Chronic myelomonocytic leukemia (CMML) is a type of cancer that starts in blood-forming cells of the bone marrow and involves the blood and other organs such as the spleen. CMML shows characteristics of myelodysplastic syndrome, a disorder that produces abnormal looking blood cells, and myeloproliferative disorder, a condition characterized by the overproduction of blood cells. Due to its similarities to multiple disorders, CMML is difficult to diagnose.
Gene mutations are present in more than 90% of patients with CMML. The three most common gene mutations found are TET2, ASXL1 (epigenetic regulators), and SRSF2 (spliceosome components). Of these, thus far, only ASXL1 mutations have been shown to adversely impact overall survival of patients with CMML (Patnaik M et al. Leukemia 2014).
In a recent study, Mayo Clinic researchers used a 27-gene-panel assay to identify additional gene mutations in CMML and to determine if the number of mutations present indicates better or worse survival or the need for treatment sooner. The study was published in the Blood Cancer Journal.
“In selecting the gene-panel assay, we identified myeloid-relevant genes that are frequently mutated in myeloid neoplasms, including CMML. We decided to test the entire panel to elaborate on the frequency of the mutations and to determine the significance of more than one mutation on the disease outcome,” said Mrinal Patnaik, M.B.B.S., Consultant in the Division of Hematology and first author on this paper. Dr. Patnaik’s team had developed the Molecular Mayo Model, a novel, contemporary, molecularly integrated CMML prognostic model (Patnaik M et al. Leukemia 2014).
“In using the Molecular Mayo Model, we were the first group to incorporate gene mutations (ASXL1 frame shift and non-sense mutations) with clinical parameters. This allowed stratification of patients in to four categories; low, intermediate-1, intermediate-2, and high, with differential survival rates; helping us to appropriately categorize different treatment approaches,” said Dr. Patnaik.
Given the previous knowledge that the presence of ASXL1 mutations negatively impact overall survival for patients with CMML, Mayo Clinic researchers were more interested in how the other 26 genes in the panel would perform.
“We knew that the presence of ASXL1 mutations would have a negative impact on survival; however, different studies have conflicting results on how other genes impact the disease outcome,” added Dr. Patnaik.
The study confirmed that the presence of ASXL1 gene mutations is associated with poor overall survival for patients with CMML. However, researchers also found that the presence of TET2 gene mutations with an absence of ASXL1 gene mutations resulted in superior outcomes.
“Our study found that the presence of TET2 mutations, combined with the absence of ASXL1 mutations, was a favorable finding for patients with CMML. This was a novel finding for us, as we didn’t see this result in any previous research,” said Dr. Patnaik.
This discovery will not only impact CMML research moving forward, but it will also provide physicians with tools to accurately diagnose and treat patients with CMML.
“The presence of TET2 mutations in absence of ASXL1 mutations may serve as a potential biomarker that predicts a favorable response to treatment, especially hypomethylating agents such as 5-azacitidine and decitabine,” said Dr. Patnaik. “This allows physicians to better incorporate results of next-generation sequencing in their day-to-day practice.”
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