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In vitro drug sensitivity testing can predict induction failure and early
relapse of childhood acute lymphoblastic leukemia
T Hongo, S Yajima, M Sakurai, Y Horikoshi and R Hanada
Department of Pediatrics, Hamamatsu University School of Medicine, Japan.
It is vital to develop effective therapy for children with acute
lymphoblastic leukemia (ALL), in whom no remission occurs or who suffer
relapse with current protocols. Cellular drug resistance is thought to be
an important cause of induction failure and relapse. We performed in vitro
tests of bone marrow samples in 196 children with newly diagnosed ALL with
a 4-day culture and a methyl-thiazol-tetrazolium assay. We tested 16 drugs
and calculated the 70% lethal dose (LD70) for 14 drugs and the leukemic
cell survival (LCS) rate for dexamethasone and prednisolone. For each
single drug, patients were classified into two groups, sensitive or
resistant, by median concentration of LD70 or LCS. When patients were
classified into three groups by sensitivity to four drugs of DPAV
(dexamethasone, prednisolone, L-asparaginase, and vincristine), 3-year
event-free survival (EFS; 95% confidence intervals) of the super sensitive
group (SS; sensitive to all 4 drugs) was 0.833 (0.690 to 0.976), that of
the intermediate sensitive group (IS; sensitive to 2 or 3 drugs) was 0.735
(0.609 to 0.863), and that of the relatively resistant group (RR; sensitive
to no drugs or to 1 drug) was 0.541 (0.411 to 0.670; P = .0008). We then
investigated the relationship between the above four-drug sensitivity and
the time of relapse. The SS and IS patients tended to maintain continuous
complete remission, and RR patients tended to undergo induction failure and
early and late relapse (P = .004). Initial white blood cell count,
immunologic classification, and age were also predictive factors, but the
patient numbers showed no statistical correlation between these factors and
the four-drug sensitivity groups (SS, IS, and RR). When we took three
groups SS/IS/RR and investigated the EFS for various clinical groups, DPAV
sensitivity strongly influenced EFS in the standard-risk ALL (P = .016). In
vitro drug sensitivity testing provides additional prognostic information
about childhood ALL, and early detection of drug resistance at the time
chemotherapy commences may provide a successful strategy for
individualizing treatment, as the results indicate de novo resistance to
front-line drugs and suggest alternative, second-line drugs.
Volume 89,
Issue 8,
pp. 2959-2965,
04/15/1997
Copyright © 1997 by The American Society of Hematology
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