CEBPA- Associated Familial Acute Myeloid Leukemia (AML)

Clinical characteristics: CEBPA-associated familial acute myeloid leukemia (AML) is defined as the presence of a heterozygous germline CEBPA pathogenic variant in an individual with AML and/or family in which more than one individual has 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. 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 up to age 50 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 from 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 and/or family with AML.

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 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.

Surveillance: Similar to that for other forms of AML; because of the increased risk of late leukemia recurrence in persons with familial AML, lifelong surveillance is recommended. Asymptomatic individuals should have a CBC every six to 12 months and bone marrow examination for CBC abnormalities.

Agents/circumstances to avoid: Use of sib or related donors for HSCT without prior assessment of the germline CEBPA pathogenic variant in the donor.

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 testing for pregnancies at increased risk is possible if the germline CEBPA pathogenic variant in the family is known.