Treatment with All-Trans Retinoic Acid and Anthracycline Monochemotherapy in Children with Acute Promyelocytic Leukemia: Analysis of Three Sequential Multicenter Trials of the PETHEMA Group

The combination of all-trans retinoic acid (ATRA) and anthracycline-based chemotherapy has been adopted as the standard treatment for children and adults with acute promyelocytic leukemia (APL). However, information about therapy results in pediatric APL patients is scarce, particularly on long-term outcomes. A previous report of the PETHEMA Group (Ortega et al, JCO 2005) showed that a risk-adapted strategy combining a reduced dose of ATRA (25 mg/m²/d) and anthracycline monochemotherapy for induction and consolidation, followed by ATRA and low dose methotrexate and mercaptopurine for maintenance therapy, produced high antileukemic efficacy, moderate toxicity, and a high degree of compliance. We have now performed an updated analysis of a significantly enlarged cohort of 107 consecutive children (younger than 19 years) with APL who were enrolled in three sequential trials of the PETHEMA Group (LPA96, LPA99 and LPA2005) and followed up for a median of 71 months (range, 3–139). Induction consisted of 25 mg/m² ATRA daily until CR and 12 mg/m² idarubicin on days 2, 4, 6 and 8. In the LPA96 trial, patients in CR received three monthly chemotherapy courses: idarubicin 5 mg/m²/d × 4 (course #1), mitoxantrone 10 mg/m²/d × 5 (course #2), and idarubicin 12 mg/m²/d × 1 (course #3). Since November 1999 (LPA99 trial), for patients with intermediate or high risk of relapse (Sanz et al, Blood 2000), consolidation was slightly intensified by increasing idarubicin doses in courses #1 and #3, and by simultaneously administering 25 mg/m² ATRA together with chemotherapy in all three courses. Since July 2005, consolidation therapy in the ongoing LPA 2005 trial included the following modifications:

1. the administration of ATRA for all patients;

2. for low- and intermediate-risk patients, mitoxantrone has been reduced from five to three days in the second course; and

3. for high-risk patients, cytarabine has been added to idarubicin in the first and third course.

Maintenance therapy consisted of 50 mg/m²/d mercaptopurine orally, 15 mg/m²/week methotrexate intramuscularly, and 25 mg/m²/d ATRA for 15 days every three months. Of 1031 patients enrolled in three subsequent PETHEMA trials between November 1996 and July 2008, 107 (10%) from 43 Institutions were aged less than 19 years. WBC counts were >10×0⁹/l and >50×10⁹/l in 36 (34%) and 10 (9%), respectively; morphologically, 22 (22%) cases were hypergranular; PML/RARA isoform type was BCR1 or BCR2 in 47 (57%), and BCR3 in 35 (43%). One-hundred and one patients achieved CR (94%). In general, toxicity was manageable during consolidation and maintenance therapy. One patient died in CR during consolidation due to hepatic failure. At the end of consolidation, only 2 patients of 86 patients tested had molecular persistence (defined by positive RT-PCR of PML/RARA at 10⁻⁴ sensitivity). Ten additional relapses were observed, 5 molecular and 5 clinical relapses. Apart from 2 clinical relapses and 2 molecular relapses, all these events occurred among high risk patients. The 5-year Kaplan-Meier estimates of overall, disease-free and relapse-free survival were 89%, 86% and 86%, respectively. These results show a higher incidence of hyperleucocytosis in pediatric patients than in adults with genetically proven APL (p=0.05) and confirm the high antileukemic efficacy, low toxicity and high degree of compliance of three subsequent PETHEMA trials using a risk-adapted strategy with ATRA and anthracycline-based chemotherapy for induction and consolidation therapy.