RESUMO
PURPOSE: To evaluate the prognostic value of minimal residual disease (MRD) in patients with acute myeloid leukemia (AML) with NPM1 mutation (NPM1(mut)). PATIENTS AND METHOD: RNA-based real-time quantitative polymerase chain reaction (RQ-PCR) specific for the detection of six different NPM1(mut) types was applied to 1,682 samples (bone marrow, n = 1,272; blood, n = 410) serially obtained from 245 intensively treated younger adult patients who were 16 to 60 years old. RESULTS: NPM1(mut) transcript levels as a continuous variable were significantly associated with prognosis after each treatment cycle. Achievement of RQ-PCR negativity after double induction therapy identified patients with a low cumulative incidence of relapse (CIR; 6.5% after 4 years) compared with RQ-PCR-positive patients (53.0%; P < .001); this translated into significant differences in overall survival (90% v 51%, respectively; P = .001). After completion of therapy, CIR was 15.7% in RQ-PCR-negative patients compared with 66.5% in RQ-PCR-positive patients (P < .001). Multivariable analyses after double induction and after completion of consolidation therapy revealed higher NPM1(mut) transcript levels as a significant factor for a higher risk of relapse and death. Serial post-treatment assessment of MRD allowed early detection of relapse in patients exceeding more than 200 NPM1(mut)/10(4) ABL copies. CONCLUSION: We defined clinically relevant time points for NPM1(mut) MRD assessment that allow for the identification of patients with AML who are at high risk of relapse. Monitoring of NPM1(mut) transcript levels should be incorporated in future clinical trials to guide therapeutic decisions.
Assuntos
Leucemia Mieloide Aguda/genética , Mutação , Neoplasia Residual/genética , Proteínas Nucleares/genética , Adolescente , Adulto , Áustria , Medula Óssea/metabolismo , Análise Mutacional de DNA , Feminino , Alemanha , Humanos , Leucemia Mieloide Aguda/terapia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Neoplasia Residual/terapia , Nucleofosmina , Prognóstico , Recidiva , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
BACKGROUND: High-dose methotrexate is the standard of care for patients with newly diagnosed primary CNS lymphoma. The role of whole brain radiotherapy is controversial because delayed neurotoxicity limits its acceptance as a standard of care. We aimed to investigate whether first-line chemotherapy based on high-dose methotrexate was non-inferior to the same chemotherapy regimen followed by whole brain radiotherapy for overall survival. METHODS: Immunocompetent patients with newly diagnosed primary CNS lymphoma were enrolled from 75 centres and treated between May, 2000, and May, 2009. Patients were allocated by computer-generated block randomisation to receive first-line chemotherapy based on high-dose methotrexate with or without subsequent whole brain radiotherapy, with stratification by age (<60 vs ≥60 years) and institution (Berlin vs Tübingen vs all other sites). The biostatistics centre assigned patients to treatment groups and informed local centres by fax; physicians and patients were not masked to treatment group after assignment. Patients enrolled between May, 2000, and August, 2006, received high-dose methotrexate (4 g/m(2)) on day 1 of six 14-day cycles; thereafter, patients received high-dose methotrexate plus ifosfamide (1·5 g/m(2)) on days 3-5 of six 14-day cycles. In those assigned to receive first-line chemotherapy followed by radiotherapy, whole brain radiotherapy was given to a total dose of 45 Gy, in 30 fractions of 1·5 Gy given daily on weekdays. Patients allocated to first-line chemotherapy without whole brain radiotherapy who had not achieved complete response were given high-dose cytarabine. The primary endpoint was overall survival, and analysis was per protocol. Our hypothesis was that the omission of whole brain radiotherapy does not compromise overall survival, with a non-inferiority margin of 0·9. This trial is registered with ClinicalTrials.gov, number NCT00153530. FINDINGS: 551 patients (median age 63 years, IQR 55-69) were enrolled and randomised, of whom 318 were treated per protocol. In the per-protocol population, median overall survival was 32·4 months (95% CI 25·8-39·0) in patients receiving whole brain radiotherapy (n=154), and 37·1 months (27·5-46·7) in those not receiving whole brain radiotherapy (n=164), hazard ratio 1·06 (95% CI 0·80-1·40; p=0·71). Thus our primary hypothesis was not proven. Median progression-free survival was 18·3 months (95% CI 11·6-25·0) in patients receiving whole brain radiotherapy, and 11·9 months (7·3-16·5; p=0·14) in those not receiving whole brain radiotherapy. Treatment-related neurotoxicity in patients with sustained complete response was more common in patients receiving whole brain radiotherapy (22/45, 49% by clinical assessment; 35/49, 71% by neuroradiology) than in those who did not (9/34, 26%; 16/35, 46%). INTERPRETATION: No significant difference in overall survival was recorded when whole brain radiotherapy was omitted from first-line chemotherapy in patients with newly diagnosed primary CNS lymphoma, but our primary hypothesis was not proven. The progression-free survival benefit afforded by whole brain radiotherapy has to be weighed against the increased risk of neurotoxicity in long-term survivors.
Assuntos
Antimetabólitos Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Neoplasias do Sistema Nervoso Central/radioterapia , Irradiação Craniana , Linfoma/tratamento farmacológico , Linfoma/radioterapia , Metotrexato/administração & dosagem , Idoso , Antimetabólitos Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias do Sistema Nervoso Central/mortalidade , Distribuição de Qui-Quadrado , Irradiação Craniana/efeitos adversos , Citarabina/administração & dosagem , Intervalo Livre de Doença , Fracionamento da Dose de Radiação , Feminino , Alemanha , Humanos , Ifosfamida/administração & dosagem , Estimativa de Kaplan-Meier , Linfoma/mortalidade , Masculino , Metotrexato/efeitos adversos , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Radioterapia Adjuvante , Medição de Risco , Fatores de Risco , Taxa de Sobrevida , Fatores de Tempo , Resultado do TratamentoRESUMO
Currently no standard treatment exists for patients with posttransplant lymphoproliferative disorders relapsed or refractory to chemotherapy after failure of reduction in immunosuppression. We have analyzed the effects of single-agent rituximab treatment in eight patients (seven adult, one pediatric) in this setting. Three patients had been salvaged with rituximab several times. In the seven adults, rituximab salvage therapy achieved complete remission (CR) in three patients (43%) and partial remission in one (14%). In the pediatric patient, a PR was obtained that could be reinduced on relapse with repeated administrations of rituximab. Patients achieving CR either remained in CR or were successfully salvaged again with single-agent rituximab. At a median follow-up of 69 months, median progression-free survival was 9 months and no relevant therapy-associated toxicity was observed. Single-agent rituximab salvage therapy is an effective treatment option in this setting of intensively pretreated patients, with virtually no therapy-associated toxicity.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Transtornos Linfoproliferativos/complicações , Transtornos Linfoproliferativos/tratamento farmacológico , Neoplasias/tratamento farmacológico , Adulto , Anticorpos Monoclonais Murinos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ciclofosfamida/administração & dosagem , Progressão da Doença , Intervalo Livre de Doença , Doxorrubicina/administração & dosagem , Humanos , Terapia de Imunossupressão , Transtornos Linfoproliferativos/etiologia , Neoplasias/mortalidade , Prednisona/administração & dosagem , Rituximab , Terapia de Salvação , Análise de Sobrevida , Sobreviventes , Falha de Tratamento , Resultado do Tratamento , Vincristina/administração & dosagemRESUMO
BACKGROUND: Gemcitabine and mitoxantrone are active agents for the treatment of metastatic breast cancer. Due to different modes of action and a favorable toxicity profile they are suitable for combination therapy. This phase I trial was initiated to determine the optimal doses for the combination in patients with metastatic breast cancer. Secondary objectives included the evaluation of the safety and efficacy of the regimen. PATIENTS AND METHODS: Patients with metastatic breast cancer were treated with gemcitabine (1000-1400 mg/m(2)) on days 1, 8 and 15 and mitoxantrone (10-14 mg/m(2)) on day 8. Treatment was repeated every 4 weeks for a maximum of 8 cycles. Doses were assigned at registration according to the escalation scheme. RESULTS: Twenty-six patients received a total of 93 cycles at 5 different dose levels. The maximum tolerated doses were 1200 mg/m(2) gemcitabine and 14 mg/m(2) mitoxantrone with grade 4 neutropenia being the dose limiting toxicity. Recommended phase II doses, however, are gemcitabine 1200 mg/m(2) and mitoxantrone 12 mg/m(2) based on a similar median dose intensity and a more favorable toxicity profile. Predominant toxicity was myelosuppression. Most common non-hematological toxicities were nausea, vomiting, alopecia and elevation of liver enzymes. Twenty-one patients were assessable for response. Four patients achieved a partial response accounting for an overall response rate of 19%. In addition, 12 patients (57%) had stable disease and 5 patients (24%) failed to response to the treatment. Median duration of response and duration of clinical benefit were 14 and 9 months, respectively. CONCLUSION: In this phase I study of gemcitabine and mitoxantrone, the DLT was neutropenia. Recommended phase II doses are gemcitabine 1200 mg/m(2) and mitoxantrone 12 mg/m(2).
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Adulto , Idoso , Antimetabólitos Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Esquema de Medicação , Feminino , Seguimentos , Humanos , Dose Máxima Tolerável , Pessoa de Meia-Idade , Mitoxantrona/administração & dosagem , Neutropenia/induzido quimicamente , GencitabinaRESUMO
Liposomal daunorubicin replacing conventional anthracyclines may reduce toxicity and enhance efficacy of chemotherapy. In this phase I study, we evaluated liposomal daunorubicin (DaunoXome) in combination with vincristine and dexamethasone for toxicity, pharmacokinetics and potential efficacy in patients with multiple myeloma. The main objective was to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of liposomal daunorubicin combined with vincristine and dexamethasone (VLDD). Additionally, pharmacokinetics were determined at higher dose levels. Seventeen multiple myeloma patients were enrolled in this trial; 76% of the patients had relapsed or refractory multiple myeloma. Successive cohorts received liposomal daunorubicin at doses of 40, 60, 80 and 100 mg/m2 on day 1 in combination with vincristine 1.4 mg/m2 (day 1) and oral dexamethasone (40 mg, days 1-4). DLT occurred at 100 mg/m2. Liposomal daunorubicin at 80 mg/m2 was well tolerated in this protocol and should be used for further phase II studies with the VLDD regimen. In this phase I trial, 64% of the patients achieved a partial remission or a minor response.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Daunorrubicina/efeitos adversos , Daunorrubicina/farmacocinética , Mieloma Múltiplo/tratamento farmacológico , Adulto , Idoso , Daunorrubicina/administração & dosagem , Dexametasona/administração & dosagem , Relação Dose-Resposta a Droga , Feminino , Humanos , Infusões Intravenosas , Lipossomos , Masculino , Pessoa de Meia-Idade , Vincristina/administração & dosagemRESUMO
We undertook a prospective study to evaluate the role of the combination of fludarabine and cyclophosphamide in patients with low-grade non-Hodgkin's lymphoma. Twenty-seven patients with low-grade non-Hodgkin's lymphoma were treated with i.v. fludarabine (30 mg/m ) and cyclophosphamide (250 mg/m ) on days 1-3. Cycles were given at 4-week intervals for a maximum of six courses. Fourteen patients (52%) were previously untreated, 13 patients (48%) had been treated with at least one chemotherapy regimen before. Of the 27 patients, 11 (41%) obtained a complete and 13 (48%) a partial remission, thus the overall response rate was 89%. The remission rate in untreated patients was slightly higher than in pretreated patients (93 versus 85%). The toxicity was mild, no treatment-related mortality occurred. Neutropenia was the most common side effect, grade 4 neutropenia of rather short duration was observed in less than 7% of the cycles. At the end of the treatment, the mean CD4 count was 155/ l and the mean CD8 count 204/ l. Severe infections did not occur. These results show that the combination of fludarabine and cyclophosphamide in the doses used in this study is an effective regimen with manageable toxicity in low-grade non-Hodgkin's lymphoma.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/toxicidade , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma não Hodgkin/tratamento farmacológico , Vidarabina/análogos & derivados , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Relação CD4-CD8 , Ciclofosfamida/administração & dosagem , Intervalo Livre de Doença , Humanos , Linfoma não Hodgkin/patologia , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Estudos Prospectivos , Indução de Remissão , Vidarabina/administração & dosagemRESUMO
The prospective multicenter NOA-03 trial, conducted by the Neuro-Oncology Working Group (NOA) of the German Cancer Society, was initiated to define the feasibility and efficacy of single-agent high-dose methotrexate therapy without concomitant radiotherapy in immunocompetent patients with primary central nervous system lymphoma. Thirty-seven patients (median age, 60 years) received 179 biweekly courses of 8 g/m2 methotrexate. Response was assessed after 3 and 6 courses. We had planned to enter 105 patients into the trial. Since fewer than the projected 18 of 37 patients achieved a complete response after an intermediate analysis, the trial was closed. In intention-to-treat analysis, 11 of 37 patients (29.7%) achieved complete response, whereas 14 of 37 patients (37.8%) were found to have progressive disease. The median relapse-free survival among complete response patients was 13.7 months. Multivariate logistic regression analysis revealed that corticosteroid application during the first methotrexate course was associated with complete response. The regimen was well tolerated, but, unlike previously reported results, the activity of high-dose methotrexate was only moderate.