Clinical and genetic predictors of prognosis in myelodysplastic syndromes

Abstract

Myelodysplastic syndromes are a collection of clonal hematopoietic disorders with a wide range of clinical manifestations and eventual outcomes. Accurate prediction of a patient's prognosis is useful to define the risk posed by the disease and which treatment options are most appropriate. Several models have been created to help predict the prognosis for patients with myelodysplastic syndromes. The International Prognostic Scoring System (IPSS) has been the standard tool used to risk stratify MDS patients since its publication in 1997. Other models have since been created to improve upon the IPSS, including the recent Revised International Prognostic Scoring System. Most models include the presence or severity of peripheral blood cytopenias, the proportion of bone marrow blasts, and specific karyotype abnormalities. Other factors including age, performance status, co-morbidities, transfusion dependence, and molecular biomarkers can further refine the prediction of prognosis in some models. Novel, disease specific biomarkers with prognostic value in myelodysplastic syndromes including cell surface markers, gene expression profiles, and high resolution copy number analyses have been proposed but not yet adopted clinically. Somatic abnormalities in recurrently mutated genes are the most informative prognostic biomarkers not currently considered by clinical risk models. Mutations in specific genes have independent prognostic significance and, unlike cytogenetic abnormalities, are present in the majority of myelodysplastic syndrome cases. However, mutational information can be complex and there are challenges to its clinical implementation. Despite these limitations, DNA sequencing can refine the prediction of prognosis for myelodysplastic syndrome patients and has become increasingly available in the clinic where it will help improve the care of patients with myelodysplastic syndromes.

Figure 1.

International Prognostic Scoring System Revised (IPSS-R). Karyotype abnormalities, bone marrow blast proportion, and severity of peripheral blood cytopenias are scored and used to assign MDS patients into one of five risk groups with significant differences in median survival and probability of developing AML. The cut offs shown for the 5 risk groups can be adjusted for age. The values shown here are for 70-year old patients. This figure is adapted from Steensma DP. (Copyright American Society of Hematology, used with permission).

Figure 2.

Somatic mutations are associated with disease risk and MDS subtype. (A) Kaplan-Meier curve from Papaemmanuil et al. showing leukemia-free survival in 595 MDS patients stratified by the number of tumor mutations identified. (B) Similar figure from Bejar et al. demonstrating the relationship between overall survival and mutation number in 439 MDS patients. (C) Data from Haferlach et al. showing differences in mutation number across MDS subtypes. Reprinted with permission.

Figure 3.

Combining somatic mutations with known risk factors and prognostic models. (A–C) Data from Bejar et al. is used to compare overall survival in patients with one or more prognostically adverse mutations (in TP53, EZH2, RUNX1, ASXL1, or ETV6) to unmutated patients within each of the IPSS-R ‘lower’ risk groups. Mutations identify added disease risk in each of the categories. (D) Overall survival of patients with complex disease karyotypes is strongly stratified by TP53 mutation status. Patients with both a complex karyotype and TP53 mutation have a very short overall survival whereas complex karyotype patients without a TP53 mutation have a survival that is comparable to that of MDS patients with non-complex karyotypes. (E) Overall survival in 611 MDS patients examined by Haferlach et al. and stratified according to a mutation-only prognostic model considering the weighted contribution of mutations in 14 genes. (F) Overall survival in the same 611 patients risk stratified by a prognostic model that combines both clinical features and the mutation status of 14 genes. Reprinted with permission.