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 in 263 patients (52%) with chronic lymphocytic leukemia. Higher bax/bcl-2 was associated with low Rai stage, lymphocyte doubling time >12 months, beta-2 microglobulin <2.2 mg/dl, soluble CD23<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 subgroups (37 patients), 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.
CLINICAL SIGNIFICANCE OF BAX/BCL-2 RATIO IN CHRONIC LYMPHOCYTIC LEUKEMIA
ROSSI, Davide;GAIDANO, Gianluca;
2016-01-01
Abstract
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 in 263 patients (52%) with chronic lymphocytic leukemia. Higher bax/bcl-2 was associated with low Rai stage, lymphocyte doubling time >12 months, beta-2 microglobulin <2.2 mg/dl, soluble CD23<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 subgroups (37 patients), 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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
