RESUMEN
Primary central nervous system lymphoma (PCNSL) is a rare and frequently fatal lymphoma subtype. The programmed death-1 (PD-1) pathway has emerged as a potential therapeutic target, but the effectiveness of PD-1 antibody sintilimab in combination with immunochemotherapy as a frontline treatment for PCNSL remains to be determined. In this phase 2 trial (ChiCTR1900027433) with a safety run-in, we included patients aged 18-70 with newly diagnosed PCNSL. Participants underwent six 21-day cycles of a SMTR regimen, which includes sintilimab (200 mg, Day 0), rituximab (375 mg/m2, Day 0), methotrexate (3.0 g/m2, Day 1 or 1.0 g/m2 for patients aged ≥65 years), and temozolomide (150 mg/m2/d, Days 1-5). Among 27 evaluable patients, the overall response rate (ORR) was 96.3% (95% confidence interval: 81-99.9%), with 25 complete responses. At a median follow-up of 24.4 months, the medians for duration of response, progression-free survival (PFS), and overall survival were not reached. The most common grade 3-4 treatment-related toxicities were increased levels of alanine aminotransferase (17.9%) and aspartate aminotransferase (14.3%). Additionally, baseline levels of interferon-α and the IL10/IL6 ratio in cerebrospinal fluid emerged as potential predictors of PFS, achieving areas under the curve of 0.88 and 0.84, respectively, at 2 years. Whole-exome sequencing revealed a higher prevalence of RTK-RAS and PI3K pathway mutations in the durable clinical benefit group, while a greater frequency of Notch and Hippo pathway mutations in the no durable benefit group. These findings suggest the SMTR regimen is highly efficacious and tolerable for newly diagnosed PCNSL, warranting further investigation.
Asunto(s)
Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias del Sistema Nervioso Central , Metotrexato , Rituximab , Temozolomida , Humanos , Masculino , Femenino , Persona de Mediana Edad , Metotrexato/administración & dosificación , Metotrexato/uso terapéutico , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Rituximab/administración & dosificación , Temozolomida/administración & dosificación , Temozolomida/farmacología , Neoplasias del Sistema Nervioso Central/tratamiento farmacológico , Neoplasias del Sistema Nervioso Central/genética , Neoplasias del Sistema Nervioso Central/inmunología , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/farmacología , Adulto , Linfoma/tratamiento farmacológico , Linfoma/genética , Linfoma/inmunologíaRESUMEN
BACKGROUND: Immune checkpoint blockade with anti-programmed cell death 1 (PD-1) antibodies has demonstrated efficacy in multiple tumor types. Nofazinlimab is a humanized rat antibody targeting PD-1. A first-in-human study of nofazinlimab conducted in Australia found no dose-limiting toxicities (DLTs) and the maximum tolerated dose (MTD) was not reached in the range of 1-10 mg/kg. OBJECTIVE: We evaluated nofazinlimab for multiple advanced malignancies in Chinese patients. PATIENTS AND METHODS: This was a phase 1a/1b, open-label, multicenter, dose-escalation/expansion trial. In phase 1a, patients received an abbreviated dose escalation of nofazinlimab at 60 mg and 200 mg every 3 weeks (Q3W) to determine DLTs and the recommended phase 2 dose (RP2D). In phase 1b, patients received the RP2D (monotherapy/combination) in six arms by tumor type; DLTs were evaluated for nofazinlimab plus lenvatinib in the unresectable hepatocellular carcinoma (uHCC) arm. Safety (continuously monitored in patients who received nofazinlimab) and efficacy (patients with measurable baseline disease) were assessed. RESULTS: Overall, 107 patients were eligible and received nofazinlimab. In phase 1a, no DLTs were observed; the RP2D was 200mg Q3W. In phase 1b, no DLTs were observed with nofazinlimab plus lenvatinib. The safety profile was consistent with that observed in the first-in-human study (NCT03475251). In phase 1b, 21/88 (23.9%) patients achieved confirmed objective responses, 26 (29.5%) had stable disease, and 9/20 (45.0%) patients with uHCC achieved confirmed objective responses to nofazinlimab plus lenvatinib. CONCLUSIONS: Nofazinlimab was well tolerated in Chinese patients. Preliminary efficacy was encouraging, particularly for nofazinlimab plus lenvatinib in uHCC, which is being studied in an ongoing phase 3 trial. CLINICAL TRIAL REGISTRATION: NCT03809767; registered 18 January 2019.
Asunto(s)
Linfoma , Neoplasias , Humanos , Masculino , Femenino , Persona de Mediana Edad , Linfoma/tratamiento farmacológico , Neoplasias/tratamiento farmacológico , Anciano , Adulto , China , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/farmacología , Dosis Máxima Tolerada , Pueblos del Este de AsiaRESUMEN
BACKGROUND: The rarity of primary central nervous system lymphoma (PCNSL) and treatment heterogeneity contributes to a lack of prognostic models for evaluating posttreatment remission. This study aimed to develop and validate radiomic-based models to predict the durable response (DR) to high-dose methotrexate (HD-MTX)-based chemotherapy in PCNSL patients. METHODS: A total of 159 patients pathologically diagnosed with PCNSL between 2011 and 2021 across two institutions were enrolled. According to the NCCN guidelines, the DR was defined as the remission lasting ≥1 year after receiving HD-MTX-based chemotherapy. For each patient, a total of 1218 radiomic features were extracted from prebiopsy T1 contrast-enhanced MR images. Multiple machine-learning algorithms were utilized for feature selection and classification to build a radiomic signature. The radiomic-clinical integrated models were developed using the random forest method. Model performance was externally validated to verify its clinical utility. RESULTS: A total of 105 PCNSL patients were enrolled after excluding 54 cases with ineligibility. The training and validation cohorts comprised 76 and 29 individuals, respectively. Among them, 65 patients achieved DR. The radiomic signature, consisting of 8 selected features, demonstrated strong predictive performance, with area under the curves of 0.994 in training cohort and 0.913 in validation cohort. This signature was independently associated with the DR in both cohorts. Both the radiomic signature and integrated models significantly outperformed the clinical models in two cohorts. Decision curve analysis underscored the clinical utility of the established models. CONCLUSIONS: This radiomic signature and integrated models have the potential to accurately predict the DR to HD-MTX-based chemotherapy in PCNSL patients, providing valuable therapeutic insights.
Asunto(s)
Neoplasias del Sistema Nervioso Central , Imagen por Resonancia Magnética , Metotrexato , Humanos , Metotrexato/uso terapéutico , Metotrexato/administración & dosificación , Masculino , Femenino , Persona de Mediana Edad , Neoplasias del Sistema Nervioso Central/tratamiento farmacológico , Neoplasias del Sistema Nervioso Central/diagnóstico por imagen , Neoplasias del Sistema Nervioso Central/patología , Imagen por Resonancia Magnética/métodos , Anciano , Linfoma/tratamiento farmacológico , Linfoma/diagnóstico por imagen , Linfoma/patología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Adulto , Pronóstico , Aprendizaje Automático , Resultado del Tratamiento , Estudios Retrospectivos , RadiómicaRESUMEN
Antibody-drug conjugate(ADC)contain monoclonal antibodies that target-specific tumor antigens, cytotoxic payloads, and linkers. ADCs use antibodies to selectively act on tumors, making them more effective and less toxic. In Japan, 4 drugs are approved as ADCs for leukemia and lymphoma: gemtuzumab ozogamicin(GO)consists of an anti-CD33 monoclonal antibody bound to calicheamicin via a linker, approved for relapsed/refractory acute myeloid leukemia. Brentuximab vedotin (BV)has anti-CD30 antibodies bound to MMAE via a linker and is approved for CD30-positive Hodgkin's lymphoma, peripheral T-cell lymphoma, and cutaneous T-cell lymphoma. BV, in combination with multi-agent chemotherapy, resulted in significantly prolonged progression-free survival(PFS)in classical Hodgkin's lymphoma and peripheral T-cell lymphoma compared to the control group. Inotuzumab ozogamicin(IO)has an anti-CD22 antibody bound to calicheamicin via a linker, approved for relapsed/refractory CD22-positive B-cell acute lymphoblastic leukemia. In relapsed/refractory B-cell acute lymphoblastic leukemia, IO showed a higher complete remission rate than the control group. Polatuzumab vedotin(PV)has an anti-CD79b monoclonal antibody bounds to MMAE via a linker, approved for diffuse large B-cell lymphoma(DLBCL). In DLBCL patients with an international prognostic index score(IPI score)of 2 or higher, the combination of PV plus rituximab, cyclophosphamide, doxorubicin, and prednisone(PV+R-CHP)extended PFS at 2 years compared with R-CHOP(rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone), which has long been the standard of care. As shown, ADCs exhibit high therapeutic efficacy in leukemia and lymphoma treatment, but many aspects of their resistance mechanisms remain unclear and require further research.
Asunto(s)
Inmunoconjugados , Leucemia , Linfoma , Humanos , Inmunoconjugados/uso terapéutico , Leucemia/tratamiento farmacológico , Leucemia/inmunología , Linfoma/tratamiento farmacológico , Linfoma/inmunología , Antineoplásicos/uso terapéuticoRESUMEN
BACKGROUND Fermenting bacilli producing lactic acid, including Bifidobacterium spp., are supposed to have low pathogenicity and no virulence for humans. Probiotics consisting of those fermenting bacilli can prevent and treat symptomatic gastrointestinal conditions, such as diarrhea. We use probiotics even in cancer patients, those who are immunocompromised, because a preferable effect to the intestinal commensal microbiome has been shown in a recent report. Some case reports warn of a rare risk of bloodstream infection caused by probiotics. However, complete prohibition of probiotic use in cancer patients abandons the benefits. CASE REPORT A 75-year-old Japanese woman with malignant lymphoma was treated with immune-chemotherapy regimen consisting of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP). The patient had onset of febrile neutropenia during chemotherapy and had Bifidobacterium breve bloodstream infection on day 8 after the eighth R-CHOP treatment. She had usually eaten commercial yogurt every morning. This yogurt was produced from only Lactobacillus bulgaricus and Streptococcus thermophilus. It did not contain Bifidobacterium breve. The bloodstream infection in this case looked like it derived from her food; however, it was not associated with her habitual foods. The patient was treated with meropenem for 8 days and experienced complete remission of the bloodstream infection. CONCLUSIONS We speculate that fermenting bacilli can also be a source of bloodstream infection, not necessarily associated with probiotic strains, in cancer patients treated with chemotherapy. Additionally, we recommend that probiotics can alleviate alimentary tract symptoms in immunocompromised patients.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Probióticos , Humanos , Femenino , Anciano , Probióticos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Ciclofosfamida/uso terapéutico , Doxorrubicina/uso terapéutico , Doxorrubicina/efectos adversos , Vincristina/uso terapéutico , Infecciones por Bifidobacteriales/microbiología , Rituximab/uso terapéutico , Rituximab/efectos adversos , Prednisona/uso terapéutico , Bacteriemia/tratamiento farmacológico , Bacteriemia/microbiología , Bifidobacterium breve , Linfoma/tratamiento farmacológicoAsunto(s)
Neoplasias del Sistema Nervioso Central , Humanos , Neoplasias del Sistema Nervioso Central/tratamiento farmacológico , Inmunoterapia Adoptiva , Proyectos Piloto , Productos Biológicos/uso terapéutico , Vacunas contra el Cáncer/uso terapéutico , Linfoma/tratamiento farmacológico , Linfoma/diagnósticoRESUMEN
BACKGROUND: Autologous stem cell transplantation (ASCT) is a pivotal treatment for lymphoma patients. The BeEAM regimen (Bendamustine, Etoposide, Cytarabine, Melphalan) traditionally relies on cryopreservation, whereas the CEM regimen (Carboplatin, Etoposide, Melphalan) has been optimized for short-duration administration without the need for cryopreservation. This study rigorously compares the clinical and safety profiles of the BeEAM and CEM regimens. METHODS: A controlled, randomized clinical trial was conducted with 58 lymphoma patients undergoing ASCT at the International Medical Center (IMC) in Cairo, Egypt. Patients were randomly assigned to either the BeEAM (n = 29) or CEM (n = 29) regimen, with an 18-month follow-up period. Clinical and safety outcomes were meticulously compared, focusing on time to engraftment for neutrophils and platelets, side effects, length of hospitalization, transplant-related mortality (TRM), and survival rates. RESULTS: The findings demonstrate a significant advantage for the CEM regimen. Neutrophil recovery was markedly faster in the CEM group, averaging 8.5 days compared to 14.5 days in the BeEAM group (p < 0.0001). Platelet recovery was similarly expedited, with 11 days in the CEM group versus 23 days in the BeEAM group (p < 0.0001). Hospitalization duration was substantially shorter for CEM patients, averaging 18.5 days compared to 30 days for those on BeEAM (p < 0.0001). Furthermore, overall survival (OS) was significantly higher in the CEM group at 96.55% (95% CI: 84.91-99.44%) compared to 79.31% (95% CI: 63.11-89.75%) in the BeEAM group (p = 0.049). Progression-free survival (PFS) was also notably superior in the CEM group, at 86.21% (95% CI: 86.14-86.28%) versus 62.07% (95% CI: 61.94-62.20%) in the BeEAM group (p = 0.036). CONCLUSION: The CEM regimen might demonstrate superiority over the BeEAM regimen, with faster neutrophil and platelet recovery, reduced hospitalization time, and significantly improved overall and progression-free survival rates. Future studies with longer duration and larger sample sizes are warranted. TRIAL REGISTRATION: This study is registered on ClinicalTrials.gov under the registration number NCT05813132 ( https://clinicaltrials.gov/ct2/show/NCT05813132 ). (The first submitted registration date: is March 16, 2023).
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Clorhidrato de Bendamustina , Carboplatino , Citarabina , Etopósido , Trasplante de Células Madre Hematopoyéticas , Linfoma , Melfalán , Acondicionamiento Pretrasplante , Trasplante Autólogo , Humanos , Trasplante de Células Madre Hematopoyéticas/métodos , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Femenino , Masculino , Citarabina/administración & dosificación , Citarabina/efectos adversos , Citarabina/uso terapéutico , Etopósido/administración & dosificación , Etopósido/efectos adversos , Etopósido/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Melfalán/administración & dosificación , Melfalán/efectos adversos , Melfalán/uso terapéutico , Adulto , Linfoma/terapia , Linfoma/mortalidad , Linfoma/tratamiento farmacológico , Persona de Mediana Edad , Acondicionamiento Pretrasplante/métodos , Clorhidrato de Bendamustina/administración & dosificación , Clorhidrato de Bendamustina/efectos adversos , Carboplatino/administración & dosificación , Carboplatino/efectos adversos , Carboplatino/uso terapéutico , Adulto Joven , Adolescente , Resultado del TratamientoRESUMEN
Proteolysis targeting chimeras (PROTAC) are bifunctional chimeric molecules capable of directly degrading binding proteins through the ubiquitin-proteasome pathway. PROTACs have demonstrated significant potential in overcoming drug resistance and targeting previously untreatable targets. However, several limitations still need to be addressed, including their high molecular weight resulting in poor membrane permeability and bioavailability. In this study, we proposed that cancer-targeted penetrating peptides could enhance the cell permeability of PROTACs. We developed 26 novel targeted penetrating peptides for leukemia and lymphoma cells, among which C9C-f(3Bta) and Cyclo-C9C-R exhibited superior membrane permeability, targetability, and stability. By combining C9C-f(3Bta) and Cyclo-C9C-R with IMA-PROTAC, we effectively enhanced the anti-proliferative activity of IMA-PROTAC, facilitated degradation of Bcr-Abl protein in K562 cells, and reduced downstream STAT5 phosphorylation. Furthermore, the combined application promoted cell apoptosis while blocking G1 phase progression. HPLC-MRM-MS revealed that the combination of C9C-f(3Bta) or Cyclo-C9C-R with IMA-PROTAC significantly enhanced intracellular IMA-PROTAC content. In summary, our proof-of-concept study validated the hypothesis that combining PROTACs with targeted penetrating peptides can improve protein degradation efficiency as well as anti-proliferative capabilities.
Asunto(s)
Antineoplásicos , Apoptosis , Proliferación Celular , Leucemia , Linfoma , Proteolisis , Humanos , Leucemia/tratamiento farmacológico , Leucemia/patología , Leucemia/metabolismo , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Proteolisis/efectos de los fármacos , Linfoma/tratamiento farmacológico , Linfoma/patología , Linfoma/metabolismo , Proliferación Celular/efectos de los fármacos , Apoptosis/efectos de los fármacos , Descubrimiento de Drogas , Ensayos de Selección de Medicamentos Antitumorales , Relación Estructura-Actividad , Péptidos de Penetración Celular/química , Péptidos de Penetración Celular/farmacología , Péptidos de Penetración Celular/síntesis química , Estructura Molecular , Células K562 , Relación Dosis-Respuesta a Droga , Sistemas de Liberación de MedicamentosRESUMEN
BACKGROUND: Symptom networks offer a theoretical basis for developing personalised and precise symptom management strategies. However, symptom networks in lymphoma patients during chemotherapy have been rarely reported. This study intends to establish contemporaneous symptom networks in lymphoma patients during chemotherapy and explore the centrality indices and density in these symptom networks. METHODS AND ANALYSIS: This is a single-centre prospective cross-sectional study. A total of 315 lymphoma patients admitted to the Lymphoma Department of Shanxi Bethune Hospital since 1 June 2024 will be selected as the study subjects. The patient-reported outcome measures of General Data Questionnaire and Lymphoma Symptom Assessment Scale will be assessed. R package will be used to construct a contemporaneous symptom network, explore the relationship between core and analysed symptoms and analyse the predictive role of network density on patient prognosis. ETHICS AND DISSEMINATION: This study adheres to the principles of the Declaration of Helsinki and relevant ethical guidelines. Ethical approval has been obtained from Shanxi Bethune Hospital Ethics Committee (approval number: YXLL-2023-186). The final outcomes will be published in a peer-reviewed journal and disseminated through a conference.
Asunto(s)
Linfoma , Humanos , Estudios Transversales , Estudios Prospectivos , Linfoma/tratamiento farmacológico , Medición de Resultados Informados por el Paciente , Evaluación de Síntomas/métodos , Antineoplásicos/uso terapéutico , Antineoplásicos/efectos adversos , Encuestas y Cuestionarios , Femenino , Proyectos de Investigación , MasculinoAsunto(s)
Bevacizumab , Hemorragia Gastrointestinal , Humanos , Hemorragia Gastrointestinal/inducido químicamente , Hemorragia Gastrointestinal/etiología , Bevacizumab/efectos adversos , Bevacizumab/uso terapéutico , Masculino , Inhibidores de la Angiogénesis/efectos adversos , Inhibidores de la Angiogénesis/uso terapéutico , Anciano , Hemostasis/efectos de los fármacos , Linfoma/tratamiento farmacológico , Linfoma/complicaciones , Femenino , Persona de Mediana EdadRESUMEN
Biomarkers for immune checkpoint inhibitors (ICIs) response and resistance include PD-L1 expression and other environmental factors, among which the gut microbiome (GM) is gaining increasing interest especially in lymphomas. To explore the potential role of GM in this clinical issue, feces of 30 relapsed/refractory lymphoma (Hodgkin and primary mediastinal B-cell lymphoma) patients undergoing ICIs were collected from start to end of treatment (EoT). GM was profiled through Illumina, that is, 16S rRNA sequencing, and subsequently processed through a bioinformatics pipeline. The overall response rate to ICIs was 30.5%, with no association between patients clinical characteristics and response/survival outcomes. Regarding GM, responder patients showed a peculiar significant enrichment of Lachnospira, while non-responder ones showed higher presence of Enterobacteriaceae (at baseline and maintained till EoT). Recognizing patient-related factors that may influence response to ICIs is becoming critical to optimize the treatment pathway of heavily pretreated, young patients with a potentially long-life expectancy. These preliminary results indicate potential early GM signatures of ICIs response in lymphoma, which could pave the way for future research to improve patients prognosis with new adjuvant strategies.
Asunto(s)
Microbioma Gastrointestinal , Inhibidores de Puntos de Control Inmunológico , Humanos , Microbioma Gastrointestinal/efectos de los fármacos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Masculino , Femenino , Persona de Mediana Edad , Adulto , Anciano , Linfoma/tratamiento farmacológico , Linfoma/microbiología , Adulto Joven , Pronóstico , Resultado del TratamientoRESUMEN
Background: Autologous stem cell transplantation (ASCT) is a potentially curative strategy for relapse or refractory(r/r) aggressive lymphoma. However, a proportion of lymphoma patients who are at high risk of mobilization failure fail to mobilize stem cells and cannot proceed to ASCT. The aim of this study is to explore the efficacy and safety of Etoposide combined with Cytarabine (EA) plus G-CSF mobilization in poor mobilizers (PMs) with r/r aggressive lymphoma. Methods: This retrospective study analyzed the outcomes of chemo-mobilization based on EA (Etoposide 0.1 g/m2, qd d1~3; AraC 0.5 g/m2, q12h d1~3) in 98 patients with r/r aggressive lymphoma. Of these, 39 patients met the criteria for predicted PMs as proposed by the Gruppo Italiano Trapianto di Midollo Osseo working group. Results: Of the 39 PMs, 38(97.4%) patents harvested adequate mobilization (≥2×106 CD34+ cells/kg), while 31(79.5%) patients achieved optimal mobilization (≥5×106 CD34+ cells/kg). Overall, the mean number of CD34+ cells/kg collected was 17.99(range: 1.08~83.07) ×106 with an average of 1.4 apheresis sessions, and the number was 15.86(range: 0.37~83.07) ×106 for the first apheresis, respectively. A single apheresis procedure was sufficient to reach the target yield of adequate mobilization in 35(89.7%) PMs, while 76.9% of PMs achieved optimal collection within two apheresis sessions. We observed acceptable hematological toxicity and antibiotic usage exposure in 26 patients with a mean duration of 3.6 days. No grade 4 infection or mobilization-related mortality was recorded. Most patients underwent ASCT and achieved successful hematopoietic recovery with prompt engraftment duration, except for one NK/T-cell lymphoma patient who succumbed to severe septicemia after receiving conditioning chemotherapy. Conclusion: Our findings indicate that EA plus G-CSF is an effective and tolerable CD34+ stem cell mobilization strategy for patients with r/r lymphoma, including those predicted to be PMs. This regimen could be an option for patients with r/r lymphoma, particularly those undergoing mobilization for salvage ASCT therapy.
Asunto(s)
Citarabina , Etopósido , Factor Estimulante de Colonias de Granulocitos , Movilización de Célula Madre Hematopoyética , Linfoma , Humanos , Etopósido/administración & dosificación , Etopósido/uso terapéutico , Movilización de Célula Madre Hematopoyética/métodos , Citarabina/administración & dosificación , Citarabina/uso terapéutico , Masculino , Femenino , Factor Estimulante de Colonias de Granulocitos/administración & dosificación , Adulto , Persona de Mediana Edad , Linfoma/terapia , Linfoma/mortalidad , Linfoma/tratamiento farmacológico , Estudios Retrospectivos , Anciano , Adulto Joven , Trasplante de Células Madre Hematopoyéticas/métodos , Trasplante Autólogo , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Recurrencia , Resultado del Tratamiento , AdolescenteRESUMEN
Despite the potential of neutralizing antibodies in the management of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), clinical research on its efficacy in Chinese patients remains limited. This study is aimed at investigating the therapeutic effect of combination of antiviral therapy with neutralizing monoclonal antibodies for recurrent persistent SARS-CoV-2 pneumonia in patients with lymphoma complicated by B cell depletion. A prospective study was conducted on Chinese patients who were treated with antiviral nirmatrelvir/ritonavir therapy and the neutralizing antibody tixagevimab-cilgavimab (tix-cil). The primary outcome was the rate of recurrent SARS-CoV-2 infection. Five patients with lymphoma experienced recurrent SARS-CoV-2 pneumonia and received tix-cil treatment. All patients had a history of CD20 monoclonal antibody use within the year preceding SARS-CoV-2 infection, and two patients also had a history of Bruton's tyrosine kinase (BTK) inhibitor use. These patients had notably low lymphocyte counts and exhibited near depletion of B cells. All five patients tested negative for serum SARS-CoV-2 IgG and IgM antibodies. None of the patients developed reinfection with SARS-CoV-2 pneumonia after antiviral and tix-cil treatment during the 6-month follow-up period. In conclusion, the administration of antiviral and SARS-CoV-2-neutralizing antibodies showed encouraging therapeutic efficacy against SARS-CoV-2 pneumonia in patients with lymphoma complicated by B cell depletion, along with the potential preventive effect of neutralizing antibodies for up to 6 months.
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Anticuerpos Neutralizantes , Antivirales , Tratamiento Farmacológico de COVID-19 , COVID-19 , Linfoma , Ritonavir , SARS-CoV-2 , Humanos , Masculino , Anticuerpos Neutralizantes/uso terapéutico , Persona de Mediana Edad , Femenino , Antivirales/uso terapéutico , SARS-CoV-2/inmunología , Linfoma/tratamiento farmacológico , Linfoma/complicaciones , COVID-19/inmunología , COVID-19/complicaciones , Ritonavir/uso terapéutico , Anciano , Estudios Prospectivos , Adulto , Anticuerpos Monoclonales Humanizados/uso terapéutico , Resultado del Tratamiento , Combinación de Medicamentos , Recurrencia , Lopinavir/uso terapéutico , Anticuerpos Antivirales/inmunología , Anticuerpos Antivirales/uso terapéuticoRESUMEN
Lymphoma, a blood tumor, has become the ninth most common cancer in the world in 2020. Targeted inhibition is one of the important treatments for lymphoma. At present, there are many kinds of targeted drugs for the treatment of lymphoma. Studies have shown that Histone deacetylase, Bruton's tyrosine kinase and phosphoinositide 3-kinase all play an important role in the occurrence and development of tumors and become important and promising inhibitory targets. This article mainly expounds the important role of these target protein in tumors, and introduces the mechanism of action, structure-activity relationship and clinical research of listed small molecule inhibitors of these targets, hoping to provide new ideas for the treatment of lymphoma.
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Agammaglobulinemia Tirosina Quinasa , Antineoplásicos , Linfoma , Bibliotecas de Moléculas Pequeñas , Humanos , Linfoma/tratamiento farmacológico , Linfoma/metabolismo , Linfoma/patología , Antineoplásicos/farmacología , Antineoplásicos/química , Agammaglobulinemia Tirosina Quinasa/antagonistas & inhibidores , Agammaglobulinemia Tirosina Quinasa/metabolismo , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/farmacología , Histona Desacetilasas/metabolismo , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Histona Desacetilasas/farmacología , Inhibidores de Histona Desacetilasas/química , Relación Estructura-Actividad , Inhibidores de las Quinasa Fosfoinosítidos-3/farmacología , Inhibidores de las Quinasa Fosfoinosítidos-3/química , Inhibidores de las Quinasa Fosfoinosítidos-3/uso terapéutico , Terapia Molecular DirigidaRESUMEN
PURPOSE: Ibrutinib is a first-in-class inhibitor of Bruton tyrosine kinase. We previously reported the safety and short-term antitumor activity of ibrutinib in 20 patients with relapsed or refractory (r/r) primary central nervous system (CNS) lymphoma (PCNSL) or secondary CNS lymphoma (SCNSL). PATIENTS AND METHODS: We enrolled 26 additional patients with r/r PCNSL/SCNSL into the dose-expansion cohort of the trial into a combined cohort of 46 patients (31 with PCNSL and 15 with SCNSL). Patients received ibrutinib at 560 or 840 mg daily in the dose-escalation cohort and ibrutinib at 840 mg daily in the expansion cohort. The median follow-up was 49.9 and 62.1 months for patients with PCNSL and SCNSL, respectively. We sequenced DNA from available tumor biopsies and cerebrospinal fluid collected before and during ibrutinib therapy. RESULTS: Tumor responses were observed in 23/31 (74%) patients with PCNSL and 9/15 (60%) patients with SCNSL, including 12 complete responses in PCNSL and 7 in SCNSL. The median progression-free survival (PFS) for PCNSL was 4.5 months [95% confidence interval (CI), 2.8-9.2] with 1-year PFS at 23.7% (95% CI, 12.4%-45.1%). The median duration of response in the 23 PCNSL responders was 5.5 months. The median PFS in SCNSL was 5.3 months (95% CI, 1.3-14.5) with a median duration of response of 8.7 months for the 9 responders. Exploratory biomarker analysis suggests that mutations in TBL1XR1 may be associated with a long-term response to ibrutinib in PCNSL (P = 0.0075). Clearance of ctDNA from cerebrospinal fluid was associated with complete and long-term ibrutinib responses. CONCLUSIONS: Our study confirms single-agent activity of ibrutinib in r/r CNS lymphoma and identifies molecular determinants of response based on long-term follow-up.
Asunto(s)
Adenina , Neoplasias del Sistema Nervioso Central , Recurrencia Local de Neoplasia , Piperidinas , Humanos , Adenina/análogos & derivados , Adenina/uso terapéutico , Piperidinas/uso terapéutico , Masculino , Femenino , Neoplasias del Sistema Nervioso Central/tratamiento farmacológico , Neoplasias del Sistema Nervioso Central/secundario , Neoplasias del Sistema Nervioso Central/mortalidad , Persona de Mediana Edad , Anciano , Adulto , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/patología , Anciano de 80 o más Años , Resistencia a Antineoplásicos , Linfoma/tratamiento farmacológico , Linfoma/mortalidad , Linfoma/patología , Pirazoles/uso terapéutico , Pirazoles/administración & dosificación , Pirazoles/efectos adversos , Pirimidinas/uso terapéutico , Pirimidinas/administración & dosificación , Pirimidinas/efectos adversos , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/administración & dosificación , Resultado del Tratamiento , Agammaglobulinemia Tirosina Quinasa/antagonistas & inhibidores , Agammaglobulinemia Tirosina Quinasa/genética , MutaciónRESUMEN
Primary central nervous system lymphoma (PCNSL) is a group of malignant brain tumors with a poor prognosis, and new therapeutic approaches for this tumor urgently need to be investigated. Formulated from a long-standing anti-inflammatory drugs, ACT001 has demonstrated in clinical research to be able to pass through the blood-brain barrier (BBB) and affect the central nervous system. The effects of ACT001 on PCNSL cell apoptosis, proliferation and immune-related indexes were detected by flow cytometry, and the efficacy of ACT001 was verified in vivo by constructing a mouse PCNSL tumor model. ACT001 significantly inhibited PCNSL cell proliferation and induced apoptosis in vitro. In addition, ACT001 can significantly inhibit the PD-1/PD-L1 expression and restore the function of T cells, so that the immune system cannot allow tumor cells to escape. In vivo experiments show that co-infusion of ACT001 and T cells effectively inhibits PCNSL tumor growth in NSG mice. Our work describes the inhibitory effect of ACT001 on the PCNSL cell line and demonstrated the inhibitory effect of ACT001 on immune checkpoints.
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Apoptosis , Proliferación Celular , Neoplasias del Sistema Nervioso Central , Linfoma , Linfocitos T , Animales , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Ratones , Apoptosis/efectos de los fármacos , Neoplasias del Sistema Nervioso Central/tratamiento farmacológico , Neoplasias del Sistema Nervioso Central/patología , Neoplasias del Sistema Nervioso Central/inmunología , Linfoma/tratamiento farmacológico , Linfoma/patología , Linfoma/inmunología , Humanos , Antígeno B7-H1/metabolismo , Ratones Endogámicos NOD , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Antineoplásicos/farmacología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Lymphoid tumor patients often exhibit resistance to standard therapies or experience relapse post-remission. Relapse is driven by Tumor Initiating Cells (TICs), a subset of tumor cells capable of regrowing the tumor and highly resistant to therapy. Growing cells in 3D gels is a method to discern tumorigenic cells because it strongly correlates with tumorigenicity. The finding that TICs, rather than differentiated tumor cells, grow in 3D gels offers a unique opportunity to unveil TIC-specific signaling pathways and therapeutic targets common to various cancer types. Here, we show that culturing lymphoid cells in 3D gels triggers reactive oxygen species (ROS) production, leading to non-tumor lymphoid cell death while enabling the survival and proliferation of a subset of lymphoma/leukemia cells, TICs or TIC-like cells. Treatment with the antioxidant N-acetylcysteine inhibits this lethality and promotes the growth of primary non-tumor lymphoid cells in 3D gels. A subset of lymphoma cells, characterized by an increased abundance of the antioxidant glutathione, escape ROS-induced lethality, a response not seen in non-tumor cells. Reducing glutathione production in lymphoma cells, either through pharmacological inhibition of glutamate cysteine ligase (GCL), the enzyme catalyzing the rate-limiting step in glutathione biosynthesis, or via knockdown of GCLC, the GCL catalytic subunit, sharply decreased cell growth in 3D gels and xenografts. Tumor cells from B-cell lymphoma/leukemia patients and λ-MYC mice, a B-cell lymphoma mouse model, overproduce glutathione. Importantly, pharmacological GCL inhibition hindered lymphoma growth in female λ-MYC mice, suggesting that this treatment holds promise as a therapeutic strategy for female lymphoma/leukemia patients.
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Glutatión , Linfoma , Células Madre Neoplásicas , Especies Reactivas de Oxígeno , Animales , Humanos , Femenino , Linfoma/patología , Linfoma/metabolismo , Linfoma/tratamiento farmacológico , Glutatión/metabolismo , Ratones , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Células Madre Neoplásicas/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Masculino , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Carcinogénesis/patología , Carcinogénesis/efectos de los fármacos , Carcinogénesis/metabolismoRESUMEN
BACKGROUND: Dogs with lymphoma that fail cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy (CHOP) before completion of their protocol are commonly thought to have poor long-term outcome, but no previous studies have evaluated the effect of early relapse on progression-free interval (PFI) or overall survival time (OST) for patients undergoing rescue chemotherapy. OBJECTIVE: Correlate rescue treatment outcomes in dogs with multicentric lymphoma with outcomes after 1st-line CHOP chemotherapy. METHODS: Data were collected from 6 previous retrospective or prospective studies in 187 dogs with multicentric lymphoma that received 1st-line CHOP chemotherapy and then received either lomustine (CCNU), L-asparaginase and prednisone (LAP), or rabacfosadine (RAB, Tanovea), with or without prednisone or L-asparaginase. RESULTS: The PFI after initiation of CHOP chemotherapy was significantly associated with response rate postprogression, PFI, and postrescue survival time (ST) for both rescue protocols. Immunophenotype (B- vs T-cell) was not significantly associated with response, PFI or OST for LAP but was significantly associated with response and PFI for RAB. CONCLUSION: Dogs that experience short PFI during or after 1st-line CHOP chemotherapy had lower response rates to rescue treatment, with shorter PFI and ST. Immunophenotype did not significantly affect outcome with LAP but was associated with PFI for RAB.
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Protocolos de Quimioterapia Combinada Antineoplásica , Ciclofosfamida , Enfermedades de los Perros , Doxorrubicina , Linfoma , Prednisona , Vincristina , Animales , Perros , Enfermedades de los Perros/tratamiento farmacológico , Vincristina/uso terapéutico , Ciclofosfamida/uso terapéutico , Ciclofosfamida/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Prednisona/uso terapéutico , Prednisona/administración & dosificación , Doxorrubicina/uso terapéutico , Femenino , Masculino , Linfoma/veterinaria , Linfoma/tratamiento farmacológico , Asparaginasa/uso terapéutico , Resultado del Tratamiento , Estudios Retrospectivos , Lomustina/uso terapéutico , Progresión de la Enfermedad , Estudios Prospectivos , Alanina/análogos & derivados , PurinasRESUMEN
Left ventricular dysfunction in dogs after the administration of doxorubicin (DOX) has been extensively examined. However, the effects of DOX on right ventricular (RV) function remain unknown. Therefore, the present study investigated whether the chemotherapy treatment with DOX decreases RV function. Twelve dogs (five with multicentric lymphoma, four with hemangiosarcoma, two with thyroid cancer, and one with lung adenocarcinoma) that received at least two doses of DOX were prospectively enrolled. Echocardiography and the measurement of troponin I were performed prior to each administration of DOX and approximately one month after the last administration. Right ventricular function was assessed by the RV fractional area change and RV Tei index. Two (n=4), three (n=3), four (n=3), and five (n=2) doses of DOX were administered. While no significant differences were observed in the RV fractional area change, the RV Tei index was significantly impaired after two doses of DOX. Troponin I level significantly increased after four doses. Cumulative doses of DOX correlated with the RV Tei index (r=0.77, P<0.001). The present results demonstrated that the chemotherapy treatment with DOX decreased RV function in a dose-dependent manner in dogs.
Asunto(s)
Antibióticos Antineoplásicos , Enfermedades de los Perros , Doxorrubicina , Ecocardiografía , Troponina I , Animales , Perros , Doxorrubicina/administración & dosificación , Enfermedades de los Perros/tratamiento farmacológico , Masculino , Femenino , Antibióticos Antineoplásicos/uso terapéutico , Troponina I/sangre , Ecocardiografía/veterinaria , Función Ventricular Derecha/efectos de los fármacos , Disfunción Ventricular Derecha/veterinaria , Disfunción Ventricular Derecha/tratamiento farmacológico , Linfoma/veterinaria , Linfoma/tratamiento farmacológico , Estudios Prospectivos , Hemangiosarcoma/veterinaria , Hemangiosarcoma/tratamiento farmacológicoRESUMEN
Over the past 30 years the incorporation of monoclonal antibody (mAb) treatments into the management of hematologic malignancies has led to significant improvements in patient outcomes. The key limitation of mAb treatments is the necessity for target antigen presentation on major histocompatibility complex (MHC) and costimulatory molecules to elicit a cytotoxic immune response. With the advent of bispecific antibodies (BsAbs), these limitations can be overcome through direct stimulation of cytotoxic T cells, thus limiting tumor cell evasion. BsAbs are rapidly being incorporated into treatment regimens for hematologic malignancies, and there are now seven FDA-approved treatments in this class, six of which have been approved in the past year. In this review we describe the function, complications, and clinical trial data available for CD3 BsAbs in the treatment of lymphoma, myeloma, and leukemia.