Risk assessment by monitoring expression levels of partial tandem duplications in the MLL gene in acute myeloid leukemia during therapy

Abstract

Background and objectives: A partial tandem duplication within the MLL-gene (MLL-PTD) can be found in 8% of all patients with karyotypically normal acute myeloid leukemia (AML), a group in which polymerase chain reaction-(PCR) based minimal residual disease analysis has not, so far, been possible.

Design and methods: A sensitive real-time PCR assay to quantify MLL-PTD transcripts was established and expression ratios assessed in diagnostic and follow-up samples. The prognostic significance of MLL-PTD expression levels was evaluated in 145 MLL-PTD positive patients at diagnosis and in 44 patients during and after treatment.

Results: Paired samples from 16 patients evaluated at diagnosis and relapse for the presence of the MLL-PTD were analyzed in parallel and all samples were positive at both time points. Overall, 173 samples from 44 patients were analyzed during follow-up (median sample number: 4/patient (range 2-17)). Nineteen patients were evaluable for MRD within the first 2 months, 15 patients within 4 months, and 19 patients within 6 months after the start of therapy. A >or= 2 log reduction of MLL-PTD expression in comparison to < 2 log reduction within 2, 4, and 6 months after start of therapy was found to be significantly associated with longer overall survival (p=0.029, p=0.007, and p=0.022, respectively). A molecular relapse was detected in 2 cases, in each case preceeding clinical manifestation by 35 days.

Interpretation and conclusions: These data suggest that MLL-PTD is a stable marker and can be used as a prognostically important marker of MRD in patients with karyotypically normal AML.