RESUMEN
Imatinib is effective for the treatment of chronic myeloid leukemia (CML). However even undetectable BCR-ABL1 by Q-RT-PCR does not equate to eradication of the disease. Digital-PCR (dPCR), able to detect 1 BCR-ABL1 positive cell out of 10(7) , has been recently developed. The ISAV study is a multicentre trial aimed at validating dPCR to predict relapses after imatinib discontinuation in CML patients with undetectable Q-RT-PCR. CML patients under imatinib therapy since more than 2 years and with undetectable PCR for at least 18 months were eligible. Patients were monitored by standard Q-RT-PCR for 36 months. Patients losing molecular remission (two consecutive positive Q-RT-PCR with at least 1 BCR-ABL1/ABL1 value above 0.1%) resumed imatinib. The study enrolled 112 patients, with a median follow-up of 21.6 months. Fifty-two of the 108 evaluable patients (48.1%), relapsed; 73.1% relapsed in the first 9 months but 14 late relapses were observed between 10 and 22 months. Among the 56 not-relapsed patients, 40 (37.0% of total) regained Q-RT-PCR positivity but never lost MMR. dPCR results showed a significant negative predictive value ratio of 1.115 [95% CI: 1.013-1.227]. An inverse relationship between patients age and risk of relapse was evident: 95% of patients <45 years relapsed versus 42% in the class ≥45 to <65 years and 33% of patients ≥65 years [P(χ(2) ) < 0.0001]. Relapse rates ranged between 100% (<45 years, dPCR+) and 36% (>45 years, dPCR-). Imatinib can be safely discontinued in the setting of continued PCR negativity; age and dPCR results can predict relapse.
Asunto(s)
Proteínas de Fusión bcr-abl/metabolismo , Mesilato de Imatinib/administración & dosificación , Leucemia Mielógena Crónica BCR-ABL Positiva , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Adulto , Factores de Edad , Anciano , Femenino , Estudios de Seguimiento , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/epidemiología , Leucemia Mielógena Crónica BCR-ABL Positiva/metabolismo , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , RecurrenciaRESUMEN
OBJECTIVE: To determine the efficacy and toxicity of danusertib (formerly PHA-739358) administered i.v. over two different dosing schedules with equivalent dose intensity in patients with metastatic castration-resistant prostate cancer with progressive disease after docetaxel-based treatment. PATIENTS AND METHODS: In this open-label, multicentre phase II trial 88 patients were randomly assigned (1:1 ratio) to receive either danusertib 330 mg/m(2) over 6 h i.v. on days 1, 8 and 15 (arm A, n = 43) or 500 mg/m(2) over 24 h i.v. on days 1 and 15 (arm B, n = 38), every 4 weeks. The primary endpoint chosen for this exploratory study was PSA response rate at 3 months. RESULTS: Sixty patients (31/43 in arm A and 29/38 in arm B) were evaluable for the primary endpoint. Median progression-free survival was 12 weeks in both arms. PSA response occurred in one patient in each arm; best overall response was stable disease in eight (18.6%) and 13 (34.2%) patients in arms A and B, respectively. Eleven out of 81 (13.6%) treated patients had stable disease for ≥6 months. Danusertib was generally well tolerated; the most common grade 3 and 4 drug-related adverse event was neutropenia which occurred in 37.2% (arm A) and 15.8% (arm B) of the patients. CONCLUSION: Danusertib monotherapy shows minimal efficacy in patients with castration-resistant prostate cancer. Further studies are required to establish specific biomarkers predictive for either response or prolonged disease stabilization.