Rare hereditary disorders can predispose individuals to subsequent leukemia, and advances in technology now allow for a better understanding of the underlying etiology. In particular, genomic studies have identified several new genetic syndromes and associated genes that increase the risk for acute myeloid leukemia (AML). These include CEBPA-associated predisposition to AML (fAML-CEBPA) and familial platelet disorder with associated myeloid malignancy (RUNX1) among others.

For some of these syndromes, AML may be the primary manifestation and an acute occurrence (fAML-CEBPA); in other syndromes, AML may arise in the context of other hematologic abnormalities, such as antecedent thrombocytopenia (RUNX1, ETV6, and ANKRD26). Individuals with still other syndromes may also be at risk for developing nononcologic manifestations, including neurologic and other types of dysfunctions or immunodeficiency (SAMD9, SAMD9L, and GATA2). Increasing awareness of these syndromes along with greater access to clinical genetic counseling and testing options has allowed more individuals with predispositions to AML to be identified.

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However, once the risk is known, what is the next step, if any? A paper published in the Journal of Clinical Oncology explored whether preemptive hematopoietic stem cell transplantation (pHSCT) is beneficial in these patients and if pHSCT should be offered to patients at increased genetic risk for AML as a means of preventing development of the disease.

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“There are many factors to consider when determining which patients might be ideal candidates for pHSCT,” explained author Kayla Hamilton, MS, CGC, of the St Jude Children’s Research Hospital in Memphis, Tennessee, in an interview with Hematology Advisor. “One of the key factors is the penetrance of the specific leukemia predisposition syndrome that an individual has.”

She pointed out that those with a 90% risk of leukemia would be more likely to derive benefit from a transplant compared with those with a 20% risk of leukemia. “However, other factors must also be considered, such as the average age of onset of leukemia, the age and health of the patient, whether [the patient is expected to have] antecedent thrombocytopenia/myelodysplastic syndrome, and the availability of a suitable donor,” Hamilton explained.

Hamilton and colleagues noted that it is uncertain whether pHSCT will confer the same benefit to patients with predisposition to AML compared with patients who have active disease. Given the number of clinical and ethical variables that must be considered, making this decision can be quite complicated.

In addition to the variation in risk conferred by different syndromes, the spectrum of tumors is variable across conditions that predispose patients to AML. In some cases, the predisposition is primarily for a myeloid neoplasm and, in theory, the risk can then be entirely mitigated with pHSCT. Other individuals, however, are also at risk for solid tumors, and in those cases, pHSCT will not prevent cancer, though it may correct immunologic abnormalities that accompany certain syndromes, such as GATA2-associated myelodysplastic syndrome.