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Between 2011 and 2012, a phase II trial evaluated the use of the RiBVD (rituximab, bendamustine, velcade and dexamethasone) combination as first-line treatment for mantle cell lymphoma (MCL) patients over the age of 65. We have now re-examined the classic prognostic factors, adding an assessment of TP53 mutation status. Patients (N=74; median age 73 years) were treated with the RiBVD combination. Median progression-free survival (mPFS) was 79 months and median overall survival (mOS) was 111 months. TP53 mutation status was available for 54/74 (73%) patients. TP53 mutations (TP53mt) were found in 12 patients (22.2%). In multivariate analysis, among the prognostic factors (PF) evaluated, only TP53mt and an albumin level (Alb) 3.6 g/dL were independently associated with a shorter mPFS. A hazard ratio (HR) of 3.16 (1.3-9.9, P=0.014) was obtained for TP53mt versus TP53 wild-type (wt), and 3.6 (1.39-9.5, P=0.009) for Alb <3.6 g/dL versus Alb ≥3.6 g/dL. In terms of mOS, multivariate analysis identified three PF: TP53mt (HR: 5.9 [1.77-19.5, P=0.004]), Alb <3.6 g/dL (HR: 5.2 [1.46- 18.5, P=0.011]), and ECOG=2 (HR: 3.7 [1.31-10.6, P=0.014]). Finally, a score combining TP53 status and Alb distinguished three populations based on the presence of 0, 1, or 2 PF. For these populations, mPFS was 7.8 years, 28 months, and 2.5 months, respectively. Our prolonged follow-up confirmed the efficacy of the RiBVD regimen, comparing it favorably to other regimens. TP53mt and hypoalbuminemia emerge as strong PF that can be easily integrated into prognostic scores for older adult patients with MCL.

Stage IIB Hodgkin lymphoma (HL) patients, with a mediastinum-to-thorax (M/T) ratio of ≥0.33 or extranodal localization have a poor prognosis and are treated either as limited or advanced stage. We compared these two approaches in patients included in two randomized phase III trials enrolling previously untreated early (H10) or advanced stage HL (AHL2011). We included HL patients with Ann-Arbor stage IIB with M/T ≥0.33 or extranodal involvement enrolled in the H10 or AHL2011 trials with available positron emission tomography at baseline (PET0) and after two cycles of chemotherapy (PET2). Baseline total metabolic tumor volume (TMTV) was calculated using the 41% SUVmax method. PET2 response assessment used the Deauville score. One hundred and fourty-eight patients were eligible, including 83 enrolled in the AHL2011 trial and 65 in the H10 trial. The median TMTV value was 155.5 mL (range, 8.3-782.9 mL), 165.6 mL in AHL2011 and 147 mL in H10. PET2 positivity rates were 16.9% (n=14) and 9.2% (n=6) in AHL2011 and H10 patients, respectively. With a median follow-up of 4.1 years (95% confidence interval [CI]: 3.9-4.4), overall 4-year PFS was 88.0%, 87.0% in AHL2011 and 89.2% in H10. In univariate and mutivariate analyses, baseline TMTV and PET2 response influenced significantly progression-free survival (hazard ratio [HR]=4.94, HR=3.49 respectively). Notably, among the 16 patients who relapsed, 13 (81%) had a baseline TMTV baseline ≥155 mL. Upfront ABVD plus radiation therapy or upfront escBEACOPP without radiotherapy provide similar patient's outcome in high-risk stage IIB HL. TMTV is useful to stratify these patients at baseline.

Histological transformation into diffuse large B-cell lymphoma is a rare complication in patients with Waldenström macroglobulinemia (WM) usually associated with a poor prognosis. The objective of this study was to develop and validate a prognostic index for survival in transformed WM patients. Through this multicenter, international collaborative effort, we developed a scoring system based on data from 133 patients with transformed WM who were evaluated between 1995 and 2016 (training cohort). Univariate and multivariate analyses were used to propose a prognostic index with 2-year survival after transformation as an end-point. For external validation, a data set of 67 patients was used to evaluate the performance of the model (validation cohort). By multivariate analysis, three adverse covariates were identified as independent predictors of 2-year survival after transformation: elevated serum LDH (2 points), platelet count < 100 x 109/L (1 point) and any previous treatment for WM (1 point). Three risk groups were defined: low-risk (0-1 point, 24% of patients), intermediate-risk (2-3 points, 59%, hazard ratio (HR) = 3.4) and high-risk (4 points, 17%, HR = 7.5). Two-year survival rates were 81%, 47%, and 21%, respectively (P < 0.0001). This model appeared to be a better discriminant than the International Prognostic Index (IPI) and the revised IPI (R-IPI). We validated this model in an independent cohort. This easy-to-compute scoring index is a robust tool that may allow identification of groups of transformed WM patients with different outcomes and could be used for improving the development of risk-adapted treatment strategies.

We present results of a prospective, multicenter, phase II study evaluating rituximab, bendamustine, bortezomib and dexamethasone as first-line treatment for patients with mantle cell lymphoma aged 65 years or older. A total of 74 patients were enrolled (median age, 73 years). Patients received a maximum of six cycles of treatment at 28-day intervals. The primary objective was to achieve an 18-month progression-free survival rate of 65% or higher. Secondary objectives were to evaluate toxicity and the prognostic impact of mantle cell lymphoma prognostic index, Ki67 expression, [ 18 F]fluorodeoxyglucose-positron emission tomography and molecular minimal residual disease, in peripheral blood or bone marrow. With a median follow-up of 52 months, the 24-month progression-free survival rate was 70%, hence the primary objective was reached. After six cycles of treatment, 91% (54/59) of responding patients were analyzed for peripheral blood residual disease and 87% of these (47/54) were negative. Four-year overall survival rates of the patients who did not have or had detectable molecular residual disease in the blood at completion of treatment were 86.6% and 28.6%, respectively ( P <0.0001). Neither the mantle cell lymphoma index, nor fluorodeoxyglucose-positron emission tomography nor Ki67 positivity (cut off of ≥30%) showed a prognostic impact for survival. Hematologic grade 3-4 toxicities were mainly neutropenia (51%), thrombocytopenia (35%) and lymphopenia (65%). Grade 3-4 non-hematologic toxicities were mainly fatigue (18.5%), neuropathy (15%) and infections. In conclusion, the tested treatment regimen is active as frontline therapy in older patients with mantle cell lymphoma, with manageable toxicity. Minimal residual disease status after induction could serve as an early predictor of survival in mantle cell lymphoma. ClinicalTrials.gov: NCT 01457144 ., (Copyright© 2019 Ferrata Storti Foundation.)

The underlying in vivo mechanisms of rituximab action remain incompletely understood in chronic lymphocytic leukemia. Recent data suggest that circulating micro-ribonucleic acids correlate with chronic lymphocytic leukemia progression and response to rituximab. Our study aimed at identifying circulating micro-ribonucleic acids that predict response to rituximab monotherapy in chronic lymphocytic leukemia patients. Using a hierarchical clustering of micro-ribonucleic acid expression profiles discriminating 10 untreated patients with low or high lymphocyte counts, we found 26 micro-ribonucleic acids significantly deregulated. Using individual real-time reverse transcription polymerase chain reaction, the expression levels of micro-ribonucleic acids representative of these two clusters were further validated in a larger cohort (n=61). MiR-125b and miR-532-3p were inversely correlated with rituximab-induced lymphodepletion ( P =0.020 and P =0.001, respectively) and with the CD20 expression on CD19 + cells ( P =0.0007 and P <0.0001, respectively). In silico analyses of genes putatively targeted by both micro-ribonucleic acids revealed a central role of the interleukin-10 pathway and CD20 (MS4A1) family members. Interestingly, both micro-ribonucleic acids were negatively correlated with MS4A1 expression, while they were positively correlated with MS4A3 and MSA47 Our results identify novel circulating predictive biomarkers for rituximab-mediated lymphodepletion efficacy in chronic lymphocytic leukemia, and suggest a novel molecular mechanism responsible for the rituximab mode of action that bridges miR-125b and miR-532-3p and CD20 family members. ( clinicaltrials.gov Identifier: 01370772 )., (Copyright© Ferrata Storti Foundation.)

Mediastinal gray zone lymphoma, B-cell lymphomas with intermediate features between classical Hodgkin lymphoma and primary mediastinal B-cell lymphoma, have not been well described in the literature. We report the clinical characteristics and outcomes of a large retrospective series of 99 cases centrally reviewed by a panel of hematopathologists, with a consensus established for the diagnosis. Cases were defined as classical Hodgkin lymphoma-like morphology (64.6%) with primary mediastinal B-cell lymphoma immunophenotype, primary mediastinal B-cell lymphoma-like morphology (30.3%) with classical Hodgkin lymphoma or composite (5.1%) (synchronous occurrence of classical Hodgkin lymphoma and primary mediastinal B-cell lymphoma). The median age was 32 years (13-83 years); 55% were women. Thirteen of 81 evaluable cases (16%) were Epstein-Barr virus-positive. Twenty-eight percent of patients presented primary refractory disease (progression under first-line treatment or relapse within one year). The 3-year event-free and overall survival rates were 63% and 80%, respectively. Patients treated with a standard regimen (RCHOP/ABVD) had worse event-free survival (P=0.003) and overall survival (P=0.02) than those treated with a dose-intensive chemotherapy (high-dose RCHOP/escalated BEACOPP). Rituximab added to chemotherapy was not associated with better event-free survival (P=0.55) or overall survival (P=0.88). Radiotherapy for patients in complete remission had no impact on event-free survival. In multivariate prognostic analysis, ECOG-PS and anemia were the strongest factors associated with a shorter event-free survival and overall survival, respectively. In conclusion, this report describes the largest series of mediastinal gray zone lymphoma. Our data suggest that a dose-intensive treatment might improve the outcome of this rare and aggressive disease., (Copyright© Ferrata Storti Foundation.)

We assessed the long-term results of autologous stem-cell transplantation for patients with first-relapsed or refractory Hodgkin lymphoma included in the prospective Lymphoma Study Association/Société Française de Greffe de Moelle H96 trial. This large multicenter phase II trial evaluated a risk-adapted strategy with single or tandem autologous stem-cell transplantation for 245 Hodgkin lymphoma patients. Poor-risk patients (n=150) had primary refractory Hodgkin lymphoma (n=77) or ≥2 risk factors at first relapse (n=73) and were eligible for tandem autologous stem-cell transplantation. Intermediate-risk patients (n=95) had one risk factor at first relapse and were eligible for single autologous stem-cell transplantation. With a median follow-up of 10.3 years, 10-year freedom from second failure and overall survival rates were, respectively: 64% (95% CI, 54% to 74%) and 70% (95% CI, 61% to 80%) for the intermediate-risk group, and 41% (95% CI, 33% to 49%) and 47% (95% CI, 39% to 55%) for the poor-risk group. Considering only patients who did not relapse after completing autologous stem-cell transplantation, the 15-year cumulative incidences of second primary malignancies were 24% for the 70 intermediate-risk patients and 2% for the 75 poor-risk ones. With long-term follow-up, the risk-adapted strategy remains appropriate. Tandem autologous stem-cell transplantation can still be considered an option for poor-risk patients, but integration of positron-emission tomography findings and new drugs may help to refine the need for a second autologous stem-cell transplant and possibly improve outcomes of patients with first-relapsed or refractory Hodgkin lymphoma., (Copyright© Ferrata Storti Foundation.)

The purpose of our study is to determine the outcome of patients with systemic non-Hodgkin lymphoma presenting with neurologic localization at diagnosis, as well as the impact of consolidation in terms of high-dose therapy followed by autologous stem cell transplantation. Newly diagnosed non-Hodgkin lymphoma patients with concomitant systemic and neurological involvement at diagnosis were included in this study. Sixty patients (37 males; 25 females) were included. Median age was 61 years (23-85 years). Histological subtype was mainly diffuse large B-cell lymphoma (n = 54; 90%). The International prognostic index was over 2 in 41 (72%) patients. Median number of extranodal sites was 2 (range: 1-5). Central nervous system involvement alone was documented in 48 patients. Paravertebral involvement with epidural mass and cord compression and positive cerebrospinal fluid were present in 7 patients. Five patients had both central nervous system and epidural involvement. First-line chemotherapy was mainly anthracycline-based (88%) plus high-dose methotrexate (74%) with or without cytarabine. Consolidation with high-dose therapy followed by autologous stem cell transplantation was performed in 19 patients. For the whole population, overall response rate after induction chemotherapy was 76%. Three-year progression-free survival and overall survival were 42 ± 7% and 44 ± 7%, respectively. For patients under 66 years of age, consolidation strategy using high-dose therapy followed by autologous stem cell transplantation positively impacted 3-year overall survival and progression free survival (P = 0.008) and (P = 0.003), respectively. In multivariate analysis, high-dose therapy had a positive impact on 3-year overall survival and progression-free survival for the whole population as well as for patients under 66 years old in CR after induction therapy (OS [HR=0.22 (0.07-0.67)] and progression-free survival [HR = 0.17 (0.05-0.54)]). In conclusion, non-Hodgkin lymphoma prognosis with concomitant systemic and neurological involvement at diagnosis is poor with a high risk of relapse when treated with conventional chemotherapies alone. This retrospective study supports the feasibility and the potential benefit of a consolidative strategy with high-dose therapy followed by autologous stem cell transplantation in this subset of patients. This strategy and the best intensive chemotherapy regimen remain to be validated in prospective trials., (Copyright© Ferrata Storti Foundation.)

Background: We analyzed detailed characteristics and salvage treatment in 175 follicular lymphoma patients from the FL2000 study who were in progression after first-line therapy with or without addition of rituximab to chemotherapy and interferon., Design and Methods: The impact of using autologous stem cell transplantation and/or rituximab administration at first progression was investigated, taking into account initial therapy. With a median follow up of 31 months, 3-year event free and overall survival rates after progression were 50% (95%CI 42-58%) and 72% (95%CI 64-78%), respectively., Results: The 3-year event free rate of rituximab re-treated patients (n=112) was 52% (95%CI 41-62%) versus 40% (95%CI 24-55%) for those not receiving rituximab second line (n=53) (P=0.075). There was a significant difference in 3-year overall survival between patients receiving autologous stem cell transplantation and those not: 92% (95%CI 78-97%) versus 63% (95%CI 51-72%) (P=0.0003), respectively. In multivariate analysis, both autologous stem cell transplantation and period of progression/relapse affected event free and overall survival., Conclusions: Regardless of front-line rituximab exposure, this study supports incorporating autologous stem cell transplantation in the therapeutic approach at first relapse for follicular lymphoma patients.