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Chapter 8 Pharmacogenomics and Hematologic Diseases 89

DRUG DEVELOPMENT of 70 known translocation partners. The resulting chimeric oncop-
roteins interact with another methyltransferase—DOT1-like histone
Optimizing the selection and dosage of medications is a principal H3K79 methyltransferase (DOT1L)—which then methylates lysin
goal of pharmacogenomics. Another important application is in drug 79 in the globular region of histone H3 (H3K79) at MLL target
development, which is evolving in parallel with improved insights genes, causing aberrant gene expression and leukemogenesis. Inhibi-
into the mechanisms by which medications exert their pharmaco- tion of DOT1L has emerged as an attractive concept for therapeutic
logic effects. Such improved insights into the mechanism(s) of drug intervention in MLL-R leukemias, and in vitro and animal studies
action in target cells can help elucidate mechanisms that confer have shown that the recently designed small molecular inhibitors of
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drug resistance (e.g., inactivation of thiopurines via NT5C2), and DOT1L selectively target MLL-R leukemia cells. A phase I trial
they will facilitate the development of strategies to further enhance (NCT01684150) for the clinical evaluation of the epidrug EPZ-5676
efficacy. This knowledge can be used as a basis to engineer drugs was initiated for patients older than 18 years with MLL-R leukemias,
that amplify treatment effects or bypass resistance mechanisms, and if this approach proves to be successful, it remains primed for
or both. testing in infants with MLL-R ALL.
Here we focus on examples to show how insights from pharma- A different approach focuses on targeting the class III receptor
cogenomic investigations have helped to develop novel strategies tyrosine kinase (RTK) FMS-like tyrosine kinase-3 (FLT3). Using
to further improve outcome in subgroups of children with ALL genome-wide gene expression analyses, the FLT3 wild-type gene was
who still have a poor outcome despite intensive treatment with identified as being overexpressed in MLL-R ALL. FLT3 inhibitors
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current multiagent risk-adapted therapies (so-called high-risk ALL have been shown to inhibit growth in cells that overexpress FLT3.
[HR-ALL]). Although excellent outcomes with 5-year event-free The COG AALL0631 trial investigates the combination of the FLT3
survival of higher than 85% can be achieved in childhood ALL inhibitor lestaurtinib given after induction therapy in combination
in more developed countries, ALL is still a leading cause of death with an intensive chemotherapy backbone in children with MLL-R
from disease in children older than 1 year, and treatment of children infant ALL, and this approach may also help to improve outcomes
with HR-ALL remains one of the greatest challenges in pediatric in this poor prognostic ALL subtype.
oncology. HR-ALL features include the resistance of leukemia cells
to steroids and multidrug therapy (clearance of leukemia blasts in
the peripheral blood, bone marrow, and sanctuary sites), and the Identification of Novel Therapies for
presence of certain genetic alterations in leukemia cells—for instance, “BCR–ABL1-like” ALL
mixed-lineage leukemia rearrangements (MLL-R), the BCR–ABL1
fusion gene (Ph-ALL), and the recently identified so-called In contrast to the prognostically favorable BCP-ALL subtypes
“Ph-like ALL.” 23,24 ETV6-RUNX1, TCF3-PBX1, and hyperdiploid ALL (which
The introduction of TKIs in the treatment of Ph-ALL has led to account for almost 50% of childhood ALL cases), BCP-ALL with
a significant improvement in outcome, as demonstrated by results the BCR–ABL1 (or Philadelphia [Ph]) fusion gene responds poorly
from the Children’s Oncology Group (COG) AALL0031 trial. The to conventional ALL therapy, and patients with Ph-ALL belong to
following sections focus on further examples of the development the HR-ALL group. Ph-ALL is rare in children (1–15 years, 4.2%),
of novel approaches to treat infants, children, and adolescents with but is more common in adolescents (16–20 years, 5.9%) and young
HR-ALL. adults (21–39 years, 22%); and this is a contributor to the overall
poor prognosis of adolescents and young adults (AYAs) with ALL.
In 2009, genome-wide trancriptome analyses identified a subtype
Identification of Novel Therapies for MLL-Rearranged of HR-BCP-ALL that has a gene expression profile similar to that of
Infant ALL Ph-ALL. 23,24 In contrast to Ph-ALL, leukemia cells in the identified
subtype did not harbor the BCR–ABL1 fusion gene; therefore this
Infants (age <1 year) with BCP-ALL have long been recognized to HR-ALL subtype has been named Ph-like ALL. Ph-like ALL is more
have very poor outcomes when treated with ALL standard therapy. common, but has the same age distribution pattern as Ph-ALL (i.e.,
The identification that transcriptome profiles separate infant ALL 1–15 years, 11.9%; 16–20 years, 20.6%; 21–39 years, 27.4%). It
from ALL and acute myeloid leukemia (AML), and that infant was speculated that genetic alterations that can influence tyrosine
ALL blast cells are highly sensitive to cytarabine in vitro, provided kinase signaling pathways similar to those downstream of BCR–
the rationale to establish an ALL/AML hybrid treatment concept. ABL1 might be involved in the pathogenesis of Ph-like ALL. Indeed,
Indeed, Interfant-99 hybrid therapy resulted in better, but still kinase-activating alterations (fusions, deletions, or point mutations)
poor, outcomes, and further improvements of infant ALL therapy were recently identified in a comprehensive analysis, which included
are needed. Of note, the pharmacokinetics of many conventional transcriptome, whole-genome, and whole-exome sequencing in 91%
antileukemia drugs differ between infants and older children, and of 154 patients with Ph-like ALL. 28
recently an intensive induction therapy concept (with intensive This large-scale investigation corroborated and extended previous
dosing of standard ALL medications) in the COG AALL0631 trial findings in Ph-like ALL and identified two major subgroups, distin-
had to be modified because of a high rate of fatal toxicities during guished by the type of cytokine receptor or kinase alterations. For
this treatment phase. Therefore, the unique drug metabolism profile example, 60% of adolescents with Ph-like ALL had rearrangements
in infants (i.e., developmental pharmacology) needs to be considered in the lymphoid signaling receptor gene CRLF2 (encoding cytokine
when planning future infant ALL trials and novel, less toxic therapies receptor-like factor 2) and concomitant mutations in JAK1 or JAK2
are needed. (which encode the Janus kinases [JAKs]). These rearrangements
About 80% of infants with ALL have rearrangements of the (e.g., the frequently observed PAX5–JAK2 fusion), when ectopically
MLL gene (MLL-R) at 11q23 and MLL translocations. Recently, expressed in cell lines, activated JAK-STAT signaling and conferred
next-generation sequencing approaches were used in a Pediatric cytokine-independent proliferation that can be suppressed by the
Cancer Genome Project investigation and identified that infant JAK2 inhibitor ruxolitinib in vitro. The second major subgroup
MLL-R ALL has one of the lowest frequencies of somatic mutations within the Ph-like ALL cohort was identified to have fusions that
of any as yet sequenced cancer, with a mean of 1.3 nonsilent muta- involve the nonreceptor Abelson-related (ABL)-class kinase genes
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tions. Wild-type MLL is a histone methyltransferase that targets (e.g., ABL1 and ABL2), as well as activated oncogenic signaling
lysine 4 on histone 3 (H3K4), and leukemias carrying MLL-R (i.e., pathways and cellular proliferation that is potentially inhibited by
BCP-ALL in infants and older age groups, and AML in adults) can be TKIs such as dasatinib. Other less frequently observed targetable
considered as prototypical cancers driven by dysregulated epigenetic alterations affect the NTRK3 gene, which encodes the neurotrophic
mechanisms. MLL rearrangements lead to the loss of the catalytic tyrosine kinase receptor type 3, and ETV6 (ets variant 6)–NTRK3
methyltransferase domain, with subsequent in-frame fusion to one fusions have been shown to respond to the ALK inhibitor crizotinib