Is a variant of Acute Myeloid Leukemia (AML) associated with Down syndrome?

Myeloid Leukemia Associated with Down Syndrome

Yes, a specific variant of Acute Myeloid Leukemia (AML) is associated with Down syndrome and is recognized as a distinct entity in the WHO classification of myeloid neoplasms. 1

Classification and Recognition

• The WHO classification specifically lists "Myeloid leukemia associated with Down syndrome" as a distinct entity under "Myeloid proliferations related to Down syndrome" 1
• This classification also includes "Transient abnormal myelopoiesis" (also called transient myeloproliferative disorder), which is unique to newborns with Down syndrome 1
• These conditions are considered separate from other types of AML due to their unique clinical, biological, and genetic features 1

Clinical and Biological Features

• Children with Down syndrome have a significantly increased risk (approximately 150-fold) of developing AML compared to the general population 2
• The most common subtype of AML in Down syndrome patients is acute megakaryoblastic leukemia (AMKL or FAB M7) 3, 4
• Myeloid leukemia in Down syndrome patients typically presents at a younger age, often before 4 years of age 5, 4
• The condition is characterized by unique genetic alterations, particularly mutations in the GATA1 gene 3, 6

Transient Abnormal Myelopoiesis (TAM)

• Approximately 10% of newborns with Down syndrome develop transient abnormal myelopoiesis 6
• TAM resembles acute leukemia but typically resolves spontaneously within 4-8 weeks 4
• Despite resolution, a significant proportion (20-30%) of infants with TAM subsequently develop AML, usually around 2-3 years of age 4
• TAM blast cells are often monoclonal and predominantly megakaryoblastic in nature 4, 6

Immunophenotypic Characteristics

• The immunophenotype of blast cells in Down syndrome-associated myeloid leukemia is distinctive: CD33+/CD13+/-/CD38+/CD117+/CD34+/-/CD7+/CD56+/-/CD36+/CD71+/CD42b+/CD4dim+/TPO-R+/EPO-R-/IL-3-Rα+/IL-6-Rα- 6
• This immunophenotypic profile differs significantly from non-Down syndrome patients with morphologically similar diseases 6
• CD34 expression is observed in 93% of TAM cases but only 50% of Down syndrome-associated AML cases 6

Clinical Management

• Babies with Down syndrome should undergo complete blood count screening to detect transient myelodysplasia of the newborn 7
• Referral to a pediatric hematologist/oncologist is recommended due to the significantly higher risk (20 times) of developing leukemia compared to the general population 7
• The prognosis for Down syndrome-associated AML is generally more favorable than non-Down syndrome AML, particularly when appropriate treatment protocols are used 3

Other Leukemias in Down Syndrome

• While AML (particularly AMKL) is strongly associated with Down syndrome, these patients also have an increased risk (20-fold) of developing acute lymphoblastic leukemia (ALL) 2
• The development of both AML and ALL in the same Down syndrome patient is rare but has been reported 2

Genetic Basis

• The presence of trisomy 21 appears to specifically predispose to abnormal proliferation of megakaryoblasts, explaining the predominance of megakaryoblastic leukemia in Down syndrome 4
• Cases of TAM have been reported in individuals with mosaicism for trisomy 21, with the abnormal proliferating cells derived from the cytogenetically abnormal population 4

Understanding this distinct entity is crucial for proper diagnosis, management, and treatment of affected individuals with Down syndrome.