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Expert Critique

FROM THE ASCO Reading Room

Amit Reddy, MBBS Postdoctoral Fellow Mitchell Cancer Institute, University of South Alabama

During the last couple of years there has been more exploration of new biomarkers to make better diagnoses and therapy decisions for patients with myelodysplastic syndromes (MDS). The current approach is based on peripheral cytopenias and subjective dysplastic morphologic characterizations. The diagnosis of MDS is also quite challenging because many cases have overlapping features with other diseases such as leukemia.

As described here, a research team is evaluating the potential use of apoptosis-associated speck-like protein (ACS), which is involved inn NLRP3 inflammasome-directed pyroptotic cell death, and these ACS specks are released into the plasma after cell death. An observational study was done which inspected ACS specks in MDS patients versus healthy controls, and patients with other types of leukemia. The researchers found that the percentage of ACS specks was considerably greater in MDS patients and that patients with two or more MDS-related somatic gene mutations also had more specks. The investigators deduced from this that ACS specks are a strong marker for pyroptosis in MDS.

Another potential MDS prognostic biomarker being considered is a segment of microRNA encoded by chromosome 1q labeled miRNA-194-5p, found to be involved in the growth of blood cancers such as MDS. The study investigated 65 MDS patients and 11 healthy controls, and showed that the miRNA-194-5p expression was increased five times in MDS patients and that low expression of this microRNA was associated with a considerable decline in overall survival. A larger cohort study must now be done to validate these findings.

Another study showed that p53 protein mutations are associated with worse prognosis and advancement from MDS to acute myelogenous leukemia. The retrospective study involved 47 MDS patients and 10 control patients with non-Hodgkin lymphoma. p53 expression could thus be considered to be a significant risk factor when analyzing survival rates.

Full Critique

New biomarkers are being explored to improve the diagnosis and management of patients with myelodysplastic syndromes (MDS).

"Investigation of MDS biomarkers has increased over the last several years," Kathy McGraw, PhD, a research scientist at Moffitt Cancer Center in Tampa, Fla., told the Reading Room via email. "One reason for this is a need to find objective diagnostic tools that can aid diagnosis of MDS, which is currently based on peripheral cytopenias and subjective dysplastic morphologic characterization. MDS diagnosis can be particularly difficult in cases with overlapping features such as CMML [chronic myelomonocytic leukemia].

"Biomarkers may also direct treatment strategies, offering patients the best chance for response," said McGraw, who is part of a research team evaluating one novel marker. "Furthermore, they may be utilized to monitor response, or lack of, that can identify the need to change therapies. In MDS, there are limited biomarkers that accomplish any of these features, which is why it is so important that we identify novel markers that can aid patient diagnosis and treatment."

ACS Specks

McGraw and colleagues focused on the ACS (apoptosis-associated speck-like protein containing a caspase recruitment domain) protein, which, they explained, is involved in NLRP3 inflammasome-directed pryoptotic cell death, a driver of MDS pathogenesis. During inflammasome assembly, the ACS adaptor protein polymerizes into large filamentous clusters -- "ACS specks" -- which are released into the plasma after cell death. The specks, approximately 1-3 µm in diameter, are resistant to proteolytic degradation because of their prion-like structure.

In an observational study published in , McGraw's group examined ACS specks in patients with MDS versus healthy controls; patients with type 2 diabetes; and patients with other hematologic cancers including CMML, acute lymphocytic leukemia, chronic myelogenous leukemia, and multiple myeloma. The investigators used confocal and electron microscopy to visualize the specks, and flow cytometry to quantify them, in the peripheral blood of study participants.

The log₁₀-transformed mean percentage of ACS specks was significantly higher in patients with MDS than in healthy controls (-0.41 versus -0.67; P=0.034). The percentage of specks was also significantly greater in patients with MDS than in individuals with every other type of hematological cancer (P<0.05 for all) except for myelofibrosis (P=0.19).

In addition, patients with MDS who had at least two MDS-related somatic gene mutations had significantly more specks than those with one or no mutations (-0.22 versus -0.53; P=0.008). The authors concluded that ACS specks were a robust marker for pyroptosis in MDS (AUC=0·888), and that a cutoff of 0.80 maximized sensitivity at 0.84 (95% CI 0.65–0.91) and specificity at 0.87 (95% CI 0.58–0.97).

With some refinements, such as an optimal assay for ACS speck detection, this biomarker "could be used as an objective companion diagnostic tool aiding in a more accurate diagnosis of patients, with potentially the unique ability to distinguish between MDS and overlap syndromes," McGraw said. "Further, they may be utilized to evaluate the extent of pyroptotic cell death, which currently there are no makers for, and may aid in monitoring disease progression or even predicting response to novel therapies that are currently being investigated."

MicroRNA-194-5p

Another potential diagnostic and prognostic biomarker being studied is a segment of microRNA encoded by chromosome 1q labeled miRNA-194-5p. MicroRNA deregulation is involved in the development of hematologic cancers including MDS, said Seong-Ho Kang, MD, PhD, of the Chosun University College of Medicine in Gwangju, South Korea, and colleagues, writing in .

Kang and colleagues analyzed and compared the expression of miRNA-194-5p and other microRNAs in 65 patients with MDS and 11 healthy controls. The researchers found that miRNA-194-5p expression was five times higher in the MDS patients than in the controls (P=0.002), and that patients with low miRNA-194-5p expression had significantly decreased overall survival (P=0.049).

"Although these findings need to be validated in a larger patient population, our results indicate that miR-194-5p is a candidate diagnostic biomarker for MDS and that low miR-194-5p expression could be associated with poor overall survival for MDS patients," the team wrote.

P53 Protein

Mutations in the p53 gene have been associated with a poorer prognosis and progression to acute myeloid leukemia (AML) in MDS. Emöke Horváth, MD, and colleagues at the University of Medicine and Pharmacy in Targu-Mures, Romania, the expression of the p53 protein as a predictor of risk.

The researchers retrospectively analyzed bone marrow biopsies from 47 patients with MDS and 10 control patients with non-Hodgkin lymphoma. Based on blast cell count, the MDS patients were classified as being at either low or high risk for progression to AML (<5% and >5%). The rate of p53 expression was assessed with immunohistochemical staining and morphometric quantification.

The proportion of p53-positive nuclei in the biopsy samples was significantly higher in the MDS patients than in the controls (median of 7.70% versus 1.62%; P<0.001). It was also significantly higher in the high-risk group compared with the low-risk group (9.16% versus 4.49%; P=0.017). Mean survival was shorter in the high-risk than the low-risk group (6 months versus 22 months; P=0.008).

"P53 expression, together with the bone marrow blast count, proved to be a significant risk predictor when analyzing survival," Horváth and co-authors concluded.