RESUMO
BACKGROUND: The occurrence of nephrotoxicity with vancomycin is approximately 17%, but can increase to 35% when combined with other nephrotoxic agents. Patients with hematologic malignancies may be at greater risk for vancomycin-induced nephrotoxicity due to nephrotoxic chemotherapy and tumor lysis syndrome. OBJECTIVE: The primary objective of this study was to determine the occurrence of nephrotoxicity in adult patients with leukemia receiving vancomycin. METHODS: A retrospective review approved by the Institutional Review Board was conducted on adult patients with leukemia who received at least one dose of vancomycin during hospital admission between 1 January 2009 and 30 April 2009. RESULTS: Forty patients had an occurrence of nephrotoxicity (16%) while 210 patients did not have an occurrence of nephrotoxicity. In multivariate analysis, variables significantly associated with development of nephrotoxicity included active disease status (odds ratio, 4.38 [95% CI 1.1-29.4], p = 0.0291), concomitant intravenous acyclovir administration (odds ratio, 3.83 [95% CI, 1.6-8.9]; p = 0.0022), and concomitant amphotericin administration (odds ratio, 4.26 [95% CI, 1.9-9.4]; p = 0.0004). CONCLUSION: The occurrence of nephrotoxicity in patients with leukemia treated with vancomycin was 16% in our study, similar to previously published reports. Active disease status and concomitant use of intravenous acyclovir and amphotericin were identified as significant risk factors for development of nephrotoxicity. The presence of risk factors for vancomycin nephrotoxicity should be evaluated prior to initiation of therapy to determine appropriateness of use.
Assuntos
Antibacterianos/efeitos adversos , Nefropatias/induzido quimicamente , Leucemia/patologia , Vancomicina/efeitos adversos , Aciclovir/administração & dosagem , Aciclovir/efeitos adversos , Administração Intravenosa , Adulto , Idoso , Anfotericina B/administração & dosagem , Anfotericina B/efeitos adversos , Antibacterianos/administração & dosagem , Feminino , Humanos , Nefropatias/epidemiologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Estudos Retrospectivos , Fatores de Risco , Vancomicina/administração & dosagemRESUMO
IMPORTANCE OF THE FIELD: Over the last few decades, advances in acute lymphoblastic leukemia (ALL) therapy have led to long-term survival rates of > 80% in children; however, comparable rates have yet to be achieved in adults, and a large majority of patients relapse from their disease. AREAS COVERED IN THIS REVIEW: The review describes historical therapy and advancements in ALL treatment over the past few decades, while providing a concise review of the future direction of ALL therapy. Literature was collected through peer reviewed journals and the Pharmaprojects drug profile for ALL. WHAT THE READER WILL GAIN: Current information regarding prognostic factors for relapse, salvage therapy options and emerging drugs are provided in the review. TAKE HOME MESSAGE: Development of new drugs with novel mechanisms, unique formulations of existing medications, as well as manipulation of current combinations of drugs remain vital to the success in adult ALL.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Drogas em Investigação/uso terapêutico , Neoplasia Residual/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Adulto , Idoso , Criança , Intervalo Livre de Doença , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Terapia de Salvação/métodos , Transplante de Células-TroncoAssuntos
Antineoplásicos/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Antineoplásicos/administração & dosagem , Benzamidas , Dasatinibe , Gerenciamento Clínico , Progressão da Doença , Esquema de Medicação , Resistencia a Medicamentos Antineoplásicos , Humanos , Mesilato de Imatinib , Piperazinas/uso terapêutico , Inibidores de Proteínas Quinases/administração & dosagem , Pirimidinas/administração & dosagem , Pirimidinas/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Tiazóis/administração & dosagem , Tiazóis/uso terapêuticoRESUMO
UNLABELLED: Decitabine improves overall survival (OS) and reduces risk of progression to acute myeloid leukemia (AML) in myelodysplastic syndromes (MDS). In this retrospective analysis of data from 2 decitabine studies (n = 162), hemoglobin level ≥ 10 g/dL, platelet count ≥ 50 10(3)/µL, and lack of chromosome 5 or 7 abnormalities predicted longer OS. Identifying potential prognostic factors for survival may guide decitabine treatment decisions and improve outcomes. BACKGROUND: Myelodysplastic syndromes (MDS) progress to acute myeloid leukemia (AML) in approximately 30% of patients. Identification of risk factors for progression to AML and overall survival (OS) would help guide treatment decisions. PATIENTS AND METHODS: We investigated prognostic factors for progression to AML and survival in 163 patients with MDS treated with decitabine 15 mg/m(2) over 3 hours every 8 hours for 3 days every 6 weeks (n = 74) or 20 mg/m(2) over 1 hour daily for 5 days every 4 weeks (n = 89). RESULTS: Multivariate analysis of pooled baseline data revealed that only study effect was associated with progression to AML. A hemoglobin value at least 10 g/dL, platelet count at least 50 × 10(3)/µL, and lack of chromosome 5 or 7 abnormalities were associated with longer OS. CONCLUSIONS: Patients with certain prognostic factors should be considered for other interventions in addition to decitabine treatment.
Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Azacitidina/análogos & derivados , Síndromes Mielodisplásicas/tratamento farmacológico , Síndromes Mielodisplásicas/mortalidade , Idoso , Azacitidina/uso terapêutico , Decitabina , Progressão da Doença , Feminino , Humanos , Leucemia Mieloide Aguda , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/diagnóstico , Razão de Chances , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Resultado do TratamentoRESUMO
Although imatinib revolutionized the management of chronic myeloid leukemia (CML), recent data indicate a transformation in the treatment approach likely in the near future. The superiority of second-generation tyrosine kinase inhibitors (TKIs) over imatinib in newly diagnosed disease has been recognized. Several investigational agents specific for those patients with the T315I mutation remain under evaluation. In Philadelphia-positive (Ph-positive) acute lymphoblastic leukemia (ALL), the addition of imatinib improved response rates. However, short remission durations with single agent therapy limit the benefit on survival. Early molecular remissions achieved with dasatinib will enable more patients to proceed to stem cell transplant (SCT), with increased likelihood of positive outcomes post-SCT.
Assuntos
Antineoplásicos/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos , Humanos , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/uso terapêutico , Resultado do TratamentoRESUMO
Earlier use of more potent tyrosine kinase inhibitors such as dasatinib improves response rates for patients with chronic myeloid leukemia (CML). The SRC-ABL Tyrosine Kinase Inhibition Activity Research Trials series displayed dasatinib efficacy in patients with all phases of CML who are resistant or intolerant to imatinib. More recently, dasatinib has been shown to induce rapid and high rates of response and has gained approval for newly diagnosed patients with CML in chronic phase. The future of CML therapy may incorporate more potent tyrosine kinase inhibitors such as dasatinib into initial treatment for newly diagnosed patients. The ability of dasatinib to induce rapid and high rates of response with a low progression to advanced forms of CML may translate into improvements in survival.
Assuntos
Antineoplásicos/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/uso terapêutico , Tiazóis/uso terapêutico , Ensaios Clínicos como Assunto , Dasatinibe , Avaliação Pré-Clínica de Medicamentos , HumanosRESUMO
IMPORTANCE OF THE FIELD: Although the introduction of imatinib revolutionized the management of chronic myeloid leukemia (CML), some patients exhibit resistance or intolerance to the drug. Nilotinib induces high and rapid rates of cytogenetic and molecular responses. With recent approval for newly diagnosed patients with chronic phase CML, the current algorithm for treatment will probably be transformed. AREAS COVERED IN THIS REVIEW: This review will describe evaluations of nilotinib in all phases of CML from 1995 to the present. Early preclinical data and Phase I, Phase II and Phase III evaluations will demonstrate the role of nilotinib in newly diagnosed CML, as well as in imatinib-resistant or imatinib-intolerant disease. WHAT THE READER WILL GAIN: Mutations in the BCR-ABL kinase domain are responsible for the majority of resistance to imatinib. In comparison with imatinib, nilotinib displays increased selectivity and potency at inhibiting proliferation of BCR-ABL expressing cells. Although several mutations, including T315I, remain resistant to nilotinib, activity in all phases of CML has been reported. TAKE HOME MESSAGE: Nilotinib induces high and rapid rates of cytogenetic and molecular response, with less progression to advanced forms of disease compared with imatinib. Considering that the rapid achievement of these clinical milestones has been associated with positive long-term outcomes, nilotinib as initial therapy in patients with CML in chronic phase represents the future in CML treatment. Longer follow-up is necessary to recognize survival advantages.
Assuntos
Antineoplásicos/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Pirimidinas/uso terapêutico , Animais , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Benzamidas , Resistencia a Medicamentos Antineoplásicos , Humanos , Mesilato de Imatinib , Leucemia Mielogênica Crônica BCR-ABL Positiva/fisiopatologia , Piperazinas/efeitos adversos , Piperazinas/farmacologia , Piperazinas/uso terapêutico , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/efeitos adversos , Pirimidinas/farmacologia , Resultado do TratamentoRESUMO
Chronic myeloid leukemia (CML) is a progressive and often fatal myeloproliferative disorder. The hallmark of CML is an acquired chromosomal translocation known as the Philadelphia chromosome (Ph) that results in the synthesis of the BCR-ABL fusion protein, a constitutively active tyrosine kinase (TK). The introduction of imatinib, a TK inhibitor (TKI) specific for BCR-ABL, was a major breakthrough in CML therapy. Although most patients respond to first-line imatinib therapy, some experience a loss of response (resistance) or require treatment discontinuation because of toxicity (intolerance). In patients for whom standard-dose imatinib therapy (400 mg/day) fails, imatinib dose escalation (600-800 mg/day) is a second-line option. However, high-dose imatinib is not an appropriate approach for patients experiencing drug toxicity, and there remain questions over the durability of responses achieved with this strategy. Alternative second-line options include the newer TKIs dasatinib and nilotinib. A substantial amount of long-term data for these agents is available. Although both are potent and specific BCR-ABL TKIs, dasatinib and nilotinib exhibit unique pharmacologic profiles and response patterns relative to different patient characteristics, such as disease stage and BCR-ABL mutational status. To optimize therapeutic benefit, clinicians should select treatment based on each patient's historical response, adverse event tolerance level, and risk factors.
Assuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Algoritmos , Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Benzamidas , Dasatinibe , Feminino , Humanos , Mesilato de Imatinib , Masculino , Piperazinas/administração & dosagem , Piperazinas/uso terapêutico , Pirimidinas/administração & dosagem , Pirimidinas/uso terapêutico , Tiazóis/administração & dosagem , Tiazóis/uso terapêuticoRESUMO
BACKGROUND: No data exists that directly compares hemoglobin and hematocrit levels between cancer patients with and without occurrence of thrombosis during treatment with erythropoiesis stimulating agents (ESAs). OBJECTIVE: To determine the association of hemoglobin and hematocrit levels with the occurrence of thrombosis in cancer patients treated with ESAs. METHODS: A retrospective case-control study approved by the Institutional Review Board was conducted on cancer patients billed for epoetin or darbepoetin between 1 July 2002 and 30 June 2007. Cases were defined as patients billed for thrombosis while controls were defined as patients not billed for thrombosis. RESULTS: Sixteen patients had an occurrence of thrombosis (cases) and were matched to 16 patients that did not have an occurrence of thrombosis (controls) based on age, sex, and cancer type. The mean peak hemoglobin levels for cases and controls were 12.6 +/- 1.2 g/dL versus 12.6 +/- 1.4 g/dL (p = 0.9). The mean peak hematocrit levels for cases and controls were 37.3 +/- 3.8% versus 37.9 +/- 4.3% (p = 0.8). For the 16/586 (2.7%) patients with thrombosis, the mean hemoglobin and hematocrit at time of thrombosis were 9.6 +/- 1.0 g/dL and 28.9 +/- 3.1%. A significant identifiable risk factor for thrombosis between the cases and controls was history of thrombosis 31.3% versus 0% (p = 0.04). CONCLUSION: There was no statistical difference in peak hemoglobin and hematocrit levels between patients with thrombosis and those without thrombosis. Further study is warranted to determine if these levels are true risk factors for thrombosis.
Assuntos
Anemia/tratamento farmacológico , Hematínicos/efeitos adversos , Hematócrito , Hemoglobinas/metabolismo , Trombose/induzido quimicamente , Anticoagulantes/uso terapêutico , Estudos de Casos e Controles , Darbepoetina alfa , Epoetina alfa , Eritropoetina/efeitos adversos , Eritropoetina/análogos & derivados , Eritropoetina/uso terapêutico , Feminino , Hematínicos/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/complicações , Neoplasias/tratamento farmacológico , Proteínas Recombinantes , Estudos Retrospectivos , Fatores de Risco , Trombose/complicações , Trombose/prevenção & controle , Fatores de TempoRESUMO
The outcome of salvage therapy for relapsed acute lymphoblastic leukemia (ALL) remains poor. Salvage therapy mimics regimens with activity in newly diagnosed ALL. Novel strategies under investigation as monotherapy or in combination with chemotherapy improve the treatment of relapsed disease. For some ALL subsets, specific therapies are indicated. The addition of targeted therapy in Philadelphia chromo some-positive ALL has improved responses in relapsed patients without resistance to available tyrosine kinase inhibitors. Nelarabine demonstrates activity as monotherapy in T-cell ALL and is approved by the US Food and Drug Administration. Clofarabine, a second-generation purine analogue approved in pediatric leukemia, has shown activity in adult acute leukemias including ALL and acute myeloid leukemia. The role of pegaspargase in adult ALL requires further investigation. The benefit of matched related-donor allogeneic stem cell transplantation is significant for standard-risk ALL but not for high-risk ALL. Development of new drugs and agents tailored to subset-specific cytogenetic-molecular characteristics remains vital to success in treating adult ALL.