In chronic lymphocytic leukemia the balance between the pro-apoptotic and anti-apoptotic members of the bcl-2 family is involved in the pathogenesis, chemorefractoriness and clinical outcome. Moreover, the recently proposed anti-bcl-2 molecules, such as ABT-199, have emphasized the potential role of of bcl-2 family proteins in the context of target therapies. We investigated bax/bcl-2 ratio by flow cytometry in 502 patients and identified a cut off of 1.50 to correlate bax/bcl-2 ratio with well-established clinical and biological prognosticators. Bax/bcl-2 was 1.50 or over in 263 patients (52%) with chronic lymphocytic leukemia. Higher bax/bcl-2 was associated with low Rai stage, lymphocyte doubling time over 12 months, beta-2 microglobulin less than 2.2 mg/dL, soluble CD23 less than 70 U/mL and a low risk cytogenetic profile (P<0.0001). On the other hand, lower bax/bcl-2 was correlated with unmutated IGHV (P<0.0001), mutated NOTCH1 (P<0.0001) and mutated TP53 (P=0.00007). Significant shorter progression-free survival and overall survival were observed in patients with lower bax/bcl-2 (P<0.0001). Moreover, within IGHV unmutated (168 patients) and TP53 mutated (37 patients) subgroups, higher bax/bcl-2 identified cases with significant longer PFS (P=0.00002 and P=0.039). In multivariate analysis of progression-free survival and overall survival, bax/bcl-2 was an independent prognostic factor (P=0.0002 and P=0.002). In conclusion, we defined the prognostic power of bax/bcl-2 ratio, as determined by a flow cytometric approach, and highlighted a correlation with chemoresistance and outcome in chronic lymphocytic leukemia. Finally, the recently proposed new therapies employing bcl-2 inhibitors prompted the potential use of bax/bcl-2 ratio to identify patients putatively resistant to these molecules.
DEL PRINCIPE, M.I., Dal Bo, M., Bittolo, T., BUCCISANO, F., Rossi, F., Zucchetto, A., et al. (2015). Clinical significance of bax/bcl-2 ratio in chronic lymphocytic leukemia. HAEMATOLOGICA, 101(1), 77-85.
|Tipologia:||Articolo su rivista|
|Citazione:||DEL PRINCIPE, M.I., Dal Bo, M., Bittolo, T., BUCCISANO, F., Rossi, F., Zucchetto, A., et al. (2015). Clinical significance of bax/bcl-2 ratio in chronic lymphocytic leukemia. HAEMATOLOGICA, 101(1), 77-85.|
|IF:||Con Impact Factor ISI|
|Settore Scientifico Disciplinare:||Settore MED/06 - Oncologia Medica|
|Revisione (peer review):||Esperti anonimi|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.3324/haematol.2015.131854|
|Stato di pubblicazione:||Pubblicato|
|Data di pubblicazione:||gen-2015|
|Titolo:||Clinical significance of bax/bcl-2 ratio in chronic lymphocytic leukemia|
|Autori:||DEL PRINCIPE, MI; Dal Bo, M; Bittolo, T; BUCCISANO, F; Rossi, F; Zucchetto, A; Rossi, D; Bomben, R; Maurillo, L; CEFALO, M; De Santis, G; VENDITTI, A; Gaidano, G; AMADORI, S; DE FABRITIIS, P; Gattei, V; DEL POETA, G|
|Appare nelle tipologie:||01 - Articolo su rivista|