Attempts to Optimize Post-Induction Treatment in Childhood Acute Myeloid Leukemia without Core Binding Factors: A Report From the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG)

With intensive chemotherapy and optimal risk stratification, 80–90 % of children with acute myeloid leukemia (AML) achieve complete remission (CR) which translates into a long-term disease-free survival in as many as 50–60% of patients. We have previously reported that risk stratified therapy and intensive use of cytarabine improved the outcome of childhood AML in AML99 study with 5-year event free survival (EFS) of 61.6% and 5-year overall survival (OS) of 75.6% (Tsukimoto I. J Clin Oncol 2009;27:4007–13), which gave us an additional impetus to reduce the number of consolidation courses with more restrictive indication for stem cell transplantation (SCT). We here report the outcome of successor nation-wide multi-institutional study AML-05, focusing on the AML patients without core binding factor (CBF).

47 eligible children (age <18 years) with de novo AML (acute promyelocytic leukemia and Down syndrome patients were excluded). Three patients were excluded from the efficacy analyses: one protocol violation, 1 changing to non-JPLSG member hospital at the patient's request, and 1 withdrawal of the JPLSG institutional membership. After 2 courses of common induction therapies, patients were stratified by the specific cytogenetic characters and morphological treatment response into 3 risk groups. Low risk (LR) children were defined as those with t(8;21) or inv(16), and good bone marrow response (BMR) to the first induction course. High risk (HR) children were those with abnormalities of monosomy 7, 5q-, t(16;21)(p11;q22), t(9;22), FLT3-ITD, and/or poor BMR to the first induction course. Intermediate risk (IR) children were those who were neither LR or HR group. Only patients assigned to HR were candidate for SCT in first CR in AML-05, whereas patients with IR were also allocated to SCT, if HLA-matched siblings were available in the former AML99. Patients with CR after two courses of induction therapy further received 3 courses of consolidation chemotherapy in AML-05; whereas 4 courses of consolidation therapy were given in AML99. The total cumulative dose of anthracyclines, Mitoxantrone and Idarubicin, was 375 mg/m² in the IR/HR chemotherapy both in AML-05 and AML99. Conversion rate of 5:1 was used to compare the cumulative dose of Daunorubicin and Mitoxantrone/Idarubicin.

Three-year EFS and 3y-OS of all 444 patients was 55.3% (95%CI, 50.2 – 60.1%) and 73.2% (68.3 – 77.5%), respectively. The median follow-up period for living patients was 3.1 years (range, 0.8 – 5.4 years). Two hundred eighty-nine non-CBF-AML patients [t(9;11), N=39 (13.5%); 11q23, N=27 (9.3%); Normal, N=81 (28.0%); Others, N=137 (47.4%)] in the AML-05 and 151 patients [t(9;11), N=15 (9.9%); 11q23, N=26 (17.2%); Normal, N=53 (35.1%); Others, N=55 (36.4%)] in AML99 were compared. There were no significant differences in basic characteristics such as sex and age/WBC at diagnosis. Incidence of FLT3-ITD in AML-05 cohort were identical to that in AML99 [AML-05 cohort, N= 42/289 (14.5%); AML99, N= 15/82 (18.2%), p=0.41]. CR rate in AML-05 was inferior to that in AML99 (81.0% vs. 90.7%, p = 0.008). There was no significant differences in 3y-EFS of non-CBF AML among 2 cohort [47.5% in AML-05 (95%CI, 41.2– 53.6%) vs. 49.7% in AML99 (41.5 – 57.3%), p= 0.43], however, there was a tendency of lower 3y-OS among them [62.8% in AML-05 (95%CI, 56.2– 68.7%) vs. 70.9% in AML99 (62.9 – 77.4%), p = 0.083]. The early death within 42 days in AML-05 (2.1%) were equivalent to that of AML99 (2.0%), whereas non-relapsed mortality were significantly increased in AML-05 compared with that of AML99 [44/289 (15.2%) in AML-05; 11/151 (7.3%) in AML99, p=0.022], which was due to increased mortality among infants. SCT rate in the 1^stCR was lower in the non-CBF AML-05 compared with that in AML99 [47/289 (16.3%) in AML-05; 40/151 (26.4%) in AML99, p=0.011].

Reduction on consolidation chemotherapy courses from four to three, together with incorporation of repetitive cycles of high-dose cytarabine were adequate for non-CBF childhood AML, and did not compromise the treatment results in AML-05 despite of adaptation of more restrictive indication for SCT in 1^st CR. Non-CBF-AML is a cytogenetically heterogeneous disease, hence the mechanism underlying these prognostic differences should be studied.

No relevant conflicts of interest to declare.