RESUMO
PURPOSE: Nelarabine is effective in inducing remission in patients with relapsed and refractory T-cell acute lymphoblastic leukemia (T-ALL) but has not been fully evaluated in those with newly diagnosed disease. PATIENTS AND METHODS: From 2007 to 2014, Children's Oncology Group trial AALL0434 (ClinicalTrials.gov identifier: NCT00408005) enrolled 1,562 evaluable patients with T-ALL age 1-31 years who received the augmented Berlin-Frankfurt-Muenster (ABFM) regimen with a 2 × 2 pseudo-factorial randomization to receive escalating-dose methotrexate (MTX) without leucovorin rescue plus pegaspargase (C-MTX) or high-dose MTX (HDMTX) with leucovorin rescue. Intermediate- and high-risk patients were also randomly assigned after induction to receive or not receive six 5-day courses of nelarabine that was incorporated into ABFM. Patients who experienced induction failure were nonrandomly assigned to HDMTX plus nelarabine. Patients with overt CNS disease (CNS3; ≥ 5 WBCs/µL with blasts) received HDMTX and were randomly assigned to receive or not receive nelarabine. All patients, except those with low-risk disease, received cranial irradiation. RESULTS: The 5-year event-free and overall survival rates were 83.7% ± 1.1% and 89.5% ± 0.9%, respectively. The 5-year disease-free survival (DFS) rates for patients with T-ALL randomly assigned to nelarabine (n = 323) and no nelarabine (n = 336) were 88.2% ± 2.4% and 82.1% ± 2.7%, respectively (P = .029). Differences between DFS in a four-arm comparison were significant (P = .01), with no interactions between the MTX and nelarabine randomizations (P = .41). Patients treated with the best-performing arm, C-MTX plus nelarabine, had a 5-year DFS of 91% (n = 147). Patients who received nelarabine had significantly fewer isolated and combined CNS relapses compared with patients who did not receive nelarabine (1.3% ± 0.63% v 6.9% ± 1.4%, respectively; P = .0001). Toxicities, including neurotoxicity, were acceptable and similar between all four arms. CONCLUSION: The addition of nelarabine to ABFM therapy improved DFS for children and young adults with newly diagnosed T-ALL without increased toxicity.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamento farmacológico , Adolescente , Arabinonucleosídeos/administração & dosagem , Arabinonucleosídeos/efeitos adversos , Asparaginase/administração & dosagem , Asparaginase/efeitos adversos , Criança , Estudos de Coortes , Intervalo Livre de Doença , Feminino , Humanos , Leucovorina/administração & dosagem , Leucovorina/efeitos adversos , Masculino , Metotrexato/administração & dosagem , Metotrexato/efeitos adversos , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/efeitos adversos , Prednisona/administração & dosagem , Prednisona/efeitos adversos , Resultado do TratamentoRESUMO
PURPOSE: Early intensification with methotrexate (MTX) is a key component of acute lymphoblastic leukemia (ALL) therapy. Two different approaches to MTX intensification exist but had not been compared in T-cell ALL (T-ALL): the Children's Oncology Group (COG) escalating dose intravenous MTX without leucovorin rescue plus pegaspargase escalating dose, Capizzi-style, intravenous MTX (C-MTX) regimen and the Berlin-Frankfurt-Muenster (BFM) high-dose intravenous MTX (HDMTX) plus leucovorin rescue regimen. PATIENTS AND METHODS: COG AALL0434 included a 2 × 2 randomization that compared the COG-augmented BFM (ABFM) regimen with either C-MTX or HDMTX during the 8-week interim maintenance phase. All patients with T-ALL, except for those with low-risk features, received prophylactic (12 Gy) or therapeutic (18 Gy for CNS3) cranial irradiation during either the consolidation (C-MTX; second month of therapy) or delayed intensification (HDMTX; seventh month of therapy) phase. RESULTS: AALL0434 accrued 1,895 patients from 2007 to 2014. The 5-year event-free survival and overall survival rates for all eligible, evaluable patients with T-ALL were 83.8% (95% CI, 81.2% to 86.4%) and 89.5% (95% CI, 87.4% to 91.7%), respectively. The 1,031 patients with T-ALL but without CNS3 disease or testicular leukemia were randomly assigned to receive ABFM with C-MTX (n = 519) or HDMTX (n = 512). The estimated 5-year disease-free survival ( P = .005) and overall survival ( P = .04) rates were 91.5% (95% CI, 88.1% to 94.8%) and 93.7% (95% CI, 90.8% to 96.6%) for C-MTX and 85.3% (95% CI, 81.0%-89.5%) and 89.4% (95% CI, 85.7%-93.2%) for HDMTX. Patients assigned to C-MTX had 32 relapses, six with CNS involvement, whereas those assigned to HDMTX had 59 relapses, 23 with CNS involvement. CONCLUSION: AALL0434 established that ABFM with C-MTX was superior to ABFM plus HDMTX for T-ALL in approximately 90% of patients who received CRT, with later timing for those receiving HDMTX.
Assuntos
Antimetabólitos Antineoplásicos/administração & dosagem , Metotrexato/administração & dosagem , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamento farmacológico , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Asparaginase/administração & dosagem , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Humanos , Lactente , Leucovorina/administração & dosagem , Masculino , Polietilenoglicóis/administração & dosagem , Leucemia-Linfoma Linfoblástico de Células T Precursoras/mortalidade , Adulto JovemRESUMO
The Children's Oncology Group (COG) develops and implements multi-institutional clinical trials with the primary goal of assessing the efficacy and safety profile of treatment regimens for various pediatric cancers. However, the monetary costs of treatment regimens are not measured. AALL0232 was a COG randomized phase III trial for children with acute lymphoblastic leukemia that found that dexamethasone (DEX) was a more effective glucocorticoid than prednisone (PRED) in patients younger than 10 years, but PRED was equally effective and less toxic in older patients. In addition, high-dose methotrexate (HD-MTX) led to better survival than escalating doses of methotrexate (C-MTX). Cost data from the Pediatric Health Information System database were merged with clinical data from the COG AALL0232 trial. Total and component costs were compared between treatment arms and across hospitals. Inpatient costs were higher in the HD-MTX and DEX arms when compared to the C-MTX and PRED arms at the end of therapy. There was no difference in cost between these arms at last follow-up. Considerable variation in total costs existed across centers to deliver the same therapy that was driven by differences in inpatient days and pharmacy costs. The more effective regimens were found to be more expensive during therapy but were ultimately cost-neutral in longer term follow-up. The variations in cost across centers suggest an opportunity to standardize resource utilization for patients receiving similar therapies, which could translate into reduced healthcare expenditures.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/economia , Custos de Medicamentos , Gastos em Saúde , Custos Hospitalares , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Adolescente , Adulto , Fatores Etários , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Asparaginase/administração & dosagem , Asparaginase/efeitos adversos , Asparaginase/economia , Criança , Pré-Escolar , Análise Custo-Benefício , Dexametasona/administração & dosagem , Dexametasona/efeitos adversos , Dexametasona/economia , Intervalo Livre de Doença , Esquema de Medicação , Feminino , Seguimentos , Hospitalização/economia , Humanos , Lactente , Recém-Nascido , Leucovorina/administração & dosagem , Leucovorina/efeitos adversos , Leucovorina/economia , Masculino , Metotrexato/administração & dosagem , Metotrexato/efeitos adversos , Metotrexato/economia , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/efeitos adversos , Polietilenoglicóis/economia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/economia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/mortalidade , Prednisona/administração & dosagem , Prednisona/efeitos adversos , Prednisona/economia , Adulto JovemRESUMO
Purpose Survivors of childhood acute lymphoblastic leukemia (ALL) are at risk for neurocognitive deficits that are associated with treatment, individual, and environmental factors. This study examined the impact of different methotrexate (MTX) and corticosteroid treatment strategies on neurocognitive functioning in children with high-risk B-lineage ALL. Methods Participants were randomly assigned to receive high-dose MTX with leucovorin rescue or escalating dose MTX with PEG asparaginase without leucovorin rescue. Patients were also randomly assigned to corticosteroid therapy that included either dexamethasone or prednisone. A neurocognitive evaluation of intellectual functioning (IQ), working memory, and processing speed (PS) was conducted 8 to 24 months after treatment completion (n = 192). Results The method of MTX delivery and corticosteroid assignment were unrelated to differences in neurocognitive outcomes after controlling for ethnicity, race, age, gender, insurance status, and time off treatment; however, survivors who were age < 10 years at diagnosis (n = 89) had significantly lower estimated IQ ( P < .001) and PS scores ( P = .02) compared with participants age ≥ 10 years. In addition, participants who were covered by US public health insurance had estimated IQs that were significantly lower ( P < .001) than those with US private or military insurance. Conclusion Children with high-risk B-lineage ALL who were age < 10 years at diagnosis are at risk for deficits in IQ and PS in the absence of cranial radiation, regardless of MTX delivery or corticosteroid type. These data may serve as a basis for developing screening protocols to identify children who are at high risk for deficits so that early intervention can be initiated to mitigate the impact of therapy on neurocognitive outcomes.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cognição/efeitos dos fármacos , Inteligência/efeitos dos fármacos , Memória de Curto Prazo/efeitos dos fármacos , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Tempo de Reação/efeitos dos fármacos , Corticosteroides/administração & dosagem , Adultos Sobreviventes de Eventos Adversos na Infância , Fatores Etários , Asparaginase/administração & dosagem , Criança , Dexametasona/administração & dosagem , Feminino , Humanos , Seguro Saúde , Leucovorina/administração & dosagem , Masculino , Medicaid , Metotrexato/administração & dosagem , Polietilenoglicóis/administração & dosagem , Leucemia-Linfoma Linfoblástico de Células Precursoras B/psicologia , Prednisona/administração & dosagem , Estados UnidosRESUMO
Minimal residual disease (MRD) is highly prognostic in pediatric B-precursor acute lymphoblastic leukemia (B-ALL). In Children's Oncology Group high-risk B-ALL study AALL0232, we investigated MRD in subjects randomized in a 2 × 2 factorial design to receive either high-dose methotrexate (HD-MTX) or Capizzi methotrexate (C-MTX) during interim maintenance (IM) or prednisone or dexamethasone during induction. Subjects with end-induction MRD ≥0.1% or those with morphologic slow early response were nonrandomly assigned to receive a second IM and delayed intensification phase. MRD was measured by 6-color flow cytometry in 1 of 2 reference labs, with excellent agreement between the two. Subjects with end-induction MRD <0.01% had a 5-year event-free survival (EFS) of 87% ± 1% vs 74% ± 4% for those with MRD 0.01% to 0.1%; increasing MRD amounts was associated with progressively worse outcome. Subjects converting from MRD positive to negative by end consolidation had a relatively favorable 79% ± 5% 5-year disease-free survival vs 39% ± 7% for those with MRD ≥0.01%. Although HD-MTX was superior to C-MTX, MRD retained prognostic significance in both groups (86% ± 2% vs 58% ± 4% for MRD-negative vs positive C-MTX subjects; 88% ± 2% vs 68% ± 4% for HD-MTX subjects). Intensified therapy given to subjects with MRD >0.1% did not improve either 5-year EFS or overall survival (OS). However, these subjects showed an early relapse rate similar to that seen in MRD-negative ones, with EFS/OS curves for patients with 0.1% to 1% MRD crossing those with 0.01% to 0.1% MRD at 3 and 4 years, thus suggesting that the intensified therapy altered the disease course of MRD-positive subjects. Additional interventions targeted at the MRD-positive group may further improve outcome. This trial was registered at www.clinicaltrials.gov as #NCT00075725.
Assuntos
Antineoplásicos/administração & dosagem , Neoplasia Residual/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Asparaginase/administração & dosagem , Criança , Pré-Escolar , Dexametasona/administração & dosagem , Intervalo Livre de Doença , Relação Dose-Resposta a Droga , Feminino , Citometria de Fluxo , Humanos , Quimioterapia de Indução , Estimativa de Kaplan-Meier , Leucovorina/administração & dosagem , Quimioterapia de Manutenção , Masculino , Metotrexato/administração & dosagem , Polietilenoglicóis/administração & dosagem , Leucemia-Linfoma Linfoblástico de Células Precursoras B/mortalidade , Prednisona/administração & dosagem , Prognóstico , Modelos de Riscos Proporcionais , Fatores de RiscoRESUMO
Pediatric patients who experience a bone marrow relapse of precursor-B acute lymphoblastic leukemia are cured <50% of the time. This study was designed to determine if intensification of therapies with known activity in this disease would improve the cure rates for patients with relapsed acute lymphoblastic leukemia. Patients were treated with intensive asparaginase during induction followed by repeated cycles of ifosfamide/etoposide and cytarabine/idarubicin. Patients with well-matched related donors were encouraged to undergo hematopoietic stem cell transplant as consolidation. The results of this study demonstrate no significant difference in disease-free survival in patients who received chemotherapy alone (45%) or chemotherapy followed by allogeneic stem cell transplant (50%). Furthermore, results from this study show no significant difference in event-free survival (39.9%±6.2%) or overall survival (41.6%±6.1%) at 8 years when compared with previous studies using less intensive regimens. Our results suggest that alternative therapies are needed to improve cure rates for pediatric patients with relapsed leukemia.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Adolescente , Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras B/mortalidade , Recidiva , Indução de Remissão , Resultado do TratamentoRESUMO
Methotrexate clearance can influence the cure of and toxicity in children with acute lymphoblastic leukemia (ALL). We estimated methotrexate plasma clearance for 1279 patients with ALL treated with methotrexate (24-hour infusion of a 1 g/m2 dose or 4-hour infusion of a 2 g/m2 dose) on the Children's Oncology Group P9904 and P9905 protocols. Methotrexate clearance was lower in older children (P = 7 x 10(-7)), girls (P = 2.7 x 10(-4)), and those who received a delayed-intensification phase (P = .0022). A genome-wide analysis showed that methotrexate clearance was associated with polymorphisms in the organic anion transporter gene SLCO1B1 (P = 2.1 x 10(-11)). This replicates findings using different schedules of high-dose methotrexate in St Jude ALL treatment protocols; a combined meta-analysis yields a P value of 5.7 x 10(-19) for the association of methotrexate clearance with SLCO1B1 SNP rs4149056. Validation of this variant with 5 different treatment regimens of methotrexate solidifies the robustness of this pharmacogenomic determinant of methotrexate clearance. This study is registered at http://www.clinicaltrials.gov as NCT00005585 and NCT00005596.
Assuntos
Estudo de Associação Genômica Ampla , Metotrexato/farmacocinética , Transportadores de Ânions Orgânicos/genética , Polimorfismo de Nucleotídeo Único , Adolescente , Alelos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Criança , Pré-Escolar , Relação Dose-Resposta a Droga , Feminino , Frequência do Gene , Genótipo , Humanos , Lactente , Infusões Intravenosas , Leucovorina/administração & dosagem , Modelos Lineares , Transportador 1 de Ânion Orgânico Específico do Fígado , Masculino , Taxa de Depuração Metabólica , Metotrexato/administração & dosagem , Análise Multivariada , Transportadores de Ânions Orgânicos/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismoRESUMO
PURPOSE: Successful therapeutic interventions to prevent disease progression in patients with nonmetastatic osteosarcoma have included surgery with adjuvant chemotherapy. Presurgical chemotherapy has been advocated for these patients because of putative improvement in event-free survival (EFS). The advantages of presurgical chemotherapy include early administration of systemic chemotherapy, shrinkage of primary tumor, and pathologic identification of risk groups. The theoretic disadvantage is that it exposes a large tumor burden to marginally effective chemotherapy. The contribution of chemotherapy and surgery timing has not been tested rigorously. PATIENTS AND METHODS: Between 1986 and 1993, we conducted a prospective trial in patients with nonmetastatic osteosarcoma who were assigned randomly to immediate surgery or presurgical chemotherapy. Except for the timing of surgery (week 0 or 10), patients received 44 weeks of identical combination chemotherapy that included high-dose methotrexate with leucovorin rescue, doxorubicin, cisplatin, bleomycin, cyclophosphamide, and dactinomycin. RESULTS: One hundred six patients were enrolled onto this study. Six were excluded from analysis. Of the remaining 100 patients, 45 were randomly assigned to immediate chemotherapy, and 55 were randomly assigned to immediate surgery. Sixty-seven patients remain disease-free. At 5 years, the projected EFS +/- SE is 65% +/- 6% (69% +/- 8% for immediate surgery and 61% +/- 8% for presurgical chemotherapy; P =.8). The treatment arms had similar incidence of limb salvage (55% for immediate surgery and 50% for presurgical chemotherapy). CONCLUSION: Chemotherapy was effective in both treatment groups. There was no advantage in EFS for patients given presurgical chemotherapy.