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More Extensive Gene Profiling Urged in AML, MDS

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Translating Genetic Results Into Clinical Practice

The findings of Dr. 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 [the] FLT3, NPM1, and CEBPA [genes]." These results also "challenge the field to address at what point data are compelling enough to change routine practice," said Dr. Lucy A. Godley.

The findings of Dr. Walter and colleagues also are challenging, since "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 was examined for mutations of particular clinical significance might be more affordable and the results easier to understand," she said.

Dr. Godley is in the section of hematology-oncology in the department of medicine at the University of Chicago. She reported ties to Celgene. These remarks were adapted from her editorial accompanying the two reports (N. Engl. J. Med. 2012 March 14 [doi:10.1056/NEJMe1200409]).


 

FROM THE NEW ENGLAND JOURNAL OF MEDICINE

More detailed genetic profiling of patients with acute myeloid leukemia and of those with precursor myelodysplastic syndromes is likely to improve prognostic and therapeutic decision making, according to two separate studies published online March 14 in the New England Journal of Medicine.

In one study, investigators found that the presence of DNMT3A and NPM1 mutations and MLL translocations predicted an improved outcome when patients received high-dose daunorubicin instead of the standard dose in induction chemotherapy for acute myeloid leukemia (AML).

The results suggest that "mutational profiling can be used to determine which patients will benefit from dose-intensive induction therapy," wrote Jay P. Patel of the human oncology and pathogenesis program at Memorial Sloan-Kettering Cancer Center, New York, and his associates.

In the other study, researchers reported that "nearly all" of the bone marrow cells were clonally derived in paired samples of skin and bone marrow from seven patients with myelodysplastic syndromes (MDS) and secondary AML. Founding clones and daughter subclones in all seven paired samples had recurrent gene mutations, including at least one mutation in a coding gene.

"Although clonality is not sufficient to define malignant transformation, it is a cardinal manifestation of most human cancers, and our findings suggest that the myelodysplastic syndromes and secondary AML are both highly clonal hematologic cancers," said Dr. Matthew J. Walter of the departments of internal medicine and genetics at the Siteman Cancer Center, Washington University, St. Louis, and his associates.

Mutational Analysis of Trial Results

In the first study, researchers performed a more-extensive mutational analysis than is typically done to better discriminate among patients with different prognoses.

"Previous studies have suggested that mutational analysis of [the genes] CEBPA, NPM1, and FLT3-ITD can be used to stratify risk among patients with intermediate-risk AML," wrote Mr. Patel and his colleagues.

"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 ... and to identify molecularly defined subgroups of patients who would benefit from dose-intensified induction therapy."

For DNA extraction and profiling, the investigators used diagnostic samples of bone marrow and peripheral blood from 398 patients who were participating in the phase III ECOG (Eastern Cooperative Oncology Group) E1900 clinical trial in which two doses of induction therapy were tested. They found that 97.3% of the study subjects had mutations in 18 genes, and performed extensive mutational analysis of these 18 candidate genes.

The results led them to identify three distinct risk groups. Patients with favorable genetic profiles had a 3-year overall survival of 64% and had not yet reached a median survival; those with intermediate-risk genetic profiles had a 3-year survival of 42% and a median survival of 25 months; and those with unfavorable genetic profiles had a 3-year overall survival of 12% and a median survival of 10 months.

These findings were then validated in a separate group of 104 patients from the same clinical trial. The value of the genetic risk profiles was confirmed, with the favorable, intermediate, and unfavorable profiles accurately predicting patient outcomes independently of patient age, white cell count, induction dose, transplantation status, and type of postremission therapy, Mr. Patel and his colleagues said (N. Engl. J. Med. 2012 March 14 [doi:10.1056/NEJMoa1112304]).

Moreover, the 3-year overall survival rate in patients with a mutation in the DNMT3A or NPM1 genes or a MLL translocation was 44% with high-dose chemotherapy vs. 25% with the standard dose. In patients with other genotypes, it was 35% with the high-dose regimen and 39% with the standard dose.

"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," they noted.

Founding MDS Clones Persist in AML

In the second study, Dr. Walter and his associates used bone marrow biopsy specimens from seven patients who progressed from MDS to AML to define changes in the proportion of clonal cells and the genetic architecture that took place during that progression.

Several genes have already been identified that show recurrent mutations during this process, "but our understanding of the total number and clonal distribution of mutations in this disease is limited," they noted.

For each subject, DNA sequences were obtained from samples of normal skin, bone marrow obtained during the MDS stage, and bone marrow obtained during the secondary AML stage, to analyze mutations. In all seven samples, the founding clones (containing 182-660 mutations) persisted in the secondary samples, while acquiring at least one new mutation predicting translational consequences.

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