Patient outcomes are poor for aggressive B-cell non-Hodgkin's lymphomas not responding to or progressing within 12 months after first-line therapy. Tisagenlecleucel is an anti-CD19 chimeric antigen ...receptor T-cell therapy approved for diffuse large B-cell lymphoma after at least two treatment lines.
We conducted an international phase 3 trial involving patients with aggressive lymphoma that was refractory to or progressing within 12 months after first-line therapy. Patients were randomly assigned to receive tisagenlecleucel with optional bridging therapy (tisagenlecleucel group) or salvage chemotherapy and autologous hematopoietic stem-cell transplantation (HSCT) (standard-care group). The primary end point was event-free survival, defined as the time from randomization to stable or progressive disease at or after the week 12 assessment or death. Crossover to receive tisagenlecleucel was allowed if a defined event occurred at or after the week 12 assessment. Other end points included response and safety.
A total of 322 patients underwent randomization. At baseline, the percentage of patients with high-grade lymphomas was higher in the tisagenlecleucel group than in the standard-care group (24.1% vs. 16.9%), as was the percentage with an International Prognostic Index score (range, 0 to 5, with higher scores indicating a worse prognosis) of 2 or higher (65.4% vs. 57.5%). A total of 95.7% of the patients in the tisagenlecleucel group received tisagenlecleucel; 32.5% of the patients in the standard-care group received autologous HSCT. The median time from leukapheresis to tisagenlecleucel infusion was 52 days. A total of 25.9% of the patients in the tisagenlecleucel group had lymphoma progression at week 6, as compared with 13.8% of those in the standard-care group. The median event-free survival in both groups was 3.0 months (hazard ratio for event or death in the tisagenlecleucel group, 1.07; 95% confidence interval, 0.82 to 1.40; P = 0.61). A response occurred in 46.3% of the patients in the tisagenlecleucel group and in 42.5% in the standard-care group. Ten patients in the tisagenlecleucel group and 13 in the standard-care group died from adverse events.
Tisagenlecleucel was not superior to standard salvage therapy in this trial. Additional studies are needed to assess which patients may obtain the most benefit from each approach. (Funded by Novartis; BELINDA ClinicalTrials.gov number, NCT03570892.).
Bruton tyrosine kinase is a clinically validated target in mantle cell lymphoma. Acalabrutinib (ACP-196) is a highly selective, potent Bruton tyrosine kinase inhibitor developed to minimise ...off-target activity.
In this open-label, phase 2 study, oral acalabrutinib (100 mg twice per day) was given to patients with relapsed or refractory mantle cell lymphoma, until disease progression or unacceptable toxicity. The primary endpoint was overall response assessed according to the Lugano classification, and safety analyses were done in all participants. This trial is registered with ClinicalTrials.gov, number NCT02213926.
From March 12, 2015, to Jan 5, 2016, 124 patients with relapsed or refractory mantle cell lymphoma were enrolled and all patients received treatment; median age 68 years. Patients received a median of two (IQR 1–2) previous therapies. At a median follow-up of 15·2 months, 100 (81%) patients achieved an overall response and 49 (40%) patients achieved a complete response. The Kaplan-Meier estimated medians for duration of response, progression-free survival, and overall survival were not reached; the 12-month rates were 72% (95% CI 62–80), 67% (58–75), and 87% (79–92%), respectively. The most common adverse events were primarily grade 1 or 2 and were headache (47 38%), diarrhoea (38 31%), fatigue (34 27%), and myalgia (26 21%). The most common grade 3 or worse adverse events were neutropenia (13 10%), anaemia (11 9%), and pneumonia (six 5%). There were no cases of atrial fibrillation and one case of grade 3 or worse haemorrhage. The median duration of treatment was 13·8 months. Treatment was discontinued in 54 (44%) patients, primarily due to progressive disease (39 31%) and adverse events (seven 6%).
Acalabrutinib treatment provided a high rate of durable responses and a favourable safety profile in patients with relapsed or refractory mantle cell lymphoma. These findings suggest an important role for acalabrutinib in the treatment of this disease population.
Acerta Pharma, a member of the AstraZeneca Group.
Mantle-cell lymphoma is generally incurable. Despite high rates of complete response after initial immunochemotherapy followed by autologous stem-cell transplantation, patients have relapses. We ...investigated whether rituximab maintenance therapy at a dose of 375 mg per square meter of body-surface area administered every 2 months for 3 years after transplantation would prolong the duration of response.
In a phase 3 trial involving 299 patients who were younger than 66 years of age at diagnosis, we randomly assigned 240 patients to receive rituximab maintenance therapy or to undergo observation after autologous stem-cell transplantation (120 patients per group); 59 patients did not undergo randomization. The primary end point was event-free survival (with an event defined as disease progression, relapse, death, allergy to rituximab, or severe infection) after transplantation among patients who underwent randomization.
After four courses of immunochemotherapy induction (rituximab, dexamethasone, cytarabine, and a platinum derivative R-DHAP), the overall response rate was 89%, and the complete response rate 77%. Transplantation was performed in 257 patients. The median follow-up from randomization after transplantation was 50.2 months (range, 46.4 to 54.2). Starting from randomization, the rate of event-free survival at 4 years was 79% (95% confidence interval CI, 70 to 86) in the rituximab group versus 61% (95% CI, 51 to 70) in the observation group (P=0.001). The rate of progression-free survival at 4 years was 83% (95% CI, 73 to 88) in the rituximab group versus 64% (95% CI, 55 to 73) in the observation group (P<0.001). The rate of overall survival was 89% (95% CI, 81 to 94) in the rituximab group versus 80% (95% CI, 72 to 88) in the observation group (P=0.04). According to a Cox regression unadjusted analysis, the rate of overall survival at 4 years was higher in the rituximab group than in the observation group (hazard ratio for death, 0.50; 95% CI, 0.26 to 0.99; P=0.04).
Rituximab maintenance therapy after transplantation prolonged event-free survival, progression-free survival, and overall survival among patients with mantle-cell lymphoma who were younger than 66 years of age at diagnosis. (Funded by Roche and Amgen; LyMa ClinicalTrials.gov number, NCT00921414 .).
Summary Background Short intensive chemotherapy is the standard of care for adult patients with Burkitt's leukaemia or lymphoma. Findings from single-arm studies suggest that addition of rituximab to ...these regimens could improve patient outcomes. Our objective was to test this possibility in a randomised trial. Methods In this randomised, controlled, open-label, phase 3 trial, we recruited patients older than 18 years with untreated HIV-negative Burkitt's lymphoma (including Burkitt's leukaemia) from 45 haematological centres in France. Exclusion criteria were contraindications to any drug included in the chemotherapy regimens, any serious comorbidity, poor renal (creatinine concentration >150 μmol/L) or hepatic (cirrhosis or previous hepatitis B or C) function, pregnancy, and any history of cancer except for non-melanoma skin tumours or stage 0 (in situ) cervical carcinoma. Patients were stratified into two groups based on disease extension (absence group B or presence group C of bone marrow or central nervous system involvement). Patients were further stratified in group C according to age (<40 years, 40–60 years, and >60 years) and central nervous system involvement. Participants were randomly assigned in each group to either intravenous rituximab injections and chemotherapy (lymphome malin B LMB) or chemotherapy alone by the Groupe d'Etude des Lymphomes de l'Adulte datacentre. Randomisation was stratified by treatment group and centre using computer-assisted permuted-block randomisation (block size of four; allocation ratio 1:1). We gave rituximab (375 mg/m2 ) on day 1 and day 6 during the first two courses of chemotherapy (total of four infusions). The primary endpoint is 3 year event-free survival (EFS). We analysed all patients who had data available according to their originally assigned group. This trial is registered with ClinicalTrials.gov , number NCT00180882. Results Between Oct 14, 2004, and Sept 7, 2010, we randomly allocated 260 patients to rituximab or no rituximab (group B 124 patients 64 no rituximab; 60 rituximab; group C 136 patients 66 no rituximab; 70 rituximab). With a median follow-up of 38 months (IQR 24–59), patients in the rituximab group achieved better 3 year EFS (75% 95% CI 66–82) than did those in the no rituximab group (62% 53–70; log-rank p stratified by treatment group=0·024). The hazard ratio estimated with a Cox model stratified by treatment group, assuming proportionality, was 0·59 for EFS (95% CI 0·38–0·94; p=0·025). Adverse events did not differ between the two treatment groups. The most common adverse events were infectious (grade 3–4 in 137 17% treatment cycles in the rituximab group vs 115 15% in the no rituximab group) and haematological (mean duration of grade 4 neutropenia of 3·31 days per cycle 95% CI 3·01–3·61 vs 3·38 days per cycle 3·05–3·70) events. Interpretation Addition of rituximab to a short intensive chemotherapy programme improves EFS in adults with Burkitt's leukaemia or lymphoma. Funding Gustave Roussy Cancer Campus, Roche, Chugai, Sanofi.
Purpose
Lymphoma lesion detection and segmentation on whole-body FDG-PET/CT are a challenging task because of the diversity of involved nodes, organs or physiological uptakes. We sought to ...investigate the performances of a three-dimensional (3D) convolutional neural network (CNN) to automatically segment total metabolic tumour volume (TMTV) in large datasets of patients with diffuse large B cell lymphoma (DLBCL).
Methods
The dataset contained pre-therapy FDG-PET/CT from 733 DLBCL patients of 2 prospective LYmphoma Study Association (LYSA
)
trials. The first cohort (
n
= 639) was used for training using a 5-fold cross validation scheme. The second cohort (
n
= 94) was used for external validation of TMTV predictions. Ground truth masks were manually obtained after a 41% SUVmax adaptive thresholding of lymphoma lesions. A 3D U-net architecture with 2 input channels for PET and CT was trained on patches randomly sampled within PET/CTs with a summed cross entropy and Dice similarity coefficient (DSC) loss. Segmentation performance was assessed by the DSC and Jaccard coefficients. Finally, TMTV predictions were validated on the second independent cohort.
Results
Mean DSC and Jaccard coefficients (± standard deviation) in the validations set were 0.73 ± 0.20 and 0.68 ± 0.21, respectively. An underestimation of mean TMTV by − 12 mL (2.8%) ± 263 was found in the validation sets of the first cohort (
P
= 0.27). In the second cohort, an underestimation of mean TMTV by − 116 mL (20.8%) ± 425 was statistically significant (
P
= 0.01).
Conclusion
Our CNN is a promising tool for automatic detection and segmentation of lymphoma lesions, despite slight underestimation of TMTV. The fully automatic and open-source features of this CNN will allow to increase both dissemination in routine practice and reproducibility of TMTV assessment in lymphoma patients.
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.
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.
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%).
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 .).
Abstract
The prognostic value of
18
F-Fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) at baseline or the predictive value of minimal residual disease (MRD) detection ...appear as potential tools to improve mantle cell lymphoma (MCL) patients’ management. The LyMa-101, a phase 2 trial of the LYSA group (ClinicalTrials.gov:NCT02896582) reported induction therapy with obinutuzumab, a CD20 monoclonal antibody. Herein, we investigated the added prognostic value of radiomic features (RF) derived from FDG-PET/CT at diagnosis for MRD value prediction. FDG-PET/CT of 59 MCL patients included in the LyMa-101 trial have been independently, blindly and centrally reviewed. RF were extracted from the disease area with the highest uptake and from the total metabolic tumor volume (TMTV). Two models of machine learning were used to compare several combinations for prediction of MRD before autologous stem cell transplant consolidation (ASCT). Each algorithm was generated with or without constrained feature selections for clinical and laboratory parameters. Both algorithms showed better discrimination performances for negative vs positive MRD in the lesion with the highest uptake than in the TMTV. The constrained use of clinical and biological features showed a clear loss in sensitivity for the prediction of MRD status before ASCT, regardless of the machine learning model. These data plead for the importance of FDG-PET/CT RF compared to clinical and laboratory parameters and also reinforced the previously made hypothesis that the prognosis of the disease in MCL patients is linked to the most aggressive contingent, within the lesion with the highest uptake.
The microenvironment strongly influences mantle cell lymphoma (MCL) survival, proliferation, and chemoresistance. However, little is known regarding the molecular characterization of lymphoma niches. ...Here, we focused on the interplay between MCL cells and the associated monocytes/macrophages. Using circulating MCL cells (n = 58), we showed that, through the secretion of CSF1 and, to a lesser extent, IL-10, MCL polarized monocytes into specific CD163
M2-like macrophages (MϕMCL). In turn, MϕMCL favored lymphoma survival and proliferation ex vivo. We next demonstrated that BTK inhibition abrogated CSF1 and IL-10 production in MCL cells, leading to the inhibition of macrophage polarization and consequently resulting in the suppression of microenvironment-dependent MCL expansion. In vivo, we showed that CSF1 and IL-10 plasma concentrations were higher in MCL patients than in healthy donors, and that monocytes from MCL patients overexpressed CD163. Further analyses of serial samples from ibrutinib-treated patients (n = 8) highlighted a rapid decrease of CSF1, IL-10, and CD163 in responsive patients. Finally, we showed that targeting the CSF1R abrogated MϕMCL-dependent MCL survival, irrespective of their sensitivity to ibrutinib. These data reinforced the role of the microenvironment in lymphoma and suggested that macrophages are a potential target for developing novel therapeutic strategies in MCL.
Summary
Extranodal NK/T‐cell lymphoma, nasal type is a rare and aggressive form of lymphoma, historically associated with poor prognosis. We report here the results of a retrospective multi‐centre ...study evaluating the efficacy of MGAD (methotrexate, gemcitabine, L‐asparaginase and dexamethasone) regimen (two cycles) combined with ‘sandwich’ radiotherapy in 35 patients with localised newly diagnosed extranodal NK/T‐cell lymphoma. Thirty‐two patients (91%) reached complete remission. With a long median follow‐up of 59.6 months, progression‐free and overall survival at 2 and 5 years were 71%, 80% and 53%, 73%, respectively. Around one third of the patients experienced relapse within a median time of 14.5 months. Side‐effects were manageable with grades 3–4 cytopenias, mucositis and infection in 50%, 24% and 21% of the cases, respectively. Monitoring of asparaginase activity was performed in 13 patients and showed inactivation of the drug in seven (54%) patients. Our results indicate that a short therapy by sandwich MGAD chemoradiotherapy is a tolerable and effective treatment option in localised newly diagnosed extranodal NK/T‐cell lymphoma patients.
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