Myelodysplasia-Related Changes Have Adverse Prognostic Significance in Children with Acute Myeloid Leukemia; A Report From the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG).

The 2008 WHO classification expanded the category of acute myeloid leukemia (AML) with multilineage dysplasia of the 2001 WHO classification into AML with myelodysplasia-related changes (AML-MRC). Although AML with multilineage dysplasia (AML-MLD) is diagnosed based on morphological features alone, AML-MRC includes AML with a previous history of myelodysplastic syndrome or myeloproliferative neoplasms and AML with a myelodysplasia-related cytogenetic abnormality as well as AML-MLD. Since this category of AML has been believed to be rare in children, its clinical impact on children remains unknown. We developed a comprehensive and prospective central review system in a clinical trial for pediatric AML, in which unexpected high incidence of AML-MRC was found. Thus, we evaluated the clinical characteristics and prognostic significance of AML-MRC in children.

JPLSG AML-05, registered at http://www.umin.ac.jp/ctr/as UMIN000000511, is a nation-wide multi-institutional study for children (age <18 years) with de novo AML from 11/1/2006 to 12/31/2010 (acute promyelocytic leukemia and myeloid leukemia associated with Down syndrome excluded). On the trial, morphology was prospectively diagnosed by a central review system. A diagnosis of AML-MLD was made by the presence of dysplasia in 50% or more of the cells in 2 or more lineages. Cytogenetic tests were carried out in regional laboratories, but reports were reviewed centrally. Mutations of FLT3 were examined for all patients.

Among 447 eligible patients recruited, a total of 93 patients (20.8%) were diagnosed as AML-MRC; 34 from morphological features, 65 from myelodysplasia-related cytogenetic abnormalities and six from the both. The cases with AML-MRC included 48 boys and 45 girls with a median age of 3 years (range; 0–17 years). Ten patients with AML-MRC had FLT3-internal tandem duplication (ITD). Three-year probability of event-free survival (3y-pEFS) and 3-year probability of overall survival (3y-pOS) at the 93 patients was 37.1% (95%CI, 26.9 – 47.3%) and 56.8% (95%CI, 45.2 – 66.8%), respectively. The median follow-up of alive patients as of May 2012 was 3.4 years (range;1.3–5.3 years). Comparison of the clinical outcome of AML-MRC with AML, not otherwise specified (AML-NOS)(n=111), showed that AML-MRC had a lower complete remission rate after two induction courses(67.7% vs 85.6%, p<0.01), and worse 3y-pEFS (37.1% vs 53.8%, p= 0.02), but that 3y-pOS (56.8% vs 68.9%, p= 0.05) and 3 year probability of relapse-free survival after achieving complete remission (46.9.% vs 62.8%, p= 0.06) were similar. Although no differences were seen in sex and WBC count at diagnosis between AML-MRC and AML-NOS, the median age or the incidence of FLT3-ITD positivity of AML-MRC was lower than that of AML-NOS. In Cox regression analysis, adjusted hazard ratio (HR) of patients diagnosed with AML-MRC for EFS was significantly worse compared to those diagnosed with AML-NOS after controlling for these baseline patients and disease characteristics (HR 1.7,p<0.01).

Our study suggests that AML-MRC is not rare in children. AML-MRC had adverse prognostic significance in children partly due to the low induction rate. Induction chemotherapy awaits further improvement for children with AML-MRC.

No relevant conflicts of interest to declare.