1. ¹Our Lady of Mercy Cancer Center, New York Medical College, Bronx, NY, USA
2. ²Dana Farber Cancer Institute, Boston, MA, USA
3. ³White Plains Hospital, White Plains, NY, USA
4. ⁴University of Rochester Cancer Center, Rochester, NY, USA
5. ⁵Decatur Memorial Hospital, Decatur, IL, USA
6. ⁶Iowa Blood and Cancer Care, Cedar Rapids, IA, USA
7. ⁷Evanston Hospital, Evanston, IL, USA
8. ⁸Northwestern University Feinberg School of Medicine, Chicago, IL, USA
9. ⁹The Eastern Cooperative Oncology Group, Boston, MA, USA

Correspondence: Dr PH Wiernik, Comprehensive Cancer Center, Our Lady of Mercy Hospital, Our Lady of Mercy Cancer Center, New York Medical College, 600 East 233rd Street, Bronx, NY 10466 USA. Fax +1 718 920 1162; E-mail: PWiernik@aol.com

¹⁰Current address: University of Maryland Greenebaum Cancer Center, Baltimore, MD, USA.

Received 19 April 2004; Accepted 26 July 2004; Published online 9 September 2004.

Abstract

The Eastern Cooperative Oncology Group (ECOG) performed a phase 2 study in B-cell chronic lymphocytic leukemia (CLL) of oral theophylline, a methylxanthine that inhibits cyclic nucleotide phosphodiesterases, thereby inducing the intracellular accumulation of cyclic adenosine monophosphate (cAMP). In 25 patients with Rai stages 0–I, theophylline, 200 mg given orally every 12 h was well tolerated. There was one complete response after 22.5 months of treatment, which continues at 27+ months, and 18 other patients had stable disease. In vitro exposure of patients' lymphocytes to aminophylline (75–250 g/ml), the soluble form of theophylline, resulted in dose- and time-dependent induction of apoptosis in 9/20 patients studied. Apoptosis was documented flow-cytometrically by monitoring the expression of bcl-2 and bax, forward light scatter, fluorescence intensity of binding of CD45 antibody, and the binding of annexin. Patients whose leukemic lymphocytes were susceptible to apoptosis induction by aminophylline in vitro experienced a significantly longer progression-free survival than patients whose cells were resistant to the drug in culture (P=0.025). This suggests that in a CLL population treated with theophylline, induction of an apoptotic response to the drug in vitro is prognostic for absence of clinical progression.