Published in Cancer Detection and Prevention 2000; 24(Supplement 1).

Relapsed acute promyelocytic leukemia previously treated with all-trans retinoic acid: clinical experience with a new synthetic retinoid, Am-80

M Takeuchi MD, T Yano MD 2, K Takahashi MD 1, K Shudo MD 3, M Harada MD 2, R Ueda MD 4, R Ohno MD 5

1 Dept Internal Medicine, National Sanatorium Minami Okayama Hospital, Tsukubo Gun, Japan, 2 Second Dept Internal Medicine, Okayama University Medical School, Okayama, Japan, 3 Faculty of Pharmaceutical Sciences, Tokyo University, Tokyo, Japan, 4 Second Dept Internal Medicine, Nagoya City University, Nagoya, Japan, 5 Third Dept Internal Medicine, Hamamatsu College of Medicine, Hamamatsu, Japan,

(AIMS) All-trans retinoic acid (ATRA), a potent differentiating drug for acute promyelocytic leukemia (APL), induces a high incidence of complete remission (CR) in patients with APL and is now established as a first-line therapy. However, ATRA resistance has become a clinical problem. Patients who relapsed after ATRA-induced CR have had difficulty in obtaining a second CR with ATRA therapy. Although several mechanisms have beeen postulated, treatment strategies to overcome resistance have not been established. (METHODS) We used a new synthetic retinoid, Am-80, as reinduction therapy for APL relapse after from ATRA-induced CR at a daily 6 mg/m2 dose. Am-80 was several times more potent than ATRA in inducing differentiation in vitro and had no binding affinity for cytoplasmic retinoic acid-binding protein, the increased expression of which is considered to be one important mechanism of ATRA resistance. (RESULTS) There were 24 evaluable patients; 14 (58%) achieved CR between days 20 and 58 (median, 37 days). Adverse effects included retinoic acid syndrome(n=1), hyperleukocytosis(n=1), xerosis(n=9), cheilitis (n=8), hypertriglyceridemia (n=16), and hypercholesterolemia(n=15). (CONCLUSIONS) Am-80 is active in APL after relapse from ATRA-induced CR. Now clinical phase 2 study of Am-80 is ongoing in Japan. We are hopeful of establishing the strategy to overcome ATRA resistance.

KEY WORDS: Am-80, acute promyelocytic leukemia, all-trans retinoic acid, differentiation therapy.

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Paper presented at the International Symposium on Impact of Biotechnology on Cancer Diagnostic & Prognostic Indicators; Geneva, Switzerland; October 28 - 31, 2000; in the section on differentiation therapy.