RESUMO
A 13-year-old neutered male Lagotto Romagnolo dog had ultrasonographic and computed tomographic findings of pneumatosis intestinalis after presentation to the emergency department because of progressive diarrhea and hyporexia. Further investigations produced a diagnosis of multicentric lymphoma, and treatment with chemotherapy was commenced. Clinical remission of lymphoma was achieved and coincided with resolution of pneumatosis intestinalis on subsequent computed tomographic imaging. Key clinical message: Consider underlying pathology such as neoplasia in cases of pneumatosis intestinalis after excluding surgical emergent causes.
Présence d'une pneumatose intestinale chez un chien atteint d'un lymphome multicentriqueUn chien Lagotto Romagnolo mâle castré de 13 ans a présenté des résultats échographiques et tomodensitométriques de pneumatose intestinale après sa présentation au service des urgences en raison d'une diarrhée progressive et d'une hyporexie. Des examens complémentaires ont permis de poser un diagnostic de lymphome multicentrique et un traitement par chimiothérapie a été débuté. Une rémission clinique du lymphome a été obtenue et a coïncidé avec la résolution de la pneumatose intestinale sur l'imagerie par tomodensitométrie ultérieure.Message clinique clé :Envisager une pathologie sous-jacente telle qu'une néoplasie dans les cas de pneumatose intestinale après avoir exclu les causes d'origine chirurgicale.(Traduit par Dr Serge Messier).
Assuntos
Doenças do Cão , Linfoma , Pneumatose Cistoide Intestinal , Animais , Cães , Masculino , Doenças do Cão/diagnóstico por imagem , Doenças do Cão/tratamento farmacológico , Doenças do Cão/diagnóstico , Pneumatose Cistoide Intestinal/veterinária , Pneumatose Cistoide Intestinal/diagnóstico por imagem , Pneumatose Cistoide Intestinal/complicações , Pneumatose Cistoide Intestinal/diagnóstico , Linfoma/veterinária , Linfoma/complicações , Linfoma/tratamento farmacológicoAssuntos
Neoplasias do Sistema Nervoso Central , Tiotepa , Humanos , Neoplasias do Sistema Nervoso Central/terapia , Neoplasias do Sistema Nervoso Central/patologia , Tiotepa/administração & dosagem , Tiotepa/uso terapêutico , Pessoa de Meia-Idade , Masculino , Feminino , Adulto , Linfoma/terapia , Linfoma/diagnóstico , Linfoma/tratamento farmacológico , Autoenxertos , Transplante de Células-Tronco Hematopoéticas/métodos , Idoso , Transplante Autólogo , Resultado do TratamentoRESUMO
BACKGROUND: Double-hit lymphoma (DHL) with c-MYC gene translocation is highly aggressive and has a poor prognosis. In DHL cells, activation-induced cytidine deaminase (AID) promotes antibody class switch recombination (CSR), ultimately leading to c-MYC gene translocation caused by Myc/IgH DNA double-strand breaks. However, currently there is still no method to suppress the expression of AID. METHODS: In this study, we compared the clinical significance of AID expression in DHL, Additionally, two human double-hit lymphoma cell lines were used to analyze the effect of imatinib mesylate on c-MYC in vitro, and the therapeutic effect was also evaluated in xenograft mouse models. RESULTS: Imatinib mesylate downregulated the AID and c-MYC proteins in patients with chronic myelogenous leukemia associated with DHL. In addition, imatinib mesylate reduced AID and c-MYC expression in SU-DHL-4 and OCI-Ly18 DHL cells. Imatinib mesylate exerted significant inhibitory effects on the proliferation and metastasis of SU-DHL-4 and OCI-Ly18 cells. Finally, imatinib mesylate reduced not only tumor burden in DHL mouse models, but also AID and c-MYC expression in vivo. CONCLUSION: These findings reveal that imatinib mesylate effectively reduces the carcinogenic function of c-MYC in DHL, providing novel strategies for developing therapies targeting c-MYC-driven DHL.
Assuntos
Citidina Desaminase , Mesilato de Imatinib , Proteínas Proto-Oncogênicas c-myc , Ensaios Antitumorais Modelo de Xenoenxerto , Mesilato de Imatinib/farmacologia , Animais , Humanos , Citidina Desaminase/genética , Citidina Desaminase/metabolismo , Camundongos , Proteínas Proto-Oncogênicas c-myc/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , Linhagem Celular Tumoral , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Feminino , Antineoplásicos/farmacologia , Translocação Genética , Masculino , Proliferação de Células/efeitos dos fármacos , Linfoma/tratamento farmacológico , Linfoma/patologia , Linfoma/genética , Linfoma/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacosRESUMO
BACKGROUND: Results of conventional induction chemotherapies in primary central nervous system lymphoma (PCNSL) need to be improved. Ibrutinib, a BTK inhibitor, and lenalidomide, an immunomodulatory drug, have shown promising results at relapse, supporting to further assess their individual use in combination with high-dose methotrexate-based chemotherapy. METHODS: Patients with newly diagnosed PCNSL were randomized to receive four 28-day cycles of ibrutinib or lenalidomide in combination with R-MPV (rituximab, methotrexate, procarbazine, vincristine and prednisone) in a 3 + 3 design. Responders then received a consolidation with R-Cytarabine and an intensive chemotherapy with autologous stem cell transplantation. The objective of the phase IB study was to define the recommended phase II dose (RP2D) based on the dose-limiting toxicity (DLT) occurring during the first induction cycle. RESULTS: Twenty-six patients (median age 52) were randomized. Four DLTs were observed: one grade 5 aspergillosis and pneumocystosis, one grade 4 catheter-related infection and two grade 3 increased alanine aminotransferase levels. RP2D of ibrutinib and lenalidomide were 560 mg daily (D3-14 and D17-28) and 15 mg daily (D1-21) respectively, in combination with R-MPV. In both arms, the most frequent grade ≥3 treatment-related adverse events were hepatic cytolysis, neutropenia and infections. One grade 4 Lyell's syndrome was reported at cycle 2 in the lenalidomide arm. After 4 induction cycles, the overall response rates were 76.9% and 83.3% in the lenalidomide and ibrutinib arm, respectively. CONCLUSION: Targeted induction therapies combining lenalidomide or ibrutinib with R-MPV are feasible for first-line PCNSL. The safety profile is consistent with the known safety profiles of R-MPV and both targeted therapies. The phase II part of the study is ongoing. TRIAL REGISTRATION: NCT04446962.
Assuntos
Adenina , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias do Sistema Nervoso Central , Lenalidomida , Piperidinas , Pirazóis , Pirimidinas , Humanos , Lenalidomida/administração & dosagem , Lenalidomida/uso terapêutico , Lenalidomida/efeitos adversos , Adenina/análogos & derivados , Adenina/administração & dosagem , Pessoa de Meia-Idade , Piperidinas/administração & dosagem , Piperidinas/uso terapêutico , Piperidinas/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Masculino , Feminino , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Idoso , Adulto , Pirimidinas/administração & dosagem , Pirimidinas/uso terapêutico , Pirimidinas/efeitos adversos , Pirazóis/administração & dosagem , Pirazóis/uso terapêutico , Pirazóis/efeitos adversos , Vincristina/administração & dosagem , Vincristina/uso terapêutico , Vincristina/efeitos adversos , Rituximab/administração & dosagem , Rituximab/uso terapêutico , Rituximab/efeitos adversos , Metotrexato/administração & dosagem , Metotrexato/uso terapêutico , Prednisona/administração & dosagem , Prednisona/uso terapêutico , Prednisona/efeitos adversos , Linfoma/tratamento farmacológicoRESUMO
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.
Assuntos
Neoplasias do Sistema Nervoso Central , Imageamento por Ressonância Magnética , Metotrexato , Humanos , Metotrexato/uso terapêutico , Metotrexato/administração & dosagem , Masculino , Feminino , Pessoa de Meia-Idade , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Neoplasias do Sistema Nervoso Central/diagnóstico por imagem , Neoplasias do Sistema Nervoso Central/patologia , Imageamento por Ressonância Magnética/métodos , Idoso , Linfoma/tratamento farmacológico , Linfoma/diagnóstico por imagem , Linfoma/patologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Adulto , Prognóstico , Aprendizado de Máquina , Resultado do Tratamento , Estudos Retrospectivos , RadiômicaRESUMO
Primary central nervous system (CNS) lymphoma (PCNSL) is a rare and aggressive lymphoma that affects the CNS without other systemic involvement. High-dose methotrexate (HDMTX)-based regimens are recommended frontline treatment, followed by consolidation with either high-dose chemotherapy, whole brain radiation (WBRT) +/- sequential temozolomide (TMZ), or autologous stem cell transplant (autoSCT). Despite advancements with HDMTX and rituximab, up to half of patients will relapse. Treatment for relapsed or refractory (R/R) disease varies widely as preferred regimens are not well-established. Our study aimed to provide real-world characterization of R/R PCNSL therapies. The secondary objective was characterization of consolidation methods after frontline treatment. This retrospective, descriptive analysis included 54 adult PCNSL patients that received a HDMTX-based frontline regimen between 4/1/2016 and 7/1/2022. Patients receiving HDMTX for the purpose of secondary CNS lymphoma, non-B cell origin PCNSL, and intraocular lymphoma were excluded. Thirty-one patients (57%) received consolidation therapy with rituximab and high-dose cytarabine (R-HDAC), WBRT, or both. Thirteen patients (24%) proceeded with autoSCT. Twenty-five patients had disease progression, with 17 patients receiving second line treatment. The second line treatments were WBRT (24%), clinical trial (18%), rituximab with lenalidomide (R2; 18%), re-induction with HDMTX-based regimens (18%), ibrutinib with rituximab (12%) and R-HDAC (12%). Seven patients progressed, and all received third line treatment. Treatments varied, including R2; ibrutinib +/- HDMTX; rituximab, methotrexate, and cytarabine; R-HDAC; R-nivolumab; and WBRT. Five patients received a fourth line regimen of R +/- lenalidomide, R-HDMTX, or nivolumab monotherapy. Regimens used for the three patients who received fifth line treatment and beyond included R-TMZ and pembrolizumab monotherapy in addition to previously described regimens. Regimen selection is varied and highly dependent on physician preference and patient factors, including clinical trial eligibility, prior therapies, performance status, organ function, and treatment intent. Prospective clinical trials are needed to guide optimal management.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias do Sistema Nervoso Central , Humanos , Neoplasias do Sistema Nervoso Central/terapia , Feminino , Masculino , Pessoa de Meia-Idade , Idoso , Estudos Retrospectivos , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma/terapia , Linfoma/tratamento farmacológico , Linfoma/patologia , Metotrexato/administração & dosagem , Metotrexato/uso terapêutico , Terapia Combinada , Idoso de 80 Anos ou maisRESUMO
BACKGROUND: Primary central nervous system lymphoma (PCNSL) requires effective & well-tolerated treatment strategies. The use of high-dose methotrexate (HD-MT) with or without intra-thecal methotrexate (IT-MT) and whole-brain radiotherapy (WBRT) has emerged as a prominent approach for PCNSL. This systematic review aims to assess the efficacy and safety of these treatment modalities. METHODS: A comprehensive search strategy identified relevant studies from PubMed, EMBASE, and Cochrane Library. The following search terms were used: "high-dose methotrexate", "primary central nervous system lymphoma", "intra-thecal methotrexate", and "whole-brain radiotherapy". We included randomized controlled trials (RCTs), cohort studies & case-controlled studies evaluating the use of HD-MT with or without IT-MT and whole-brain radiotherapy in the treatment of confirmed PCNSL. Data extraction & quality assessment was conducted by two independent reviewers. Primary outcomes include overall survival (OS), progression-free survival (PFS) & treatment-related adverse events (TRAEs). Secondary outcomes were neurological function and quality of life (QOL) assessments. The risk of bias in individual studies was assessed using the Cochrane Risk of Bias Tool for randomized trials and the Newcastle-Ottawa Scale for observational studies. RESULTS: We identified 5 studies, consisting of 1 RCT, 3 cohort studies, and 1 case-controlled study. Pooled analysis revealed that HD-MT with or without IT-MT and whole-brain radiotherapy significantly improved both OS and PFS compared to other treatment modalities but we found no significant difference between patients who received HD-MT with or without IT-MT. Combination therapy was generally well-tolerated, with manageable TRAE. Subgroup analyses stratified by age, disease stage, and other relevant factors demonstrated consistent efficacy and safety profiles across different patient populations. The risk of bias assessment indicated that the majority of the included studies had low-moderate risk of bias. CONCLUSIONS: There was no significant difference between patients who received HD-MT with or without IT-MT plus radiotherapy, emphasizing the comparable efficacy of these treatment modalities. Combination therapy was generally well-tolerated, with manageable TRAE. This highlights the favourable safety profile of HD-MT with fewer side effects compared with the combination of IT-MT.
Assuntos
Neoplasias do Sistema Nervoso Central , Linfoma , Metotrexato , Humanos , Metotrexato/uso terapêutico , Metotrexato/farmacologia , Neoplasias do Sistema Nervoso Central/radioterapia , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Linfoma/radioterapia , Linfoma/tratamento farmacológico , Feminino , MasculinoRESUMO
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.
Assuntos
Linfoma , Neoplasias , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Linfoma/tratamento farmacológico , Neoplasias/tratamento farmacológico , Idoso , Adulto , China , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/farmacologia , Dose Máxima Tolerável , População do Leste AsiáticoRESUMO
Aims/Background We aimed to investigate the impact of postoperative chemotherapy (POCT) on survival in patients with primary central nervous system lymphoma (PCNSL) using data from the Surveillance, Epidemiology, and End Results (SEER) database. Methods This study included 786 PCNSL patients, of which 605 received chemotherapy after surgery, and 181 did not. Data from the SEER registry database (2007-2020) were used to analyze PCNSL. Baseline information, including age, sex, race, marital status, primary tumour site, histological type, summary stage, surgical procedures, chemotherapy, and radiotherapy, was analyzed. Propensity Score Matching (PSM) (1:1) was employed to balance the effects of confounding variables between the two groups. Subsequently, Cox regression and bidirectional stepwise regression were used to identify independent prognostic factors. Kaplan-Meier (K-M) survival curves were constructed to assess the impact of POCT on patient prognosis. Additionally, two cases of PCNSL with typical magnetic resonance imaging appearances were presented. Results Multivariate Cox regression results revealed that age older than 60 years (hazard ratio [HR] = 1.786; 95% confidence interval [CI]: 1.272-2.509; p = 0.001) and absence of POCT (HR = 2.841; 95% CI: 2.159-3.738; p < 0.001) were independent prognostic risk factors, while primary tumour locations in the meninges (HR = 0.136; 95% CI: 0.032-0.569; p = 0.006) and other nervous system regions (HR = 0.552; 95% CI: 0.326-0.936; p = 0.027), as well as histological morphologies such as diffuse large B-cell lymphoma (HR = 0.233; 95% CI: 0.128-0.425; p < 0.001) and non-Hodgkin lymphoma (HR = 0.559; 95% CI: 0.356-0.876; p = 0.011), were associated with favourable patient outcomes. K-M curves demonstrated that the group undergoing POCT had a significantly more favourable prognosis compared to the non-POCT group, before (HR = 0.454; 95% CI: 0.343-0.600; p < 0.0001) or after PSM (HR = 0.580; 95% CI: 0.431-0.780; p < 0.0001). For patients with PCNSL, those with tumours located in the infratentorial region (HR = 0.231; 95% CI: 0.078-0.682; p = 0.046), supratentorial region (HR = 0.250; 95% CI: 0.163-0.383; p < 0.0001), overlapping brain regions (HR = 0.201; 95% CI: 0.056-0.727; p = 0.0058), and those who underwent biopsy (HR = 0.740; 95% CI: 0.463-1.182; p = 0.003), subtotal resection (STR) (HR = 0.490; 95% CI: 0.265-0.906; p = 0.0064), or gross total resection (GTR) (HR = 0.613; 95% CI: 0.292-1.287; p = 0.0003) had better prognoses in the postoperative chemotherapy group compared to the non-chemotherapy group. Conclusion POCT significantly improves the prognosis of PCNSL patients and identifies the characteristics of the benefiting population. This information aids clinical practitioners in designing personalized treatment plans for individuals and advancing precise treatment.
Assuntos
Neoplasias do Sistema Nervoso Central , Programa de SEER , Humanos , Feminino , Masculino , Neoplasias do Sistema Nervoso Central/mortalidade , Neoplasias do Sistema Nervoso Central/terapia , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Neoplasias do Sistema Nervoso Central/cirurgia , Pessoa de Meia-Idade , Idoso , Prognóstico , Linfoma/mortalidade , Linfoma/terapia , Linfoma/tratamento farmacológico , Linfoma/patologia , Adulto , Estimativa de Kaplan-Meier , Modelos de Riscos Proporcionais , Quimioterapia Adjuvante , Pontuação de PropensãoRESUMO
BACKGROUND/AIM: Treatment of primary central nervous system lymphoma (PCNSL) includes high dose methotrexate-based polychemotherapy (HD-MTX). This study aimed to identify early predictive factors of methotrexate (MTX) delayed elimination. PATIENTS AND METHODS: We prospectively included all patients with newly-diagnosed PCNSL. Daily serum and urinary creatinine and ionogram were collected. We generated two independent cohorts: a training cohort (TC) and a confirmatory cohort (CC). RESULTS: We included for analysis 64 cures of HD-MTX (20 patients) in the TC and 59 cures (22 patients) in the CC. Median elimination time of MTX was 95 h and 96 h in the TC and CC, respectively. In multivariate analysis, older age (p=0.004), low Karnofsky Performance Status (p=0.036) and high urinary K+ (p=0.001) were associated with delayed MTX elimination. An optimal cutoff for urinary K+ was defined. In the CC, we confirmed that high urinary K+ (p=0.004) remained associated with delayed MTX elimination. CONCLUSION: High urinary K+ may be predictive of delayed MTX elimination in primary central nervous system lymphoma. Its relevance as a decision-making factor needs to be validated in additional prospective studies.
Assuntos
Neoplasias do Sistema Nervoso Central , Linfoma , Metotrexato , Potássio , Humanos , Metotrexato/administração & dosagem , Metotrexato/uso terapêutico , Metotrexato/urina , Neoplasias do Sistema Nervoso Central/urina , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Feminino , Masculino , Idoso , Pessoa de Meia-Idade , Linfoma/tratamento farmacológico , Linfoma/urina , Potássio/urina , Potássio/sangue , Estudos Prospectivos , Antimetabólitos Antineoplásicos/uso terapêutico , Antimetabólitos Antineoplásicos/administração & dosagem , Adulto , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêuticoRESUMO
The monoclonal antibody rituximab improves clinical outcome in the treatment of CD20-positive lymphomatous neoplasms, and it is an established drug for treatment of these cancers. Successful mRNA COVID-19 (SARS-CoV-2) vaccination is extremely important for lymphoma patients because they tend to be elderly with comorbidities which leaves them at increased risk of poor outcomes once infected by Coronavirus. Anti-CD20 therapies such as rituximab, deplete B-cell populations and can affect vaccine efficacy. Therefore, a knowledge of the effect of COVID-19 vaccination in this group is critical. We followed a cohort of 28 patients with CD20-positive lymphomatous malignancies treated with rituximab that started prior to their course of COVID-19 vaccination, including boosters. We assayed for vaccine "take" in the humoral (IgG and IgA) and cellular compartment. Here, we show that short-term and long-term development of IgG and IgA antibodies directed toward COVID-19 spike protein are reduced in these patients compared to healthy controls. Conversely, the robustness and breath of underlying T-cell response is equal to healthy controls. This response is not limited to specific parts of the spike protein but spans the spike region, including response to the conserved Receptor Binding Domain (RBD). Our data informs on rational vaccine design and bodes well for future vaccination strategies that require strong induction of T-cell responses in these patients.
Assuntos
Anticorpos Antivirais , Vacinas contra COVID-19 , COVID-19 , Linfoma , Rituximab , SARS-CoV-2 , Humanos , Rituximab/uso terapêutico , COVID-19/imunologia , COVID-19/prevenção & controle , Feminino , Masculino , Idoso , SARS-CoV-2/imunologia , Pessoa de Meia-Idade , Vacinas contra COVID-19/imunologia , Linfoma/imunologia , Linfoma/tratamento farmacológico , Linfoma/terapia , Anticorpos Antivirais/imunologia , Anticorpos Antivirais/sangue , Glicoproteína da Espícula de Coronavírus/imunologia , Imunoglobulina G/imunologia , Imunoglobulina G/sangue , Imunoglobulina A/imunologia , Imunoglobulina A/sangue , Antígenos CD20/imunologia , Idoso de 80 Anos ou mais , Vacinação , Vacinas de mRNARESUMO
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.
Assuntos
Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias do Sistema Nervoso Central , Metotrexato , Rituximab , Temozolomida , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Metotrexato/administração & dosagem , Metotrexato/uso terapêutico , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Rituximab/administração & dosagem , Temozolomida/administração & dosagem , Temozolomida/farmacologia , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Neoplasias do Sistema Nervoso Central/genética , Neoplasias do Sistema Nervoso Central/imunologia , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/farmacologia , Adulto , Linfoma/tratamento farmacológico , Linfoma/genética , Linfoma/imunologiaRESUMO
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).
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Cloridrato de Bendamustina , Carboplatina , Citarabina , Etoposídeo , Transplante de Células-Tronco Hematopoéticas , Linfoma , Melfalan , Condicionamento Pré-Transplante , Transplante Autólogo , Humanos , Transplante de Células-Tronco Hematopoéticas/métodos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Feminino , Masculino , Citarabina/administração & dosagem , Citarabina/efeitos adversos , Citarabina/uso terapêutico , Etoposídeo/administração & dosagem , Etoposídeo/efeitos adversos , Etoposídeo/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Melfalan/administração & dosagem , Melfalan/efeitos adversos , Melfalan/uso terapêutico , Adulto , Linfoma/terapia , Linfoma/mortalidade , Linfoma/tratamento farmacológico , Pessoa de Meia-Idade , Condicionamento Pré-Transplante/métodos , Cloridrato de Bendamustina/administração & dosagem , Cloridrato de Bendamustina/efeitos adversos , Carboplatina/administração & dosagem , Carboplatina/efeitos adversos , Carboplatina/uso terapêutico , Adulto Jovem , Adolescente , Resultado do TratamentoRESUMO
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.
Assuntos
Anticorpos Neutralizantes , Antivirais , Tratamento Farmacológico da COVID-19 , COVID-19 , Linfoma , Ritonavir , SARS-CoV-2 , Humanos , Masculino , Anticorpos Neutralizantes/uso terapêutico , Pessoa de Meia-Idade , Feminino , Antivirais/uso terapêutico , SARS-CoV-2/imunologia , Linfoma/tratamento farmacológico , Linfoma/complicações , COVID-19/imunologia , COVID-19/complicações , Ritonavir/uso terapêutico , Idoso , Estudos Prospectivos , Adulto , Anticorpos Monoclonais Humanizados/uso terapêutico , Resultado do Tratamento , Combinação de Medicamentos , Recidiva , Lopinavir/uso terapêutico , Anticorpos Antivirais/imunologia , Anticorpos Antivirais/uso terapêuticoAssuntos
Bevacizumab , Hemorragia Gastrointestinal , Humanos , Hemorragia Gastrointestinal/induzido quimicamente , Hemorragia Gastrointestinal/etiologia , Bevacizumab/efeitos adversos , Bevacizumab/uso terapêutico , Masculino , Inibidores da Angiogênese/efeitos adversos , Inibidores da Angiogênese/uso terapêutico , Idoso , Hemostasia/efeitos dos fármacos , Linfoma/tratamento farmacológico , Linfoma/complicações , Feminino , Pessoa de Meia-IdadeRESUMO
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.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Probióticos , Humanos , Feminino , Idoso , Probióticos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ciclofosfamida/uso terapêutico , Doxorrubicina/uso terapêutico , Doxorrubicina/efeitos adversos , Vincristina/uso terapêutico , Infecções por Bifidobacteriales/microbiologia , Rituximab/uso terapêutico , Rituximab/efeitos adversos , Prednisona/uso terapêutico , Bacteriemia/tratamento farmacológico , Bacteriemia/microbiologia , Bifidobacterium breve , Linfoma/tratamento farmacológicoRESUMO
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.
Assuntos
Linfoma , Humanos , Estudos Transversais , Estudos Prospectivos , Linfoma/tratamento farmacológico , Medidas de Resultados Relatados pelo Paciente , Avaliação de Sintomas/métodos , Antineoplásicos/uso terapêutico , Antineoplásicos/efeitos adversos , Inquéritos e Questionários , Feminino , Projetos de Pesquisa , MasculinoRESUMO
High-dose therapy followed by autologous hematopoietic cell transplant (AHCT) remains a viable consolidation strategy for a subset of patients with relapsed or refractory (R/R) lymphomas. BEAM (carmustine, etoposide, cytarabine, and melphalan) is widely recognized as the predominant conditioning regimen due to its satisfactory efficacy and tolerability. Nevertheless, shortages of carmustine and melphalan have compelled clinicians to explore alternative conditioning regimens. The aim of this study was to compare the toxicity and transplant outcomes following BEAM, CBV (carmustine, etoposide, cyclophosphamide), BuMel (busulfan, melphalan), and BendaEAM (bendamustine, etoposide, cytarabine, melphalan). We retrospectively analyzed data from 213 patients (CBV 65, BuMel 42, BEAM 68, BendaEAM 38) with R/R lymphomas undergoing AHCT between 2014 and 2020. Multivariate models were employed to evaluate toxicity and transplant outcomes based on conditioning type. Among grade III to IV toxicities, oral mucositis was more frequently observed with BuMel (45%) and BendaEAM (24%) compared to BEAM (15%) and CVB (6%, P ≤ .001). Diarrhea was more common with BendaEAM (42%) and less frequent with BuMel (7%, P = .01). Acute kidney injury was only found after BendaEAM (11%). Febrile neutropenia and infectious complications were more frequent following BendaEAM. Frequencies of other treatment-related toxicities did not significantly differ according to conditioning type. BendaEAM (odds ratio [OR] 3.07, P = .014) and BuMel (OR 4.27, P = .002) were independently associated with higher grade III to IV toxicity up to D+100. However, there were no significant differences in relapse/progression, nonrelapse mortality, progression-free survival, or overall survival among the four regimens. BuMel and BendaEAM were associated with a higher rate of grade III to IV toxicity. Carmustine-based regimens appeared to be less toxic and safer; however, there were no significant differences in transplant outcomes. The utilization of alternative preparative regimens due to drug shortages may potentially lead to increased toxicity after AHCT for lymphoma.
Assuntos
Carmustina , Citarabina , Transplante de Células-Tronco Hematopoéticas , Linfoma , Melfalan , Condicionamento Pré-Transplante , Transplante Autólogo , Humanos , Condicionamento Pré-Transplante/métodos , Masculino , Feminino , Pessoa de Meia-Idade , Linfoma/tratamento farmacológico , Linfoma/terapia , Adulto , Carmustina/uso terapêutico , Estudos Retrospectivos , Citarabina/uso terapêutico , Melfalan/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Idoso , Etoposídeo/uso terapêutico , Bussulfano/uso terapêutico , Resultado do Tratamento , Ciclofosfamida/uso terapêuticoRESUMO
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.
Assuntos
Antineoplásicos , Apoptose , Proliferação de Células , Leucemia , Linfoma , Proteólise , Humanos , Leucemia/tratamento farmacológico , Leucemia/patologia , Leucemia/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Proteólise/efeitos dos fármacos , Linfoma/tratamento farmacológico , Linfoma/patologia , Linfoma/metabolismo , Proliferação de Células/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Descoberta de Drogas , Ensaios de Seleção de Medicamentos Antitumorais , Relação Estrutura-Atividade , Peptídeos Penetradores de Células/química , Peptídeos Penetradores de Células/farmacologia , Peptídeos Penetradores de Células/síntese química , Estrutura Molecular , Células K562 , Relação Dose-Resposta a Droga , Sistemas de Liberação de MedicamentosRESUMO
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.