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The second article in our editorial theme series focuses on understanding the stratification systems in myelodysplastic syndromes (MDS). We focus on the revised International Prognostic Scoring System (IPSS-R) and IPSS-Molecular (IPSS-M). The MDS Hub has previously reported on the development and use of the IPSS-M for MDS risk stratification and prognosis. Real-world data comparing the IPSS-R and the IPSS-M has also been reported on the MDS Hub.
During the European Hematology Association (EHA) 2023 Congress, Hasse presented an overview of MDS risk stratification systems, including the development of the IPSS-R and IPSS-M and their pros and cons.1 Huber presented a poster comparing the IPSS-M and the European LeukemiaNet (ELN) 2022 risk classification.3 In addition, Baer et al.4 recently published a validation study of the IPSS-M in Leukemia. Here, we summarize the key points.
The IPSS was established in 1997 and incorporates bone marrow blasts, cytopenias, and cytogenetics as relevant prognostic parameters. The IPSS enabled the stratification of prognostic subgroups for overall survival (OS) and acute myeloid leukemia (AML)-free survival; however, it was not an optimal stratification system due to several limitations such as:
These limitations led to the development of a cytogenetic prognostic system in 2012, based on an international dataset of 2,902 patients.2 This system included 19 cytogenetic categories (Figure 1) which demonstrated higher prognostic value compared with the previous IPSS (95% vs 81%) and became an integral part of the IPSS-M.
Figure 1. New cytogenetic prognostic system*
*Adapted from Hasse.1
The International Working Group for Prognosis in MDS recognized the limitations of both the IPSS and the cytogenetic prognostic system, and proposed the following revisions:
The IPSS-R was subsequently developed based on data from 7,012 patients from 18 databases, with a median age of 71 years. The IPSS-R included cytogenetics, bone marrow blasts, hemoglobin, platelets, and absolute neutrophil count as prognostic variables, with very low, low, intermediate, high, and very high prognostic subgroups. Figure 2 lists the pros and cons of the IPSS-R.
Figure 2. Pros and cons of the IPSS-R*
Allo-HSCT, allogeneic hematopoietic stem cell transplantation; Aza, azacitidine; ESMO, European Society for Clinical Oncology; IPSS-R, Revised International Prognostic Scoring System; JSH, Japanese Society of Hematology; MDS, myelodysplastic syndrome; NCCN, National Comprehensive Cancer Network.
*Adapted from Hasse.1
With recent findings, adding molecular data to the IPSS-R became important to improve its availability, diagnostic relevance (including proof of clonality in cytopenias and definition of the 5th edition World Health Organization molecularly defined measurable residual disease entities), reproducible molecular consensus profile, pathogenetic meaning, and prognostic impact. Based on these factors, the IPSS-M was proposed to achieve:
The IPSS-M was based on data from 2,957 patients from 24 centers globally, encompassing 3,073 cytogenetic aberrations and 9,339 mutations across 124 genes. It provides a comprehensive genetic profile of patients with MDS and considers bone marrow blasts, platelets, hemoglobin, IPSS-R cytogenetic risk groups, 17 prognostically dominant gene mutations, and several gene mutations from a panel of 15 genes. The IPSS-M is categorized into six prognostic subgroups of very low, low, moderate low, moderate high, high, high, and very high. The pros and cons of the IPSS-M are shown in Figure 3.
Figure 3. Pros and cons of the IPSS-M*
EMA, European Medicine Agency; FDA, Food and Drug Administration; FISH, fluorescent in situ hybridization; IPSS-M, International Prognostic Scoring System-molecular; IPSS-R, Revised IPSS; MDS, myelodysplastic syndrome; NGS, next-generation sequencing; PCR, polymerase chain reaction.
*Adapted from Hasse.1
This retrospective cohort study evaluated prognostication in 137 patients with MDS/AML, 626 patients with MDS, and 686 patients with AML using IPSS-M and ELN 2022 risk stratification systems.
The real-world cohort study involved data from 626 patients diagnosed with de novo MDS between September 2005 and January 2020, with a median follow-up of 9.5 years. Comparison of the validation cohort with the original publications of the IPSS-M showed that both were comparable in terms of assignment to risk categories (Figure 4) and prognostic separation for OS and leukemia-free survival.5
Individual risk categorization based on both the IPSS-R and IPSS-M in 452 patients showed:
Figure 4. Risk categories in validation vs the original IPSS-M cohort*
IPSS-M, International Prognostic Scoring System-Molecular.
*Adapted from Baer, et al.4
Harrell’s concordance index to assess the correlation between outcomes based on the IPSS-R and IPSS-M is shown in Figure 5. Age was not considered in either cohort and may have contributed to the lowest OS.
Figure 5. Harrell’s C-index for IPSS-R and IPSS-M*
IPSS-M, International Prognostic Scoring System-Molecular; IPSS-R, IPSS-Revised.
*Adapted from Baer, et al.4
The IPSS-M requires 37 parameters in total including TP53 multihit status (TP53multi, combinations of mutations, deletion or copy neutral loss of heterozygosity), KMT2A, FLT3 aberrations, NPM1 mutations, and pattern of co-mutations of SF3B1.
The IPSS-R continues to be the gold standard in MDS prognostication, particularly when the use of the IPSS-M is not possible. Although the IPSS-M provides improved prognostication tools by using validated parameters and up-to-date molecular data, further research is needed to establish its feasibility. However, the ELN 2022 classification does not apply to patients with MDS/AML, and the inclusion of MDS/AML patients in clinical trials assessing adverse risk AML may not be justifiable. Comprehensive molecular analysis is becoming a new standard of MDS prognostication; however, not all laboratories can offer broad molecular genetic panels. As such, laboratories and clinicians must provide a comprehensive set of all types of data in the future, enabling the IPSS-R and the IPSS-M to deliver more meaningful prognostic scores.
Real-world validation of the IPSS-M risk stratification model for MDS and comparison to IPSS-R
The MDS Hub summarizes several presentations from ASH 2022 discussing the implementation of IPSS-M and comparing the prognostic ability of this model with...
New IPSS-Molecular model for MDS risk stratification and prognosis
Bernard, et al. evaluated the combined prognostic power of hematologic, cytogenetic, and somatic gene mutation parameters in the development and use of a clinical-molecular...
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