Molecular Analysis Should Guide Treatment Individualization in AML

Silas Inman @silasinman
Published: Monday, Feb 23, 2015

Dr. Stefan Faderl

Stefan Faderl, MD

Cytogenetic and molecular data are becoming increasingly important in the individualization of treatment for patients of acute myeloid leukemia (AML), according to a presentation by Stefan Faderl, MD, at the 2015 International Congress on Hematologic Malignancies.

In his talk, Faderl, from the John Theurer Cancer Center at the Hackensack University Medical Center in New Jersey, examined potential treatments and investigational approaches for patients with a variety of risk factors and molecular aberrations. Each example characterized the importance of cytogenetic information and proper risk stratification.

"Cytogenetic-molecular data are becoming increasingly crucial, not only at the initial point of making a diagnosis, or prognosticating, but also in the identification of treatment targets," Faderl said. "There are exciting new treatments in clinical studies, which hopefully at some point will make it into clinical practice."

Intermediate Risk Younger Patients With AML

Risk stratification is generally conducted early in the treatment process for patients with AML, based on karyotype. This process has been refined over time to further classify the intermediate-risk population, in an attempt to better define outcomes.

"Traditionally, karyotyping has been one of the most important pretreatment factors to determine posttreatment outcomes, as far as it relates to relapse and survival," Faderl explained. "FLT3 mutations, NPM1, and CEBPA have formed the basis for revised risk stratification models, which have allowed for the some intermediate risk patients to be reassigned to other risk groups."

This redefinition of risk created favorable, intermediate-1, intermediate-2, and adverse subgroups. The favorable group is defined by core binding factor (CBF) AML while those with KIT mutations were moved to an intermediate-1 group. Adverse risk is characterized by TP53 mutations, monosomal karyotype, and other complex cytogenetic abnormalities.

The intermediate-2 risk group is classified by having no discernable favorable or adverse karyotype features. Treatment for these patients includes standard induction chemotherapy with 7 days of cytarabine and 3 days of daunorubicin (7+3). With this treatment, the projected 4-year overall survival (OS) rate is approximately 20% to 40% for this group of patients, Faderl explained.

Clinical studies have attempted to improve the standard 7+3 regimen with some success, in limited subgroups. High-dose daunorubicin (90 mg/m2) has been explored but has been found to elicit similar outcomes to the standard dose of the drug (60 mg/m2).

Additionally, studies have explored high-dose cytarabine (3 g/m2), with some improvements in efficacy along with a significant increase in mortality and side effects. In younger patients with adverse risk AML, there were some benefits with high-dose cytarabine.

"For younger patients, high-dose cytarabine seemed to particularly improve remissions in poor-risk AML, such as secondary or AML associated with poor-risk cytogenetics, indicating that higher-dose cytarabine might be able to overcome resistance associated with these particular clinical situations," Faderl said.

Clinical studies have sought to add novel agents onto the standard 7+3 regimen, Faderl notes. The SAL-SORAML trial examined standard therapy plus sorafenib (n = 134) or placebo (n = 133) in younger patients with newly diagnosed AML.1 In the study, sorafenib at 800 mg was given regardless of FLT3-ITD status, which was present in 17% of patients.

The complete remission (CR) was the same in both arms, at approximately 60%. The median event-free survival (EFS) was 20.5 months in the sorafenib arm versus 9.2 months with placebo. Additionally, the 3-year EFS rate was 40% with sorafenib versus 22% with placebo (P = .013).

The median relapse-free survival (RFS) was not yet reached in the sorafenib arm versus 23 months with placebo. The 3-year RFS rate was 56% versus 38% and the 3-year OS rate was 63% versus 56%, for sorafenib and placebo, respectively.

Common post-remission treatments for younger patients with intermediate-2 risk AML include allogeneic stem cell transplant (SCT), autologous SCT, or chemotherapy. In most situations, transplant induces better long-term outcomes than chemotherapy, Faderl noted.

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