Leukemia (2003) 17, 339–342  2003 Nature Publishing Group All rights reserved 0887-6924/03 $25.00 www.nature.com/leu Early onset of chemotherapy can reduce the incidence of ATRA syndrome in newly diagnosed acute promyelocytic leukemia (APL) with low white blood cell counts: results from APL 93 trial S de Botton, S Chevret, V Coiteux, H Dombret, M Sanz, J San Miguel, D Caillot, A Vekhoff, M Gardembas, A Stamatoulas, E Conde, A Guerci, C Gardin, M Fey, D Cony Makhoul, O Reman, J de la Serna, F Lefrere, C Chomienne, L Degos and P Fenaux for the European APL group Treatment combining ATRA and chemotherapy (CT) has improved the outcome of APL patients, by comparison with CT alone. ATRA syndrome is a life-threatening complication of ATRA treatment whose prophylaxis remains somewhat contro- versial. In APL93 trial, newly diagnosed APL patients 65 years and with initial WBC counts below 5000/mm 3 were randomized between ATRA until CR achievement followed by CT (ATRA → CT) and ATRA with early addition of CT, on day 3 of ATRA treat- ment (ATRA + CT). The incidence of ATRA syndrome in the ATRA → CT arm was 18% (22/122) as compared to 9.2% (17/184) in the ATRA + CT arm (P = 0.035). In the ATRA → CT arm, three (2.5%) patients died from ATRA syndrome, as compared to one (0.5%) in the ATRA + CT group. Early addition of chemotherapy to ATRA in newly diagnosed APL with low WBC counts signifi- cantly reduced the incidence of ATRA syndrome. Leukemia (2003) 17, 339–342. doi:10.1038/sj.leu.2402807 Keywords: acute promyelocytic leukemia; ATRA syndrome; prophylaxis chemotherapy Introduction Treatment combining ATRA and anthracycline (AraC) chemo- therapy has improved the prognosis of APL. 1–7 ATRA syn- drome, a life-threatening complication of ATRA treatment of uncertain pathogenesis, 8–13 can be observed in 5 to 25% of APL cases. 7,14–19 It is characterized, generally in a context of increasing WBC counts, by fever, weight gain, respiratory dis- tress with lung infiltrates, pleural and sometimes pericardial effusion, and possible renal failure. 20 Mortality of ATRA syn- drome ranges from 5% to 30%, 7,14–19 although it has improved recently due to earlier recognition and better treatment. Its prophylaxis remains somewhat controversial, consisting of early addition of chemotherapy to ATRA in case of increas- ing WBC counts for some groups, 2,18 whereas other groups prefer the addition of high-dose steroids only in this situ- ation. 19 In a randomized trial, we found that early addition of chemotherapy to ATRA in newly diagnosed APL significantly reduced the incidence of ATRA syndrome. Patients and methods APL 93 trial Between 1993 and 1998, patients with newly diagnosed APL were eligible based on the following criteria: (1) diagnosis of APL, based on morphological criteria; (2) age 75 years or less; and (3) informed consent. Diagnosis had to be subsequently Correspondence: P. Fenaux, Service d’He ´matologie Clinique, Ho ˆpital Avicenne, 125 route de Stalingrad, 93009 Bobigny, France; Fax: 33 (0)1 48 95 54 50/99 Received 27 May 2002; accepted 30 August 2002 confirmed by the presence of t(15;17) or PML-RAR gene rearrangement. Induction treatment was stratified on age and initial WBC counts. Patients aged 65 or less years with WBC less than 5000/l were randomized between ATRA followed by CT (ATRA → CT group) and ATRA + CT (ATRA + CT). In the ATRA → CT group, patients received ATRA 45 mg/m 2 /day orally until CR or for a maximum of 90 days. After CR achieve- ment, they received a course of daunorubicin (DNR) 60 mg/m 2 /day for 3 days and Ara-C 200 mg/m 2 /day for 7 days (course I). However, course I was added to ATRA if WBC rose above 6000/l, 10 000/l, or 15 000/l by days 5, 10 and 15 of ATRA treatment, respectively, as from our experience, patients were at higher risk of ATRA syndrome above those thresholds. CT was also to be immediately added if clinical signs of ATRA syndrome developed, irrespective of the WBC count. Patients randomized to the ATRA + CT group received the same combination of ATRA and CT, but CT course I was started on day 3 of ATRA treatment. Patients with WBC > 5000/l at presentation or aged 66 to 75 years and with WBC less than 5000/l were not randomized and received ATRA + CT course I from day 1 (high WBC group) and the same treat- ment as in the ATRA → CT group (elderly group), respectively. Patients who achieved CR received two consolidation CT courses, and were offered a second randomization testing both intermittent ATRA and continuous CT with 6-mercaptop- urine and methotrexate, both scheduled for 2 years, using a (2 × 2) design. Diagnosis and treatment of ATRA syndrome Diagnosis of ATRA syndrome was made on clinical grounds by the association of at least three of the following signs, in the absence of other causes: fever, weight gain, respiratory distress, lung infiltrates, pleural or pericardial effusion, hypo- tension, and renal failure. 15,20 When ATRA syndrome was suspected, the recommended approach was to (1) start treatment with dexamethasone (DXM) (10 mg/12 h intravenously) for at least 3 days; (2) add the first course of CT (if CT had not already been started); (3) discontinue ATRA if the patient had received at least 20 days of ATRA or if ATRA syndrome was life-threatening and did not rapidly improve with CT and DXM. Statistical methods Rank sum test of Wilcoxon and Fisher’s exact test were used for comparisons. Relapse, EFS and survival curves were esti- mated by the Kaplan–Meier method and compared by the log rank test. Cox models were used to estimate the effect of ATRA