Chlorambucil Plus Theophylline vs Chlorambucil Alone as a Front Line Therapy for B-Cell Chronic Lymphatic Leukemia

Abstract

B-cell chronic lymphatic leukemia (B-CLL) has emerged as a prototype of malignancies characterized by a defective apoptosis that leads to a progressive accumulation of monoclonal B cells in the bone marrow, lymphoid tissues and peripheral blood. Chlorambucil, an aromatic derivative of nitrogen mustards, is the most common treatment for chronic lymphatic leukemia (CLL). The response rate with its use is 40 to 60%, with 3 to 10% only of patients achieving a complete response (CR). To improve response rates, chlorambucil has been combined with steroids or other agents. Theophylline, a methylxanthine commonly used as a treatment for asthma, has been shown to induce apoptosis in CLL cells both in vitro and in vivo. Chlorambucil induces apoptosis in CLL cells as well and synergy has been shown between the two drugs without affecting the normal B lymphocytes. The aim of this work was to evaluate the potential utility of this combination as a therapeutic modality for B-CLL. A total of 210 B-CLL patients were recruited and randomized to receive either chlorambucil in an oral dose of 0.1 mg/kg/day indefinitely (109 patients) or chlorambucil 0.1 mg/kg/day plus theophylline 200 mg bid, orally (101 patients). The main endpoints were overall survival from the time of randomization, disease status after 9 months and time to disease progression. After 9 months of treatment, clinical and hematological remission was achieved in 14 patients (12.8%) in the chlorambucil group, compared to 26 (25.7%) in the chlorambucil plus theophylline group (P value 0.01). Partial remission was observed for 38 patients (34.9%) in the chlorambucil group and 36 patients (35.7%) in the chlorambucil plus theophylline group. In patients treated with chlorambucil alone, the median progression-free survival (PFS) was 30 months and in patients treated with chlorambucil plus theophylline it was 44 months. Probabilities of PFS at 24 months for the chlorambucil-treated patients were 59% and 85% for the chlorambucil plus theophylline-treated patients. The difference was statistically significant (P = 0.006). The 3-year and 5-year overall survival rates were, respectively 75% and 38% in the chlorambucil group as opposed to 76% and 46% in the chlorambucil plus theophylline group. The median survival time was 55 months in the chlorambucil group and 56 months in the chlorambucil plus theophylline group. Forty-nine patients died in the chlorambucil group compared to 44 patients in the chlorambucil plus theophylline group (P = 0.371). The trial has demonstrated that adding theophylline to the standard treatment of B-CLL significantly increases effectiveness of treatment in terms of tumor response and time to disease progression. It could not improve the overall survival. Treatment with theophylline does not compromise quality of life or add significant toxicity. As newer drugs have recently become available for treating patients with CLL like fludarabine, further trials are needed to evaluate the effect of combining theophylline with these drugs.