INCIDENCE, CLINICAL-FEATURES, AND OUTCOME OF ALL-TRANS-RETINOIC ACID SYNDROME IN 413 CASES OF NEWLY-DIAGNOSED ACUTE PROMYELOCYTIC LEUKEMIA

All trans-retinoic acid (ATRA) syndrome is a life-threatening complica tion of uncertain pathogenesis that can occur during the treatment of acute promyelocytic leukemia (APL) by ATRA. Since its initial descript ion, however, no large series of ATRA syndrome has been reported in de tail. We analyzed cases of ATRA syndrome observed in an ongoing Europe an trial of treatment of newly diagnosed APL. In this trial, patients 65 years of age or less with an initial white blood cell count (WBC) l ess than 5,000/mu L were initially randomized between ATRA followed by chemotherapy (CT) (ATRA-CT group) or ATRA with CT started on day 3: p atients with WBC greater than 5,000/mu L received ATRA and CT from day 1; patients aged 66 to 75 received ATRA-GT. In patients with initial WBC less than 5,000/mu L and allocated to ATRA-->CT, CT was rapidly ad ded if WBC was greater than 6,000, 10,000, 15,000/mu L by days 5, 10, and 15 of ATRA treatment. A total of 64 (15%) of the 413 patients incl uded in this trial experienced ATRA syndrome during induction treatmen t. Clinical signs developed after a median of 7 days (range, 0 to 35 d ays). In two of them, they were in fact present before the onset of AT RA. In 11 patients, they occurred upon recovery from the phase of apla sia due to the addition of CT. Respiratory distress (89% of the patien ts), fever (81%), pulmonary infiltrates (81%), weight gain (50%), pleu ral effusion (47%), renal failure (39%), pericardial effusion (19%), c ardiac failure (17%), and hypotension (12%) were the main clinical sig ns, and 63 of the 64 patients had at least three of them. Thirteen pat ients required mechanical ventilation and two dialysis. A total of 60 patients received CT in addition to ATRA as per protocol or based on i ncreasing WBC; 58 also received high dose dexamethasone (DXM); ATRA wa s stopped when clinical signs developed in 30 patients. A total of 55 patients (86%) who experienced ATRA syndrome achieved complete remissi on (CR), as compared with 94% of patients who had no ATRA syndrome (P = .07) and nine (14%) died of ATRA syndrome (5 cases), sepsis (2 cases ), leukemic resistance (1 patient), and central nervous system (CNS) b leeding (1 patient). None of the patients who achieved CR and received ATRA for maintenance had ATRA syndrome recurrence. No significant pre dictive factors of ATRA syndrome, including pretreatment WBC, could be found. Kaplan Meier estimates of relapse, event-free survival (EFS), and survival at 2 years were 32% +/- 10%, 63% +/- 8%, and 68% +/- 7% i n patients who had ATRA syndrome as compared with 15% +/- 3%, 77% +/- 2%, and 80% +/- 2% in patients who had no ATRA syndrome (P = .05, P = .003, and P = .03), respectively In a stepwise Cox model that also inc luded pretreatment prognostic variables, ATRA syndrome remained predic tive for EFS and survival. In conclusion, in this multicenter trial wh ere CT was rapidly added to ATRA in case of high or increasing WBC cou nts and DXM generally also used at the earliest clinical sign, the inc idence of ATRA syndrome was 15%, but ATRA syndrome was responsible for death in only 1.2% of the total number of patients treated. However, occurrence of ATRA syndrome was associated with lower EFS and survival . (C) 1998 by The American Society of Hematology.