Journal
HAEMATOLOGICA
Volume 101, Issue 1, Pages 77-85Publisher
FERRATA STORTI FOUNDATION
DOI: 10.3324/haematol.2015.131854
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Funding
- Ministero dell'Universita e della Ricerca Scientifica e Tecnologica (MURST), Programmi di Ricerca di Interesse Nazionale
- Ministero della Salute (Ricerca Finalizzata Istituto di Ricovero e Cura a Carattere Scientifico [IRCCS], Rome, Italy
- Associazione Italiana Ricerca Cancro (AIRC) [IG-13227]
- Progetto Ricerca Finalizzata I.R.C.C.S. [RF-2009-1469205, RF2010-2307262]
- Progetto Giovani Ricercatori [GR-20091475467, GR-2010-2317594, GR-2011-02347441, GR2011-02346826]
- Fondazione Cariplo [2012-0689]
- Associazione Italiana contro leLeucemie, Linfomi e Mielomi (AIL), Venezia Section, Pramaggiore Group, Italy
- Fondazione per la Vita di Pordenone, Italy
- Ricerca Scientifica Applicata, Regione Friuli Venezia Giulia (Linfonet Project), Trieste, Italy
- 5x1000 Intramural Program, Centro di Riferimento Oncologico, Aviano, Italy
- Beat-Leukemia fellowship
- Ministero della Salute, Rome, Italy
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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.
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