329American Society of Clinical Oncology and the National Comprehensive Cancer
Network recommend testing for the FLT3 mutation, and determination of FLT3
status as a standard of care for patients diagnosed with AML.
Activating internal tandem duplication (ITD) mutations in FLT3 (FLT3-ITD) are
associated with a poor prognosis. Scientifi c evidence including the lack of convinc-
ing clinical activity of early FLT3 inhibitors suggests that FLT3-ITD probably rep-
resents a passenger lesion. Point mutations have been reported at three residues
within the kinase domain of FLT3-ITD that confer substantial in vitro resistance in
AML patients to AC220 (quizartinib), an active investigational inhibitor of FLT3
(Smith et al. 2012 ). These fi ndings demonstrate that FLT3-ITD can represent a
driver lesion and valid therapeutic target in human AML. AC220-resistant FLT3
kinase domain mutants represent high-value targets for future FLT3 inhibitor devel-
opment efforts.
Risk stratifi cation in AML is currently based on pretreatment characteristics. It
remains to be established whether relapse risk can be better predicted through
assessment of minimal residual disease (MRD). One proposed marker is the Wilms
tumor gene WT1, which is overexpressed in most patients with AML, thus provid-
ing a putative target for immunotherapy. An international collaborative study coor-
dinated by the European Leukemia Network (ELN) consortium on standardization
of WT1 testing for risk stratifi cation in AML has been published (Cilloni et al.
2009 ). The objective of this study was to select the best-performing WT1 assay and
to assess the value of WT1 monitoring during AML treatment to estimate the risk of
relapse. Results of the study show that the high performance WT1 assay designed
by the ELN group is adapted to MRD assessment. This specifi c assay developed and
validated in the context of this study, WT1 Profi leQuant ® (QIAGEN Marseille) is
CE marked and can be used with most RQ-PCR instruments. Application of a stan-
dardized WT1 assay provides independent prognostic information in AML, lending
support to incorporation of early assessment of MRD to develop more robust risk
scores, to enhance risk stratifi cation, and to identify patients who may benefi t from
allogeneic transplantation.
Cytarabine (ara-C) is the most effective agent for the treatment of childhood
AML but aberrant expression of enzymes involved in the transport/metabolism of
ara-C could explain drug resistance. Human equilibrative nucleoside transporter-1
(hENT1) mRNA expression and ara-C sensitivity have been correlated with three-
fold lower hENT1 mRNA levels in resistant patients. Thus decreased expression of
hENT1, which transports ara-C across the cell membrane, is a major factor in ara-C
resistance in childhood AML. In 2011, Clavis Pharma received a Norwegian gov-
ernment grant to develop a fl ow cytometry method for the detection and quantifi ca-
tion of human hENT1 in patients suffering from AML, which will enable the
selection of the sub-population of AML patients who are likely to benefi t most from
treatment with the novel anticancer drug elacytarabine.
Because response of AML patient to cytarabine-based standard-of-care treat-
ment is variable, stratifi cation into subgroups by biomarker-predicted response may
lead to improved clinical outcomes. Cell mitochondrial depolarization to proapop-
totic signaling BH3-only peptides has been assessed as a surrogate for the function
Personalized Management of Cancers of Various Organs