Published in the September 2012 Newsletter

Performing extensive mutational testing in patients with acute myeloid leukemia (AML) has the potential to inform risk stratification, improve prognostic models, and guide treatment decision-making, according to the results of an ECOG study published in the March 22, 2012 issue of the New England Journal of Medicine.

The study, which was undertaken by the ECOG Leukemia Laboratory Committee, analyzed the prognostic value of recently identified recurrent somatic mutations in AML using diagnostic samples contributed by patients enrolled in E1900, a phase 3 therapeutic clinical trial. E1900 (NCT00049517) showed that induction chemotherapy with cytarabine plus high-dose vs. standard-dose daunorubicin improved complete remission and overall survival rates in patients aged 16 to 60 years with AML.

To conduct the current analysis, scientists performed mutational testing on 18 genes in 398 E1900 participants younger than 60 years of age with AML who received induction chemotherapy with high-dose or standard-dose daunorubicin. The prognostic findings were validated in an independent cohort of 104 E1900 participants.

Levine and colleagues reported that at least one somatic alteration was identified in 97.3% of patients. The analysis also showed that internal tandem duplication mutations in FLT3, partial tandem duplication mutation in MLL, and mutations in ASXL1 and PHF6 were correlated with reduced overall survival, whereas CEBPA and IDH2 mutations were correlated with improved overall survival. Furthermore, in patients with DNMT3A mutations, NPM1 mutations, or MLL translocations, treatment with high-dose vs. standard-dose daunorubicin improved survival—a benefit that did not, however, extend to patients with wild-type DNMT3A, NPM1, or MLL.

Ari M. Melnick, MD“Our research shows that a more detailed genetic analysis, such as the one we performed, may lead to improved risk stratification and identification of patients who can most benefit from a more intensive induction chemotherapy regimen,” states Ari M. Melnick, MD, Chair of the ECOG Leukemia Laboratory Committee.  “The challenge will be to obtain genetic information in a timely and affordable way to prospectively influence treatment decisions.” Dr. Melnick is an Associate Professor at the Weill Cornell Medical College, where he is also Director of the Raymond and Beverly Sackler Center for Biomedical and Physical Sciences, Director of the Internal Medicine Research Residency, and Director of the Epigenomics Core Facility.

The ECOG Leukemia Translational Studies Laboratory assisted the ECOG Leukemia Committee in carrying out this breakthrough research.  These programs bring together researchers from ECOG member institutions and non-member institutions alike. Additionally, researchers from both types of institutions have applied for and been given access to ECOG clinical specimens through these programs.

“Major accomplishments in the area of leukemia research are made possible by the outstanding scientists and biostatisticians in the program who support selected pilot studies proposed by ECOG members, and non-members alike,” says Elisabeth M. Paietta, PhD, Director of the Leukemia Translational Studies Laboratory and Co-Chair of the Leukemia Laboratory Committee. “This widespread involvement in our program has greatly expanded the scope and impact of ECOG-related leukemia research.” Dr. Paietta is a Professor in the Department of Medicine (Oncology) at the Albert Einstein College of Medicine of Yeshiva University.  

Related NEJM Editorial

In an editorial commenting on the study findings, Lucy A. Godley, MD, PhD, from the University of Chicago, acknowledged that investigators made “very economical use” of previously collected patient data to provide important information about the types and prognostic value of mutations found in primary AML. Dr. Godley questioned, however, whether the findings are sufficiently promising to increase the number of genetic mutations beyond those that are currently being analyzed at presentation of AML. Additionally, she stressed the importance of implementing new molecular evaluations in a thoughtful way—one in which patient benefit is optimized.

Citation: Patel JP, Gönen M, Figueroa ME, et al. Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. New Engl J Med. 2012;366(12):1079-1089.

Related editorial citation: Godley LA. Profiles in leukemia [editorial]. New Engl J Med. 2012;366(12):1152-1153.

Background on the E1900 Study

E1900, a randomized phase 3 trial developed by the Eastern Cooperative Oncology Group Leukemia Committee, evaluated the effect of induction therapy with cytarabine combined with either standard-dose daunorubicin (45 mg/m2/day) or high-dose daunorubicin (90 mg/m2/day) on outcome in patients with acute myeloid leukemia (AML).

In total, 657 patients with AML (median age, 48 years; age range, 17 to 60 years) were enrolled in the study; of these, 582 patients were assessable. Complete remission was achieved by 57.3% of patients (168/293) receiving standard-dose daunorubicin and 70.6% of patients (204/289) receiving high-dose daunorubicin (P < .001); median overall survival was 15.7 and 23.7 months, respectively (P = .003). The incidence of serious adverse events was similar in the two treatment arms.

Citation: Fernandez HF, Sun Z, Yao X, et al. Anthracycline dose intensification in acute myeloid leukemia. N Engl J Med. 2009;361(13):1249-1259.

Trial registration at NCT00049517