predicts outcome in acute myeloid leukemia (AML) The amount of spontaneous apoptosis detected by bax/bcl-2 ratio

Abstract The inability to undergo apoptosis is a crucial mechanism of multidrug resistance in acute myeloid leukemia (AML) and the analysis of mitochondrial apoptotic proteins may represent a significant prognostic tool to predict outcome. Bcl-2 and bax oncoproteins were evaluated in 255 de novo AML patients (pts) by flow cytometry using an anti-bcl-2 monoclonal antibody (MoAb) and an anti-bax MoAb. The results were expressed as an index (bax/bcl-2), obtained by dividing bax mean fluorescence intensity (MFI) and bcl-2 MFI. Lower bax/bcl-2 was associated with FAB M0-M1 classes (P=0.00001) and CD34 >20% (P<0.00001). There were striking inverse correlations between CD34 or CD117 MFI and bax/bcl-2 values (r=.-40, P<0.000001 and r=-.29, P=0.000002), confirming that immaturity is consistent with this index. Moreover, lower bax/bcl-2 levels were correlated with poor risk cytogenetics (P=0.0002). A significant higher complete remission (CR) rate was found in pts with higher bax/bcl-2 (79% vs 45%; P=0.00001). Also, both a longer overall survival (OS) and disease free survival (DFS) were observed in pts with higher bax/bcl-2 (P=0.00001 and =0.019). Noteworthy, bax/bcl-2 levels accurately predicted the clinical response and outcome of pts with normal or unknown cytogenetics. Indeed, within this subset of 147 pts, higher bax/bcl-2 was significantly associated both with a higher CR rate (86% vs 42%; P<0.00001) and a longer OS (P=0.0016). The independent prognostic value of bax/bcl-2 was confirmed in multivariate analysis. Therefore, mitochondrial oncoproteins, such as bcl-2 and bax, represent both sensitive indicators of clinical outcome and potential targets of novel pro-apoptotic molecules in order to circumvent chemoresistance.From bloodjournal.hematologylibrary.org by guest on June 7, 2013. For personal use only.