Using Molecular Markers in AML for Prediction, Treatment, and Monitoring

Jerald P. Radich, MD

Several molecular markers for acute myelocytic leukemia (AML) are now used at top-tier cancer centers for prediction, treatment selection, and monitoring response.

But there is room for progress and more research is needed to identify markers beyond simple cytogenetics, said Jerald P. Radich, MD, in the Division of Cancer Research at the Fred Hutchinson Cancer Research Center in Seattle, Washington. Radich spoke at the National Comprehensive Cancer Network’s 6th Annual Congress on Hematologic Malignancies in New York, New York, September 9-10.

Conventional prognostic factors include age, performance status, and cytogenetics. In AML, as people get older they accumulate more cytogenetic risk factors. In clinical practice, 3 different cytogenetic markers are used at Fred Hutchinson and other research centers: Flt3-ITD, NPM1, and CEBPA mutations. The presence of Flt3- ITD predicts increased rates of relapse and lower overall survival rates (ie, poor prognosis), while NPM1 and CEBPA mutations predict improved prognosis. There can be overlap of these markers in a given AML patient, Radich explained.

In good-risk patients, the presence of C-kit mutations (occurring in 20% to 50% of AML) downgrades risk status to intermediate risk, with a 4-year survival of 40%, he said. In patients with intermediate risk AML and normal karyotypes, about 84% will have mutations; about 50% will have NPM1, about 31% will have Flt3-ITD, and these can overlap. About 14% of patients will have CEBPA mutations. The presence of all 3 mutations predicts improved outcomes.

Radich said that a further refinement in predicting clinical course is quantifying the amount of Flt3-ITD present; patients with high amounts of this mutation will have worse outcomes. “We think it is important to identify the presence of Flt3-IDT and to measure the amount that is present,” he said.

Patients with NPM1 mutations have a better clinical course, and those with Flt3-ITD wild-type and NPM1 mutations fare the best, Radich said. “This drives them from intermediate risk to improved risk,” he commented. Poor-risk patients are those with deletions of 5q and 7. Patients with 2 or more monosomy karyotypes have a poor prognosis.

The presence of minimal residual disease (MRD) predicts relapse, even in a patient with complete response (CR) to induction and/or consolidation chemotherapy. Quantification of MRD defines the level of risk, Radich said. Molecular assays for MRD allow selection of therapy, he added. Flow cytometry should be used to measure MRD, because “it is exquisitely sensitive to phenotype,” he said.

MRD pretransplant also predicts outcome. Posttransplant, MRD-negative patients have a good prognosis, while those who are MRD-positive have a poor prognosis. “Just because you identify MRD early does not mean you can improve outcome,” Radich told attendees.

The field is moving toward use of cytogenetics and molecular testing for risk stratification of patients enrolled in clinical trials. “Using this testing up front allows you to choose the appropriate regimen 48 hours later,” he said. A major problem is lack of funding for this research.

He cited the following areas for improvement: the need for better prognostic and diagnostic markers; the ability to identify a priori the 15% of AML patients who will be nonresponders to conventional chemotherapy; and a method for figuring out how to change therapy according to development of new clones as the disease progresses.