CD33 expression and P-glycoprotein-mediated drug efflux inversely correlate and predict clinical outcome in patients with acute myeloid leukemia treated with gemtuzumab ozogamicin monotherapy

被引：151

作者：

Walter, Roland B. ^{[1
]}

Gooley, Ted A.

van der Velden, Vincent H. J.

Loken, Michael R.

van Dongen, Jacques J. M.

Flowers, David A.

Bernstein, Irwin D.

Appelbaum, Frederick R.

机构：

[1] Fred Hutchinson Canc Res Ctr, Clin Res Div, Seattle, WA 98104 USA

[2] Univ Washington, Dept Med, Div Hematol, Seattle, WA 98195 USA

[3] Univ Rotterdam, Ctr Med, Dept Immunol, Erasmus MC, Rotterdam, Netherlands

[4] HematoLog, Seattle, WA USA

[5] Univ Washington, Dept Pediat, Seattle, WA 98195 USA

[6] Univ Washington, Dept Med, Div Med Oncol, Seattle, WA 98195 USA

来源：

BLOOD | 2007年 / 109卷 / 10期

关键词：

D O I：

10.1182/blood-2006-09-047399

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Gemtuzumab ozogamicin (GO) contains an anti-CD33 antibody to facilitate uptake of a toxic calicheamicin-gamma(1) derivative. While recent in vitro data demonstrated a quantitative relationship between CD33 expression and GO cytotoxicity, previous correlative studies failed to identify a significant association between CD33 expression and clinical outcome. Studying patients undergoing GO monotherapy for relapsed acute myeloid leukemia (AML), we now find that AML blasts of responders have a significantly higher mean CD33 level and lower P-glycoprotein (Pgp) activity compared with nonresponders. CD33 expression and Pgp activity are inversely correlated. While both variables are associated with outcome, Pgp remains significantly associated with outcome even after adjusting for CD33, whereas CD33 does not show such an association after adjusting for Pgp. The inverse relationship between CD33 and Pgp suggests a maturation-stage-dependent expression of both proteins, and offers the rationale for using cell differentiation-promoting agents to enhance GO-induced cytotoxicity.

引用

页码：4168 / 4170

页数：3

共 25 条

[1]

Appelbaum F R, 1999, Semin Hematol, V36, P2

[2] Gemtuzumab ozogamicin in the treatment of acute myeloid leukemia [J].

Giles, F ;

Estey, E ;

O'Brien, S .

CANCER, 2003, 98 (10) :2095-2104

[3] Internalization and cell cycle-dependent killing of leukemic cells by Gemtuzumab Ozogamicin: rationale for efficacy in CD33-negative malignancies with endocytic capacity [J].

Jedema, I ;

Barge, RMY ;

van der Velden, VHJ ;

Nijmeijer, BA ;

van Dongen, JJM ;

Willemze, R ;

Falkenburg, JHF .

LEUKEMIA, 2004, 18 (02) :316-325

[4] Differences in CD33 intensity between various myeloid neoplasms [J].

Jilani, I ;

Estey, E ;

Huh, Y ;

Joe, Y ;

Manshouri, T ;

Yared, M ;

Giles, F ;

Kantarjian, H ;

Cortes, J ;

Thomas, D ;

Keating, M ;

Freireich, E ;

Albitar, M .

AMERICAN JOURNAL OF CLINICAL PATHOLOGY, 2002, 118 (04) :560-566

[5] Final report of the efficacy and safety of gemtuzumab ozogamicin (Mylotarg) in patients with CD33-positive acute myeloid leukemia in first recurrence [J].

Larson, RA ;

Sievers, EL ;

Stadtmauer, EA ;

Löwenberg, B ;

Estey, EH ;

Dombret, H ;

Theobald, M ;

Voliotis, D ;

Bennett, JM ;

Richie, M ;

Leopold, LH ;

Berger, MS ;

Sherman, ML ;

Loken, MR ;

van Dongen, JJM ;

Bernstein, ID ;

Appelbaum, FR .

CANCER, 2005, 104 (07) :1442-1452

[6]

Leith CP, 1999, BLOOD, V94, P1086

[7]

Leith CP, 1997, BLOOD, V89, P3323

[8]

Leone G, 2004, HAEMATOLOGICA, V89, P634

[9] CD33-directed therapy with gemtuzumab ozogamicin in acute myeloid leukemia: progress in understanding cytotoxicity and potential mechanisms of drug resistance [J].

Linenberger, ML .

LEUKEMIA, 2005, 19 (02) :176-182

[10] Multidrug-resistance phenotype and clinical responses to gemtuzumab ozogamicin [J].

Linenberger, ML ;

Hong, T ;

Flowers, D ;

Sievers, EL ;

Gooley, TA ;

Bennett, JM ;

Berger, MS ;

Leopold, LH ;

Appelbaum, FR ;

Bernstein, ID .

BLOOD, 2001, 98 (04) :988-994

← 1 2 3 →