Page 144 - Haematologica Vol. 109 - July 2024

ARTICLE - Patterns of lower risk MDS progresion
and exacerbation of co-existing comorbidities significantly affect the disease burden, and affect quality of life and OS in low-risk disease.6,7 The LR-MDAS model suggested that almost a third of the LR MDS patients stratified by the IPSS progress or die within a short time after diagnosis. It incorporated age, hemoglobin, severity of thrombocytope- nia, karyotype, and BM blasts ≥4% as variables, and divided patients into 3 groups, upstaging 25% of LR MDS patients into the higher risk disease category.
Historically, 30-40% of MDS patients progress to AML; how- ever, unfortunately, the majority of patients are thought to succumb from disease complications, namely cytopenia or an interplay of cytopenia with comorbidities. The patterns of LR MDS disease progression and causes of mortality are not well delineated in literature. Disease progression can be in the form of further BM failure associated with more severe cytopenias or increased myeloblasts with transformation to higher risk disease and/or AML. The molecular phenotypes associated with different patterns of disease progression and clonal evolution have not been well studied.
Hence, we undertook this study to better delineate fac- tors that can help identify patients with LR MDS at risk for progression and/or death early in their disease course who may benefit from early intervention rather than the “wait and watch” approach.
Methods
Patient selection
We identified 1,914 patients with an established diagnosis of very low- and low-risk MDS as per the IPSS-R from the Moffitt Cancer Center MDS database. Laboratory values and prognostic scores were determined at the time of diagnosis or referral prior to treatment. The study was approved by the Institutional Review Board. We divided our patients into 4 cohorts based on the pattern of their disease progression: 1) patients who remained in the low-risk MDS category throughout their period of follow-up (LR-LR); 2) patients who progressed from LR to HR MDS (LR-HR) without AML transformation; 3) patients who progressed from LR to HR MDS and then AML (LR-HR-AML); and 4) patients who di- rectly progressed from LR MDS to AML (LR-AML).
Characterization of mutational profile
Next generation sequencing (NGS) was performed on pe- ripheral blood or BM as a part of standard work up during patients’ initial presentation. The NGS panels targeted up to 406 genes across multiple platforms: FoundationOne Heme, Genoptix Myeloid Molecular Profile, Genoptix NexCourse Complete, Illumina TruSight Myeloid-54, and the Moffitt 98-gene Myeloid Action Panel.
Definitions of survival
Overall survival (OS) was measured from time of diagnosis
A.G. Jain et al. until death or censored at time of last patient follow-up.
For patients that progressed to AML, leukemia-free survival (LFS) was calculated from the time of diagnosis to devel- opment of AML.
Statistical methods
Categorical variables were compared using Fisher’s exact and χ2 tests, and quantitative data were compared using the Mann-Whitney U test. Time-to-event analyses were assessed using the Kaplan-Meier method. The log-rank test was used to compare OS between groups. Statistical analyses were performed using IBM SPSS statistics version 26.
Results
We divided the patients with low-risk and very low-risk MDS into the 4 cohorts described above. The majority of the patients, 68% (N=1,300) remained in LR-MDS without progressing to high-risk MDS or AML, 16.5% patients (N=317) progressed from low-risk to high-risk MDS (LR-HR) without AML transformation, 6.5% patients (N=124) progressed from low-risk to high-risk MDS and then AML (LR-HR-AML), and 9% patients (N=173) progressed from low-risk MDS directly to AML (LR-AML). At a median follow-up of 99 months, the median OS for the LR-LR, LR-HR, LR-HR-AML, and LR-AML groups was 80.7, 61.2, 48.3, and 42.8 months, respectively (P<0.0001) (Figure 1). The median time to progression to AML in the LR-HR-AML and LR-AML groups was 29 months, and the median time to progress from LR to HR-MDS was
Figure 1. Overall survival of the 4 cohorts. At a median follow up of 99 months, the median overall survival (OS) for the pa- tients who remained in the low-risk (LR) myelodysplastic syn- dromes (MDS) category throughout their period of follow-up (LR-LR), patients who progressed from LR to high-risk (HR) MDS without acute myeloid leukemia (AML) transformation (LR-HR), patients who progressed from LR to HR MDS and then AML (LR- HR-AML), and patients who directly progressed from LR MDS to AML (LR-AML) was 80.7, 61.2, 48.3, and 42.8 months, respec- tively.
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