Rethinking Genetic Profiles in Acute Myeloid Leukemia: It’s All in the CEBPA-Mutated Family

Though familial leukemia is rare, its prevalence is likely underestimated due to variations in disease phenotype and latency, as well as a lack of systematically collected data on family history. To better understand the underlying evolution of leukemia, Kiran Tawana, MD, Centre for Haemato-Oncology, Barts Cancer Institute in London, and colleagues examined the genetic events initiating the disease and detailed the clinical progression of acute myeloid leukemia (AML) across 10 families harboring germline CCAAT/enhancer binding protein-alpha (CEBPA) mutations.

Somatic CEBPA mutations occur in 10 to 15 percent of sporadic normal karyotype AML, Dr. Tawana and authors explained. In the current study, the researchers collected clinical data from 10 CEBPA-mutated families, in whom 24 members were diagnosed with AML.

Using whole-exome and deep sequencing to genetically profile the cancers and define patterns of clonal evolution, the researchers analyzed primary samples from seven AML patients with two episodes of disease recurrence. Somatic CEBPA mutations were tested at diagnosis and relapse in six patients.

Comprehensive clinical and genetic profiling revealed novel disease insights, most notably a new pattern of disease evolution, Dr. Tawana told ASH Clinical News. “The study demonstrates the importance of recognizing suspected cases of familial leukemia in order to improve patient management,” she added.

The median follow-up was 7.5 years (range, 2-46 years), and four patients died within the first year of diagnosis, while one patient was lost to follow-up. Ninety-six percent of patients (n=23) were treated with induction chemotherapy, which included an anthracycline and/or cytarabine regimen.

Both the molecular and clinical profiles of familial cancers resembled those of sporadic CEBPA-double mutation AML, the authors observed, except for one important regard. “In contrast to multiple reports describing the stability of CEBPA mutations in sporadic AML, the opposite was observed in familial AML, with different mutations identified at disease recurrence.” Deep sequencing of paired samples at diagnosis and relapse confirmed that relapse-associated CEBPA mutations were absent at diagnosis, suggesting that recurrence was triggered by novel, independent clones arising from the germline mutations.

Recurrence of familial AML appeared to be sensitive to chemotherapy, with the median survival post-relapse being eight years for familial AML compared with 16 months for sporadic CEBPA-double mutations (and 3.5 months for CEBPA-single mutations (p=0.01; p=0.006 familial vs. sporadic CEBPAA-single mutations; p=0.03 for familial vs. all sporadic).

In terms of clinical outcomes, overall survival in familial AML was longer than in sporadic CEBPA-single mutations (p=0.003). The complete remission rate for familial AML was 91 percent (n=21), though disease recurrence was frequent:

  • The cumulative incidence of relapse in familial AML was 56 percent at 10 years in 11 patients, presenting at a median of 27 months following the initial diagnosis.
  • Three patients experienced three or more disease episodes over a period of 17 to 20 years.

Overall, the researchers found that the majority of the familial AML cases presented at an early age (median=24.5 years; range=1.75-46 years), and germline CEBPA mutations were associated with the occurrence of de novo disease without a preceding dysplastic or cytopenic phase, which is unlike other leukemia-predisposition syndromes.

“This collaborative study describes disease evolution and outcomes in a rare but important subset of patients with germline CEBPA mutations,” Dr. Tawana said, “and also highlights the need for reevaluation of genetic profiles at AML recurrence in all leukemia predisposition syndromes to determine whether these findings are universal or unique to germline CEBPA mutations.”

Limitations of the study include a small patient population and a comparator group of sporadic CEBPA mutations was not part of the formal clinical trial, thus it may introduce bias.

The findings, the authors concluded, “reinforce the need for long-term surveillance of families with germline CEBPA mutations. With improved clinical awareness and ongoing research efforts, we hope to provide a foundation for evidence-based genetic counseling and tailored management of this unique patient population.”


Tawana K, Wang J, Renneville A, et al. Disease evolution and outcomes in familial AML with germline CEBPA mutations. Blood. 2015 July 10. [Epub ahead of print]