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Blood, Vol. 94 No. 8 (October 15), 1999:
pp. 2836-2843
In Vitro Evaluation of Fludarabine in Combination With Cyclophosphamide
and/or Mitoxantrone in B-Cell Chronic Lymphocytic Leukemia
Beatriz Bellosillo,
Neus Villamor,
Dolors Colomer,
Gabriel Pons,
Emili Montserrat, and
Joan Gil
From the Departament de Ciències Fisiològiques II,
Universitat de Barcelona, Campus de Bellvitge, L'Hospitalet, Spain;
and the Unitat d'Hematopatologia, Servei d'Hematologia, Institut
d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS),
Hospital Clínic, Barcelona, Spain.
B-chronic lymphocytic leukemia (B-CLL) is characterized by the
accumulation of long-lived CD5+ B lymphocytes. We have
analyzed the effect in vitro of the combination of fludarabine with
cyclophosphamide and/or mitoxantrone on cells from 20 B-CLL patients.
Mafosfamide, the active form of cyclophosphamide in vitro, increased
the cytotoxicity of fludarabine in all of the patients studied and
produced a significant synergistic effect (P < .01) after 48 hours of incubation. The addition of mitoxantrone to this combination
increased the cytotoxic effect in cells from 8 patients, but in the
remaining 12 patients no significant increase was observed. The effect
of fludarabine and mafosfamide was dose-dependent. Mafosfamide and
fludarabine had a synergistic effect in inducing apoptosis of B-CLL
cells as determined by DNA staining with propidium iodide and analysis
of phosphatidylserine exposure. Mafosfamide significantly increased the
apoptosis induced by fludarabine on CD19+ cells
(P = .007), but not on CD3+ cells (P
= .314). Cell viability was correlated with a decrease in Mcl-1
levels and an increase in p53 levels. These results support that
fludarabine in combination with cyclophosphamide and/or mitoxantrone can be highly effective in the treatment of B-CLL.
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