Level of minimal residual disease after consolidation therapy predicts outcome in acute myeloid leukemia

Abstract

We used flow cytometry to quantify minimal residual disease (MRD) in 56 patients with acute myeloid leukemia (AML) expressing a leukemia-associated phenotype. Thirty-four patients aged 18 to 60 years were entered into the AML-10 protocol (induction, consolidation, and autologous stem-cell transplantation [ASCT]), whereas 22 patients older than 60 years received the AML-13 protocol (induction, consolidation, and consolidation II). After induction, the level of MRD that was best associated with treatment outcome was 4.5 × 10−4 residual leukemic cells. However, the outcome in patients with at least 4.5 × 10−4 cells (n = 26) was not significantly different from that in patients with fewer leukemic cells (n = 30); there were 15 (58%) relapses in the first group and 12 (40%) relapses in the second. After consolidation, the most predictive MRD cutoff value was 3.5 × 10−4cells: 22 patients had an MRD level of 3.5 × 10−4 cells or higher and 17 (77%) of these patients had relapse, compared with 5 of 29 patients (17%) with lower MRD levels (P < .001). An MRD level of 3.5 × 10−4 cells or higher after consolidation was significantly correlated with poor or intermediate-risk cytogenetic findings, a multidrug resistance 1 (MDR1) phenotype, short duration of overall survival, and short duration of relapse-free survival (P = .014, .031, .00022, and .00014, respectively). In multivariate analysis, this MRD status was significantly associated with a high frequency of relapse (P < .001) and a short duration of overall (P = .025) and relapse-free survival (P = .007). ASCT did not alter the prognostic effect of high MRD levels after consolidation: the relapse rate after transplantation was 70%. Thus, we found that an MRD level of 3.5 × 10−4 cells or higher at the end of consolidation strongly predicts relapse and is significantly associated with an MDR1 phenotype and intermediate or unfavorable cytogenetic findings.

Postremission sequential monitoring of minimal residual disease by WT1 Q‐PCR and multiparametric flow cytometry assessment predicts relapse and may help to address risk‐adapted therapy in acute myeloid leukemia patients

“…In particular, a very early time-point for WT1 monitoring (postinduction) [15,35,[36][37][38][39][41][42][43], but also a later time-point (postconsolidation or pre-allo-SCT) [38,[41][42][43] have been reported to significantly predict the outcome. Concerning LAIP-MFC sensitivity and efficiency, our data are concordant with those reported by the GIMEMA group and suggest that the most accurate predictive time-point of MRD assessment is probably after consolidation [14,44]. In particular, we have seen that, within favorable and intermediate-risk groups, MRD positivity after consolidation predicts relapse in about 40% of MRD-positive AML patients, but the accuracy of relapse prediction increases to 75% when the evaluation of MRD positivity is made after intensification.…”

Determination of minimal residual disease in leukaemia patients

“…In one study, 46 of 53 patients had phenotypes that were found at frequencies of less than one in 10 4 cells in normal bone marrow, while seven had phenotypes found in normal bone marrow but at frequencies of less than one in 10 3 (San Miguel et al, 1997). In another study, 65 of 93 patients had a phenotype suitable for detection of one leukaemic cell in 10 4 normal cells (Venditti et al, 2000).…”

Absence of leukaemic CD34+ cells in acute myeloid leukaemia is of high prognostic value: a longstanding controversy deciphered

“…At present, it is well established that MRD assessment is an important factor in predicting risk of relapse and/or death (Venditti et al, 2000;San Miguel et al, 2001;Feller et al, 2004;Kern et al, 2004;D ıez-Campelo et al, 2009;Terwijn et al, 2013). MRD assessment will therefore be included in risk group stratification in upcoming clinical studies (e.g.…”