Acute Leukemias - Republican Scientific Medical Library

a 19.3 · Getting to Know Chemotherapy: The Role of Pharmacogenetics and Mechanisms of Drug Resistance 243
cleosides and 2'-deoxyribose-a-1-phosphate. PNP deficiency
or inhibition suppresses the proliferation of human
T-cells due to subsequent accumulation of deoxyguanosine
triphosphate (dGTP), which leads to allosteric
inhibition of ribonucleoside diphosphate reductase
(RNR), an enzyme necessary for DNA synthesis.
As patients with inherited PNP deficiency are characterized
by profound suppression of T-cell immunity, inhibition
of this purine salvage enzyme is predominantly
targeted at T-cell hematologic malignancies although
in vitro studies indicated that B-lineage ALL cells are
susceptible to PNP inhibition as well.
Several phase I and II trials are underway to investigate
the safety profile and clinical activity of forodesine
in patients with advanced T-cell malignancies. In
a phase I/II multicenter dose escalation study, 15 patients
with various hematologic malignancies (including
six patients with B-lineage ALL) received forodesine at
doses from 40 mg/m 2 up to 135 mg/m 2 intravenously
(typically given every 12 h for 4 days following one single
infusion in the first day) [49]. There was one complete
response at 135 mg/m 2 and hematologic benefits
for six other patients (including five with ALL). Maximum
PNP inhibition was achieved at 40 mg/m 2 . Duvic
et al. treated 13 patients with cutaneous T-cell lymphoma
(CTCL) or Sezary syndrome with forodesine at dose
between 40 mg/m 2 and 135 mg/m 2 per infusion [50].
They report one complete and two partial responses.
Overall, nine patients showed at least an improvement
in skin lesions and/or a pharmacodynamic response.
A phase II study of forodesine in relapsed T-cell ALL
is being conducted at MD Anderson Cancer Center.
An oral formulation of forodesine will become available
for clinical studies in the near future.
19.3 Getting to Know Chemotherapy:
The Role of Pharmacogenetics
and Mechanisms of Drug Resistance
Although development of new drugs remains crucial,
further understanding of the pharmacodynamics and
pharmacokinetics of existing agents can help to increase
their efficacy. Considerations of drug metabolism
and pharmacogenetics are therefore becoming increasingly
important to assess sensitivity to chemotherapy
and prognosis. Many antineoplastic agents display a
wide range of interpatient variability of their steady
state plasma and intracellular levels, which may influ-
ence response and outcome to therapy [51]. Polymorphisms
in expression of various genes account for differences
in drug absorption, distribution, and metabolism.
Thymidylate synthase (TS) is an important target of
methotrexate. Homozygosity for a triple-tandem repeat
polymorphism of the TS gene has been associated with
increased levels of the enzyme, and with worse prognosis
in children with ALL [52]. Polymorphisms of
the methylenetetrahydrofolate reductase (MTHFR) gene
have been correlated with a higher incidence of adverse
events, but also greater sensitivity of leukemic blasts to
methotrexate [53, 54]. In a study by Evans et al., patients
with low methotrexate concentrations had significantly
shorter CR durations and methotrexate clearance was
an independent prognostic factor for remission duration
[55]. Polymorphisms affecting the thiopurine
methyltransferase (TPMT) gene may likewise lead to increased
sensitivity to 6-mecaptopurine, to a higher risk
of acute hematopoietic adverse events, but also to a
more favorable leukemia-free survival [56]. Most of
these studies have been conducted in children with
ALL and it is unknown how these pharmacokinetic
variables contribute to the outcome in adult ALL. There
is growing interest in adult ALL as well, to designing
programs that allow monitoring of pharmacogenetic
properties and individualize dose and schedule of therapy
accordingly.
Differences in sensitivity of ALL cells to chemotherapy
are also based on cytogenetic-molecular characteristics
determining, among other things, drug disposition
and clearance [51]. Several karyotype abnormalities
have been described that have been associated with altered
responsiveness to therapy. Patients with hyperdiploid
cytogenetics are highly sensitive to antimetabolite-type
chemotherapy. In many cases, the leukemic
cells of these patients harbor additional copies of a gene
coding for cellular methotrexate transporters, and higher-than-average
concentrations of intracellular methotrexate
polyglutamates have been demonstrated in vitro
after treatment with methotrexate in leukemic blasts of
these patients [57]. Patients whose cells harbor a TEL-
AML1 fusion [as seen in translocation t(12;21)] are more
sensitive to asparaginase [58]. ALL with translocation
t(4;11) and MLL rearrangements have increased sensitivity
to cytarabine possibly by overexpression of cellular
cytarabine receptors [59]. Phenotypes resistant to
standard doses of methotrexate include T-lineage ALL
where high doses of methotrexate have been associated
with better outcome and ALL associated with transloca