Cebpa-Associated Familial Acute Myeloid Leukemia (Aml)

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

Suggestive Findings

CEBPA-associated familial AML should be suspected in individuals with the following clinical and supportive laboratory findings:

Clinical findings

• Individuals with AML who also have a family history of AML
• Individuals who have developed AML at an early age (<50 years)

Supportive laboratory findings

• Young individuals with AML whose leukemic cells have a pathogenic variant in both copies of CEBPA
• Normal karyotype in leukemic cells
• A preponderance of French-American-British (FAB) Cooperative Group AML Classification subtypes M1 or M2 as established by morphologic analysis of peripheral blood or bone marrow blasts
• Auer rods seen in blasts (i.e., abnormal, needle-shaped or round, light blue or pink-staining inclusions found in the cytoplasm of leukemic cells)
• Aberrant CD7 expression on blasts as demonstrated by flow cytometry

Note: A provisional diagnostic category of "AML with mutated CEBPA" was proposed in the WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues [Arber et al 2008]. This classification is primarily intended for sporadic AML and does not distinguish familial forms of disease or the presence of a pathogenic variant in one or both copies of CEBPA; only the latter have favorable prognostic significance in AML.

For this GeneReview, the following definitions are used:

CEBPA-associated familial AML is defined by the presence of a germline CEBPA pathogenic variant. Germline variants may be inherited across multiple generations or develop de novo in parental germ cells, prior to their transmission. Once inherited, they are present in every cell of an individual as part of their unique genetic make-up. Germline CEBPA pathogenic variants typically coincide with a family history of AML and the diagnosis is established by either of the following:

• Detection of a germline CEBPA pathogenic variant in a specimen that contains only non-leukemic cells from an individual with AML
• Detection of a shared germline CEBPA pathogenic variant in affected (and possibly asymptomatic) members of an AML pedigree

Sporadic CEBPA-associated AML is defined as AML in which a somatic CEBPA pathogenic variant(s) is acquired in leukemic cells alone; these variants are absent in all of the individual's non-leukemic cells (see Molecular Genetics).

Establishing the Diagnosis

The diagnosis of CEBPA-associated familial AML is established in a proband with a confirmed germline CEBPA pathogenic variant (see Table 1). Because CEBPA-associated familial AML develops from cells that have a pathogenic (cancer-predisposing) variant in both copies of CEBPA, leukemic cells frequently demonstrate both a germline and a somatic CEBPA variant at AML diagnosis. The germline pathogenic variant is typically a frameshift located in the CEBPA region encoding the N-terminal C/EBPα protein, while the second somatic pathogenic variant acquired in leukemic cells is typically in the region encoding the C-terminal (see Molecular Genetics).

Note: In the literature, the terms CEBPAdm and CEBPAsm may be used. These terms refer to leukemic cells with a pathogenic variant in both copies of CEBPA ("double mutation") or in only one copy of CEBPA ("single mutation"). These terms alone do not specify if the pathogenic variant is germline or somatic (see Molecular Pathogenesis).

Molecular testing approaches include single-gene testing and use of a multigene panel:

• Single-gene testing. Sequence analysis of CEBPA is performed in a non-leukemic specimen.
  Note: (1) Testing for a germline pathogenic variant should not be performed on blood or bone marrow during active AML. Testing a non-involved specimen, such as cells obtained by buccal swab/saliva, skin biopsy or cultured dendritic cells, is imperative. (2) It should be noted that CEBPA pathogenic variants are found in the leukemic cells of approximately 9% of persons with AML, including 15%-18% of persons with normal-karyotype AML [Arber et al 2008, Renneville et al 2008]. However, few of these individuals have a germline CEBPA pathogenic variant. (3) Testing of blood or bone marrow during complete remission from AML may also be performed to detect germline variants. The percentage of residual leukemic cells in remission samples is negligible, ensuring that somatic variants are not falsely classified as germline variants.
• A multigene panel that includes CEBPA and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Clinical Description

Germline CEBPA pathogenic variants were first associated with the autosomal dominant transmission of acute myeloid leukemia (AML) in 2004 [Smith et al 2004]. Over the last decade, more than ten families have been reported, all manifesting a highly penetrant AML phenotype as described above. Given the limited number of individuals described in the literature, it is possible that the true range of clinical phenotypes may vary [Pabst & Mueller 2009] and ongoing investigation of this syndrome is essential.

The age of onset of CEBPA-associated familial AML is variable, but appears to be earlier than sporadic AML. Disease onset has been reported in persons as young as 1.8 years [Debeljak et al 2013] and older than 45 years [Pabst et al 2008]. By contrast, the median age at diagnosis of persons with sporadic AML is 65 years.

From an analysis of ten pedigrees with CEBPA-associated familial AML, the disease follows a course similar to sporadic AML with CEBPA pathogenic variants in both copies (CEBPAdm). The prognosis of individuals with familial AML appears to be favorable, with ten-year overall survival (OS) reaching 67%, compared to 54% OS of younger adults with sporadic AML associated with two CEBPA pathogenic variants and 29% OS with sporadic AML associated with a single CEBPA pathogenic variant [Tawana et al 2015].

Individuals with CEBPA-associated familial AML who have been cured of their initial disease may be at greater risk of developing recurrent, independent leukemic episodes that are characterized by a different somatic CEBPA pathogenic variant from that observed in the original tumor clone. This phenomenon contrasts with relapse in individuals with sporadic AML, where CEBPA pathogenic variants are stable throughout the disease course [Tiesmeier et al 2003, Shih et al 2006, Hollink et al 2011].

Genotype-Phenotype Correlations

To date, the majority of germline CEBPA pathogenic variants are frameshift variants located in the N-terminal of the gene (preceding the internal start codon). Individuals commonly present with AML (of FAB subtypes M1, M2 or M4) following the acquisition of somatic CEBPA (and additional) pathogenic variants.

Penetrance

Analysis of pedigrees reported to date suggests that germline CEBPA pathogenic variants exhibit high penetrance for the development of AML [Nickels et al 2013, Tawana et al 2015]. The penetrance of pathogenic variants may vary within and between families; data from ten families with germline CEBPA pathogenic variants revealed that more than 80% of confirmed or presumed obligate adult heterozygotes have developed disease to date [Tawana et al 2015].

Prevalence

CEBPA-associated familial AML is very rare, with only eleven pedigrees reported as of this writing [Smith et al 2004, Sellick et al 2005, Pabst et al 2008, Renneville et al 2009, Nanri et al 2010, Stelljes et al 2011, Taskesen et al 2011, Xiao et al 2011, Debeljak et al 2013, Tawana et al 2015].

It has been suggested that 5%-10% of individuals with presumed sporadic CEBPA-associated AML, may have a germline CEBPA pathogenic variant. Pabst et al [2008] reported that two of 18 individuals (11%) with CEBPA-associated AML had a germline CEBPA pathogenic variant and a family history of AML. A larger series reported by Taskesen et al [2011] identified a germline CEBPA pathogenic variant in five of 71 individuals (7%); two of the five had a family history of AML.

Evaluations Following Initial Diagnosis of CEBPA-Associated Familial AML

To establish the extent of disease and needs of an individual newly diagnosed with AML, the following evaluations are recommended:

• Cardiac scan in individuals with a personal history of – or signs and symptoms suspicious for – heart disease and in those who have received previous anthracycline therapy
• HLA typing in anticipation of hematopoietic stem cell transplantation (HSCT)
• Lumbar puncture (LP) if symptoms suggest central nervous system disease. The timing of LP in AML is controversial.
• Consultation with a clinical geneticist and/or genetic counselor

Evaluation of an individual with a confirmed diagnosis of CEBPA-associated familial AML should include:

• Assembly of a detailed pedigree to identify additional affected individuals and potential carriers of the inherited pathogenic variant;
• Recommendation of consultation with a genetic counselor for all at-risk family members;
• Molecular testing of family members at risk using buccal, salivary or skin DNA. Peripheral blood DNA may also be used in individuals with no history of preceding hematologic disease and normal complete blood count (CBC).
  • Comprehensive evaluation and screening of family members enables improved characterization of the clinical manifestations and penetrance within the pedigree.
  • Family members without the inherited pathogenic variant may be offered human leukocyte antigen (HLA) typing to assess their compatibility for stem cell donation to their affected relative.

Note: In all familial leukemia syndromes with a known inherited pathogenic variant, it is essential that screening of the pathogenic variant be performed in all relatives at risk prior to consideration of stem cell donation.

Treatment of Manifestations

Management of CEBPA-associated familial AML does not differ from that of sporadic CEBPA-associated AML [National Comprehensive Cancer Network 2009, Döhner et al 2010].

Treatment usually includes cytarabine/anthracycline-based induction and cytarabine-based consolidation chemotherapy with or without HSCT according to clinical, cytogenetic, and molecular risk. For younger individuals with AML (even those without a clear family history), there is now increasing awareness that germline variants should be investigated and excluded prior to consideration of HSCT using sib/related donors. Specific treatment strategies are based on characteristics of the individual, response to chemotherapy, treatment setting, and protocol (if the individual is enrolled in a clinical trial). Note: Whenever possible, persons with AML should be treated as part of a clinical trial protocol.

Relapses are treated with cytarabine-based salvage chemotherapy followed by allogeneic HSCT (if a suitable donor is available and if cure is the intent of treatment).

Prevention of Secondary Complications

Prevention of secondary complications is similar to that for other types of AML:

• Supportive care includes blood products such as red blood cell and platelet transfusions as needed and treatment of infections with antibiotics.
• Prophylactic antibiotics and antifungal agents are administered during periods of severe neutropenia including the consolidation and post-transplantation periods [National Comprehensive Cancer Network 2009].

Surveillance

Affected individuals. Surveillance for CEBPA-associated familial AML is similar to that for other forms of AML. There are no generally accepted minimal residual disease (MRD) markers in CEBPA-associated AML or in most other AML subtypes with normal karyotypes.

Individuals are monitored and evaluated in accordance with administered treatment, clinical course, symptoms, and protocol, if enrolled in clinical trials. When complete remission is achieved and intensification therapy is complete, individuals are monitored with:

• CBC and platelet counts every one to three months for two years with the frequency decreasing to every three to six months for up to five years;
• Bone marrow aspiration when cytopenia and/or an abnormal peripheral blood smear are present.

Note: The use of flow cytometry for MRD monitoring is controversial.

Individuals with a germline CEBPA pathogenic variant who are cured of their initial disease episode may be at risk for new leukemic episodes, often occurring after a prolonged period of remission (>3 years post presentation) [Pabst et al 2009, Tawana et al 2015]. In light of these data, lifelong clinical surveillance is warranted to ensure prompt recognition and appropriate management of disease recurrence. Repeat testing of CEBPA at recurrence is important to help distinguish conventional relapse from new, independent leukemic episodes.

Asymptomatic carriers. Asymptomatic individuals with a pathogenic CEBPA germline variant may be reviewed with CBC profiling every six to 12 months. Bone marrow examination may be performed if there is an appropriate clinical indication (e.g., abnormalities in CBC). Referral for post-testing genetic counseling should be considered as appropriate.

Agents/Circumstances to Avoid

Use of sib or related donors for HSCT without prior assessment of the pathogenic germline variant in these individuals.

Evaluation of Relatives at Risk

To date, all individuals with germline pathogenic CEBPA variants have presented with overt AML without any preceding blood count abnormalities or myelodysplasia, this in contrast with other familial leukemia syndromes such as those associated with germline RUNX1 or GATA2 pathogenic variants [Nickels et al 2013].

The decision to test for an inherited pathogenic variant is ultimately governed by personal choice, the reassurance of regular clinical follow up, and provision of genetic counseling. It is noteworthy that clinical monitoring may enable earlier diagnosis (and treatment) of AML, hence minimizing the risks associated with delayed presentation (e.g., severe anemia, neutropenic sepsis, and severe hemorrhage), providing further rationale for molecular evaluation of at-risk relatives. There are currently no preemptive treatments available for asymptomatic carriers of a germline CEBPA pathogenic variant.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.