title: Clinical significance of bax/bcl-2 ratio in chronic lymphocytic leukemia.
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 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.
authors.affiliation: Ematologia, Dipartimento di Biomedicina e Prevenzione, S. Eugenio Hospital and Università Tor Vergata, Roma, Italy.
authors.forename: Maria Ilaria
authors.initials: MI
authors.lastname: Del Principe
authors.affiliation: Unità Clinica e Sperimentale Onco-Ematologica, Centro di Riferimento Oncologico, I.R.C.C.S., Aviano, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Dal Bo
authors.affiliation: Unità Clinica e Sperimentale Onco-Ematologica, Centro di Riferimento Oncologico, I.R.C.C.S., Aviano, Italy.
authors.forename: Tamara
authors.initials: T
authors.lastname: Bittolo
authors.affiliation: Ematologia, Dipartimento di Biomedicina e Prevenzione, S. Eugenio Hospital and Università Tor Vergata, Roma, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Buccisano
authors.affiliation: Unità Clinica e Sperimentale Onco-Ematologica, Centro di Riferimento Oncologico, I.R.C.C.S., Aviano, Italy.
authors.forename: Francesca Maria
authors.initials: FM
authors.lastname: Rossi
authors.affiliation: Unità Clinica e Sperimentale Onco-Ematologica, Centro di Riferimento Oncologico, I.R.C.C.S., Aviano, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Zucchetto
authors.affiliation: Ematologia, Università del Piemonte Orientale, Novara, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Rossi
authors.affiliation: Unità Clinica e Sperimentale Onco-Ematologica, Centro di Riferimento Oncologico, I.R.C.C.S., Aviano, Italy.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Bomben
authors.affiliation: Ematologia, Dipartimento di Biomedicina e Prevenzione, S. Eugenio Hospital and Università Tor Vergata, Roma, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Maurillo
authors.affiliation: Ematologia, Dipartimento di Biomedicina e Prevenzione, S. Eugenio Hospital and Università Tor Vergata, Roma, Italy.
authors.forename: Mariagiovanna
authors.initials: M
authors.lastname: Cefalo
authors.affiliation: Ematologia, Dipartimento di Biomedicina e Prevenzione, S. Eugenio Hospital and Università Tor Vergata, Roma, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: De Santis
authors.affiliation: Ematologia, Dipartimento di Biomedicina e Prevenzione, S. Eugenio Hospital and Università Tor Vergata, Roma, Italy.
authors.forename: Adriano
authors.initials: A
authors.lastname: Venditti
authors.affiliation: Ematologia, Università del Piemonte Orientale, Novara, Italy.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Gaidano
authors.affiliation: Ematologia, Dipartimento di Biomedicina e Prevenzione, S. Eugenio Hospital and Università Tor Vergata, Roma, Italy.
authors.forename: Sergio
authors.initials: S
authors.lastname: Amadori
authors.affiliation: Ematologia, Dipartimento di Biomedicina e Prevenzione, S. Eugenio Hospital and Università Tor Vergata, Roma, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: de Fabritiis
authors.affiliation: Unità Clinica e Sperimentale Onco-Ematologica, Centro di Riferimento Oncologico, I.R.C.C.S., Aviano, Italy.
authors.forename: Valter
authors.initials: V
authors.lastname: Gattei
authors.affiliation: Ematologia, Dipartimento di Biomedicina e Prevenzione, S. Eugenio Hospital and Università Tor Vergata, Roma, Italy g.delpoeta@tin.it del.principe@med.uniroma2.it.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Del Poeta
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D002699:Chlorambucil / Q000008:administration & dosage; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000097:blood / Q000188:drug therapy / Q000401:mortality; D008297:Male; D008875:Middle Aged; D011237:Predictive Value of Tests; D011239:Prednisolone / Q000008:administration & dosage; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000097:blood*; D012189:Retrospective Studies; D000069283:Rituximab / Q000008:administration & dosage; D015996:Survival Rate; D014740:Vidarabine / Q000008:administration & dosage / Q000031:analogs & derivatives; D051028:bcl-2-Associated X Protein / Q000097:blood*
chemical_list: C494826:BAX protein, human; C000595707:BCL2 protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D002699:Chlorambucil; D000069283:Rituximab; D011239:Prednisolone; D014740:Vidarabine; C024352:fludarabine