INDUCTION IN-VITRO OF APOPTOSIS IN CHRONI C LYMPHOCYTIC-LEUKEMIA B-LYMPHOCYTES BY THEOPHYLLIN - THERAPEUTIC APPLICATIONS

In a case of indolent stage A chronic lymphocytic leukemia (C.L.L.), t reated for ten years only by theophylline for bronchial asthma, we obs erved spontaneous apoptosis of B lymphocytes (10%). As suggested by th ese case report, we described new properties of methylxanthine derivat ives. In vitro, theophylline increased spontaneous apoptosis after 72 hours in culture of 6 patients by a mean percentage of 80-90% in B-C.L .L. blood lymphocytes (control 20%). Dose-dependent apoptosis involves cyclic nucleotides (AMPc). Using identical theophylline doses, we did not observe apoptosis of normal peripheral blood B lymphocytes. Accor ding to French ethical rules, we treated 8 patients with the same dose s of theophylline than for bronchial asthma without responses. On the other hand, in 12 aggressive forms of C.L.L., resistant or in relapsed after alkylating agents, methylxanthine derivatives appeared a powerf ul adjuvant of chlorambucil treatment. We observed 11 responses with l ess dose of alkylating agents than in previous treatment : decrease in the concentration of blood lymphocytes (11 patients) and clinical rem issions (8 patients). Mechanism of action and future of this new drugs combination in the treatment of C.L.L. are discussed.