The quality of molecular response to chemotherapy is predictive for the outcome of AML1-ETO-positive AML and is independent of pretreatment risk factors

Abstract

The outcome of 45 AML1-ETO-positive acute myeloid leukemia (AML) patients was analyzed with special emphasis on the quality of molecular response to therapy. Patients received double induction therapy, either 6-thioguanine, cytarabine, and daunorubicin (TAD9)/high-dose cytosine arabinoside plus mitoxantrone (HAM) or HAM/HAM, followed by consolidation therapy (TAD9) according to the AML-Cooperative group 92 trial (AMLCG92) and AML-Cooperative group 99 trial (AMLCG99). All cases underwent cytomorphological, cytogenetical and molecular genetic analyses. AML1-ETO transcript levels were quantitatively assessed at diagnosis and during follow-up by real-time reverse transcriptase-polymerase chain reaction (RT-PCR). The median reduction of initial AML1-ETO expression level was 4 log (range 0-5) after both induction and consolidation therapies. The quality of molecular response after induction as well as consolidation therapies had significant impact on the cumulative incidence of relapse (P ¼ 0.021 and P ¼ 0.001, respectively), event free survival (EFS: P ¼ 0.001 and P ¼ 0.001, respectively) and overall survival (OS: P ¼ 0.013 and P ¼ 0.014, respectively). HAM/HAM improved the molecular response to induction therapy (P ¼ 0.042) but after consolidation, no differences in molecular response were detectable between TAD9/HAM and HAM/HAM. Patient-or disease-related factors had no impact on the molecular response to induction or consolidation therapy. The current study demonstrates that quantification of AML1-ETO transcript levels is a powerful tool for prediction of prognosis that is independent of pretreatment risk factors, and may be helpful for directing therapeutic decisions in the future.

Prognostic factors for acute myeloid leukaemia in adults - biological significance and clinical use

“…This did not translate into different survival, probably because patients in CR with <3-log reduction after the first consolidation therapy proceeded to allogeneic HSCT instead of two further HD-AraC consolidation cycles. Previous studies demonstrated a negative prognostic impact on survival of increased MRD levels after induction and after consolidation therapy (Krauter et al, 2003;Schnittger et al, 2003;Weisser et al, 2007) or persistence or reocurrence of positive MRD level after end of therapy (Yin et al, 2012) for patients with CBF leukaemias.…”

MRD-directed risk stratification treatment may improve outcomes of t(8;21) AML in the first complete remission: results from the AML05 multicenter trial

“…Several small, retrospective cohort studies have suggested that monitoring MRD using real-time quantitative reverse transcriptasepolymerase chain reaction (RQ-PCR) may identify patients at high risk for relapse. [19][20][21][22][23][24] Two studies found that a reduction in MRD (RUNX1/RUNX1T1 transcript levels) of ,3 logs compared with pretreatment levels was a significant predictor of relapse after 2 courses of consolidation or within 3 to 4 months after achieving complete remission (CR). 19,21 Because HSCT exhibits the strongest anti-leukemia effects, we hypothesize that HSCT can decrease the relapse rate and improve the outcomes of patients with t(8;21) AML who are classified as high risk according to their MRD status.…”

Minimal residual disease levels assessed by NPM1 mutation–specific RQ-PCR provide important prognostic information in AML

“…[1][2][3][4] Common targets for polymerase chain reaction (PCR)-based MRD detection are mainly fusion transcripts, eg, RUNX1-RUNX1T1 (previously AML1-ETO), CBFB-MYH11, PML-RARA, and MLL-gene fusions. [1][2][3][4][5][6][7][8] Because fusion genes are present in only approximately 25% of AML, further markers like MLL-PTD, FLT3-LM, 7,9 and ectopic expression of WT1 and EVI1 have recently been established as additional sensitive and valuable targets. [10][11][12] Our potential to further expand the number of patients with AML that may benefit from analysis of MRD is closely dependent upon the availability of new molecular markers that allow us to identify new leukemia entities in the context of the poorly characterized group of AML with normal karyotype (NK; 40%-50% of cases in multicenter studies).…”