Phase III Trial of All-Trans Retinoic Acid (ATRA) vs Daunorubicin (D) and Cytosine Arabinoside (A) as Induction Therapy and ATRA vs Observation as Maintenance Therapy for Children with Newly Diagnosed Acute Promyelocytic Leukemia (APL).

Between April 1992 and February 1995, 71 children with locally diagnosed APL were enrolled on the national trial (ECOG E2491) to test ATRA during induction and maintenance (MAINT). Induction consisted of either ATRA, 45 mg/m2/d orally, or 1–2 cycles of D, 45 mg/m2/d IV bolus days 1–3, plus A, 100 mg/m2/day by continuous intravenous (IV) infusion days 1–7. All patients (pts) achieving complete remission (CR) were scheduled to receive two cycles of consolidation chemotherapy consisting of one cycle the same as induction followed by A, 2 gm/m2 IV over one hour every 12 hours days 1–4, plus D, 45 mg/m2/d IV bolus days 1–2. Pts on both arms were then randomized to receive either MAINT ATRA, 45 mg/m2/d orally for one year, or observation (OBS). Fifty-three children with the (15;17) translocation or centrally reviewed M3 FAB APL are the subject of this report. These patients were aged 1–18 years (median 12 years; only 2 < 2 yrs). A female predominance was noted (60% female). The distribution by race was: White 35, African American 7, Hispanic 8, Asian 2, and Filipino 1 patient. No extramedullary disease was proven at diagnosis. Twenty-seven patients were reported to have bleeding symptoms at diagnosis. The median WBC at study entry was 3.2 (4.2 for the DA arm, 2.6 for the ATRA arm). Only one patient was noted to have the M3v subtype. Twenty-seven pts were treated on the ATRA induction arm and 26 on the DA induction arm. A CR rate of 70% was obtained (ATRA CR 81%, DA CR 58%, P=0.08) after Induction and 3 additional patients achieved a CR after cross-over to DA (overall CR=75%). The 3 year DFS from achieving CR was 49% (DA 46%, ATRA 51%, P=0.33). Thirty-three patients reached maintenance therapy after CR- 16 in the OBS arm and 17 in the MAINT ATRA arm. The 3 year DFS from the start of MAINT was 48%( MAINT ATRA 75%, OBS 19%, P=0.0001). The 5 year OS was 68% (DA 62%, ATRA 73%, P=0.33). Induction toxicity data for 53 patients treated on this study included: four patients had a Grade III/IV hemorrhage during induction (DA 3, ATRA 1), intracranial hemorrhage(ICH) in 3, retinoic acid syndrome (RAS) in 2, pseudotumor cerebri definite in 2 and probable in 6, typhlitis in 2, and pancreatitis in 1. Four lethal toxicities occurred including two from ICH and one each from infection and RAS. (DA 3, ATRA 1) In conclusion, 1) the outcome for children with APL is excellent when treated with ATRA and anthracycline-based induction; 2) ATRA as maintenance resulted in a statistically significant advantage in DFS; 3) the salvage rate for relapsed patients appeared promising.