IMMUNOPHENOTYPING INVESTIGATION OF MINIMAL RESIDUAL DISEASE IS A USEFUL APPROACH FOR PREDICTING RELAPSE IN ACUTE MYELOID-LEUKEMIA PATIENTS

A high complete remission rate is currently achieved in patients with acute myeloid leukemia (AML). However, many patients eventually relaps e due to the persistence of low numbers of residual leukemic cells tha t are undetectable by conventional cytomorphologic criteria (minimal r esidual disease [MRD]). Using immunophenotypic multiparametric flow cy tometry, we have investigated in sequential studies (diagnosis and fol low-up) the impact of MRD detection on the outcome of 53 AML patients that had achieved morphologic remission with standard AML protocols an d displayed at diagnosis an aberrant phenotype. Patients were studied at diagnosis with a panel of 35 monoclonal antibodies in triple staini ng combinations for detection of aberrant or uncommon phenotypic featu res. According to these features, a patient's probe was custom-built a t diagnosis for the identification of possible residual leukemic cells during follow-up. The level of MRD at the end of induction and intens ification therapy correlated with the number of relapses and relapse-f ree survival (RFS), Thus, patients with more than 5 x 10(-3) residual cells (5 residual cells among 1,000 normal bone marrow [BM] cells) ide ntified as leukemic by immunophenotyping in the first remission BM sho wed a significant higher rate of relapse (67% v 20% for patients with less than 5 x 10(-3) residual cells; P = .002) and a lower median RFS (17 months v not reached; P = .01). At the end of intensification, wit h a cut-off value of 2 x 10(-3) leukemic cells, AML patients also sepa rated into two distinct groups with relapse rates of 69% versus 32% (P = .02), respectively, and median RFS of 16 months versus not reached (P = .04). In addition, overall survival was also significantly relate d to the level of residual cells in the marrow obtained at the end of induction and particularly after intensification therapy (P = .008). F urthermore, we have explored whether residual disease was related with the functional expression of multidrug resistance (MDR-1) at diagnosi s as assessed by the rhodamine-123 assay. Patients with greater than o r equal to 5 x 10(-3) residual leukemic cells at the end of induction therapy had a significantly higher rhodamine-123 efflux (mean, 56% +/- 24%) than those with less than 5 x 10(-3) residual cells (mean, 32% /- 31%; P = .04). Finally, multivariate analysis showed that the numbe r of residual cells at the end of induction or intensification therapy was the most important prognostic factor for prediction of RFS. Overa ll, our results show that immunophenotypical investigation of MRD stro ngly predicts outcome in patients with AML and that the number of resi dual leukemic cells correlates with multidrug resistance. (C) 1997 by The American Society of Hematology.