A randomized comparison of all transretinoic acid (ATRA) followed by chemotherapy and ATRA plus chemotherapy and the role of maintenance therapy in newly diagnosed acute promyelocytic leukemia

All transretinoic acid (ATRA) followed by daunorubicin (DNR)-AraC chemother apy (CT) has improved the outcome of acute promyelocytic leukemia (APL) by comparison to CT alone. In a randomized trial, (1) we compared 2 induction schedules (ATRA followed by CT [ATRA-CT] and ATRA plus CT [ATRA+CT, with CT added on day 3 of ATRA treatment]) and (2) we assessed the role of mainten ance treatment. Four hundred thirteen patients less than or equal to 75 yea rs of age and with newly diagnosed APL were included. Induction treatment w as stratified on white blood cell (WBC) count and age: patients less than o r equal to 65 years of age and with an initial WBC count of less than or eq ual to 5,000/pL (n = 208) were randomized between ATRA-->CT and ATRA+CT (in itially randomized patients); patients with a WBC count greater than (high WBC count group, n = 163) and patients 66 to 75 years of age with a WBC cou nt greater than 5,000/mu L (elderly group, n = 42) were not initially rando mized and received ATRA+CT from day 1 and ATRA-->CT, respectively. All pati ents achieving CR received 2 additional DNR-AraC courses (only 1 in patient s 66 to 75 years of age) and were then randomized for maintenance between n o treatment, intermittent ATRA (15 days every 3 months) for 2 years, contin uous low-dose CT (6 mercaptopurine+methotrexate) for 2 years, or both, usin g a 2-by-2 factorial design. Overall, 381 (92%) of the patients achieved co mplete remission (CR), 31 (7%) suffered an early death, and only 1 patient had leukemic resistance. ATRA syndrome occurred in 64 patients (15%) and wa s fatal in 5 cases. The CR rate was similar in all induction treatment grou ps. Event-free survival (EFS) was significantly lower in the high WBC group (P = .0002) and close to significance in the elderly group (P = .086) as c ompared with initially randomized patients. Relapse at 2 years was estimate d at 6% in the ATRA+CT group, versus 16% in the ATRA-->CT group (P = .04, r elative risk [RR] = .41). EFS at 2 years was estimated at 84% in the ATRA+C T group, versus 77% in the ATRA-CT group (P = .1, RR = .62). Two hundred ei ghty-nine patients were randomized for maintenance. The 2-year relapse rate was 11% in patients randomized to continuous maintenance CT and 27% in pat ients randomized to no CT (P = .0002) end 13% in patients randomized to int ermittent ATRA and 25% in patients randomized to no ATRA (P = .02). An addi tive effect of continuous maintenance CT and intermittent ATRA was seen, an d only 6 of the 74 patients who received both maintenance treatments had re lapsed. Overall survival was improved in patients who received maintenance CT (P = .01), and there was a trend for better survival in patients who rec eived maintenance ATRA (P = .22). Our findings strongly suggest that early addition of chemotherapy to ATRA and maintenance therapy combining continuo us CT end intermittent ATRA can reduce the incidence of relapse in APL. Thi s effect already translates into significantly better survival for maintena nce treatment with continuous CT. (C) 1999 by The American Society of Hemat ology.