RESUMEN
This Good Practice Paper provides recommendations for the baseline investigation, risk stratification and use of prophylactic interventions for patients with large B-cell lymphoma at risk of central nervous system relapse. Recent evidence which has questioned the role of high-dose methotrexate in this clinical scenario is discussed in detail.
RESUMEN
Prophylactic high-dose methotrexate (HD-MTX) is often used for diffuse large B-cell lymphoma (DLBCL) patients at high risk of central nervous system (CNS) relapse, despite limited evidence demonstrating efficacy or the optimal delivery method. We conducted a retrospective, international analysis of 1384 patients receiving HD-MTX CNS prophylaxis either intercalated (i-HD-MTX) (n = 749) or at the end (n = 635) of R-CHOP/R-CHOP-like therapy (EOT). There were 78 CNS relapses (3-year rate 5.7%), with no difference between i-HD-MTX and EOT: 5.7% vs 5.8%, P = .98; 3-year difference: 0.04% (-2.0% to 3.1%). Conclusions were unchanged on adjusting for baseline prognostic factors or on 6-month landmark analysis (n = 1253). In patients with a high CNS international prognostic index (n = 600), the 3-year CNS relapse rate was 9.1%, with no difference between i-HD-MTX and EOT. On multivariable analysis, increasing age and renal/adrenal involvement were the only independent risk factors for CNS relapse. Concurrent intrathecal prophylaxis was not associated with a reduction in CNS relapse. R-CHOP delays of ≥7 days were significantly increased with i-HD-MTX vs EOT, with 308 of 1573 (19.6%) i-HD-MTX treatments resulting in a delay to subsequent R-CHOP (median 8 days). Increased risk of delay occurred in older patients when delivery was later than day 10 in the R-CHOP cycle. In summary, we found no evidence that EOT delivery increases CNS relapse risk vs i-HD-MTX. Findings in high-risk subgroups were unchanged. Rates of CNS relapse in this HD-MTX-treated cohort were similar to comparable cohorts receiving infrequent CNS prophylaxis. If HD-MTX is still considered for certain high-risk patients, delivery could be deferred until R-CHOP completion.
Asunto(s)
Neoplasias del Sistema Nervioso Central , Linfoma de Células B Grandes Difuso , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias del Sistema Nervioso Central/tratamiento farmacológico , Neoplasias del Sistema Nervioso Central/patología , Neoplasias del Sistema Nervioso Central/prevención & control , Ciclofosfamida , Doxorrubicina , Humanos , Linfoma de Células B Grandes Difuso/patología , Metotrexato , Recurrencia Local de Neoplasia/tratamiento farmacológico , Prednisona , Estudios Retrospectivos , Rituximab/uso terapéutico , VincristinaRESUMEN
Mantle cell lymphoma (MCL) is a mature B-cell lymphoma with a variable clinical course and historically poor prognosis. Management is challenging in part due to the heterogeneity of the disease course, with indolent and aggressive subtypes now well recognised. Indolent MCL is often characterised by a leukaemic presentation, SOX11 negativity and low proliferation index (Ki-67). Aggressive MCL is characterised by rapid onset widespread lymphadenopathy, extra-nodal involvement, blastoid or pleomorphic histology and high Ki-67. Tumour protein p53 (TP53) aberrations in aggressive MCL are recognised with clear negative impact on survival. Until recently, trials have not addressed these specific subtypes separately. With the increasing availability of targeted novel agents and cellular therapies, the treatment landscape is constantly evolving. In this review, we describe the clinical presentation, biological factors, and specific management considerations of both indolent and aggressive MCL and discuss current and potential future evidence which may help move to a more personalised approach.
Asunto(s)
Antineoplásicos , Linfoma de Células B , Linfoma de Células del Manto , Adulto , Humanos , Linfoma de Células del Manto/terapia , Linfoma de Células del Manto/tratamiento farmacológico , Antígeno Ki-67 , Antineoplásicos/uso terapéutico , Linfoma de Células B/tratamiento farmacológico , Progresión de la EnfermedadRESUMEN
Management of classical Hodgkin lymphoma in older patients is challenging due to poor tolerance of the chemotherapy regimens used in younger patients. We modified the BEACOPP regimen (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisolone), whereby bleomycin and etoposide were removed and cyclophosphamide dose was reduced, for older patients with co-morbidities. Here we present data from the first 41 patients treated with 'ACOPP' across 3 centres, demonstrating that it can be delivered, with a favourable toxicity profile (TRM 2%) and promising efficacy (2-year PFS and OS, 73% (95% CI: 52-94) and 93% (95% CI: 80-100) respectively).
Asunto(s)
Enfermedad de Hodgkin , Humanos , Anciano , Enfermedad de Hodgkin/patología , Vincristina/efectos adversos , Estudios Retrospectivos , Procarbazina/efectos adversos , Etopósido/efectos adversos , Ciclofosfamida/efectos adversos , Doxorrubicina/efectos adversos , Bleomicina/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Prednisona/efectos adversosRESUMEN
PURPOSE OF REVIEW: Central nervous system (CNS) relapse in patients with diffuse large B-cell lymphoma (DLBCL) is an uncommon but devastating complication with an overall survival of less than 6âmonths. This article will review the recent updates on CNS prophylaxis including new potential advances in the identification of high-risk patients. RECENT FINDINGS: The identification of patients at a high risk of CNS relapse is based on clinical and biological features has improved over recent years; however, the of different CNS prophylaxis strategies including intrathecal chemotherapy and high-dose methotrexate have been recently questioned in several large retrospective studies. The analysis of cell-free circulating tumor DNA (ctDNA) in the cerebrospinal fluid has been shown to identify patients with a high risk of CNS involvement and work is ongoing to identify how this can be used as a prognostic biomarker. SUMMARY: Recent clinical retrospective data have questioned the effectiveness of intrathecal and high-dose methotrexate in the prevention of CNS relapse in high-risk DLBCL patients. The role of more sensitive methods to detect CNS involvement and the benefit of novel therapies in CNS relapse prevention are currently under evaluation.
Asunto(s)
Neoplasias del Sistema Nervioso Central , Linfoma de Células B Grandes Difuso , Humanos , Metotrexato/uso terapéutico , Rituximab , Estudios Retrospectivos , Neoplasias del Sistema Nervioso Central/tratamiento farmacológico , Neoplasias del Sistema Nervioso Central/prevención & control , Recurrencia Local de Neoplasia/prevención & control , Recurrencia Local de Neoplasia/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Sistema Nervioso Central/patología , Ciclofosfamida , Doxorrubicina , VincristinaRESUMEN
CNS relapse in the brain parenchyma, eyes, or leptomeninges is an uncommon but devastating complication of diffuse large B-cell lymphoma. CNS prophylaxis strategies, typically involving intrathecal or high-dose antimetabolites, have been developed in the front-line treatment setting with the aim to reduce this subsequent risk. Clinical and biological features associated with elevated risk are increasingly well defined and are discussed in this Review. This Review summarises both the historical and current developments in this challenging field, provides a nuanced discussion regarding current reasons for and against standard prophylactic measures, outlines evidence for the timing of prophylactic measures when delivered, and reflects on possible future developments.
Asunto(s)
Neoplasias del Sistema Nervioso Central , Linfoma de Células B Grandes Difuso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias del Sistema Nervioso Central/tratamiento farmacológico , Neoplasias del Sistema Nervioso Central/patología , Neoplasias del Sistema Nervioso Central/prevención & control , Humanos , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/patología , Metotrexato/uso terapéutico , Recurrencia Local de Neoplasia/patologíaRESUMEN
Given advanced age, comorbidities, and immune dysfunction, chronic lymphocytic leukemia (CLL) patients may be at particularly high risk of infection and poor outcomes related to coronavirus disease 2019 (COVID-19). Robust analysis of outcomes for CLL patients, particularly examining effects of baseline characteristics and CLL-directed therapy, is critical to optimally manage CLL patients through this evolving pandemic. CLL patients diagnosed with symptomatic COVID-19 across 43 international centers (n = 198) were included. Hospital admission occurred in 90%. Median age at COVID-19 diagnosis was 70.5 years. Median Cumulative Illness Rating Scale score was 8 (range, 4-32). Thirty-nine percent were treatment naive ("watch and wait"), while 61% had received ≥1 CLL-directed therapy (median, 2; range, 1-8). Ninety patients (45%) were receiving active CLL therapy at COVID-19 diagnosis, most commonly Bruton tyrosine kinase inhibitors (BTKi's; n = 68/90 [76%]). At a median follow-up of 16 days, the overall case fatality rate was 33%, though 25% remain admitted. Watch-and-wait and treated cohorts had similar rates of admission (89% vs 90%), intensive care unit admission (35% vs 36%), intubation (33% vs 25%), and mortality (37% vs 32%). CLL-directed treatment with BTKi's at COVID-19 diagnosis did not impact survival (case fatality rate, 34% vs 35%), though the BTKi was held during the COVID-19 course for most patients. These data suggest that the subgroup of CLL patients admitted with COVID-19, regardless of disease phase or treatment status, are at high risk of death. Future epidemiologic studies are needed to assess severe acute respiratory syndrome coronavirus 2 infection risk, these data should be validated independently, and randomized studies of BTKi's in COVID-19 are needed to provide definitive evidence of benefit.
Asunto(s)
Infecciones por Coronavirus/complicaciones , Leucemia Linfocítica Crónica de Células B/complicaciones , Neumonía Viral/complicaciones , Adulto , Agammaglobulinemia Tirosina Quinasa/antagonistas & inhibidores , Anciano , Anciano de 80 o más Años , Antiinflamatorios/uso terapéutico , Antivirales/uso terapéutico , Betacoronavirus/aislamiento & purificación , COVID-19 , Infecciones por Coronavirus/terapia , Femenino , Humanos , Inmunización Pasiva , Leucemia Linfocítica Crónica de Células B/terapia , Masculino , Persona de Mediana Edad , Pandemias , Neumonía Viral/terapia , Inhibidores de Proteínas Quinasas/uso terapéutico , SARS-CoV-2 , Análisis de Supervivencia , Resultado del Tratamiento , Sueroterapia para COVID-19RESUMEN
Mantle cell lymphoma (MCL) presenting in elderly, unfit patients represents a clinical challenge. Front-line 'attenuated' or low-intensity immunochemotherapy is often employed, although outcomes are relatively unexplored. We report outcomes of attenuated immunochemotherapy in 95 patients with MCL across 19 centres in the UK and Ireland considered unfit for full-dose rituximab-bendamustine or rituximab-cyclophosphamide, doxorubicin, vincristine, prednisolone (R-CHOP). Regimens examined were rituximab-cyclophosphamide, vincristine, prednisolone (R-CVP) (n = 19), dose-attenuated R-CHOP (n = 22), dose attenuated rituximab-bendamustine (n = 24) and rituximab-chlorambucil (n = 30). The primary outcome was progression-free survival (PFS). The secondary outcomes included overall response, overall survival (OS) and toxicity. The median (range) age was 79 (58-89) years and 50% were aged ≥80 years. The median (range) Cumulative Illness Rating Scale-Geriatric score was 6 (0-24). The median PFS for all patients was 15 months [95% confidence interval (CI) 8·7-21·2) and median OS was 31·4 months (95% CI 19·7-43·2). By multivariable analysis (MVA), the only clinical factor associated with an inferior PFS was blastoid morphology [hazard ratio (HR) 2·90, P = 0·01). Notably, higher treatment intensity (R-CHOP/R-bendamustine composite) provided an independently superior PFS compared with R-CVP/R-chlorambucil (MVA HR 0·49, P = 0·02). Factors associated with inferior OS by MVA were Eastern Cooperative Oncology Group Performance Status (HR 2·14, P = 0·04), blastoid morphology (HR 4·08, P = 0·001) and progression of disease at <24 months status (HR 5·68, P < 0·001). Overall, survival after front-line dose-attenuated immunochemotherapy is unsatisfactory. Clinical trials investigating novel agents such as Bruton tyrosine kinase and B-cell lymphoma 2 inhibitors in this specific clinical setting are warranted.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Ciclofosfamida/uso terapéutico , Linfoma de Células del Manto/tratamiento farmacológico , Prednisona/uso terapéutico , Rituximab/uso terapéutico , Vincristina/uso terapéutico , Factores de Edad , Anciano , Anciano de 80 o más Años , Doxorrubicina/uso terapéutico , Femenino , Humanos , Inmunoterapia , Irlanda/epidemiología , Linfoma de Células del Manto/epidemiología , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Análisis de Supervivencia , Resultado del Tratamiento , Reino Unido/epidemiologíaRESUMEN
Ibrutinib is an established treatment for relapsed/refractory (R/R) mantle cell lymphoma (MCL) and clinical trial data supports use at second line compared to later relapse. We aimed to investigate outcomes and tolerability for ibrutinib when given second line in a real-world setting. Our multicentre retrospective analysis included 211 R/R MCL patients, median age 73 years, receiving ibrutinib second-line within the United Kingdom's National Health Service. Overall response to ibrutinib was 69% (complete response 27%). The median progression-free survival (PFS) was 17·8 months (95% CI 13·1-22·2) and median overall survival (OS) 23·9 months (95% CI 15·0-32·8). Drug-related adverse event led to dose reduction in 10% of patients and discontinuation in 5%. In patients with progressive disease, accounting for 100 of 152 patients stopping ibrutinib, 43% received further systemic therapy. Post-ibrutinib rituximab, bendamustine and cytarabine (R-BAC) showed a trend toward improved survival compared to alternative systemic treatments (post-ibrutinib median OS 14·0 months, 95% CI 8·1-19·8, vs. 3·6 months, 95% CI 2·6-4·5, P = 0·06). Our study confirms the clinical benefit and good tolerability of ibrutinib at first relapse in a real-world population. Patients progressing on ibrutinib had limited survival but outcomes with R-BAC in select patients were promising.
Asunto(s)
Adenina/análogos & derivados , Agammaglobulinemia Tirosina Quinasa/antagonistas & inhibidores , Linfoma de Células del Manto/tratamiento farmacológico , Piperidinas/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Adenina/administración & dosificación , Adenina/efectos adversos , Adenina/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Clorhidrato de Bendamustina/administración & dosificación , Clorhidrato de Bendamustina/uso terapéutico , Citarabina/administración & dosificación , Citarabina/uso terapéutico , Progresión de la Enfermedad , Femenino , Humanos , Linfoma de Células del Manto/diagnóstico , Linfoma de Células del Manto/mortalidad , Masculino , Persona de Mediana Edad , Evaluación de Resultado en la Atención de Salud , Piperidinas/administración & dosificación , Piperidinas/efectos adversos , Supervivencia sin Progresión , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/efectos adversos , Recurrencia , Estudios Retrospectivos , Rituximab/administración & dosificación , Rituximab/uso terapéutico , Medicina Estatal/organización & administración , Reino Unido , Privación de TratamientoRESUMEN
The sphingomyelin pathway is important in cell regulation and determining cellular fate. Inhibition of sphingosine kinase isoform 1 (SK1) within this pathway, leads to a buildup of sphingosine and ceramide, two molecules directly linked to cell apoptosis, while decreasing the intracellular concentration of sphingosine-1-phosphate (S1P), a molecule linked to cellular proliferation. Recently, an inhibitor capable of inhibiting SK1 in vitro was identified, but also shown to be ineffective in vivo. A set of compounds designed to assess the impact of synthetic modifications to the hydroxynaphthalene ring region of the template inhibitor with SK1 to obtain a compound with increased efficacy in vivo. Of these fifteen compounds, 4A was shown to have an IC50 = 6.55 µM with improved solubility and in vivo potential.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/antagonistas & inhibidores , Diseño de Fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Humanos , Concentración 50 Inhibidora , Modelos Moleculares , Simulación del Acoplamiento Molecular , Estructura Molecular , Conformación Proteica , Relación Estructura-ActividadRESUMEN
Certain commensal and pathogenic bacteria produce colibactin, a small-molecule genotoxin that causes interstrand cross-links in host cell DNA. Although colibactin alkylates DNA, the molecular basis for cross-link formation is unclear. Here, we report that the colibactin biosynthetic enzyme ClbL is an amide bond-forming enzyme that links aminoketone and ß-keto thioester substrates in vitro and in vivo. The substrate specificity of ClbL strongly supports a role for this enzyme in terminating the colibactin NRPS-PKS assembly line and incorporating two electrophilic cyclopropane warheads into the final natural product scaffold. This proposed transformation was supported by the detection of a colibactin-derived cross-linked DNA adduct. Overall, this work provides a biosynthetic explanation for colibactin's DNA cross-linking activity and paves the way for further study of its chemical structure and biological roles.
Asunto(s)
Amidohidrolasas/metabolismo , ADN Bacteriano/metabolismo , Proteínas de Escherichia coli/metabolismo , Péptidos/metabolismo , Policétidos/metabolismo , Amidohidrolasas/química , Dominio Catalítico , Ciclopropanos/química , Ciclopropanos/metabolismo , ADN Bacteriano/química , Escherichia coli/genética , Escherichia coli/metabolismo , Proteínas de Escherichia coli/química , Proteínas de Escherichia coli/genética , Células HeLa , Humanos , Espectroscopía de Resonancia Magnética , Mutación , Péptido Hidrolasas/genética , Péptido Hidrolasas/metabolismo , Especificidad por SustratoRESUMEN
Despite containing an α-amino acid, the versatile cofactor S-adenosylmethionine (SAM) is not a known building block for nonribosomal peptide synthetase (NRPS) assembly lines. Here we report an unusual NRPS module from colibactin biosynthesis that uses SAM for amide bond formation and subsequent cyclopropanation. Our findings showcase a new use for SAM and reveal a novel biosynthetic route to a functional group that likely mediates colibactin's genotoxicity.
Asunto(s)
Ciclopropanos/química , Ciclopropanos/metabolismo , Péptido Sintasas/metabolismo , Péptidos/metabolismo , Policétidos/metabolismo , S-Adenosilmetionina/metabolismo , Escherichia coli/metabolismo , Péptido Sintasas/química , Péptidos/química , Policétidos/química , S-Adenosilmetionina/químicaAsunto(s)
Neoplasias del Sistema Nervioso Central , Linfoma de Células B Grandes Difuso , Humanos , Metotrexato , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/prevención & control , Rituximab/uso terapéutico , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Neoplasias del Sistema Nervioso Central/tratamiento farmacológico , Neoplasias del Sistema Nervioso Central/prevención & control , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Vincristina , Ciclofosfamida , DoxorrubicinaRESUMEN
Human-associated microorganisms have the potential to biosynthesize numerous secondary metabolites that may mediate important host-microbe and microbe-microbe interactions. However, there is currently a limited understanding of microbiome-derived natural products. A variety of complementary discovery approaches have begun to illuminate this microbial "dark matter," which will in turn allow detailed mechanistic studies of the effects of these molecules on microbiome and host. Herein, we review recent efforts to uncover microbiome-derived natural products, describe the key approaches that were used to identify and characterize these metabolites, discuss potential functional roles of these molecules, and highlight challenges related to this emerging research area.
Asunto(s)
Microbioma Gastrointestinal/fisiología , Consorcios Microbianos/fisiología , Antibacterianos/biosíntesis , Antifúngicos/metabolismo , Antineoplásicos/metabolismo , Humanos , Biosíntesis de Péptidos Independientes de Ácidos Nucleicos/fisiología , Péptidos/metabolismo , Policétidos/metabolismoAsunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Antivirales/uso terapéutico , COVID-19/mortalidad , Leucemia Linfocítica Crónica de Células B/mortalidad , SARS-CoV-2/efectos de los fármacos , Adulto , Anciano , Anciano de 80 o más Años , COVID-19/complicaciones , COVID-19/terapia , COVID-19/virología , Manejo de la Enfermedad , Quimioterapia Combinada , Femenino , Estudios de Seguimiento , Humanos , Leucemia Linfocítica Crónica de Células B/epidemiología , Leucemia Linfocítica Crónica de Células B/terapia , Leucemia Linfocítica Crónica de Células B/virología , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , SARS-CoV-2/aislamiento & purificación , Tasa de Supervivencia , Estados Unidos/epidemiologíaRESUMEN
The kinamycin family of aromatic polyketide natural products contains an atypical angucycline ring system substituted with a diazo group. The enzymatic chemistry involved in constructing both of these structural features has been largely unexplored. Here we report the in vivo and in vitro production of seongomycin, a shunt product from this pathway, and stealthin C, a proposed biosynthetic precursor to the kinamycins. We show that a single enzyme, the flavin-dependent monooxygenase AlpJ, can generate these metabolites from N-acetyl-l-cysteine and l-cysteine, respectively, and that the synthesis of stealthin C likely proceeds via a nonenzymatic S-N-type Smiles rearrangement. This unexpected route to stealthin C reveals a distinct approach to install aromatic amino groups in metabolites and raises questions about the intermediacy of this species in kinamycin production.
Asunto(s)
Productos Biológicos/metabolismo , Compuestos Heterocíclicos de 4 o más Anillos/metabolismo , Oxigenasas de Función Mixta/metabolismo , Productos Biológicos/química , Compuestos Heterocíclicos de 4 o más Anillos/química , Oxigenasas de Función Mixta/química , Estructura Molecular , Streptomyces/química , Streptomyces/metabolismoAsunto(s)
Enfermedades de la Médula Ósea , Enfermedad de Erdheim-Chester , Anciano , Enfermedades de la Médula Ósea/diagnóstico por imagen , Enfermedades de la Médula Ósea/metabolismo , Enfermedades de la Médula Ósea/patología , Enfermedad de Erdheim-Chester/diagnóstico por imagen , Enfermedad de Erdheim-Chester/metabolismo , Enfermedad de Erdheim-Chester/patología , Humanos , MasculinoAsunto(s)
Neoplasias del Sistema Nervioso Central , Linfoma de Células B Grandes Difuso , Sistema Nervioso Central , Neoplasias del Sistema Nervioso Central/tratamiento farmacológico , Neoplasias del Sistema Nervioso Central/prevención & control , Humanos , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Metotrexato/efectos adversos , Recurrencia Local de Neoplasia , Estudios RetrospectivosRESUMEN
Polyketides represent an important class of secondary metabolites that interact with biological targets connected to a variety of disease-associated pathways. Remarkably, nature's assembly lines, polyketide synthases, manufacture these privileged structures through a combinatorial mixture of just a few structural units. This review highlights the role of these structural elements in shaping a polyketide's conformational preferences, the use of computer-based molecular modeling and solution NMR studies in the identification of low-energy conformers, and the importance of conformational analogues in probing the bound conformation. In particular, this review covers several examples wherein conformational analysis complements classic structure-activity relationships in the design of biologically active natural product analogues.