RESUMEN
OBJECTIVE: Clofarabine is used to treat acute lymphoblastic leukaemia, but evidence of its safety and effectiveness in Japanese patients is limited. We evaluated the safety and effectiveness of clofarabine in patients with relapsed/refractory acute lymphoblastic leukaemia in real-world clinical practice in Japan. METHODS: An observational, multicenter, post-marketing, all-case surveillance was conducted for safety. Effectiveness analyses were conducted in patients aged ≤21 years and those treated with clofarabine monotherapy and combination therapy (clofarabine plus etoposide and cyclophosphamide). RESULTS: In the all-case survey, 260 of 264 registered patients were eligible for safety analysis. Among the 225 patients eligible for effectiveness analysis, 139 were aged ≤21 years. For monotherapy and combination therapy, 20/31 and 34/88 patients were eligible, respectively. In the all-case survey, the median age was 16.0 years, and 47.7% of patients were <15 years old. Adverse drug reaction incidence was 83.5% and the most common were hematologic toxicities. The best overall response rates in the population aged ≤21 years were complete remission, 29.7%; complete remission without platelet recovery, 7.3% and partial remission, 10.9%. The rest (52.2%) were classified as ineffective. The sum of complete remission, complete remission without platelet recovery and partial remission rates (effectiveness rate) was 47.8% (66/138 patients). The effectiveness rates in the monotherapy and combination therapy surveys were 10.0% (2/20 patients) and 58.8% (20/34 patients), respectively. CONCLUSIONS: These post-marketing surveys provide real-world evidence of the safety and effectiveness of clofarabine regimens, including monotherapy and combination therapy in Japanese patients with relapsed/refractory acute lymphoblastic leukaemia. The safety and effectiveness profiles were comparable with those of previous prospective studies.
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Protocolos de Quimioterapia Combinada Antineoplásica , Clofarabina , Leucemia-Linfoma Linfoblástico de Células Precursoras , Vigilancia de Productos Comercializados , Humanos , Clofarabina/administración & dosificación , Clofarabina/uso terapéutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Masculino , Femenino , Adolescente , Adulto , Adulto Joven , Japón , Niño , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Persona de Mediana Edad , Preescolar , Anciano , Ciclofosfamida/administración & dosificación , Ciclofosfamida/efectos adversos , Ciclofosfamida/uso terapéutico , Etopósido/administración & dosificación , Etopósido/efectos adversos , Resultado del Tratamiento , Arabinonucleósidos/efectos adversos , Arabinonucleósidos/administración & dosificación , Arabinonucleósidos/uso terapéutico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Pueblos del Este de AsiaRESUMEN
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.
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Clofarabina , Histiocitosis de Células de Langerhans , Humanos , Clofarabina/uso terapéutico , Clofarabina/administración & dosificación , Histiocitosis de Células de Langerhans/tratamiento farmacológico , Masculino , Femenino , Adulto , Adolescente , Niño , Persona de Mediana Edad , Preescolar , Adulto Joven , Anciano , Recurrencia , Proteínas Proto-Oncogénicas B-raf/genética , Lactante , Resultado del Tratamiento , Terapia Recuperativa , Nucleótidos de Adenina/uso terapéutico , Nucleótidos de Adenina/administración & dosificación , Nucleótidos de Adenina/efectos adversos , Arabinonucleósidos/uso terapéutico , Arabinonucleósidos/administración & dosificación , Arabinonucleósidos/efectos adversosRESUMEN
INTRODUCTION: Nelarabine is now increasingly being used for the treatment of relapsed T-cell acute lymphoblastic leukemia/lymphoma, and about 18% of patients experience ≥ grade 3 toxicity. Despite the increasing use of this drug, there are no guidelines for managing its neurotoxicity. We would like to share our experience with one such case. CASE REPORT: A sixteen-year-old girl with T-lymphoblastic lymphoma received Nelarabine as part of her relapse treatment. Three weeks post-treatment, patient presented with worsening encephalopathy, bulbar palsy, and seizures. MANAGEMENT AND OUTCOME: After a detailed evaluation, Nelarabine neurotoxicity was strongly considered and was managed with a combination of steroids, intravenous immunoglobulin, and aminophylline, with almost complete recovery starting at 72 hours of treatment initiation. DISCUSSION: Despite the increasing use of this drug, guidelines for the management of the neurological adverse effects of Nelarabine are lacking. The above-mentioned combination of drugs worked for our patient, but larger numbers are needed to validate this as an approved treatment regimen.
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Arabinonucleósidos , Síndromes de Neurotoxicidad , Leucemia-Linfoma Linfoblástico de Células T Precursoras , Humanos , Arabinonucleósidos/efectos adversos , Arabinonucleósidos/uso terapéutico , Femenino , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamiento farmacológico , Síndromes de Neurotoxicidad/etiología , Adolescente , Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéuticoAsunto(s)
Leucemia-Linfoma Linfoblástico de Células Precursoras , Leucemia-Linfoma Linfoblástico de Células T Precursoras , Humanos , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Arabinonucleósidos/uso terapéutico , Linfocitos TRESUMEN
Nelarabine is approved for the treatment of relapsed/refractory (R/R) T-cell acute lymphoblastic leukemia (T-ALL) patients who relapse following at least two different chemotherapy regimens. Previous studies have evaluated the efficacy and safety of nelarabine with chemotherapy in the treatment of R/R T-ALL. However, the results are inconsistent. This review aimed to summarize findings on efficacy and safety data in R/R T-ALL patients administered with the drug nelarabine. The present review conducted a comprehensive search of MEDLINE (via PubMed), WHO Clinical Trial Registry, Clinical Trials.gov, and Cochrane Central Register of Controlled Trials until 15 January 2022. Thirteen studies fulfilled the eligibility criteria with a total of 2508 patients. The efficacy of nelarabine was studied in terms of complete remission (CR) and partial remission (PR). Included studies reported overall random-effects pooled prevalence of CR and PR were 37.2 (95% CI: 22.8, 51.5) and 10.2 (95% CI: 4.9, 15.5), respectively. Most common adverse events associated with nelarabine were neutropenia, thrombocytopenia, fatigue, infections, and reversible peripheral neuropathy. Nelarabine is being used as salvage therapy as a bridge to hematopoietic stem cell transplantation and the findings of this meta-analysis indicate that it is an effective and safe treatment to be used in addition to the first-line treatment for R/R T-ALL.
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Leucemia-Linfoma Linfoblástico de Células T Precursoras , Arabinonucleósidos/efectos adversos , Arabinonucleósidos/uso terapéutico , Humanos , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamiento farmacológico , Terapia Recuperativa , Linfocitos TRESUMEN
Myeloid sarcomas represent a heterogeneous group of diseases with a tumoral presentation of acute myeloid leukemia. The clinical presentation of these hematologic cancers is typically aggressive and thus rapidly fatal in the absence of treatment, which relies on intensive chemotherapy that is sometimes followed by allogeneic hematopoietic stem-cell transplant (AHSCT). However, the global treatment strategy for these lesions is currently not well established. We report the case of a patient presenting with a highly refractory mediastinal myeloid sarcoma with uncommon morphologic and phenotypic characteristics and a clonal TCR rearrangement. The patient's disease was progressive despite multiple courses of intensive chemotherapy and a combination of nelarabine and venetoclax finally led to a complete metabolic response consolidated by an AHSCT. This treatment regimen, which has never been reported before, was very well tolerated especially on the neurologic and hematologic levels. This case underlines the clinical, histologic and molecular heterogeneity of what is called myeloid sarcoma and the importance of next-generation sequencing analysis of the tumor mass with both myeloid and lymphoid panels to better classify this rare entity and identify therapeutic targets.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias del Mediastino/tratamiento farmacológico , Neoplasias del Mediastino/patología , Sarcoma Mieloide/tratamiento farmacológico , Sarcoma Mieloide/patología , Antineoplásicos/uso terapéutico , Arabinonucleósidos/uso terapéutico , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Trasplante de Células Madre Hematopoyéticas , Humanos , Masculino , Persona de Mediana Edad , Sulfonamidas/uso terapéuticoRESUMEN
T-cell ALL (T-ALL) is an aggressive malignancy of T-cell progenitors. Although survival outcomes in T-ALL have greatly improved over the past 50 years, relapsed and refractory cases remain extremely challenging to treat and those who cannot tolerate intensive treatment continue to have poor outcomes. Furthermore, T-ALL has proven a more challenging immunotherapeutic target than B-ALL. In this review we explore our expanding knowledge of the basic biology of T-ALL and how this is paving the way for repurposing established treatments and the development of novel therapeutic approaches.
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Antineoplásicos/uso terapéutico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/terapia , Antineoplásicos/administración & dosificación , Antineoplásicos Inmunológicos/uso terapéutico , Apoptosis/efectos de los fármacos , Arabinonucleósidos/uso terapéutico , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Quinasas Ciclina-Dependientes/antagonistas & inhibidores , Heterogeneidad Genética , Humanos , Inmunoterapia , Inmunoterapia Adoptiva , Inhibidores de las Cinasas Janus/uso terapéutico , Terapia Molecular Dirigida , Proteínas de Neoplasias/antagonistas & inhibidores , Inhibidores de las Quinasa Fosfoinosítidos-3/uso terapéutico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Receptor Notch1/antagonistas & inhibidores , Receptores de Interleucina-7/antagonistas & inhibidores , Terapia Recuperativa/métodos , Transducción de Señal/efectos de los fármacos , Sulfonamidas/uso terapéutico , Terapias en Investigación/métodos , Terapias en Investigación/tendencias , Resultado del TratamientoRESUMEN
PURPOSE: The Children's Oncology Group (COG) protocol AALL0434 evaluated the safety and efficacy of multi-agent chemotherapy with Capizzi-based methotrexate/pegaspargase (C-MTX) in patients with newly diagnosed pediatric T-cell lymphoblastic lymphoma (T-LL) and gained preliminary data using nelarabine in high-risk patients. PATIENTS AND METHODS: The trial enrolled 299 patients, age 1-31 years. High-risk (HR) patients had ≥ 1% minimal detectable disease (MDD) in the bone marrow at diagnosis or received prior steroid treatment. Induction failure was defined as failure to achieve a partial response (PR) by the end of the 4-week induction. All patients received the augmented Berlin-Frankfurt-Muenster (ABFM) C-MTX regimen. HR patients were randomly assigned to receive or not receive 6 5-day courses of nelarabine incorporated into ABFM. Patients with induction failure were nonrandomly assigned to ABFM C-MTX plus nelarabine. No patients received prophylactic cranial radiation; however, patients with CNS3 disease (CSF WBC ≥ 5/µL with blasts or cranial nerve palsies, brain/eye involvement, or hypothalamic syndrome) were ineligible. RESULTS: At end-induction, 98.8% of evaluable participants had at least a PR. The 4-year event-free survival (EFS) and overall survival (OS) were 84.7% ± 2.3% and 89.0% ± 2.0%. The 4-year disease-free survival (DFS) from end-induction was 85.9% ± 2.6%. There was no difference in DFS observed between the HR and standard-risk groups (P = .29) or by treatment regimen (P = .55). Disease stage, tumor response, and MDD at diagnosis did not demonstrate thresholds that resulted in differences in EFS. Nelarabine did not show an advantage for HR patients. CNS relapse occurred in only 4 patients. CONCLUSION: COG AALL0434 produced excellent outcomes in one of the largest trials ever conducted for patients with newly diagnosed T-LL. The COG ABFM regimen with C-MTX provided excellent EFS and OS without cranial radiation.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Arabinonucleósidos/uso terapéutico , Asparaginasa/uso terapéutico , Metotrexato/uso terapéutico , Polietilenglicoles/uso terapéutico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamiento farmacológico , Adolescente , Adulto , Factores de Edad , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Arabinonucleósidos/efectos adversos , Asparaginasa/efectos adversos , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Metotrexato/efectos adversos , Polietilenglicoles/efectos adversos , Leucemia-Linfoma Linfoblástico de Células T Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/mortalidad , Supervivencia sin Progresión , Estudios Prospectivos , Factores de Tiempo , Estados Unidos , Adulto JovenRESUMEN
Adult T-cell acute lymphoblastic leukemia (T-ALL) is a heterogeneous group of acute leukemias that account for about one third of all cases of Philadelphia chromosome (Ph)-negative ALL. Recently, a molecular classifier using the mutational status of NOTCH1, FBXW7, RAS, and PTEN (NFRP) has been shown to distinguish low- vs high-risk groups in adult T-ALL patients treated using the Berlin-Frankfurt-Münster ALL protocol. However, it is unknown if this molecular classifier can stratify adult T-ALL patients treated with hyper-CVAD ± nelarabine. We identified a relatively small cohort of 27 adults with T-ALL who were uniformly treated with hyper-CVAD ± nelarabine with available mutational analysis at time of diagnosis. The most commonly mutated genes in this group were NOTCH1 (52%), NRAS (22%), DNMT3A (19%), KRAS (15%), and TP53 (7%). The NFRP molecular classifier failed to stratify overall survival (OS; P = .84) and relapse-free survival (RFS; P = .18) in this cohort. We developed a new stratification model combining K/NRAS and TP53 mutations as high-risk factors and showed that mutations in these genes predicted poorer OS (P = .03) and RFS (P = .04). While the current study is limited by cohort size, these data suggest that the NFRP molecular classifier might not be applicable to adult T-ALL patients treated with hyper-CVAD ± nelarabine. RAS/TP53 mutation status, however, was useful in risk stratification in adults with T-ALL.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , GTP Fosfohidrolasas/genética , Proteínas de la Membrana/genética , Recurrencia Local de Neoplasia/epidemiología , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamiento farmacológico , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteína p53 Supresora de Tumor/genética , Adolescente , Adulto , Arabinonucleósidos/uso terapéutico , Ciclofosfamida/uso terapéutico , Análisis Mutacional de ADN/estadística & datos numéricos , Dexametasona/uso terapéutico , Supervivencia sin Enfermedad , Doxorrubicina/uso terapéutico , Registros Electrónicos de Salud/estadística & datos numéricos , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Mutación , Recurrencia Local de Neoplasia/prevención & control , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/mortalidad , Pronóstico , Medición de Riesgo/métodos , Medición de Riesgo/estadística & datos numéricos , Vincristina/uso terapéuticoRESUMEN
Acute Lymphoblastic Leukemia (ALL) represents 30% of all childhood cancers and children younger than 5â¯years old have the highest risk for developing ALL. Existing ALL drugs do not respond in approximately 20% of treatment. Therefore, drug development studies against ALL must be continued with either developing existing drugs or discovering new ones. In this study, we evaluated the U.S Food and Drug Administration (FDA) approved ALL drugs according to their physicochemical and pharmaceutical properties, and Nelarabine was found to have the highest bioactivity score. Using the key strategy of bioisosterism commonly accepted by medicinal chemists, we investigated in silico ADME properties, drug-likeness, and biological activity of new designed twenty-four compounds including Nelarabine. The results were evaluated in terms of two classifications: broad spectrum biological activity and filtering of five different drug likeness criteria of the literature including Lipinski's rule of five. We interestingly observed that silicon incorporated compounds exhibited better performance on both criteria by targeting broader spectrum of drug receptors including G-protein coupled receptor (GPCR), ion channel modulator, kinase inhibitor, protease and enzyme inhibitor and by satisfying all of five different drug-likeness criteria reported in the literature. Design compound C19 appeared as a potential drug candidate for further pharmacological research.
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Antineoplásicos/química , Arabinonucleósidos/química , Arabinonucleósidos/uso terapéutico , Descubrimiento de Drogas/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Disponibilidad Biológica , Niño , Preescolar , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Lactante , Recién Nacido , Silicio , Estados Unidos , United States Food and Drug AdministrationRESUMEN
PURPOSE OF REVIEW: Patients with relapsed T cell acute lymphoblastic leukemia (T-ALL) have limited therapeutic options and a poor prognosis. Although a variety of salvage chemotherapy regimens may be used, response rates are unsatisfactory. This article summarizes current approaches and promising emerging strategies for the treatment of relapsed T-ALL. RECENT FINDINGS: Although nelarabine is the only agent approved specifically for T-ALL, recent studies have identified a variety of genetic alterations and signaling pathways that are critical in its pathogenesis. Based on these findings, a number of small-molecule inhibitors and other targeted therapies are being studied for relapsed T-ALL, including gamma-secretase inhibitors, BCL-2 inhibitors, cyclin-dependent kinase inhibitors, and mTOR inhibitors. In addition, pre-clinical studies of chimeric antigen receptor T cells targeting CD5 and CD7 as well as the monoclonal antibody daratumumab have shown promising results for T-ALL. Relapsed T-ALL currently remains challenging to treat, but recent pre-clinical studies of targeted and immunotherapeutic agents have shown encouraging results. A number of clinical trials investigating these approaches for T-ALL are currently underway.
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Anticuerpos Monoclonales/uso terapéutico , Arabinonucleósidos/uso terapéutico , Resistencia a Antineoplásicos/efectos de los fármacos , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamiento farmacológico , Vincristina/uso terapéutico , Antineoplásicos/uso terapéutico , Humanos , Liposomas/química , Recurrencia Local de Neoplasia , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patología , Terapia Recuperativa/métodos , Vincristina/químicaAsunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Arabinonucleósidos/farmacología , Benzamidas/farmacología , Citosina/análogos & derivados , Resistencia a Antineoplásicos/efectos de los fármacos , Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Isoindoles/farmacología , Leucemia Mieloide Aguda/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Arabinonucleósidos/uso terapéutico , Benzamidas/uso terapéutico , Línea Celular Tumoral , Citosina/farmacología , Citosina/uso terapéutico , Roturas del ADN de Doble Cadena/efectos de los fármacos , Reparación del ADN/efectos de los fármacos , Resistencia a Antineoplásicos/genética , Proteínas HSP90 de Choque Térmico/metabolismo , Humanos , Isoindoles/uso terapéutico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologíaRESUMEN
INTRODUCTION: Acute myeloid leukemia (AML) remains a poor prognosis hematological malignancy. The introduction of aggressive chemotherapy with allogeneic stem cell transplantation has resulted in improved clinical outcomes in younger patients. However, the treatment results in unfit elderly AML population remain disappointing. New strategies should be introduced to improve the prognosis in this group of patients. Areas covered: This review presents and discusses the mechanism of action, safety and efficacy of sapacitabine in AML patients. Expert opinion: Sapacitabine, a novel nucleoside analog, seemed to be a promising new agent for AML treatment. Its oral bioavailability and tolerable toxicity profile allow the drug to be used in an outpatient setting, especially in elderly unfit patients. Sapacitabine is known to have antileukemic activity in randomized clinical trials. In AML patients, sapacitabine monotherapy offered no advantage over low-intensity cytarabine treatment, and the combination of sapacitabine with decitabine was not significantly more effective than decitabine alone. However, the oral administration of sapacitabine allows it to be used in AML maintenance therapy.
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Antineoplásicos/uso terapéutico , Arabinonucleósidos/uso terapéutico , Citosina/análogos & derivados , Leucemia Mieloide Aguda/tratamiento farmacológico , Anciano , Antineoplásicos/farmacología , Arabinonucleósidos/farmacología , Citosina/farmacología , Citosina/uso terapéutico , Humanos , Pronóstico , Resultado del TratamientoRESUMEN
AIM: The analysis of experience of nelarabine use in refractory/relapsed T-cell acute lymphoblastic leukemia (T-ALL) depending on the immunophenotype and the line of therapy. MATERIALS AND METHODS: All the patients with relapsed or refractory T-ALL aged from 0 to 18 years who received treatment with nelarabine as a part of the therapeutic element R6 were included in the study. For all patients a detailed immunological analysis of leukemia cells with discrimination of immunological variants TI, TII, TIII or TIV was performed. Patients administered with nelarabine as a first therapeutic element were referred to the first-line therapy group, other patients were referred to the second-line therapy group. Nelarabine was ad- ministered as intravenous infusion at a dose of 650 mg/m2, on days 1-5. Allogeneic hematopoietic stem cells transplantation (allo-HSCT) was considered for all patients. RESULTS: From 2009 to 2017, 54 patients with refractory/relapsed T-ALL were treated with nelarabine. Five-year event-free survival (EFS) and overall survival (OS) was 28% for all patients, cumulative risk of relapse (CIR) was 27%. EFS was significantly higher in nelarabine first-line therapy group in comparison with second-line therapy group (34±8% vs 8±8%, p=0,05). In patients after allo-HSCT EFS, OS and CIR were 51±10%, 50±10% and 39,1±9,5% accordingly. The best results were achieved in patients with TI immunophenotype. No toxicity-related mortality as well as severe neurologic complications or discontinuation of therapy associated with use of nelarabine were reported. CONCLUSION: The use of nelarabine is an effective strategy for the treatment of relapsed and refractory T-ALL. The best treatment outcomes were obtained in patients with TI immunophenotype and in the first-line therapy group. Optimal dosage regimens can be established dur- ing controlled clinical trials.
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Antineoplásicos/uso terapéutico , Arabinonucleósidos/uso terapéutico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamiento farmacológico , Profármacos/uso terapéutico , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Arabinonucleósidos/efectos adversos , Arabinonucleósidos/farmacocinética , Ensayos Clínicos como Asunto , Humanos , Inyecciones Intravenosas , Leucemia-Linfoma Linfoblástico de Células T Precursoras/mortalidad , Profármacos/efectos adversos , Profármacos/farmacocinética , Supervivencia sin Progresión , RecurrenciaRESUMEN
Nelarabine, a water soluble prodrug of 9-ß-D-arabinofuranosylguanine (ara-G), is a T-cell specific purine nucleoside analogue. Given its activity in relapsed and refractory T acute lymphoblastic leukemia (T-ALL) and T lymphoblastic lymphoma (T-LBL), we sought to define its role in the frontline treatment of adult patients. Therefore, we conducted a single arm phase 2 study to determine the safety and efficacy of nelarabine in combination with hyper-CVAD in newly diagnosed patients. For induction/consolidation, patients received eight cycles of hyper-CVAD alternating with high-dose methotrexate and cytarabine plus two cycles of nelarabine given at a dose of 650 mg/m2 intravenously daily for 5 days. This was followed by thirty months of POMP maintenance chemotherapy with two additional cycles of nelarabine given instead of cycles 6 and 7 of POMP maintenance. Sixty-seven patients, including 40 with T-ALL and 26 with T-LBL, were enrolled. Complete response rates in both T-ALL and T-LBL were 87% and 100% respectively. Grade 3 to 4 neurotoxic adverse events were reported in 5 patients. There were 21 relapses (31%) including 2 after allogeneic stem cell transplantation. Median duration of follow-up was 42.5 months. The 3-year complete remission duration (CRD) and overall survival (OS) rates were 66% and 65%, respectively. Compared to our historic hyper-CVAD data, there was no survival benefit with the addition of nelarabine. In conclusion, hyper-CVAD plus nelarabine was well tolerated and active in the frontline treatment of adult T-ALL/LBL patients.
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Arabinonucleósidos/uso terapéutico , Inmunofenotipificación/métodos , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamiento farmacológico , Adolescente , Adulto , Anciano , Arabinonucleósidos/administración & dosificación , Arabinonucleósidos/farmacología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Leucemia-Linfoma Linfoblástico de Células T Precursoras/mortalidad , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patología , Análisis de Supervivencia , Adulto JovenRESUMEN
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.
Asunto(s)
Nucleótidos de Adenina/uso terapéutico , Envejecimiento , Antimetabolitos Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Arabinonucleósidos/uso terapéutico , Quimioterapia de Inducción , Leucemia Mieloide Aguda/tratamiento farmacológico , Vidarabina/análogos & derivados , Nucleótidos de Adenina/efectos adversos , Nucleótidos de Adenina/economía , Anciano , Anciano de 80 o más Años , Antimetabolitos Antineoplásicos/efectos adversos , Antimetabolitos Antineoplásicos/economía , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/economía , Arabinonucleósidos/efectos adversos , Arabinonucleósidos/economía , Estudios de Casos y Controles , Enfermedad Hepática Inducida por Sustancias y Drogas/economía , Enfermedad Hepática Inducida por Sustancias y Drogas/epidemiología , Enfermedad Hepática Inducida por Sustancias y Drogas/mortalidad , Enfermedad Hepática Inducida por Sustancias y Drogas/terapia , Clofarabina , Estudios de Cohortes , Terapia Combinada/economía , Ahorro de Costo , Costos y Análisis de Costo , Citarabina/efectos adversos , Citarabina/economía , Citarabina/uso terapéutico , Factor Estimulante de Colonias de Granulocitos/efectos adversos , Factor Estimulante de Colonias de Granulocitos/economía , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Costos de Hospital , Humanos , Incidencia , Quimioterapia de Inducción/efectos adversos , Quimioterapia de Inducción/economía , Tiempo de Internación , Leucemia Mieloide Aguda/economía , Leucemia Mieloide Aguda/mortalidad , Michigan/epidemiología , Persona de Mediana Edad , Neutropenia/inducido químicamente , Neutropenia/economía , Neutropenia/mortalidad , Neutropenia/terapia , Puntaje de Propensión , Estudios Retrospectivos , Análisis de Supervivencia , Centros de Atención Terciaria , Vidarabina/efectos adversos , Vidarabina/economía , Vidarabina/uso terapéuticoAsunto(s)
Arabinonucleósidos/uso terapéutico , Transfusión de Linfocitos/métodos , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patología , Leucemia-Linfoma Linfoblástico de Células T Precursoras/terapia , Sobrevivientes , Adulto , Humanos , Masculino , Recurrencia , Trasplante Homólogo , Resultado del TratamientoRESUMEN
Tumor-targeted drug delivery with simultaneous cancer imaging is highly desirable for personalized medicine. Herein, we report a supramolecular approach to design a promising class of multifunctional nanoparticles based on molecular recognition of nucleobases, which combine excellent tumor-targeting capability via aptamer, controlled drug release, and efficient fluorescent imaging for cancer-specific therapy. First, an amphiphilic prodrug dioleoyl clofarabine was self-assembled into micellar nanoparticles with hydrophilic nucleoside analogue clofarabine on their surface. Thereafter, two types of single-stranded DNAs that contain the aptamer motif and fluorescent probe Cy5.5, respectively, were introduced onto the surface of the nanoparticles via molecular recognition between the clofarabine and the thymine on DNA. These drug-containing multifunctional nanoparticles exhibit good capabilities of targeted clofarabine delivery to the tumor site and intracellular controlled drug release, leading to a robust and effective antitumor effect in vivo.