Soluble p53 Predict for Poor Response to Fludara

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[1500] Clinical Significance of Soluble p53 in

B-chronic lymphocytic leukemia.

Giovanni Del Poeta, Luca Maurillo, o Venditti,

Giovanna Suppo, Francesco Buccisano, Tamburini,

Ilaria Del Principe, Kathleen A. Scornajenghi,

a Piccioni, Bruno, Masi,

Amadori. Hematology, University " Tor Vergata " , Rome,

Italy

An understanding of the biology of B-cell chronic

lymphocytic leukemia (B-CLL) has led to the concept

that several different B-cell diseases are represented

under this name. Reports from the literature have

showed that variability in the bcl-2 family of

proteins, p53 mutations, various chromosomal

abormalities and CD38 expression corresponds to

variability of the clinical course of disease and

response to therapy.

It is well known that high p53 protein levels are

significantly correlated with mutations in the gene

and with disease progression and poor prognosis

(Cordone et al, Blood, 1998). Moreover, p53 gene

deletion predicts for non-response to therapy with

purine analogs and for poor survival in B-CLL (Dohner

et al, Blood, 1995).

In order to define the precise role of p53 protein in

determining the B-CLL heterogeneous clinical activity,

we performed immunoenzymatic assays (Euroclone) for

p53 wild-type and mutant forms (sp53) on plasma of 172

patients (pts), median age 65 years, 90 males and 82

females, all fulfilling the recommended diagnostic

criteria for B-CLL, with dim surface immunoglobulins

and CD5+/CD23+ immunological pattern. The threshold

for considering B-CLL cases as " p53 positive " was set

at sp53 3.5 U/ml (range 0.1-18.3). With regard to pts

characteristics, 51 had low modified Rai stage, 109

intermediate stage and 12 high stage. Ninenty-four pts

were treated, 47 with chlorambucil at conventional

doses and 47 with six courses of fludarabine

monophosphate. Forty-seven pts were sp53 positive

(47/172; 27.3%). Sp53 was significantly and directly

correlated both with soluble CD23 (sCD23) levels

(r=0.31, p=00003) and with CD38 percentages determined

by flow cytometry (r=0.28, p=0.0002). Almost all

(43/47) sp53 positive pts were within

intermediate/high Rai stages (p<0.00001) and 10/12 pts

with lymphocyte doubling time (LDT) < 12 months were

sp53 positive (p=0.00004). Beta2-microglobulin >2.2

mg/ml was significantly associated with sp53 3.5 U/ml

(34/46; p=0.0005).

Furthermore, the presence of three or more

intrathoracic /abdominal lymphadenopathies (>3 cm in

diameter) and/or splenomegaly was significantly

correlated with sp53 3.5 (39/47; p<0.00001).

Twenty-one out of 47 sp53 positive pts were treated

with fludarabine and only 6 pts achieved a complete

remission (CR) (28% vs 54%; p=0.013).

With regard to clinical outcome, sp53 positive pts

showed both a significant shorter progression-free

survival (PFS) (5% vs 66% at 8 years ; p<0.00001) and

overall survival (OS) (51% vs 98% at 10 years;

p=0.00001). In multivariate analysis, sp53 was

confirmed in being an independent prognostic factor

with regard to PFS (p=0.00008) and OS (p=0.044)

together with CD38 expression. Therefore, high sp53

levels identify pts in advanced clinical stages and

predict for poor response to fludarabine and worse PFS

or OS.

In conclusion, sp53 protein represents a significant

additional biological parameter in order to enucleate

a " high risk " B-CLL subset candidate for novel

therapeutic approaches.

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