RESUMO
Over 50% of patients with systemic LCH are not cured with front-line therapies, and data to guide salvage options are limited. We describe 58 patients with LCH who were treated with clofarabine. Clofarabine monotherapy was active against LCH in this cohort, including heavily pretreated patients with a systemic objective response rate of 92.6%, higher in children (93.8%) than adults (83.3%). BRAFV600E+ variant allele frequency in peripheral blood is correlated with clinical responses. Prospective multicentre trials are warranted to determine optimal dosing, long-term efficacy, late toxicities, relative cost and patient-reported outcomes of clofarabine compared to alternative LCH salvage therapy strategies.
Assuntos
Clofarabina , Histiocitose de Células de Langerhans , Humanos , Clofarabina/uso terapêutico , Clofarabina/administração & dosagem , Histiocitose de Células de Langerhans/tratamento farmacológico , Masculino , Feminino , Adulto , Adolescente , Criança , Pessoa de Meia-Idade , Pré-Escolar , Adulto Jovem , Idoso , Recidiva , Proteínas Proto-Oncogênicas B-raf/genética , Lactente , Resultado do Tratamento , Terapia de Salvação , Nucleotídeos de Adenina/uso terapêutico , Nucleotídeos de Adenina/administração & dosagem , Nucleotídeos de Adenina/efeitos adversos , Arabinonucleosídeos/uso terapêutico , Arabinonucleosídeos/administração & dosagem , Arabinonucleosídeos/efeitos adversosRESUMO
Astrocytes play multiple important roles in brain physiology. However, depending on the stimuli, astrocytes may exacerbate inflammatory reactions, contributing to the development and progression of neurological diseases. Therefore, therapies targeting astrocytes represent a promising area for the development of new brain drugs. Thiazolidinones are heterocyclic compounds that have a sulfur and nitrogen atom and a carbonyl group in the ring and represent a class of compounds of great scientific interest due to their pharmacological properties. The aim of this study was to investigate the effect of 3-(3-(diethylamino)propyl)-2-(4-(methylthio)phenyl)thiazolidin-4-one (DS27) on cell proliferation and morphology, oxidative stress parameters, activity of the enzymes ectonucleotidases and acetylcholinesterase (AChE) and interleukin 6 (IL-6) levels in primary astrocyte cultures treated with lipopolysaccharide (LPS), to model neuroinflammation. The astrocyte culture was exposed to LPS (10 µg/ml) for 3 h and subsequently treated with compound DS27 for 24 and 48 h (concentrations ranging to 10-100 µM). LPS induced an increase in astrocyte proliferation, AChE activity, IL-6 levels, oxidative damage, ATP and ADP and a reduction in AMP hydrolysis in rat primary astrocyte cultures. DS27 treatment was effective in reversing these alterations induced by LPS. Our findings demonstrated that DS27 is able to modulate cholinergic and purinergic signaling, redox status, and the levels of pro-inflammatory cytokines in LPS-induced astrocyte damage. These glioprotective effects of DS27 may be very important for improving neuroinflammation, which is associated with many brain diseases.
Assuntos
Astrócitos , Lipopolissacarídeos , Ratos , Animais , Astrócitos/metabolismo , Lipopolissacarídeos/farmacologia , Acetilcolinesterase/metabolismo , Nucleotídeos de Adenina/efeitos adversos , Interleucina-6 , Doenças Neuroinflamatórias , Hidrólise , Estresse Oxidativo , Inflamação/tratamento farmacológico , Células CultivadasRESUMO
We hereby report our multicentre, retrospective experience with CLARA in patients with fludarabine/cytarabine/G-CSF (FLAG) refractory AML. The study included all consecutive R/R AML patients, who received CLARA salvage during October 2010-October 2015 period. All patients were unresponsive to FLAG salvage chemotherapy regimen and did not undergo previous allo-HCT. A total of 40 patients were included. Following CLARA 5 (12.5%) patients experienced induction mortality and 10 (25%) patients achieved CR. 25 (62.5%) patients were unresponsive to CLARA. 7 (17.5%) out of 10 patients in CR received allo-HCT. Median overall survival of patients who achieved CR after CLARA was 24.5 months (8.5-54.5) and 3 months (2.5-5), in patients who underwent and didn't allo-HCT, respectively. Our results indicate that CLARA may be good alternative even in FLAG refractory AML patients and can be used as a bridge to allo-HCT, who have a suitable donor and able to tolerate the procedure.
Assuntos
Nucleotídeos de Adenina/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Arabinonucleosídeos/administração & dosagem , Citarabina/administração & dosagem , Leucemia Mieloide Aguda/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Terapia de Salvação/métodos , Nucleotídeos de Adenina/efeitos adversos , Adolescente , Adulto , Idoso , Arabinonucleosídeos/efeitos adversos , Clofarabina , Citarabina/efeitos adversos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Fator Estimulador de Colônias de Granulócitos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Vidarabina/análogos & derivados , Adulto JovemRESUMO
The 5-year overall survival (OS) in patients ≥ 60 years old with acute myeloid leukemia (AML) remains < 10%. Clofarabine-based induction (CLO) provides an alternative to low-intensity therapy (LIT) and palliative care for this population, but supporting data are conflicted. Recently, our institution adopted the FLAG regimen (fludarabine, cytarabine, and granulocyte colony-stimulating factor) based on data reporting similar outcomes to CLO in elderly patients with AML unable to tolerate anthracycline-based induction. We retrospectively analyzed the efficacy and safety of patients ≥ 60 years old with AML treated with FLAG or CLO over the past 10 years. We performed a propensity score match that provided 32 patients in each group. Patients treated with FLAG had a higher CR/CRi rate (65.6 vs. 37.5%, P = 0.045) and OS (7.9 vs. 2.8 months, P = 0.085) compared to CLO. Furthermore, FLAG was better tolerated with significantly less grade 3/4 toxicities and a shorter duration of neutropenia (18.5 vs. 30 days, P = 0.002). Finally, we performed a cost analysis that estimated savings to be $30,000-45,000 per induction with FLAG. Our study supports the use of FLAG both financially and as an effective, well-tolerated high-dose treatment regimen for elderly patients with AML. No cases of cerebellar neurotoxicity occurred.
Assuntos
Nucleotídeos de Adenina/uso terapêutico , Envelhecimento , Antimetabólitos Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Arabinonucleosídeos/uso terapêutico , Quimioterapia de Indução , Leucemia Mieloide Aguda/tratamento farmacológico , Vidarabina/análogos & derivados , Nucleotídeos de Adenina/efeitos adversos , Nucleotídeos de Adenina/economia , Idoso , Idoso de 80 Anos ou mais , Antimetabólitos Antineoplásicos/efeitos adversos , Antimetabólitos Antineoplásicos/economia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/economia , Arabinonucleosídeos/efeitos adversos , Arabinonucleosídeos/economia , Estudos de Casos e Controles , Doença Hepática Induzida por Substâncias e Drogas/economia , Doença Hepática Induzida por Substâncias e Drogas/epidemiologia , Doença Hepática Induzida por Substâncias e Drogas/mortalidade , Doença Hepática Induzida por Substâncias e Drogas/terapia , Clofarabina , Estudos de Coortes , Terapia Combinada/economia , Redução de Custos , Custos e Análise de Custo , Citarabina/efeitos adversos , Citarabina/economia , Citarabina/uso terapêutico , Fator Estimulador de Colônias de Granulócitos/efeitos adversos , Fator Estimulador de Colônias de Granulócitos/economia , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Custos Hospitalares , Humanos , Incidência , Quimioterapia de Indução/efeitos adversos , Quimioterapia de Indução/economia , Tempo de Internação , Leucemia Mieloide Aguda/economia , Leucemia Mieloide Aguda/mortalidade , Michigan/epidemiologia , Pessoa de Meia-Idade , Neutropenia/induzido quimicamente , Neutropenia/economia , Neutropenia/mortalidade , Neutropenia/terapia , Pontuação de Propensão , Estudos Retrospectivos , Análise de Sobrevida , Centros de Atenção Terciária , Vidarabina/efeitos adversos , Vidarabina/economia , Vidarabina/uso terapêuticoRESUMO
Relapsed/refractory acute myeloid leukemia (AML) has an extremely poor prognosis. We describe 17 children and adolescents with relapsed/refractory AML who received clofarabine, cyclophosphamide, and etoposide. Seven patients (41%) responded: 4 with a complete response (CR); 1 with CR with incomplete platelet recovery; and 2 with a partial response. Additionally, 4 developed hypocellular marrow without evidence of leukemia; 5 patients had resistant disease; and 1 suffered early toxic death. After further therapy including transplantation, 4 patients (24%) are alive without evidence of disease at a median of 60 months. This anthracycline-free regimen may be studied for relapsed or refractory AML, but due to the high risk of marrow aplasia reduced doses of clofarabine and cyclophosphamide should be used.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/terapia , Nucleotídeos de Adenina/administração & dosagem , Nucleotídeos de Adenina/efeitos adversos , Adolescente , Adulto , Aloenxertos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Arabinonucleosídeos/administração & dosagem , Arabinonucleosídeos/efeitos adversos , Criança , Pré-Escolar , Clofarabina , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Intervalo Livre de Doença , Etoposídeo/administração & dosagem , Etoposídeo/efeitos adversos , Feminino , Seguimentos , Transplante de Células-Tronco Hematopoéticas , Humanos , Lactente , Masculino , Taxa de SobrevidaRESUMO
BACKGROUND: Fludarabine and clofarabine are purine nucleoside analogues with established clinical activity in patients with acute myeloid leukemia (AML). METHODS: Herein, the authors evaluated the efficacy and safety of idarubicin and cytarabine with either clofarabine (CIA) or fludarabine (FIA) in adults with newly diagnosed AML. Adults with newly diagnosed AML who were deemed suitable for intensive chemotherapy were randomized using a Bayesian adaptive design to receive CIA (106 patients) or FIA (76 patients). Patients received induction with idarubicin and cytarabine, plus either clofarabine or fludarabine. Responding patients could receive up to 6 cycles of consolidation therapy. Outcomes were compared with a historical cohort of patients who received idarubicin and cytarabine. RESULTS: The complete remission/complete remission without platelet recovery rate was similar among patients in the CIA and FIA arms (80% and 82%, respectively). The median event-free survival was 13 months and 12 months, respectively (P = .91), and the median overall survival was 24 months and not reached, respectively (P = .23), in the 2 treatment arms. CIA was associated with more adverse events, particularly transaminase elevation, hyperbilirubinemia, and rash. Early mortality was similar in the 2 arms (60-day mortality rate of 4% for CIA vs 1% for FIA; P = .32). In an exploratory analysis of patients aged <50 years, FIA was found to be associated with improved survival compared with idarubicin and cytarabine (2-year event-free survival rate: 58% vs 30% [P = .05] and 2-year overall survival rate: 72% vs 36% [P = .009]). CONCLUSIONS: CIA and FIA have similar efficacy in younger patients with newly diagnosed AML, although FIA is associated with a better toxicity profile. Cancer 2017;123:4430-9. © 2017 American Cancer Society.
Assuntos
Nucleotídeos de Adenina/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Arabinonucleosídeos/administração & dosagem , Citarabina/administração & dosagem , Idarubicina/administração & dosagem , Leucemia Mieloide Aguda/tratamento farmacológico , Vidarabina/análogos & derivados , Nucleotídeos de Adenina/efeitos adversos , Adolescente , Adulto , Idoso , Arabinonucleosídeos/efeitos adversos , Clofarabina , Citarabina/efeitos adversos , Humanos , Idarubicina/efeitos adversos , Leucemia Mieloide Aguda/patologia , Pessoa de Meia-Idade , Terapia Neoadjuvante , Resultado do Tratamento , Vidarabina/administração & dosagem , Vidarabina/efeitos adversos , Adulto JovemRESUMO
Common side effects of clofarabine (CFB) are liver toxicity, particularly a transient elevation of transaminases and skin toxicity. We studied the correlation of pharmacokinetic (PK) parameters with these toxicities and the efficacy of CFB in patients with relapsed or refractory acute myeloid leukemia. Clofarabine PK parameters showed large inter-individual variability. A higher CFB area under the curve was significantly associated with higher transaminase levels (p = .011 for aspartate aminotransferase (AST), adjusted for age, sex, cumulated CFB dosage, baseline AST, and glomerular filtration rate (GFR)). No significant association could be found between maximum concentration and the liver toxicity parameters. The occurrence of skin toxicity and the response to re-induction chemotherapy evaluated at day 15 were also not associated with PK. In conclusion, a higher individual CFB exposure is associated with increased liver toxicity reflected by elevated liver enzymes, without having an impact on anti-leukemic efficacy.
Assuntos
Nucleotídeos de Adenina/efeitos adversos , Nucleotídeos de Adenina/farmacocinética , Antimetabólitos Antineoplásicos/efeitos adversos , Antimetabólitos Antineoplásicos/farmacocinética , Arabinonucleosídeos/efeitos adversos , Arabinonucleosídeos/farmacocinética , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/patologia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Área Sob a Curva , Clofarabina , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Testes de Função Hepática , Masculino , Pessoa de Meia-Idade , Recidiva , Pele/efeitos dos fármacos , Pele/patologia , Resultado do TratamentoAssuntos
Nucleotídeos de Adenina/administração & dosagem , Antimetabólitos Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Arabinonucleosídeos/administração & dosagem , Quimioterapia de Consolidação , Leucemia Mieloide Aguda/tratamento farmacológico , Nucleotídeos de Adenina/efeitos adversos , Adolescente , Adulto , Antimetabólitos Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Arabinonucleosídeos/efeitos adversos , Clofarabina , Quimioterapia de Consolidação/efeitos adversos , Quimioterapia de Consolidação/mortalidade , Citarabina/administração & dosagem , Progressão da Doença , Intervalo Livre de Doença , Feminino , Humanos , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Tempo , Resultado do Tratamento , Adulto JovemRESUMO
Purpose To evaluate the efficacy and safety of a clofarabine-based combination (CLARA) versus conventional high-dose cytarabine (HDAC) as postremission chemotherapy in younger patients with acute myeloid leukemia (AML). Patients and Methods Patients age 18 to 59 years old with intermediate- or unfavorable-risk AML in first remission and no identified donor for allogeneic stem-cell transplantation (SCT) were eligible. Two hundred twenty-one patients were randomly assigned to receive three CLARA or three HDAC consolidation cycles. The primary end point was relapse-free survival (RFS). To handle the confounding effect of SCT that could occur in patients with late donor identification, hazard ratios (HRs) of events were adjusted on the time-dependent treatment × SCT interaction term. Results At 2 years, RFS was 58.5% (95% CI, 49% to 67%) in the CLARA arm and 46.5% (95% CI, 37% to 55%) in the HDAC arm. Overall, 110 patients (55 in each arm) received SCT in first remission. On the basis of a multivariable Cox-adjusted treatment × SCT interaction, the HR of CLARA over HDAC before or in absence of SCT was 0.65 (95% CI, 0.43 to 0.98; P = .041). In a sensitivity analysis, when patients who received SCT in first remission were censored at SCT time, 2-year RFS was 53.3% (95% CI, 39% to 66%) in the CLARA arm and 31.0% (95% CI, 19% to 43%) in the HDAC arm (HR, 0.63; 95% CI, 0.41 to 0.98; P = .043). Gain in RFS could be related to the lower cumulative incidence of relapse observed in the CLARA arm versus the HDAC arm (33.9% v 46.4% at 2 years, respectively; cause-specific HR, 0.61; 95% CI, 0.40 to 0.94; P = .025). CLARA cycles were associated with higher hematologic and nonhematologic toxicity than HDAC cycles. Conclusion These results suggest that CLARA might be considered as a new chemotherapy option in younger patients with AML in first remission.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Nucleotídeos de Adenina/administração & dosagem , Nucleotídeos de Adenina/efeitos adversos , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Arabinonucleosídeos/administração & dosagem , Arabinonucleosídeos/efeitos adversos , Clofarabina , Quimioterapia de Consolidação , Citarabina/administração & dosagem , Intervalo Livre de Doença , Feminino , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Transplante de Células-Tronco Hematopoéticas , Humanos , Leucemia Mieloide Aguda/terapia , Masculino , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
Clofarabine has demonstrated antileukemic activity in acute myeloid leukemia (AML) but has yet to be critically evaluated in younger adults in the frontline with standard chemotherapy. We compared 2 induction regimens in newly diagnosed patients ages 18 to 65 with acute myeloid leukemia (AML)/high-risk myelodysplastic syndromes, that is, idarubicine-cytarabine (cycle I) and amsacrine-cytarabine (cycle II) without or with clofarabine (10 mg/m2 on days 1-5 of each of both cycles). Consolidation involved chemotherapy with or without hematopoietic stem cell transplantation. Event-free survival (EFS, primary endpoint) and other clinical endpoints and toxicities were assessed. We randomized 402 and 393 evaluable patients to the control or clofarabine induction treatment arms. Complete remission rates (89%) did not differ but were attained faster with clofarabine (66% vs 75% after cycle I). Clofarabine added grades 3 to 4 toxicities and delayed hematological recovery. At a median follow-up of 36 months, the study reveals no differences in overall survival and EFS between the control (EFS, 35% ± 3 [standard error] at 4 years) and clofarabine treatments (38% ± 3) but a markedly reduced relapse rate (44% ± 3 vs 35% ± 3) in favor of clofarabine and an increased death probability in remission (15% ± 2 vs 22% ± 3). In the subgroup analyses, clofarabine improved overall survival and EFS for European Leukemia Net (ELN) 2010 intermediate I prognostic risk AML (EFS, 26% ± 4 vs 40% ± 5 at 4 years; Cox P = .002) and for the intermediate risk genotype NPM1 wild-type/FLT3 without internal-tandem duplications (EFS, 18% ± 5 vs 40% ± 7; Cox P < .001). Clofarabine improves survival in subsets of intermediate-risk AML only. HOVON-102 study is registered at Netherlands Trial Registry #NTR2187.
Assuntos
Nucleotídeos de Adenina/uso terapêutico , Antimetabólitos Antineoplásicos/uso terapêutico , Arabinonucleosídeos/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Nucleotídeos de Adenina/efeitos adversos , Adolescente , Adulto , Idoso , Antimetabólitos Antineoplásicos/efeitos adversos , Arabinonucleosídeos/efeitos adversos , Clofarabina , Quimioterapia de Consolidação/métodos , Humanos , Quimioterapia de Indução/métodos , Leucemia Mieloide Aguda/mortalidade , Pessoa de Meia-Idade , Nucleofosmina , Indução de Remissão , Risco , Taxa de Sobrevida , Adulto JovemAssuntos
Nucleotídeos de Adenina/uso terapêutico , Arabinonucleosídeos/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/métodos , Leucemia Mieloide/terapia , Síndromes Mielodisplásicas/terapia , Doença Aguda , Nucleotídeos de Adenina/efeitos adversos , Adulto , Idoso , Antimetabólitos Antineoplásicos/efeitos adversos , Antimetabólitos Antineoplásicos/uso terapêutico , Arabinonucleosídeos/efeitos adversos , Clofarabina , Terapia Combinada , Feminino , Febre/etiologia , Humanos , Leucemia Mieloide/patologia , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/patologia , Neutropenia/etiologia , Análise de SobrevidaRESUMO
BACKGROUND: The outcome of patients with higher-risk myelodysplastic syndromes (MDS) after hypomethylating agent (HMA) failure is poor. This study evaluated the safety and activity of a combination of low-dose clofarabine and cytarabine for these patients. METHODS: Seventy patients with higher-risk MDS who had no response, progressed, or relapsed after at least 4 cycles of HMA therapy were treated. RESULTS: The median age was 72 years. Thirty-nine percent of the patients had high-risk disease according to the International Prognostic Scoring System, and 50% of the patients had poor-risk cytogenetics. Twenty-three percent of the patients had therapy-related MDS. The median number of prior cycles of HMA was 6 (range, 4-45). The overall response rate was 44%. The 6-week mortality rate was 9%. Grade 3 and higher nonhematologic toxicities were rare, but infections occurred in 52% of the patients, and fever of unknown origin occurred in 33%. The median overall survival (OS) was 10 months (95% confidence interval, 1-37 months). Thirteen percent of the patients underwent allogeneic stem cell transplantation. The responding patients had a median OS of 22 months, whereas the nonresponding patients had a median OS of 4 months. A complex karyotype was associated with worse response rates and OS. CONCLUSIONS: The combination of low-dose clofarabine and cytarabine is clinically active in these patients with few treatment options. Cancer 2017;123:629-637. © 2016 American Cancer Society.
Assuntos
Nucleotídeos de Adenina/efeitos adversos , Arabinonucleosídeos/efeitos adversos , Citarabina/efeitos adversos , Síndromes Mielodisplásicas/tratamento farmacológico , Neoplasias/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Clofarabina , Metilação de DNA/efeitos dos fármacos , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/induzido quimicamente , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/patologia , Proteínas de Neoplasias/genética , Neoplasias/complicações , Neoplasias/epidemiologia , Neoplasias/patologia , Resultado do TratamentoRESUMO
Cutaneous complications are common in patients with leukemia. However, the cause is not always immediately clear, as there are often numerous potential etiologies. Thrombocytopenia or coagulopathy can result in ecchymoses or petechiae, whereas extramedullary (EM) involvement by leukemia can present as a rash. Leukemia can also result in skin manifestations via indirect means, including several types of paraneoplastic phenomena. Moreover, various agents routinely used to treat leukemia-most notably cytarabine (cytosine arabinoside)-can precipitate quite profound skin eruptions. Finally, infections, including fungal invasion of the skin, can be responsible for rashes, as can the vast array of antimicrobials that are administered to leukemia patients.
Assuntos
Antineoplásicos/efeitos adversos , Leucemia/patologia , Síndromes Paraneoplásicas/patologia , Neoplasias Cutâneas/patologia , Nucleotídeos de Adenina/efeitos adversos , Nucleotídeos de Adenina/uso terapêutico , Antineoplásicos/uso terapêutico , Arabinonucleosídeos/efeitos adversos , Arabinonucleosídeos/uso terapêutico , Clofarabina , Citarabina/efeitos adversos , Citarabina/uso terapêutico , Dermatomicoses/etiologia , Dermatomicoses/patologia , Etoposídeo/efeitos adversos , Etoposídeo/uso terapêutico , Humanos , Leucemia/complicações , Leucemia/tratamento farmacológico , Mastocitose/patologia , Mastocitose/secundário , Niacinamida/efeitos adversos , Niacinamida/análogos & derivados , Niacinamida/uso terapêutico , Síndromes Paraneoplásicas/etiologia , Compostos de Fenilureia/efeitos adversos , Compostos de Fenilureia/uso terapêutico , Dermatopatias Bacterianas/etiologia , Dermatopatias Bacterianas/patologia , Neoplasias Cutâneas/secundário , SorafenibeRESUMO
A phase 1 study was conducted to evaluate the safety, pharmacokinetics (PK), efficacy and pharmacogenetic characteristics of clofarabine in seven Japanese pediatric patients with relapsed/refractory acute lymphoblastic leukemia (ALL). Patients in Cohort 1 received clofarabine 30 mg/m(2)/day for 5 days, followed by 52 mg/m(2)/day for 5 days in subsequent cycles. Cohort 2 patients were consistently treated with 52 mg/m(2)/day for 5 days. No more than six cycles were performed. Every patient had at least one ≥Grade 3 adverse event (AE). AEs (≥Grade 3) related to clofarabine were anaemia, neutropenia, febrile neutropenia, thrombocytopenia, alanine aminotransferase increased, aspartate aminotransferase increased, haemoglobin decreased, and platelet (PLT) count decreased. C max and AUC of clofarabine increased in a dose-dependent fashion, but its elimination half-life (T 1/2) did not appear to be dependent on dose or duration of treatment. Clofarabine at 52 mg/m(2)/day shows similarly tolerable safety and PK profiles compared to those in previous studies. No complete remission (CR), CR without PLT recovery, or partial remission was observed. Since clofarabine is already used as a key drug for relapsed/refractory ALL patients in many countries, the efficacy of clofarabine in Japanese pediatric patients should be evaluated in larger study including more patients, such as by post-marketing surveillance.
Assuntos
Nucleotídeos de Adenina/administração & dosagem , Arabinonucleosídeos/administração & dosagem , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Nucleotídeos de Adenina/efeitos adversos , Nucleotídeos de Adenina/farmacocinética , Adolescente , Arabinonucleosídeos/efeitos adversos , Arabinonucleosídeos/farmacocinética , Criança , Pré-Escolar , Clofarabina , Relação Dose-Resposta a Droga , Meia-Vida , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Recidiva , Resultado do TratamentoRESUMO
BACKGROUND: Current outcome of very early relapse of acute lymphoblastic leukemia (ALL) in children remains poor. As a single agent, clofarabine provided a response rate of 26% in childhood ALL second relapse and, in combination with cyclophosphamide and etoposide, a 44% complete remission and complete remission without platelet recovery (CR+CRp) rate. Further multi-drug combinations need to be investigated. We used the VANDA regimen as a template, cytarabine being replaced by clofarabine. PATIENTS AND METHODS: A phase I study combining escalating doses of clofarabine (25% increments from 20 to 40 mg/m(2)/d) with fixed doses of mitoxantrone, etoposide, asparaginase, and dexamethasone was undertaken in children presenting with very early or second or post-transplant ALL relapse. RESULTS: Twenty patients were enrolled, 19 were evaluable. Four patients had previously been allografted. Dose-limiting toxicity (DLT) appeared at dose level 3 (32 mg/m(2)), one out of six patients experienced a liver DLT. At dose level 4 (40 mg/m(2)), four DLT occurred (two fungal infection and two liver DLT). The maximum tolerated dose (MTD) of clofarabine was thus determined to be 32 mg/m(2). There was no toxic death. Eleven (57.9%) patients achieved a CR. Six patients proceeded to allogeneic stem cell transplantation. CONCLUSION: Clofarabine MTD was 32 mg/m(2)/d in this combination which appeared feasible and effective in this population.
Assuntos
Nucleotídeos de Adenina/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Arabinonucleosídeos/administração & dosagem , Recidiva Local de Neoplasia/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Nucleotídeos de Adenina/efeitos adversos , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Arabinonucleosídeos/efeitos adversos , Asparaginase/uso terapêutico , Criança , Pré-Escolar , Clofarabina , Dexametasona/uso terapêutico , Relação Dose-Resposta a Droga , Etoposídeo/uso terapêutico , Feminino , Humanos , Masculino , Dose Máxima Tolerável , Mitoxantrona/uso terapêutico , Terapia de Salvação/métodos , Adulto JovemRESUMO
This is the case of a 24-year-old woman with relapsed acute undifferentiated leukemia who developed subacute encephalopathy with hemiparesis and dysarthria after treatment with high dose and intrathecal methotrexate, clofarabine, and cytarabine that resolved rapidly and completely after the administration of corticosteroids. We hypothesize that clofarabine might predispose to methotrexate-induced central nervous system toxicity by increasing endothelial permeability (capillary leak syndrome) and suggest that corticosteroids are effective in the treatment of this type of encephalopathy.
Assuntos
Nucleotídeos de Adenina/efeitos adversos , Corticosteroides/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Arabinonucleosídeos/efeitos adversos , Metotrexato/efeitos adversos , Metilprednisolona/uso terapêutico , Síndromes Neurotóxicas/etiologia , Nucleotídeos de Adenina/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Arabinonucleosídeos/administração & dosagem , Clofarabina , Citarabina/administração & dosagem , Citarabina/efeitos adversos , Quimioterapia Combinada , Feminino , Humanos , Leucemia/tratamento farmacológico , Metotrexato/administração & dosagem , Síndromes Neurotóxicas/tratamento farmacológico , Adulto JovemRESUMO
Clofarabine is an effective drug in relapsed leukemia and lymphoma that has some adverse effects which can be fatal like capillary leak syndrome (CLS). Identification and management of CLS is important that may result in mortality. Although prophylactic treatment with steroids may prevent CLS and improve survival, intravenous immunoglobulins are used in the treatment with great success in steroid resistant cases. However, the knowledge about the effects and the dose of intravenous immunoglobulins (IVIG) in pediatric patients is limited. Herein, we reported a patient with relapsed lymphoma who developed CLS successfully and was treated with IVIG.
Assuntos
Nucleotídeos de Adenina/efeitos adversos , Arabinonucleosídeos/efeitos adversos , Imunoglobulinas Intravenosas/administração & dosagem , Linfoma/tratamento farmacológico , Síndrome de Vazamento Capilar/induzido quimicamente , Pré-Escolar , Clofarabina , Humanos , Linfoma/complicações , Linfoma/patologia , MasculinoAssuntos
Encéfalo/patologia , Exoftalmia/etiologia , Histiocitose Sinusal/complicações , Histiocitose Sinusal/patologia , Nucleotídeos de Adenina/efeitos adversos , Nucleotídeos de Adenina/uso terapêutico , Arabinonucleosídeos/efeitos adversos , Arabinonucleosídeos/uso terapêutico , Clofarabina , Feminino , Histiocitose Sinusal/tratamento farmacológico , Humanos , Imageamento por Ressonância Magnética , Adulto JovemRESUMO
We investigated protracted low-dose oral Clofarabine for the treatment of myelodysplastic syndromes (MDS). Adults with an International Prognostic Scoring System (IPSS) score of INT-1 or higher who had failed first line therapy were eligible. INT-1 patients had to be transfusion-dependent. We started with oral Clofarabine at 5mg (fixed dose) daily for 10 consecutive days on a 28-day cycle. Toxicity prompted a modification to 1mg PO daily for 10 days and then 1mg PO daily for 7 days. Patients received treatment indefinitely until loss of response or unacceptable toxicity. Nine patients (5 women) were enrolled and evaluable (median age 65 years; range 55-81). A 10-day regimen of oral Clofarabine at 5mg/day induced Grade IV pancytopenia. A dose of 1 mg/day for 7/28 days was very well tolerated without significant toxicity. Three patients had responses (2 with responses lasting up to 21 and 51 cycles) defined as stable disease in spite of no significant change on bone marrow evaluation. Low-dose oral Clofarabine (1mg daily for 7/28 days) proved both effective and safe for patients with MDS who had failed prior therapy. This patient population is particularly sensitive to more protracted Clofarabine treatment schedules.
Assuntos
Nucleotídeos de Adenina/administração & dosagem , Antineoplásicos/administração & dosagem , Arabinonucleosídeos/administração & dosagem , Síndromes Mielodisplásicas/tratamento farmacológico , Nucleotídeos de Adenina/efeitos adversos , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Arabinonucleosídeos/efeitos adversos , Clofarabina , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Falha de TratamentoRESUMO
New anticancer medications are rapidly entering the clinical arena offering patients with previously resistant cancers the promise of more effective therapies capable of extending their lives. However, adverse renal consequences develop in treated patients with underlying risk factors, requiring the nephrology community to be familiar with the nephrotoxic effects. The most common clinical nephrotoxic manifestations of these drugs include acute kidney injury, varying levels of proteinuria, hypertension, electrolyte disturbances, and at times chronic kidney disease. Thus, to practice competently in the 'onco-nephrology' arena, nephrologists will garner benefit from an update on older drugs with newly recognized nephrotoxic potential as well as newer agents, which may be associated with kidney injury. With that in mind, this brief update is meant to provide clinicians with the currently available evidence on the nephrotoxicity of a group of anticancer medications.