Table 2. Acute Leukemias of Ambiguous Lineage According to the WHO Classification of Tumors of Hematopoietic and Lymphoid Tissuesa continued...
Molecular abnormalities associated with an unfavorable prognosis include the following:
Chromosomes 5 and 7: Chromosomal abnormalities associated with poor prognosis in adults with AML include those involving chromosome 5 (monosomy 5 and del(5q)) and chromosome 7 (monosomy 7).[26,38] These cytogenetic subgroups represent approximately 2% and 4% of pediatric AML cases, respectively, and are also associated with poor prognosis in children.[29,38,63,64,65] In the past, patients with del(7q) were also considered to be at high risk of treatment failure and data from adults with AML support a poor prognosis for both del(7q) and monosomy 7. However, outcome for children with del(7q), but not monosomy 7, appears to be comparable to that of other children with AML.[30,65] The presence of del(7q) does not abrogate the prognostic significance of favorable cytogenetic characteristics (e.g., inv(16) and t(8;21)).[26,65,66]
Chromosome 3 (inv(3)(q21;q26) or t(3;3)(q21;q26)) and EVI1 overexpression: The inv(3) and t(3;3) abnormalities involving the EVI1 gene located at chromosome 3q26 are associated with poor prognosis in adults with AML,[26,38,67] but are very uncommon in children (<1% of pediatric AML cases).[29,40,68]
FLT3 mutations: Presence of a FLT3-ITD mutation appears to be associated with poor prognosis in adults with AML, particularly when both alleles are mutated or there is a high ratio of the mutant allele to the normal allele.[70,71]FLT3-ITD mutations also convey a poor prognosis in children with AML.[56,72,73,74,75,76] The frequency of FLT3-ITD mutations in children is lower than that observed in adults, especially for children younger than 10 years, for whom 5% to 10% of cases have the mutation (compared with approximately 30% for adults).[74,75,77] A longer length of the ITD segment of FLT3-ITD has been reported to be associated with a poorer outcome.
Presence of the FLT3-ITD mutation is strongly associated with the microgranular variant (M3v) of APL and with hyperleukocytosis.[73,79,80] It remains unclear whether FLT3 mutations are associated with poorer prognosis in patients with APL who are treated with modern therapy that includes all-trans retinoic acid.[80,81,82,83]
Activating point mutations of FLT3 have also been identified in both adults and children with AML,[70,74,84] though the clinical significance of these mutations is not clearly defined. FLT3-ITD and point mutations occur in 30% to 40% of children and adults with APL.[73,79,81,82] The prognostic significance of this mutation in APL is unclear, although a mutant to wild type allelic ratio of greater than or equal to 0.5 may be associated with a worse outcome.