"We have found that the proportion of neoplastic bone marrow cells is indistinguishable [between] myelodysplastic-syndrome and secondary-AML samples, suggesting that the myelodysplastic syndromes are as clonal as secondary AML," Dr. Walter and his colleagues said (N. Engl. J. Med. 2012 March 14 [doi:10.1056/NEJMoa1106968]).
There are three major clinical implications, according to the authors.
First, MDS is currently distinguished from secondary AML based on hand counting of bone marrow myeloblasts – a method prone to inaccuracy but nonetheless relied upon to drive major treatment decisions. "Ultimately, identifying the patterns of pathogenic mutations and their clonality in bone marrow samples ... should lead to greater diagnostic certainty and improved prognostic algorithms," the investigators said.
Second, the dominant AML clone was derived from a founding MDS clone in every case, suggesting that "therapies targeted to these early mutations might be the most effective strategy for eliminating disease-propagating cells and improving the rate of response to traditional chemotherapy."
Third, it is possible that progression from MDS to AML "is driven not only by the presence of recurrent mutations ... but also by the clone ([that is], founding vs. daughter) in which they arise." Combining genotyping of samples with analysis of the clonal architecture "may yield more informative biomarkers and a better understanding of the pathogenesis of the myelodysplastic syndrome," Dr. Walter and his associates said.
Dr. Patel’s study was supported by the National Cancer Institute Physical Sciences Oncology Center, Gabrielle’s Angel Fund, the Starr Cancer Consortium, the Peter Solomon Fund, the American Society of Hematology, the Leukemia and Lymphoma Society, the Fund for Scientific Research Flanders, Burroughs Wellcome, the Sackler Center for Biomedical and Research Sciences, and the Howard Hughes Medical Institute. One of Dr. Patel’s associates reported ties to Agios, Incyte, and Novartis. Dr. Walter’s study was supported by the National Institutes of Health, the Howard Hughes Medical Institute, and the National Center for Research Resources. He and his associates reported no financial conflicts of interest.