Real-World Validation of Molecular International Prognostic Scoring System for Myelodysplastic Syndromes

Abstract

Purpose: Myelodysplastic syndromes (MDS) are heterogeneous myeloid neoplasms in which a risk-adapted treatment strategy is needed. Recently, a new clinical-molecular prognostic model, the Molecular International Prognostic Scoring System (IPSS-M) was proposed to improve the prediction of clinical outcome of the currently available tool (Revised International Prognostic Scoring System [IPSS-R]). We aimed to provide an extensive validation of IPSS-M.

Methods: A total of 2,876 patients with primary MDS from the GenoMed4All consortium were retrospectively analyzed.

Results: IPSS-M improved prognostic discrimination across all clinical end points with respect to IPSS-R (concordance was 0.81 v 0.74 for overall survival and 0.89 v 0.76 for leukemia-free survival, respectively). This was true even in those patients without detectable gene mutations. Compared with the IPSS-R based stratification, the IPSS-M risk group changed in 46% of patients (23.6% and 22.4% of subjects were upstaged and downstaged, respectively).In patients treated with hematopoietic stem cell transplantation (HSCT), IPSS-M significantly improved the prediction of the risk of disease relapse and the probability of post-transplantation survival versus IPSS-R (concordance was 0.76 v 0.60 for overall survival and 0.89 v 0.70 for probability of relapse, respectively). In high-risk patients treated with hypomethylating agents (HMA), IPSS-M failed to stratify individual probability of response; response duration and probability of survival were inversely related to IPSS-M risk.Finally, we tested the accuracy in predicting IPSS-M when molecular information was missed and we defined a minimum set of 15 relevant genes associated with high performance of the score.

Conclusion: IPSS-M improves MDS prognostication and might result in a more effective selection of candidates to HSCT. Additional factors other than gene mutations can be involved in determining HMA sensitivity. The definition of a minimum set of relevant genes may facilitate the clinical implementation of the score.

Trial registration: ClinicalTrials.gov NCT04889729.

FIG 1.

Molecular landscape of patients with MDS from the GenoMed4all cohort. (A) Frequency of mutations of the 31 genes included into IPSS-M score in 2,876 patients from the GenoMed4All cohort. Colors linked to the bars represent the gene function. (B) Frequency of mutations on genomic features grouped according to IPSS-M criteria. (C and D) Frequency of gene mutations and chromosomal abnormalities broken down by MDS subtypes according to 2016 WHO criteria and IPSS-R risk category, respectively. Mutations on genes are grouped according to IPSS-M criteria as main effect genes (gene labels are highlighted in blue) and residual genes (gene labels are highlighted in dark green). (E) Kaplan-Meier probability estimates of OS across numbers of oncogenic alterations per patient (gene mutations and cytogenetic abnormalities). P value is from log-rank test. Frequency of IPSS-M–related gene mutations and chromosomal abnormalities broken down by MDS subtypes according to 2022 WHO criteria and ICC criteria is available in the Data Supplement. ICC, International Consensus Classification of Myeloid Neoplasms and Acute Leukemia; MDS, myelodysplastic syndromes; MDS 5q-, MDS with isolated deletion of long arm of chromosome five; MDS-EB1, MDS with excess of blasts, type 1; MDS-EB2, MDS with excess of blasts, type 2; MDS-MLD, MDS with multilineage dysplasia; MDS-RS-MLD, MDS with ring sideroblasts and multilineage dysplasia; MDS-RS-SLD, MDS with ring sideroblasts and single-lineage dysplasia; MDS-SLD, MDS with single-lineage dysplasia; MDS-U, MDS unclassifiable; IPSS-R, Revised International Prognostic Scoring System; IPSS-M, Molecular International Prognostic Scoring System; OS, overall survival.

FIG 2.

Clinical assessment of IPSS-R and IPSS-M in the GenoMed4All MDS cohort. Kaplan-Meier probability estimates of (A and B) OS and (C and D) LFS for 2,876 patients with MDS from the GenoMed4All cohort stratified by IPSS-R and IPSS-M risk categories, respectively. P values are from log-rank test. (E) Restratification of IPSS-R to IPSS-M risk groups in the MDS cohort. Each bar represents an IPSS-R category and shows the percentage of patients that is restratified in the IPSS-M categories (indicated with different colors). (F) Distribution of the restratified patients in each IPSS-R category, counting the proportion of patients who are downstaged (highlighted in blue) and upstaged (highlighted in red) with the IPSS-M classification. (G) Distribution of the restratified patients in each IPSS-R category, counting the proportion of patients with more than one shift in IPSS-M risk category (downstaged and upstaged cases are highlighted in blue and in red, respectively). (H-I) Fraction of explained variation related to the IPSS-M prognostic factors for OS and LFS, respectively. IPSS-R, Revised International Prognostic Scoring System; IPSS-M, Molecular International Prognostic Scoring System; LFS, leukemia-free survival; MDS, myelodysplastic syndromes; OS, overall survival.

FIG 3.

Clinical assessment of IPSS-R and IPSS-M in 964 MDS patients from the GenoMed4All cohort who received allogeneic stem-cell transplantation (HSCT). (A) Kaplan-Meier probability estimates of OS and (B) cumulative incidence of disease relapse (estimated with a competing risk approach including NRM) for 964 patients from the GenoMed4All cohort who received HSCT, stratified by IPSS-M risk categories. P values are from log-rank test. (C) Restratification of IPSS-R to IPSS-M risk groups in the MDS cohort. Each bar represents an IPSS-R category and shows the percentage of patients that is restratified in the IPSS-M categories (indicated with different colors). HSCT, hematopoietic stem-cell transplantation; IPSS-M, Molecular International Prognostic Scoring System; IPSS-R, Revised International Prognostic Scoring System; LFS, leukemia-free survival; MDS, myelodysplastic syndromes; NRM, nonrelapse mortality; OS, overall survival.

FIG 4.

Clinical assessment of IPSS-R and IPSS-M in patients with MDS from the GenoMed4All cohort who received HMA. (A) Kaplan-Meier probability estimates of OS of patients with MDS from the GenoMed4All cohort who received HMA (n = 268) stratified by IPSS-M risk categories. P values are from log-rank test. (B) Restratification of IPSS-R to IPSS-M risk groups in the HMA-treated MDS patients. Each bar represents an IPSS-R category and shows the percentage of patients that is restratified in the IPSS-M categories (indicated with different colors). HMA, hypomethylating agents; IPSS-M, Molecular International Prognostic Scoring System; IPSS-R, Revised International Prognostic Scoring System; LFS, leukemia-free survival; MDS, myelodysplastic syndromes; OS, overall survival.

FIG 5.

Accuracy of IPSS-M prediction when molecular information was missed. (A) Impact of a missing information from each of the IPSS-M genomic feature on the accuracy of IPSS-M risk prediction in GenoMed4all (n = 2,876) and IWG-PM cohorts (n = 2,957). The height of the bar is proportional to the accuracy loss in IPSS-M prediction in the presence of a missing genomic feature, estimated as the percentage of patients classified in the wrong risk category. (B) Prediction of IPSS-M accuracy in the presence of a combination of missing genomic features in the GenoMed4all and IWG-PM cohorts (starting from missing information on residual genes and then considering the main effect genes ordered by their prognostic weights estimated on probability of LFS). The accuracy was estimated as the number of patients classified in the correct risk category divided by the patient population's size. IPSS-M, Molecular International Prognostic Scoring System; IPSS-R, Revised International Prognostic Scoring System; IWG-PM, International Working Group for Prognosis in MDS; LFS, leukemia-free survival.