Acute Leukemias - Republican Scientific Medical Library

a References 71
The ability of immunophenotyping, using 4-color
FACS technology, to identify a leukemia-associated phenotype
(LAP) has significantly increased the sensitivity
of MRD detection in patients with AML. An Italian
study by Buccisano and colleague [144] used this technique
to evaluate MRD at two time points, at the end
of induction and following consolidation, in a total of
92 patients. The threshold discriminating MRD- from
MRD+ cases was set at 3.5´ 10(–4) residual leukemic
cells. The results showed that the MRD status at the
end of consolidation was the most significant predictor
of outcome with 5-year actuarial probability of RFS and
OS at 5 years of 71% and 64%, respectively, for MRD–
patients, compared to 13% and 16%, respectively, for
those in the MRD+ patients. Interestingly, the majority
of patients with MRD+ status at the end of consolidation
relapsed following autologous HSCT.
Controversy exists as to the prognostic significance
of FMS-like receptor tyrosine kinase (FLT3) mutations.
Although the exact mechanism by which FLT3 mutation
exerts increased relapse risk remains to be defined, it
appears to relate to an increased regrowth potential
caused by a cytokine-independent phenotype rather
than resistance to conventional chemotherapy, making
it another possible therapeutic target. Recent data from
Del Poeta and colleagues [145] suggest that the bax/bcl-2
ratio is a predictor of both OS and time to relapse. However,
the value of this index in risk stratifying AML patients
remains to be defined. In patients with APL, more
sensitive techniques such as RT-PCR to detect PML-
RARa transcript, especially when rises in transcript
quantity are seen serially, correlate with increased probability
of hematological relapse [110] and such data are
now used to identify patients who require early salvage
therapy with arsenic trioxide and subsequent HSCT. All
these approaches are of value in detecting patients at a
high risk of relapse in whom early intervention could be
justified.
4.8 Summary
The treatment of patients with relapsed or refractory
AML is generally disappointing and remains a major
challenge. Depending on a number of prognostic factors,
particularly the duration of CR1, many patients
can achieve a CR2 with salvage chemotherapy. However,
most of such patients are unlikely to be cured without
some form of allogeneic HSCT. Many new antileukemic
agents with a variety of novel mechanisms of action are
now available and are undergoing rigorous study in the
context of clinical trials as single agents and in combination
with chemotherapy. Many of these new agents
are directed towards specific genetic mutations, which
may perturb specific signal transduction pathways upon
which leukemia cells depend for growth and proliferation.
New transplant strategies hold promise to provide
more patients with the potentially potent GVL effect.
Future directions include the identification of more sensitive
prognostic factors, the development of therapy, directed
at specific molecular targets based on the biology
of the specific subtype of AML, the identification of
more sophisticated and sensitive methods to detect
MRD, the exploitation of GVL with RIC allo-HSCT
and alternative donors. Gene expression profiling will
likely facilitate the identification and classification of
specific genetic subtypes of AML and direct future therapy
[146].
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