Phase II study of theophylline in chronic lymphocytic leukemia: a study of the Eastern Cooperative Oncology Group (E4998).
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 microg/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.
Wiernik
P H
PH
Our Lady of Mercy Cancer Center, New York Medical College, Bronx, NY 10466, USA. PWiernik@aol.com <PWiernik@aol.com>
Paietta
E
E
Goloubeva
O
O
Lee
S J
SJ
Makower
D
D
Bennett
J M
JM
Wade
J L
JL
Ghosh
C
C
Kaminer
L S
LS
Pizzolo
J
J
Tallman
M S
MS
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000187:drug effects*; D001402:B-Lymphocytes / Q000187:drug effects*; D000242:Cyclic AMP / Q000378:metabolism; D005260:Female; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D015996:Survival Rate; D013806:Theophylline / Q000627:therapeutic use*; D014665:Vasodilator Agents / Q000627:therapeutic use*; D051028:bcl-2-Associated X Protein
C494826:BAX protein, human; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D014665:Vasodilator Agents; D051028:bcl-2-Associated X Protein; D013806:Theophylline; D000242:Cyclic AMP