RESUMO
Early relapse detection in acute myeloid leukemia is possible using standardized real-time quantitative polymerase chain reaction (RQ-PCR) protocols. However, optimal sampling intervals have not been defined and are likely to vary according to the underlying molecular lesion. In 74 patients experiencing hematologic relapse and harboring aberrations amenable to RQ-PCR (mutated NPM1 [designated NPM1c], PML-RARA, RUNX1-RUNX1T1, and CBFB-MYH11), we observed strikingly different relapse kinetics. The median doubling time of the CBFB-MYH11 leukemic clone was significantly longer (36 days) than that of clones harboring other markers (RUNX1-RUNX1T1, 14 days; PML-RARA, 12 days; and NPM1c, 11 days; P < .001). Furthermore, we used a mathematical model to determine frequency of relapse detection and median time from detection of minimal residual disease to hematologic relapse as a function of sampling interval length. For example, to obtain a relapse detection fraction of 90% and a median time of 60 days, blood sampling every sixth month should be performed for CBFB-MYH11 leukemias. By contrast, in NPM1c(+)/FLT3-ITD(-), NPM1c(+)/FLT3-ITD(+), RUNX1-RUNX1T1, and PML-RARA leukemias, bone marrow sampling is necessary every sixth, fourth, and fourth and second month, respectively. These data carry important implications for the development of optimal RQ-PCR monitoring schedules suitable for evaluation of minimal residual disease-directed therapies in future clinical trials.
Assuntos
Biomarcadores Tumorais/biossíntese , Subunidade alfa 2 de Fator de Ligação ao Core/biossíntese , Subunidade beta de Fator de Ligação ao Core/biossíntese , Regulação Leucêmica da Expressão Gênica , Leucemia Mieloide Aguda/metabolismo , Cadeias Pesadas de Miosina/biossíntese , Proteínas Nucleares/biossíntese , Proteínas de Fusão Oncogênica/biossíntese , Biomarcadores Tumorais/genética , Medula Óssea/metabolismo , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Subunidade beta de Fator de Ligação ao Core/genética , Feminino , Humanos , Cinética , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Masculino , Monitorização Fisiológica/métodos , Cadeias Pesadas de Miosina/genética , Neoplasia Residual , Proteínas Nucleares/genética , Nucleofosmina , Proteínas de Fusão Oncogênica/genética , Proteína 1 Parceira de Translocação de RUNX1 , Recidiva , Estudos Retrospectivos , Fatores de TempoRESUMO
We hypothesized that Wilms tumour 1 gene (WT1) expression levels in acute myeloid leukaemia (AML) patients might have predictive value and reveal molecular relapse kinetics. WT1 level was determined at diagnosis, during therapy and post-therapy follow-up in 89 patients who reached first complete remission (CR1) (952 samples, median 8 samples/patient, range 2-38). CR1 bone marrow (BM) WT1 level above normal (based on 39 healthy donors) was an independent adverse prognostic factor regarding both disease-free survival [hazard ratio (HR) 4.46, P = 0.001] and overall survival (HR 2.62, P = 0.019). By grouping 34 BM and 99 peripheral blood (PB) complete remission samples in monthly intervals prior to clinical relapse, disease development was delineated and a simple mathematical model constructed, that allowed for the prediction of relapse detection rates (RDRs) as well as median times [t(m)s] from WT1 positivity to clinical relapse. BM sampling was required to obtain RDRs above 93% and t(m)s above 67 d. Acceptable RDRs and t(m)s (81% and 44 d, respectively) could be acquired by bimonthly PB sampling. In conclusion, CR1 WT1 expression is an independent prognostic factor in AML. According to our model, BM is superior for relapse prediction, but PB samples are useful when shorter sampling intervals are possible.