FUNCTIONAL EXPRESSION OF MDR-1 IN ACUTE MYELOID-LEUKEMIA - CORRELATION WITH THE CLINICAL-BIOLOGICAL, IMMUNOPHENOTYPICAL, AND PROGNOSTIC DISEASE CHARACTERISTICS

Up till now, clinical data on the possible prognostic influence of mul tidrug resistance (MDR) in hematological malignancies have been incons istent, probably due to technical pitfalls. Moreover, in most studies qualitative information on the presence/absence of MDR-1 expression ha s been used instead of quantitative results. In addition, results usua lly refer to the total BM population and not specifically to blast cel ls. In the present study we analyzed the expression of MDR-1 in a seri es of 50 newly diagnosed de novo AML using a double-staining technique : (a) monoclonal antibodies for the specific identification of blast c ells and (b) the rhodamine-123 efflux assay, which allows a quantitati ve and calibrated measurement of MDR-1 function. Expression of MDR-1 w as correlated with clinical, biological, and immunophenotypical diseas e characteristics. All patients were uniformly treated according to th e AML 87/91 protocols of the Spanish Pethema Cooperative Group; the me dian age was 51+/-19 years and the FAB distribution was as follows: 2 M-0, 9 M-1, 9 M-2, 12 M-3, 11 M-4, 5 M-5, and 2 M-6 cases. Upon groupi ng the 50 AML patients analyzed according to the level of rh123 elimin ation, it was observed that those cases with greater than or equal to 30% decrease in rh123 fluorescence displayed higher WBC counts (9 +/- 12 vs 37 +/- 73 x 10(9)/l, p = 0.02) and platelet numbers (94 +/- 11 v s 35 +/- 25 x 10(9)/l, p = 0.02), together with a higher incidence of extramedullary involvement (35% vs 24%, p = 0.02). Half of the patient s (47%) displaying a low rh123 elimination (<30%) showed M-3 morpholog y, while among the 33 patients with a higher rate of rh123 elimination (greater than or equal to 30%), only four (12%) corresponded to the M -3 morphological subtype (p=0.0006). From the immunophenotypic point o f view, a low rate of rh123 elimination was associated with a lower ex pression of HLADR antigen (p=0.003) and a higher expression of CD117 ( p=0.01). Regarding the possible prognostic influence of MDR1 expressio n, we found that a high rate of rh123 elimination (>30%) was associate d with a tendency towards poor disease outcome, illustrated by both a lower complete remission rate with the first cycle of chemotherapy (36 % vs 56%) and a lower median disease-free survival (22 months vs media n DFS not reached), although differences did not reach statistical sig nificance (p=0.1 in both comparisons). This data shows that although M DR-1 can be a relevant parameter in the evaluation of AML patients, la rger series of patients using appropiate techniques for specifically a nalyzing the MDR of blast cells will be necessary in order to establis h the final clinical value of this parameter.