The Natural History of Lower Risk MDS: Factors Predicting Progression to High-Risk Myelodysplastic Syndrome and Acute Myeloid Leukemia in Patients with Very Low and Low Risk MDS According to the R-IPSS Criteria

Introduction:

Patients (pts) with myelodysplastic syndrome (MDS) are divided into risk categories: very low (VL), low (LR), intermediate, high (HR) and very high, using the revised international prognostic scoring system (R-IPSS). The natural history of lower risk MDS is not well described. Some patients present with a rapidly progressive form of LR-MDS leading to worsening cytopenia and or increase bone marrow (BM) blasts with or without progression to acute myeloid leukemia (AML). The aim of this study was to evaluate the patterns of progression and factors that can predict progression to HR-MDS and/or AML.

Methods:

We studied a large cohort of lower risk MDS pts (n=1914) defined as VL and LR R-IPSS MDS at Moffitt Cancer Center. We divided our patients into 4 cohorts based on the natural history of their disease progression pattern: 1) Pts who remained low risk MDS throughout their period of follow up (LR-LR), 2) Pts who progressed from LR to HR MDS (LR-HR) without AML transformation, 3) Pts who progressed from LR to HR MDS and then AML (LR-HR-AML) and 4) Pts who progressed from LR MDS to AML directly (LR-AML).

Results:

Majority of pts 68% (1300) remained in LR-MDS, 16.5 % (317) progressed from low risk to high risk MDS (LR-HR) without AML transformation, 6.5% (124) progressed from low risk to high risk MDS and then AML (LR-HR-AML) and 9% pts (173) progressed from low risk MDS to AML directly (LR-AML). At a median follow up of 199 months (mo), the median OS for the LR-LR, LR-HR, LR-HR-AML and LR-AML groups was 80.7, 61.2, 48.3, 42.8 mo, respectively (Figure 1; p<.0001). The median time to progression to AML in LR-HR-AML and LR-AML groups was 29 mo, and the median time to progress from LR to HR-MDS was 22 mo.

Table 1 shows baseline characteristics of the four cohorts. Clinical and laboratory risk factors for progression included male gender (p<0.0001), low absolute neutrophil count (ANC) (p=.04), low platelet count (p<.001), high BM blasts (p<0.001), ferritin >1000 mcg/L (p<.0001), albumin <3.5 g/dL (p=.012). Pathologic risk factors for progression included multi-lineage dysplasia (MLD) (p<.001) and lack of ring sideroblasts (p<.0001). Pts with Del5q abnormality had a higher rate of progression to HR-MDS (p=.001). Among patients with marked BM fibrosis (n=49), 18% progressed directly to AML (p=.009). Rates of progression were not different when patients were stratified by lower risk MD Anderson model. Table 1 summarizes treatment patterns among the cohorts, as expected, more pts in the LR-AML (53.8%) and LR-HR-AML (87.9%) cohorts were treated with hypomethylating agents.

Gene mutations associated with an increased risk of direct or indirect AML progression included SRSF2 (p<.0001) and NRAS (p=.003). Mutations in IDH1 (p=.0001), IDH2 (p=.029) and NPM1 (p<.0001) were more common in patients with direct AML transformation from lower risk. Mutations associated with progression to both higher risk disease only, without AML and/or direct/indirect AML were ASXL1 (p= 0.009), TP53 (p<0.0001), RUNX1 (p<.0001), CBL (p=.0074). The presence of an ETV6 mutation was associated with progression to HR-MDS but not AML (p<.0001). PHF6 mutations were associated with progression to HR-MDS and then AML (p=.0093). SF3B1 mutation was associated with less progression (p<.0001) (Figure 2).

We divided the pts into 3 subgroups based on estimated median OS (<2, 2-5 and >5 years) and found that 398 patients (31%) in the LR-LR cohort fall in the <2 years category, and 171 (13%) died within 2 years of diagnosis without disease progression to HR-MDS and/or AML. Among 61 cases with documented cause of death, 18 pts (29%) died from cytopenia and MDS related complications.

Conclusion:

To our knowledge this is one of the largest cohorts to describe natural history of LR-MDS pts and the first study to detail the different patterns of disease progression including progressing to HR-MDS without AML transformation (16.5%), HR-MDS to AML (6.5%) and directly to AML (9%). We identified the clinical and molecular factors associated with different patterns of disease progression. For pts who remained in LR-MDS, one-third had estimated median OS < 2 years and one-third of deaths within 2 years were MDS related. Identifying those LR-MDS pts with higher risk of disease progression or disease related death within 2 years will be crucial to tailor therapy accordingly.

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