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


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.


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.
Weisser
Martin
M
Laboratory for Leukemia Diagnostics, Medical Department III, Klinikum Grosshadern, Ludwig-Maximilians-University, Munich, Germany. martin.weisser@med.uni-muenchen.de
Kern
Wolfgang
W
Schoch
Claudia
C
Hiddemann
Wolfgang
W
Haferlach
Torsten
T
Schnittger
Susanne
S
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor; D020440:Gene Duplication; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D007621:Karyotyping; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis* / Q000235:genetics* / Q000628:therapy; D008875:Middle Aged; D051788:Myeloid-Lymphoid Leukemia Protein / Q000096:biosynthesis / Q000235:genetics*; D011379:Prognosis; D012008:Recurrence; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018570:Risk Assessment; D013997:Time Factors
D014408:Biomarkers, Tumor; C497422:KMT2A protein, human; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase