Dissemination patterns of Hodgkin lymphoma using a probability network model based on [18F]-FDG PET/CT.

PURPOSE: The preferred hypothesis for the dissemination patterns of Hodgkin lymphoma (HL) is the contiguity hypothesis. However, this hypothesis is based on studies performed before the advent of [18F]-FDG PET/CT which is now the established reference for HL staging. This study aims to extract the dissemination patterns of HL using [18F]-FDG PET/CT and a probability network model. METHODS: We retrospectively analyzed [18F]-FDG PET/CT performed for initial staging of patients with classical HL. The HL involvement status (presence of absence) was reported for 19 supra- and infra-diaphragmatic lymph node regions and 4 extranodal regions (lung, spleen, liver, and osteo- medullary). The analysis of HL dissemination was carried out using HL involvement status for all regions through 3 distinct methods: comparison of nearby lymph node regions, correlation assessment between all regions and relationship strength between all regions using Ising network model. RESULTS: A total of 196 patients were included. Our results showed strong relationships between nearby involved lymph node regions (for example between the left pelvic and the abdominal lymph node regions (relationship strength = 0.980)) and between more distant regions (for example between right and left axillary lymph node regions (strength = 0.714)). Furthermore, involvement of the infra-diaphragmatic lymph node regions was significantly correlated with Ann Arbor stage IV (phi = 0.56, p < 0.001). CONCLUSION: This study confirms the hypothesis of lymphatic dissemination of HL in a contiguous mode, with additional links between more distant regions. These predictable dissemination patterns could be useful for the initial staging assessment of patients with HL using [18F]-FDG PET/CT.

Work and education interruption in long-term Hodgkin lymphoma survivors: an analysis among patients from nine EORTC-LYSA trials.

BACKGROUND: Disease-specific studies on the impact of Hodgkin lymphoma (HL) on education or work interruption and resumption are lacking. MATERIAL AND METHODS: In a cross-sectional study conducted among long-term HL survivors enrolled from 1964 to 2004 in nine randomised EORTC-LYSA trials, the interruption and resumption of education/work was investigated. Survivors alive 5-44 years after diagnosis who were studying or working at time of diagnosis were included (n = 1646). Patient and treatment characteristics were obtained from trial records. Education and work outcomes were collected using the Life Situation Questionnaire. Logistic regression was used to model education or work interruption; Cox regression was used to study resumption rates. RESULTS: Among survivors studying at time of diagnosis (n = 323), 52% (95% CI: 46-57%) interrupted their education; however, it was resumed within 24 months by 92% (95% CI: 87-96%). The probability of interruption decreased with time: the more recent the treatment era, the lower the risk (OR 0.70 per 10 years, 95% CI: 0.49-1.01). Treatment with radiotherapy (yes vs. no) was associated with a higher education resumption rate (HR 2.01, 95% CI 1.07-3.78) whereas age, sex, stage, radiotherapy field and chemotherapy were not.Among survivors working at time of diagnosis (n = 1323), 77% (95% CI: 75-79%) interrupted their work. However, it was resumed within 24 months by 86% (95% CI: 84%-88%). Women were more likely to interrupt their work as compared to men (OR 1.90, 95% CI: 1.44-2.51) and, when interrupted, less likely to resume work (HR 0.70, 95% CI: 0.61-0.80). Survivors with a higher educational level were less likely to interrupt their work (OR 0.68 for university vs. no high school, 95% CI: 0.46-1.03); and when interrupted, more likely to resume work (HR 1.50 for university vs. no high school, 95% CI: 1.21-1.86). Increasing age was also associated with lower resumption rates (HR 0.62 for age ≥50 vs. 18-29 years, 95% CI: 0.41-0.94). CONCLUSION: An interruption in education/work was common among long-term HL survivors. However, most of the survivors who interrupted their studies or work had resumed their activities within 24 months. In this study, no associations between survivors' characteristics and failure to resume education were observed. Female sex, age ≥50 years, and a lower level of education were found to be associated with not resuming work after treatment for HL.

Attenuated cytarabine, etoposide, dexamethasone plus rituximab (R-Mini-CYVE) regimen for patients with relapsed or refractory B-cell non-Hodgkin's lymphoma not eligible for intensive chemotherapy.

OBJECTIVES: To evaluate the efficacy and tolerability of an attenuated immunochemotherapy regimen based on cytarabine, etoposide and dexamethasone plus rituximab (R-mini-CYVE) in patients with relapsed or refractory B-cell non-Hodgkin's lymphoma (NHL). METHODS: We included pretreated adult patients with B-cell NHL who were ineligible for high-dose immunochemotherapy (HDT). Cytarabine and etoposide were given at four different dose levels, depending on the patient's frailty. Up to 8 cycles were administered. RESULTS: Between 2013 and 2019, 56 patients with diffuse large B-cell lymphoma (n = 45, 80%) and indolent B-cell lymphoma (n = 11, 20%) were included. Median age was 75 (range: 36-88). Nineteen patients (35%) had a performance status ≥2. Patients received a median of 4 cycles of R-mini-CYVE. The objective response and the complete response rates were 50% and 33%, respectively. Median progression-free survival and overall survival times were 5.7 (95% CI: 0.5-10.9) and 14.7 (95% CI: 3.5-25.9) months, respectively. Grade ≥3 anaemia, thrombocytopenia and neutropenia occurred in 44%, 55% and 60% of the patients, respectively. The most frequent non-haematological grade ≥3 adverse events were sepsis (21%), fatigue (13%) and cytarabine-related neurotoxicity (5%). CONCLUSION: R-mini-CYVE demonstrated a meaningful antitumour efficacy and an acceptable safety profile in patients with relapsed/refractory B-cell NHL who were ineligible for HDT.

Poor predictive value of positive interim FDG-PET/CT in primary mediastinal large B-cell lymphoma.

PURPOSE: Though commonly used to assess response to therapy, the prognostic value of interim FDG-PET/CT in Primary Mediastinal Large B-cell Lymphoma (PMBCL) is unclear. METHODS: We conducted a retrospective study on 36 consecutive patients treated at our institution for a PMBCL between 2006 and 2014. All patients with a positive interim FDG-PET/CT had undergone histological restaging consisting either in a surgical debulking of the residual lesion (15 patients) or a CT-guided core needle biopsy (two patients). All FDG-PET/CT were secondarily reviewed according to the more recent Deauville criteria. RESULTS: Interim FDG-PET/CT was considered positive in 17/36 patients using visual evaluation. Among these patients, 14 had a Deauville score of 4. Histological restaging was negative in all but one case, showing inflammation and/or fibrosis. After a median follow-up of 48.5 months, a total of five patients have relapsed, two patients in the positive FDG-PET/CT group, and three patients in the negative FDG-PET/CT group, respectively. CONCLUSIONS: These data indicate that a positive interim FDG-PET/CT does not reflect persistence of active disease in the vast majority of PMBCL cases. The relapse rate appears similar regardless of interim FDG-PET/CT results and interpretation criteria. This suggests that interim FDG-PET/CT has a poor positive predictive value, thus kt should be used with caution in PMBCL.

Nodular lymphocyte predominant Hodgkin lymphoma: a Lymphoma Study Association retrospective study.

Nodular lymphocyte predominant Hodgkin lymphoma represents a distinct entity from classical Hodgkin lymphoma. We conducted a retrospective study to investigate the management of patients with nodular lymphocyte predominant Hodgkin lymphoma. Clinical characteristics, treatment and outcome of adult patients with nodular lymphocyte predominant Hodgkin lymphoma were collected in Lymphoma Study Association centers. Progression-free survival (PFS) and overall survival (OS) were analyzed, and the competing risks formulation of a Cox regression model was used to control the effect of risk factors on relapse or death as competing events. Among 314 evaluable patients, 82.5% had early stage nodular lymphocyte predominant Hodgkin lymphoma. Initial management consisted in watchful waiting (36.3%), radiotherapy (20.1%), rituximab (8.9%), chemotherapy or immuno-chemotherapy (21.7%), combined modality treatment (12.7%), or radiotherapy plus rituximab (0.3%). With a median follow-up of 55.8 months, the 10-year PFS and OS estimates were 44.2% and 94.9%, respectively. The 4-year PFS estimates were 79.6% after radiotherapy, 77.0% after rituximab alone, 78.8% after chemotherapy or immuno-chemotherapy, and 93.9% after combined modality treatment. For the whole population, early treatment with chemotherapy or radiotherapy, but not rituximab alone (Hazard ratio 0.695 [0.320-1.512], P=0.3593) significantly reduced the risk of progression compared to watchful waiting (HR 0.388 [0.234-0.643], P=0.0002). Early treatment appears more beneficial compared to watchful waiting in terms of progression-free survival, but has no impact on overall survival. Radiotherapy in selected early stage nodular lymphocyte predominant Hodgkin lymphoma, and combined modality treatment, chemotherapy or immuno-chemotherapy for other patients, are the main options to treat adult patients with a curative intent.

Upfront consolidation combining yttrium-90 ibritumomab tiuxetan and high-dose therapy with stem cell transplantation in poor-risk patients with diffuse large B cell lymphoma.

We evaluated the safety and efficacy of standard-dose yttrium-90 (Y(90)) ibritumomab tiuxetan combined with high-dose BEAM (carmustine, etoposide, cytarabine, and melphalan) after first-line induction treatment in young patients with poor prognoses diffuse large B cell lymphoma (DLBCL) (clinicaltrials.gov: NCT00689169). Seventy-five high-risk (≥2 International Prognostic Index [IPI] factors) consecutive DLBCL patients (≤65 years old) in complete remission (CR) or partial remission (PR) after rituximab chemotherapy were treated with Y(90) ibritumomab tiuxetan and BEAM regimen followed by autologous stem cell transplantation (ASCT). The median follow-up was 34 months. Of the 75 patients, 71 underwent ASCT and were eligible for analysis. Median time to reach a neutrophil count of >500/µL and platelet count of >20,000/µL was 11 days. Mucositis ≥3 (51%) occurred in most patients. Other adverse events were similar to those seen with BEAM alone. The overall response rate was 86%; 59 patients (83%) achieved a CR or unconfirmed CR. The 2-year event-free survival (EFS), overall survival (OS), and disease-free survival were 79%, 83%, and 91%, respectively. Disease status (CR/PR) and positron emission tomography (PET) findings before transplantation did not predict treatment failure. The IPI (2 versus >2) and maximum tumor diameter of ≥10 cm at diagnosis appeared to be prognosis factors for OS but not for EFS. Adding Y(90) ibritumomab tiuxetan to BEAM is safe and does not increase transplantation-related toxicity. First-line consolidation with Y(90) ibritumomab tiuxetan and high-dose chemotherapy induced high rates of EFS and OS in poor-prognosis patients with DLBCL, regardless of PET status after induction treatment and warrants a randomized study.

Dose-dense rituximab-CHOP compared with standard rituximab-CHOP in elderly patients with diffuse large B-cell lymphoma (the LNH03-6B study): a randomised phase 3 trial.

BACKGROUND: Immunochemotherapy with rituximab and cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) has become the standard of care for elderly patients with diffuse large B-cell lymphoma. We aimed to ascertain if a dose-dense R-CHOP regimen administered every 2 weeks (R-CHOP14) was superior to the standard 3-week schedule (R-CHOP21). METHODS: We did a randomised phase 3 trial at 83 centres in four countries. 602 patients aged 60-80 years with untreated diffuse large B-cell lymphoma and at least one adverse prognostic factor (age-adjusted international prognostic index ≥ 1) were eligible for the study. We randomly allocated individuals to R-CHOP-ie, rituximab (375 mg/m(2)), cyclophosphamide (750 mg/m(2)), doxorubicin (50 mg/m(2)), vincristine (1.4 mg/m(2), up to 2 mg) all on day 1, and prednisone 40 mg/m(2) daily for 5 days-administered every 14 days (n=304) or every 21 days (n=298) for eight cycles. We did permuted-block randomisation (block size four, allocation ratio 1:1) stratified by centre and number of adverse prognostic factors. The primary endpoint was event-free survival. Our analysis was of the intention-to-treat population, and we present the final analysis. This study is registered with ClinicalTrials.gov, number NCT00144755. FINDINGS: Two patients allocated R-CHOP21 were ineligible for the study and were excluded from analyses. After median follow-up of 56 months (IQR 27-60), 3-year event-free survival was 56% (95% CI 50-62) in the R-CHOP14 group and 60% (55-66) in the R-CHOP21 group (hazard ratio 1.04, 95% CI 0.82-1.31; p=0.7614). Grade 3-4 neutropenia occurred in 224 (74%) of 304 patients allocated R-CHOP14 and 189 (64%) of 296 assigned R-CHOP21, despite increased use of granulocyte colony-stimulating factor in the R-CHOP14 group compared with the R-CHOP21 group. 143 (47%) patients in the R-CHOP14 group received at least one red-blood-cell transfusion versus 93 (31%) in the R-CHOP21 group (p=0.0001). 35 (12%) patients allocated R-CHOP14 received at least one platelet transfusion versus 25 (8%) assigned R-CHOP21 (p=0.2156). 155 (51%) patients who were assigned R-CHOP14 had at least one serious adverse event compared with 140 (47%) who were allocated R-CHOP21. INTERPRETATION: In elderly patients with untreated diffuse large B-cell lymphoma and at least one adverse prognostic factor, a 2-week dose-dense R-CHOP regimen did not improve efficacy compared with the 3-week standard schedule. The frequency of toxic side-effects was similar between regimens, but R-CHOP14 was associated with increased need for red-blood-cell transfusion. FUNDING: Groupe d'Etude des Lymphomes de l'Adulte (GELA), Amgen.

Prognostic Value of Baseline Tumor Burden and Tumor Dissemination Extracted From 18 F-FDG PET/CT in a Cohort of Adult Patients With Early or Advanced Hodgkin Lymphoma.

PURPOSE: We aimed to assess the prognostic value of baseline tumor burden and dissemination parameters extracted from 18 F-FDG PET/CT in patients with early or advanced Hodgkin lymphoma (HL) treated with ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) or escalated BEACOPP (increased bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone). PATIENTS AND METHODS: Patients aged ≥18 years with classical Hodgkin lymphoma were retrospectively included. Progression-free survival (PFS) analysis of dichotomized clinicobiological and PET/CT parameters (SUV max , TMTV, TLG, D max , and D bulk ) was performed. Optimal cutoff values for quantitative metrics were defined as the values maximizing the Youden index from receiver operating characteristic analysis. PFS rates were estimated with Kaplan-Meier curves, and the log-rank test was used to assess statistical significance. Hazard ratios were calculated using Cox proportional hazards models. RESULTS: With a median age of 32 years, 166 patients were enrolled. A total of 111 patients had ABVD or ABVD-like treatment with or without radiotherapy and 55 patients with escalated BEACOPP treatment. The median follow-up was 55 months. Only International Prognostic Score (IPS >1), TMTV >107 cm 3 , and TLG >1628 were found to be significant prognostic factors for PFS on univariate analysis. Multivariate analysis revealed that IPS and TLG were independently prognostic and, combined, identified 4 risk groups ( P < 0.001): low (low TLG and low IPS; 4-year PFS, 95%), intermediate-low (high IPS and low TLG; 4-year PFS, 79%), intermediate-high (low IPS and high TLG; 4-year PFS, 78%), and high (high TLG and high IPS; 4-year PFS, 71%). CONCLUSIONS: Combining baseline TLG with IPS could improve PFS prediction.

Cytokine gene polymorphisms and progression-free survival in classical Hodgkin lymphoma by EBV status: results from two independent cohorts.

BACKGROUND: Cytokines are important immune mediators of classical Hodgkin lymphoma (CHL) pathogenesis, and circulating levels at diagnosis may help predict prognosis. Germline single nucleotide polymorphisms (SNPs) in immune genes have been correlated with cytokine production and function. METHODS: We investigated whether selected germline SNPs in IL10 (rs1800890, rs1800896, rs1800871, rs1800872), TNFA (rs1800629), IL6 (rs1800795), ILRN (rs419598), INFG (rs2430561) and CCL17 (rs223828) were associated with circulating levels of related cytokines at diagnosis and progression-free survival (PFS) in CHL. Patients were from France (GELA, N=464; median age=32years) and the United States (Iowa/Mayo Specialized Program Of Research Excellence [SPORE], N=239; median age=38years); 22% of 346 CHL cases with EBV tumor status were positive. RESULTS: There was no association with any of the SNPs with cytokine levels. Overall, there was no association of any of the SNPs with PFS. In exploratory analyses by EBV status, TNFA rs1800629 (HRAA/AG=2.41; 95%CI, 1.17-4.94) was associated with PFS in EBV-negative GELA patients, with similar trends in the SPORE patients (HRAA/AG=1.63; 95%CI, 0.61-4.40). In a meta-analysis of the two studies, TNFA (HRAA/AG=2.11; 95%CI, 1.18-3.77; P=0.01) was statistically significant, and further adjustment for the international prognostic system did not alter this result. CONCLUSIONS: This study showed that germline variation in TNFA was associated with CHL prognosis for EBV-negative patients, which will require confirmation. These results support broader studies on the differential impact of genetic variation in immune genes on EBV-positive vs. EBV-negative CHL pathogenesis.

Long-term follow up of the FL2000 study comparing CHVP-interferon to CHVP-interferon plus rituximab in follicular lymphoma.

Anti-CD20-containing chemotherapy regimens have become the standard of care for patients with follicular lymphoma needing cytotoxic therapy. Four randomized trials demonstrated a clinical benefit for patients treated with rituximab. However, no long-term follow up (i.e. > 5 years) of these trials is yet available. Between May 2000 and May 2002, 358 newly diagnosed patients with high tumor burden follicular lymphoma were randomized to receive cyclophosphamide, adriamycin, etoposide and prednisolone plus interferon-α2a or a similar chemotherapy-based regimen plus rituximab, and outcome was up-dated. With a median follow up of 8.3 years, addition of rituximab remained significantly associated with prolonged event-free survival (primary end point) (P=0.0004) with a trend towards a benefit for overall survival (P=0.076). The Follicular Lymphoma International Prognostic Index score was strongly associated with outcome for both event-free and overall survival in univariate analysis and its prognostic value remained highly significant after adjusting for other significant covariates in multivariate models (P<0.0001 and P=0.001, respectively). Considering long-term toxicity, the addition of rituximab in the first-line setting was confirmed as safe with regards to development of secondary malignancies. Long-term follow up of patients with follicular lymphoma treated in the FL2000 study confirms the sustained clinical benefit of rituximab without long-term toxicity.

Multicenter phase II study of plitidepsin in patients with relapsed/refractory non-Hodgkin's lymphoma.

This phase II clinical trial evaluated the efficacy, safety and pharmacokinetics of plitidepsin 3.2 mg/m(2) administered as a 1-hour intravenous infusion weekly on days 1, 8 and 15 every 4 weeks in 67 adult patients with relapsed/refractory aggressive non-Hodgkin's lymphoma. Patients were divided into two cohorts: those with non-cutaneous peripheral T-cell lymphoma (n=34) and those with other lymphomas (n=33). Efficacy was evaluated using the International Working Group criteria (1999). Of the 29 evaluable patients with non-cutaneous peripheral T-cell lymphoma, six had a response (overall response rate 20.7%; 95% confidence interval, 8.0%-39.7%), including two complete responses and four partial responses. No responses occurred in the 30 evaluable patients with other lymphomas (including 27 B-cell lymphomas). The most common plitidepsin-related adverse events were nausea, fatigue and myalgia (grade 3 in <10% of cases). Severe laboratory abnormalities (lymphopenia, anemia, thrombocytopenia, and increased levels of transaminase and creatine phosphokinase) were transient and easily managed by plitidepsin dose adjustments. The pharmacokinetic profile did not differ from that previously reported in patients with solid tumors. In conclusion, plitidepsin monotherapy has clinical activity in relapsed/refractory T-cell lymphomas. Combinations of plitidepsin with other chemotherapeutic drugs deserve further evaluation in patients with non-cutaneous peripheral T-cell lymphoma. (clinicaltrials.gov identifier: NCT00884286).

Classical Hodgkin's lymphoma: the Lymphoma Study Association guidelines for relapsed and refractory adult patients eligible for transplant.

The Hodgkin's Lymphoma Committee of the Lymphoma Study Association (LYSA) gathered in 2012 to prepare guidelines on the management of transplant-eligible patients with relapsing or refractory Hodgkin's lymphoma. The working group is made up of a multidisciplinary panel of experts with a significant background in Hodgkin's lymphoma. Each member of the panel of experts provided an interpretation of the evidence and a systematic approach to obtain consensus was used. Grades of recommendation were not required since levels of evidence are mainly based on phase II trials or standard practice. Data arising from randomized trials are emphasized. The final version was endorsed by the scientific council of the LYSA. The expert panel recommends a risk-adapted strategy (conventional treatment, or single/double transplantation and/or radiotherapy) based on three risk factors at progression (primary refractory disease, remission duration < 1 year, stage III/IV), and an early evaluation of salvage chemosensitivity, including (18)fluorodeoxy glucose-positron emission tomography interpreted according to the Deauville scoring system. Most relapsed or refractory Hodgkin's lymphoma patients chemosensitive to salvage should receive high-dose therapy and autologous stem-cell transplantation as standard. Efforts should be made to increase the proportion of chemosensitive patients by alternating non-cross-resistant chemotherapy lines or exploring the role of novel drugs.

Impact of rituximab on stem cell mobilization following ACVBP regimen in poor-risk patients with diffuse large B-cell lymphoma: results from a large cohort of patients.

BACKGROUND: The ACVBP regimen is an efficient induction regimen for poor-risk patients with diffuse large B-cell lymphoma (DLBCL) before consolidative autologous stem cell transplantation. Adjunction of the monoclonal anti-CD20 antibody rituximab (R-ACVBP) was recently found to be superior to ACVBP alone. This study assessed the impact of rituximab on stem cell mobilization in two similar consecutive groups of patients treated with ACVBP in two prospective, controlled trials. STUDY DESIGN AND METHODS: The first trial (LNH-98B-3) involved 137 patients treated with ACVBP alone. In the second trial (LNH-03-3B), 91 patients received an R-ACVBP regimen. Stem cell mobilization was performed after a course of (R)-ACVBP. RESULTS: The median peak numbers of blood CD34+ cell counts recorded before the first apheresis procedure in the ACVBP and R-ACVBP groups were 69×10(6) and 63×10(6) /L, respectively (p=0.55). The median numbers of CD34+ cells collected were 7.1×10(6) and 6.0×10(6) CD34+ cells/kg for the ACVBP and R-ACVBP groups, respectively (p=0.13). The median number of apheresis procedures required for gathering the minimum amount of CD34+ cells (2×10(6) /kg) was the same in the two groups. CONCLUSION: When compared with ACVBP alone, adjunction of rituximab does not impair stem cell mobilization.

[The history of Hodgkin lymphoma]. / Historique du lymphome de Hodgkin.

THE HISTORY OF HODGKIN LYMPHOMA. Hodgkin lymphoma was initially considered to be caused by infectious agents. The Hodgkin and Reed-Sternberg tumor cells are derived from mature B cells and transforming events were identified. Staging laparotomy has been discontinued for clinical evaluation with the progress of medical imaging. For seven decades, clinical trials have allowed to define risk factors, to improve standard treatments with the optimal use of chemotherapy and radiotherapy. A risk adapted strategy and early response to chemotherapy are mandatory to reduce long-term consequences of treatment.

HISTORIQUE DU LYMPHOME DE HODGKIN. Une origine infectieuse du lymphome de Hodgkin a été initialement suspectée. L'origine des cellules tumorales, les mécanismes oncogéniques permettant leur survie et leur prolifération sont de connaissance plus récente. Après l'abandon de la laparotomie exploratrice, les progrès de l'imagerie médicale ont été continus. Pendant sept décennies, les essais cliniques ont permis de définir les facteurs de risque, d'améliorer les traitements de référence avec une utilisation optimale de la chimiothérapie et de la radiothérapie. La stratégie adaptée au risque et à la réponse précoce à la chimiothérapie est nécessaire pour limiter les conséquences tardives des traitements.

Intensified chemotherapy with ACVBP plus rituximab versus standard CHOP plus rituximab for the treatment of diffuse large B-cell lymphoma (LNH03-2B): an open-label randomised phase 3 trial.

BACKGROUND: The outcome of diffuse large B-cell lymphoma has been substantially improved by the addition of the anti-CD20 monoclonal antibody rituximab to chemotherapy regimens. We aimed to assess, in patients aged 18-59 years, the potential survival benefit provided by a dose-intensive immunochemotherapy regimen plus rituximab compared with standard treatment plus rituximab. METHODS: We did an open-label randomised trial comparing dose-intensive rituximab, doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone (R-ACVBP) with subsequent consolidation versus standard rituximab, doxorubicin, cyclophosphamide, vincristine, and prednisone (R-CHOP). Random assignment was done with a computer-assisted randomisation-allocation sequence with a block size of four. Patients were aged 18-59 years with untreated diffuse large B-cell lymphoma and an age-adjusted international prognostic index equal to 1. Our primary endpoint was event-free survival. Our analyses of efficacy and safety were of the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00140595. FINDINGS: One patient withdrew consent before treatment and 54 did not complete treatment. After a median follow-up of 44 months, our 3-year estimate of event-free survival was 81% (95% CI 75-86) in the R-ACVBP group and 67% (59-73) in the R-CHOP group (hazard ratio [HR] 0·56, 95% CI 0·38-0·83; p=0·0035). 3-year estimates of progression-free survival (87% [95% CI, 81-91] vs 73% [66-79]; HR 0·48 [0·30-0·76]; p=0·0015) and overall survival (92% [87-95] vs 84% [77-89]; HR 0·44 [0·28-0·81]; p=0·0071) were also increased in the R-ACVBP group. 82 (42%) of 196 patients in the R-ACVBP group experienced a serious adverse event compared with 28 (15%) of 183 in the R-CHOP group. Grade 3-4 haematological toxic effects were more common in the R-ACVBP group, with a higher proportion of patients experiencing a febrile neutropenic episode (38% [75 of 196] vs 9% [16 of 183]). INTERPRETATION: Compared with standard R-CHOP, intensified immunochemotherapy with R-ACVBP significantly improves survival of patients aged 18-59 years with diffuse large B-cell lymphoma with low-intermediate risk according to the International Prognostic Index. Haematological toxic effects of the intensive regimen were raised but manageable. FUNDING: Groupe d'Etudes des Lymphomes de l'Adulte and Amgen.

Rituximab maintenance for 2 years in patients with high tumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): a phase 3, randomised controlled trial.

BACKGROUND: Patients with follicular lymphoma can have long survival times, but disease progression typically occurs 3-5 years after initial treatment. We assessed the potential benefit of 2 years of rituximab maintenance after first-line treatment in patients with follicular lymphoma receiving a rituximab plus chemotherapy regimen. METHODS: The randomised, open-label PRIMA study was undertaken in 223 centres in 25 countries. 1217 patients with previously untreated follicular lymphoma needing systemic therapy received one of three non-randomised immunochemotherapy induction regimens used in routine practice. 1019 patients achieving a complete or partial response were then randomly assigned to receive 2 years of rituximab maintenance therapy (375 mg/m(2) every 8 weeks) or observation. Treatment was assigned equally by centralised block randomisation, stratified by induction regimen, response, region, and centre. Neither the participants nor those giving the interventions, assessing outcomes, and analysing data were masked to group assignments. The primary endpoint was progression-free survival (PFS). Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00140582. FINDINGS: 505 patients were assigned to rituximab maintenance and 513 to observation (one patient died during randomisation). With a median follow-up of 36 months (IQR 30-42), PFS was 74·9% (95% CI 70·9-78·9) in the rituximab maintenance group (130 patients progressed) and 57·6% (53·2-62·0) in the observation group (218 progressed; hazard ratio [HR] 0·55, 95% CI 0·44-0·68, p<0·0001). 2 years after randomisation, 361 patients (71·5%) in the rituximab maintenance group were in complete or unconfirmed complete response versus 268 (52·2%) in the observation group (p=0·0001). Overall survival did not differ significantly between groups (HR 0·87, 95% CI 0·51-1·47). Grade 3 and 4 adverse events were recorded in 121 patients (24%) in the rituximab maintenance group and 84 (17%) in the observation group (risk ratio 1·46, 95% CI 1·14-1·87; p=0·0026). Infections (grades 2-4) were the most common adverse event, occurring in 197 (39%) and 123 (24%) patients, respectively (risk ratio 1·62, 95% CI 1·35-1·96; p<0·0001). INTERPRETATION: 2 years of rituximab maintenance therapy after immunochemotherapy as first-line treatment for follicular lymphoma significantly improves PFS. FUNDING: Groupe d'Etude des Lymphomes de l'Adulte (GELA) and F Hoffmann-La Roche.

Long-term outcome of patients in the LNH-98.5 trial, the first randomized study comparing rituximab-CHOP to standard CHOP chemotherapy in DLBCL patients: a study by the Groupe d'Etudes des Lymphomes de l'Adulte.

We report the outcome of patients included in the LNH-98.5 study, which compared cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) to rituximab plus CHOP (R-CHOP) therapy in 399 patients with diffuse large B-cell lymphoma (DLBCL) aged 60 to 80 years, with a median follow-up time of 10 years. Clinical event information was updated in all living patients (with the exception of 3 patients) in 2009. Survival end points were improved in patients treated with R-CHOP: the 10-year progression-free survival was 36.5%, compared with 20% with CHOP alone, and the 10-year overall survival was 43.5% compared with 27.6%. The same risk of death due to other diseases, secondary cancers, and late relapses was observed in both study arms. Relapses occurring after 5 years represented 7% of all disease progressions. The results from the 10-year analysis confirm the benefits and tolerability of the addition of rituximab to CHOP. Our findings underscore the need to treat elderly patients as young patients, with the use of curative chemotherapy.

Employment situation among long-term Hodgkin lymphoma survivors in Europe: an analysis of patients from nine consecutive EORTC-LYSA trials.

PURPOSE: Little is known about the employment situation of long-term Hodgkin lymphoma (HL) survivors despite their young age at diagnosis and the favorable prognosis of the disease. In this cross-sectional study, we aim to describe the employment situation in a cohort of long-term HL survivors compared to the general population and investigate the associations with disease characteristics and treatment exposure. METHODS: HL survivors > 25 years (n = 1961) were matched 1:25 to controls (n = 49,025) from the European Union Labour Force Survey. Individual treatment information was obtained from trial records. Employment and socio-demographic characteristics were collected using the Life Situation Questionnaire. Logistic regression models were used to estimate associations between disease and treatment characteristics with employment status and work-related attitudes. RESULTS: At employment assessment, 69.7% of survivors (95% CI: 67.6-71.7%) were working; of these, 68.9% (95% CI: 66.3-71.3%) worked full-time, a figure comparable to that of controls (p value 0.17). The risk of not working was associated with increasing age at diagnosis, increasing age at survey, female sex, lower educational level, and relapse history. Of those who were at work during treatment, 16.8% (95% CI: 14.5-19.3%) stated their income had subsequently decreased, which was attributed to their HL by 65.4% (95% CI: 57.5-72.8). Among those not at work, 25.1% (95% CI: 20.7-29.8) survivors were disabled compared to only 14.5% (95% CI: 13.8-15.3%) of controls. CONCLUSIONS: In this cohort of HL survivors, employment status was comparable to that of the general population. However, increasing age at follow-up, female sex, lower educational level, and relapse history are risk factors for unemployment, a perceived decrease in income, and disability. IMPLICATIONS FOR CANCER SURVIVORS: To further improve follow-up care, special attention should be paid to these vulnerable subgroups.

Management of fertility in patients treated for Hodgkin's lymphoma.

The risk of developing premature ovarian failure and azoospermia is a major concern in long-term survivors treated for Hodgkin's lymphoma. Alkylating chemotherapy containing procarbazine and/or cyclophosphamide causes prolonged azoospermia in 90-100% of men and premature ovarian failure in 5-25% of women under the age of 30. The risk of infertility increases with the cumulative dose of alkylating agents and the risk is high after salvage therapy including conditioning and autologous or allogeneic transplantation. The doxorubicin-bleomycin-vinblastine-dacarbazine regimen is associated with a lower risk of gonadal damage; the rate of infertility is less than 10%. The risk of premature ovarian failure is limited after the doxorubicin-bleomycin-vinblastine-dacarbazine regimen. However, age is an important factor; women over 30 years of age are at a much higher risk of ovarian failure. Semen cryopreservation should be routinely offered, especially before initial treatment with bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisolone or salvage therapy with high-dose chemotherapy and autologous transplantation. For women with a stable partner, in vitro fertilization for embryo cryopreservation is a routine procedure but can only be offered to a small number of patients and requires a delay in treatment initiation for at least four weeks. Cryopreservation of mature or immature oocytes remains experimental. Ovarian tissue cryopreservation is promising but has so far resulted in only a small number of pregnancies and births. This method, usually involving the removal of an entire ovary, is only proposed before treatment leading to a high risk of infertility. Analogs of LHRH were investigated in order to preserve fertility in women but are not recommended in the absence of studies demonstrating their effectiveness. The risk of secondary infertility should be discussed with patients from the time of the diagnosis and requires multidisciplinary collaboration between hematologists and Assisted Reproductive Techniques (ART) teams.