Is a New Classification and Prognosis System Possible for Myelodysplastic Syndromes?

A deep dive into 3 clinical cases of patients with myelodysplastic syndromes (MDS) is highlighting the heterogeneity of the clonal disorder while offering insight into the possibility of a next-generation classification and prognosis system.

According to the researchers of the review, integrating novel, high-impact individual risk parameters into conventional risk stratification systems, such as revised International Prognostic Scoring System (IPSS-R), may better define patient subgroups, thus creating a more enhanced classification and prognostic scoring system for patients.

The 3 cases reviewed in the analysis include: (1) a man aged 63 years who presented to his general practitioner with moderate anemia and was also experiencing moderate fatigue since having a viral infection 10 weeks prior; (2) another man aged 63 years who presented with moderate anemia but normal absolute neutrophil and platelet counts; and (3) a woman aged 65 years who had known MDS with isolated del(5q) and confirmed TET2 and DNMT3A somatic mutations.

Using the first case report, the researchers highlighted how some of these novel factors could fit into traditional risk stratification systems. For example, adding age to the IPSS-R may upstage patients classified as intermediate risk to higher risk disease.

“Patients with an intermediate-risk IPSS-R score represent a group with a highly divergent clinical outcome due to widely variable disease courses. Age ≥66 years, peripheral blood blasts ≥2%, and history of [red blood cell] transfusion have been identified as additional stratification factors for this challenging subgroup of patients with MDS,” pose the researchers. “These factors, all of them associated with inferior survival, enable the classification of patients with IPSS-R intermediate-risk MDS into 2 prognostic subgroups (intermediate-favorable vs intermediate-adverse) with significant divergent outcomes.”

The details of the first case report coupled with those of the second case report also emphasize the implications that somatic mutations have in patient care and prognosis. Both cases include similar laboratory values, bone marrow blast counts, karyotypes, and risk classification scores; however, the patient in the first case report carried somatic mutations associated with a more favorable outcome (TET2, DNMT3A, SF3B1) while the second case report carried mutations associated with a worse prognosis (ASXL1, ETV6, U2AF1).

Honing in on SF3B1 mutations specifically, which was seen in the first case report, the researchers note that the mutation’s presence in patients with MDS with ring sideroblasts define a homogenous subgroup of patients with isolated erythroid dysplasia and favorable prognosis.

“This molecular discrepancy in both cases is associated with completely different individual risks of disease progression and survival,” wrote the researchers. “It becomes clear that the currently available prognostic scoring systems are not sufficient to derive personalized and precise therapeutic decisions in the absence of data on molecular abnormalities.”

The presence of a TP53 mutation in the third case report also stuck out to the researchers, who explained that the presence of the mutation significantly impacts the prognosis of patients, being independently associated with poor overall survival (OS) even after adjusting for clinical variables.

The mutation can also have implications for clinical outcomes and prognostic groups independent of clinical prognostic scoring systems, say the researchers, who alluded to a retrospective study of over 200 patients with MDS. Patients with a TP53 variant allele frequency (VAF) >40% had a median OS of 124 days compared with patients with VAF <20% whose OS was not reached.

Reference

Kubasch A, Platzbecker U. Patient stratification in myelodysplastic syndromes: how a puzzle may become a map. Hematology Am Soc Hematol Educ Program.2020;2020(1):418-425.