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Introduction: This paper presents results from Cohort B (rearranged during transfection [RET], fusion-positive) of the Blood First Assay Screening Trial in patients with advanced non-small cell lung cancer (NSCLC) screened for genetic alterations using blood-based next-generation sequencing. Material and methods: Adults with advanced RET fusion-positive NSCLC received alectinib 900 mg twice daily (BID) in Phase I. Enrolment closed prematurely with Phase II uninitiated. Results: Among eight treated patients, confirmed best overall responses in evaluable patients were stable disease (4/5) and progressive disease (1/5). One dose-limiting toxicity (death, unknown cause) was considered by the investigator to be related to treatment and underlying disease. Serious adverse events (SAEs) occurred in five patients, and SAEs that may be related to treatment occurred in two patients. Conclusions: Alectinib showed limited activity in advanced RET fusion-positive NSCLC, and further investigation was not conducted due to the development of selective RET inhibitors pralsetinib and selpercatinib. No new safety signals were observed, and the safety profile of alectinib was in line with previous reports at the 600 mg BID dose.
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OBJECTIVES: The epidemiology and clinical course of candidaemia in patients with acute leukaemia, a population frequently exposed to antifungals, have not been extensively studied. In the present contemporary series of acute leukaemia patients, we describe patient characteristics, Candida species and MIC distributions and investigate the association between antifungal resistance and all-cause mortality. METHODS: We performed a retrospective review of medical records and microbiological data of adult patients with acute leukaemia or high-risk myelodysplastic syndrome with at least one positive blood culture for Candida species at the MD Anderson Cancer Center between January 2008 and October 2012. Susceptibility was defined according to the 2012 epidemiological cut-off values and clinical breakpoints. RESULTS: We identified 67 episodes of candidaemia in 65 patients. Almost all episodes (94%) occurred in patients who were receiving antifungal agents, 71% in patients receiving an echinocandin. Almost all isolates (99%) were of non-albicans Candida species [most frequently Candida parapsilosis (32%), Candida tropicalis (23%) and Candida glabrata (20%)]. Caspofungin non-susceptibility was significantly associated with fluconazole resistance (Pâ<â0.001). Non-susceptibility to caspofungin and multidrug resistance were associated with excess 14 day [adjusted HR (aHR) 3.02 (95% CI 1.28-7.09), Pâ=â0.011 and aHR 3.02 (95% CI 1.27-7.14), Pâ=â0.012, respectively] and 30 day [aHR 2.96 (95% CI 1.38-6.37), Pâ=â0.005 and aHR 2.86 (95% CI 1.31-6.21), Pâ=â0.008, respectively] all-cause mortality. CONCLUSIONS: In patients with acute leukaemia, a shift in candidaemia epidemiology was noted with a 99% predominance of non-albicans species. Non-susceptibility of Candida strains to caspofungin or multidrug resistance were independent markers of poor outcome in this patient population.
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Candida/clasificación , Candida/efectos de los fármacos , Candidemia/microbiología , Candidemia/mortalidad , Farmacorresistencia Fúngica Múltiple , Equinocandinas/farmacología , Leucemia/complicaciones , Adulto , Anciano , Candida/aislamiento & purificación , Candidemia/epidemiología , Caspofungina , Equinocandinas/uso terapéutico , Femenino , Humanos , Lipopéptidos , Masculino , Pruebas de Sensibilidad Microbiana , Persona de Mediana Edad , Estudios Retrospectivos , Análisis de Supervivencia , Adulto JovenRESUMEN
INTRODUCTION: Acute lymphoblastic leukemia (ALL) is typically treated with complex multi-agent chemotherapy regimens over a prolonged time period. Long-term outcomes depend on the age of the patient and the biological characteristics of the leukemic cells. While pediatric patients achieve cure more often than adults, therapy can continue to be improved for all patients with this disease. AREAS COVERED: The current management strategy for ALL is reviewed. Recently, targeted therapies have been shown to improve survival in subsets of patients, most notably in those with Philadelphia chromosome-positive ALL or with leukemic cells that express the surface antigen CD20. Several innovative compounds are under investigation, and the most promising ones to date will be discussed. EXPERT OPINION: The incorporation of monoclonal antibody therapy represents a targeted and powerful approach to the management of ALL. Bispecific T-cell engaging agents, such as blinatumomab, are able to facilitate immune-mediated killing of leukemia cells. Immunoconjugates (i.e., monoclonal antibodies linked to various cytotoxins) allow small doses of very potent chemotherapy to be delivered directly to a leukemia cell with hope of sparing normal tissue. As the genetic and molecular characterization of ALL is more completely understood, patients will receive treatment plans that are more individualized than previously possible.
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Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos/uso terapéutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , HumanosRESUMEN
Allogeneic stem cell transplantation (allo-SCT) is the only potentially curative treatment for myelodysplastic syndrome (MDS). Recently, hypomethylating agents (HMAs) have been shown to improve survival in patients with high-risk MDS. We conducted a retrospective case-control study to compare survival with these treatment modalities in patients with untreated MDS. Controls were identified using a departmental database and transplant patients were matched in at least three of the following five criteria: year of diagnosis, age, blast percentage, International Prognostic Scoring System cytogenetic risk, and time from diagnosis to treatment. Median overall survival (OS) was 26 and 25 months for, respectively, allo-SCT [(n = 53); range, 2-210 months] and HMA [(n = 40); range, 2-98 months] (P = 0.89). Four-year survival rates were 24 and 23% for allo-SCT patients and the nontransplant cohort, respectively. Patients undergoing allo-SCT after 2000 had longer median OS compared with those transplanted before 2000 (41 versus 7 months, P=0.001). These results would suggest that prospective studies are needed to delineate the timing and efficacy of allo-SCT in the HMA era.
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Antimetabolitos Antineoplásicos/uso terapéutico , Azacitidina/análogos & derivados , Azacitidina/uso terapéutico , Trasplante de Células Madre Hematopoyéticas , Síndromes Mielodisplásicos/terapia , Adulto , Anciano , Antimetabolitos Antineoplásicos/farmacología , Azacitidina/farmacología , Metilasas de Modificación del ADN/antagonistas & inhibidores , Decitabina , Femenino , Humanos , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/mortalidad , Síndromes Mielodisplásicos/patología , Proyectos de Investigación , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Tasa de Supervivencia , Factores de Tiempo , Trasplante Homólogo , Resultado del TratamientoRESUMEN
Acute lymphoblastic leukemia (ALL) in adults is a very challenging disease. Adults tend to present with higher-risk features and are unable to tolerate chemotherapy regimens as intense as those administered to children. The overall treatment plan for adult ALL is modeled after the pediatric paradigm and includes multi-agent chemotherapy in the forms of induction, consolidation, maintenance, and central nervous system prophylaxis. Most patients will go into complete remission but often relapse; relapse is typically indicative of chemotherapy-refractory disease. Salvage therapy generally consists of cytotoxic agents from drug classes the patient has had limited or no exposure to. The results of conventional chemotherapy for relapsed ALL are unacceptable. The goal of therapy in these patients is to achieve a second remission followed by allogeneic stem-cell transplantation. Monoclonal antibodies directed at cell-surface antigens offer a targeted approach to treating leukemia and other cancers. Anti-CD20 monoclonal antibodies have been shown to improve survival when used in the frontline setting. Novel, highly active antibodies directed at CD19 and CD22 are being investigated in the relapsed and refractory settings. These agents will likely be explored as components of first-line therapy as clinical development continues.
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Terapia Molecular Dirigida , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Terapia Recuperativa , Terapias en Investigación , Adulto , Humanos , PronósticoRESUMEN
Acute myeloid leukemia is most often diagnosed in patients older than 60 years of age. Overall, these patients have a poor prognosis, partly because they are typically unable to tolerate intensive chemotherapy regimens traditionally offered to younger individuals. Furthermore, responses attained in these older patients are not durable, with most experiencing relapse within 1-2 years. Therefore, new strategies are needed to improve the outcome of older patients with acute myeloid leukemia. Tosedostat is an orally available aminopeptidase inhibitor shown to have activity in leukemia. This commentary discusses the background and results of an ongoing Phase II evaluation of tosedostat in elderly patients with relapsed or refractory acute myeloid leukemia. The data available to date is analyzed and future perspectives regarding the development of this agent is discussed.
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Antineoplásicos/uso terapéutico , Glicina/análogos & derivados , Ácidos Hidroxámicos/uso terapéutico , Leucemia Mieloide Aguda/tratamiento farmacológico , Administración Oral , Anciano , Anciano de 80 o más Años , Aminopeptidasas/antagonistas & inhibidores , Antineoplásicos/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Ensayos Clínicos Fase II como Asunto , Glicina/administración & dosificación , Glicina/uso terapéutico , Humanos , Ácidos Hidroxámicos/administración & dosificación , Persona de Mediana Edad , Recurrencia , Terapia RecuperativaRESUMEN
Tumor mutational burden (TMB) is being explored as a predictive biomarker for cancer immunotherapy outcomes in non-small cell lung cancer. BFAST (NCT03178552)-an open-label, global, multicohort trial-evaluated the safety and efficacy of first-line targeted therapies or immunotherapy in patients with unresectable Stage IIIB or IV advanced or metastatic non-small cell lung cancer who were selected for biomarker status using blood-based targeted next-generation sequencing. In the Phase 3 cohort C evaluating blood-based (b)TMB as a biomarker of atezolizumab efficacy, patients with bTMB of ≥10 (N = 471) were randomized 1:1 to receive atezolizumab or platinum-based chemotherapy per local standard of care. Cohort C did not meet its primary endpoint of investigator-assessed progression-free survival in the population with bTMB of ≥16 (hazard ratio, 0.77; 95% confidence interval: 0.59, 1.00; P = 0.053). Adverse events leading to treatment withdrawal occurred in 10% of patients in the atezolizumab arm and 20% in the chemotherapy arm. Adverse events of special interest occurred in 42% of patients in the atezolizumab arm and 26% in the chemotherapy arm. A prespecified exploratory analysis compared the bTMB clinical trial assay with the FoundationOne Liquid Companion Diagnostic assay and showed high concordance between assays. Additional exploration of bTMB to identify optimal cutoffs, confounding factors, assay improvements or cooperative biomarkers is warranted.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Anticuerpos Monoclonales Humanizados/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Biomarcadores de Tumor/genética , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Humanos , Inmunoterapia , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genéticaRESUMEN
INTRODUCTION: The Blood First Assay Screening Trial is an ongoing open-label, multicohort study, prospectively evaluating the relationship between blood-based next-generation sequencing (NGS) detection of actionable genetic alterations and activity of targeted therapies or immunotherapy in treatment-naive advanced or metastatic NSCLC. We present data from the ALK-positive cohort. METHODS: Patients aged more than or equal to 18 years with stage IIIB or IV NSCLC and ALK rearrangements detected by blood-based NGS using hybrid capture technology (FoundationACT) received alectinib 600 mg twice daily. Asymptomatic or treated central nervous system (CNS) metastases were permitted. Primary end point was investigator-assessed objective response rate (ORR; Response Evaluation Criteria in Solid Tumors version 1.1). Secondary end points were independent review facility-assessed ORR, duration of response, progression-free survival (PFS), overall survival, and safety. Exploratory end points were investigator-assessed ORR in patients with baseline CNS metastases and relationship between circulating biomarkers and response. RESULTS: In total, 2219 patients were screened and blood-based NGS yielded results in 98.6% of the cases. Of these, 119 patients (5.4%) had ALK-positive disease; 87 were enrolled and received alectinib. Median follow-up was 12.6 months (range: 2.6-18.7). Confirmed ORR was 87.4% (95% confidence interval [CI]: 78.5-93.5) by investigator and 92.0% (95% CI: 84.1-96.7) by independent review facility. Investigator-confirmed 12-month duration of response was 75.9% (95% CI: 63.6-88.2). In 35 patients (40%) with baseline CNS disease, investigator-assessed ORR was 91.4% (95% CI: 76.9-98.2). Median PFS was not reached; 12-month investigator-assessed PFS was 78.4% (95% CI: 69.1-87.7). Safety data were consistent with the known tolerability profile of alectinib. CONCLUSIONS: These results reveal the clinical application of blood-based NGS as a method to inform clinical decision-making in ALK-positive NSCLC.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Quinasa de Linfoma Anaplásico/genética , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Estudios de Cohortes , Crizotinib , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Inhibidores de Proteínas Quinasas/uso terapéuticoAsunto(s)
Antimetabolitos Antineoplásicos/administración & dosificación , Citarabina/administración & dosificación , Leucemia Mieloide Aguda/tratamiento farmacológico , Esquema de Medicación , Genes Duplicados , Humanos , Leucemia Mieloide Aguda/genética , Inducción de Remisión , Tirosina Quinasa 3 Similar a fms/genéticaAsunto(s)
Alopurinol/efectos adversos , Enfermedades Renales/inducido químicamente , Síndrome de Lisis Tumoral/fisiopatología , Urato Oxidasa/administración & dosificación , Alopurinol/farmacología , Costos de los Medicamentos , Humanos , Hipoxantina/metabolismo , Urato Oxidasa/economía , Xantina/metabolismoAsunto(s)
Proteínas de Fusión bcr-abl/antagonistas & inhibidores , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Antineoplásicos/uso terapéutico , Benzamidas , Dasatinib , Humanos , Mesilato de Imatinib , Piperazinas/uso terapéutico , Proteínas Proto-Oncogénicas c-abl/genética , Proteínas Proto-Oncogénicas c-bcr/genética , Pirimidinas/uso terapéutico , Tiazoles/uso terapéuticoAsunto(s)
Proteínas de Fusión bcr-abl/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Inhibidores de Proteínas Quinasas/administración & dosificación , Proteínas Tirosina Quinasas/genética , Protocolos Antineoplásicos , Ensayos Clínicos Fase III como Asunto , Células Clonales/patología , Resistencia a Antineoplásicos/efectos de los fármacos , Resistencia a Antineoplásicos/genética , Proteínas de Fusión bcr-abl/metabolismo , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/fisiopatología , Mutación , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Tirosina Quinasas/metabolismo , Insuficiencia del TratamientoRESUMEN
The advent of tyrosine kinase inhibitors (TKIs) has drastically changed the treatment outcome of chronic myeloid leukemia (CML). Imatinib was the first TKI approved, and has been considered the standard of care for more than a decade. Second generation compounds, namely dasatinib and nilotinib, are highly effective in newly diagnosed patients as well as those who fail imatinib. Bosutinib and ponatinib have also become available as second line options. With five agents from which to choose, selecting a TKI has become a challenge. Multiple tests are now available to determine a patient's disease status, making the ideal monitoring strategy unclear. The gold standard for response to TKI therapy remains the achievement of complete cytogenetic response. This review will discuss the practical aspects of selecting a TKI and monitoring a patient once on therapy, including when to consider a treatment change. Other relevant issues, including cost, compliance, role of allogeneic hematopoietic cell transplantation, and discontinuation of TKIs will also be covered.
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Antineoplásicos/uso terapéutico , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Comorbilidad , Manejo de la Enfermedad , Costos de los Medicamentos , Trasplante de Células Madre Hematopoyéticas , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/terapia , Leucemia Mieloide de Fase Crónica/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/efectos adversos , Retratamiento , Insuficiencia del Tratamiento , Resultado del TratamientoRESUMEN
Conventional cytotoxic chemotherapy for adult acute lymphoblastic leukemia (ALL) is not adequate to cure most patients of the disease. Complete remission is achieved in the majority of patients, but responses are often not durable. Allogeneic stem cell transplant is used for patients with high risk features, including those who are positive for minimal residual disease after induction and consolidation therapy. Nevertheless, transplant is a toxic intervention, and does not guarantee long-term disease-free survival. Monoclonal antibodies target surface antigens present on leukemic blasts, with the aim of minimizing off-target toxicity. Rituximab, an antibody directed against CD20, prolongs the survival of younger adults with ALL when added to chemotherapy in the frontline setting. Novel agents, such as the cytotoxin-antibody conjugate inotuzumab, and the bispecific T-cell engaging compound blinatumomab, have exhibited marked antileukemic activity in the relapsed setting. As these agents continue in clinical development, it will be important to eventually incorporate them in the frontline treatment approach. We review current strategies for treating adult ALL, with a focus on novel and targeted therapies that are under development.
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Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Trasplante de Células Madre Hematopoyéticas , Humanos , Terapia Molecular Dirigida , Inducción de Remisión , Terapia Recuperativa , Resultado del TratamientoRESUMEN
UNLABELLED: We evaluated whether clofarabine-containing chemotherapy predisposed patients to hepatic toxicity (particularly venoocclusive disease [VOD]) after allogeneic stem cell transplantation (allo-SCT). In the group who received clofarabine and subsequent transplantation, there were no cases of VOD, and liver toxicity was comparable to a control group who received standard acute myeloid leukemia (AML) chemotherapy. Other transplant-specific outcomes, including overall survival (OS), were also similar when compared with the control group. BACKGROUND: Clofarabine is actively being investigated as a component of frontline chemotherapy for acute myeloid leukemia (AML). Hepatotoxicity is 1 of the primary adverse events associated with clofarabine and can occasionally can include severe venoocclusive disease (VOD). PATIENTS AND METHODS: Many patients with AML undergo allogeneic stem cell transplantation (allo-SCT), a procedure that is also associated with hepatotoxicity. We identified AML patients undergoing allo-SCT and stratified them according to whether they received clofarabine-containing (clofarabine, idarubicin, and cytarabine [CIA]) or non-clofarabine-containing cytarabine-based induction/consolidation chemotherapy (idarubicin and cytarabine [ara-C] [IA]). We compared both groups for differences in posttransplantation hepatotoxicity, VOD, and other transplantation outcomes. Forty-two patients were identified (20 receiving CIA and 22 receiving IA). Patient and transplant characteristics were similar. All patients receiving clofarabine-based treatment received CIA within 2.5 months of their allo-SCT. RESULTS: There was no difference in the incidence of VOD in the 30 days after transplantation (0 CIA, 1 IA; P = 1.0). Rates of grade 3/4 hepatotoxicity also did not differ between groups. Acute graft-versus-host disease (GVHD), early relapse, and survival were also not significantly different. CONCLUSIONS: We conclude that clofarabine-containing chemotherapy does not adversely impact the outcome of allo-SCT. Specifically, it does not predispose patients to an increased risk of hepatotoxicity, VOD, GVHD, or relapse.
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Nucleótidos de Adenina/uso terapéutico , Antineoplásicos/uso terapéutico , Arabinonucleósidos/uso terapéutico , Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda/terapia , Nucleótidos de Adenina/administración & dosificación , Nucleótidos de Adenina/efectos adversos , Adulto , Anciano , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Arabinonucleósidos/administración & dosificación , Arabinonucleósidos/efectos adversos , Clofarabina , Femenino , Enfermedad Injerto contra Huésped/etiología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Leucemia Mieloide Aguda/mortalidad , Hepatopatías/etiología , Masculino , Persona de Mediana Edad , Inducción de Remisión , Acondicionamiento Pretrasplante , Trasplante Homólogo , Resultado del TratamientoRESUMEN
The Philadelphia chromosome is the most common cytogenetic abnormality found in adult patients diagnosed with acute lymphoblastic leukemia. The result of this abnormality is the BCR-ABL protein, a constitutively active kinase involved in cell signaling and survival. When managed with multiagent chemotherapy regimens alone, patients have traditionally had an inferior outcome in terms of remission duration and overall survival when compared with patients who are Philadelphia chromosome-negative. Small-molecule tyrosine kinase inhibitors, such as imatinib and dasatinib, directly inhibit the BCR-ABL kinase, offering a targeted approach as a therapeutic option. As a result of several clinical trials with adequate follow-up, imatinib combined with chemotherapy represents the current standard of care for patients with newly diagnosed disease. Allogeneic stem cell transplantation has previously been the only modality to offer the potential for a cure, and it still should be considered for all patients deemed able to tolerate such an intervention. Second-generation tyrosine kinase inhibitors, such as dasatinib, may further improve the outcome in these patients. The role of molecular monitoring and the use of tyrosine kinase inhibitors after stem cell transplantation are areas of active investigation, and the results of ongoing trials will help to clarify the optimal management of these patients.