Improved Remission Induction Rate of Childhood AML: Preliminary Results of the AML02 Trial.

The multicenter AML02 trial randomly assigns patients to receive high-dose or low-dose cytarabine (A), daunorubicin (D), and etoposide (E) as Induction I; all subsequent therapy is risk-adapted. Pharmacokinetic, pharmacodynamic, and gene expression studies are performed after exposure to high-dose or low-dose cytarabine. Patients with no response (NR, ≥ 25% bone marrow blasts) to Induction I receive low-dose ADE + gemtuzumab ozogamicin (GO) as Induction II, whereas all others receive ADE. Minimal residual disease (MRD) is monitored by flow cytometry and is defined as ≥ 0.1% cells with leukemia-associated immunophenotypes among bone marrow mononuclear cells. Patients who are MRD⁺ after induction therapy receive GO as a single agent before consolidation chemotherapy or stem cell transplantation. Among the 112 patients enrolled since October 2002, 37 had -7, FAB M6 or M7, FLT3 internal tandem duplication (ITD), or MDS or treatment-related AML and were classified as high-risk (HR); 32 had AML1-ETO, CBFβ-MYH11, or MLL-AF9 (low-risk; LR); the remaining 43 were considered as standard-risk (SR). The rate of complete response (CR, <5% bone marrow blasts) was 84% after Induction I and 97% after Induction II. Of the 3 patients who did not attain CR, 2 had partial responses and 1 died of streptococcal sepsis during Induction II. CR rates differed according to risk group after Induction I (LR, 100%; SR, 91%, HR 61%) but not after Induction II (LR, 100%; SR, 98%, HR 94%). The association between risk groups and MRD (determined successfully in 95% of cases) was more striking: the rate of MRD negativity after Induction I was 88% in LR, 59% in SR, and 26% in HR patients; after Induction II, rates were 97%, 82%, and 53%, respectively. Response to initial therapy was particularly poor among patients with a FLT3-ITD: only 1 of 11 patients was MRD-negative after Induction I and only 3 were MRD-negative after Induction II. 5 of the 6 patients who had NR to Induction I attained CR after subsequent treatment with ADE + GO and all 6 had dramatic reductions in MRD levels (from a median of 26% to a median of 0.24%). An additional 14 patients with MRD levels 0.1% to 5.6% received GO at the beginning of consolidation: 9 became MRD-negative. Overall, there were 4 deaths from infection (2 bacterial, 1 fungal, 1 viral), which occurred during induction (1), consolidation (1), and after completion of chemotherapy (2). Because CNS relapse occurred in 3 of the first 33 patients treated, intrathecal therapy was changed from cytarabine alone to triple combination therapy with methotrexate, hydrocortisone, and cytarabine; none of the 79 subsequent patients has had a CNS relapse. The 1-year event-free and overall survival estimates are 76.8% (SE, 5.1%) and 89.1% (SE, 3.8%). In conclusion, AML02 therapy has produced a high overall remission rate and low treatment-related mortality, which we attribute to excellent supportive care and to the use of risk- and MRD-adapted therapy.