Clinical significance of P-glycoprotein expression and function for response to induction chemotherapy, relapse rate and overall survival in acute leukemia

Background and Objectives. A multidrug-resistance (MDR) phenotype mediated by P-glycoprotein (P-gp) contributes to chemotherapy failure in acute leuke mia. However, the exact prognostic significance of this resistance mechanis m is still unclear, mostly due to methodologic problems in P-gp detection. We therefore investigated whether P-gp expression levels or functional P-gp activity better predict response to induction chemotherapy, relapse rate a nd overall survival in acute leukemia. Design and Methods. We examined cell samples of 121 adults with de novo acu te myeloid leukemia (AML) and 102 children with newly diagnosed acute lymph oblastic leukemia (ALL) for P-gp expression and functional P-gp activity by now cytometry. P-gp function was determined by the rhodamine 123 (rh123)-e fflux test (AML n=121, ALL n=102) and P-gp expression levels using the P-gp specific monoclonal antibodies (moabs) MRK-16 (AML n=51, ALL n=31), 4.E3 ( AML n=35, ALL n=32), or UIC-2 (AML n=68, ALL n=50). We correlated our findi ngs with the immunophenotype, FAB morphology, cytogenetics and clinical dat a of the examined patients. Results. P-gp expression levels as detected by MRK-16 and 4.E3 were very lo w and did not differ between AML and ALL as estimated using relative fluore scence intensity (RFI) values and D-values by Kolmogorow-Smirnov (KS) stati stics. For moab UIC-2, P-gp expression levels were higher in AML than in AL L. Within AML, moab UIC-2 mainly reacted with myelomonocytic-differentiated leukemic cells of the FAB M4/5 subtypes. No correlation between P-gp expre ssion levels as detected by MRK-16, 4.E3 or UIC-2 and the response to induc tion chemotherapy or relapse rate, both in AML and ALL, was observed. Howev er, a prognostic impact of P-gp expression levels on overall survival in AM L was seen for moab MRK-16. Moreover, within AML, P-gp function was higher in immature blast cells as defined by immunophenotype and FAB morphology an d correlated with response to induction chemotherapy, relapse rate, overall survival as well as cytogenetic risk groups. In ALL, the overall functiona l P-gp activity was lower than in AML and did not correlate with immunophen otypic subgroups, response to induction chemotherapy, relapse rate or overa ll survival. Interpretation and Conclusions. Our data demonstrate a prognostic impact of P-gp in AML but not ALL and indicate that the functional rh123-efflux assa y should be preferred for now cytometric P-gp evaluation in acute leukemia compared with P-gp expression analysis by monoclonal antibodies. (C) 2000, Ferrata Storti Foundation.