Core binding factor (CBF) acute myeloid leukemia: is molecular monitoring by RT–PCR useful clinically?

Abstract

Clonal chromosomal abnormalities are the most important prognostic indicators in acute myeloid leukemia (AML). Two of the most prevalent cytogenetic subtypes of adult primary AML, t(8;21)(q22;q22) and inv(16)(p13q22)/t(16;16)(p13;q22), are characterized by disruption of the AML1(CBFA2, RUNX1) and CBFbeta genes, respectively, which encode subunits of core binding factor (CBF), a regulator of normal hematopoiesis. At the molecular level, t(8;21) and inv(16)/t(16;16) result in the creation of novel fusion genes, AML1/ETO and CBFbeta/MYH11, respectively, which encode fusion transcripts readily detectable by the reverse transcription-polymerase chain reaction (RT-PCR). Although the detection of t(8;21) or inv(16)/t(16;16) in adult patients with primary AML represents a favorable independent prognostic indicator for achievement of cure following intensive chemotherapy or stem cell transplantation, a substantial number of these patients (i.e. 40-50%) relapse and eventually die of their disease. Therefore, timely identification and therapeutic stratification of those patients deemed at high risk for disease relapse could ultimately result in a further improvement of clinical outcome within these cytogenetic subgroups of AML. As relapse is likely to occur as the result of failure of treatment to completely eradicate leukemic blasts, the detection of the AML1/ETO and CBFbeta/MYH11 fusion transcripts using sensitive RT-PCR assays has been utilized as a surrogate marker for resistant disease and, in turn, to predict disease recurrence during remission. The purpose of this paper is to review the applicability of this strategy to the clinical management of t(8;21) and inv(16)/t(16;16) primary AML, here collectively referred to as CBF AML.

Prognostic value of minimal residual disease (MRD) in acute myeloid leukemia (AML) with favorable cytogenetics [t(8;21) and inv(16)]

“…11,12,30,33,34 The presence of MRD has been associated with an increased risk of relapse in most clinical studies. [6][7][8][9][10][11][12][13][14][15][16][17][18] In our series we demonstrated that both FC and RQ-PCR may provide complementary information in the MRD follow-up of t (8,21) and inv(16) AML patients. Previous studies using multiparametric FC have shown the prognostic value of MRD identification after AML treatment.…”

“…Monitoring MRD by molecular or immunophenotypic methods seem to be of interest to define those patients with a high risk of relapse. [6][7][8][9][10][11][12][13][14][15][16][17][18] Molecular techniques based on the detection of gene-fusion products are restricted to AML with specific chromosomal rearrangements, whereas multiparametric flow cytometry (FC) may be applied to more than 80% of AML cases. Accordingly, MRD in AML with t(8;21) and inv(16) AML may be analyzed using both methods.…”

Survival is poorer in patients with secondary core‐binding factor acute myelogenous leukemia compared with de novo core‐binding factor leukemia

“…Because of the presence of unique transcripts, CBF AML is amenable to molecular monitoring of disease. 15-17 Multiple log reductions in fusion transcripts after induction and consolidation therapies are associated with better EFS. 16 Interventions designed to be implemented at times of molecular progression of disease or lack of optimal molecular response may improve outcome in patients with CBF AML, including secondary CBF AML.…”

Reanalysis of Cancer Drugs

“…The translocation (8;21)(q22;q22) and inversion or translocation of chromosome 16, which are commonly found in de novo AML, are associated with disruption of the core binding factor (CBF) transcription factor. These abnormalities define the CBF AML subtype, which is associated with the most favorable risk, including response to therapy (55). A Cancer and Leukemia Group B trial found higher overall survival with high-versus low-dose cytarabine therapy in CBF AML; complete response rates were about 90%, and overall survival was Ͼ50% at 5 years in these patients (56).…”