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Polymorphic thiopurine methyltransferase in erythrocytes is indicative of
activity in leukemic blasts from children with acute lymphoblastic leukemia
HL McLeod, MV Relling, Q Liu, CH Pui and WE Evans
Pharmaceutical Department, St. Jude Children's Research Hospital, Memphis,
TN 38105, USA.
The activity of thiopurine methyltransferase (TPMT) exhibits genetic
polymorphism, with approximately 1 in 300 individuals inheriting TPMT
deficiency as an autosomal recessive trait, and about 11% having
intermediate activity (ie, heterozygotes). Patients with TPMT deficiency
accumulate excessive concentrations of 6-thioguanine nucleotides (TGNs) and
develop severe toxicity when treated with standard dosages of
mercaptopurine. High TPMT activity has been associated with lower
concentrations of TGNs, yielding a higher risk of treatment failure in
children with acute lymphoblastic leukemia (ALL). As the biochemical basis
of these pharmacodynamic relationships has not been fully elucidated, we
investigated the variability and relationship of TPMT activity in
erythrocytes and lymphoblasts from children with ALL. A 58-fold range of
erythrocyte TPMT activity was found among 119 patients receiving ALL
chemotherapy (0.6 to 34.9 U/mL packed erythrocytes), but relatively low
intrapatient variability (coefficient of variation, 13.5%) was observed
over 1 year. A 27-fold range in TPMT activity was observed in leukemic
blasts obtained from 42 patients at initial diagnosis (3.3 to 88.9 U/1 x
10(9) cells). TPMT activity in leukemic blasts at diagnosis was
significantly correlated with TPMT in erythrocytes before therapy (rs =
.75, P < .0001, N = 13). These data document extensive interpatient
variability of TPMT activity in ALL blasts and establish its linkage to
polymorphic TPMT activity in erythrocytes, providing a new mechanism by
which erythrocytes serve as prognostic markers of mercaptopurine metabolism
and TPMT activity in children with ALL.
Volume 85,
Issue 7,
pp. 1897-1902,
04/01/1995
Copyright © 1995 by The American Society of Hematology
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