RESUMEN
Neurofibromatosis type 1 (NF1) is a common tumor-predisposition disorder due to germline mutations in the tumor suppressor gene NF1. A virtually pathognomonic finding of NF1 is the plexiform neurofibroma (PN), a benign, likely congenital tumor that arises from bi-allelic inactivation of NF1. PN can undergo transformation to a malignant peripheral nerve sheath tumor, an aggressive soft-tissue sarcoma. To better understand the non-NF1 genetic contributions to PN pathogenesis, we performed whole-exome sequencing, RNASeq profiling and genome-wide copy-number determination for 23 low-passage Schwann cell cultures established from surgical PN material with matching germline DNA. All resected tumors were derived from routine debulking surgeries. None of the tumors were considered at risk for malignant transformation at the time; for example, there was no pain or rapid growth. Deep (~500X) NF1 exon sequencing was also conducted on tumor DNA. Non-NF1 somatic mutation verification was performed using the Ampliseq/IonTorrent platform. We identified 100% of the germline NF1 mutations and found somatic NF1 inactivation in 74% of the PN. One individual with three PNs had different NF1 somatic mutations in each tumor. The median number of somatic mutations per sample, including NF1, was one (range 0-8). NF1 was the only gene that was recurrently somatically inactivated in multiple tumors. Gene Set Enrichment Analysis of transcriptome-wide tumor RNA sequencing identified five significant (FDR<0.01) and seven trending (0.01⩽FDR<0.02) gene sets related to DNA replication, telomere maintenance and elongation, cell cycle progression, signal transduction and cell proliferation. We found no recurrent non-NF1 locus copy-number variation in PN. This is the first multi-sample whole-exome and whole-transcriptome sequencing study of NF1-associated PN. Taken together with concurrent copy-number data, our comprehensive genetic analysis reveals the primacy of NF1 loss as the driver of PN tumorigenesis.
Asunto(s)
Neurofibroma Plexiforme/patología , Neurofibromatosis 1/patología , Neurofibromina 1/deficiencia , Carcinogénesis/genética , Carcinogénesis/metabolismo , Carcinogénesis/patología , Replicación del ADN , Dosificación de Gen , Genes Supresores de Tumor , Mutación de Línea Germinal , Humanos , Neurofibroma Plexiforme/genética , Neurofibroma Plexiforme/metabolismo , Neurofibromatosis 1/genética , Neurofibromatosis 1/metabolismo , Neurofibromina 1/genética , TranscriptomaRESUMEN
CONTEXT: Ectopic Cushing syndrome due to ACTH secretion from metastatic medullary thyroid cancer (MTC) is associated with significant morbidity and mortality. OBJECTIVE: The aim of the study was to describe the first case of Cushing syndrome associated with MTC in a pediatric patient and the successful reversal of Cushing syndrome with tyrosine kinase inhibitor (vandetanib) therapy. PATIENT AND METHODS: A 17-year-old Brazilian adolescent presented with metastatic MTC and associated ACTH-dependent ectopic Cushing syndrome in the context of multiple endocrine neoplasia type 2B. When the patient was treated with the tyrosine kinase inhibitor vandetanib, rapid decrease in serum cortisol and improvement of clinical symptoms were observed. CONCLUSION: We describe the first pediatric case of clinical and biochemical improvement of paraneoplastic MTC-related Cushing syndrome after treatment with vandetanib. Vandetanib and possibly other tyrosine kinase inhibitors may be a novel beneficial option in patients with neuroendocrine tumor-related ectopic Cushing syndrome.
Asunto(s)
Síndrome de Cushing/etiología , Neoplasia Endocrina Múltiple Tipo 2b/complicaciones , Neoplasias Primarias Secundarias/complicaciones , Piperidinas/uso terapéutico , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Quinazolinas/uso terapéutico , Neoplasias de la Tiroides/complicaciones , Adolescente , Hormona Adrenocorticotrópica/metabolismo , Carcinoma Neuroendocrino , Ensayos Clínicos Fase I como Asunto , Ensayos Clínicos Fase II como Asunto , Humanos , Masculino , Neoplasias Primarias Secundarias/metabolismo , Neoplasias Primarias Secundarias/secundario , Neoplasias de la Tiroides/metabolismo , Neoplasias de la Tiroides/secundarioRESUMEN
OBJECTIVE: Interferon has antiproliferative and antiangiogenic properties. We sought to evaluate preliminary efficacy and determine the recommended phase II dose (RP2D) for pegylated interferon-α-2b (PI) in patients with unresectable progressive or symptomatic plexiform neurofibromas (PN). METHODS: PI was administered weekly in cohorts of 3-6 patients during the dose-finding phase and continued for up to 2 years. Twelve patients were treated at the RP2D to further evaluate toxicity and activity. RESULTS: Thirty patients (median age 9.3 years, range 1.9-34.7 years) were enrolled. No dose-limiting toxicity (DLT) was seen in patients treated at the 3 µg/kg dose level (DL) during the first 4 weeks. All 5 patients treated at the 4.5 µg/kg DL came off study or required dose reductions for behavioral toxicity or fatigue. Similar DLT on the 3 µg/kg DL became apparent over time. There was 1 DLT (myoclonus) in 12 patients enrolled at the 1.0 µg/kg DL. Eleven of 16 patients with pain showed improvement and 13 of 14 patients with a palpable mass had a decrease in size. Five of 17 patients (29%) who underwent volumetric analysis had a 15%-22% decrease in volume. Three of 4 patients with documented radiographic progression prior to enrollment showed stabilization or shrinkage. CONCLUSIONS: The RP2D of PI for pediatric patients with PN is 1 µg/kg/wk. Clinical and radiographic improvement and cessation of growth can occur. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that pegylated interferon-α-2b in patients with unresectable, progressive, symptomatic, or life-threatening PNs results in radiographic reduction or stabilization of PN size.
Asunto(s)
Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Interferón-alfa/administración & dosificación , Interferón-alfa/efectos adversos , Neurofibroma Plexiforme/tratamiento farmacológico , Polietilenglicoles/administración & dosificación , Polietilenglicoles/efectos adversos , Adolescente , Adulto , Antivirales/administración & dosificación , Antivirales/efectos adversos , Niño , Preescolar , Progresión de la Enfermedad , Esquema de Medicación , Femenino , Humanos , Lactante , Inyecciones Subcutáneas , Interferón alfa-2 , Imagen por Resonancia Magnética , Masculino , Neurofibroma Plexiforme/diagnóstico por imagen , Neurofibroma Plexiforme/patología , Radiografía , Proteínas Recombinantes , Resultado del TratamientoRESUMEN
OBJECTIVE: To describe the characteristics of children enrolled in treatment trials for neurofibromatosis type 1 (NF1)-related plexiform neurofibroma (PN), PN tumor burden, PN-related complications, and treatment outcomes and to highlight the differences between characteristics of children with NF1 vs children with cancers entered on early phase drug trials. METHODS: Pre-enrollment characteristics and complications of PN were retrospectively analyzed in a cohort of 59 children with NF1-related PN treated on 1 of 7 clinical trials at the NIH between 1996 and 2007. Outcome was analyzed in a subset of 19 patients enrolled in phase I trials. Comparisons to children with cancer were made from a similar analysis performed recently. RESULTS: The median age at enrollment was 8 years. The median PN volume was 555 mL. Most patients had no prior chemotherapy or radiation, but nearly half had previous surgery for PN. PN-associated complications and NF1 manifestations were common, including pain (53%), other tumors (18%), and hypertension (8%). Investigational drug therapy was well tolerated. A median of 10 treatment cycles was administered. Patients with NF1-related PN were younger, had better performance score, had less prior therapy, and remained on study longer than cancer patients. CONCLUSIONS: Children with NF1-related plexiform neurofibroma (PN) enrolled in clinical trials had large tumors with substantial morbidity. Clinical trials in these children provide information about drug tolerance, cumulative toxicity, and pharmacokinetics in a younger population than early phase pediatric cancer trials. This report may aid in the evaluation of the applicability of traditional pediatric cancer trial designs and endpoints for NF1-related PN.
Asunto(s)
Antineoplásicos/uso terapéutico , Ensayos Clínicos Fase I como Asunto , Ensayos Clínicos Fase II como Asunto , Neurofibroma Plexiforme/tratamiento farmacológico , Neurofibromatosis 1/tratamiento farmacológico , Neoplasias Abdominales/complicaciones , Neoplasias Abdominales/tratamiento farmacológico , Neoplasias Abdominales/patología , Adolescente , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Niño , Preescolar , Estudios de Cohortes , Femenino , Neoplasias de Cabeza y Cuello/complicaciones , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/patología , Humanos , Hipertensión/etiología , Lactante , Masculino , Neurofibroma Plexiforme/complicaciones , Neurofibroma Plexiforme/patología , Neurofibromatosis 1/complicaciones , Neurofibromatosis 1/patología , Dolor/etiología , Estudios Retrospectivos , Neoplasias Torácicas/complicaciones , Neoplasias Torácicas/tratamiento farmacológico , Neoplasias Torácicas/patología , Resultado del Tratamiento , Adulto JovenAsunto(s)
Antineoplásicos/uso terapéutico , Neoplasias/tratamiento farmacológico , Farmacología Clínica/tendencias , Factores de Edad , Niño , Ensayos Clínicos como Asunto , Ensayos de Selección de Medicamentos Antitumorales/métodos , Ensayos de Selección de Medicamentos Antitumorales/tendencias , Humanos , Neoplasias/genética , Neoplasias/mortalidad , Farmacología Clínica/métodos , Tecnología Farmacéutica/métodos , Tecnología Farmacéutica/tendenciasRESUMEN
OBJECTIVE: To longitudinally analyze changes in plexiform neurofibroma (PN) volume in relation to age and body growth in children and young adults with neurofibromatosis type 1 and inoperable, symptomatic, or progressive PNs, using a sensitive, automated method of volumetric MRI analysis. METHODS: We included patients 25 years of age and younger with PNs entered in a natural history study or in treatment trials who had volumetric MRI over > or =16 months. RESULTS: We studied 49 patients (median age 8.3 years) with 61 PNs and a median evaluation period of 34 months (range 18 to 70). The PN growth rates varied among patients, but were constant within patients. Thirty-four patients (69%) experienced > or =20% increase in PN volume during the observation period. PN volume increased more rapidly than body weight over time (p = 0.026). Younger patients had the most rapid PN growth rate. CONCLUSIONS: Volume increase of plexiform neurofibromas is a realistic and meaningful trial endpoint. In most patients plexiform neurofibroma growth rate exceeded body growth rate. The youngest patients had the fastest plexiform neurofibroma growth rate, and clinical drug development should be directed toward this population. Age stratification for clinical trials for plexiform neurofibromas should be considered.
Asunto(s)
Envejecimiento/patología , Peso Corporal , Interpretación de Imagen Asistida por Computador/métodos , Imagenología Tridimensional/métodos , Imagen por Resonancia Magnética/métodos , Neurofibroma Plexiforme/patología , Neurofibromatosis 1/patología , Niño , Femenino , Humanos , Masculino , Invasividad Neoplásica , Estadística como AsuntoRESUMEN
PURPOSE: To determine the maximum tolerated dose and the toxicity profile of the PDGF receptor pathway inhibitor SU101 in pediatric patients with refractory solid tumors, and to define the plasma pharmacokinetics of SU101 and its active metabolite SU0020 in children. EXPERIMENTAL DESIGN: Patients between 3 and 21 years of age with CNS malignancy, neuroblastoma, or sarcoma refractory to standard therapy were eligible. The starting dose of SU101 was 230 mg/m(2) per day administered as a 96-h continuous infusion every 21 days. Blood for pharmacokinetic analysis was obtained during the first cycle. RESULTS: Entered into the trial were 27 patients, and 24 were fully evaluable for toxicity. Dose-limiting central nervous system toxicity was observed in two patients at the 440 mg/m(2) per day dose level. Non-dose-limiting toxicities included nausea, vomiting, headache, fatigue, abdominal discomfort, diarrhea, pruritus, anorexia, constipation, and paresthesias. There were no complete or partial responses. One patient with rapidly progressive desmoplastic small round-cell tumor experienced symptomatic improvement and prolonged stable disease. Steady-state concentrations of SU101 were rapidly achieved and proportional to dose. The concentration of SU0020 was 100- to 1000-fold greater than that of SU101. The median clearance of SU0020 was 0.19 l/day per m(2) and its terminal elimination half-life was 14 days. CONCLUSIONS: SU101 administered on this schedule was generally well tolerated. The maximum tolerated dose of SU101 is 390 mg/m(2) per day for 4 days repeated every 3 weeks. The neurotoxicity observed at the 440 mg/m(2) per day dose level suggests that patients receiving repetitive cycles must be monitored closely, as SU0020 may accumulate over time.
Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias del Sistema Nervioso Central/tratamiento farmacológico , Isoxazoles/uso terapéutico , Adolescente , Adulto , Compuestos de Anilina/sangre , Antineoplásicos/farmacocinética , Neoplasias del Sistema Nervioso Central/metabolismo , Niño , Preescolar , Relación Dosis-Respuesta a Droga , Femenino , Semivida , Humanos , Isoxazoles/farmacocinética , Leflunamida , Imagen por Resonancia Magnética , Masculino , Nitrilos/sangre , Tomografía Computarizada por Rayos X , Resultado del TratamientoRESUMEN
The Kind-Philipp foundation invited a group of international experts from academia, industry, and regulatory institutions to discuss aspects of new drug development in pediatric oncology. The current design, conduct and infrastructure of clinical trials in Europe and the United States, recent regulatory changes of drug development, and the impact of the likely availability of more targeted anti-cancer agents on drug development for pediatric cancers were discussed. This included a review of risk factors, surrogate markers, novel targets, and new anti-cancer agents for pediatric cancers. A special effort was made to define the requirements of well performed clinical trials, including target evaluation, trial design, use of pharmacokinetic (PK) studies, surrogate markers, ethical, and statistical aspects. The greater need for collaboration beyond the National level was recognized.
Asunto(s)
Leucemia , Oncología Médica , Pediatría , Farmacología , Niño , Alemania , HumanosRESUMEN
PURPOSE: To determine the maximum tolerated dose and describe the toxicities of 9-cis-retinoic acid (9cRA, ALRT1057) administered p.o. tid in pediatric patients with refractory cancer and to study the pharmacokinetics of 9cRA and determine whether systemic drug exposure changes with chronic dosing. PATIENTS AND METHODS: Children with refractory cancer (stratified by age, < or =12 and >12 years) were treated with p.o. 9cRA for 28 consecutive days. The starting dose was 50 mg/m(2)/day divided into 3 doses with planned escalations to 65, 85, and 110 mg/m(2)/day. Pharmacokinetic sampling was performed on days 1 and 29 of the first cycle. RESULTS: Of the 37 patients entered, 18 patients < or =12 years of age and 11 patients >12 years of age were evaluable for toxicity. In patients >12 years of age, dose-limiting headache occurred in 2/2 patients at the 110 mg/m(2)/day dose level; 1/8 patients at 85 mg/m(2)/day developed dose-limiting pseudotumor cerebri. In patients < or =12 years of age, 3/5 patients at the starting dose level of 50 mg/m(2)/day developed dose-limiting pseudotumor cerebri; and 0/6 patients experienced dose-limiting toxicity at 35 mg/m(2)/day. Reversible non-dose-limiting hepatotoxicity was observed in 15 patients across all of the dose levels. There was considerable interpatient variability in 9cRA plasma concentrations. Peak plasma concentrations of 9cRA occurred at a median of 1.5 h after a p.o. dose, and the harmonic-mean terminal half-life was 43 min. By day 29 of 9cRA administration, the plasma 9cRA area under the curve declined by an average of 65% from day 1 values. CONCLUSIONS: The dose-limiting toxicity of 9cRA in pediatric patients was neurotoxicity, primarily pseudotumor cerebri. Younger children tolerate significantly lower doses of 9cRA than older children. Similar to all-trans-retinoic acid, the pharmacokinetics of 9cRA demonstrated a wide degree of interpatient variability and decreased over time when administered on a daily basis. The recommended Phase II dose of 9cRA in patients < or =12 and >12 years of age is 35 and 85 mg/m(2)/day, respectively.
Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias/tratamiento farmacológico , Tretinoina/uso terapéutico , Adolescente , Adulto , Factores de Edad , Alitretinoína , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Área Bajo la Curva , Niño , Preescolar , Relación Dosis-Respuesta a Droga , Femenino , Cefalea/inducido químicamente , Humanos , Hígado/enzimología , Masculino , Náusea/inducido químicamente , Neoplasias/metabolismo , Enfermedades de la Piel/inducido químicamente , Transaminasas/efectos de los fármacos , Transaminasas/metabolismo , Resultado del Tratamiento , Tretinoina/efectos adversos , Tretinoina/farmacocinética , Triglicéridos/sangre , Vómitos/inducido químicamenteRESUMEN
PURPOSE: In preclinical studies, thioguanine (TG) has been shown to be more potent than the standard acute lymphoblastic leukemia (ALL) maintenance agent, mercaptopurine (MP), suggesting that TG may be more efficacious than MP in the treatment of childhood ALL. As part of a pilot trial in which TG was used in place of MP, we studied the plasma pharmacokinetics of oral TG and measured steady-state plasma and CSF TG concentrations during a continuous intravenous infusion (CIVI) in children with newly diagnosed standard-risk ALL. METHODS: Nine plasma samples were collected after each patient's first 60 mg/m2 oral TG dose during maintenance. CIVI TG (20 mg/m2/h over 24 h) was administered during the consolidation phase of therapy, and simultaneous plasma and CSF samples were collected near the end of the infusion. TG was measured by reverse-phase HPLC with ultraviolet detection. Erythrocyte TG nucleotide (TGN) concentrations were measured 7 days after a course of CIVI TG and prior to the start of each maintenance cycle. RESULTS: After oral TG (n = 35), the mean (+/- SD) peak plasma concentration was 0.46 +/- 0.68 microM and the AUC ranged from 0.18 to 9.5 microM.h (mean 1.5 microM.h). Mean steady-state plasma and CSF TG concentrations during CIVI (n = 33) were 2.7 and 0.5 microM, respectively. The mean (+/- SD) TG clearance was 935 +/- 463 ml/min per m2. Plasma TG concentrations did not correlate with erythrocyte TGN concentrations after oral or CIVI TG. The 8-OH-TG metabolite was detected in plasma and CSF. CONCLUSIONS: TG concentrations that are cytotoxic to human leukemia cell lines can be achieved in plasma after a 60 mg/m2 oral dose of TG and in plasma and CSF during CIVI of TG.
Asunto(s)
Antimetabolitos Antineoplásicos/farmacocinética , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Tioguanina/farmacocinética , Administración Oral , Antimetabolitos Antineoplásicos/líquido cefalorraquídeo , Antimetabolitos Antineoplásicos/uso terapéutico , Antimetabolitos Antineoplásicos/orina , Área Bajo la Curva , Cromatografía Líquida de Alta Presión/métodos , Eritrocitos/metabolismo , Humanos , Infusiones Intravenosas , Proyectos Piloto , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Tioguanina/líquido cefalorraquídeo , Tioguanina/uso terapéutico , Tioguanina/orinaRESUMEN
The novel methotrexate (MTX) rescue agent carboxypeptidase-G(2) (CPDG(2)) converts >98% of plasma MTX to 2, 4-diamino-N(10)-methylpteroic acid (DAMPA) and glutamate in patients with MTX-induced renal failure and delayed MTX excretion. DAMPA is eliminated more rapidly than MTX in these patients, suggesting nonrenal elimination. The pharmacokinetics and metabolism of DAMPA were studied in four nonhuman primates with reverse-phase HPLC with UV, photodiode array detection, and mass spectroscopy. The mean peak plasma DAMPA concentration was 51 microM and the plasma disposition was described by a three-compartment open model with first order elimination. The mean clearance of DAMPA was 1.9 l/kg/h and the mean terminal half-life was 51 min. Forty-six percent of the dose was excreted in the urine as parent compound. Three DAMPA metabolites, hydroxy-DAMPA, DAMPA-glucuronide, and hydroxy-DAMPA-glucuronide, were identified in plasma and urine. These metabolites also were identified in plasma from patients who received CPDG(2) as an MTX rescue agent. The cytotoxicity of DAMPA and its effect on MTX cytotoxicity were assessed in the Molt-4 human leukemic cell line. DAMPA was not cytotoxic and did not significantly alter the cytotoxicity of MTX. In nonhuman primates metabolism of DAMPA is a major route of DAMPA elimination, and metabolism underlies the more rapid elimination of DAMPA versus MTX in patients with MTX-induced renal dysfunction after administration of CPDG(2).
Asunto(s)
Antineoplásicos/farmacocinética , Metotrexato/análogos & derivados , Animales , Antineoplásicos/metabolismo , Antineoplásicos/farmacología , Cromatografía Líquida de Alta Presión , Humanos , Inyecciones Intravenosas , Macaca mulatta , Masculino , Espectrometría de Masas , Metotrexato/metabolismo , Metotrexato/farmacocinética , Metotrexato/farmacología , Células Tumorales CultivadasRESUMEN
PURPOSE: Raltitrexed (Tomudex), ZD1694) is a novel quinazoline folate analog that selectively inhibits thymidylate synthase. Intracellularly, raltitrexed is polyglutamated to its active form which can be retained in cells for prolonged periods. The pharmacokinetics of raltitrexed in plasma and cerebrospinal fluid (CSF) were studied in a nonhuman primate model. METHODS: Animals received 3 mg/m(2) (n = 1), 6 mg/m(2) (n = 3), or 10 mg/m(2) (n = 3) i.v. over 15 min, and frequent plasma samples were obtained over 48 h. CSF samples were drawn from an indwelling 4th ventricular Ommaya reservoir over 48 h. Plasma and CSF raltitrexed concentrations were measured with a novel, sensitive enzyme inhibition assay with a lower limit of quantification of 0.005 microM. A three-compartment pharmacokinetic model was fitted to the raltitrexed plasma concentration-time data. RESULTS: The plasma concentration-time profile of raltitrexed was triexponential with a rapid initial decline and a prolonged terminal elimination phase (t(1/2) > 24 h), which was related to retention of raltitrexed in a deep tissue compartment. At the peak approximately 30% of the administered dose was in the deep tissue compartment, and 24 h after the dosing >20% of the administered dose remained in the body with >99% in the deep tissue compartment. The mean peak (end of infusion) plasma concentrations after the 3, 6, and 10 mg/m(2) doses were 1.5, 2.4 and 4.8 microM, respectively. The clearance of raltitrexed ranged from 110 to 165 ml/min per m(2), and the steady-state volume of distribution exceeded 200 l/m(2). The CSF penetration of raltitrexed was limited (0.6 to 2.0%) and drug could only be detected in the CSF following a 10 mg/m(2 )dose. CONCLUSIONS: The elimination of raltitrexed is triexponential with a prolonged terminal elimination phase. The pharmacokinetic profile is consistent with extensive polyglutamation and intracellular retention of ralitrexed. The three-compartment model presented here may be useful for the analysis of the pharmacokinetics of raltitrexed in humans.
Asunto(s)
Antimetabolitos Antineoplásicos/farmacocinética , Quinazolinas/farmacocinética , Tiofenos/farmacocinética , Timidilato Sintasa/antagonistas & inhibidores , Animales , Antimetabolitos Antineoplásicos/sangre , Antimetabolitos Antineoplásicos/líquido cefalorraquídeo , Semivida , Infusiones Intravenosas , Macaca mulatta , Masculino , Tasa de Depuración Metabólica , Modelos Biológicos , Quinazolinas/sangre , Quinazolinas/líquido cefalorraquídeo , Sensibilidad y Especificidad , Tiofenos/sangre , Tiofenos/líquido cefalorraquídeoRESUMEN
Microplate reader assays offer several advantages over conventional spectrophotometric assays. We adapted the dihydrofolate reductase (DHFR) enzyme inhibition assay for use in a 96-well microplate reader to measure plasma methotrexate (MTX) concentrations. The assay is linear from 0.01 to 0.1 micromol/L. The within-run CVs at 0.03 micromol/L and 0.08 micromol/L MTX were 4.0% and 2.7%, respectively, and the interday (total) CVs were 7.6% and 1.8%. Cross-reactivity with the inactive MTX metabolite 2, 4-diamino-N10-methylpteroic acid (DAMPA) was 3.9%, significantly less than that described with commercial immunoassays; with 7-hydroxymethotrexate cross-reactivity was 1.7%. In addition to sensitivity and specificity, the advantages of this assay are small sample volumes, simultaneous analysis of multiple samples, and rapid turnaround. Because of its greater specificity, the DHFR enzyme inhibition assay may be useful when DAMPA is present in plasma samples and HPLC is not available.
Asunto(s)
Metotrexato/sangre , Tetrahidrofolato Deshidrogenasa/sangre , Antagonistas del Ácido Fólico/sangre , Humanos , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , TemperaturaRESUMEN
PURPOSE: Methotrexate nephrotoxicity can lead to delayed methotrexate elimination and the development of life-threatening toxicity, which may not be preventable with the standard rescue agent leucovorin. In preclinical studies, we previously demonstrated that carboxypetidase-G2 (CPDG2) rapidly hydrolyzes methotrexate to nontoxic metabolites. A protocol for the compassionate use of CPDG2 in patients who develop nephrotoxicity while receiving high-dose methotrexate was therefore developed. The pharmacologic and clinical outcome of CPDG2 rescue administered with thymidine and leucovorin in 20 patients is presented here. METHODS: Patients with high-dose methotrexate-induced renal dysfunction received one to three doses of CPDG2, 50 U/kg body weight intravenously (i.v.), thymidine 8 g/m2/d by continuous i.v. infusion, and standard pharmacokinetically guided leucovorin rescue. Plasma concentrations of methotrexate and its inactive metabolite 4-deoxy-4-amino-N10-methylpteroic acid (DAMPA) were measured before and after CPDG2 using high-pressure liquid chromatography (HPLC). Tolerance of CPDG2 and thymidine, development of methotrexate toxicities, and recovery of renal function were monitored. RESULTS: Twenty patients who received high-dose methotrexate for osteosarcoma (n = 11), lymphoid cancers (n = 8), and gastric cancer (n = 1) developed nephrotoxicity (median serum creatinine, 3.2 mg/dL) and elevated plasma methotrexate concentrations (median, 201 mumol/L at hour 46). CPDG2 and thymidine rescue was well tolerated and resulted in a rapid 95.6% to 99.6% reduction in the plasma methotrexate concentration. Methotrexate-related toxicity was mild to moderate. Serum creatinine returned to normal values at a median of 22 days. CONCLUSION: CPDG2, thymidine, and leucovorin rescue was highly effective in 20 patients at high risk for developing life-threatening methotrexate toxicity after the onset of methotrexate-induced nephrotoxicity and delayed methotrexate excretion.
Asunto(s)
Antídotos/uso terapéutico , Antimetabolitos Antineoplásicos/efectos adversos , Carboxipeptidasas/uso terapéutico , Enfermedades Renales/inducido químicamente , Riñón/efectos de los fármacos , Leucovorina/uso terapéutico , Metotrexato/efectos adversos , Timidina/uso terapéutico , Adolescente , Adulto , Antimetabolitos Antineoplásicos/administración & dosificación , Antimetabolitos Antineoplásicos/sangre , Carboxipeptidasas/efectos adversos , Niño , Preescolar , Femenino , Humanos , Lactante , Riñón/metabolismo , Enfermedades Renales/metabolismo , Enfermedades Renales/prevención & control , Linfoma no Hodgkin/sangre , Linfoma no Hodgkin/tratamiento farmacológico , Masculino , Metotrexato/administración & dosificación , Metotrexato/sangre , Persona de Mediana Edad , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangre , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Sarcoma/sangre , Sarcoma/tratamiento farmacológico , Timidina/efectos adversosRESUMEN
Prompt and appropriate management measures are critical in order to achieve a favorable outcome after a major overdose of intrathecally (IT) administered methotrexate (MTX). Published information available to guide clinicians in the immediate management of this medical emergency is scant. Herein we describe a 6-year-old boy with acute lymphoblastic leukemia who received an inadvertent overdose of 600 mg of IT administered MTX instead of the intended dose of 12 mg. Severe acute neurotoxicity developed rapidly. Lumbar puncture and drainage of 15 mL of cerebrospinal fluid 2 hours after administration resulted in removal of 32% of the administered drug. Ventriculolumbar perfusion with 240 mL of warmed isotonic saline through ventricular and lumbar catheters for 3 hours resulted in removal of a total of 90% of the drug within 8 1/2 hours after administration. IT administration of 2,000 U of carboxypeptidase G2 (CPDG2), an enzyme that inactivates MTX, resulted in a further 150-fold reduction in cerebrospinal fluid MTX concentration. The patient experienced complete recovery. To our knowledge, this is the first reported case of the use of IT instillation of CPDG2 for the treatment of an overdose of IT administered MTX in a human, and it is only the second reported favorable outcome after an IT overdose of more than 500 mg of MTX. Minor IT overdoses of MTX can be managed by immediate lumbar drainage alone. Major overdoses may also necessitate prompt ventriculolumbar perfusion, IT instillation of CPDG2, and further supportive measures for a successful outcome after this infrequent but potentially catastrophic event.
Asunto(s)
Antimetabolitos Antineoplásicos/envenenamiento , Metotrexato/antagonistas & inhibidores , Metotrexato/envenenamiento , gamma-Glutamil Hidrolasa/administración & dosificación , Antimetabolitos Antineoplásicos/administración & dosificación , Antimetabolitos Antineoplásicos/líquido cefalorraquídeo , Niño , Sobredosis de Droga/tratamiento farmacológico , Humanos , Inyecciones Espinales , Región Lumbosacra , Masculino , Metotrexato/administración & dosificación , Metotrexato/líquido cefalorraquídeo , Perfusión , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológicoRESUMEN
BACKGROUND: High dose methotrexate (HDMTX) induced renal failure is a medical emergency, as methotrexate (MTX) is primarily eliminated by renal excretion. High doses of leucovorin (LV) do not necessarily prevent toxicity in the presence of sustained elevated plasma MTX concentrations. The bacterial enzyme carboxypeptidase-G2 (CPDG2) hydrolyzes MTX into inactive metabolites and has been demonstrated to lower plasma MTX concentrations to nontoxic levels rapidly in the nonhuman primate after HDMTX infusion. Therefore, CPDG2 was evaluated as a rescue agent in a patient with acute renal dysfunction secondary to HDMTX: METHODS: A 16 year old patient with osteosarcoma experienced acute renal dysfunction after HDMTX administration, which resulted in markedly elevated and sustained plasma MTX concentrations. She received three doses of CPDG2 on the fifth day after HDMTX: Plasma MTX concentrations were determined before and after CPDG2 administration. RESULTS: The plasma MTX concentrations decreased from 60 to 1.2 microM within 15 minutes after the first dose of CPDG2. No rebound increase in plasma MTX concentrations or adverse reactions to the enzyme were observed. The patient developed only mild mucositis. Serum creatinine at the time of CPDG2 administration was 5 mg/dl and returned to normal within 7 weeks of enzyme administration. CONCLUSIONS: Carboxypeptidase-G2 rapidly, markedly, and persistently lowered plasma MTX concentrations to a level that could be rescued safely with LV. Based on the experience with this patient and on preclinical studies in nonhuman primates, CPDG2 appears to be more effective than hemodialysis or hemoperfusion, and may prove beneficial for patients at risk for life-threatening toxicity secondary to delayed excretion of MTX.