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A Refined Prognostic Scoring System for Myelodysplastic Syndromes: The IPSS-M
Myelodysplastic syndromes (MDS) are highly heterogeneous myeloid malignancies that range from chronic mild cytopenias to acute myeloid leukemia transformation. The current International Prognostic Scoring System – Revised (IPSS-R) utilizes hematologic parameters, including bone marrow myeloblast percentage, plus cytogenetic markers to assess patient risk. Now, an international working group proposes incorporating relevant gene mutations into the IPSS-R.
Banked pretreatment bone marrow samples were obtained from patients with primary MDS, secondary or treatment-related MDS, and MDS/MPD (myeloproliferative disorder) overlap syndromes; a myeloid blast count <20% was required for study inclusion. The investigators used a panel of 152 myeloid-related genes to assess both gene mutations and loss of heterozygosity (LOH).
An initial discovery cohort of 2957 patients included 234 with secondary MDS and 370 with MDS/MPD. A median of four gene mutations were identified in over 90% of patients, with roughly half having only mutations and a third having mutations plus cytogenetic alterations. Mutations in TP53, FLT3, and KMT2A (MLL) were associated with poor outcomes, while SF3B1 mutations were favorable unless accompanied by coexisting adverse mutations. Incorporating gene mutation status into the IPSS-R reclassified risk in 46% of all patients.
The findings were confirmed in a subsequent validation cohort of 754 patients, leading to the proposed IPSS – Molecular Risk Score (IPSS-M) with six risk categories ranging from very low (median overall survival >10 years) to very high (median OS 1 year). The presence of multiple coexisting TP53 mutations or mutation plus LOH (TP53multihit) was the strongest predictor of poor outcome across all MDS treatment modalities.
This study confirms the utility of specific genetic markers in risk stratification for MDS and its subtypes. The IPSS-M provides a robust tool that will be useful for risk-adapted clinical trials and precision medicine–based selection of therapy. As noted by the authors, the lack of available infrastructure and the cost of genomic analysis will limit its application in many centers; a more streamlined selection of the highest-priority molecular markers will be helpful in addressing these limitations. The tool is available online.
Bernard E et al.
Title: Molecular international prognostic scoring system for myelodysplastic syndromes.
Source: NEJM Evid 2022 Jun 12; [e-pub]. (Abstract/FREE Full Text)