Large B-cell lymphoma (LBCL) accounts for about one-third of adult lymphoma cases. Diagnosis requires specialized hematopathology laboratories, with immunophenotypic analysis essential for confirming B-cell lineage and identifying variants. MYC and BCL2 rearrangements indicate a poor prognosis. Staging and prognosis rely on positron emission tomography computed tomography (PET-CT). The International Prognostic Index (IPI) aids risk stratification. PET-CT is critical for assessing treatment response and guiding strategies. First-line management for LBCL can be informed by interim PET to assess chemosensitivity, with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or polatuzumab vedotin rituximab, cyclophosphamide, doxorubicin, and prednisone (Pola-R-CHP) for advanced stages depending on IPI scores. Primary mediastinal B-cell lymphoma (PMBCL) management favors R-CHOP given every 14 days (R-CHOP14) or dose-adjusted etoposide, doxorubicin, vincristine, cyclophosphamide, prednisone, and rituximab (DA-EPOCH-R) without radiotherapy in complete responders. Elderly patients, unfit or not (≥80 years or <80 with poor fitness), need geriatric assessment to guide therapy, often R-miniCHOP or non-anthracycline regimens. Frail patients should have adapted treatments. Prephase corticosteroids improve performance status, and supportive treatment should be optimized. The value of central nervous system (CNS) prophylaxis remains uncertain. CNS-IPI scores and specific anatomical sites help identify high-risk patients; magnetic resonance imaging (MRI) and colony-stimulating factor (CSF) analysis are recommended. Approximately 30%-40% of patients with LBCL experience relapsed or refractory disease after 1L treatment. Treatment strategies vary based on the timing of relapse (<1 year or ≥1 year). For those refractory or relapsing within <1 year and fit for therapy, chimeric antigen receptor T (CART) are the gold standard in 2L. CART in CART-naïve patients and bispecific antibodies appear to be the best approach in 3L. Follow-up includes clinical examination for 2 years and management for long-term side effects, such as cardiotoxicity, osteoporosis, immune dysfunction, neurocognitive impairment, endocrine dysfunction, fatigue, neuropathy, and mental distress.

• Publication type
• Journal Article MeSH

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

BACKGROUND: Despite recent advances in the treatment of aggressive lymphomas, a significant fraction of patients still succumbs to their disease. Thus, novel therapies are urgently needed. As the anti-CD20 antibody rituximab and the CD19-targeting antibody tafasitamab share distinct modes of actions, we investigated if dual-targeting of aggressive lymphoma B-cells by combining rituximab and tafasitamab might increase cytotoxic effects. METHODS: Antibody single and combination efficacy was determined investigating different modes of action including direct cytotoxicity, antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) in in vitro and in vivo models of aggressive B-cell lymphoma comprising diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma (BL). RESULTS: Three different sensitivity profiles to antibody monotherapy or combination treatment were observed in in vitro models: while 1/11 cell lines was primarily sensitive to tafasitamab and 2/11 to rituximab, the combination resulted in enhanced cell death in 8/11 cell lines in at least one mode of action. Treatment with either antibody or the combination resulted in decreased expression of the oncogenic transcription factor MYC and inhibition of AKT signaling, which mirrored the cell line-specific sensitivities to direct cytotoxicity. At last, the combination resulted in a synergistic survival benefit in a PBMC-humanized Ramos NOD/SCID mouse model. CONCLUSION: This study demonstrates that the combination of tafasitamab and rituximab improves efficacy compared to single-agent treatments in models of aggressive B-cell lymphoma in vitro and in vivo.

• Keywords
• CD19, CD20, antibody therapy, lymphoma, rituximab, tafasitamab, tumor immunology,
• MeSH
• Burkitt Lymphoma * drug therapy   MeSH
• Lymphoma, Large B-Cell, Diffuse * drug therapy   MeSH
• Antibodies, Monoclonal, Humanized MeSH
• Leukocytes, Mononuclear MeSH
• Mice, Inbred NOD MeSH
• Mice, SCID MeSH
• Mice MeSH
• Rituximab pharmacology   therapeutic use   MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Antibodies, Monoclonal, Humanized MeSH
• Rituximab MeSH
• tafasitamab MeSH Browser

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

• Publication type
• Journal Article 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

Tafasitamab (MOR208), an Fc-modified, humanized, anti-CD19 monoclonal antibody, combined with the immunomodulatory drug lenalidomide was clinically active with a good tolerability profile in the open-label, single-arm, phase II L-MIND study of patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) ineligible for autologous stem-cell transplantation. To assess long-term outcomes, we report an updated analysis with ≥35 months' follow-up. Patients were aged >18 years, had received one to three prior systemic therapies (including ≥1 CD20-targeting regimen) and Eastern Cooperative Oncology Group performance status 0-2. Patients received 28-day cycles of tafasitamab (12 mg/kg intravenously), once weekly during cycles 1-3, then every 2 weeks during cycles 4-12. Lenalidomide (25 mg orally) was administered on days 1-21 of cycles 1-12. After cycle 12, progression-free patients received tafasitamab every 2 weeks until disease progression. The primary endpoint was best objective response rate. After ≥35 months' follow-up (data cut-off: October 30, 2020), the objective response rate was 57.5% (n=46/80), including a complete response in 40.0% of patients (n=32/80) and a partial response in 17.5% of patients (n=14/80). The median duration of response was 43.9 months (95% confidence interval [95% CI]: 26.1-not reached), the median overall survival was 33.5 months (95% CI: 18.3-not reached) and the median progression-free survival was 11.6 months (95% CI: 6.3-45.7). There were no unexpected toxicities. Subgroup analyses revealed consistent long-term efficacy results across most subgroups of patients. This extended follow-up of L-MIND confirms the long duration of response, meaningful overall survival, and well-defined safety profile of tafasitamab plus lenalidomide followed by tafasitamab monotherapy in patients with relapsed/refractory diffuse large B-cell lymphoma ineligible for autologous stem cell transplantation. ClinicalTrials.gov identifier: NCT02399085.

• MeSH
• Transplantation, Autologous MeSH
• Lymphoma, Large B-Cell, Diffuse * diagnosis   drug therapy   MeSH
• Antibodies, Monoclonal, Humanized MeSH
• Lenalidomide therapeutic use   MeSH
• Humans MeSH
• Antineoplastic Combined Chemotherapy Protocols adverse effects   MeSH
• Hematopoietic Stem Cell Transplantation * MeSH
• Treatment Outcome MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Clinical Trial, Phase II MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Antibodies, Monoclonal, Humanized MeSH
• Lenalidomide MeSH
• tafasitamab MeSH Browser

Non-Hodgkin lymphomas (NHLs) are lymphoid malignancies of B- or T-cell origin. Despite great advances in treatment options and significant improvement of survival parameters, a large part of NHL patients either present with a chemotherapy-refractory disease or experience lymphoma relapse. Chemotherapy-based salvage therapy of relapsed/refractory NHL is, however, capable of re-inducing long-term remissions only in a minority of patients. Immunotherapy-based approaches, including bispecific antibodies, immune checkpoint inhibitors and genetically engineered T-cells carrying chimeric antigen receptors, single-agent or in combination with therapeutic monoclonal antibodies, immunomodulatory agents, chemotherapy or targeted agents demonstrated unprecedented clinical activity in heavily-pretreated patients with NHL, including chemotherapy-refractory cases with complex karyotype changes and other adverse prognostic factors. In this review, we recapitulate currently used immunotherapy modalities in NHL and discuss future perspectives of combinatorial immunotherapy strategies, including patient-tailored approaches.

• Keywords
• CAR T-cells, bispecific antibodies, immune checkpoint inhibitors, immunomodulatory agents, non-Hodgkin lymphomas,
• Publication type
• Journal Article MeSH
• Review MeSH