Specific Mutations in AML Affect Response to Therapy
(HealthDay News) – Patients with acute myeloid leukemia (AML) harboring specific combinations of mutations benefit from high-dose daunorubicin; and the majority of bone marrow cells in myelodysplastic syndromes and secondary AML are clonal and harbor multiple mutations, according to two studies published online March 14 in the New England Journal of Medicine.
Jay P. Patel, from the Memorial Sloan-Kettering Cancer Center in New York City, and colleagues conducted a mutational analysis of 18 genes in 398 patients with AML, <60 years old, who were randomly assigned to receive induction therapy with high-dose or standard-dose daunorubicin. Prognostic findings were validated in a cohort of 104 patients. At least one somatic mutation was identified in 97.3% of the patients. For patients with DNMT3A or NPM1 mutations or MLL translocations, high-dose daunorubicin improved the rate of survival compared with standard-dose daunorubicin; no difference in effect was observed for patients with other types of mutations.
In an effort to identify secondary AML-specific somatic mutations, Matthew J. Walter, MD, from Washington University in St. Louis, and colleagues performed whole genome sequencing of paired samples of skin and bone marrow from seven patients with secondary AML. Bone marrow samples obtained during the antecedent myelodysplastic-syndrome stage were genotyped, and recurrent mutations in coding genes were identified. Regardless of the myeloblast count, the researchers found that approximately 85% of bone marrow cells were clonal in the myelodysplastic-syndrome and secondary-AML samples. Progression to acute leukemia was defined by the persistence of an antecedent clone harboring 182–660 somatic mutations and the emergence of one or more subclones, each harboring multiple new mutations. All of the founding clones and subclones contained at least one mutation in a coding gene.
"Genetic evolution of secondary AML is a dynamic process shaped by multiple cycles of mutation acquisition and clonal selection," the authors write.
One author of the Patel study disclosed financial relationships with the pharmaceutical industry.