RESUMO
Diffuse large B-cell lymphoma (DLBCL) accounts for approximately 40% of all malignant lymphomas, making it the most common subtype. Molecular genetic studies have elucidated the pathogenesis of DLBCL and the causes of its poor prognosis. This basic research has led to the development of novel molecularly targeted therapies that target molecules and cellular antigens in relevant signaling pathways or epigenetic enzymes. Treatment with polatuzumab vedotin, rituximab, cyclophosphamide, doxorubicin, and prednisone has become the standard of care for newly diagnosed CD20-positive DLBCL with an International Prognostic Index score of 2 to 5, based on its reported efficacy for this indication. In addition, the development of immunotherapy such as anti-CD19-chimeric antigen receptor (CAR)-T therapy and bispecific antibodies such as epcoritamab, mosunetuzumab, and glofitamab has led to a paradigm shift in treatment of relapsed/refractory DLBCL. This review summarizes the evolution of treatment development for DLBCL, as well as the results of the current clinical standard of care and new therapies that are expected to become the standard of care.
Assuntos
Linfoma Difuso de Grandes Células B , Humanos , Linfoma Difuso de Grandes Células B/terapia , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Imunoterapia/métodos , Terapia de Alvo Molecular , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêuticoRESUMO
Patients with relapsed/refractory (r/r) diffuse large B-cell lymphoma (DLBCL) show varied responses to PD-1 monoclonal antibody (mAb) containing regimens. The mechanisms and predictive biomarkers for the efficacy of this regimen are unclear. This study retrospectively collected r/r DLBCL patients who received PD-1 mAb and rituximab regimens as salvage therapy. Clinical and genomic features were collected, and mechanisms were explored by multiplex immunofluorescence and digital spatial profiling. An artificial neural network (ANN) model was constructed to predict the response. Between October 16th, 2018 and May 4th, 2023, 50 r/r DLBCL patients were collected, 29 were response patients and 21 were non-response patients. CREBBP (p = 0.029) and TP53 (p = 0.015) alterations were statistically higher in non-response patients. Patients with PD-L1 CPS ≥ 5 were correlated with a longer overall survival (OS) than those with PD-L1 CPS < 5 (median OS: not reached vs. 9.7 months, hazard ratio [HR]: 3.8, 95% confidence interval [CI] 0.64-22.44, p = 0.016). Immune-related pathways were activated in response patients. The proportion and spatial organization of tumor-infiltrating immune cells affect the response. PD-L1 CPS level, age, and alterations of TP53, MYD88, CREBBP, EP300, GNA13 were used to build an ANN predictive model that showed high prediction efficiency (training set area under curve [AUC] of 0.97 and test set AUC of 0.94). The proportion and spatial distribution of tumor-infiltrating immune cells may be related to the function of immune-related pathways, thereby influencing the efficacy of PD-1 mAb containing regimens. The ANN predictive model showed potential value in predicting the responses of r/r DLBCL patients received PD-1 mAb and rituximab regimens.
Assuntos
Linfoma Difuso de Grandes Células B , Receptor de Morte Celular Programada 1 , Humanos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/imunologia , Linfoma Difuso de Grandes Células B/mortalidade , Masculino , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Feminino , Pessoa de Meia-Idade , Estudos Retrospectivos , Idoso , Adulto , Rituximab/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/imunologia , Biomarcadores Tumorais , Prognóstico , Inibidores de Checkpoint Imunológico/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Redes Neurais de Computação , Resistencia a Medicamentos Antineoplásicos , Idoso de 80 Anos ou mais , Genômica/métodos , MultiômicaRESUMO
Treatment of relapsed or refractory diffuse large B-cell lymphoma is difficult. The de novo diffuse large B-cell lymphoma has better prognosis than the transformed diffuse large B-cell lymphoma. The response of CHOP or a similar regimen has an important role in determining response to salvage therapy, in relapse or refractory diffuse large B-cell lymphoma patients. Patients who are non-responder to initial treatment have a very poor chance of responding to therapy for relapse. This was a small scale observational study and was conducted from January 2017 to December 2020 in National Institute of Cancer Research and Hospital, Bangladesh. A total of 34 patients with relapsed or refractory diffuse large B-cell lymphoma were identified at hematology department in National Institute of Cancer Research and Hospital, 28 of them were treated with ICE chemotherapy and 6 with R-ICE chemotherapy as second line regimen. Overall response rate to 2nd line chemotherapy was 64.8%, with 32.4% (11 patients) complete remission and 32.4% (11 patients) partial remission. Median overall survival to second line regimen was 10 months, corresponding to a 4 year overall survival of 32.4% and a 4 year progression free survival was 17.6%. Patient with stable disease/progressive disease median overall survival was 7 months compared with 15 months for complete remission and 9 months for partial remission (p<0.001). Median overall survival was significantly better in patients with international prognostic index 0-2 compared in those with international prognostic index >2 (p=0.010). However improvement of salvage efficacy is an urgent need with new drugs. Further studies are necessary to determine whether this regimen will improve outcomes of relapsed or refractory diffuse large B-cell lymphoma patients.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Carboplatina , Etoposídeo , Ifosfamida , Linfoma Difuso de Grandes Células B , Rituximab , Humanos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/mortalidade , Etoposídeo/administração & dosagem , Etoposídeo/uso terapêutico , Masculino , Feminino , Ifosfamida/administração & dosagem , Pessoa de Meia-Idade , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Rituximab/uso terapêutico , Rituximab/administração & dosagem , Adulto , Carboplatina/administração & dosagem , Carboplatina/uso terapêutico , IdosoAssuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Linfoma Difuso de Grandes Células B , Humanos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Indução de Remissão , Terapia de Alvo Molecular/métodosRESUMO
Polatuzumab vedotin, an antibody-drug conjugate targeting CD79B, is the first new drug approved for first-line therapy of diffuse large B-cell lymphoma in more than two decades, although factors determining treatment responses to polatuzumab vedotin remain unknown. Two new studies identified central mechanisms of lower sensitivity, namely reduced accessibility of the CD79B epitope through N-linked glycosylation of CD79B and lower CD79B surface expression levels due to the activity of the KLHL6 E3 ligase. See related article by Corcoran et al., p. 1653 (6) See related article by Meriranta et al. (7).
Assuntos
Imunoconjugados , Humanos , Imunoconjugados/uso terapêutico , Imunoconjugados/farmacologia , Antígenos CD79 , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais/farmacologia , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma de Células B/tratamento farmacológicoRESUMO
INTRODUCTION: The diffuse large B-cell lymphoma (Dlbcl) is the most common non-Hodgkin lymphoma and at highest incidence among the elderly. Despite the improved outcomes of patients treated with the first-line (1L) standard of care until the end of 2022, composed by rituximab and polychemotherapy (R-Chop), during the last 20 years, the rate of relapsed and refractory Dlbcl (rrDlbcl) remains elevated. This study has identified and analyzed patients newly diagnosed with Dlbcl and treated with 1L, from the perspective of the Italian National Health Service (Ssn). METHODS: From the administrative database of Fondazione Ricerca e Salute (ReS) including ~5.5 million inhabitants/year in Italy, adults with a new in-hospital Dlbcl diagnosis (index date) and treated with 1L in 2018, 2019, 2020 and 2021 were identified and characterized in terms of demographics and comorbidities during a period (from 4 to 8 years) preceding index date. From 1 to 4 years following index date (follow-up), overall survival (Kaplan-Meier curves), percentage distribution of patients by line of therapy including dispensation/administration of chemo-immunotherapy, hemopoietic stem cell transplantation (Hsct), and direct healthcare costs charge to the Ssn, were evaluated. RESULTS: Overall, from the ReS database, 206 patients newly diagnosed with Dlbcl and treated with 1L from 2018 to 2021 in Italy (incidence from 0.9 to 1.7 x100,000 adult inhabitants) were identified. They were mainly older (median age 68 [56; 75] years), males (56%) and affected by ≥2 comorbidities (52%), mostly cardiometabolic. During 4 years of follow-up, 56% of cases in 2018 survived. During the first follow-up year: 73%, 80%, 100% and 35% of cases in 2018, 2019, 2020 and 2021, respectively, received a 2L; 42% and 64% of cases in 2018 and 2020, respectively, received a 3L. At least one Hsct was found as a 2L among cases in 2018, 2020 and 2021. On average, each patient newly diagnosed with Dlbcl and treated with 1L from 2018 to 2021 caused a total expenditure directly charged to the Ssn ranging from 20,000 to 30,000 during the first follow-up year (chemo-immunotherapy accounted for 40-53%), which reduced with time in favor of other drugs and Hsct. CONCLUSIONS: This analysis confirms the high rate of rrDlbcl and the high economic impact charged to the SSN to support first the chemo-immunotherapy, then the chronic care and the absence of standardized further lines of therapy for patients with rrDlbcl.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Bases de Dados Factuais , Linfoma Difuso de Grandes Células B , Humanos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/terapia , Linfoma Difuso de Grandes Células B/epidemiologia , Itália , Masculino , Idoso , Feminino , Pessoa de Meia-Idade , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/economia , Idoso de 80 Anos ou mais , Adulto , Rituximab/administração & dosagem , Estimativa de Kaplan-Meier , Transplante de Células-Tronco Hematopoéticas , Custos de Cuidados de Saúde/estatística & dados numéricos , Vincristina/administração & dosagem , Seguimentos , Ciclofosfamida/administração & dosagem , Ciclofosfamida/uso terapêutico , Doxorrubicina/administração & dosagem , Prednisona/administração & dosagem , Prednisona/uso terapêuticoRESUMO
Bruton tyrosine kinase inhibitor (BTKi)â¯combined with rituximab-based chemotherapy benefits diffuse large B-cell lymphoma (DLBCL) patients. However, drug resistance is the major cause of relapse and death of DLBCL. In this study, we conducted a comprehensive analysis BTKi-resistance related genes (BRRGs) and established a 10-gene (CARD16, TRIP13, PSRC1, CASP1, PLBD1, CARD6, CAPG, CACNA1A, CDH15, and NDUFA4) signature for early identifying high-risk DLBCL patients. The resistance scores based on the BRRGs signature were associated with prognosis. Furthermore, we developed a nomogram incorporating the BRRGs signature, which demonstrated excellent performance in predicting the prognosis of DLBCL patients. Notably, tumor immune microenvironment, biological pathways, and chemotherapy sensitivity were different between high- and low-resistance score groups. Additionally, we identified TRIP13 as a key gene in our model. TRIP13 was found to be overexpressed in DLBCL and BTKi-resistant DLBCL cell lines, knocking down TRIP13 suppresses cell proliferation, promotes cell apoptosis, and enhances the apoptosis effect of BTKi on DLBCL cells by regulating the Wnt/ß-catenin pathway. In conclusion, our study presents a novel BRRGs signature that could serve as a promising prognostic marker in DLBCL, and TRIP13 might be a potential therapeutic target for resistant DLBCL.
Assuntos
Tirosina Quinase da Agamaglobulinemia , Resistencia a Medicamentos Antineoplásicos , Linfoma Difuso de Grandes Células B , Humanos , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/genética , Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Tirosina Quinase da Agamaglobulinemia/genética , Tirosina Quinase da Agamaglobulinemia/metabolismo , Prognóstico , Linhagem Celular Tumoral , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Microambiente Tumoral/genética , Microambiente Tumoral/efeitos dos fármacos , Feminino , Masculino , Apoptose/efeitos dos fármacos , Apoptose/genética , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , ATPases Associadas a Diversas Atividades CelularesRESUMO
First-line treatment for advanced-stage diffuse large B-cell lymphoma (DLBCL) typically involves 6x R-CHOP21 or 6x R-CHOP21 with two additional rituximab administrations (6x R-CHOP21 + 2 R). In contemporary practice, this treatment choice might be guided by interim PET scan results. This nationwide, population-based study investigates the comparative effectiveness of these treatment regimens in an era where interim PET-guided treatment decisions were not standard practice. Utilizing the Netherlands Cancer Registry, we identified 1577 adult patients diagnosed with advanced-stage DLBCL between 2014-2018 who completed either 6x R-CHOP21 (43%) or 6x R-CHOP21 + 2 R (57%). We used propensity scores to assess differences in event-free survival (EFS) and overall survival (OS). At five years, EFS (hazard ratio of 6x R-CHOP21 + 2 R versus 6x R-CHOP21 [HR] = 0.89; 95% confidence interval [CI], 0.72-1.09) and OS (HR = 0.93; 95% CI, 0.73-1.18) were not significantly different between both regimens. In exploratory risk-stratified analysis according to the International Prognostic Index (IPI), high-IPI patients (i.e., scores of 4-5) benefit most from 6x R-CHOP21 + 2 R (5-year absolute risk difference of EFS = 16.8%; 95% CI, -0.4%-34.1% and OS = 12.1%; 95% CI, -5.4-29.6%). Collectively, this analysis reveals no significant differences on average in EFS and OS between the two treatments. However, the potential benefits for high-risk patients treated with 6x R-CHOP21 + 2 R underscore the need for future research.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Ciclofosfamida , Doxorrubicina , Linfoma Difuso de Grandes Células B , Prednisona , Rituximab , Vincristina , Humanos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/mortalidade , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Rituximab/uso terapêutico , Rituximab/administração & dosagem , Vincristina/uso terapêutico , Vincristina/administração & dosagem , Ciclofosfamida/uso terapêutico , Ciclofosfamida/administração & dosagem , Doxorrubicina/uso terapêutico , Doxorrubicina/administração & dosagem , Prednisona/uso terapêutico , Prednisona/administração & dosagem , Adulto , Idoso de 80 Anos ou mais , Estadiamento de Neoplasias , Resultado do Tratamento , Países Baixos/epidemiologiaRESUMO
The identification of new compounds with potential activity against CXC chemokine receptor type 4 (CXCR4) has been broadly studied, implying several chemical families, particularly AMD3100 derivatives. Molecular modeling has played a pivotal role in the identification of new active compounds. But, has its golden age ended? A virtual library of 450,000 tetraamines of general structure 8 was constructed by using five spacers and 300 diamines, which were obtained from the corresponding commercially available cyclic amines. Diversity selection was performed to guide the virtual screening of the former database and to select the most representative set of compounds. Molecular docking on the CXCR4 crystal structure allowed us to rank the selection and identify those candidate molecules with potential antitumor activity against diffuse large B-cell lymphoma (DLBCL). Among them, compound A{17,18} stood out for being a non-symmetrical structure, synthetically feasible, and with promising activity against DLBCL in in vitro experiments. The focused study of symmetrical-related compounds allowed us to identify potential pre-hits (IC50~20 µM), evidencing that molecular design is still relevant in the development of new CXCR4 inhibitor candidates.
Assuntos
Antineoplásicos , Receptores CXCR4 , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/química , Linhagem Celular Tumoral , Desenho de Fármacos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Modelos Moleculares , Simulação de Acoplamento Molecular , Receptores CXCR4/antagonistas & inibidores , Receptores CXCR4/química , Receptores CXCR4/metabolismo , Relação Estrutura-AtividadeRESUMO
Drug resistance is a critical impediment to efficient therapy of diffuse large B-cell lymphoma (DLBCL) patients. Recent studies have highlighted the association between ferroptosis and drug resistance that has been reported. Fatty acid synthase (FASN) is always related to a poor prognosis. In this study, we investigate the impact of FASN on drug resistance in DLBCL and explore its potential modulation of ferroptosis mechanisms. The clinical correlation of FASN mRNA expression was first analyzed to confirm the role of FASN on drug resistance in DLBCL based on the TCGA database. Next, the impact of FASN on ferroptosis was investigated in vitro and in vivo. Furthermore, a combination of RNA-seq, western blot, luciferase reporter, and ChIP experiments was employed to elucidate the underlying mechanism. The prognosis for patients with DLBCL was worse when FASN was highly expressed, particularly in those undergoing chemotherapy for Adriamycin (ADM). FASN promoted tumor growth and resistance of DLBCL to ADM, both in vitro and in vivo. It is noteworthy that this effect was achieved by inhibiting ferroptosis, since Fer-1 (a ferroptosis inhibitor) treatment significantly recovered the effects of silencing FASN on inhibiting ferroptosis, while Erastin (a ferroptosis inducer) treatment attenuated the impact of overexpressing FASN. Mechanistically, FASN activated NF-κB/STAT3 signaling pathway through phosphorylating the upstream IKKα and IκBα, and the activated STAT3 promoted GPX4 expression by directly binding to GPX4 promoter. FASN inhibits ferroptosis in DLBCL via NF-κB/STAT3/GPX4 signaling pathway, indicating its critical role in mediating ADM resistance of DLBCL.
Assuntos
Doxorrubicina , Resistencia a Medicamentos Antineoplásicos , Ácido Graxo Sintase Tipo I , Ferroptose , Linfoma Difuso de Grandes Células B , NF-kappa B , Fosfolipídeo Hidroperóxido Glutationa Peroxidase , Fator de Transcrição STAT3 , Humanos , Ferroptose/efeitos dos fármacos , Ferroptose/genética , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/metabolismo , Linfoma Difuso de Grandes Células B/patologia , Linfoma Difuso de Grandes Células B/tratamento farmacológico , NF-kappa B/metabolismo , Camundongos , Animais , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/genética , Resistencia a Medicamentos Antineoplásicos/genética , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Ácido Graxo Sintase Tipo I/metabolismo , Ácido Graxo Sintase Tipo I/genética , Fator de Transcrição STAT3/metabolismo , Linhagem Celular Tumoral , Ensaios Antitumorais Modelo de Xenoenxerto , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Feminino , Masculino , Transdução de Sinais/efeitos dos fármacos , Camundongos Nus , PrognósticoRESUMO
INTRODUCTION: COVID-19 can have severe consequences for immunocompromised individuals, including those with hematological malignancies. Prolonged infections causing pneumonia and lung injury are rare in patients with diffuse large B-cell lymphoma (DLBCL) treated with chimeric antigen receptor T-cell (CAR-T). CASE PRESENTATION: A 43-year-old male with a history of DLBCL, in remission for 2 years after CAR-T therapy, developed a persistent COVID infection, as confirmed via positive polymerase chain reaction. This slowly progressed to symptomatic hypoxemic pneumonitis and biopsy-proven diffuse alveolar damage, which responded to corticosteroid treatment. DISCUSSION: COVID-19 poses increased risks to patients with a history of hematologic malignancies and can lead to severe respiratory distress and mortality. Studies have shown prolonged pneumonitis may require corticosteroids for improvement. However, data on appropriate regimen for managing prolonged COVID-19 pneumonitis are lacking. CONCLUSIONS: This case highlights challenges of the treatment of COVID-19 infections in immunocompromised individuals with hematological malignancies. Corticosteroid treatment shows benefits, but dosing and duration should be based on individual patient response. Extended monitoring, individualized treatment plans, and research are crucial for optimizing outcomes in this vulnerable population.
Assuntos
COVID-19 , Linfoma Difuso de Grandes Células B , SARS-CoV-2 , Humanos , Masculino , Linfoma Difuso de Grandes Células B/tratamento farmacológico , COVID-19/complicações , Adulto , Imunoterapia Adotiva/efeitos adversos , Corticosteroides/uso terapêutico , Lesão Pulmonar/etiologia , Hospedeiro ImunocomprometidoRESUMO
Bispecific antibodies (bsAbs) are an emerging therapy in the treatment of large B-cell lymphomas (LBCLs). There is a gap in the research on the safety and efficacy of bsAbs in adults with LBCL, with current research focusing on the wider non-Hodgkin's lymphoma population. To address this research gap, we conducted a systematic review aiming to evaluate the safety and efficacy outcomes of bsAbs in adults with LBCL. A systematized search was conducted in PubMed, EMBASE, and CENTRAL on 10 April 2024. Interventional clinical trials were eligible for inclusion. Observational studies, reviews, and meta-analyses were excluded. According to the Revised Risk of Bias Assessment Tool for Nonrandomized Studies, the included studies were largely of a high quality for safety outcome reporting, but of mixed quality for efficacy outcome reporting. Due to the heterogeneity of the included studies, the results were discussed as a narrative synthesis. Nineteen early phase studies were evaluated in the final analysis, with a pooled sample size of 1332 patients. Nine bsAbs were investigated across the studies as monotherapy (nine studies) or in combination regimes (10 studies). The rates of cytokine release syndrome were variable, with any grade events ranging from 0 to 72.2%. Infection rates were consistently high across the reporting studies (38-60%). Cytopenias were found to be common, in particular, anemia (4.4-62%), thrombocytopenia (3.3-69%), and neutropenia (4.4-70%). Immune effector cell-associated neurotoxicity syndrome (ICANS) and grade ≥3 adverse events were not commonly reported. Promising efficacy outcomes were reported, with median overall response rates of 95-100% in the front-line and 36-91% in terms of relapsed/refractory disease. The results of this systematic review demonstrate that bsAbs are generally well-tolerated and effective in adults with LBCL. BsAbs appear to have superior tolerability, but inferior efficacy to CAR T-cell therapies in adults with LBCL. Future research on safety and efficacy should focus on evaluating adverse event timing and management, the impact on the patient's quality of life, the burden on the healthcare system, and overall survival outcomes.
Assuntos
Anticorpos Biespecíficos , Adulto , Humanos , Anticorpos Biespecíficos/administração & dosagem , Anticorpos Biespecíficos/efeitos adversos , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/efeitos adversos , Ensaios Clínicos como Assunto , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/imunologia , Resultado do TratamentoRESUMO
AIMS: To understand treatment patterns, healthcare resource utilization (HCRU), and the economic burden of diffuse large B-cell lymphoma (DLBCL) in elderly adults in the US. MATERIALS AND METHODS: This retrospective database analysis utilized US Centers for Medicare and Medicaid Services Medicare fee-for-service administrative claims data from 2015 to 2020 to describe DLBCL patient characteristics, treatment patterns, HCRU, and costs among patients aged ≥66 years. Patients were indexed at DLBCL diagnosis and required to have continuous enrollment from 12 months pre-index until 3 months post-index. HCRU and costs (USD 2022) are reported as per-patient per-month (PPPM) estimates. RESULTS: A total of 11,893 patients received ≥1-line (L) therapy; 1,633 and 391 received ≥2 L and ≥3 L therapies, respectively. Median (Q1, Q3) age at 1 L, 2 L, and 3 L initiation, respectively, was 76 (71, 81), 77 (72, 82), and 77 (72, 82) years. The most common therapy was R-CHOP (70.9%) for 1 L and bendamustine ± rituximab for 2 L (18.7%) and 3 L (17.4%). CAR T was used by 14.8% of patients in 3 L. Overall, 39.6% (1 L), 42.1% (2 L), and 47.8% (3 L) of patients had all-cause hospitalizations. All-cause mean (median [Q1-Q3]) costs PPPM during each line were $22,060 ($20,121 [$16,676-$24,597]) in 1 L, $30,027 ($20,868 [$13,416-$31,016]) in 2 L, and $47,064 ($25,689 [$15,555-$44,149]) in 3 L, with increasing costs driven primarily by inpatient expenses. Total all-cause 3 L mean (median [Q1-Q3]) costs PPPM for patients with and without CAR T were $153,847 ($100,768 [$26,534-$253,630]) and $28,466 ($23,696 [$15,466-$39,107]), respectively. CONCLUSIONS: No clear standard of care exists in 3 L therapy for older adults with relapsed/refractory DLBCL. The economic burden of DLBCL intensifies with each progressing line of therapy, thus underscoring the need for additional therapeutic options.
Assuntos
Revisão da Utilização de Seguros , Linfoma Difuso de Grandes Células B , Medicare , Humanos , Linfoma Difuso de Grandes Células B/economia , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Estados Unidos , Estudos Retrospectivos , Idoso , Masculino , Feminino , Idoso de 80 Anos ou mais , Medicare/economia , Protocolos de Quimioterapia Combinada Antineoplásica/economia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Aceitação pelo Paciente de Cuidados de Saúde/estatística & dados numéricos , Recursos em Saúde/economia , Recursos em Saúde/estatística & dados numéricos , Gastos em Saúde/estatística & dados numéricos , Fatores Etários , Doxorrubicina/uso terapêutico , Doxorrubicina/economia , Rituximab/economia , Rituximab/uso terapêuticoRESUMO
Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma entity, and its incidence increases with age. There is a paucity of data regarding use of biweekly R-CHOP (R-CHOP-14) in patients ≥80 years of age. We performed a retrospective cohort study of patients with DLBCL aged ≥80 years treated with R-CHOP-14 and R-miniCHOP in two academic tertiary centers in Germany between 01/01/2005 and 12/30/2019. Overall, 79 patients were included. Median age was 84 years (range 80-91). Despite higher CR rates with R-CHOP-14 (71.4% vs. 52.4%), no statistically significant difference could be found between patients treated with R-CHOP-14 and R-miniCHOP regarding overall survival (OS) (p = .88, HR 0.94, 95% CI = 0.47-1.90) and progression-free survival (PFS) (p = .26, HR 0.66, 95% CI = 0.32-1.36). At a median follow-up of 40 months, the 2-year OS rates were 56% with R-CHOP-14 and 53% with R-miniCHOP. Two-year PFS rates were 46% for R-CHOP-14 and 50% for R-mini-CHOP. Relative dose intensity of chemotherapy did not correlate with OS (p = .72). With the caveat of a retrospective cohort study, we conclude that lacking a difference in OS, R-miniCHOP should be preferred for most patients with untreated DLBCL aged ≥80 years.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Ciclofosfamida , Doxorrubicina , Linfoma Difuso de Grandes Células B , Prednisona , Rituximab , Vincristina , Humanos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/mortalidade , Linfoma Difuso de Grandes Células B/diagnóstico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ciclofosfamida/uso terapêutico , Ciclofosfamida/administração & dosagem , Estudos Retrospectivos , Vincristina/uso terapêutico , Vincristina/administração & dosagem , Vincristina/efeitos adversos , Idoso de 80 Anos ou mais , Masculino , Feminino , Doxorrubicina/uso terapêutico , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Prednisona/uso terapêutico , Prednisona/administração & dosagem , Rituximab/administração & dosagem , Resultado do TratamentoRESUMO
Diffuse large B-cell lymphomas (DLBCLs) are heterogeneous cancers that still require better and less toxic treatments. SIRT3, a member of the sirtuin family of NAD+-dependent protein deacylase, is critical for DLBCL growth and survival. A mitochondria-targeted SIRT3 small-molecule inhibitor, YC8-02, exhibits promising activity against DLBCL. However, YC8-02 has several limitations including poor solubility. Here, we report our medicinal chemistry efforts that led to an improved mitochondria-targeted SIRT3 inhibitor, SJ-106C, achieved by using a triethylammonium group, which helps to increase both solubility and SIRT3 inhibition potency. SJ-106C, while still inhibiting SIRT1 and SIRT2, is enriched in the mitochondria to help with SIRT3 inhibition. It is more active against DLBCL than other solid tumor cells and effectively inhibits DLBCL xenograft tumor growth. The findings provide useful insights for the development of SIRT3 inhibitors and mitochondrial targeting agents and further support the notion that SIRT3 is a promising druggable target for DLBCL.
Assuntos
Antineoplásicos , Linfoma Difuso de Grandes Células B , Mitocôndrias , Sirtuína 3 , Sirtuína 3/antagonistas & inibidores , Sirtuína 3/metabolismo , Humanos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/patologia , Linfoma Difuso de Grandes Células B/metabolismo , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Animais , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Linhagem Celular Tumoral , Camundongos , Ensaios Antitumorais Modelo de Xenoenxerto , Proliferação de Células/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
Many therapies are available for the treatment of relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) after ≥ 2 lines of therapy, albeit with scant evidence on the comparative effectiveness of these therapies. This study used inverse probability of treatment weighting to indirectly compare treatment outcomes of epcoritamab from the EPCORE NHL-1 trial with individual patient data from clinical practice cohorts treated with chemoimmunotherapy (CIT) and novel therapies (polatuzumab-based regimens, tafasitamab-based regimens, and chimeric antigen receptor T-cell [CAR T] therapies) for third-line or later R/R large B-cell lymphoma (LBCL) and DLBCL. In this analysis, epcoritamab demonstrated significantly better response rates and overall survival rates than CIT, polatuzumab-based regimens, and tafasitamab-based regimens. No statistically significant differences in response rates or survival were found for epcoritamab compared with CAR T in R/R LBCL.
Assuntos
Anticorpos Monoclonais Humanizados , Linfoma Difuso de Grandes Células B , Humanos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/terapia , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/administração & dosagem , Resultado do Tratamento , Imunoterapia/métodos , Imunoterapia Adotiva/métodos , Masculino , Feminino , Pessoa de Meia-Idade , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Idoso , Adulto , Recidiva Local de Neoplasia/tratamento farmacológicoRESUMO
The antemortem diagnosis of secondary cardiac involvement by lymphoma remains suboptimal. Prognosis is worse with delayed diagnosis as the tumor burden increases with the multicompartment participation. Chemotherapy may improve survival, but there is a risk of mortality due to treatment-related complications, such as myocardial rupture and fatal arrhythmias. Modified chemotherapy regimens may prevent such complications, but the data are limited. We report the case of a 72-year-old woman diagnosed with diffuse large B-cell lymphoma with cardiac involvement, where early diagnosis prevented cardiac complications from the disease and its treatment as well. The aim of this case report is to highlight the fact that cardiac involvement in lymphoma is frequent and can be easily missed, leading to complications. Treatment requires an individualized approach.
Assuntos
Neoplasias Cardíacas , Linfoma Difuso de Grandes Células B , Humanos , Feminino , Idoso , Linfoma Difuso de Grandes Células B/patologia , Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Neoplasias Cardíacas/patologia , Neoplasias Cardíacas/complicações , Ecocardiografia , Septo Interatrial/patologia , Septo Interatrial/diagnóstico por imagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêuticoAssuntos
Tirosina Quinase da Agamaglobulinemia , Antineoplásicos , Linfoma Difuso de Grandes Células B , Inibidores de Proteínas Quinases , Humanos , Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Antineoplásicos/uso terapêutico , AnimaisRESUMO
Diffuse large B-cell lymphoma (DLBCL) is an aggressive non-Hodgkin lymphoma with limited response to chemotherapy. Histone acetylation is reduced in DLBCL. Chidamide, a histone deacetylase inhibitor, shows promise in lymphomas but needs further investigation for DLBCL. Our study indicated that chidamide effectively suppresses DLBCL both in vitro and in vivo. High-throughput RNA sequencing analysis provided comprehensive evidence that chidamide markedly influences crucial signaling pathways in DLBCL, including the MAPK, MYC and p53 pathway. Additionally, we observed substantial variability in the sensitivity of DLBCL cells to chidamide, and identified that elevated expression of BCL6 might confer resistance to chidamide in DLBCL. Moreover, our investigations revealed that BCL6 inhibited chidamide-induced histone acetylation by recruiting histone deacetylase (HDACs), leading to drug resistance in DLBCL cells. Furthermore, we found that lenalidomide targeted BCL6 degradation through the ubiquitination pathway and restore the sensitivity of drug-resistant DLBCL to chidamide. Collectively, these findings provided valuable insights into the global impact of chidamide on DLBCL and highlight the potential of targeting HDACs as a therapeutic strategy for DLBCL. Identifying BCL6 as a biomarker for predicting the response to chidamide and the combination therapy with BCL6 inhibition has the potential to lead to more personalized and effective treatments for DLBCL patients.
Assuntos
Aminopiridinas , Benzamidas , Resistencia a Medicamentos Antineoplásicos , Inibidores de Histona Desacetilases , Linfoma Difuso de Grandes Células B , Proteínas Proto-Oncogênicas c-bcl-6 , Humanos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/metabolismo , Linfoma Difuso de Grandes Células B/genética , Inibidores de Histona Desacetilases/farmacologia , Proteínas Proto-Oncogênicas c-bcl-6/genética , Proteínas Proto-Oncogênicas c-bcl-6/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Benzamidas/farmacologia , Linhagem Celular Tumoral , Animais , Camundongos , Aminopiridinas/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto/métodos , Feminino , Lenalidomida/farmacologia , Lenalidomida/uso terapêutico , Antineoplásicos/farmacologia , Camundongos SCIDRESUMO
Tumor flare reaction (TFR) is characterized by an increase in lesion size during immune-based therapy, often resembling disease progression. It signifies inflammation at the tumor site and is frequently seen in immunotherapy, where it is termed "tumor pseudoprogression." The exact mechanisms behind TFR remain unclear. We report the case of a 62-year-old Japanese man with relapsed and refractory diffuse large B cell lymphoma treated with epcoritamab. On day 10 of the first epcoritamab cycle, after two subcutaneous injections of epcoritamab, the cutaneous lymphoma lesions became swollen. This was identified as TFR, and was managed with a three-day course of intravenous dexamethasone at 12 mg/day. The third injection, scheduled for day 15, was delayed by 1 week. Four doses of epcoritamab were completed over the initial 35-day period. A skin biopsy was performed on day 30. Histopathological examination showed CD20+ large atypical lymphocytes forming residual nodules, encircled by CD4+ and CD8+ lymphocytes, with a predominance of CD8+ T cells over CD4+ T cells. Although infrequent, TFR may be a significant indicator of tumor response to epcoritamab therapy. The diagnosis of TFR could be underestimated, and proper identification and understanding of its clinicopathological features are crucial for its effective management.