A randomized trial comparing the CD19-specific CAR T-cell therapy tisagenlecleucel with salvage chemotherapy followed by high-dose therapy and autologous hematopoietic stem-cell transplantation in ...patients with refractory or early relapsed aggressive B-cell lymphoma did not show a longer event-free survival with CAR T cells.
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.
The use of rituximab every 2 months for 3 years after immunochemotherapy and autologous stem-cell transplantation prolonged progression-free and overall survival among patients with mantle-cell ...lymphoma.
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.
The combination of rituximab and lenalidomide achieved results that were similar to those of rituximab plus chemotherapy in the treatment of previously untreated patients with advanced follicular ...lymphoma.
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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