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Continuous treatment with all-trans retinoic acid causes a progressive
reduction in plasma drug concentrations: implications for relapse and
retinoid "resistance" in patients with acute promyelocytic leukemia
[published erratum appears in Blood 1992 Aug 1;80(3):855]
J Muindi, SR Frankel, WH Miller , A Jakubowski, DA Scheinberg, CW Young, E Dmitrovsky and RP Warrell
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York,
NY 10021.
Although all-trans retinoic acid (RA) induces complete remission in a high
proportion of patients with acute promyelocytic leukemia (APL), all groups
have described clinical relapses despite continued RA treatment. This
finding suggests that resistance to the cytodifferentiating effects of the
retinoid had been acquired. To investigate potential mechanisms of clinical
resistance to RA, we serially evaluated the clinical pharmacology of the
drug in APL patients treated with this agent. Leukemic cells from patients
relapsing from RA treatment were cultured in the presence of RA and
examined for evidence of morphologic maturation. We also studied messenger
RNA expression of the newly described gene product of the (15;17)
translocation in APL, PML/RA receptor-alpha (PML/RAR-alpha). Serial
pharmacokinetic studies showed that continuous daily RA treatment was
associated with a marked decrease in plasma drug concentrations at the time
of relapse compared with the initial day of therapy. Doubling the RA dose
in six patients failed to reinduce response at the time of relapse and also
failed to significantly augment plasma RA concentrations. However, leukemic
cells obtained at the time of relapse from four patients retained in vitro
sensitivity to the differentiating activity of RA (10(-6) mol/L). No change
was observed in the pattern of PML/RAR-alpha expression assessed by
Northern blot analysis at the time of relapse compared with pretreatment in
two patients who were tested. These results indicate that clinical relapse
and "resistance" to continuous treatment with all- trans RA in APL is
associated with progressive reduction of plasma concentrations, potentially
to levels below those that sustain differentiation of leukemic cells in
vivo. Long-term success of this treatment will require the development of
strategies that circumvent this pharmacologic phenomenon.
Volume 79,
Issue 2,
pp. 299-303,
01/15/1992
Copyright © 1992 by The American Society of Hematology
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