive infiltrate of small lymphocytes. Its behavior was intermediate between the other two forms, particularly when considering only cases with a "non-germinal B-cell" profile, whereas "germinal center" cases resembled PCFCCL. Our data confirmed the aggressive behavior of PCDLBC-LT, which often coexpressed MYC and BCL2. The impact of single factors on 5-year survival was documented, particularly histogenetic profile in PCDLBCL and BCL2 translocation in PCFCCL. Our study confirms that a further group-PCDLBCL-NOS-exists, which can be recognized through a careful combination of histopathologic criteria coupled with adequate clinical information., (© 2016 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Relapsed or refractory diffuse large B-cell lymphoma (DLBCL) not suitable for high dose chemotherapy with autologous stem cell transplantation (ASCT) has a dismal prognosis and no standard therapy. We designed an Italian multicenter retrospective study aimed at evaluating the safety and efficacy of rituximab plus bendamustine (R-B) as salvage treatment in patients not eligible for ASCT because of age and/or comorbidity or in patients with post-ASCT recurrence. Fifty-five patients with a median age of 76 years were included. The overall response rate was 50%, including 28% complete remission and 22% partial remission. The median overall survival (OS) was 10.8 months. The median progression free survival (PFS) was 8.8 months. Eleven patients are still alive and in complete remission at last follow-up (12-71 months). Toxicity was moderate, mainly grades 1 and 2. R-B showed promising efficacy results with an acceptable toxicity profile and should be further investigated, possibly in combination with novel drugs.

An update at 7 years was conceived for our multicenter phase II study in which 55 elderly high-risk untreated diffuse large B-cell lymphoma patients were treated with (90)Y-ibritumomab tiuxetan after a short course of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP) as long-term follow-up analyses of this combined therapeutic modality are lacking. The overall response rate to the entire regimen was 80%, including 73% (40/55) of complete response (CR) rate and 7% (4/55) of partial response rate. At the time of writing, 24/55 (43.6%) patients experienced a progression disease and 20 of 40 (50%) patients who obtained a CR are still alive in continuous CR. With a median follow-up of 7 years, the disease-free survival was 43.3% and the progression-free survival was 36.1%. The overall survival at 7.9 years was 38.9% (27 deaths mainly because of lymphoma). Two patients developed secondary hematological malignancies, an acute myeloid leukemia and a myelodysplastic syndrome, at 4 and 3 years from radioimmunotherapy, respectively. Our data confirm the feasibility, efficacy and safety of four cycles of R-CHOP followed by radioimmunotherapy consolidation even in the long term: this combination allows dispensing less chemotherapy in a frail group of patients without invalidating response quality and duration.

Purpose: The quantitative assessment of Positron Emission Tomography (PET) scans using standardized uptake value and derived parameters proved to be superior to traditional qualitative assessment in several retrospective or mono-centric prospective reports. Since different scanners give different quantitative readings, a program for clinical trial qualification (CTQ) is mandatory to guarantee a reliable and reproducible use of quantitative PET in prospective multi-centre clinical trials and in every-day clinical life., Methods: We set up, under the auspices of Italian Foundation on Lymphoma (FIL), a CTQ program consisting of the PET/CT scan acquisition and analysis of (18)F and (68)Ge NEMA/IEC image quality phantoms for the reduction of inter-scanner variability. Variability was estimated on background activity concentration (BAC) and sphere to background ratio (SBR)., Results: The use of a (68)Ge phantom allowed reducing the inter-scanner variability among different scanners from 74.0% to 20.5% in BAC and from 63.3% to 17.4% in SBR compared to using the (18)F phantom. The CTQ criteria were fulfilled at first round in 100% and 28% of PET scanners with (68)Ge and (18)F respectively., Conclusions: The (68)Ge phantom proved a reliable tool for PET scanner qualification, able to significantly reduce the potential sources of error while increasing the reproducibility of PET derived quantitative parameter measurement., (Copyright © 2016 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.)

Background: Recent studies show that the risk of VTE in NHL pts is similar to that observed in high risk solid tumors (i.e. pancreatic, ovarian cancer). VTE in NHL occurs in most cases within three months from diagnosis and can have substantial impact on treatment delivery and outcome as well as on quality of life. However few data are available on potential predictors., Aims: To better clarify the epidemiology of early (within six months from treatment start) VTE in NHL we conducted a pooled data analysis of 12 clinical trials from FIL. Our analysis included basic demographic features, lymphoma-related characteristics as well the Khorana score (based on histology, BMI, platelets WBC and HB counts) which is extensively used in solid tumors to predict VTE risk., Patients and Methods: From Jan. 2010 to Dec. 2014, all pts with B-cell NHL enrolled in prospective clinical trials from FIL for frontline treatment were included. For 9 studies study period included the entire trial population was included. The analyses were conducted based on CRFs as well as pharmacovigilance reports. VTE definition and grading was stated according to standard criteria of toxicity (CTCAE V4.0). Cumulative incidence of VTE from the study enrollment was estimated using the method described by Gooley et al. accounting for death from any causes as a competing risk. The Fine & Gray survival model was used to identify predictors of VTE among NHL pts. Factors predicting the grade of VTE were investigated using an ordinal logistic regression model. This pooled data analysis was approved by local IRB., Results: Overall, 1,717 patients belonging to 12 studies were evaluated. Eight were phase I/II or II (25% of pts) and 4 phase III (75% of pts). M/F ratio was 1.41, Median age was 57, (IQ range (IQR) 49-66). Histologies were: DLCL-B 34%, FL 41%, MCL 18%, other 6%. Median BMI was 25 (IQR 22-28). Median Hb, WBC and platelets counts were 13g/dl) (IQR 11.5-14.2), 7.1*10^(9)/l (IQR 5.6-10.3), 224*10^(9)/l (IQR 169-298), respectively. 1189 pts were evaluable Khorana score: 58% low risk, 30% intermediate risk, 12% were high risk. Human erythropoetin support was given to 9% of patients. All pts received Rituximab. Planned therapeutic programs included ASCT in 27% of pts, conventional chemotherapy in 67% a conventional chemotherapy plus lenalidomide in 6%. Overall 59 any grade VTE episodes occurred in 51 pts (2.9%), including 21 grade III-IV VTE (18 pts). None was fatal. Median time from study enrolment to VTE was 63 days (IQR: 35-110). Considering death as a competitive event the 6 months cumulative incidence of VTE was 2,2% in low risk Khorana score, 4.5% (95%IC: 2.3-6.7) in intermediate and 6.6% (95%IC: 2.4-10.8) in high risk (p=0.012) (figure 1). Khorana score was predictive also for grade III-IV events as they were 0,7% (95% CI:0.1-1.4) in low risk and 2.0% (95% CI:0.8-3.3) in intermediate-high risk (p=0.048). The results were similar also after excluding lenalidomide containing studies. The Fine and Gray multivariate analyses, adjusted for age and stage, showed that Khorana score (intermediate risk adjHR=1.96; 95%IC: 0.84-4.56 and high risk adjHR=3.81; 95%IC: 1.51-9.58) and DLCL-B histotype (adjHR=2.58; 95% CI: 1.01-6.55) were independently associated to an increased risk of VTE. Moreover an ordinal logistical regression model indicated that the increase of one point in the Khorana score resulted in an increased risk of VTE (OR=1.85; 95% CI: 1.23-2.79)., Conclusions: Our results suggest that DLCL-B histotype and Khorana score are predictors of VTE in NHL. The latter might become a simple and effective tool to assess the risk of VTE in NHL. Prospective validation including also patients not eligible for clinical trials is needed., (© 2016 Elsevier Ltd. All rights reserved.)

Purpose: Treatment of secondary CNS dissemination in patients with aggressive lymphomas remains an important, unmet clinical need. Herein, we report the final results of a multicenter phase II trial addressing a new treatment for secondary CNS lymphoma based on encouraging experiences with high doses of antimetabolites in primary CNS lymphoma and with rituximab plus high-dose sequential chemoimmunotherapy (R-HDS) in relapsed aggressive lymphoma., Patients and Methods: HIV-negative patients with aggressive B-cell lymphoma and secondary CNS involvement at diagnosis or relapse, age 18 to 70 years, and Eastern Cooperative Oncology Group performance status ≤ 3 were enrolled and treated with high-doses of methotrexate and cytarabine, followed by R-HDS (cyclophosphamide, cytarabine, and etoposide) supported by autologous stem-cell transplantation (ASCT). Treatment included eight doses of rituximab and four doses of intrathecal liposomal cytarabine. The primary end point was 2-year event-free survival; the planned accrual was 38 patients., Results: Thirty-eight patients were enrolled; CNS disease was detected at presentation in 16 patients. Toxicity was usually hematologic and manageable, with grade 4 febrile neutropenia in 3% of delivered courses and grade 4 nonhematologic toxicity in 2% of delivered courses. Four patients died because of toxicity. Autologous stem cells were successfully collected in 24 (89%) of 27 patients (median, 10 × 10(6)/kg); 20 patients underwent ASCT. Complete response was achieved in 24 patients (complete response rate, 63%; 95% CI, 48% to 78%). At a median follow-up of 48 months, 17 patients remained relapse free, with a 2-year event-free survival rate of 50% ± 8%. At 5 years, 16 patients were alive, with a 5-year overall survival rate of 41% ± 8% for the whole series and 68% ± 11% for patients who received transplantation. Systemic (extra-CNS) and/or meningeal disease did not affect outcome., Conclusion: The combination of high doses of antimetabolites, R-HDS, and ASCT is feasible and effective in patients age 18 to 70 years old with secondary CNS lymphoma, and we propose it as a new standard therapeutic option., (© 2015 by American Society of Clinical Oncology.)

The International Extranodal Lymphoma Study Group (IELSG) 26 study was designed to evaluate the role of (18)F-fluorodeoxyglucose (18FDG) positron emission tomography/computed tomography (PET/CT) in the management of primary mediastinal (thymic) large B-cell lymphoma (PMBCL). We examined the prognostic impact of functional PET parameters at diagnosis. Metabolic activity defined by the maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) was measured on baseline 18FDG PET/CT following a standard protocol in a prospectively enrolled cohort of 103 PMBCL patients. All received combination chemoimmunotherapy with doxorubicin- and rituximab-based regimens; 93 had consolidation radiotherapy. Cutoff values were determined using the receiver-operating characteristic curve. At a median follow-up of 36 months, progression-free survival (PFS) and overall survival (OS) were 87% and 94%, respectively. In univariate analysis, elevated MTV and TLG were significantly associated with worse PFS and OS. Only TLG retained statistical significance for both OS (P = .001) and PFS (P < .001) in multivariate analysis. At 5 years, OS was 100% for patients with low TLG vs 80% for those with high TLG (P = .0001), whereas PFS was 99% vs 64%, respectively (P < .0001). TLG on baseline PET appeared to be a powerful predictor of PMBCL outcomes and warrants further validation as a biomarker. The IELSG 26 study was registered at www.clinicaltrials.gov as #NCT00944567., (© 2015 by The American Society of Hematology.)

We performed a multicenter study to validate the concept that a simple comprehensive geriatric assessment (CGA) can identify elderly, non-fit patients with diffuse large B-cell lymphoma (DLBCL) in whom curative treatment is not better then palliation, and to analyze potential benefits of treatment modulation after further subdividing the non-fit category by CGA criteria. One hundred and seventy-three patients aged > 69 treated with curative or palliative intent by clinical judgement only were grouped according to CGA into fit (46%), unfit (16%) and frail (38%) categories. Two-year overall survival (OS) was significantly better in fit than in non-fit patients (84% vs. 47%; p < 0.0001). Survival in unfit and frail patients was not significantly different. Curative treatment slightly improved 2-year OS in unfit (75% vs. 45%) but not in frail patients (44% vs. 39%). CGA was confirmed as very efficient in identifying elderly patients with DLBCL who can benefit from a curative approach. Further efforts are needed to better tailor therapies in non-fit patients.

Follicular lymphoma (FL) patients experience multiple remissions and relapses and commonly receive multiple treatment lines. A crucial question is whether anthracyclines should be used at first-line or whether they would be better "reserved" for relapse and whether FL outcome can be optimized by definite sequences of treatments. Randomized trials can be hardly designed to address this question. In this retrospective multi-institutional study, time-to-next-treatment after first relapse was analyzed in 510 patients who had received either alkylating agents- or anthracycline- or nucleoside analogs-based chemotherapy with/without rituximab at first-line and different second-line therapies. After a median of 42 months, median time-to-next-treatment after relapse was 41 months (CI95%:34-47 months). After adjustment for covariates, first-line anthracycline-based chemotherapy with/without rituximab was associated with better time-to-next-treatment after any salvage than alkylating agents-based chemotherapy with/without rituximab or nucleoside analogs-based chemotherapy with/without rituximab (HR:0.74, P = 0.027). The addition of rituximab to first-line chemotherapy had no significant impact (HR:1.22, P = 0.140). Autologs stem cell transplantation performed better than any other salvage treatment (HR:0.53, P < 0.001). First-line anthracycline-based chemotherapy significantly improved time-to-next-treatment even in patients receiving salvage autologs stem cell transplantation (P = 0.041). This study supports the concept that in FL previous treatments significantly impact on the outcome of subsequent therapies. The outcome of second-line treatments, either with salvage chemoimmunotherapy or with autologs stem cell transplantation, was better when an anthracycline-containing regimen was used at first-line., (© 2014 Wiley Periodicals, Inc.)

Purpose: To assess the role of [18F]fluorodeoxyglucose ([18F]FDG) positron emission tomography/computed tomography (PET/CT) after rituximab and anthracycline-containing chemoimmunotherapy in patients with primary mediastinal large B-cell lymphoma (PMLBCL)., Patients and Methods: Among 125 patients prospectively enrolled, 115 were eligible for central review of PET/CT scans at the completion of standard chemoimmunotherapy, by using a five-point scale. Consolidation radiotherapy (RT) was permitted and given to 102 patients., Results: Fifty-four patients (47%) achieved a complete metabolic response (CMR), defined as a completely negative scan or with residual [18F]FDG activity below the mediastinal blood pool (MBP) uptake. In the remaining 61 patients (53%), the residual uptake was higher than MBP uptake but below the liver uptake in 27 (23%), slightly higher than the liver uptake in 24 (21%), and markedly higher in 10 (9%). CMR after chemoimmunotherapy predicted higher 5-year progression-free survival (PFS; 98% v 82%; P=.0044) and overall survival (OS; 100% v 91%; P=.0298). Patients with residual uptake higher than MBP uptake but below liver uptake had equally good outcomes without any recurrence. Using the liver uptake as cutoff for PET positivity (boundary of score, 3 to 4) discriminated most effectively between high or low risk of failure, with 5-year PFS of 99% versus 68% (P<.001) and 5-year OS of 100% versus 83% (P<.001)., Conclusion: More than 90% of patients are projected to be alive and progression-free at 5 years, despite a low CMR rate (47%) after chemoimmunotherapy. This study provides a basis for using PET/CT to define the role of RT in PMLBCL., (© 2014 by American Society of Clinical Oncology.)

Purpose: This study aimed to evaluate the efficacy and safety of the treatment with (90)Y-ibritumomab tiuxetan following a short-course of rituximab with cyclophosphamide-adriamycin-vincristine-prednisone (R-CHOP) in high-risk elderly patients with previously untreated diffuse large B-cell lymphoma (DLBCL)., Experimental Design: From December 2006 to October 2008, 55 high-risk elderly (age > or =60 years) untreated DLBCL patients were treated in seven Italian institutions with a short-course of chemotherapy consisting of four cycles of R-CHOP21 followed by (90)Y-ibritumomab tiuxetan 6 to 10 weeks later., Results: Of the 55 patients, 48 underwent radioimmunotherapy. The overall response rate to the entire treatment regimen was 80%, including 73% complete remissions and 7% partial remissions. Eight (50%) of the 16 patients who achieved less than a complete response with CHOP improved their remission status after (90)Y-ibritumomab tiuxetan administration. With a median follow-up of 18 months, the 2-year progression-free survival was estimated to be 85%, with a 2-year overall survival of 86%. (90)Y-ibritumomab tiuxetan toxicity consisted of grade 3 to 4 hematologic toxicity in 28 of 48 patients, mainly neutropenia (23 patients) and thrombocytopenia (15 patients). Red cells and/or platelets transfusions were given to three patients., Conclusion: This study evaluated the feasibility, efficacy, and safety of a short-course R-CHOP21 regimen followed by (90)Y-ibritumomab tiuxetan in high-risk elderly DLBCL patients., ((c) 2010 AACR.)

Background: Chemotherapy with high-dose methotrexate is the conventional approach to treat primary CNS lymphomas, but superiority of polychemotherapy compared with high-dose methotrexate alone is unproven. We assessed the effect of adding high-dose cytarabine to methotrexate in patients with newly diagnosed primary CNS lymphoma., Methods: This open, randomised, phase 2 trial was undertaken in 24 centres in six countries. 79 patients with non-Hodgkin lymphoma exclusively localised into the CNS, cranial nerves, or eyes, aged 18-75 years, and with Eastern Cooperative Oncology Group performance status of 3 or lower and measurable disease were centrally randomly assigned by computer to receive four courses of either methotrexate 3.5 g/m(2) on day 1 (n=40) or methotrexate 3.5 g/m(2) on day 1 plus cytarabine 2 g/m(2) twice a day on days 2-3 (n=39). Both regimens were administered every 3 weeks and were followed by whole-brain irradiation. The primary endpoint was complete remission rate after chemotherapy. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00210314., Findings: All randomly assigned participants were analysed. After chemotherapy, seven patients given methotrexate and 18 given methotrexate plus cytarabine achieved a complete remission, with a complete remission rate of 18% (95% CI 6-30) and 46% (31-61), respectively, (p=0.006). Nine patients receiving methotrexate and nine receiving methotrexate plus cytarabine achieved a partial response, with an overall response rate of 40% (25-55) and 69% (55-83), respectively, (p=0.009). Grade 3-4 haematological toxicity was more common in the methotrexate plus cytarabine group than in the methotrexate group (36 [92%] vs six [15%]). Four patients died of toxic effects (three vs one)., Interpretation: In patients aged 75 years and younger with primary CNS lymphoma, the addition of high-dose cytarabine to high-dose methotrexate provides improved outcome with acceptable toxicity compared with high-dose methotrexate alone., Funding: Swiss Cancer League.

Background: Third-generation regimens (MACOP-B [methotrexate/leucovorin (LV)/doxorubicin/cyclophosphamide/vincristine/ prednisone/bleomycin] or VACOP-B [etoposide/LV/doxorubicin/cyclophosphamide/vincristine/prednisone/bleomycin]) in combination with local radiation therapy seem to improve lymphoma-free survival of primary mediastinal large B-cell lymphoma (PMLBCL). Recently, the superiority of R-CHOP (rituximab plus cyclophosphamide/doxorubicin/vincristine/ prednisone) over CHOP-like regimens has been demonstrated in elderly and younger patients with low-risk diffuse large B-cell lymphoma., Patients and Methods: Retrospectively, between February 2002 and July 2006, 45 previously untreated patients with PMLBCL were treated with a combination of a third-generation chemotherapy regimen (MACOP-B or VACOP-B), concurrent rituximab, and mediastinal radiation therapy., Results: Twenty-six (62%) patients achieved a complete response (CR), and 15 (36%) obtained a partial response after MACOP-B/VACOP-B plus rituximab. After radiation therapy, the CR rate was 80%. At a median follow-up of 28 months, among the 34 patients who obtained a CR, 3 relapsed after 16, 19, and 22 months, respectively. Projected overall survival was 80% at 5 years; the relapse-free survival (RFS) curve of the 34 patients who achieved CR was 88% at 5 years., Conclusion: In this retrospective study, in patients with PMLBCL, combined-modality treatment using the MACOP-B/VACOP-B regimen plus rituximab induces a high remission rate, with patients having a > 80% chance of surviving relapse free at 5 years. In comparison with historical data on MACOP-B/VACOP-B without rituximab, there are no statistically significant differences in terms of CR and RFS rates.

Background: We investigated the addition of rituximab to dose-dense and high-dose chemotherapy with autologous stem cell transplantation in patients with untreated poor-prognosis diffuse large B-cell lymphoma., Design and Methods: Ninety-four young patients (age, 18-60) with stage III-IV diffuse large B-cell lymphoma at intermediate/high or high risk according to the age-adjusted International Prognostic Index were enrolled into a phase II trial. The treatment was as follows: four courses of bi-weekly rituximab-cyclophosphamide-epirubicin-vincristine-prednisone (R-MegaCEOP14), two courses of rituximab-mitoxantrone-cytarabine-dexamethasone (R-MAD) and carmustine-etoposide-cytarabine-melphalan (BEAM) with autologous stem cell transplantation., Results: The complete response and toxic death rates were 82% and 5%, respectively. Failure-free survival and overall survival rates at 4 years were 73% and 80%, respectively. The outcomes of these patients were retrospectively compared to those of 41 patients with similar characteristics enrolled into a previous phase II trial of high-dose chemotherapy without rituximab. This historical group was treated with eight weekly infusions of methotrexate-doxorubicin-cyclophosphamide-vincristine-prednisone-bleomycin (MACOP-B), two courses of MAD and BEAM with autologous stem cell transplantation. The 4-year failure-free survival rates for the rituximab and historical groups were 73% versus 44%, respectively (p=0.001); the 4-year overall survival rates were 80% and 54%, respectively (p=0.002). A Cox's multivariable model was applied to adjust the effect of treatment for unbalanced or important prognostic factors: failure and death risks were significantly reduced in the rituximab group compared to the historical group, with an adjusted hazard ratio of 0.44 (p=0.01) for failure-free survival and 0.46 (p=0.02) for overall survival., Conclusions: These results suggest that the addition of rituximab to high-dose chemotherapy is effective and safe in diffuse large B-cell lymphoma with a poor-prognosis and such regimens need to be compared to dose-dense chemoimmunotherapy without autologous stem cell transplantation in randomized trials.

Recently, management of limited stage diffuse large cell lymphoma (DLCL) is trending toward a low intensity chemotherapy approach. Since 1993 we have used a brief weekly (6 weeks) chemotherapy scheme (Doxorubicin, Cyclophosphamide, Bleomycin, Vincristine, and Prednisone = ACOP-B) followed by involved field radiotherapy in 207 consecutive patients with well defined localized DLCL without age limit (median 57 years, range 18-85). Treatment was completed as designed in 183 of 207 patients (88%). One hundred and ninety-nine patients (96%) achieved complete remission. At a median follow-up of 66 months 170 patients are alive (82%), 168 of them free of disease. Twenty-nine patients experienced relapse after achieving a complete remission. Kaplan-Meier, risk of relapse was 24% after 13 years. Thirty (14.5%) patients have died, 14 (6.8%) due to lymphoma progression, one due to regimen toxicity and 15 (7.2%) from other causes while remaining in complete remission. The probability of overall survival and event free survival at 13 years was 78% (95% CI 70-87%) and 63% (95% CI 50-75), respectively. Crude rate of secondary malignancy was 5.26 /1000 person-years. The ACOP-B regimen plus involved field radiotherapy is well tolerated both short and long term and is an effective chemotherapy scheme for very well defined limited stage aggressive non-Hodgkin lymphomas in all age categories.

We investigated lymphoma risk following hepatitis infection in a case-control study of 274 incident lymphoma cases, defined according to the WHO classification, and 336 population controls in Sardinia, Italy. Part of our study population (198 cases and 219 controls) was included in the EPILYMPH study of Hepatitis C virus (HCV) infection in relation to non-Hodgklin's lymphoma risk. Based on questionnaire information on whether and at what age a diagnosis of hepatitis was posed by a physician, systematic anti-HCV antibodies testing in cases and controls by enzyme-linked immunoassay, and HCV-RNA assessment by PCR analyses in positive samples, we investigated more in detail whether hepatitis non-C is also associated with lymphoma risk, and whether risk varies by clinical form of hepatitis (acute or chronic infection). After adjusting by age, gender, education, and area of birth whether from the study area or elsewhere in Italy, a previous generic diagnosis of hepatitis was associated with a significantly elevated lymphoma risk [odds ratio (OR) = 1.8; 95% CI 1.1, 2.8], which was equally increased for hepatitis B (OR = 1.8; 95% CI 0.9, 3.5), for HCV positive subjects overall (OR = 2.0; 95% CI 0.8, 4.8), and for hepatitis non-B non-C (OR = 1.6; 95% CI 0.7, 3.9). Once concurrent infection from other hepatitis viruses was excluded, acute or chronic hepatitis C was the only one showing a consistent risk increase in all lymphoma subtypes, but follicular lymphoma. Some indications of an excess risk of lymphoma were observed also for acute, but not chronic forms of hepatitis B and hepatitis non-B, non C. Self-limited hepatitis C did not show an association. No significant heterogeneity in the risk of major lymphoma subtype was observed. Our results confirm a role of either acute or chronic active HCV infection in lymphomagenesis. Further studies are warranted to test the hypothesis that acute infection from other hepatitis viruses might also increase lymphoma risk.