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Accumulation of methotrexate and methotrexate polyglutamates in
lymphoblasts at diagnosis of childhood acute lymphoblastic leukemia: a
pilot prognostic factor analysis
VM Whitehead, DS Rosenblatt, MJ Vuchich, JJ Shuster, A Witte and D Beaulieu
Penny Cole Hematology Research Laboratory, McGill University-Montreal
Children's Hospital Research Institute, Canada.
Lymphoblasts in bone marrow samples, obtained from 43 children with acute
lymphoblastic leukemia at diagnosis, were incubated with 1.0 mumols/L [3H]
methotrexate for 24 hours in vitro. Nonexchangeable methotrexate and
methotrexate polyglutamates were separated and quantitated. Event-free
survival at 5 years was 38% +/- 9% for all 43 patients (27 failures), and
44% +/- 10% for the 35 with non-T, non-B- cell acute lymphoblastic leukemia
(20 failures). Of these 35 children, those whose lymphoblasts accumulated
more than 100 pmol methotrexate and 500 pmol methotrexate polyglutamates
per billion cells experienced better 5-year event-free survival than those
whose lymphoblasts did not (65% +/- 12% v 22% +/- 9%, P = .010). This
difference characterized "good-risk" patients who were female (P = .014),
less than age 7 at diagnosis (P = .005), or had low initial white blood
cell counts (less than 20 X 10(9)/L, P = .018). Findings were similar for
the 43 children with acute lymphoblastic leukemia and for the "good-risk"
children in this total group. Thus, the ability of lymphoblasts to
accumulate methotrexate and form methotrexate polyglutamates may be
important to the curative properties of current therapy of acute
lymphoblastic leukemia in children, particularly for "good-risk" patients.
In such patients, inherent rather than acquired drug resistance may be the
initial event leading to treatment failure.
Volume 76,
Issue 1,
pp. 44-49,
07/01/1990
Copyright © 1990 by The American Society of Hematology
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