RESUMEN
To date, plasma cell (PC)-targeted therapies have been limited by suboptimal PC depletion and antibody rebound. We hypothesized this is partly because of PC residence in protective bone marrow (BM) microenvironments. The purpose of this proof-of-concept study was to examine the effects of the CXCR4 antagonist, plerixafor, on PC BM residence; its safety profile (alone and in combination with a proteasome inhibitor, bortezomib); and the transcriptional effect on BMPCs in HLA-sensitized kidney transplant candidates. Participants were enrolled into 3 groups: group A (n = 4), plerixafor monotherapy; and groups B (n = 4) and C (n = 4), plerixafor and bortezomib combinations. CD34+ stem cell and PC levels increased in the blood after plerixafor treatment. PC recovery from BM aspirates varied depending on the dose of plerixafor and bortezomib. Single-cell RNA sequencing on BMPCs from 3 group C participants pretreatment and posttreatment revealed multiple populations of PCs, with a posttreatment enrichment of oxidative phosphorylation, proteasome assembly, cytoplasmic translation, and autophagy-related genes. Murine studies demonstrated dually inhibiting the proteasome and autophagy resulted in greater BMPC death than did monotherapies. In conclusion, this pilot study revealed anticipated effects of combined plerixafor and bortezomib on BMPCs, an acceptable safety profile, and suggests the potential for autophagy inhibitors in desensitization regimens.
Asunto(s)
Compuestos Heterocíclicos , Trasplante de Riñón , Humanos , Animales , Ratones , Bortezomib/farmacología , Bortezomib/uso terapéutico , Células Plasmáticas , Médula Ósea , Complejo de la Endopetidasa Proteasomal , Ácidos Borónicos/farmacología , Ácidos Borónicos/uso terapéutico , Pirazinas/farmacología , Pirazinas/uso terapéutico , Movilización de Célula Madre Hematopoyética , Proyectos Piloto , Compuestos Heterocíclicos/farmacología , Inhibidores de Proteasoma/farmacología , Inhibidores de Proteasoma/uso terapéutico , Receptores CXCR4RESUMEN
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a neurotoxin that damages dopaminergic neurons. Zebrafish has been shown to be a suitable model organism to investigate the molecular pathways in the pathogenesis of Parkinson's disease and also for potential therapeutic agent research. Boron has been shown to play an important role in the neural activity of the brain. Boronic acids are used in combinatorial approaches in drug design and discovery. The effect of 3-pyridinylboronic acid which is an important sub-class of heterocyclic boronic acids has not been evaluated in case of MPTP exposure in zebrafish embryos. Accordingly, this study was designed to investigate the effects of 3-pyridinylboronic acid on MPTP exposed zebrafish embryos focusing on the molecular pathways related to neurodegeneration and apoptosis by RT-PCR. Zebrafish embryos were exposed to MPTP (800 µM); MPTP + Low Dose 3-Pyridinylboronic acid (50 µM) (MPTP + LB) and MPTP + High Dose 3-Pyridinylboronic acid (100 µM) (MPTP + HB) in well plates for 72 hours post fertilization. Results of our study showed that MPTP induced a P53 dependent and Bax mediated apoptosis in zebrafish embryos and 3-pyridinylboronic acid restored the locomotor activity and gene expressions related to mitochondrial dysfunction and oxidative stress due to the deleterious effects of MPTP, in a dose-dependent manner.
Asunto(s)
Intoxicación por MPTP , Pez Cebra , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina/metabolismo , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina/farmacología , Animales , Ácidos Borónicos/metabolismo , Ácidos Borónicos/uso terapéutico , Modelos Animales de Enfermedad , Intoxicación por MPTP/tratamiento farmacológico , Intoxicación por MPTP/metabolismo , Intoxicación por MPTP/patología , Ratones , Ratones Endogámicos C57BL , Piridinas , Pirrolidinas/metabolismo , Pirrolidinas/uso terapéutico , Pez Cebra/metabolismoRESUMEN
The comparative efficacy of ceftazidime-avibactam and meropenem-vaborbactam for treatment of carbapenem-resistant Enterobacteriaceae (CRE) infections remains unknown. This was a multicenter, retrospective cohort study of adults with CRE infections who received ceftazidime-avibactam or meropenem-vaborbactam for ≥72 hours from February 2015 to October 2018. Patients with a localized urinary tract infection and repeat study drug exposures after the first episode were excluded. The primary endpoint was clinical success compared between treatment groups. Secondary endpoints included 30- and 90-day mortality, adverse events (AE), 90-day CRE infection recurrence, and development of resistance in patients with recurrent infection. A post hoc subgroup analysis was completed comparing patients who received ceftazidime-avibactam monotherapy, ceftazidime-avibactam combination therapy, and meropenem-vaborbactam monotherapy. A total of 131 patients were included (ceftazidime-avibactam, n = 105; meropenem-vaborbactam, n = 26), 40% of whom had bacteremia. No significant difference in clinical success was observed between groups (62% versus 69%; P = 0.49). Patients in the ceftazidime-avibactam arm received combination therapy more often than patients in the meropenem-vaborbactam arm (61% versus 15%; P < 0.01). No difference in 30- and 90-day mortality resulted, and rates of AE were similar between groups. In patients with recurrent infection, development of resistance occurred in three patients that received ceftazidime-avibactam monotherapy and in no patients in the meropenem-vaborbactam arm. Clinical success was similar between patients receiving ceftazidime-avibactam and meropenem-vaborbactam for treatment of CRE infections, despite ceftazidime-avibactam being used more often as a combination therapy. Development of resistance was more common with ceftazidime-avibactam monotherapy.
Asunto(s)
Antibacterianos/uso terapéutico , Compuestos de Azabiciclo/uso terapéutico , Ácidos Borónicos/uso terapéutico , Enterobacteriaceae Resistentes a los Carbapenémicos/efectos de los fármacos , Carbapenémicos , Ceftazidima/uso terapéutico , Farmacorresistencia Bacteriana Múltiple/efectos de los fármacos , Infecciones por Enterobacteriaceae/tratamiento farmacológico , Meropenem/uso terapéutico , Anciano , Estudios de Cohortes , Combinación de Medicamentos , Infecciones por Enterobacteriaceae/microbiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Resultado del Tratamiento , Infecciones Urinarias/tratamiento farmacológico , Infecciones Urinarias/microbiología , Inhibidores de beta-Lactamasas/farmacologíaRESUMEN
Bioconjugates are multifunctional constructs in which biomolecules like peptides, proteins, vitamins and nucleic acids are endowed with the properties of specific payloads. These constructs recently emerged as a new generation of high-precision therapeutics, with several representatives reaching the market. This success stimulated an intense search for new biocompatible synthetic methodologies to connect both components and to control the bioconjugate's function. Despite the remarkable advances made in this field, most of the technologies developed for the construction of bioconjugates were engineered to yield stable constructs that can endure complex physiological conditions. Because of this, the use of reversible covalent bonds in the synthesis of bioconjugates has been rather overlooked, notwithstanding the potential of this strategy to generate stimuli responsive constructs that may operate in areas like the selective delivery of drugs, live-cell imaging and new theranostic approaches. Boronic acids are a well-known class of reagents that have been widely used in modern synthesis for the formation of C-C and C-heteroatom bonds. Apart from this, boronic acids exhibit an exquisite reversible coordination profile that can be explored as a molecular construction tool featuring specific mechanisms to control the structure and biological properties of bioconjugates. In this review, the use of boronic acids in the construction of therapeutically useful bioconjugates will be discussed, focusing on the molecular mechanisms that allow the use of these reagents as bioconjugation warheads, as central pieces of linker structures and as functional payloads.
Asunto(s)
Materiales Biocompatibles/química , Ácidos Borónicos/química , Animales , Materiales Biocompatibles/uso terapéutico , Ácidos Borónicos/uso terapéutico , Sistemas de Liberación de Medicamentos , Diseño de Fármacos , Humanos , Nanomedicina TeranósticaRESUMEN
Ceftazidime/avibactam and meropenem/vaborbactam are changing the management of invasive infections due to carbapenem-resistant Enterobacteriaceae (CRE), leading to higher rates of clinical cure, decreased mortality, and decreased rates of acute kidney injury compared with colistin-based regimens. However, these 2 agents are not interchangeable with regard to management of CRE infections, and clinicians need to be aware of their differences. This review focuses on differences in the in vitro activity of these agents as a function of mechanism of carbapenem resistance, the clinical data supporting their superiority over colistin-based therapy, and the differences between agents with regard to propensity for selection of resistance. Furthermore, considerations and recommendations for hospital formularies and antibiotic stewardship programs regarding positioning of these agents are discussed.
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Antibacterianos/uso terapéutico , Compuestos de Azabiciclo/uso terapéutico , Ácidos Borónicos/uso terapéutico , Enterobacteriaceae Resistentes a los Carbapenémicos/efectos de los fármacos , Ceftazidima/uso terapéutico , Manejo de la Enfermedad , Infecciones por Enterobacteriaceae/tratamiento farmacológico , Compuestos Heterocíclicos con 1 Anillo/uso terapéutico , Meropenem/uso terapéutico , Inhibidores de beta-Lactamasas/uso terapéutico , Enterobacteriaceae Resistentes a los Carbapenémicos/aislamiento & purificación , Combinación de Medicamentos , Infecciones por Enterobacteriaceae/microbiología , HumanosRESUMEN
We have evaluated the activity of meropenem-vaborbactam against clinical isolates of Pseudomonas aeruginosaandAcinetobacter baumannii in a neutropenic mouse thigh infection model. Data show that meropenem-vaborbactam regimens equivalent to 3-h infusions every 8 h with 2 g meropenem and 2 g vaborbactam produced bacterial killing against strains with MICs of 2 to 16 mg/liter and suggests that this combination may have utility in the treatment of infections caused by P. aeruginosa and A. baumannii.
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Infecciones por Acinetobacter/tratamiento farmacológico , Acinetobacter baumannii/efectos de los fármacos , Antibacterianos/uso terapéutico , Ácidos Borónicos/uso terapéutico , Compuestos Heterocíclicos con 1 Anillo/uso terapéutico , Meropenem/uso terapéutico , Infecciones por Pseudomonas/tratamiento farmacológico , Pseudomonas aeruginosa/efectos de los fármacos , Acinetobacter baumannii/aislamiento & purificación , Animales , Enterobacteriaceae Resistentes a los Carbapenémicos/efectos de los fármacos , Combinación de Medicamentos , Farmacorresistencia Bacteriana Múltiple , Femenino , Humanos , Ratones , Pruebas de Sensibilidad Microbiana , Pseudomonas aeruginosa/aislamiento & purificaciónRESUMEN
We report a case of a 24-year-old liver transplant recipient who developed hepatic artery thrombosis and graft failure, which was complicated by subphrenic abscess and persistent Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae bacteremia. Ceftazidime-avibactam treatment led to emergence of resistance, and alternative combination therapy failed due to persistent infection and toxicity. The infection resolved after initiation of meropenem-vaborbactam, which created a bridge to retransplantation. Treatment-emergent ceftazidime-avibactam resistance is increasingly recognized, suggesting a role for meropenem-vaborbactam.
Asunto(s)
Antibacterianos/uso terapéutico , Bacteriemia/tratamiento farmacológico , Ácidos Borónicos/uso terapéutico , Compuestos Heterocíclicos con 1 Anillo/uso terapéutico , Infecciones por Klebsiella/tratamiento farmacológico , Klebsiella pneumoniae/efectos de los fármacos , Trasplante de Hígado/efectos adversos , Meropenem/uso terapéutico , Antibacterianos/farmacología , Compuestos de Azabiciclo/farmacología , Proteínas de la Membrana Bacteriana Externa/genética , Proteínas Bacterianas/metabolismo , Enterobacteriaceae Resistentes a los Carbapenémicos/aislamiento & purificación , Ceftazidima/farmacología , Combinación de Medicamentos , Farmacorresistencia Bacteriana Múltiple , Arteria Hepática/patología , Humanos , Klebsiella pneumoniae/genética , Masculino , Pruebas de Sensibilidad Microbiana , Terapia Recuperativa/métodos , Trombosis/patología , Adulto Joven , beta-Lactamasas/metabolismoRESUMEN
ß-Lactams are the most successful antibacterials, yet their use is threatened by resistance, importantly as caused by ß-lactamases. ß-Lactamases fall into two mechanistic groups: the serine ß-lactamases that utilise a covalent acyl-enzyme mechanism and the metallo ß-lactamases that utilise a zinc-bound water nucleophile. Achieving simultaneous inhibition of both ß-lactamase classes remains a challenge in the field. Vaborbactam is a boronate-based inhibitor that reacts with serine-ß-lactamases to form covalent complexes that mimic tetrahedral intermediates in catalysis. Vaborbactam has recently been approved for clinical use in combination with the carbapenem meropenem. Here we show that vaborbactam moderately inhibits metallo-ß-lactamases from all 3 subclasses (B1, B2 and B3), with a potency of around 20-100 fold below that by which it inhibits its current clinical targets, the Class A serine ß-lactamases. This result contrasts with recent investigations of bicyclic boronate inhibitors, which potently inhibit subclass B1 MBLs but which presently lack activity against B2 and B3 enzymes. These findings indicate that cyclic boronate scaffolds have the potential to inhibit the full range of ß-lactamases and justify further work on the development of boronates as broad-spectrum ß-lactamase inhibitors.
Asunto(s)
Antibacterianos/uso terapéutico , Ácidos Borónicos/uso terapéutico , beta-Lactamasas/uso terapéutico , Antibacterianos/farmacología , Ácidos Borónicos/farmacología , Humanos , beta-Lactamasas/farmacologíaRESUMEN
Multiple myeloma (MM) is characterized by clonal expansion of malignant plasma cells in the bone marrow (BM). Despite the significant advances in treatment, MM is still a fatal malignancy. This is mainly due to the supportive role of the BM microenvironment in differentiation, migration, proliferation, survival, and drug resistance of the malignant plasma cells. The BM microenvironment is composed of a cellular compartment (stromal cells, osteoblasts, osteoclasts, endothelial cells, and immune cells) and a non-cellular compartment. In this review, we discuss the interaction between the malignant plasma cell and the BM microenvironment and the strategy to target them.
Asunto(s)
Médula Ósea/efectos de los fármacos , Trasplante de Células Madre Hematopoyéticas , Gammopatía Monoclonal de Relevancia Indeterminada/terapia , Mieloma Múltiple/terapia , Células Plasmáticas/fisiología , Microambiente Tumoral/efectos de los fármacos , Inhibidores de la Angiogénesis/uso terapéutico , Animales , Médula Ósea/inmunología , Ácidos Borónicos/uso terapéutico , Bortezomib , Humanos , Lenalidomida , Mieloma Múltiple/mortalidad , Pirazinas/uso terapéutico , Análisis de Supervivencia , Talidomida/análogos & derivados , Talidomida/uso terapéutico , Resultado del TratamientoRESUMEN
The recently approved combination of meropenem and vaborbactam (Vabomere) is highly active against Gram-negative pathogens, especially Klebsiella pneumoniae carbapenemase (KPC)-producing, carbapenem-resistant Enterobacteriaceae We evaluated the efficacy of meropenem-vaborbactam against three clinically relevant isolates in a murine pyelonephritis model. The data indicate that the combination of meropenem and vaborbactam significantly increased bacterial killing compared to that with the untreated controls. These data suggest that this combination may have utility in the treatment of complicated urinary tract infections due to KPC-producing, carbapenem-resistant Enterobacteriaceae.
Asunto(s)
Antibacterianos/uso terapéutico , Ácidos Borónicos/uso terapéutico , Enterobacteriaceae Resistentes a los Carbapenémicos/efectos de los fármacos , Escherichia coli/efectos de los fármacos , Klebsiella pneumoniae/efectos de los fármacos , Meropenem/uso terapéutico , Pielonefritis/tratamiento farmacológico , Infecciones Urinarias/tratamiento farmacológico , Inhibidores de beta-Lactamasas/uso terapéutico , Animales , Proteínas Bacterianas/metabolismo , Enterobacteriaceae Resistentes a los Carbapenémicos/aislamiento & purificación , Modelos Animales de Enfermedad , Combinación de Medicamentos , Humanos , Klebsiella pneumoniae/aislamiento & purificación , Klebsiella pneumoniae/metabolismo , Ratones , Pruebas de Sensibilidad Microbiana , Pielonefritis/microbiología , Infecciones Urinarias/microbiología , beta-Lactamasas/metabolismoRESUMEN
Meropenem-vaborbactam (Vabomere) is highly active against Gram-negative pathogens, especially Klebsiella pneumoniae carbapenemase (KPC)-producing, carbapenem-resistant Enterobacteriaceae The objective of these studies was to evaluate the efficacy of meropenem alone and in combination with vaborbactam in mouse thigh and lung infection models. Thighs or lungs of neutropenic mice were infected with KPC-producing carbapenem-resistant Enterobacteriaceae, with meropenem MICs ranging from ≤0.06 to 8 mg/liter in the presence of 8 mg/liter vaborbactam. Mice were treated with meropenem alone or meropenem in combination with vaborbactam every 2 h for 24 h to provide exposures comparable to 2-g doses of each component in humans. Meropenem administered in combination with vaborbactam produced bacterial killing in all strains tested, while treatment with meropenem alone either produced less than 0.5 log CFU/tissue of bacterial killing or none at all. In the thigh model, 11 strains were treated with the combination of meropenem plus vaborbactam (300 plus 50 mg/kg of body weight). This combination produced from 0.8 to 2.89 logs of bacterial killing compared to untreated controls at the start of treatment. In the lung infection model, two strains were treated with the same dosage regimen of meropenem and vaborbactam. The combination produced more than 1.83 logs of bacterial killing against both strains tested compared to untreated controls at the start of treatment. Overall, these data suggest that meropenem-vaborbactam may have utility in the treatment of infections due to KPC-producing carbapenem-resistant Enterobacteriaceae.
Asunto(s)
Antibacterianos/uso terapéutico , Ácidos Borónicos/uso terapéutico , Enterobacteriaceae Resistentes a los Carbapenémicos/efectos de los fármacos , Enterobacter cloacae/efectos de los fármacos , Escherichia coli/efectos de los fármacos , Klebsiella pneumoniae/efectos de los fármacos , Meropenem/uso terapéutico , Infecciones del Sistema Respiratorio/tratamiento farmacológico , Infecciones de los Tejidos Blandos/tratamiento farmacológico , Inhibidores de beta-Lactamasas/uso terapéutico , Animales , Antibacterianos/farmacocinética , Proteínas Bacterianas/metabolismo , Ácidos Borónicos/farmacocinética , Enterobacteriaceae Resistentes a los Carbapenémicos/aislamiento & purificación , Modelos Animales de Enfermedad , Combinación de Medicamentos , Femenino , Humanos , Meropenem/farmacocinética , Ratones , Pruebas de Sensibilidad Microbiana , Neutropenia/tratamiento farmacológico , Infecciones del Sistema Respiratorio/microbiología , Infecciones del Sistema Respiratorio/patología , Infecciones de los Tejidos Blandos/microbiología , Muslo/microbiología , Muslo/patología , Inhibidores de beta-Lactamasas/farmacocinética , beta-Lactamasas/metabolismoRESUMEN
Meropenem-vaborbactam is a carbapenem and ß-lactamase inhibitor combination that is newly indicated for the treatment of complicated urinary tract infections (cUTI), including adult pyelonephritis. Vaborbactam was developed due to emergence of carbapenem-resistant strains of Enterobacteriaceae. In a phase I trial, patients that received meropenem-vaborbactam 2-2 g intravenously over 3 h every 8 h, Cmax was 58.2 ± 10.8 µg/mL for meropenem and 59.0 ± 8.4 µg/mL for vaborbactam. AUC0-8 was 186 ± 33.6 µg ⢠h/mL for meropenem and 204 ± 34.6 µg ⢠h/mL for vaborbactam. Vss = 16.3 ± 2.6 L for meropenem and 17.6 ± 2.6 L for vaborbactam. Protein binding for vaborbactam averaged 33% in humans. Plasma clearance ranged from 10.42 ± 1.85 to 14.77 ± 2.84 L/h. One phase III trial evaluated efficacy for meropenem-vaborbactam 2-2 g intravenously every 8 h versus piperacillin-tazobactam 4-0.5 g intravenously every 8 h in complicated UTI. It found non-inferiority and statistical superiority for meropenem in overall success at the end of treatment primary end point. In another phase III trial evaluating efficacy in carbapenem-resistant Enterobacteriaceae (CRE) infections, meropenem-vaborbactam 2-2 g intravenously every 8 h was associated with decreased 28-day mortality and increased clinical cure compared with a best available therapy group.
Asunto(s)
Antibacterianos/uso terapéutico , Ácidos Borónicos/uso terapéutico , Enterobacteriaceae Resistentes a los Carbapenémicos/efectos de los fármacos , Infecciones por Enterobacteriaceae/tratamiento farmacológico , Infecciones por Enterobacteriaceae/microbiología , Tienamicinas/uso terapéutico , Animales , Antibacterianos/farmacología , Ácidos Borónicos/farmacología , Enterobacteriaceae Resistentes a los Carbapenémicos/fisiología , Carbapenémicos/farmacología , Carbapenémicos/uso terapéutico , Ensayos Clínicos como Asunto , Infecciones por Enterobacteriaceae/diagnóstico , Humanos , Meropenem , Pruebas de Sensibilidad Microbiana , Tienamicinas/farmacología , Distribución Tisular , Resultado del Tratamiento , Infecciones Urinarias/tratamiento farmacológico , Infecciones Urinarias/microbiología , Inhibidores de beta-Lactamasas/farmacología , Inhibidores de beta-Lactamasas/uso terapéuticoRESUMEN
OBJECTIVE: To review the pharmacology, spectrum of activity, pharmacokinetics, pharmacodynamics, safety, efficacy, administration, and considerations for clinical use of meropenem/vaborbactam (M/V). DATA SOURCES: A literature search using PubMed and clinicaltrials.gov (June 2013 to December 2017) was conducted using the search terms meropenem, vaborbactam, RPX7009, biapenem, RPX2003, and carbavance. References from relevant articles and conference abstracts were also reviewed. STUDY SELECTION AND DATA EXTRACTION: Preclinical, phase I studies, and phase III studies written in the English language were evaluated. DATA SYNTHESIS: M/V is a novel carbapenem/ß-lactamase inhibitor antimicrobial with in vitro activity against nearly 99% of Klebsiella pneumoniae carbapenemase-producing Enterobacteriaceae. M/V is approved for the treatment of adults with complicated urinary tract infections (cUTIs), including pyelonephritis. In a phase III cUTI trial (TANGO I), 98.4% of patients treated with M/V experienced overall clinical success compared with 94% of patients treated with piperacillin/tazobactam (95% CI = 0.7 to 9.1). When compared with best available therapy for carbapenem-resistant Enterobacteriaceae (CRE) infections in TANGO II, patients receiving M/V were more likely to achieve clinical cure at both the end of therapy (64.3% vs 33.3%, P = 0.04) as well as at the test of cure (57.1% vs 26.7%, P = 0.04). The most common adverse effects associated with M/V were headache, infusion-site reactions, and diarrhea. CONCLUSION: M/V has a valuable role in the treatment of CRE and should be used judiciously to preserve its use for resistant infections.
Asunto(s)
Antibacterianos/uso terapéutico , Infecciones Bacterianas/tratamiento farmacológico , Ácidos Borónicos/uso terapéutico , Meropenem/uso terapéutico , Animales , Antibacterianos/química , Antibacterianos/farmacocinética , Antibacterianos/farmacología , Ácidos Borónicos/química , Ácidos Borónicos/farmacocinética , Ácidos Borónicos/farmacología , Humanos , Meropenem/química , Meropenem/farmacocinética , Meropenem/farmacologíaRESUMEN
This article discusses eight drugs recently approved by the FDA, including their indications and contraindications, precautions, dosage, and nursing considerations. The article also includes summary charts on 14 recently approved antineoplastic drugs and four drugs approved for rare disorders.
Asunto(s)
Aprobación de Drogas , Acetatos/uso terapéutico , Ácidos Borónicos/uso terapéutico , Combinación de Medicamentos , Fluoroquinolonas/uso terapéutico , Humanos , Meropenem , Metronidazol/análogos & derivados , Metronidazol/uso terapéutico , Nitroimidazoles/uso terapéutico , Proteína Relacionada con la Hormona Paratiroidea/uso terapéutico , Péptidos/uso terapéutico , Prostaglandinas F Sintéticas/uso terapéutico , Quinazolinas/uso terapéutico , Tienamicinas/uso terapéutico , Estados Unidos , United States Food and Drug AdministrationRESUMEN
Mantle cell lymphoma (MCL) is a rare and aggressive form of non-Hodgkin's lymphoma that generally affects older individuals and continues to have one of the worst outcomes of all the lymphomas. Over the last decade, there has been a widespread adoption of cytarabine-based therapy in younger patients, and the incorporation of rituximab into chemotherapeutic regimens has become an evidence-based standard of care. However MCL remains a largely incurable disease, and following relapse, it can be a challenge to manage. Although it is possible to define prognosis reliably, there are, as yet, no clear diagnostic or response-adjusted parameters that can help to guide therapeutic decisions. However, there are a number of highly active targeted therapies that are moving into the clinic that are set to transform the therapeutic paradigm for this disease in the very near future. This review will explore the molecular pathogenesis of MCL and the current and evolving therapeutic strategies for this disease.
Asunto(s)
Linfoma de Células del Manto/terapia , Anticuerpos Monoclonales de Origen Murino/uso terapéutico , Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Ácidos Borónicos/uso terapéutico , Bortezomib , Ensayos Clínicos como Asunto , Citarabina/uso terapéutico , Humanos , Linfoma de Células del Manto/genética , Oncología Médica/métodos , Mutación , Tomografía de Emisión de Positrones , Pronóstico , Pirazinas/uso terapéutico , Rituximab , Resultado del TratamientoRESUMEN
CAN2007 was a phase 1/2 study of once- and twice-weekly single-agent bortezomib in relapsed primary systemic amyloid light chain amyloidosis (AL) amyloidosis. Seventy patients were treated, including 18 and 34 patients at the maximum planned doses on the once- and twice-weekly schedules. This prespecified final analysis provides mature response and long-term outcomes data after 3-year additional follow-up since the last report. In the once-weekly 1.6 mg/m(2) and twice-weekly 1.3 mg/m(2) bortezomib groups, final hematologic response rates were 68.8% and 66.7%; 80% of patients in each group sustained their response for ≥1 year. One-year progression-free rates were 72.2% and 76.8%. Median overall survival (OS) was 62.1 months and not reached; 4-year OS rates were 75.0% and 63.0%. Low baseline difference in κ/λ free light-chain level was associated with higher hematologic complete response rates and longer OS. At data cutoff, 40 (57%) patients had received subsequent therapy, including 19 (27%) retreated with bortezomib, 11 (58%) of whom achieved complete or partial hematologic responses. Four patients received prolonged bortezomib for between 3.5 and 5.6 years, with no new safety concerns, highlighting the feasibility of long-term therapy. Single-agent bortezomib produced durable hematologic responses and promising long-term OS in relapsed AL amyloidosis. This trial was registered at www.clinicaltrials.gov as #NCT00298766.
Asunto(s)
Amiloidosis/tratamiento farmacológico , Antineoplásicos/uso terapéutico , Ácidos Borónicos/uso terapéutico , Pirazinas/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/efectos adversos , Ácidos Borónicos/efectos adversos , Bortezomib , Femenino , Estudios de Seguimiento , Humanos , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas , Masculino , Persona de Mediana Edad , Pirazinas/efectos adversos , Recurrencia , Análisis de SupervivenciaRESUMEN
Various translocations and mutations have been identified in myeloma, and certain aberrations, such as t(4;14) and del17, are linked with disease prognosis. To investigate mutational prevalence in myeloma and associations between mutations and patient outcomes, we tested a panel of 41 known oncogenes and tumor suppressor genes in tumor samples from 133 relapsed myeloma patients participating in phase 2 or 3 clinical trials of bortezomib. DNA mutations were identified in 14 genes. BRAF as well as RAS genes were mutated in a large proportion of cases (45.9%) and these mutations were mutually exclusive. New recurrent mutations were also identified, including in the PDGFRA and JAK3 genes. NRAS mutations were associated with a significantly lower response rate to single-agent bortezomib (7% vs 53% in patients with mutant vs wild-type NRAS, P = .00116, Bonferroni-corrected P = .016), as well as shorter time to progression in bortezomib-treated patients (P = .0058, Bonferroni-corrected P = .012). However, NRAS mutation did not impact outcome in patients treated with high-dose dexamethasone. KRAS mutation did not reduce sensitivity to bortezomib or dexamethasone. These findings identify a significant clinical impact of NRAS mutation in myeloma and demonstrate a clear example of functional differences between the KRAS and NRAS oncogenes.
Asunto(s)
Antineoplásicos/uso terapéutico , Ácidos Borónicos/uso terapéutico , GTP Fosfohidrolasas/genética , Proteínas de la Membrana/genética , Mieloma Múltiple/tratamiento farmacológico , Mutación , Proteínas Proto-Oncogénicas/genética , Pirazinas/uso terapéutico , Proteínas ras/genética , Bortezomib , Estudios de Cohortes , Relación Dosis-Respuesta a Droga , Humanos , Mieloma Múltiple/diagnóstico , Mieloma Múltiple/genética , Mieloma Múltiple/patología , Pronóstico , Proteínas Proto-Oncogénicas p21(ras) , Análisis de SupervivenciaRESUMEN
Waldenström macroglobulinemia (WM) is a distinct B-cell lymphoproliferative disorder for which clearly defined criteria for the diagnosis, initiation of therapy, and treatment strategy have been proposed as part of the consensus panels of International Workshops on WM (IWWM). As part of the IWWM-7 and based on recently published and ongoing clinical trials, the panels updated treatment recommendations. Therapeutic strategy in WM should be based on individual patient and disease characteristics (age, comorbidities, need for rapid disease control, candidacy for autologous transplantation, cytopenias, IgM-related complications, hyperviscosity, and neuropathy). Mature data show that rituximab combinations with cyclophosphamide/dexamethasone, bendamustine, or bortezomib/dexamethasone provided durable responses and are indicated for most patients. New monoclonal antibodies (ofatumumab), second-generation proteasome inhibitors (carfilzomib), mammalian target of rapamycin inhibitors, and Bruton's tyrosine kinase inhibitors are promising and may expand future treatment options. A different regimen is typically recommended for relapsed or refractory disease. In selected patients with relapsed disease after long-lasting remission, reuse of a prior effective regimen may be appropriate. Autologous stem cell transplantation may be considered in young patients with chemosensitive disease and in newly diagnosed patients with very-high-risk features. Active enrollment of patients with WM in clinical trials is encouraged.
Asunto(s)
Macroglobulinemia de Waldenström/terapia , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales Humanizados , Anticuerpos Monoclonales de Origen Murino/uso terapéutico , Antineoplásicos/uso terapéutico , Clorhidrato de Bendamustina , Ácidos Borónicos/uso terapéutico , Bortezomib , Ensayos Clínicos como Asunto , Conferencias de Consenso como Asunto , Progresión de la Enfermedad , Everolimus , Trasplante de Células Madre Hematopoyéticas , Humanos , Factores Inmunológicos/uso terapéutico , Compuestos de Mostaza Nitrogenada/uso terapéutico , Pirazinas/uso terapéutico , Rituximab , Terapia Recuperativa , Sirolimus/análogos & derivados , Sirolimus/uso terapéutico , Resultado del Tratamiento , Vidarabina/análogos & derivados , Vidarabina/uso terapéuticoRESUMEN
Chronic graft-versus-host disease (cGVHD) following allogeneic hematopoietic stem cell transplantation (HSCT) has emerged as a predominant complication following HSCT and has a distinct etiology. We and others have previously demonstrated that bortezomib, a proteasome inhibitor, can prevent but not treat acute GVHD in mice. To assess the effects of bortezomib on cGVHD, a mouse minor histocompatibility antigen-mismatched strain combination was used to mimic clinical cGVHD sclerodermatous pathogenesis and phenotype. Treatment of ongoing cGVHD with bortezomib ameliorated cutaneous lesions, which were also associated with a reduction in total numbers of germinal center B cells and lower B-cell activating factor gene expression levels in cutaneous tissues. Importantly, lymphoma-bearing mice receiving allogeneic HSCT with bortezomib preserved graft-versus-tumor (GVT) effects. Based on these animal studies, we initiated an intrapatient dose escalation clinical trial in patients with extensive steroid-intolerant, dependent, or resistant cGVHD. Marked clinical improvement was observed in patients, which was also associated with reductions of peripheral B cells and minimal toxicity. These results indicate that bortezomib can be of significant use in the treatment of cGVHD and may also allow for maintenance of GVT. This trial was registered at www.clinicaltrials.gov as #NCT01672229.
Asunto(s)
Ácidos Borónicos/uso terapéutico , Enfermedad Injerto contra Huésped/tratamiento farmacológico , Pirazinas/uso terapéutico , Animales , Bortezomib , Enfermedad Crónica , Femenino , Enfermedad Injerto contra Huésped/etiología , Neoplasias Hematológicas/terapia , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Esclerodermia Sistémica/tratamiento farmacológico , Esclerodermia Sistémica/etiología , Esclerodermia Sistémica/patología , Piel/efectos de los fármacos , Piel/patología , Trasplante Homólogo/efectos adversos , Resultado del Tratamiento , Células Tumorales CultivadasRESUMEN
Standard carfilzomib (20 mg/m(2) cycle 1, 27 mg/m(2) thereafter; 2- to 10-minute infusion) is safe and effective in relapsed or refractory multiple myeloma (R/RMM). We report phase 2 results of carfilzomib 20 mg/m(2) on days 1 to 2 of cycle 1, 56 mg/m(2) thereafter (30-minute infusion), in R/RMM with the option of adding dexamethasone (20 mg) for suboptimal response/progression. Forty-four patients enrolled, all having prior bortezomib and immunomodulatory drugs and a median of 5 prior regimens. Of 42 response-evaluable patients, 23 (55%) achieved at least partial response (PR). Median (95% confidence interval) duration of response, progression-free, and overall survival were 11.7 (6.7-14.7), 4.1 (2.5-11.8), and 20.3 months (6.4-not estimable), respectively. High-risk cytogenetics did not impact outcomes. Treatment was active in bortezomib-refractory subgroups, but these patients tended to have poorer outcomes. Four/10 patients with prior allogeneic transplant achieved at least PR. Of 6 patients who responded, progressed and had dexamethasone added, 4 achieved at least stable disease. The most frequent grade 3/4 adverse events (AEs) possibly related to carfilzomib included lymphopenia (43%), thrombocytopenia (32%), hypertension (25%), pneumonia (18%), and heart failure (11%). Seven patients (16%) discontinued treatment due to AEs. Carfilzomib 56 mg/m(2) ± dexamethasone was tolerable and provided durable responses. This trial was registered at www.clinicaltrials.gov as #NCT01351623.