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Blood, 15 August 2001, Vol. 98, No. 4, pp. 988-994
CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
Multidrug-resistance phenotype and clinical responses to
gemtuzumab ozogamicin
Michael L. Linenberger,
Tom Hong,
David Flowers,
Eric L. Sievers,
Ted A. Gooley,
John M. Bennett,
Mark S. Berger,
Lance H. Leopold,
Frederick R. Appelbaum, and
Irwin D. Bernstein
From the Clinical Research Division, Fred Hutchinson
Cancer Research Center; Departments of Medicine and Pediatrics,
University of Washington; both of Seattle, WA; University of Rochester
Medical Center, NY; and Wyeth-Ayerst Research, Radnor, PA.
Expression of multidrug resistance (MDR) features by acute myeloid
leukemia (AML) cells predicts a poor response to many treatments. The
MDR phenotype often correlates with expression of P-glycoprotein (Pgp),
and Pgp antagonists such as cyclosporine (CSA) have been used as
chemosensitizing agents in AML. Gemtuzumab ozogamicin, an
immunoconjugate of an anti-CD33 antibody linked to calicheamicin, is
effective monotherapy for CD33+ relapsed AML. However, the
contribution of Pgp to gemtuzumab ozogamicin resistance is poorly
defined. In this study, blast cell samples from relapsed AML patients
eligible for gemtuzumab ozogamicin clinical trials were assayed for Pgp
surface expression and Pgp function using a dye efflux assay. In most
cases, surface expression of Pgp correlated with Pgp function, as
indicated by elevated dye efflux that was inhibited by CSA. Among
samples from patients who either failed to clear marrow blasts or
failed to achieve remission, 72% or 52%, respectively, exhibited
CSA-sensitive dye efflux compared with 29% (P = .003) or
24% (P < .001) among samples from responders. In vitro
gemtuzumab ozogamicin-induced apoptosis was also evaluated using an
annexin V-based assay. Low levels of drug-induced apoptosis were
associated with CSA-sensitive dye efflux, whereas higher levels
correlated strongly with achievement of remission and marrow blast
clearance. In vitro drug-induced apoptosis could be increased by CSA in
14 (29%) of 49 samples exhibiting low apoptosis in the absence of CSA.
Together, these findings indicate that Pgp plays a role in clinical
resistance to gemtuzumab ozogamicin and suggest that treatment trials
combining gemtuzumab ozogamicin with MDR reversal agents are warranted.
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