title: P-glycoprotein and terminal transferase expression identify prognostic subsets within cytogenetic risk classes in acute myeloid leukemia.
abstract: Clinical and biological features were assessed in 204 consecutive de novo adult acute myeloid leukemia (AML) patients who received intensive chemotherapy regimens. Multiparameter flow cytometric assays both of the multidrug resistance (MDR-1)-associated P-glycoprotein (PGP) using the UIC2 monoclonal antibody (MoAb), and of terminal transferase (TdT) were performed. Cytogenetic findings were obtained from 196 patients with high resolution banding. At onset, UIC2 and TdT positivities were detected in 58.5% and 24% of cases, respectively. There were strict correlations either between UIC2 negativity and FAB M3 or between TdT and FAB M0-M1 (P = 0.001 and < 0.0001, respectively). On the other hand, age was significantly associated with cytogenetic risk classes (P < 0.0001). CD34 positivity was highly correlated with TdT expression (P < 0.0001). Moreover, CD7 and CD11b were significantly represented in UIC2+ subset (P < 0.0001). Rhodamine 123 (Rh 123) efflux was significantly higher in 75 UIC2 positive patients compared to 65 UIC2 negative ones (P < 0.001). As regards to cytogenetics, TdT positivity was strongly related either to t(9;22) or single/associated anomalies of chromosome 7; on the other hand, most or all cases with t(8;21) or t(15;17) were UIC2 or TdT negative, respectively. The rate of first complete remission (CR) differed both between UIC2+ and UIC2- cases and between TdT+ and TdT- ones (40% versus 72%, P < 0.001; and 36% versus 61%, P = 0.001, respectively). The survival rates (Kaplan-Meier method) were significantly shorter either in UIC2+ or in TdT+ patients (P = 0.005 and = 0.011, respectively). UIC2 and TdT negative cases showed longer remission duration (P = 0.03 and = 0.22, respectively). The additional effect of UIC2 and TdT on prognosis allowed us to identify two subsets of patients, the first [UIC2- TdT-] at better and the second [UIC2+ TdT+] at worse clinical outcome compared to single UIC2 and TdT cases, concerning CR (P < 0.001), survival (P < 0.0001) and CR duration (P = 0.007). The combinations [UIC2+ TdT-] and [UIC2- TdT+] showed an intermediate clinical course. A strong difference was found between poor risk and intermediate/favorable risk cytogenetic classes with regard to CR rate (P < 0.0001), overall survival and CR duration (P < 0.001). Nevertheless, within the poor risk class, UIC2 positivity was able to identify patients at worst prognosis with regard to CR (P = 0.005), survival (P = 0.02) and CR duration (P = 0.015). On the other hand, UIC2 and TdT negativity allowed us to distinguish patients with longer survival (P = 0.012 and = 0.04, respectively) and CR duration (P = 0.04 and = 0.025, respectively) within the intermediate/favorable risk class. The independent prognostic value of UIC2, TdT and cytogenetic risk classes was confirmed in multivariate analysis. These results suggest that PGP and TdT expressions, together with cytogenetic findings, may represent a basic predictor of chemotherapeutic failure in AML.
authors.affiliation: Cattedra e Divisione di Ematologia, Universita Tor Vergata, Ospedale S. Eugenio, Roma, Italy. giovanni.del_poeta@schering-plough.it
authors.forename: G
authors.initials: G
authors.lastname: Del Poeta
authors.forename: A
authors.initials: A
authors.lastname: Venditti
authors.forename: R
authors.initials: R
authors.lastname: Stasi
authors.forename: G
authors.initials: G
authors.lastname: Aronica
authors.forename: M C
authors.initials: MC
authors.lastname: Cox
authors.forename: F
authors.initials: F
authors.lastname: Buccisano
authors.forename: A
authors.initials: A
authors.lastname: Tamburini
authors.forename: A
authors.initials: A
authors.lastname: Bruno
authors.forename: L
authors.initials: L
authors.lastname: Maurillo
authors.forename: A
authors.initials: A
authors.lastname: Battaglia
authors.forename: G
authors.initials: G
authors.lastname: Suppo
authors.forename: A M
authors.initials: AM
authors.lastname: Epiceno
authors.forename: B
authors.initials: B
authors.lastname: Del Moro
authors.forename: M
authors.initials: M
authors.lastname: Masi
authors.forename: S
authors.initials: S
authors.lastname: Amadori
authors.forename: G
authors.initials: G
authors.lastname: Papa
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000032:analysis*; D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D004253:DNA Nucleotidylexotransferase / Q000032:analysis*; D005260:Female; D006801:Humans; D016130:Immunophenotyping; D007621:Karyotyping; D007951:Leukemia, Myeloid / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D012307:Risk Factors
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004253:DNA Nucleotidylexotransferase