AML Mutations Predict Response to High-Dose Chemotherapy

Neil Osterweil

March 14, 2012

March 14, 2012 — A retrospective analysis has identified mutations that appear to predict which patients with acute myeloid leukemia (AML) will benefit from high-dose chemotherapy.

Investigators analyzed samples from patients with AML who were enrolled in a clinical trial. The results were published online today in the New England Journal of Medicine.

Jay P. Patel, a research trainee in the human oncology and pathogenesis program at the Memorial Sloan-Kettering Cancer Center in New York City, and colleagues studies 18 genes and identified mutations in 3 associated with improved survival of patients randomized to received high-dose daunorubicin.

"These data indicate that more detailed genetic analysis may lead to improved risk stratification and identification of patients who can benefit from more intensive induction chemotherapy. The challenge is to provide genetic information in a timely and affordable way and show that this information could prospectively influence treatment decisions," the investigators write.

Bench-to-Beside Challenge

Developing a genetic panel into a clinical assay that can be used for treatment planning will indeed be challenging, according to the author of an accompanying editorial.

"A critical question is whether the data presented by Patel and colleagues are sufficient to justify the expansion of the number of genetic mutations being examined in patients with AML at presentation, beyond the current analysis of FLT3, NPM1,and CEBPA," writes Lucy A. Godley, MD, PhD, from the section of hematology/oncology in the Department of Medicine, University of Chicago in Illinois.

"All we can do is try to keep working in the research environment to try to figure out, in the large set of mutations that occur in leukemia and other cancer, which ones have clinically useful information," said senior investigator Ross L. Levine, MD, from Sloan-Memorial, in an interview with Medscape Medical News.

To be clinically useful in the treatment of acute leukemias, genetic mutation assays will need to produce rapid results, Dr. Levine said.

Clinical Trial

The investigators looked for potential prognostic markers in DNA samples from 502 patients. All were younger than 60 years and were enrolled in the Eastern Cooperative Oncology Group (ECOG) E1900 trial, a randomized study comparing induction therapy regimens with cytarabine plus daunorubicin at doses of either 45 or 90 mg/m².

"We hypothesized that integrated mutational analysis of all known molecular alterations occurring in more than 5% of patients with AML would allow us to identify novel molecular markers of outcome in AML and to identify molecularly defined subgroups of patients who would benefit from dose-intensified induction chemotherapy," they write.

Nearly all patients (97.3%) had somatic mutations in the genes analyzed; about two thirds of the mutations were considered to have prognostic value.

The investigators found that mutations in 4 genes were associated with worse overall survival: internal tandem duplication in FLT3 (= .001), partial tandem duplication in MLL (P = .009), ASXL1 (P = .05), and PHF6 (P = .006).

In contrast, mutations in 2 other genes were associated with improved overall survival: CEBPA (P = .05) and IDH2 (P = .01). Mutations in NPM1 were also associated with better outcomes, but only when the mutations occurred in patients who also had mutations in IDH1 or IDH2, the investigators note.

Prognostic Significance

Although other studies have linked mutations of DNMT3A to adverse outcomes in patients with AML, patients in the E1900 cohort with DNMT3A mutations had better survival when treated with high-dose daunorubicin (= .04) than those with wild-type DNMT3A (P = .15).

The investigators compared patients with DNMT3A or NPM1 mutations or translocations of MLL with patients with wild-type DNMT3A and NPM1 and no MLL translocations. They found that high-dose chemotherapy induction significantly improved survival in patients with 1 or both mutations and the translocation (p = .001), but did not in patients with the wild-type genes and no MLL translocations (P = .67)

The finding held up in multivariate analyses that controlled for age, white cell count, transplant status, treatment-related death, and response to chemotherapy (P = .008 for patients with mutations, and P = .34 for patients with wild-type genes), "suggesting that high-dose anthracycline chemotherapy provides a benefit in genetically defined subgroups of patients with AML," Patel and colleagues write.

Pointing to the increasingly complex genetic portrait of AML, Dr. Godley notes that "it may be overwhelming for clinicians to receive a report with hundreds of gene mutations and expect them to make rational clinical decisions. An approach in which a fixed panel of genes is examined for mutations of particular clinical significance might be more affordable and the results easier to understand."

Dr. Levine agreed, noting that "it's a challenge to us and to our colleagues in the field to ask how we can deliver this information clinically."

The study was supported by grants from the National Cancer Institute, the Gabrielle's Angel Fund, the Starr Cancer Consortium, and the Peter Solomon Fund at the Memorial Sloan-Kettering Cancer Center. Dr. Levine reports serving as a consultant for Agios and Incyte; receiving institutional research grants from Novartis and Agios; and receiving travel reimbursement from the Leukemia & Lymphoma Society. His coauthors have disclosed no relevant financial relationships. Dr. Godley reports that her institution has a contract with Celgene to provide services.

N Engl J Med. Published online March 14, 2012. Abstract, Editorial

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