Clinical characteristics: CEBPA-associated familial acute myeloid leukemia (AML) is defined as AML in which a heterozygous germline CEBPA pathogenic variant is present in a family in which multiple individuals have AML. In contrast, sporadic CEBPA-associated AML is defined as AML in which a CEBPA pathogenic variant(s) is identified in leukemic cells but not in the non-leukemic cells. Too few individuals with CEBPA-associated familial AML have been reported to be certain about the natural history of the disease. In the majority of individuals, the age of onset of familial AML appears to be earlier than sporadic AML; disease onset has been reported in persons as young as age 1.8 years and older than age 45 years. The prognosis of CEBPA-associated familial AML appears to be favorable compared with sporadic CEBPA-associated AML. Individuals with CEBPA-associated familial AML who have been cured of their initial disease may be at greater risk of developing additional independent leukemic episodes in addition to the risk of relapse due to preexisting clones.
Diagnosis/testing: The diagnosis of CEBPA-associated familial AML is established by identification of a heterozygous germline CEBPA pathogenic variant in a specimen that contains only non-leukemic cells from an individual with AML, or by observing segregation of a shared germline CEBPA pathogenic variant across affected family members.
Management: Treatment of manifestations: Treatment usually includes cytarabine/anthracycline-based induction and cytarabine-based consolidation chemotherapy. Hematopoietic stem cell transplantation (HSCT) from a volunteer unrelated donor (VUD) or appropriately screened family member should be reserved for individuals failing to achieve remission following standard induction therapy or for disease recurrence. Whenever possible, persons with AML should be treated as part of a clinical trial protocol. Prevention of secondary complications: Similar to that for other types of AML (i.e., administration of blood products such as red blood cell and platelet transfusions as needed; treatment of infections with antibiotics; and use of prophylactic antibiotics and anti-fungal agents during periods of severe neutropenia). Surveillance: Similar to that for other forms of AML. Because of the increased risk of leukemia recurrence in persons with familial AML, lifelong surveillance may be warranted.
Genetic counseling: Predisposition to CEBPA-associated familial AML is inherited in an autosomal dominant manner. Most individuals diagnosed with CEBPA-associated familial AML have had an affected parent who shares the germline pathogenic variant. Germline CEBPA pathogenic variants exhibit complete or near-complete penetrance for the development of AML in families reported to date. Each child of an affected individual has a 50% chance of inheriting the germline pathogenic variant. Prenatal diagnosis for pregnancies at increased risk is possible if the germline CEBPA pathogenic variant in the family is known.
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