Relapsed Acute Promyelocytic Leukemia Previously Treated with All-Trans Retinoic Acid: Clinical Experience with a New Synthetic Retinoid, Am-80

Abstract

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 been postulated, treatment strategies to overcome resistance have not been established. We used a new synthetic retinoid, Am-80, as reinduction therapy for APL relapse after from ATRA-induced CR. Am-80 was several times more potent than ATRA in inducing differentiation in vitro. At a 6 mg/m² dose, there were 24 evaluable patients; 14(58 %) achieved CR between days 20 and 58 (median, 37 days). Clinical response correlated with the in vitro response to Am-80. Adverse effects included retinoic acid syndrome(n = 1), hyperleukocytosis(n = 1), xerosis(n = 9), cheilitis (n = 8), hypertriglyceridemia (n = 16), and hypercholesterolemia (n = 15). Am-80 is active in APL after relapse from ATRA-induced CR. Further clinical trials are needed to establish strategies to overcome ATRA resistance.

Key Words:

• Am-80
• acute promyelocytic leukemia
• all-trans retinoic acid
• PML-RARα chimeric messenger RNA
• differentiation therapy