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Prepublished online as a Blood First Edition Paper on November 7, 2002; DOI 10.1182/blood-2002-06-1714.
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Blood, 15 March 2003, Vol. 101, No. 6, pp. 2125-2131
CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
Amount of spontaneous apoptosis detected by Bax/Bcl-2 ratio
predicts outcome in acute myeloid leukemia (AML)
Giovanni Del Poeta,
Adriano Venditti,
Maria
Ilaria Del Principe,
Luca Maurillo,
Francesco Buccisano,
Anna Tamburini,
Maria Christina Cox,
Annibale Franchi,
Antonio Bruno,
Carla Mazzone,
Paola Panetta,
Giovanna Suppo,
Mario Masi, and
Sergio Amadori
From the Cattedra e Divisione Ematologia,
Università "Tor Vergata," Ospedale S. Eugenio, Roma, Italy.
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 and r = .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.

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