New IPSS Model Incorporates Genetic Data to Better Risk-Stratify MDS Patients

According to data presented at the 2021 American Society of Hematology Annual Meeting, an updated International Prognosis Scoring System (IPSS) for myelodysplastic syndromes (MDS) that incorporates gene mutations (IPSS-M) led to improved discrimination compared with the revised IPSS (IPSS-R).  The IPSS-M, which considers clinical, cytogenetic, and genetic parameters, reclassified nearly half of patients studied.

The IPSS-M score was built as a weighted sum of prognostic variables. The model consisted of:

• hemoglobin, platelets, and bone marrow blasts
• IPSS-R cytogenetic category
• 22 binary features derived from the presence of mutations in 21 predictive genes
• one feature representing the number of mutations from a group of 17 additional genes

Investigators applied scaling so that a score of 0 represented an average patient; scores of –1, 1, or 2 corresponded to half-, double-, or four-fold risk compared with an average patient.

Researchers characterized 9,339 driver mutations or short indels involving 124 genes from 2,957 patients (discovery cohort). These patients had less than 20% blasts and white blood cell count below 13×10⁹/L. Median follow-up was 3.8 years.

They then conducted correlative analyses between genetic alterations and clinical outcomes. Results were validated in an independent cohort of 718 patients.

According to the investigators, the IPSS-M resulted in improved discrimination compared with the IPSS-R for leukemia-free survival, overall survival, and leukemic transformation. Specifically, they found a 5-point increase in C-index for each endpoint in the discovery cohort and an increase of 3.4, 1.5, and 4.9 points in the validation cohort.

Based on score cutoffs, researchers established a six-risk category schema: very-low (14%), low (32%), moderate-low (11%), moderate-high (11%), high (11%), and very-high (18%). From very-low to very-high, the median leukemia-free survival was 9.7, 6.0, 4.1, 2.3, 1.7, and 0.75 years, respectively.

By merging the moderate-low and moderate-high categories to moderate, the researchers compared stratification of the IPSS-R with the IPSS-M. The IPSS-M resulted in restratification of 46% of patients. The majority (74%) were upstaged and 26% were downstaged.