IWG-PM

The International Working Group for Prognosis in MDS (IWG-PM) consists of a group of international investigators aligned through the MDS Foundation whose focus is aimed at defining the clinical and biologic features of MDS thus providing the foundation for understanding the nature and potential for progression of this spectrum of disorders. To this end the group has generated programs leading to seminal projects and publications characterizing and classifying the disease. Current group investigations include determining the impact of mutational features that further delineate disease status and potential therapeutic targets providing novel treatment approaches for MDS.

MDS Risk Assessment Calculators*

The IWG-PM under the aegis of the MDS Foundation, Inc. has developed two prognostic tools, the IPSS-M and IPSS-R Calculators, to determine a patient’s risk of progressing to Acute Myeloid Leukemia (AML).

The IPSS-M is the newest MDS prognosis calculator that combines genomic profiling with hematologic and cytogenetic parameters, improving the risk stratification of patients with MDS. This is a valuable tool for clinical decision-making, offering the prospect of tailoring diagnosis and therapeutic interventions to each patient’s molecular profile.

Web App

iPhone App

Android App

R Package

The IPSS-R is the current MDS prognosis calculator that combines hematologic and cytogenetic parameters to determine an MDS patient’s risk stratification. This calculator tool includes clinical features of marrow blasts, cytogenetics, depth of cytopenias and age as well as the additive differentiate features for patient survival of performance status, serum ferritin, LDH, beta-2 micro globulin and marrow fibrosis.

Web App

Current IWG-PM Projects

Project: Molecular Characterization of Treatment-Related MDS, Elsa Bernard, PI

Several recent publications by members of the IWG-PM led by Elsa Bernard, within the laboratory of Elli Papaemmanuil at Memorial Sloan-Kettering Cancer Center, under the aegis of the MDS Foundation, have provided major new approaches for the prognostication and molecular classification of MDS patients. A recent initial paper produced the clinical-molecular MDS prognostic risk model (IPSS Molecular or IPSS-M) (1). In this study mutations in diagnostic MDS samples from 2957 patients from 13 countries and 25 global centers were analyzed. Clinical, cytogenetic, and molecular variables were evaluated for associations with leukemic transformation and overall survival. At least one genetic driver alteration was found in 94% of patients. Multivariate analysis identified multi-hit TP53, FLT3 mutation, and MLL partial tandem duplication as top genetic predictors of adverse outcomes. SF3B1 mutation was associated with favorable outcomes, but this was modulated by co-mutation patterns. Using hematologic, cytogenetic and molecular data on 31 genes, the IPSS-M was developed as a continuous score. A discrete six-category risk schema was further derived. The IPSS-M re-stratified 46% of MDS patients compared to the IPSS-R, improving discrimination across clinical endpoints. A web calculator and an App were built that, upon entering predictor variables, outputs a patient-tailored score, its corresponding risk category, and temporal estimates for clinical endpoints. The IPSS-M prognostic risk score is personalized, interpretable and reproducible. Combining conventional parameters with genomic profiling, the IPSS-M represents a valuable tool for clinical decision-making for MDS patients. The App is available to supplement the weblink now in general use for calculating the IPSS-M. 

Because of the clinical and morphologic heterogeneity of MDS patients, a molecular taxonomic classification of MDS was developed by Bernard and IWG-PM colleagues (2).   Genomic profiling was performed on 3,233 patients with MDS or related disorders to delineate molecular subtypes and define their clinical implications. Gene mutations, copy-number alterations (CNAs), and copy-neutral loss of heterozygosity (cnLOH) were derived from targeted sequencing of a 152-gene panel, with abnormalities identified in 91, 43, and 11% of patients, respectively. Sixteen molecular groups were defined, encompassing 86% of patients, using information from 21 genes, 6 cytogenetic events, and LOH at the TP53 and TET2 loci. Two residual groups defined by negative findings (molecularly not-otherwise specified, absence of recurrent drivers) comprised 14% of the patients. The groups varied in size from 0.5% to 14% of patients and were associated with distinct clinical phenotypes and outcomes. The median bone marrow blast percentage ranged from 1.5 to 10%, and the median overall survival from 0.9 to 8.2 years. Five well characterized entities were validated, further evidence added support to 3 previously reported subsets, and 8 novel groups were described. The prognostic influence of bone marrow blasts depended on the genetic subtypes. Within genetic subgroups, therapy-related MDS and myelodysplastic/myeloproliferative neoplasms (MDS/MPN) had comparable clinical and outcome profiles to primary MDS. Thus, genetically-derived subgroups of MDS were shown to be clinically relevant and which should better inform future classification schemas.

Mutations in the UBA1 gene, which are disease-defining for VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome, have been reported in patients with MDS. Led by Dr Maria Sirenko, with the IWG-PM, the prevalence and clinical associations of UBA1 mutations in a representative cohort of patients with MDS were defined (3). In a selected cohort of 375 male patients lacking MDS disease-defining mutations or established World Health Organization (WHO) disease classification, 28 patients (7%) were identified with UBA1 p.M41T/V/L mutations. Using targeted sequencing of UBA1 in a representative MDS cohort (n = 2027), an additional 27 variants in 26 patients (1%) were identified. Among the patients with likely/pathogenic variants (2%), all were male and 63% were classified by WHO 2016 criteria as MDS with multilineage dysplasia or MDS with single-lineage dysplasia. Retrospective clinical review showed that 82% UBA1-mutant cases had VEXAS syndrome-associated diagnoses or inflammatory clinical presentation. The prevalence of UBA1 mutations in patients with MDS argues for the need for systematic screening for UBA1 in the management of MDS.

To analyze clinical outcomes of treatment-related MDS (t-MDS), Andrea Kuendgen, Meritxell Nomdedue and IWG-PM colleagues analyzed 1590 such patients compared to 4738 patients with primary MDS (p-MDS) (4). Cytogenetic profiles were the most distinctive risk factor between t- vs. p-MDS independent of treatment. Normal karyotype, del(5q), +8, del(12p), -13/del(13q), i(17q), -Y, and marker chromosomes were at least twice as frequent in p-MDS, while der(1;7), abnormalities 3q, -7, del(7q), t(11q23), double abnormalities including chromosome 7, and complex abnormalities were more frequent in t-MDS. Not only karyotype risk categories, but also single aberrations were substantially different between t- and p-MDS, with a predominance of lower-risk abnormalities in p-MDS and higher-risk abnormalities in t-MDS. These data aid clinical characterization of these distinctive MDS subtypes.

*Data for the IPSS-R & IPSS-M calculators are derived from:

• Bernard  E, Tuechler H, Greenberg PL, et al, The Molecular International Prognosis Scoring System (IPSS-M) for risk stratification in myelodysplastic syndromes. New Eng J Med Evidence. https://evidence.nejm.org/doi/full/10.1056/EVIDoa2200008. Study supported by the MDS Foundation.
• Greenberg P, Tuechler H, Schanz J, et al, Revised International Prognostic Scoring System (IPSS-R) for Myelodysplastic Syndromes. Blood 120: 2454-2465, 2012.