All-trans retinoic acid as a differentiation therapy for acute promyelocytic leukemia. I. Clinical results.

Twenty-two patients with acute promyelocytic leukemia were treated with all-trans retinoic acid (RA, 45 mg/m2 per day) for 90 days. Of the 22, four patients were previously untreated, two were resistant after conventional chemotherapy, and 16 were in first (n = 11 1, second (n = 4). or third (n = 1) relapse. We observed 14 complete response, four transient responses, one failure, and three early deaths. Length of hospitalization and number of transfusions were notably reduced in complete responders. Correction of coagulation disorders and an increase of WBCs were the first signs of all-trans RA efficacy. Morphologic analysis performed at days 0.15.30,45,60, and 90 showed that complete remissions were obtained without bone marrow (BM) hypoplasia. Presence of Auer rods in the maturing cells confirmed the differentiation effect of the treatment. At remission, the t(l5;17) initially present in 20 CUTE PROMYELOCYTIC leukemia [M3 in the A French-American-British (FAB) classification] ’,* represents 5% to 15% of cases of acute nonlymphocytic leukemia (ANLL). Several well-recognized features are characteristics of this entity: a distinct cytologic characteristic within the FAB classification (M3 or M3 variant), an associated coagulopathy often increased by ~hemotherapy,~ and a distinct chromosomal abnormality-a balanced translocation between the long arm of chromosome 15 and the long arm of chromosome 17.4 Although M3 is very sensitive to ~hemotherapy,~.~ 10% to 20% of the patients die early of fatal hemorrhage resulting from coagulopathy. Studies of the length of complete remission (CR) show controversial results, some of them indicating a greater disease-free survival than in the other ANLLs7,* An alternative approach to treatment of ANLL has been suggested in recent years by studies of leukemic cell differentiation. Of the differentiating agents, retinoic acid (RA), the active metabolite of vitamin A is the most potent. The two naturally occurring isomers of RA, all-trans RA and 13-cis RA, are active inducers of differentiation in human myeloid leukemic cell lines (HL-60, U-937, and THP-1). Although other synthetic analogues may be more potent some, like etretinate, have no effect on