2-Chlorodeoxyadenosine activity in patients with untreated chronic lymphocytic leukemia.

PURPOSE: 2-chlorodeoxyadenosine (2-CdA; cladribine) is a purine analog with activity in patients with chronic lymphocytic leukemia (CLL) who fail to respond to alkylator therapy. We conducted a phase II trial of 2-CdA in previously untreated CLL patients. PATIENTS AND METHODS: 2-CdA was administered to 20 patients with previously untreated CLL as a 0.1-mg/kg/d 7-day continuous intravenous infusion every 28 to 35 days until maximum response or prohibitive toxicity. RESULTS: A median of four courses (range, one to nine) was administered to each patient. Five patients (25%) achieved a complete response and 12 (60%) achieved a partial response, for an overall response rate of 85%. The median response follow-up duration was 8+ months (range, 3 to 27). Myelosuppression was the principal toxicity. Four of 20 patients (20%) experienced grade III or IV thrombocytopenia. Three patients, all of whom received corticosteroid therapy, developed opportunistic infections at a median of 19 months following discontinuation of 2-CdA therapy. CONCLUSION: 2-CdA has major activity in patients with previously untreated CLL, and the lower response rates seen in previously treated patients may be due in part to poor marrow reserve from prior therapy. Determination of the relative effectiveness of 2-CdA, fludarabine, and chlorambucil in the treatment of CLL patients will require a randomized trial.

Complete hematologic remissions in chronic-phase, Philadelphia-chromosome-positive, chronic myelogenous leukemia after 2-chlorodeoxyadenosine.

BACKGROUND: 2-Chlorodeoxyadenosine (Cladribine, Leustatin, Ortho Biotech, Raritan, NJ) (2-CdA) is a purine analog with activity in the treatment of lymphoid neoplasms. Interferon induces cytogenetic remissions in chronic myeloid leukemia (CML) and partial remissions in hairy cell leukemia, a disorder in which single courses of 2-CdA induce complete remissions. In vitro clonal growth of immature myeloid progenitors from normal marrow is markedly inhibited by 2-CdA. METHODS: 2-CdA was administered to 12 patients with Philadelphia-chromosome-positive CML, 11 chronic phase, and 1 accelerated phase, at 0.1 mg/kg/day by continuous intravenous infusion for 7 days every 28-35 days, until maximum peripheral hematologic response. RESULTS: Of 12 patients, 10 (83%) achieved complete hematologic responses and 2 (17%) partial hematologic responses after a median of two courses of 2-CdA. The median first hematologic response duration was 3 months. Of the seven patients who relapsed and were retreated with a median of two further courses of 2-CdA, five obtained responses (four complete and one partial) and two did not respond. The median second hematologic response duration was 4 months. No patient had significant Philadelphia-chromosome suppression. Reversible myelosuppression and severe cumulative T-cell immunosuppression associated with opportunistic infections in four patients were the principal toxicities. CONCLUSIONS: 2-CdA is active in CML, inducing complete hematologic responses, but the absence of cytogenetic responses and severe immunosuppression may limit its clinical use.

Calmodulin inhibition of brain membrane phosphorylation.

Calmodulin has been found to inhibit the phosphorylation of rat brain membrane proteins of molecular weight 14,900-18,900 in a dose-dependent manner. This phenomenon was seen under conditions in which calmodulin simultaneously produced a stimulatory effect on the phosphorylation of proteins of molecular weight 51,000 and above. This inhibition required calcium, but was not sensitive to cyclic AMP or increasing ATP concentration and was not due to activation of a phosphatase. These results suggest either that calmodulin induces its inhibitory effects on phosphorylation by an indirect mechanism via a presently unknown pathway, or that in addition to the kinase stimulated by calmodulin, there exists another distinct kinase which is inhibited by calmodulin.