SAN DIEGO, CA—In children with newly diagnosed acute myeloid leukemia (AML) or high risk myelodysplastic syndrome (MDS), no significant differences in efficacy or toxicity were observed between idarubicin and mitoxantrone induction and first intensification courses, results of a randomized, Phase 3 study presented at the 53rd American Society of Hematology Annual Meeting and Exposition has found.

However, patients who had a complete remission (CR) and an HLA sibling donor had a longer disease-free survival (DFS) and overall survival (OS) than those without a donor, reported Barbara De Moerloose, MD, Ghent University Hospital, Ghent, Belgium, and European Organisation for Research and Treatment of Cancer (EORTC) colleagues from France and Portugal.

Previously, a pilot study conducted by the EORTC Children’s Leukaemia Group showed the efficacy of mitoxantrone when substituted for daunorubicin in the treatment of childhood AML. Based on trials in adult patients with AML performed over the past two decades, this study sought to compare mitoxantrone and idarubicin, an agent with favorable cerebrospinal fluid penetration and greater efficacy than daunorubicin, in children. The primary efficacy endpoint was event free survival (EFS). Secondary endpoints included OS, CR rate after induction/first intensification, DFS, and toxicity.

Between March 1993 and December 2002, 227 patients <17 years of age with newly diagnosed AML (n=216) and high risk MDS (n=11), were randomized to receive either idarubicin (n=112) or mitoxantrone (n=115) in induction and first intensification, each at a dose of 10mg/m2/day for three days. Concomitant chemotherapy comprised standard dose cytarabine and etoposide in induction and high-dose cytarabine (18–36g/m2) in first intensification. For patients who achieved CR and had an HLA-identical sibling donor, allogeneic stem cell transplantation (ASCT) after first intensification was advised.

Patients who achieved CR and were without a donor received a second intensification course (including continuous infusion of standard dose cytarabine, daunorubicin 20mg/m2/day for four days, etoposide, dexamethasone, and 6-thioguanine) and a third intensification course (consisting of high dose cytarabine 12g/m2 + etoposide), followed by maintenance therapy (6-thioguanine daily + cytarabine four days/month) for 12 months. Patients with initial WBC counts ≥70×109/L received CNS irradiation after the 3rd intensification when the study began in March 1993; this was abandoned as of November 1994.

After two courses, 79.5% of idarubicin patients and 85.2% of mitoxantrone patients achieved CR, respectively. Median duration of follow up was 9.9 years (range 0.25–16). Events occurred in 65 idarubicin patients and 59 mitoxantrone patients, including failure to achieve CR (23 vs 17), relapse (35 vs 40), and death without relapse (7 vs 2). In the idarubicin group, the 5-year EFS rate was 42% (SE 4.7%) while in the mitoxantrone group, the rate was 48.4% (SE 4.7%) (HR 1.20, 95% CI: 0.84–1.71, 2-sided log rank P=0.29).

The 5-year OS rate was comparable in both arms, 59.8% in the idarubicin group vs. 57.5% in the mitoxantrone group (HR=1.03, 95% CI: 0.70-1.54, P=0.87). A benefit was observed for patients with a donor, even following adjustment for WBC count at diagnosis, age, cytogenetic features and randomized arm. Patients who reached CR and who had an HLA compatible sibling donor had a longer 5-year disease-free survival rate from CR (65.1% vs. 51.5%; HR 0.60, P=0.07) and a longer 5-year OS (78% vs. 60.7%; HR 0.49, P=0.03) rate than patients without a donor. The interval between start of induction and start of first intensification was similar in both arms, a median of 5.2 weeks, Dr. De Moerloose stated.

Grade 3/4 infection following the induction course occurred in 37.5% of patients in the idarubicin group and 25.4% of patients in the mitoxantrone group. Grade 3/4 fever occurred in 25% of idarubicin patients versus 22.8% of mitoxantrone patients. Cumulative anthracycline dosage (conversion factor 5) was 380mg/m2. Acute and late-onset cardiotoxicity was comparable in both treatment arms.