New score predicting for prognosis in PML-RARA+, AML1-ETO+, or CBFBMYH11+ acute myeloid leukemia based on quantification of fusion transcripts

Abstract

To evaluate the prognostic significance of quantitative PML-RARA, AML1-ETO, and CBFB-MYH11 fusion transcript expression, real-time polymerase chain reaction was used to analyze bone marrow samples of 349 such patients at diagnosis and 522 samples of 142 patients also during therapy (total analyses, n ‫؍‬ 859; median number of follow-up samples, 4/patient; median duration of assessment, 12 months). Lower expression levels at diagnosis correlated with better overall and event-free survival in all 3 leukemia subtypes. By combining the median expression ratio after consolidation therapy and the 75th percentile of the expression ratio at diagnosis, a new score was established that separates a group with 100% EFS from a significantly worse group (P < .0001) in each of the 3 acute myeloid leukemia subgroups. Eight patients showed increasing levels of expression during follow-up and all had relapse. In conclusion, patients at high risk for treatment failure can be identified by high levels of fusion gene expression at diagnosis or less than 3 logs of tumor reduction during the first 3 to 4 months of therapy. By combining the transcription ratios at these 2 checkpoints, a new powerful prognostic score has been established. (Blood. 2003;102:2746-2755

Wilms’ Tumor Gene (WT1) Expression and Minimal Residual Disease in Acute Myeloid Leukemia

“…The most sensitive method for this strategy involves the detection of fusion genes derived from chromosome translocations, such as PML-RARa, AML-ETO1, and CBFb-MYH11 (24,25), and more recently gene mutations such as NPM1 (26,27). Besides, more than 50% of AML lack known genetic lesions or clonality markers suitable for MRD monitoring.…”

Interactive diagnostics in the indication to allogeneic SCT in AML

“…In the reciprocal gene fusions t(15;17)/PML-RARA, t(8;21)/RUNX1-RUNX1T1 and inv(16)/CBFB-MYH11, [3][4][5] quantitative real-time PCR achieves sensitivities of 10 À5 to 10 À6 123 and thus is suitable for quantification of the residual leukemic cell load at an early time point after therapy. 5 The score of the aberrant gene expression compared after consolidation therapy and at diagnosis was shown to be significantly associated with survival.…”

“…5 The score of the aberrant gene expression compared after consolidation therapy and at diagnosis was shown to be significantly associated with survival. 124 Persistence 52 or minor decrease of transcript copy numbers 5 predicts an enhanced relapse risk.…”

“…The panel of known genetic markers is still increasing, 2 and the impact of minimal residual disease (MRD) detection was realized for several AML subtypes. [3][4][5][6] Modern therapy concepts aim to restrict the risks of transplant-related morbidity and mortality and of reduced quality of life post transplant 7 for those patients with unfavorable outcomes after standard treatment. Thus, the indication to allogeneic SCT (allo-SCT) must now integrate the complete pattern of diagnostic results at diagnosis and during follow-up of AML.…”

“…5 The measurement of the residual cell load by multiparameter flow cytometry and qPCR allows a more sensitive estimation of persistent disease than cytomorphology and an earlier detection of relapse before the morphological manifestation. 3,4 Although previously molecular MRD diagnostics were available for some reciprocal rearrangements as the t(8;21)/RUNX1-RUNX1T1 only, qPCR is currently being established for a larger spectrum of molecular markers as the NPM1 mutations, [30][31][32] the FLT3 mutations [33][34][35] and the MLL-PTD, 36 aiming to provide MRD measurement also in normal karyotype cases.…”