Amount of spontaneous apoptosis detected by Bax/Bcl-2 ratio predicts outcome in acute myeloid leukemia (AML)

• Published in: Blood 2003-03, Vol.101 (6), p.2125-2131
• Main Authors: Del Poeta, Giovanni, Venditti, Adriano, Del Principe, Maria Ilaria, Maurillo, Luca, Buccisano, Francesco, Tamburini, Anna, Cox, Maria Christina, Franchi, Annibale, Bruno, Antonio, Mazzone, Carla, Panetta, Paola, Suppo, Giovanna, Masi, Mario, Amadori, Sergio
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Aged; Aged, 80 and over; Antigens, CD34 - analysis; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Apoptosis; bcl-2-Associated X Protein; Disease-Free Survival; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Flow Cytometry; Humans; Leukemia, Myeloid, Acute - drug therapy; Leukemia, Myeloid, Acute - mortality; Leukemia, Myeloid, Acute - pathology; Middle Aged; Mitochondria - chemistry; Prognosis; Proto-Oncogene Proteins - analysis; Proto-Oncogene Proteins c-bcl-2 - analysis; Proto-Oncogene Proteins c-kit - analysis; Regression Analysis; Remission Induction; Survival Rate
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2002-06-1714

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 ratio was associated with French-American-British (FAB) M0-M1 classes (P = .000 01) and CD34 more than 20% (P < .000 01). There were striking inverse correlations between CD34 or CD117 MFI and bax/bcl-2 values (r = −.40, P < .000 001 andr = −.29, P = .000 002), confirming that immaturity is consistent with this index. Moreover, lower bax/bcl-2 levels were correlated with poor-risk cytogenetics (P = .0002). A significant higher complete remission (CR) rate was found in pts with higher bax/bcl-2 levels (79% versus 45%; P = .000 01). Also, both a longer overall survival (OS) and disease-free survival (DFS) were observed in pts with higher bax/bcl-2 levels (P = .000 01 and = .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 ratio was significantly associated both with a higher CR rate (86% versus 42%;P < .000 01) and a longer OS (P = .0016). The independent prognostic value of bax/bcl-2 ratio 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 proapoptotic molecules in order to circumvent chemoresistance.