Multidrug-resistance phenotype and clinical responses to gemtuzumab ozogamicin

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 antagoni sts such as cyclosporine (CSA) have been used as chemosensitizing agents in AML. Gemtuzumab ozogamicin, an immunoconjugate of an anti-CD33 antibody li nked to call-cheamicin, is effective monotherapy for CD33(+) relapsed AML. However, the contribution of Pgp to gemtuzumab ozogamicin resistance is poo rly defined. In this study, blast cell samples from relapsed AML patients e ligible for gemtuzumab ozogamicin clinical trials were assayed for Pgp surf ace expression and Pgp function using a dye efflux assay. In most cases, su rface expression of Pgp correlated with Pgp function, as indicated by eleva ted dye eff lux 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 eff lux compared with 29% ( P = .003) or 24% (P < .001) among samples from responders. In vitro gemtuzu mab ozogamicin-induced apoptosis was also evaluated using an annexin V-base d assay. Low levels of drug-induced apoptosis were associated with CSA-sens itive dye eff lux, whereas higher levels correlated strongly with achieveme nt of remission and marrow blast clearance. In vitro drug-induced apoptosis could be increased by CSA in 14 (29%) of 49 samples exhibiting low apoptos is in the absence of CSA. Together, these findings indicate that Pgp plays a role in clinical resistance to gemtuzumab ozogamicin and suggest that tre atment trials combining gemtuzumab ozogamicin with MDR reversal agents are warranted. (C) 2001 by The American Society of Hematology.