• Publication type
• Journal Article MeSH

BACKGROUND: Whole-body magnetic resonance imaging (wbMRI) allows general assessment of systemic cancers including lymphomas without radiation burden. AIM: To evaluate the diagnostic performance of wbMRI in the staging of diffuse large B-cell lymphoma (DLBCL), determine the value of individual MRI sequences, and assess patients' concerns with wbMRI. METHODS: In this single-center prospective study, adult patients newly diagnosed with systemic DLBCL underwent wbMRI on a 3T scanner [diffusion weighted images with background suppression (DWIBS), T2, short tau inversion recovery (STIR), contrast-enhanced T1] and fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) (reference standard). The involvement of 12 nodal regions and extranodal sites was evaluated on wbMRI and PET/CT. The utility of wbMRI sequences was rated on a five-point scale (0 = not useful, 4 = very useful). Patients received a questionnaire regarding wbMRI. RESULTS: Of 60 eligible patients, 14 (23%) were enrolled and completed the study. The sensitivity of wbMRI in the nodal involvement (182 nodal sites) was 0.84, with 0.99 specificity, positive predictive value of 0.96, negative predictive value of 0.97, and 0.97 accuracy. PET/CT and wbMRI were concordant both in extranodal involvement (13 instances) and staging (κ = 1.0). The mean scores of the utility of MRI sequences were 3.71 ± 0.73 for DWIBS, 2.64 ± 0.84 for T1, 2.14 ± 0.77 for STIR, and 1.29 ± 0.73 for T2 (P < 0.0001). Patients were mostly concerned about the enclosed environment and duration of the MRI examination (27% of patients). CONCLUSION: The wbMRI exhibited excellent sensitivity and specificity in staging DLBCL. DWIBS and contrast-enhanced T1 were rated as the most useful sequences. Patients were less willing to undergo wbMRI as a second examination parallel to PET/CT, especially owing to the long duration and the enclosed environment.

• Keywords
• Diffuse large B-cell lymphoma, Magnetic resonance imaging, Positron emission tomography/computed tomography, Preference, Staging,
• Publication type
• Journal Article MeSH

The therapeutic potential of targeting PI3K/AKT/PTEN signalling in B-cell malignancies remains attractive. Whilst PI3K-α/δ inhibitors demonstrate clinical benefit in certain B-cell lymphomas, PI3K signalling inhibitors have been inadequate in relapsed/refractory diffuse large B-cell lymphoma (DLBCL) in part, due to treatment related toxicities. Clinically, AKT inhibitors exhibit a differentiated tolerability profile offering an alternative approach for treating patients with B-cell malignancies. To explore how AKT inhibition complements other potential therapeutics in the treatment of DLBCL patients, an in vitro combination screen was conducted across a panel of DLCBL cell lines. The AKT inhibitor, capivasertib, in combination with the BCL-2 inhibitor, venetoclax, produced notable therapeutic benefit in preclinical models of DLBCL. Capivasertib and venetoclax rapidly induced caspase and PARP cleavage in GCB-DLBCL PTEN wildtype cell lines and those harbouring PTEN mutations or reduced PTEN protein, driving prolonged tumour growth inhibition in DLBCL cell line and patient derived xenograft lymphoma models. The addition of the rituximab further deepened the durability of capivasertib and venetoclax responses in a RCHOP refractory DLBCL in vivo models. These findings provide preclinical evidence for the rational treatment combination of AKT and BCL-2 inhibitors using capivasertib and venetoclax respectively alongside anti-CD20 antibody supplementation for treatment of patients with DLBCL.

• MeSH
• Apoptosis drug effects   MeSH
• Bridged Bicyclo Compounds, Heterocyclic * pharmacology   therapeutic use   MeSH
• Lymphoma, Large B-Cell, Diffuse * drug therapy   pathology   MeSH
• PTEN Phosphohydrolase metabolism   MeSH
• Humans MeSH
• Mice, SCID MeSH
• Mice MeSH
• Cell Line, Tumor MeSH
• Cell Proliferation drug effects   MeSH
• Antineoplastic Combined Chemotherapy Protocols * pharmacology   therapeutic use   MeSH
• Proto-Oncogene Proteins c-akt * metabolism   MeSH
• Proto-Oncogene Proteins c-bcl-2 * antagonists & inhibitors   metabolism   MeSH
• Pyrimidines * pharmacology   therapeutic use   MeSH
• Pyrroles pharmacology   therapeutic use   MeSH
• Rituximab pharmacology   therapeutic use   MeSH
• Sulfonamides * pharmacology   therapeutic use   MeSH
• Xenograft Model Antitumor Assays * MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• BCL2 protein, human MeSH Browser
• Bridged Bicyclo Compounds, Heterocyclic * MeSH
• capivasertib MeSH Browser
• PTEN Phosphohydrolase MeSH
• Proto-Oncogene Proteins c-akt * MeSH
• Proto-Oncogene Proteins c-bcl-2 * MeSH
• Pyrimidines * MeSH
• Pyrroles MeSH
• Rituximab MeSH
• Sulfonamides * MeSH
• venetoclax MeSH Browser

Anti-CD19 immunotherapy tafasitamab is used in combination with lenalidomide in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) who are ineligible for autologous stem cell transplant. Open-label, phase 1b, First-MIND study assessed safety and preliminary efficacy of tafasitamab + R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) ± lenalidomide as first-line therapy in patients with DLBCL. From December 2019 to August 2020, 83 adults with untreated DLBCL (International Prognostic Index 2-5) were screened and 66 were randomly assigned (33 per arm) to R-CHOP-tafasitamab (arm T) or R-CHOP-tafasitamab-lenalidomide (arm T/L) for 6 cycles. Primary end point was safety; secondary end points included end-of-treatment (EoT) overall response rate (ORR) and complete response (CR) rate. All patients had ≥1 treatment-emergent adverse event, mostly grade 1 or 2. Grade ≥3 neutropenia and thrombocytopenia occurred, respectively, in 57.6% and 12.1% (arm T) and 84.8% and 36.4% (arm T/L) of patients. Nonhematologic toxicities occurred at similar rates among arms. R-CHOP mean relative dose intensity was ≥89% in both arms. EoT ORR was 75.8% (CR 72.7%) in arm T and 81.8% (CR 66.7%) in arm T/L; best ORR across visits was 90.0% and 93.9%. Eighteen-month duration of response and of CR rates were 72.7% and 74.5% (arm T) and 78.7% and 86.5% (arm T/L); 24-month progression-free and overall survival rates were 72.7% and 90.3% (arm T) and 76.8% and 93.8% (arm T/L). Manageable safety and promising signals of efficacy were observed in both arms. Potential benefit of adding tafasitamab + lenalidomide to R-CHOP is being investigated in phase 3 frontMIND (NCT04824092). This study is registered at www.clinicaltrials.gov as #NCT04134936.

• MeSH
• Cyclophosphamide adverse effects   MeSH
• Lymphoma, Large B-Cell, Diffuse * pathology   MeSH
• Adult MeSH
• Doxorubicin adverse effects   MeSH
• Lenalidomide therapeutic use   MeSH
• Humans MeSH
• Antibodies, Monoclonal, Murine-Derived adverse effects   MeSH
• Prednisone adverse effects   MeSH
• Antineoplastic Combined Chemotherapy Protocols adverse effects   MeSH
• Rituximab adverse effects   MeSH
• Vincristine adverse effects   MeSH
• Check Tag
• Adult MeSH
• Humans MeSH
• Publication type
• Journal Article MeSH
• Clinical Trial, Phase I MeSH
• Research Support, Non-U.S. Gov't MeSH
• Randomized Controlled Trial MeSH
• Names of Substances
• Cyclophosphamide MeSH
• Doxorubicin MeSH
• Lenalidomide MeSH
• Antibodies, Monoclonal, Murine-Derived MeSH
• Prednisone MeSH
• Rituximab MeSH
• tafasitamab MeSH Browser
• Vincristine MeSH

Diffuse large B-cell lymphoma (DLBCL) represents a curable disease with a 60-70% chance of cure with current R-CHOP chemoimmunotherapy. However, 30-40% of patients are refractory or relapsing. Many attempts failed to improve the outcome of DLBCL patients, including the intensification of R-CHOP regimen, consolidation, or maintenance therapy since the introduction of R-CHOP in 2000. Better understanding of both molecular biology of lymphoma cells and the tumor microenvironment raised the hope for future improvement of DLBCL patients' survival. Novel molecular findings have initiated clinical trials exploring targeted therapy based on driver genetic alterations with an intent to improve survival of high-risk subsets of patients. But the preliminary results remain ambiguous. The approach "agnostic" to specific molecular alterations of lymphoma cell includes antibody-drug conjugates (especially polatuzumab vedotin), immunotherapy comprising different antibodies with immunomodulatory effect (tafasitamab, lenalidomide), and T-cell engaging therapy (bispecific antibodies, early use of CAR T-cell). This approach could increase the cure rates and change the current therapeutic paradigm. However, better prognostic stratification, smarter designs of clinical trials, modification of endpoints including the use of ctDNA are needed. This review covers the complexity of DLBCL management.

• Keywords
• R-CHOP, agnostic therapy, diffuse large B-cell lymphoma, first-line therapy, polatuzumab vedotin, tailored therapy,
• Publication type
• Journal Article MeSH
• Review MeSH

Malignant lymphomas represent the most common type of hematologic malignancies. The first clinically approved TDD modalities in lymphoma patients were anti-CD20 radioimmunoconjugates (RIT) 131I-tositumomab and 90Y-ibritumomab-tiuxetan. The later clinical success of the first approved antibody-drug conjugate (ADC) for the treatment of lymphomas, anti-CD30 brentuximab vedotin, paved the path for the preclinical development and clinical testing of several other ADCs, including polatuzumab vedotin and loncastuximab tesirine. Other modalities of TDD are based on new formulations of "old" cytostatic agents and their passive trapping in the lymphoma tissue by means of the enhanced permeability and retention (EPR) effect. Currently, the diagnostic and restaging procedures in aggressive lymphomas are based on nuclear imaging, namely PET. A theranostic approach that combines diagnostic or restaging lymphoma imaging with targeted treatment represents an appealing innovative strategy in personalized medicine. The future of theranostics will require not only the capability to provide suitable disease-specific molecular probes but also expertise on big data processing and evaluation. Here, we review the concept of targeted drug delivery in malignant lymphomas from RIT and ADC to a wide array of passively and actively targeted nano-sized investigational agents. We also discuss the future of molecular imaging with special focus on monoclonal antibody-based and monoclonal antibody-derived theranostic strategies.

• Keywords
• antibody–drug conjugates, liposomes, lymphoma, magnetic resonance imaging, nanomedicine, nuclear imaging, targeted drug delivery, theranostics,
• Publication type
• Journal Article MeSH
• Review MeSH