Progress in Molecular Markers that Predict Prognosis in AML

Phoebe Starr

October 2011, Vol 2, No 6 - NCCN Hematology Congress


Jerald Radich, MDNew York, NY—The era of personalized medicine is progressing. At the Fred Hutchinson Cancer Center, Seattle, WA, and at other centers, patients with intermediate-risk acute myeloid leukemia (AML) are now being tested for 3 molecular markers that predict prognosis. The goal is to use these markers for treatment selection and for monitoring response.

As people age, they accumulate more cytogenetic markers of poor prognosis, said Jerald Radich, MD, Fred Hutchinson Cancer Center, who spoke at the National Comprehensive Cancer Network 6th Congress on Hematologic Malignancies.

The 3 genetic mutations are FLT3- ITD, NPM1, and CEPBA. The FLT3- ITD mutation predicts poor prognosis whereas NPM1 and CEPBA mutations predict good prognosis. The presence of NPM1 trumps FLT3-I, meaning that NPM1 still predicts good prognosis despite the presence of FLT3-I. The presence of all 3 mutations also predicts improved outcomes.

These markers are used in addition to conventional risk factors for AML, which include age, clinical status, and cytogenetics (recurrent abnormal chromosomal aberrations). Based on cytogenetics, a patient’s prognosis is classified as favorable, intermediate, or poor.

Approximately 40% of patients with AML have a normal cytogenetic profile and are considered to have intermediate risk, but molecular markers (such as FLT3-ITD, NPM1, and CEPBA) identified by gene mutational studies can further refine risk stratification for disease progression within people with a normal cytogenetic profile.

Approximately 84% of patients with intermediate risk and normal karyotypes will have mutations: of these, approximately 50% will have NPM1, 31% will have FLT3-ITD, and 14% will have CEPBA mutations, which can overlap in the same patient.

Patients with NPM1 mutations have a better clinical course, and those with both NPM1 and FLT3-ITD mutations fare the best. “They are driven from intermediate risk to favorable risk,” Dr Radich commented.

It is important to quantify the amount of FLT3-ITD that is present in a patient with AML: the greater the amount, the greater the risk for poor prognosis, Dr Radich said.

Although a patient may have complete remission on induction/consolidation therapy, detecting the presence of minimal residual disease (MRD) predicts relapse. MRD is used before and after transplant to predict outcomes. Dr Radich cautioned that early identification of MRD does not improve outcomes.

“The best technique for quantifying MRD is flow cytometry, because it is exquisitely sensitive to phenotype,” Dr Radich noted. An important area of research is the use of cytogenetics and molecular testing for risk stratification of enrollees in clinical trials, but funding for this research seems to be drying up, Dr Radich commented.