Genetic Biomarkers in Acute Myeloid Leukemia

Will the Promise of Improving Treatment Outcomes Be Realized?

Jay Yang; Charles A Schiffer

Disclosures

Expert Rev Hematol. 2012;5(4):395-407. 

In This Article

Traditional Risk Factors

A patient's prognosis is a function of both patient- and leukemia-related variables, which can be roughly translated into a risk of early death due to complications from treatment, and death due to leukemia drug resistance, respectively. Advances in supportive care have made chemotherapy for AML patients safer. Examples include more effective antiemetics, newer antifungal agents and better blood banking and transfusion methods. As a result, the risk of death in younger patients is now largely due to leukemia-related factors. In older patients, both patient frailty and leukemia resistance remain considerable obstacles to achieving better outcomes.

Patient-related Risk Factors

Advanced age has long been known to portend a poorer prognosis in AML. Older patients have been variably described as older than 55, 60 or 65 years, but even among younger patients, increasing age is associated with poorer outcomes.[3] Much of this age-related risk is due to a higher incidence of leukemia-related risk factors, such as abnormal karyotypes, that impart resistance to therapy. Patient risk is also affected by a number of other factors besides age, including performance status, comorbid conditions and organ dysfunction.[4] The risk of 30-day mortality can be predicted by using the combination of patient age and performance status.[3] In a study from the Southwest Oncology Group, patients younger than 56 years with a performance status of 0 had an early mortality rate of 2%, whereas patients older than 75 years with a performance status of 3 had an early mortality rate of 82%. For this reason, these two factors have long been used to select patients for aggressive induction therapies. More contemporary, prospective studies have demonstrated modest early mortality rates (~11%) in older patients treated with intensive chemotherapy, so that treatment decisions should be made taking this positive trend into consideration.[5,6]

Efforts to more precisely characterize an older individual's risk have used comprehensive geriatric assessments incorporating multiple patient and disease variables.[4,7] For patients being evaluated for allogeneic transplantation, there are also global tools to more objectively assess the specific risk of this procedure.[8] Thus, even without improvements in AML-directed therapies, it is hoped that better patient selection may lead to improved outcomes.

Leukemia-related Risk Factors

Traditional disease-related prognostic risk factors include an elevated white blood cell count (>50 or 100 × 109/l), certain French–American–British subtypes (e.g., M6 and M7), certain immunophenotypic features (e.g., CD34 expression), P-glycoprotein expression and the presence of other drug resistance phenotypes. Secondary forms of AML due to previous chemotherapy or radiation and following antecedent hematological disorders (e.g., myelodysplasia) have generally poor outcomes.

Cooperative group studies conducted more than 20 years ago described recurrent karyotypic changes found in AML blasts in approximately 55% of newly diagnosed patients that were prognostically more robust than traditional factors.[9,10] Structural changes, including t(8;21)(q22;q22), inv(16)(p13.1q22) and t(16;16)(p13.1;q22), collectively called core-binding factor (CBF) leukemias, have been associated with better survival rates due to higher rates of complete remission (CR) and longer durations of remission. These karyotypes, along with t(15;17)(q22;q21), are considered favorable-risk and occur in approximately 15% of patients. Chromosomal abnormalities including deletions of 5, 5q, 7, 7q, 17p, inv(3)(q21;q26), t(3;3)(q21;q26), rearrangements of the MLL gene (11q23) and complex karyotypes (defined as either ≥three or ≥five abnormalities) are seen in approximately 25% of patients with AML and are considered adverse risk due to their association with drug resistance.

A monosomal karyotype (MK) has recently been described in approximately 10% of patients. This group is defined by either the presence of two or more autosomies or an autosomy in the presence of other chromosomal abnormalities. Outcomes for this group are extremely poor with chemotherapy alone having OSs of less than 5%, which is inferior to the survival of patients with complex cytogenetics.[11,12] Structural abnormalities of the MLL gene at chromosome band 11q23 had previously been felt to have a uniformly poor prognosis. However, recent data have shown a better prognosis for patients with t(9;11)(p21;q23) compared with other MLL rearrangements, with OSs of approximately 40%,[13] thus putting this subgroup into an intermediate-risk (IR) category.

Using karyotypic information, several cooperative groups have stratified patients by risk;[14,15] an important advance as it allowed for risk-adapted treatment and, in particular, guidance about referral for allogeneic transplant in first remission. Although the specific cytogenetic abnormalities included in each risk category vary slightly from group to group, the overall results are quite similar. In a CALGB study, the CR rates for favorable-, intermediate- and adverse-risk groups were 88, 67 and 32%, whereas the OS rates were 55, 24 and 5%, respectively.

Although these analyses provide information applicable to large cohorts of patients, such information does not always aid in the decision-making for individual patients, due to its lack of precision. For clinicians, it is bewildering when one patient with CBF leukemia is cured, and the next patient with an identical karyotype relapses despite identical treatments. Even more troublesome are the remaining 60% of patients with so-called IR disease (IR-AML), the majority of whom have normal cytogenetics (CN-AML). IR-AML also includes a number of uncommon karyotypes for which not enough data exist to make strong inferences about prognosis. This large group of patients is remarkably heterogeneous with presumably different pathogenetic mechanisms, making the optimal treatment approach unclear. Fortunately, recent advances have led to the detection of multiple molecular abnormalities that allow for the careful dissection of CN-AML.

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