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Chapter 8 Pharmacogenomics and Hematologic Diseases 87

toxicity; this association was robustly confirmed with five different P-loop of the ABL1 kinase, obstructing the ponatinib binding site,
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MTX treatment regimens in more than 1000 pediatric ALL patients. resulting in resistance to ponatinib. Moreover, it was found that
Deep sequencing of SLCO1B1 identified additional rare (minor allele additional acquisition of an E255V variant in T315I-positive CML
frequency of <1%) “damaging” nsSNPs that had larger effect sizes confers resistance to ponatinib. 19
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than the common “damaging” nsSNPs. SLCO1B1, however, is As second- and third-generation TKIs have a risk for VAEs,
associated with hepatobiliary excretion, which is a relatively minor especially in older patients with preexisting vascular disease, TKI
path for MTX elimination (<30%). Therefore, the overall contribu- selection based on cardiovascular risk factors and mutational BCR–
tion of SLCOB1B variants to explaining interindividual variability ABL1 status is of utmost importance to guide CML therapy. Upfront
in MTX pharmacokinetics is approximately 12% to 15%, and the and repeated monitoring of the mutational status of patients with
major genetic contributors remain largely unknown. BCR–ABL1-positive leukemias can help select appropriate TKIs and
tailor TKI treatment, and also has the potential to provide new
insights into mechanisms underlying selection of resistant clones
GENETIC VARIATIONS INFLUENCING DRUG TARGETS during TKI therapy.

To exert their pharmacologic effects most drugs interact with specific
target proteins, such as receptors, enzymes, or proteins involved ADVERSE DRUG EFFECTS PRESENTING AS
in signal transduction, cell cycle control, or other cellular events. HEMATOLOGIC DISORDERS
Molecular studies have revealed that many of the genes encoding
these drug targets exhibit genetic variations, which can alter the Adverse drug reactions (ADRs) constitute a major clinical problem,
sensitivity of these targets to specific medications (e.g., VKORC1 and strong evidence indicates that ADRs account for approximately
and warfarin effects). 5% of all hospital admissions and increase the length of hospitaliza-
The following section illustrates this, focusing on somatic genetic tion by approximately 2 days. Although the factors that determine
variants in chronic myeloid leukemia (CML) cells that alter the susceptibility to ADRs are unclear in most cases, there is increasing
targets of tyrosine kinase inhibitors (TKIs). interest in the role of genetic predisposition to these ADRs; the
possibility of a genetic test to identify patients at risk for rare but
serious adverse effects would be of great clinical value. Based on the
BCR–ABL1 and Tyrosine Kinase Inhibitors clinical relevance of ADRs, the FDA has provided advice on the use
of certain biomarkers (e.g., variants in TPMT, UGT1A1, CYP2C9,
Somatic genome variants caused by major structural variants, such CYP2C19) to avoid serious adverse drug effects; a full list of these
as the t(9;22) chromosomal translocation producing the BCR–ABL1 biomarkers is available on the FDA website (see Table 8.1).
fusion gene, are major mechanisms underlying many forms of CPIC recommendations on medications whose adverse effects
hematopoietic malignancies. The increased tyrosine kinase activity have been associated with variability in candidate genes and manifest
of the BCR–ABL1 protein (encoded by the chimeric BCR–ABL1 predominantly as hematologic abnormalities are listed in Table 8.2.
or “Philadelphia [Ph] chromosome”) is the driving oncogenic event In the following section, we provide information on genetic vari-
in the majority of patients with CML and in a subset of patients ants in G6PD that can cause acute hemolytic anemia (AHA) after
with ALL (Ph-ALL). This realization resulted in the development administration of certain drugs.
of specific TKIs. The treatment of CML was revolutionized with
the introduction of the first TKI imatinib, a small-molecular-weight
drug that binds to ABL1, thereby leading to inhibition of tyrosine Glucose-6-Phosphate Dehydrogenase Deficiency
phosphorylation of proteins involved in signal transduction. Ima- and Rasburicase
tinib was shown to induce durable remissions in CML patients,
which led to a paradigm shift in cancer treatment—that is, a more Occurrence of AHA after mass administration of the antimalaria
targeted therapy instead of the nonspecific inhibition of rapidly drug primaquine (PQ) was first documented in some U.S. soldiers in
dividing cells. Korea. The so-called “PQ sensitivity syndrome” was more common
Although most patients with CML have a favorable outcome among African Americans, and clinically identical to “favism” (i.e.,
when treated with imatinib, some patients eventually fail on therapy, AHA after ingestion of fava beans). The underlying biochemical (Fig.
mainly as a result of acquired point mutations in the target kinase 8.3) and genetic (variants in G6PD) causes of the clinical phenotype
ABL1 that induce drug resistance. Of note, the second-generation (i.e., AHA after PQ and fava beans) were identified, and the disease
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TKIs nilotinib and dasatinib can successfully inhibit the majority of was named G6PD deficiency. The severity of AHA in individuals
these mutation proteins that confer resistance to imatinib. However, with G6PD deficiency after treatment with drugs that induce oxida-
one relatively common variant, the T315I or “gatekeeper” variant, tive stress is influenced by host and environmental factors (Fig. 8.3).
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confers resistance to all three drugs. To overcome the resistance The G6PD gene is localized on Xq28, and currently more than
mechanisms of the T315I variant, ponatinib, which has activity 180 genetic variants have been identified, most of which are mis-
against all known single amino acid ABL1 mutations including sense mutations resulting in single-amino acid substitutions, thereby
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T315I, was designed and successfully tested in clinical trials, and affecting G6PD stability. Complete loss of G6PD is lethal; the
its use was first approved by the FDA in 2012 for patients with very rare, more complex variants, for instance, in-frame deletions
CML resistant to other TKIs. However, ponatinib was temporarily in exon 10, which affect important regions within the enzyme-like
suspended in 2013 due to serious vascular adverse events (VAEs; the substrate binding site, can cause severe transfusion-dependent
i.e., arterial and venous thromboembolic events, arterial hyperten- chronic nonspherocytic hemolytic anemia (CNSHA). Variants have
sion), and VAEs are now recognized as also limiting the use of been divided into five classes based on enzyme activity in red blood
second-generation TKIs. Moreover, the strong selective pressure cells (RBCs) and clinical presentation: class I (CNSHA, activity
of ponatinib has led to the emergence of TKI resistance due to <10%), class II (no CNSHA, activity <10%), class III (no CNSHA,
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so-called “compound mutations” in ABL1. Compound mutations >10% to 60%), class IV (normal activity; variants G6PD B and
are multiple-point variants occurring in the same BCR–ABL1 allele, G6PD A); class V (higher activity). It is estimated that about 5% of
and this drug-resistance mechanism is different to the emergence of the world’s population have G6PD deficiency, and almost all of these
multiple clones with different mutations. In a recent investigation, individuals have class II or III variants. 21
computed modeling and in vitro proliferation studies were used Drugs that have the potential to cause oxidative stress in
to analyze the impact of compound mutations in BCR–ABL1 on erythrocytes, which results in AHA in G6PD-deficient patients,
TKI resistance. Molecular dynamic simulations showed, for instance, have been recently classified into two groups: (1) predictable hemo-
that the compound mutation Y253H/E255V induced a shift in the lysis (i.e., AHA can be expected in a G6PD-deficient patient after