How low risk are low risk myelodysplastic syndromes?

ABSTRACT

Introduction

Risk stratification is crucial to the appropriate management of many diseases, but in patients with myelodysplastic syndromes (MDS), for whom expected survival can vary greatly, accurate disease prognostication is especially important. This is further supported by a relative lack of therapies in MDS, and thus we must prognosticate carefully and accurately. Currently, patients with MDS are often grouped into higher-risk (HR) versus lower-risk (LR) disease using clinical prognostic scoring systems, but these systems have limitations.

Areas covered

The authors reviewed the literature on diagnostics, prognostics, therapeutics and outcomes in MDS. Factors such as disease etiology, specific clinical characteristics, or molecular genetic information not captured in the international prognostic scoring system revised IPSS-R can alter risk stratification, and identify a subset of LR-MDS patients who actually behave more like HR-MDS.

Expert opinion

This review will describe the current identification and management of patients with LR MDS disease whose condition is likely to behave in a less favorable manner than predicted by the IPSS-R. The authors comment on clinical and molecular features which are believe to upstage a patient from lower to higher risk disease.

KEYWORDS:

• MDS
• Myelodysplastic syndrome
• Myelodysplasia
• Leukemia
• Prognosis
• Risk stratification
• Molecular genetics
• Therapy related MDS

Article highlights

• Current prognostic scoring systems may fail to capture important prognostic information at the individual level due to the lack of incorporation of salient clinical features, molecular data, and dynamic changes in risk over time.

• For TP53 mutations, the allelic state of the gene should be incorporated into risk stratification of MDS patients. ‘Multi-hit’ TP53 alterations that cause biallelic gene inactivation are associated with worse survival and fewer co-occurring mutations, whereas ‘single-hit’ cases have less complex cytogenetics, more co-occurring mutations in other genes, lower TP53 VAF, and overall survival risk similar to that of TP53-wild type MDS.

• SF3B1 mutations are, overall, a favorable prognostic marker and associated with ring sideroblasts. However, newer data suggests that co-occurrence of RUNX1 mutation, EZH2 mutation, high-risk cytogenetic abnormalities, and/or excess blasts as well as specific SF3B1 hotspot mutations may modify this risk.

• Therapy-related MDS may be higher risk, but it is a very heterogeneous group with some ‘therapy-coincident’ MDS that may be closer to average risk.

• A germline predisposition to MDS can occur as a part of a syndrome or as isolated myeloid disease, with syndromic cases likely presenting earlier and with more IPSS-R low-risk disease. However, idiosyncratic pathologic and genetic features not captured by standard assays or scoring systems suggest many of the patients are actually higher risk for evolution to leukemia.

• Future personalized prognostic scores based on prediction models are the goal for an optimized understanding of a patient’s risk to define therapeutic strategies– from observation of mild cytopenias or supportive treatments with transfusions through active chemotherapy and even early allogeneic hematopoietic stem transplantation (BMT).

Declation of Interest

A DeZern reports honoraria from consultant and advisory roles for Bristol-Myers Squibb, Geron, Gilead Sciences, Taiho, and Takeda.

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

This work was funded by R56HL159306.