Page 148 - Haematologica Vol. 109 - July 2024

ARTICLE - Patterns of lower risk MDS progresion
A.G. Jain et al.
comparable to the OS of our LR-LR (6.7 years) and LR-HR (5.1 years) cohorts.2 The median time to progression to AML in our LR-HR-AML and LR-AML groups was 29 months, and the median time to progress from LR to HR-MDS was 22 months. Greenberg et al. reported the time for 25% of patients to develop AML (AML/25%) to be around 10.8 years for the LR group and not reached for the VL risk group.2
In addition, in the study reporting the LR-MDAS model, 90% of patients died without transforming to AML.4 When we looked at patients that remained in the LR-LR cohort, we found that 13.1% of patients died within two years of diagnosis, with 29% of the patients dying from cytopenias and MDS-related complications without progressing to HR disease or to AML. Greenberg et al. also described that 27% and 40% of patients belonging to the VL and the LR catego- ries died, with 87% and 83% of patients not transforming to AML.2 In another similar study on outcomes of 531 patients with LR MDS by the Connect Myeloid Disease Registry by Komrokji et al., 54% of the 144 patients who had a follow-up BM autopsy available had a 5% increase in BM blasts. The overall rate of disease progression was about 15% in the Connect LR-MDS cohort. About 213 patients died from the 531 LR MDS patients, and 56.3% deaths were attributed to disease-related complications, followed by 14.6% related to cardiovascular disease (CVD).16 In another recent study on 2,396 LR MDS patients by Madry et al., infection (17.8%) and CVD (9.8%) were reported as the main causes of death other than disease progression. They also noted that the relative survival of patients with LR MDS decreases from 94.3% at the first year to 59.6% at five years, hence imply- ing that >40% of patients with LR-MDS die, either directly
or indirectly, from MDS-related causes within fiveyears of diagnosis.17 This further affirms our belief that there is a need to better prognosticate these LR-MDS patients that might need earlier intervention in certain cases. Allogeneic stem cell transplantation (alloSCT) is the only cure for MDS. AlloSCT is generally recommended at the time of disease progression and is avoided for LR disease due to early transplant-related mortality, in contrast to the long OS for patients with LR MDS.18-20 If we can identify the patients with LR-MDS who die early, i.e., within two years, without progression clearly related to disease, we might be able to offer them an alloSCT, and significantly improve their sur- vival and quality of life.
Despite being limited by the retrospective design, our study provides important conclusions among a large, predominant- ly treated cohort. We delineated and identified the clinical and molecular factors associated with different patterns of disease progression. For patients who remained in LR MDS, 13% died in <2 years, and for those with documented cause of death, one-third of deaths within two years were directly MDS-related. Other causes of mortality reported in LR MDS largely include cardiac events. The interplay of cytopenia and such comorbidities may be crucial, as cytopenia may exacerbate those conditions and indirectly contribute to mortality. In fact, several models incorporate comorbidities in MDS risk stratification, but do not detail the interplay be- tween cytopenia and those concomitant diseases.21,22 There is increasing evidence that certain clonal hematopoietic events, such as TET-2 somatic mutation, are associated with other comorbidities such as atherosclerosis.23,24 The impact of treating cytopenias among patients with comorbidities,
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Figure 2. Algorithm showing patterns of progression and of low-risk myelodys- plastic syndromes. IPSS-R: Revised In- ternational Prognostic Scoring System; LR-LR: patients who remained in the low-risk (LR) myelodysplastic syndromes (MDS) category throughout their period of follow-up; LR-HR: patients who pro- gressed from LR to high-risk (HR) MDS without acute myeloid leukemia (AML) transformation; LR-HR-AML: patients who progressed from LR to HR MDS and then AML; LR-AML: patients who direct- ly progressed from LR MDS to AML.