Genetics of Acute Myeloid Leukemia 

The diagnosis, prognosis, and treatment of acute myeloid leukemia (AML) has been transformed over the past 15 years from a disease defined, classed, and staged based on histologic characteristics alone to a disease classified largely based on genetic, genomic, and molecular characteristics.

The risk pattern in AML is determined not only by cytogenetic abnormalities, such as chromosomal deletions, duplications, or substitutions, but also by the elucidation of certain molecular mutations leading to over- or under-expressions of one of many proteins.

Cytogenetic studies performed on bone marrow in patients with AML play a crucial role in characterizing the leukemia, helping determine disease aggressiveness, response to treatment, and prognosis.^[1] For example, the finding of a translocation between chromosomes 15 and 17, or t(15;17), is associated with a diagnosis of acute promyelocytic leukemia (APL), a subtype of AML that is treated and monitored differently than other subtypes.^[2]

The commonly used French American British (FAB) classification^[3] as well as the more recent World Health Organization (WHO) classification^[4] use a variety of factors to classify AML as poor-risk, intermediate-risk, and better-risk disease. In general, better-risk disease is associated with long-term survival of up to 65%, medium-risk disease is associated with long-term survival of about 25%, and poor-risk disease is associated with long-term survival of less than 10%.

Cytogenetic abnormalities associated with disease risk are shown in the Table.^{[5, 6]}

Table. Cytogenetic Risk Factors (Open Table in a new window)

In addition to cytogenetic abnormalities, several molecular abnormalities have been shown to have prognostic importance in patients with AML.

FLT3 is the most commonly mutated gene in AML and appears to be activated in one third of AML cases. Internal tandem duplications (ITDs) in the juxtamembrane domain of FLT3 are seen in 25% of AML cases, while others show mutations in the activation loop of FLT3. Patients with FLT3 -ITD tend to have a poor prognosis.^[7]

Mutation in NPM1 is generally favorable; patients with this mutation show increased response to chemotherapy and improved survival. However, if present together with the FLT3 mutation, this survival benefit is negated.^[8] Mutations in CEBPA are detected in 15% of patients with normal cytogenetics and are associated with a longer remission duration and longer overall survival.^[9] Of note, the presence of c-KIT mutations in patients with otherwise favorable cytogenetic markers (eg, t(8:21), inv(16)) confers a higher risk of relapse.^[10]

Other molecular markers, such as ERG and BAALC, have been suggested to be predictive of risk and response to treatment. However, tests for these markers are not routinely available so they are not typically included in classification genetic and molecular systems.^[6]

Testing for key genetic markers in patients with AML is important for both prognostic and treatment purposes. Generally, the relatively slow turnaround time for cytogenetic and molecular testing makes it difficult to tailor the initial induction based on these factors. However, the choice of consolidation and/or maintenance therapy can often benefit from risk stratification using genetic information. Treatment decisions have been made using this information in one of two ways: in deciding on the aggressiveness of treatment, and in determining whether targeted therapy may influence the genetic or genomic aberration and specifically treat the individual’s tumor.

A classic example of the latter is seen in patients with APL. Its characteristic t(15:17) translocation leads to production of an abnormal fusion protein known as PML-RAR alpha. In normal leukocytes, the RAR protein interacts with retinoic acid to promote cellular differentiation. However, the fusion gene product between the chromosomes in patients with APL causes the retinoic acid receptor to bind more tightly to the nuclear corepressor factor. This prevents the gene from being activated with physiologic doses of retinoic acid, and differentiation from promyelocytes into leukocytes does not occur, leading to a clonal overgrowth of promyelocytes.^[2]

The discovery that supraphysiologic doses of all-trans retinoic acid (ATRA) can overcome PML-RAR alpha blockade of the retinoic acid receptor led to the use of ATRA in combination with chemotherapy in patients with APL, which yields very high rates of long-term survival.^[2]

Agents targeted toward other molecular abnormalities in AML are in development, but are not currently available in a clinical setting outside of a clinical trial.

Tailoring conventional therapy to risk level, rather than targeting single mutations, is slightly more complicated and subjective. As in all diseases, the decision of which agents to use in AML depends on many factors, including functional status and age of the patient, determination of whether the cancer is secondary to previous cancer therapy or is an abnormal clone secondary to other hematologic disorders such as myelodysplastic syndrome, and the agents and resources available to the treating physician.

Patients with favorable-risk disease (ie, those with t(8;21) or inv(16)) tend to have low relapse rates following consolidation with high-dose cytarabine. Autologous or allogeneic stem cell transplants in these situations should be reserved for patients who have relapsed disease.^[6]

Patients with poor-risk disease are rarely cured with chemotherapy alone and should be offered allogeneic transplantation in first remission. This includes patients who had intermediate-risk disease by cytogenetics but high-risk disease by molecular diagnostics, such as FLT3 -ITD. These patients also are at high risk for a relapse following transplantation, but transplant offers them the best chance of long-term remission. In an EORTC/GIMEMA trial, these poor-risk patients underwent matched-sibling stem cell transplant and had up to 43% 4-year disease-free survival.^[11]

The choice of treatment for patients with intermediate-risk disease is controversial. While some oncologists refer intermediate-risk patients in first remission for transplant, others give standard consolidation with high-dose cytarabine and only refer patients for transplant if they relapse. Neither option has yet been found categorically to be preferable.^[6]

Studies focusing on molecular markers such as FLT3, NPM1, CEBPA, BAALC, and ERG are helping to define which patients with intermediate-risk disease by cytogenetics should receive standard consolidation therapy vs transplantation, but results are still immature. The National Comprehensive Cancer Network (NCCN) currently recommends routine evaluation for CEBPA, NPM1, and FLT3 -ITD in patients with normal cytogenetics, as well as testing for c-KIT in patients with otherwise favorable cytogenetics such as inv(16) or t(8;21).^[6]

Cytogenetic testing is widely commercially available, and results are consistent and interpretable. Fluorescence in-site hybridization (FISH) can also identify cytogenetic abnormalities, but results should be used only in combination with routine cytogenetics.

Analysis of molecular markers such as FLT3 -ITD, NPM1, c-KIT, and CEBPA are less commonly available outside research institutions. If a physician is in an area where these tests are not readily available, it is recommended to preserve additional aliquots of bone marrow aspirate at the time of diagnosis. Once cytogenetic information has returned, the decision can be made whether molecular markers would further contribute to treatment decisions. For example, if the local pathology laboratory shows normal cytogenetics, it would be of use to send the additional aliquots to an outside research or academic facility to test for the FLT3 -ITD mutation, which, if present, would qualify the patient as poor-risk and therefore likely to benefit more from transplant than from conventional chemotherapy.