TY - JOUR
T1 - Phase I-II clinical and pharmacologic studies of high-dose cytosine arabinoside in refractory leukemia
AU - Kantarjian, Hagop M.
AU - Estey, Elihu H.
AU - Plunkett, William
AU - Keating, Michael J.
AU - Walters, Ronald S.
AU - Iacoboni, Stephen
AU - McCredie, Kenneth B.
AU - Freireich, Emil J.
N1 - Funding Information:
From the Division of Medicine, Departments of Hematology and Chemotherapy Research, University of Texas M. D. Anderson Hospital and Tumor Institute at Houston, Houston, Texas. This work was supported by Grant CA-32839 from the National Cancer Institute, National Institutes of Health, United States Public Health Service, Bethesda, Maryland. Dr. Kantarjian is a Special Fellow of the Leukemia Society of America. Dr. Keating is a Scholar of the Leukemia Society of America. Requests for reprints should be addressed to Dr. Hagop M. Kantarjian, M.D. Anderson Hospital and Tumor Institute, Department of Hematology, Box 47, 6723 Bertner, Houston, Texas 77030. Manuscript submitted March 8, 1985, and accepted September 6, 1985. “Current address: 401 Bicentennial, Santa Rosa, California 9540 1.
PY - 1986/9
Y1 - 1986/9
N2 - Sixty-four patients with refractory acute leukemia were treated with high-dose cytosine arabinoside given at a dosage of 3 g/m2 intravenously over two hours every 12 hours for four to 12 doses, repeated at two- to three-week intervals. Complete remissions were observed in 16 patients (25 percent), and the median duration of remission was three months (range, one to 10 months). Remission rates were similar for patients with acute myelogenous and acute lymphocytic leukemia (24 and 27 percent, respectively). Response rates were significantly higher in patients with initial remission durations of more than six months than in those with shorter remissions or those in whom there was no response to front-line therapy (41 and 9 percent; p <0.01). Similarly, patients with disease sensitive to conventional cytosine arabinoside had higher response rates than did those with resistant disease (54 and 17 percent; p = 0.03). Serial in vivo measurements of intracellular concentrations of the active metabolite of cytosine arabinoside in peripheral blasts following the initial dose demonstrated considerable individual variation. Favorable intracellular pharmacology of this active metabolite, manifested by its higher intracellular concentrations 12 hours after the first dose, by longer half-lives of active metabolite levels, and by higher values of the measured area under the curve of its accumulation and retention, was associated with higher response rates. Central nervous system toxicity occurred in 24 percent of patients, and pulmonary toxicity occurred in 22 percent; both were dose-limiting and dose-related. Other toxicities included nausea, vomiting, diarrhea, conjunctivitis, photophobia, cytosine arabinoside fever, skin rashes, and hepatic dysfunction. Response rates were similar for schedules utilizing four to six doses at two-week intervals or nine doses at three-week intervals (27 percent versus 25 percent). The schedule of 12 doses had a more rapid antileukemic effect but resulted in significantly higher toxicity and mortality rates during therapy with a similar overall response rate (21 percent). Thus, high-dose cytosine arabinoside is an effective regimen with substantial toxicity in patients with acute leukemia.
AB - Sixty-four patients with refractory acute leukemia were treated with high-dose cytosine arabinoside given at a dosage of 3 g/m2 intravenously over two hours every 12 hours for four to 12 doses, repeated at two- to three-week intervals. Complete remissions were observed in 16 patients (25 percent), and the median duration of remission was three months (range, one to 10 months). Remission rates were similar for patients with acute myelogenous and acute lymphocytic leukemia (24 and 27 percent, respectively). Response rates were significantly higher in patients with initial remission durations of more than six months than in those with shorter remissions or those in whom there was no response to front-line therapy (41 and 9 percent; p <0.01). Similarly, patients with disease sensitive to conventional cytosine arabinoside had higher response rates than did those with resistant disease (54 and 17 percent; p = 0.03). Serial in vivo measurements of intracellular concentrations of the active metabolite of cytosine arabinoside in peripheral blasts following the initial dose demonstrated considerable individual variation. Favorable intracellular pharmacology of this active metabolite, manifested by its higher intracellular concentrations 12 hours after the first dose, by longer half-lives of active metabolite levels, and by higher values of the measured area under the curve of its accumulation and retention, was associated with higher response rates. Central nervous system toxicity occurred in 24 percent of patients, and pulmonary toxicity occurred in 22 percent; both were dose-limiting and dose-related. Other toxicities included nausea, vomiting, diarrhea, conjunctivitis, photophobia, cytosine arabinoside fever, skin rashes, and hepatic dysfunction. Response rates were similar for schedules utilizing four to six doses at two-week intervals or nine doses at three-week intervals (27 percent versus 25 percent). The schedule of 12 doses had a more rapid antileukemic effect but resulted in significantly higher toxicity and mortality rates during therapy with a similar overall response rate (21 percent). Thus, high-dose cytosine arabinoside is an effective regimen with substantial toxicity in patients with acute leukemia.
UR - http://www.scopus.com/inward/record.url?scp=0022520780&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0022520780&partnerID=8YFLogxK
U2 - 10.1016/0002-9343(86)90287-1
DO - 10.1016/0002-9343(86)90287-1
M3 - Article
C2 - 3463209
AN - SCOPUS:0022520780
SN - 0002-9343
VL - 81
SP - 387
EP - 394
JO - The American journal of medicine
JF - The American journal of medicine
IS - 3
ER -