Obinutuzumab plus lenalidomide in advanced, previously untreated follicular lymphoma in need of systemic therapy: a LYSA study.

Obinutuzumab and lenalidomide (referred to as the GALEN combination) is an active immunomodulatory combination with a manageable safety profile in multiple types of lymphoma. We report efficacy and safety results for the phase 2 GALEN study in previously untreated patients with advanced follicular lymphoma (FL). Eligible patients aged ≥18 years had an Eastern Cooperative Oncology Group performance status ≤2 and high-tumor burden, grade 1 to 3a FL. Induction treatment was obinutuzumab (1000 mg IV, days 8, 15, and 22, cycle 1; day 1, cycles 2-6) plus lenalidomide (20 mg/d, days 1-21, cycle 1; days 2-22, cycles 2-6) for six 28-day cycles. Maintenance included obinutuzumab (1000 mg every 2 cycles) plus lenalidomide (10 mg, days 2-22) for ≤12 cycles (year 1) followed by obinutuzumab (1000 mg every 56 days) for 6 cycles (year 2). The primary end point was complete response rate (CRR) after induction per the 1999 International Working Group criteria. From October 2015 to February 2017, a total of 100 patients were enrolled. CRR after induction was 47%, and the overall response rate (ORR) was 92%. Post hoc analyses per the 2014 Lugano classification, including patients with missing bone marrow assessments, identified an additional 13 patients fulfilling CRR criteria, resulting in a complete metabolic response of 80% and an ORR of 94%. At a median follow-up of 3.7 years, 3-year progression-free survival and overall survival were 82% and 94%, respectively. The most common adverse event was neutropenia (48% any grade; 47% grade ≥3). Only 2% of patients presented with febrile neutropenia; others were mainly grade ≤2. No other specific grade ≥3 toxicity occurred at a frequency >3%. Overall, these results showed promising clinical efficacy for the chemotherapy-free GALEN backbone in previously untreated patients with high tumor burden FL. Except for neutropenia, the safety profile of the combination is remarkable. The study was registered at clinicaltrials.gov as #NCT01582776.

Lenalidomide maintenance fails to overcome the unfavourable prognosis of low NK-cell counts in rituximab-chemotherapy responsive elderly DLBCL patients: A LYSA group study.

Low baseline NK-cell counts (NKCCs) in patients with diffuse large B-cell lymphoma (DLBCL) are associated with a poor prognosis. The REMARC phase III trial (NCT01122472) showed that lenalidomide maintenance prolonged PFS in rituximab-chemotherapy responders. We conducted a REMARC ancillary study analysing the impact of lenalidomide maintenance on the prognostic value of low NKCCs. Blood samples from 335 elderly French patients enrolled in the REMARC trial were analysed by flow cytometry to obtain NKCCs at diagnosis (n = 220), at randomization (n = 186) and/or six months after randomization (n = 184). Baseline NKCCs < 100 cells/µl were associated with shorter PFS and OS (HRs = [2.2 (1.4, 3.3), p < 0.001] and [2.8 (1.7, 4.5), p < 0.001], respectively), independently of aaIPI. In a competing risk analysis, low NKCCs at baseline were associated with a higher risk of relapse/progression (p = 0.0025), but not of death without progression (p = 0.33). Lenalidomide did not affect the prognosis value of low baseline NKCCs (p  = 0.6349). Similar results were obtained for low NKCCs at randomization. Our results demonstrate that low NKCCs at baseline and post rituximab-chemotherapy are robust prognostic factors in DLBCL and reveal that lenalidomide has no impact on this parameter. Other therapeutic strategies aiming at improving NK-cell function could improve outcomes in DLBCL.

Prognostic relevance of sarcopenia, geriatric, and nutritional assessments in older patients with diffuse large B-cell lymphoma: results of a multicentric prospective cohort study.

This prospective study aimed to investigate the prognostic effect of sarcopenia, geriatric, and nutritional status in older patients with diffuse large B-cell lymphoma (DLBCL). Ninety-five patients with DLBCL older than 70 years who were treated with immunochemotherapy were included. The lumbar L3 skeletal muscle index (L3-SMI) was measured by computed tomography at baseline, and sarcopenia was defined as low L3-SMI. Geriatric assessment included G8 score, CIRS-G scale, Timed Up and Go test, and instrumental activity of daily living. Nutritional status was assessed using the Mini Nutritional Assessment and the body mass index, and several scores used in the literature incorporating nutritional and inflammatory biomarkers, namely the Nutritional and inflammatory status (NIS), Geriatric Nutritional Risk Index, Prognostic Nutritional Index, and Glasgow Prognostic Score.Fifty-three patients were considered sarcopenic. Sarcopenic patients displayed higher levels of inflammation markers and lower levels of prealbumin than non-sarcopenic patients. Sarcopenia was associated with NIS, but was not associated with severe adverse events and treatment disruptions. They were, however, more frequent among patients with elevated NIS. Sarcopenia did not appear in this study as a prognostic factor for progression-free survival (PFS) or overall survival (OS). However, NIS emerged as predictive of the outcome with a 2-year PFS rate of 88% in the NIS ≤ 1 group and 49% in the NIS > 1 group and a significant effect in a multivariate analysis for both PFS (p = 0.049) and OS (HR = 9.61, CI 95% = [1.03-89.66], p = 0.04). Sarcopenia was not associated with adverse outcomes, but was related to NIS, which appeared to be an independent prognostic factor.

High total metabolic tumor volume at baseline predicts survival independent of response to therapy.

Early identification of ultra-risk diffuse large B-cell lymphoma (DLBCL) patients is needed to aid stratification to innovative treatment. Previous studies suggested high baseline total metabolic tumor volume (TMTV) negatively impacts survival of DLBCL patients. We analyzed the prognostic impact of TMTV and prognostic indices in DLBCL patients, aged 60 to 80 years, from the phase 3 REMARC study that randomized responding patients to R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) into maintenance lenalidomide or placebo. TMTV was computed on baseline positron emission tomography/computed tomography using the 41% maximum standardized uptake value method; the optimal TMTV cutoff for progression-free (PFS) and overall survival (OS) was determined and confirmed by a training validation method. There were 301 out of 650 evaluable patients, including 192 patients classified as germinal center B-cell-like (GCB)/non-GCB and MYC/BCL2 expressor. Median baseline TMTV was 238 cm3; optimal TMTV cutoff was 220 cm3. Patients with high vs low TMTV showed worse/higher Eastern Cooperative Oncology Group performance status (ECOG PS) ≥2, stage III or IV disease, >1 extranodal site, elevated lactate dehydrogenase, International Prognostic Index (IPI) 3-5, and age-adjusted IPI 2-3. High vs low TMTV significantly impacted PFS and OS, independent of maintenance treatment. Although the GCB/non-GCB profile and MYC expression did not correlate with TMTV/survival, BCL2 >70% impacted PFS and could be stratified by TMTV. Multivariate analysis identified baseline TMTV and ECOG PS as independently associated with PFS and OS. Even in responding patients, after R-CHOP, high baseline TMTV was a strong prognosticator of inferior PFS and OS. Moreover, TMTV combined with ECOG PS may identify an ultra-risk DLBCL population. This trial was registered at www.clinicaltrials.gov as #NCT01122472.

Rituximab plus Lenalidomide in Advanced Untreated Follicular Lymphoma.

BACKGROUND: Rituximab plus chemotherapy has been shown to be effective in patients with advanced-stage, previously untreated follicular lymphoma; nevertheless, most patients will have a relapse. Combination immunotherapy with lenalidomide and rituximab is an immunomodulatory regimen that has shown promising activity in patients with indolent B-cell non-Hodgkin's lymphoma. METHODS: We conducted this multicenter, international, phase 3 superiority trial to evaluate rituximab plus lenalidomide, as compared with rituximab plus chemotherapy, in patients with previously untreated follicular lymphoma. Patients were randomly assigned to receive one of the two regimens, followed by maintenance monotherapy with rituximab. Treatment with rituximab plus lenalidomide consisted of 18 cycles of the two drugs, followed by rituximab maintenance therapy every 8 weeks for 12 cycles (six additional doses). Treatment with rituximab plus chemotherapy consisted of the investigator's choice of one of three rituximab-based regimens, followed by maintenance monotherapy with rituximab every 8 weeks for 12 cycles. The primary end points were complete response (confirmed or unconfirmed) at 120 weeks and progression-free survival. RESULTS: A total of 1030 patients were randomly assigned to receive rituximab plus lenalidomide (513 patients) or rituximab plus chemotherapy (517 patients). The rate of confirmed or unconfirmed complete response at 120 weeks was similar in the two groups: 48% (95% confidence interval [CI], 44 to 53) in the rituximab-lenalidomide group and 53% (95% CI, 49 to 57) in the rituximab-chemotherapy group (P=0.13). The interim 3-year rate of progression-free survival was 77% (95% CI, 72 to 80) and 78% (95% CI, 74 to 82), respectively. A higher percentage of patients in the rituximab-chemotherapy group had grade 3 or 4 neutropenia (32% vs. 50%) and febrile neutropenia of any grade (2% vs. 7%), and a higher percentage of patients in the rituximab-lenalidomide group had grade 3 or 4 cutaneous reactions (7% vs. 1%). CONCLUSIONS: Among patients with previously untreated follicular lymphoma, efficacy results were similar with rituximab plus lenalidomide and rituximab plus chemotherapy (with both regimens followed by rituximab maintenance therapy). The safety profile differed in the two groups. (Funded by Celgene; RELEVANCE ClinicalTrials.gov numbers, NCT01476787 and NCT01650701 , and EudraCT number, 2011-002792-42 .).

Lenalidomide maintenance for diffuse large B-cell lymphoma patients responding to R-CHOP: quality of life, dosing, and safety results from the randomised controlled REMARC study.

Lenalidomide maintenance therapy prolonged progression-free survival (PFS) versus placebo in elderly patients with diffuse large B-cell lymphoma (DLBCL) responding to induction chemotherapy in the phase 3 REMARC study. This subpopulation analysis assessed the impact of lenalidomide maintenance and treatment-emergent adverse events (TEAEs) on health-related quality of life (HRQOL). Global health status (GHS), and physical functioning and fatigue subscales were evaluated in patients who completed the European Organisation for Research and Treatment of Cancer quality-of-life questionnaire-C30 v3.0. The impact of TEAEs classified post hoc as subjective (patients can feel) or observable (only measurable by physicians) on dose reductions and discontinuations was assessed. Among 457 patients (lenalidomide, n = 229; placebo, n = 228), mean (standard deviation) GHS was similar between treatment arms [68·2 (20·7) Versus 72·0 (17·8)] at randomisation and remained similar during maintenance. Patients receiving lenalidomide experienced no meaningful changes in GHS, physical functioning, or fatigue. Observable TEAEs were more common (81·1% Versus 66·3%) and more likely to lead to dose reductions, than subjective TEAEs in both arms. PFS was superior in the lenalidomide arm regardless of dose reduction. Lenalidomide maintenance prolonged PFS and did not negatively impact HRQOL in patients with DLBCL despite TEAEs being more common, when compared with placebo.

Baseline 18F-FDG PET radiomic features as predictors of 2-year event-free survival in diffuse large B cell lymphomas treated with immunochemotherapy.

OBJECTIVES: To explore the prognostic value of positron emission tomography (PET) radiomic features in the field of diffuse large B cell lymphoma (DLBCL) treated with a first-line immunochemotherapy. METHODS: One-hundred thirty-two patients newly diagnosed with DLBCL were retrospectively included. PET studies were reconstructed using an ordered subset expectation maximisation algorithm with point spread function modelling. The total metabolic tumour volume (MTV) was recorded for each patient, and the volume of interest structure of the largest target lesion was used to compute 18F-FDG textural parameters. Data was randomly split into training and validation datasets. Optimal cutoff values were determined by means of 2-year event-free survival (EFS) ROC analyses. Two-year EFS analyses were performed using Kaplan-Meier survival analyses and univariable and multivariable Cox regression models. RESULTS: The median follow-up was 27 months, and the 2-year event-free survival (2y-EFS) was 77.3% in the entire population. ROC analyses for the 2y-EFS reached statistical significance for total MTV as well as four second-order metrics (homogeneity, contrast, correlation, dissimilarity) and five third-order metrics (LZE (Long-Zone Emphasis), LZLGE (Long-Zone Low-Grey Level Emphasis), LZHGE (Long-Zone High-Grey Level Emphasis), GLNU (Grey-Level Non-Uniformity) and ZP (Zone Percentage)). LZHGE displayed the highest ROC analysis accuracy (acc. = 0.76) and the best discriminant value on univariable Kaplan-Meier analysis (p < 0.0001, HR = 4.54). On multivariable analysis, including IPIaa, total MTV and LZHGE, LZHGE was the only independent predictor of 2y-EFS. These results were confirmed on the validation dataset. CONCLUSIONS: Baseline 18F-FDG PET heterogeneity of the largest lymphoma lesion is a promising predictor of 2y-EFS in newly diagnosed DLBCL treated with immunochemotherapy. KEY POINTS: •18F-FDG metabolic heterogeneity emerges as a new tool for survival prognostication of patients and has been explored in many solid tumours with promising results. • Baseline18F-FDG PET heterogeneity of the largest lymphoma lesion is an independent predictor of 2y-EFS in newly diagnosed DLBCL treated with immunochemotherapy. • DLBCL patients presenting with a heterogeneous tumour displayed a worse prognosis.

Bendamustine and rituximab in elderly patients with low-tumour burden follicular lymphoma. Results of the LYSA phase II BRIEF study.

The treatment of low-tumour burden follicular lymphoma (LTBFL) remains a challenge. Rituximab-based strategies may be improved by adding chemotherapy. This Lymphoma Study Association multicentre phase II study assessed rituximab and bendamustine in 63 patients with untreated LTBFL who were aged over 60 years old and had a follicular lymphoma International Prognostic Index (FLIPI) score ≥2. Induction comprised 4 weekly cycles of rituximab 375 mg/m2 intravenously combined with 2 cycles of bendamustine 90 mg/m2 days 1-2 with a 28-day interval, followed by twelve cycles of 375 mg/m2 rituximab maintenance therapy every 8 weeks. The primary endpoint was complete response (CR)/unconfirmed CR (CRu), at 12 weeks. Median age was 67·4 years and median FLIPI was 3. Ultimately, 18 patients (29%) had high tumour burden according to Groupe d'Etude des Lymphomes Folliculaires criteria. The 12-week CR/CRu rate was 54·0% and the overall response rate was 93·7%. Surprisingly, 3 patients died during maintenance (2 sepsis, 1 neoplasm). Progression-free survival was 85·4% at 24 months. In LTBFL patients with FLIPI ≥2, two cycles of rituximab and bendamustine result in a CR rate of 54·0%. However, the treatment-related deaths observed do not allow this regimen to be recommended for LTBFL patients aged over 60 years. EudraCT: 2010-020757-14; ClinicalTrials.gov: NCT01313611.

Diagnostic and prognostic value of baseline FDG PET/CT skeletal textural features in diffuse large B cell lymphoma.

PURPOSE: Our purpose was to evaluate the diagnostic and prognostic value of skeletal textural features (TFs) on baseline FDG PET in diffuse large B cell lymphoma (DLBCL) patients. METHODS: Eighty-two patients with DLBCL who underwent a bone marrow biopsy (BMB) and a PET scan between December 2008 and December 2015 were included. Two readers blinded to the BMB results visually assessed PET images for bone marrow involvement (BMI) in consensus, and a third observer drew a volume of interest (VOI) encompassing the axial skeleton and the pelvis, which was used to assess skeletal TFs. ROC analysis was used to determine the best TF able to diagnose BMI among four first-order, six second-order and 11 third-order metrics, which was then compared for diagnosis and prognosis in disease-free patients (BMB-/PET-) versus patients considered to have BMI (BMB+/PET-, BMB-/PET+, and BMB+/PET+). RESULTS: Twenty-two out of 82 patients (26.8%) had BMI: 13 BMB-/PET+, eight BMB+/PET+ and one BMB+/PET-. Among the nine BMB+ patients, one had discordant BMI identified by both visual and TF PET assessment. ROC analysis showed that SkewnessH, a first-order metric, was the best parameter for identifying BMI with sensitivity and specificity of 81.8% and 81.7%, respectively. SkewnessH demonstrated better discriminative power over BMB and PET visual analysis for patient stratification: hazard ratios (HR), 3.78 (P = 0.02) versus 2.81 (P = 0.06) for overall survival (OS) and HR, 3.17 (P = 0.03) versus 1.26 (P = 0.70) for progression-free survival (PFS). In multivariate analysis accounting for IPI score, bulky status, haemoglobin and SkewnessH, the only independent predictor of OS was the IPI score, while the only independent predictor of PFS was SkewnessH. CONCLUSION: The better discriminative power of skeletal heterogeneity for risk stratification compared to BMB and PET visual analysis in the overall population, and more specifically in BMB-/PET- patients, suggests that it can be useful to identify diagnostically overlooked BMI.

Correction to: Diagnostic and prognostic value of baseline FDG PET/CT skeletal textural features in diffuse large B cell lymphoma.

The formulae for Dice and Jaccard indices used to assess volumes concordance should read as follows.

Assessment of alteration in liver 18F-FDG uptake due to steatosis in lymphoma patients and its impact on the Deauville score.

AIM: Our aim was (1) to evaluate the prevalence of steatosis in lymphoma patients and its evolution during treatment; (2) to evaluate the impact of hepatic steatosis on 18F-FDG liver uptake; and (3) to study how hepatic steatosis affects the Deauville score (DS) for discriminating between responders and non-responders. METHODS: Over a 1-year period, 358 PET scans from 227 patients [122 diffuse large B cell lymphoma (DLBCL), 57 Hodgkin lymphoma (HL) and 48 Follicular lymphoma (FL)] referred for baseline (n = 143), interim (n = 79) and end-of-treatment (EoT, n = 136) PET scans were reviewed. Steatosis was diagnosed on the unenhanced CT part of PET/CT examinations using a cut-off value of 42 Hounsfield units (HU). EARL-compliant SULmax were recorded on the liver and the tumour target lesion. DS were then computed. RESULTS: Prevalence of steatosis at baseline, interim and EoT PET was 15/143 (10.5%), 6/79 (7.6%) and 16/136 (11.8%), respectively (p = 0.62).Ten out of 27 steatotic patients (37.0%) displayed a steatotic liver on all examinations. Six patients (22.2%) had a disappearance of hepatic steatosis during their time-course of treatment. Only one patient developed steatosis during his course of treatment. Liver SULmax values were significantly lower in the steatosis versus non-steatotic groups of patients for interim (1.66 ± 0.36 versus 2.15 ± 0.27) and EoT (1.67 ± 0.29 versus 2.17 ± 0.30) PET. CT density was found to be an independent factor that correlated with liver SULmax, while BMI, blood glucose level and the type of chemotherapy regimen were not. Using a method based on this correlation to correct liver SULmax, all DS4 steatotic patients on interim (n = 1) and EoT (n = 2) PET moved to DS3. CONCLUSIONS: Steatosis is actually a theoretical but not practical issue in most patients but should be recognised and corrected in appropriate cases, namely, for those patients scored DS4 with a percentage difference between the target lesion and the liver background lower than 30%.

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.

Challenges for quality and utilization of real-world data for diffuse large B-cell lymphoma in REALYSA, a LYSA cohort.

ABSTRACT: Real-world data (RWD) are essential to complement clinical trial (CT) data, but major challenges remain, such as data quality. REal world dAta in LYmphoma and Survival in Adults (REALYSA) is a prospective noninterventional multicentric cohort started in 2018 that included patients newly diagnosed with lymphoma in France. Herein is a proof-of-concept analysis on patients with first-line diffuse large B-cell lymphoma (DLBCL) to (1) evaluate the capacity of the cohort to provide robust data through a multistep validation process; (2) assess the consistency of the results; and (3) conduct an exploratory transportability assessment of 2 recent phase 3 CTs (POLARIX and SENIOR). The analysis population comprised 645 patients with DLBCL included before 31 March 2021 who received immunochemotherapy and for whom 3589 queries were generated, resulting in high data completeness (<4% missing data). Median age was 66 years, with mostly advanced-stage disease and high international prognostic index (IPI) score. Treatments were mostly rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine, and prednisone (R-CHOP 75%) and reduced dose R-CHOP (13%). Estimated 1-year event-free survival (EFS) and overall survival rates were 77.9% and 90.0%, respectively (median follow-up, 9.9 months). Regarding transportability, when applying the CT's main inclusion criteria (age, performance status, and IPI), outcomes seemed comparable between patients in REALYSA and standard arms of POLARIX (1-year progression-free survival 79.8% vs 79.8%) and SENIOR (1-year EFS, 64.5% vs 60.0%). With its rigorous data validation process, REALYSA provides high-quality RWD, thus constituting a platform for numerous scientific purposes. The REALYSA study was registered at www.clinicaltrials.gov as #NCT03869619.

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.

Bortezomib and high-dose melphalan as conditioning regimen before autologous stem cell transplantation in patients with de novo multiple myeloma: a phase 2 study of the Intergroupe Francophone du Myelome (IFM).

Autologous stem cell transplantation (ASCT) is recommended for younger patients with newly diagnosed multiple myeloma. Achieving complete response (CR) or at least very good partial response (VGPR) is a major prognostic factor for survival with 20% to 30% of patients achieving CR after ASCT. Bortezomib has shown synergistic effects with melphalan and no prolonged hematologic toxicity. In this Intergroupe Francophone du Myélome (IFM) phase 2 study, 54 untreated patients were enrolled between July and December 2007 to receive bortezomib (1 mg/m(2) x 4) and melphalan (200 mg/m(2)) as conditioning regimen (Bor-HDM). Overall, 70% of patients achieved at least VGPR, including 17 patients with CR (32%) after ASCT. No toxic deaths were observed. Bortezomib did not increase hematologic toxicity. Only 1 grade 3 to 4 peripheral neuropathy was reported. A matched control analysis was conducted comparing our cohort with patients from the IFM 2005-01 trial (HDM alone). Patients were matched for response to induction therapy and type of induction: CR was higher in the Bor-HDM group (35% vs 11%; P = .001), regardless of induction therapy. These results suggest that Bor-HDM is a safe and promising conditioning regimen. Randomized studies are needed to assess whether this conditioning regimen is superior to HDM alone. This trial was registered at www.clinicaltrials.gov as NCT00642395.

Attenuated immunochemotherapy regimen (R-miniCHOP) in elderly patients older than 80 years with diffuse large B-cell lymphoma: a multicentre, single-arm, phase 2 trial.

BACKGROUND: Diffuse large B-cell lymphoma is a common cancer in elderly patients. Although treatment has been standardised in younger patients, no prospective study has been done in patients over 80 years old. We aimed to investigate the efficacy and safety of a decreased dose of CHOP (doxorubicin, cyclophosphamide, vincristine, and prednisone) chemotherapy with a conventional dose of rituximab in elderly patients with diffuse large B-cell lymphoma. METHODS: We did a prospective, multicentre, single-arm, phase 2 study of patients aged over 80 years who had diffuse large B-cell lymphoma. Patients were included from 38 centres in France and Belgium. All patients received six cycles of rituximab combined with low-dose CHOP (R-miniCHOP) at 3-week intervals. Patients received 375 mg/m(2) rituximab, 400 mg/m(2) cyclophosphamide, 25 mg/m(2) doxorubicin, and 1 mg vincristine on day 1 of each cycle, and 40 mg/m(2) prednisone on days 1-5. The primary endpoint was overall survival, both unadjusted and adjusted for treatment and baseline prognostic factors. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, NCT01087424. FINDINGS: 150 patients were enrolled between Jan 9, 2006, and Jan 23, 2009 and 149 were included in the intention-to-treat analyses. Median age was 83 years (range 80-95). After a median follow-up of 20 months (range 0-45), the median overall survival was 29 months (95% CI 21 to upper limit not reached); 2-year overall survival was 59% (49-67%). In multivariate analyses, overall survival was only affected by a serum albumin concentration of 35 g/L or less (hazard ratio 3·2, 95% CI 1·4-7·1; p=0·0053). Median progression-free survival was 21 months (95% CI 13 to upper limit not reached), with a 2-year progression free survival of 47% (38-56). 58 deaths were reported, 33 of which were secondary to lymphoma progression. 12 deaths were attributed to toxicity of the treatment. The most frequent side-effect was haematological toxicity (grade ≥3 neutropenia in 59 patients; febrile neutropenia in 11 patients). INTERPRETATION: R-miniCHOP offers a good compromise between efficacy and safety in patients aged over 80 years old. R-miniCHOP should be considered as the new standard treatment in this subgroup of patients. FUNDING: Groupe d'Etude des Lymphomes de l'Adulte (GELA).

Ibrutinib Associated with Rituximab-Platinum Salt-Based Immunochemotherapy in B-Cell Lymphomas: Results of a Phase 1b-II Study of the LYSA Group.

In the post-rituximab era, patients with relapsed/refractory non-Hodgkin B-cell lymphoma (R/R B-NHL) responding to a platinum salt-based salvage regimen can potentially be cured after intensification followed by autologous stem cell transplantation, with the quality of the response to salvage predicting survival. The Bruton tyrosine kinase inhibitor ibrutinib, given as monotherapy or combined with other molecules, has proven effective in numerous B-cell lymphomas. To evaluate the safety of the combination of ibrutinib, rituximab, dexamethasone, and cytarabine with either cisplatin (R-DHAP) or oxaliplatin (R-DHAOx), we conducted a multicenter Phase 1b-II study in transplant-eligible R/R B-NHL patients, with ibrutinib given using a 3-by-3 dose-escalation design. The combination of R-DHAP and ibrutinib (given from Day 1 to Day 21 of each cycle) was associated with dose-limiting hematological, infectious, and renal toxicities, while we were unable to reach a dose to recommend for Phase II. R-DHAOx could only be combined with a daily dosage of 280 mg ibrutinib when administered continuously. R-DHAP combined with intermittent ibrutinib administration (from Day 5 to Day 18) was found to be highly toxic. On the other hand, when this administration schedule was combined with R-DHAOx, ibrutinib dosing could be increased up to 560 mg but with relevant toxicities. Despite a strong rationale for combining ibrutinib and R-DHAP/R-DHAOx, as both target lymphoma B-cells by different mechanisms, this approach was limited by significant toxicities.

Outcomes of older patients with diffuse large B-cell lymphoma treated with R-CHOP: 10-year follow-up of the LNH03-6B trial.

The LNH03-6B trial was a phase 3 randomized trial evaluating the efficacy of first-line rituximab, cyclophosphamide, doxorubicine, vincristine and prednisone (R-CHOP) delivered every 2 weeks (R-CHOP14) or 3 weeks (R-CHOP21) in patients with diffuse large B-cell lymphoma (DLBCL) aged 60 to 80 years with an aaIPI (age-adjusted International Prognostic Index) score ≥1 (registered as NCT00144755). We implemented a prospective long-term follow-up program at the end of this trial. The primary endpoints were progression-free survival (PFS) and overall survival (OS). Relapse patterns, PFS and OS after the first progression (PFS2 and OS2) were secondary endpoints. LNH03-6B was registered with ClinicalTrials.gov #NCT00144755. In the LNH03-6B trial, 304 and 296 patients were assigned to receive 8 cycles of R-CHOP14 or R-CHOP21, respectively. Long-term follow-up data were investigated for 256 of 384 (67%) patients still alive at the primary analysis. With a median follow-up of 10.1 years, 213 patients progressed, and 140 patients died without progression. The 10-year PFS was 40.4% (95% confidence interval, 35.9-44.9). Ten-year OS was based on 302 deaths and estimated at 50% (43-56). Of the 213 patients, 105 (49%) progressed after second-line therapy, and 77 patients died without a second progression (36%). The 1-year PFS2 and 1-year OS2 were estimated at 37.9% (95% confidence interval, 31.4-44.5) and 55.8% (95% confidence interval, 48.8-62.2), respectively. Ten years after randomization, the outcomes of patients treated for DLBCL were similar according to PFS and OS between the RCHOP-14 and R-CHOP21 groups. Progression or relapse led to poor prognosis after second-line chemotherapy in the pre CAR-T-cell era. Novel approaches in first-line and alternative treatments in second-line treatments are warranted in this population.