Clinical significance of bax/bcl-2 ratio in chronic lymphocytic leukemia

被引:57
作者
Del Principe, Maria Ilaria [1 ,2 ]
Dal Bo, Michele [3 ]
Bittolo, Tamara [3 ]
Buccisano, Francesco [1 ,2 ]
Rossi, Francesca Maria [3 ]
Zucchetto, Antonella [3 ]
Rossi, Davide [4 ]
Bomben, Riccardo [3 ]
Maurillo, Luca [1 ,2 ]
Cefalo, Mariagiovanna [1 ,2 ]
De Santis, Giovanna [1 ,2 ]
Venditti, Adriano [1 ,2 ]
Gaidano, Gianluca [4 ]
Amadori, Sergio [1 ,2 ]
de Fabritiis, Paolo [1 ,2 ]
Gattei, Valter [3 ]
Del Poeta, Giovanni [1 ,2 ]
机构
[1] S Eugenio Hosp, Dipartimento Biomed & Prevenz, Ematol, Rome, Italy
[2] Univ Roma Tor Vergata, Rome, Italy
[3] Ctr Riferimento Oncol, IRCCS, Unita Clin Sperimentale Onco Ematol, I-33081 Aviano, Italy
[4] Univ Piemonte Orientale, Ematol, Novara, Italy
关键词
SPONTANEOUS APOPTOSIS; PROTEIN EXPRESSION; CD38; EXPRESSION; BCL-2/BAX RATIO; TP53; MUTATIONS; IN-VITRO; FLUDARABINE; PROGNOSIS; SURVIVAL; DISEASE;
D O I
10.3324/haematol.2015.131854
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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/bcl2 (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.
引用
收藏
页码:77 / 85
页数:9
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