Childhood Acute Myeloid Leukemia/Other Myeloid Malignancies Treatment (PDQ®): Treatment - Health Professional Information [NCI] - Classification of Pediatric Myeloid Malignancies
Table 2. Acute Leukemias of Ambiguous Lineage According to the WHO Classification of Tumors of Hematopoietic and Lymphoid Tissuesa continued...
Molecular probes and newer cytogenetic techniques (e.g., fluorescence in situ hybridization [FISH]) can detect cryptic abnormalities that were not evident by standard cytogenetic banding studies. This is clinically important when optimal therapy differs, as in APL. Use of these techniques can identify cases of APL when the diagnosis is suspected but the t(15;17) is not identified by routine cytogenetic evaluation. The presence of the Philadelphia (Ph) chromosome in patients with AML most likely represents chronic myelogenous leukemia (CML) that has transformed to AML rather than de novo AML. Molecular methods are also being used to identify recurring gene mutations in adults and children with AML, and as described below, some of these recurring mutations have prognostic significance.
A unifying concept for the role of specific mutations in AML is that mutations that promote proliferation (Type I) and mutations that block normal myeloid development (Type II) are required for full conversion of hematopoietic stem/precursor cells to malignancy.[32,33] Support for this conceptual construct comes from the observation that there is generally mutual exclusivity within each type of mutation, such that a single Type I and a single Type II mutation are present within each case. Further support comes from genetically engineered models of AML for which cooperative events rather than single mutations are required for leukemia development. Type I mutations are commonly in genes involved in growth factor signal transduction and include mutations in FLT3, KIT, NRAS, KRAS, and PTNP11. Type II genomic alterations include the common translocations and mutations associated with favorable prognosis (t(8;21), inv(16), t(16;16), t(15;17), CEBPA, and NPM1). MLL rearrangements (translocations and partial tandem duplication) are also classified as Type II mutations.
Specific recurring cytogenetic and molecular abnormalities are briefly described below. The abnormalities are listed by those in clinical use that identify patients with favorable or unfavorable prognosis, followed by other abnormalities.
Molecular abnormalities associated with favorable prognosis include the following:
- t(8;21) (RUNX1-RUNX1T1): In leukemias with t(8;21), the RUNX1(AML1) gene on chromosome 21 is fused with the RUNX1T1 (ETO) gene on chromosome 8. The t(8;21) translocation is associated with the FAB M2 subtype and with granulocytic sarcomas.[35,36] Adults with t(8;21) have a more favorable prognosis than adults with other types of AML.[25,37] These children have a more favorable outcome compared with children with AML characterized by normal or complex karyotypes [25,38,39,40] with 5-year overall survival (OS) of 80% to 90%.[28,29] The t(8;21) translocation occurs in approximately 12% of children with AML.[28,29]
- inv(16) (CBFB-MYH11): In leukemias with inv(16), the CBF beta gene (CBFB) at chromosome band 16q22 is fused with the MYH11 gene at chromosome band 16p13. The inv(16) translocation is associated with the FAB M4Eo subtype. Inv(16) confers a favorable prognosis for both adults and children with AML [25,38,39,40] with a 5-year OS of about 85%.[28,29] Inv(16) occurs in 7% to 9% of children with AML.[28,29]
- t(15;17) (PML-RARA): AML with t(15;17) is invariably associated with APL, a distinct subtype of AML that is treated differently than other types of AML because of its marked sensitivity to the differentiating effects of all-trans retinoic acid. The t(15;17) translocation leads to the production of a fusion protein involving the retinoid acid receptor alpha and PML. Other much less common translocations involving the retinoic acid receptor alpha can also result in APL (e.g., t(11;17)(q23;q21) involving the PLZF gene). Identification of cases with the t(11;17)(q23;q21) is important because of their decreased sensitivity to all-trans retinoic acid.[42,43] APL represents about 7% of children with AML.[29,44]
- Nucleophosmin (NPM1) mutations: NPM1 is a protein that has been linked to ribosomal protein assembly and transport as well as being a molecular chaperone involved in preventing protein aggregation in the nucleolus. Immunohistochemical methods can be used to accurately identify patients with NPM1 mutations by the demonstration of cytoplasmic localization of NPM. Mutations in the NPM1 protein that diminish its nuclear localization are primarily associated with a subset of AML with a normal karyotype, absence of CD34 expression, and an improved prognosis in the absence of FLT3-internal tandem duplication (ITD) mutations in adults and younger adults.[46,47,48,49,50,51]
Studies of children with AML suggest a lower rate of occurrence of NPM1 mutations in children compared with adults with normal cytogenetics. NPM1 mutations occur in approximately 8% of pediatric patients with AML and are uncommon in children younger than 2 years.[33,52,53,54]NPM1 mutations are associated with a favorable prognosis in patients with AML characterized by a normal karyotype.[33,53,54] For the pediatric population, conflicting reports have been published regarding the prognostic significance of an NPM1 mutation when a FLT3-ITD mutation is also present, with one study reporting that an NPM1 mutation did not completely abrogate the poor prognosis associated with having a FLT3-ITD mutation,[53,55] but with other studies showing no impact of a FLT3-ITD mutation on the favorable prognosis associated with an NPM1 mutation.[33,54]
- CEBPA mutations: Mutations in the CCAAT/Enhancer Binding Protein Alpha gene (CEBPA) occur in a subset of children and adults with cytogenetically normal AML. In adults younger than 60 years, approximately 15% of cytogenetically normal AML cases have mutations in CEBPA.[50,56] Outcome for adults with AML with CEBPA mutations appears to be relatively favorable and similar to that of patients with core-binding factor leukemias.[50,56] Studies in adults with AML have demonstrated that CEBPA double-mutant, but not single-allele mutant, AML was independently associated with a favorable prognosis.[57,58,59,60]
CEBPA mutations occur in 5% to 8% of children with AML and have been preferentially found in the cytogenetically normal subtype of AML with FAB M1 or M2; 70% to 80% of pediatric patients have double-mutant alleles, which is predictive of a significantly improved survival and similar to the effect observed in adult studies.[61,62] Although both double- and single-mutant alleles of CEBPA were associated with a favorable prognosis in children with AML in one large study, a second study observed inferior outcome for patients with single CEBPA mutations. However, very low numbers of children with single-allele mutants were included in these two studies (only 13 in toto), making a conclusion regarding the prognostic significance of single-allele CEBPA mutations in children premature.