Infant acute leukemia is a rare but aggressive disease. Although infant acute leukemia is cytologically and histologically similar to acute leukemia seen in older children and adults, it displays unique and characteristic clinical and genetic characteristics. The features, as well as the extremely young age of the patients, present multiple challenges for treatment. This review focuses on the unique pathology of acute leukemia of infancy, including the genetic characteristics that are specific for these diseases.
Infant acute leukemia is a rare yet aggressive disease
Rearrangements in KMT2A are the most common genetic abnormality in infant leukemia
Megakaryoblastic differentiation is common in infant AML
Treatment of infant acute leukemia is challenging, and protocols are specifically tailored for these patients
Transient abnormal myelopoiesis frequently occurs in neonates with Down syndrome, universally harbors a truncating GATA1 mutation, and is cytologically indistinguishable from AML.
Leukemia arising in the first year of life is generally referred to as infant leukemia. Although these age-defined malignancies are rare, infant leukemias are distinct from their counterparts arising in older children both in clinical characteristics and in the underlying biology that drives tumorigenesis. As with all leukemia, those that arise in infants are subdivided into those that exhibit a hematopoietic maturation arrest and an expansion of blasts (ie, acute leukemia) and those characterized by an expansion of mature elements. Of the infant leukemias in the latter subcategory, juvenile myelomonocytic leukemia (JMML) and the related myeloproliferations associated with congenital syndromes are the most notable; mature lymphoid neoplasms and other chronic myeloid neoplasms are almost nonexistent. These chronic processes, including JMML, are covered elsewhere in this issue. Acute leukemias are by far more common in infants than their chronic counterparts. Although classifying acute leukemia as acute lymphoblastic leukemia (ALL) or acute myeloblastic leukemia (AML) is currently used for treatment and as a criterion for clinical trial enrollment, this distinction may not be as biologically relevant for infants as it is for older patients. Many infant acute leukemias show similar genetic alterations with either lymphoid or myeloid differentiation, frequently undergo a phenotypic switch upon treatment and often arise as either a mixed phenotype acute leukemia or an acute undifferentiated leukemia. , , These features point to an underlying pathologic mechanism in infant leukemia in which the inciting genetic lesion occurs in an early hematopoietic progenitor capable of either lymphoid or myeloid lineage commitment.
As expected, given both the limited age range and the limited time frame in which individuals must acquire oncogenic lesions, infant acute leukemia is quite rare, with an annual incidence of 3 to 4 cases per 100,000 individuals. As opposed to acute leukemia in older children, which shows a slight male predominance and a distinct predominance of lymphoid over myeloid differentiation, infant leukemia affects females slightly more frequently than males, and the incidence of lymphoid and myeloid lesions is relatively equal. The relatively high incidence of myeloid differentiation is particularly striking in infants younger than 1 month, in which ∼70% of acute leukemia cases are AML, whereas 20% are ALL, and the remaining 10% of cases are either undifferentiated or mixed phenotype. Of the lymphoblastic malignancies, B cell ALL (B-ALL) is significantly more frequent than T cell ALL.
The distinction of acute leukemia in infants from that in older children is quite relevant in terms of clinical characteristics. Overall, infant acute leukemia displays a more aggressive phenotype than acute leukemia in older children, and treatment algorithms that extrapolate pediatric therapeutics to infants have been suboptimal. Infants with ALL frequently present with peripheral blood hyperleukocytosis (more than 100,000/mL), and up to one-third of cases have initial white blood cell (WBC) counts greater than 200,000/mL. Hepatosplenomegaly and central nervous system involvement are common. Similarly, infants with AML have significantly higher peripheral WBC counts at diagnosis than older children with AML. The blasts frequently display monocytic or megakaryoblastic differentiation and often involve extramedullary sites. In particular, leukemic involvement of skin (leukemia cutis), typically presenting as nonblanching macules or nodules, frequently occurs in the absence of blood or marrow findings