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Blood, 1 October 2002, Vol. 100, No. 7, pp. 2277-2277
Murky waters for MRD detection in AML: flighty
FLT3/ITDs
A guiding principle in the application of MRD
monitoring in leukemia has been that the mutant genes present at
diagnosis and causally implicated in disease pathogenesis will be
harbingers of molecular relapse. This principle has been
thoroughly validated, for example, in the context of
BCR/ABL in CML. But 2 articles in this issue
indicate that FLT3/ITD may not be a suitable marker for MRD
in a subset of AML patients. Shih et al (page 2387) and Kottaridis et
al (page 2393) report the fascinating observation that some
FLT3/ITD-positive patients at diagnosis do not have detectable FLT3/ITDs at relapse, and the converse may also
be true. Furthermore, a cohort of patients had several
FLT3/ITD variants detectable at diagnosis, with
selection for one of the variants at time of relapse. These observations have several important implications. First, use of
FLT3/ITD for MRD detection must be employed with caution and
will not be of value in detecting molecular relapse in all AML patients
that are FLT3/ITD positive at diagnosis. Second, the data
indicate that FLT3/ITD is probably a secondary event in
clonal evolution of at least some AML. Viewed from another perspective,
these data provide further support for 2-hit pathogenesis of AML in
which activating mutations in FLT3 confer a proliferative and/or survival benefit to leukemia clones. Third, the data raise the
question of whether FLT3/ITD inhibition using small molecule inhibitors, analogous to imatinib, will be an effective therapy for AML or will simply select for a parent clone with an alternative second mutation that confers a proliferative signal. Indeed, one patient with FLT3/ITD at diagnosis had "substituted" a
clone with an activating mutation in RAS for the
FLT3/ITD. It seems likely (and comes as no surprise given
the more modest response rates to imatinib for CML blast crisis) that
FLT3/ITD inhibitors will need to be combined with other
agents for effective therapy of AML. Finally, FLT3,
RAS, and KIT may each be activated by
mutation in AML and confer proliferative and survival signals, but
collectively account for perhaps one-half of all AML cases. In
those cases in which FLT3, RAS, or KIT
are not mutant, it seems likely that other mutations must confer a
proliferative signal to cells. Identification of these genes will be
important in the future, as they may also be targets for small molecule inhibition.
 D. Gary Gilliland
Harvard Medical
School
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