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are much lower than the standard regimen. Physicians at St. Jude’s Children’s
Hospital (Memphis, TN) and at the Mayo Clinic (Rochester, MN) are prescreening
patients to determine if they have functional or nonfunctional enzyme thiopurine
methyl transferase (TPMT). The dosage of the components in the chemotherapeutic
cocktail are then tailored precisely to the patient’s molecular makeup − personalized
prescribing. TPMT genotype also has a substantial impact on minimal residual dis-
ease (MRD) after administration of mercaptopurine in the early course of childhood
ALL, most likely through modulation of mercaptopurine dose intensity. These fi nd-
ings support a role for MRD analyses in the assessment of genotype-phenotype
associations in multiagent chemotherapeutic trials. Investigators at St. Jude
Children’s Research Hospital have also developed a relatively simple and inexpen-
sive test that identifi es children with ALL who have responded well enough to their
fi rst round of chemotherapy that they might be successfully treated with a much less
aggressive follow-up treatment.
Genetic variation in the enzymes of the folic acid cycle, one-carbon transfer,
immune surveillance, drug metabolism and transport may determine some of the
variability in treatment response of ALL patients. Despite recent advances in this
area, further work is needed to develop clinically useful genetic predictors of leuke-
mia treatment response (Cunningham and Aplenc 2007 ).
Risk factors for CNS relapse in childhood ALL included the genetic abnormality
t(1;19)(TCF3-PBX1), any CNS involvement at diagnosis, and T-cell immunophe-
notype. At St. Jude Children’s Hospital, personalized therapy is applied based on
molecular genetics of ALL, pharmacogenetic traits of patients and pharmacody-
namic principles. The activity of drug-metabolizing enzymes of each patient is
determined prospectively and the dosage of chemotherapy is adjusted accordingly.
It was demonstrated that with effective risk-adjusted personalized chemotherapy,
prophylactic cranial irradiation can be safely omitted from the treatment of child-
hood ALL (Pui et al. 2009 ). This chemotherapy approach produced a projected cure
rate of 90 % for all the patients, which is the best treatment result reported to date.
Personalized Management of Acute Myeloid Leukemia
Two molecular tests for acute myeloid leukemia (AML) from Genzyme Diagnostics
are relevant to personalized management: FLT3 Mutation Analysis and WT1
RQ-PCR. FLT3 mutations are considered a prognostic indicator of poor survival
and response to standard chemotherapies. Approximately 30 % of patients with
AML have FLT3 mutations. WT1 RQ-PCR test is designed to detect MRD or very
low levels of disease. The WT1 gene is expressed in approximately 90 % of patients
with AML. This test allows physicians to monitor AML patients for early relapse
during and following therapy. Both of these tests may enable oncologists to better
manage their patients. Laboratory for Personalized Molecular Medicine is develop-
ing a companion diagnostic for the identifi cation of FLT3-positive AML patients
for treatment with Novartis’ midostaurin, or PKC412, a targeted small molecule
inhibitor of FLT3 tyrosine kinase, which is currently in phase III clinical trials.
10 Personalized Therapy of Cancer