RESUMEN
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an uncommon hematologic malignancy with poor outcomes. Existing data on the clinical behavior of BPDCN are limited because reported outcomes are from small retrospective series, and standardized treatment guidelines are lacking. The interleukin-3 cytotoxin conjugate tagraxofusp was recently tested in phase 1/2 trials that led to US Food and Drug Administration approval, the first ever for BPDCN. However, because there was no matched internal comparator in this or any clinical study to date, results of BPDCN trials testing new drugs are difficult to compare with alternative therapies. We therefore sought to define the clinical characteristics and outcomes of a group of patients with BPDCN treated at 3 US cancer centers in the modern era but before tagraxofusp was available. In 59 studied patients with BPDCN, the median overall survival from diagnosis was 24 months, and outcomes were similar in patients with "skin only" or with systemic disease at presentation. Intensive first-line therapy and "lymphoid-type" chemotherapy regimens were associated with better outcomes. Only 55% of patients received intensive chemotherapy, and 42% of patients underwent stem cell transplantation. Clinical characteristics at diagnosis associated with poorer outcomes included age >60 years, abnormal karyotype, and terminal deoxynucleotidyltransferase (TdT) negativity in the BPDCN cells. We also identified disease responses to pralatrexate and enasidenib in some patients. This study highlights poor outcomes for patients with BPDCN in the modern era and the need for new treatments. Outcomes from ongoing clinical trials for BPDCN can be evaluated relative to this contemporary cohort.
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Células Dendríticas/patología , Neoplasias Hematológicas/terapia , Neoplasias Cutáneas/terapia , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Benchmarking , Niño , Estudios de Cohortes , Femenino , Neoplasias Hematológicas/complicaciones , Neoplasias Hematológicas/diagnóstico , Trasplante de Células Madre Hematopoyéticas , Humanos , Masculino , Persona de Mediana Edad , Estudios Multicéntricos como Asunto , Neoplasias Cutáneas/complicaciones , Neoplasias Cutáneas/diagnóstico , Resultado del Tratamiento , Adulto JovenRESUMEN
PURPOSE OF REVIEW: The purpose of this study is to explore the recent advances in understanding the pathogenesis of leukaemias with a translocation involving the mixed lineage leukaemia (MLL) gene and therapeutic implications of these discoveries. RECENT FINDINGS: The pathogenesis of MLL-rearranged leukaemias has recently been elucidated in a flurry of clinical studies that have appeared over the past 5 years. On the basis of these studies, a phase 1 clinical trial has been initiated targeting the histone methyltransferase DOT1L with interim clinical results reported at the American Society of Hematology Annual Meeting in December 2014. SUMMARY: Acute leukaemia, both myeloid and lymphoid, that harbours a translocation involving the MLL gene at chromosome locus 11q23 has a poor prognosis, even with allogeneic bone marrow transplantation. The pathogenesis of MLL translocated leukaemias has recently been linked to aberrant activity of the histone methyltransferase DOT1. Preclinical studies of DOT1L inhibition with potent, selective inhibitors have shown successful eradication of the leukaemic clone in animal models. On the basis of these studies, a phase 1, first in man, clinical trial has been initiated with a DOT1L inhibitor, EPZ-5676.
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Antineoplásicos/uso terapéutico , N-Metiltransferasa de Histona-Lisina/genética , Leucemia Bifenotípica Aguda/tratamiento farmacológico , Leucemia Bifenotípica Aguda/genética , Metiltransferasas/antagonistas & inhibidores , Terapia Molecular Dirigida , Proteína de la Leucemia Mieloide-Linfoide/genética , Translocación Genética , Animales , Antineoplásicos/farmacología , Ensayos Clínicos como Asunto , Evaluación Preclínica de Medicamentos , N-Metiltransferasa de Histona-Lisina/metabolismo , Humanos , Leucemia Bifenotípica Aguda/metabolismo , Metiltransferasas/metabolismo , Proteína de la Leucemia Mieloide-Linfoide/metabolismo , Resultado del TratamientoRESUMEN
UNLABELLED: Genetic lesions such as BCR-ABL1, E2A-PBX1, and MLL rearrangements (MLLr) are associated with unfavorable outcomes in adult B-cell precursor acute lymphoblastic leukemia (B-ALL). Leukemia oncoproteins may directly or indirectly disrupt cytosine methylation patterning to mediate the malignant phenotype. We postulated that DNA methylation signatures in these aggressive B-ALLs would point toward disease mechanisms and useful biomarkers and therapeutic targets. We therefore conducted DNA methylation and gene expression profiling on a cohort of 215 adult patients with B-ALL enrolled in a single phase III clinical trial (ECOG E2993) and normal control B cells. In BCR-ABL1-positive B-ALLs, aberrant cytosine methylation patterning centered around a cytokine network defined by hypomethylation and overexpression of IL2RA(CD25). The E2993 trial clinical data showed that CD25 expression was strongly associated with a poor outcome in patients with ALL regardless of BCR-ABL1 status, suggesting CD25 as a novel prognostic biomarker for risk stratification in B-ALLs. In E2A-PBX1-positive B-ALLs, aberrant DNA methylation patterning was strongly associated with direct fusion protein binding as shown by the E2A-PBX1 chromatin immunoprecipitation (ChIP) sequencing (ChIP-seq), suggesting that E2A-PBX1 fusion protein directly remodels the epigenome to impose an aggressive B-ALL phenotype. MLLr B-ALL featured prominent cytosine hypomethylation, which was linked with MLL fusion protein binding, H3K79 dimethylation, and transcriptional upregulation, affecting a set of known and newly identified MLL fusion direct targets with oncogenic activity such as FLT3 and BCL6. Notably, BCL6 blockade or loss of function suppressed proliferation and survival of MLLr leukemia cells, suggesting BCL6-targeted therapy as a new therapeutic strategy for MLLr B-ALLs. SIGNIFICANCE: We conducted the first integrative epigenomic study in adult B-ALLs, as a correlative study to the ECOG E2993 phase III clinical trial. This study links for the first time the direct actions of oncogenic fusion proteins with disruption of epigenetic regulation mediated by cytosine methylation. We identify a novel clinically actionable biomarker in B-ALLs: IL2RA (CD25), which is linked with BCR-ABL1 and an inflammatory signaling network associated with chemotherapy resistance. We show that BCL6 is a novel MLL fusion protein target that is required to maintain the proliferation and survival of primary human adult MLLr cells and provide the basis for a clinical trial with BCL6 inhibitors for patients with MLLr.
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Biomarcadores de Tumor/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Biomarcadores de Tumor/análisis , Biomarcadores de Tumor/metabolismo , Complejo CD3/biosíntesis , Metilación de ADN , Proteínas de Unión al ADN/genética , Epigenómica , Proteínas de Fusión bcr-abl/genética , Perfilación de la Expresión Génica , Regulación Leucémica de la Expresión Génica , N-Metiltransferasa de Histona-Lisina , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismo , Humanos , Subunidad alfa del Receptor de Interleucina-2/genética , Proteína de la Leucemia Mieloide-Linfoide/genética , Proteínas de Fusión Oncogénica/genética , Proteínas de Fusión Oncogénica/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras B/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patología , Regiones Promotoras Genéticas , Proteínas Proto-Oncogénicas c-bcl-6RESUMEN
Progress in the last decade has improved the understanding of leukemia biology. Molecular markers in combinations with cytogenetics have improved the risk stratification of acute myeloid leukemia (AML) and informed decision-making. In parallel, several important advances in the transplant field, such as better supportive care, improved transplant technology, increased availability of alternative donors, and reduced-intensity conditioning have improved the safety as well as access of allogeneic hematopoietic cell transplantation (HCT) for a larger number of patients. In this review, the positioning of HCT in the management of patients with AML is evaluated in view of changing risk/benefit ratios associated with both conventional treatments and transplantation, and some of the controversies are addressed in light of emerging data. Increasing data demonstrate outcomes of alternative donor transplantation approaching HLA-identical sibling donors in high-risk AML supporting the inclusion of alternative donors in trials of prospective studies evaluating post remission strategies for high-risk AML. The use of reduced-intensity conditioning has expanded the eligibility of HCT to older patients with AML, and outcome data are encouraging. Continued study of HCT versus alternative therapies is required to optimize patients' outcomes in AML.
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Trasplante de Células Madre Hematopoyéticas/métodos , Leucemia Mieloide Aguda/terapia , Adulto , Trasplante de Células Madre Hematopoyéticas/tendencias , Humanos , Leucemia Mieloide Aguda/diagnóstico , Medición de Riesgo , Trasplante Homólogo , Resultado del TratamientoRESUMEN
INTRODUCTION: Cyclophosphamide-based adjuvant chemotherapy is a mainstay of treatment for women with node-positive breast cancer, but is not universally effective in preventing recurrence. Pharmacogenetic variability in drug metabolism is one possible mechanism of treatment failure. We hypothesize that functional single nucleotide polymorphisms (SNPs) in drug metabolizing enzymes (DMEs) that activate (CYPs) or metabolize (GSTs) cyclophosphamide account for some of the observed variability in disease outcomes. METHODS: We performed a retrospective cohort study of 350 women enrolled in a multicenter, randomized, adjuvant breast cancer chemotherapy trial (ECOG-2190/INT-0121). Subjects in this trial received standard-dose cyclophosphamide, doxorubicin and fluorouracil (CAF), followed by either observation or high-dose cyclophosphamide and thiotepa with stem cell rescue. We used bone marrow stem cell-derived genomic DNA from archival specimens to genotype CYP2B6, CYP2C9, CYP2D6, CYP3A4, CYP3A5, GSTM1, GSTT1, and GSTP1. Cox regression models were computed to determine associations between genotypes (individually or in combination) and disease-free survival (DFS) or overall survival (OS), adjusting for confounding clinical variables. RESULTS: In the full multivariable analysis, women with at least one CYP3A4 *1B variant allele had significantly worse DFS than those who were wild-type *1A/*1A (multivariate hazard ratio 2.79; 95% CI 1.52, 5.14). CYP2D6 genotype did not impact this association among patients with estrogen receptor (ER) -positive tumors scheduled to receive tamoxifen. CONCLUSIONS: These data support the hypothesis that genetic variability in cyclophosphamide metabolism independently impacts outcome from adjuvant chemotherapy for breast cancer.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor/genética , Neoplasias de la Mama/enzimología , Neoplasias de la Mama/genética , Citocromo P-450 CYP3A/genética , Polimorfismo de Nucleótido Simple/genética , Adulto , Neoplasias de la Mama/tratamiento farmacológico , Quimioterapia Adyuvante , Estudios de Cohortes , Ciclofosfamida/administración & dosificación , Doxorrubicina/administración & dosificación , Femenino , Fluorouracilo/administración & dosificación , Humanos , Ganglios Linfáticos/enzimología , Ganglios Linfáticos/patología , Metástasis Linfática , Persona de Mediana Edad , Estudios Retrospectivos , Tasa de Supervivencia , Tiotepa/administración & dosificación , Resultado del TratamientoAsunto(s)
Bencenosulfonatos/uso terapéutico , Leucemia Mieloide/tratamiento farmacológico , Síndromes Mielodisplásicos/tratamiento farmacológico , Piridinas/uso terapéutico , Dolor Abdominal/inducido químicamente , Enfermedad Aguda , Área Bajo la Curva , Bencenosulfonatos/efectos adversos , Bencenosulfonatos/farmacocinética , Diarrea/inducido químicamente , Relación Dosis-Respuesta a Droga , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Fatiga/inducido químicamente , Humanos , Leucemia Mieloide/metabolismo , Leucemia Mieloide/patología , Tasa de Depuración Metabólica , Síndromes Mielodisplásicos/metabolismo , Síndromes Mielodisplásicos/patología , Náusea/inducido químicamente , Niacinamida/análogos & derivados , Compuestos de Fenilurea , Fosforilación/efectos de los fármacos , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/uso terapéutico , Piridinas/efectos adversos , Piridinas/farmacocinética , Sorafenib , Resultado del TratamientoRESUMEN
BACKGROUND: In young adults with acute myeloid leukemia (AML), intensification of the anthracycline dose during induction therapy has improved the rate of complete remission but not of overall survival. We evaluated the use of cytarabine plus either standard-dose or high-dose daunorubicin as induction therapy, followed by intensive consolidation therapy, in inducing complete remission to improve overall survival. METHODS: In this phase 3 randomized trial, we assigned 657 patients between the ages of 17 and 60 years who had untreated AML to receive three once-daily doses of daunorubicin at either the standard dose (45 mg per square meter of body-surface area) or a high dose (90 mg per square meter), combined with seven daily doses of cytarabine (100 mg per square meter) by continuous intravenous infusion. Patients who had a complete remission were offered either allogeneic hematopoietic stem-cell transplantation or high-dose cytarabine, with or without a single dose of the monoclonal antibody gemtuzumab ozogamicin, followed by autologous stem-cell transplantation. The primary end point was overall survival. RESULTS: In the intention-to-treat analysis, high-dose daunorubicin, as compared with a standard dose of the drug, resulted in a higher rate of complete remission (70.6% vs. 57.3%, P<0.001) and improved overall survival (median, 23.7 vs. 15.7 months; P=0.003). The rates of serious adverse events were similar in the two groups. Median follow-up was 25.2 months. CONCLUSIONS: In young adults with AML, intensifying induction therapy with a high daily dose of daunorubicin improved the rate of complete remission and the duration of overall survival, as compared with the standard dose. (ClinicalTrials.gov number, NCT00049517.)
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Antibióticos Antineoplásicos/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Daunorrubicina/administración & dosificación , Leucemia Mielomonocítica Aguda/tratamiento farmacológico , Adolescente , Adulto , Factores de Edad , Antibióticos Antineoplásicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Terapia Combinada , Citarabina/administración & dosificación , Daunorrubicina/efectos adversos , Femenino , N-Metiltransferasa de Histona-Lisina , Humanos , Infusiones Intravenosas , Estimación de Kaplan-Meier , Leucemia Mielomonocítica Aguda/genética , Leucemia Mielomonocítica Aguda/mortalidad , Leucemia Mielomonocítica Aguda/terapia , Masculino , Persona de Mediana Edad , Mutación , Proteína de la Leucemia Mieloide-Linfoide/genética , Modelos de Riesgos Proporcionales , Inducción de Remisión/métodos , Factores de Riesgo , Trasplante de Células Madre , Adulto Joven , Tirosina Quinasa 3 Similar a fms/genéticaRESUMEN
Prospective data on the value of allogeneic hematopoietic stem cell transplantation (alloHSCT) in Philadelphia chromosome-positive (Ph(+)) acute lymphoblastic leukemia (ALL) are limited. The UKALLXII/ECOG 2993 study evaluated the outcome of assigning alloHSCT with a sibling (sib) or matched unrelated donor (MUD) to patients younger than 55 years of age achieving complete remission (CR). The CR rate of 267 patients, median age 40, was 82%. Twenty-eight percent of patients proceeded to alloHSCT in first CR. Age older than 55 years or a pre-HSCT event were the most common reasons for failure to progress to alloHSCT. At 5 years, overall survival (OS) was 44% after sib alloHSCT, 36% after MUD alloHSCT, and 19% after chemotherapy. After adjustment for sex, age, and white blood count and excluding chemotherapy-treated patients who relapsed or died before the median time to alloHSCT, only relapse-free survival remained significantly superior in the alloHSCT group (odds ratio 0.31, 95% confidence interval 0.16-0.61). An intention-to-treat analysis, using the availability or not of a matched sibling donor, showed 5-year OS to be nonsignificantly better at 34% with a donor versus 25% with no donor. This prospective trial in adult Ph(+) ALL indicates a modest but significant benefit to alloHSCT. This trial has been registered with clinicaltrials.gov under identifier NCT00002514 and as ISRCTN77346223.
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Antineoplásicos/uso terapéutico , Trasplante de Células Madre Hematopoyéticas , Cromosoma Filadelfia , Piperazinas/uso terapéutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Pirimidinas/uso terapéutico , Adolescente , Adulto , Benzamidas , Femenino , Humanos , Mesilato de Imatinib , Inmunofenotipificación , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Pronóstico , Estudios Prospectivos , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Tirosina Quinasas/antagonistas & inhibidores , ARN Mensajero/genética , ARN Mensajero/metabolismo , Inducción de Remisión , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Tasa de Supervivencia , Trasplante Homólogo , Resultado del Tratamiento , Adulto JovenRESUMEN
Acute promyelocytic leukemia (APL) was initially described as a distinct clinical entity in 1957, one year before the first meeting of the American Society of Hematology. With routine administration of all-trans retinoic acid (ATRA) combined with chemotherapy in the early 1990s and arsenic trioxide (ATO) in the late 1990s, cure can now be expected in the majority of both newly diagnosed and relapsed patients. ATRA with anthracycline-based chemotherapy for induction and consolidation followed by ATRA plus low-dose chemotherapy maintenance is currently the standard of care for newly diagnosed patients. Early institution of ATRA before the diagnosis is confirmed by genetics and aggressive blood product support are important to reduce induction mortality, which remains approximately 10% among patients entered on clinical trials, but is certainly higher when all patients are considered. The relapse rate among high-risk patients is approximately 20%, and new strategies include administration of intensified anthracyclines, intermediate- or high-dose ara-C in either induction or consolidation, or ATO as early consolidation. Central nervous system (CNS) prophylaxis for such patients and those with relapsed disease may be important to prevent the development of extramedullary disease. New therapeutic strategies have focused on minimizing chemotherapy and administering ATRA plus ATO as initial therapy. Recent studies suggest that patients who are molecularly negative after intensive consolidation may not benefit from maintenance therapy. Most exciting is the combination of ATRA and ATO, given with minimal chemotherapy only for leukocytosis, which is a very effective new strategy for patients who are unable to tolerate anthracyclines or older adults and soon may replace conventional therapy for many patients. Patients with relapsed disease do well with ATO followed by autologous hematopoietic stem cell transplantation.
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Leucemia Promielocítica Aguda/tratamiento farmacológico , Antineoplásicos/uso terapéutico , Trióxido de Arsénico , Arsenicales/uso terapéutico , Ensayos Clínicos como Asunto , Citarabina/uso terapéutico , Daunorrubicina/uso terapéutico , Supervivencia sin Enfermedad , Inhibidores de Crecimiento/uso terapéutico , Historia del Siglo XX , Humanos , Leucemia Promielocítica Aguda/historia , Persona de Mediana Edad , Recurrencia Local de Neoplasia/epidemiología , Óxidos/uso terapéutico , Tretinoina/uso terapéuticoRESUMEN
PURPOSE: Genomic features including unmutated immunoglobulin variable region heavy chain (IgVH) genes, del(11q22.3), del(17p13.1), and p53 mutations have been reported to predict the clinical course and overall survival of patients with chronic lymphocytic leukemia (CLL). In addition, ZAP-70 and Bcl-2 family proteins have been explored as predictors of outcome. PATIENTS AND METHODS: We prospectively evaluated the prognostic significance of a comprehensive panel of laboratory factors on both response and progression-free survival (PFS) using samples and data from 235 patients enrolled onto a therapeutic trial. Patients received either fludarabine (FL; n = 113) or fludarabine plus cyclophosphamide (FC; n = 122) as part of a US Intergroup randomized trial for previously untreated CLL patients. RESULTS: Complete response (CR) rates were 24.6% for patients receiving FC and 5.3% for patients receiving FL (P = .00004). PFS was statistically significantly longer in patients receiving FC (median, 33.5 months for patients receiving FC and 19.9 months for patients receiving FL; P < .0001). The occurrence of del(17p13.1) (hazard ratio, 3.428; P = .0002) or del(11q22.3) (hazard ratio, 1.904; P = .006) was associated with reduced PFS. CR and overall response rates were not significantly different based on cytogenetics, IgVH mutational status, CD38 expression, or p53 mutational status. Expression of ZAP-70, Bcl-2, Bax, Mcl-1, XIAP, Caspase-3, and Traf-1 was not associated with either clinical response or PFS. CONCLUSION: These results support the use of interphase cytogenetic analysis, but not IgVH, CD38 expression, or ZAP-70 status, to predict outcome of FL-based chemotherapy. Patients with high-risk cytogenetic features should be considered for alternative therapies.
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Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , ADP-Ribosil Ciclasa 1/análisis , Adulto , Anciano , Anciano de 80 o más Años , Apoptosis , Aberraciones Cromosómicas , Femenino , Genes p53 , Humanos , Cadenas Pesadas de Inmunoglobulina/genética , Región Variable de Inmunoglobulina/genética , Leucemia Linfocítica Crónica de Células B/genética , Leucemia Linfocítica Crónica de Células B/mortalidad , Masculino , Persona de Mediana Edad , Mutación , Estudios Prospectivos , Proteína Tirosina Quinasa ZAP-70/análisisRESUMEN
BACKGROUND: The prognosis for women with primary breast cancer and 10 or more involved axillary lymph nodes is poor. High-dose chemotherapy with autologous hematopoietic stem-cell transplantation has been reported to be effective in the adjuvant setting for patients at high risk for relapse. METHODS: We randomly assigned 540 female patients with primary breast cancer and at least 10 involved ipsilateral axillary lymph nodes to receive either six cycles of adjuvant chemotherapy with cyclophosphamide, doxorubicin, and fluorouracil (CAF) or the same adjuvant chemotherapy followed by high-dose chemotherapy with cyclophosphamide and thiotepa and autologous hematopoietic stem-cell transplantation. RESULTS: Among the 511 eligible patients, there was no significant difference in disease-free survival, overall survival, or the time to recurrence between those who received CAF alone and those who received CAF plus high-dose chemotherapy and stem-cell transplantation. Among 417 patients fulfilling strict eligibility criteria, the time to recurrence was longer for patients who underwent stem-cell transplantation than for those who received CAF alone. In the transplantation group, nine patients died of transplantation-related complications and a myelodysplastic syndrome or acute myeloid leukemia developed in nine. CONCLUSIONS: The addition of high-dose chemotherapy and autologous hematopoietic stem-cell transplantation to six cycles of adjuvant chemotherapy with CAF may reduce the risk of relapse but does not improve the outcome among patients with primary breast cancer and at least 10 involved axillary lymph nodes. Conventional-dose adjuvant chemotherapy remains the standard of care for such patients.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias de la Mama/tratamiento farmacológico , Trasplante de Células Madre Hematopoyéticas , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/terapia , Quimioterapia Adyuvante , Ciclofosfamida/administración & dosificación , Supervivencia sin Enfermedad , Doxorrubicina/administración & dosificación , Femenino , Fluorouracilo/administración & dosificación , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Metástasis Linfática , Persona de Mediana Edad , Recurrencia Local de Neoplasia/prevención & control , Pronóstico , Análisis de Supervivencia , Tamoxifeno/administración & dosificación , Tiotepa/administración & dosificación , Trasplante AutólogoRESUMEN
Significant advances have been made in the development of targeted interventions for hematologic malignancies. Progress has been made in defining the molecular pathogenesis of human leukemias. Data indicate that nonrandom, somatically acquired translocations, inversions, and other abnormalities occur in many acute leukemias. In the treatment of acute promyelocytic leukemia (APL), targeted therapy with all-trans retinoic acid (ATRA) and anthracycline-based chemotherapy leads to dramatic improvements in disease-free survival. Imatinib mesylate, a signal transduction inhibitor that inhibits tyrosine kinase activity, the protein product of the ABL proto-oncogene, has remarkable activity in patients with chronic myeloid leukemia (CML) and Philadelphia chromosome-positive (Ph(+)) acute lymphoblastic leukemia (ALL). Farnesyltransferase inhibitors (FTIs), a promising class of agents that target multiple pathways including Ras proteins, are potential anticancer therapy for a wide range of malignancies, including leukemias and myelodysplastic syndromes (MDS). There also is evidence that recombinant human erythropoietin therapy (r-HuEPO) can benefit patients with chronic lymphocytic leukemia (CLL), multiple myeloma, and lymphomas. This supplement will discuss advances in our understanding of human leukemias, including the use of unconjugated monoclonal antibodies such as Campath-1H (Wellcome, Beckenham, UK, and Ilex Oncology, San Antonio, TX) and rituximab and immunoconjugates such as gemtuzumab ozogamicin and BL-22. Although these novel therapies are beginning to fulfill their promise, continued research efforts are needed to determine the optimal role of targeted therapy in acute and chronic leukemias.
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Antineoplásicos/farmacología , Neoplasias Hematológicas/tratamiento farmacológico , Antineoplásicos/uso terapéutico , Diseño de Fármacos , Neoplasias Hematológicas/etiología , Neoplasias Hematológicas/mortalidad , Humanos , Proto-Oncogenes Mas , Resultado del TratamientoRESUMEN
BACKGROUND: The majority of adult patients who are treated for lymphoblastic disease will either develop recurrent disease or will be refractory to their initial therapy. One option for patients with recurrent/refractory disease is to administer a reinduction regimen that employs a dose-intense combination of anthracycline and cytarabine. These salvage regimens are relatively distinct from the traditional vincristine/prednisone-based programs that are used typically as primary induction therapy. The authors studied a regimen that contained high-dose cytarabine and a single high dose of idarubicin as salvage induction therapy for patients with recurrent or refractory lymphoblastic disease. METHODS: Twenty-nine previously treated adult patients with recurrent or refractory acute lymphoblastic leukemia were treated with a new intensive regimen. Eight patients had primary refractory disease. Twenty-one patients had recurrent disease, and 16 of these patients developed recurrent disease while they were still receiving their primary therapy. The treatment regimen consisted of cytarabine 3.0 g/m(2) by 3-hour infusion daily for 5 days and idarubicin 40 mg/m(2) given as a single dose on Day 3. Filgrastim (granulocyte-colony stimulating factor) 5 microg/kg administered subcutaneously every 12 hours was started on Day 7 and was continued until the absolute neutrophil count was > 5000/microL. Response was assessed using standard criteria. RESULTS: There were 11 complete responses (38%; 95% confidence interval, 20-56%). Four patients subsequently underwent allogeneic bone marrow transplantation. Moderate but acceptable toxicity was observed given the severely myelosuppressive nature of the regimen. There was only one treatment-related death (3%). Two patients, both with significant prior exposure to anthracyclines, suffered reductions in left ventricular function to the 20-30% range during episodes of severe systemic infection. After recovery from infection, the ejection fraction in one patient improved to 50%. CONCLUSIONS: The authors conclude that this regimen has moderate activity and a relatively low incidence of mortality for this high-risk group of patients. This regimen may be most suitable for patients who can undergo potentially curative allogeneic bone marrow transplantation if they achieve a complete response.