Feng, Xiaodong_ Xie, Hong-Guang - Applying pharmacogenomics in therapeutics-CRC Press (2016)

Clinical Applications of Pharmacogenomics in Cancer Therapy
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glucuronidation, prolonged SN-38 half-life, increased exposure to SN-38 (AUC), and
late-onset diarrhea. UGT1A1 expression is highly variable. Clinical evidence indicates
that the steady-state concentrations of SN-38 may vary by up to 50-fold between
UGT1A1*28 homozygous and heterozygous groups. Patients have a five- to ninefold
greater risk of grade 4 leukopenia with the standard dosage of irinotecan. 46–48
The US FDA recommends dose reduction in patients homozygous for the
UGT1A1*28 allele, and some studies recommend 20% dose reduction for patients
homozygous for UGT1A1*28. Caution and possible dose reduction are advised for
patients with heterozygous UGT1A1*28 allele (Table 6.2). 25,26,46,47
Nilotinib is indicated for the treatment of chronic myeloid leukemia (CML)
(Ph +). Nilotinib is an inhibitor of the Bcr-Abl kinase that binds to and stabilizes the
inactive conformation of the kinase domain of the Abl protein. It is also an inhibitor
of UGT1A1 in vitro, and individuals with the UGT1A1*28 (TA) 7 /(TA) 7 are at an
increased risk of hyperbilirubinemia when taking nilotinib compared to those with
the (TA) 6 /(TA) 6 or (TA) 6 /(TA) 7 genotypes. The largest increases in bilirubin were
observed in the UGT1A1*28 (TA) 7 /(TA) 7 patients. (TA) 7 /(TA) 7 polymorphism occurs
at up to 42% in individuals with African or South Asian ancestry. 27,49
The mechanism by which hyperbilirubinemia occurs with both nilotinib and
UGT1A1(TA) 7 /(TA) 7 is still unclear. Hypothetically, nilotinib inhibits UGT1A1
activity, which includes the glucuronidation of bilirubin. The already sensitized
(TA) 7 /(TA) 7 genotype will further push patients into a hyperbilirubinemia state. The
US FDA recommends, but does not require, genetic testing for UGT1A1 variants
prior to initiating or reinitiating treatment with nilotinib. 27,48,49
PATIENT CASE 2
KC is a 13-year-old boy who was diagnosed with ALL. He has finished his induction
and consolidation therapies and will need to move on to his maintenance therapy.
Question: Knowing that the maintenance portion of his therapy requires mercaptopurine
(6-MP), what should be considered for KC?
Answer: TPMT genetic testing should be considered. If KC is a PM of TPMT, a
reduction of 6-MP dose should be warranted in order to reduce side effects. 6-MP
toxicity may include drug fever, hyperpigmentation, myelosuppression (anemia,
thrombocytopenia, and neutropenia).
TPMT Polymorphisms and 6-MP
6-MP is extensively used in the maintenance chemotherapy for ALL in children.
TPMT is responsible for the S-methylation of 6-MP to 6-methylmercaptopurine,
which diverts the prodrug 6-MP from converting to 6-thioguanine for its incorporation
into DNA and suppresses tumor DNA synthesis. 6-Thioguanine is the active
metabolite of 6-MP that affects drug efficacy and toxicity.
Most large-scale PGx studies indicate that TPMT activity is highly variable and
polymorphic. Approximately 90% of individuals have high activity (EMs), 10% have
intermediate activity (IMs), and 0.3% have low activity or complete deficiency of