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 (TP53^multihit) was the strongest predictor of poor outcome across all MDS treatment modalities.