Assessment of the Molecular International Prognostic Scoring System (IPSS-M) Risk Stratification Model in Hypoplastic Myelodysplastic Syndromes

Background Hypoplastic myelodysplastic syndromes (h-MDS) represent an uncommon subtype of MDS. The new WHO 2022 classification recognized h-MDS as a distinct category. The Molecular International Prognostic Scoring System (IPSS-M) is a newly developed clinical-molecular risk stratification model for myelodysplastic syndromes that expands on the original IPSS-R by including data on somatic oncogenic mutations. Here we aimed to assess the validity of this tool in the risk stratification of h-MDS using a large cohort of patients treated at a tertiary referral center.

Methods A total of 281 h-MDS patients with annotated clinical and molecular data treated at Moffitt Cancer Center were analyzed. For estimation of the IPSS-M score, R version 4.2.1 was used to run batch-calculation using syntax code provided by the Papaemmanuil lab at MSKCC. The mean IPSS-M score was used as reference. Time-to-event analyses were estimated using the Kaplan-Meier method and groups were compared by the log-rank test. We used Cox proportional hazards models for survival endpoints.

Results We identified at least 349 driver point mutations involving up to 98 genes across 281 patients. We identified at least one gene mutation in 66.9% of pts (n=188), and 2 or more in 37% (n=104). Median overall survival (OS) was 3.2 years (95%CI, 2.8-3.5). Median leukemia-free survival (LFS) was 2.1 years (1.6-2.5). Median follow-up was 3.9 years (3.5-4.4).

281 pts (100%) were classified. Fig. 1 shows the baseline molecular characteristics of the cohort. The most prevalent mutations were TP53 (n=51, 18%), TET2 (n=37, 13%), DNMT3A (n=35, 12%), RUNX1 (n=32, 11%) and U2AF1 (n=21, 7%). Using the IPSS-M risk stratification schema, pts were classified as Very Low (3%, n=8), Low (19.9%, n=56), Moderate Low (20.3%, n=57), Moderate High (14.9%, n=42), High (20.6%, n=58) and Very High (21.4%, n=60) (Fig 2).

The IPSS-M categories showed significant separation across all examined endpoints (p<0.001). Median OS was NR, 5.8, 4.6, 3.0, 2.1 and 1.3 yrs from VL to VH subgroups respectively (Fig 2). Conversely, median LFS was NR, 5.1, 3.7, 2.7, 0.8 and 0.4 yrs from Very Low to Very High-risk categories (Fig 2).

A five-to-five mapping between the IPSS-R and IPSS-M risk subgroups (by merging moderate low and moderate high into moderate in IPSS-M) was conducted for comparison, which resulted in the restratification of 45.7% pts (128 of 280). 68% of pts classified as IPSS-R very low risk were upstaged (majority to IPSS-M low and ML/MH). 42% of pts classified as IPSS-R intermediate shifted: 23 (31%) were reclassified as IPSS-M high/very high. About 28% of pts classified as IPSS-R high were upstaged to IPSS-M very high. About 77% of pts classified as IPSS-R very high were also considered very high risk on IPSS-M, with more than 20% of the remainder cases being downstaged (majority to high risk). Furthermore, 24% of pts classified as VL risk per IPSS-R were restratified with more than 1 shift in IPSS-M. Also important was the reclassification of 25 pts (8.9%) from IPSS-R lower and intermediate risk categories into IPSS-M higher risk strata. Conversely, 19 pts (6.8%) were downstaged from higher risk categories in IPSS-M to lower and intermediate risk in IPSS-R. The restratification of pts from IPSS-R intermediate to other risk strata in IPSS-M was associated with notable differences in survival outcomes which were as poor as 1.3 yrs and as high as 5.8 yrs for those reclassified as LR (relative to 4.7 yrs).

Using the parameters established by the newly defined h-MDS WHO 2022 category, the IPSS-M model was still able to discriminate accurately between risk categories and showed separation across examined endpoints (p<0.001). A total of 216 cases were identified based on marrow cellularity < 25% with <5% marrow blasts and <2% blasts in peripheral blood. Median OS was NR, 5.4, 4.9, 3.0, 2.1 and 1.4 yrs from VL to VH risk subgroups. Median LFS was NR, 4.9, 3.9, 2.1, 0.9 and 0.3 yrs from VL to VH-risk categories.

Conclusion To our knowledge this is the first external validation of IPSS-M in a large cohort of h-MDS pts. Use of the IPSS-M model for the risk stratification of pts with h-MDS led to restratification of almost half of the cases and exposed important differences in survival outcomes. The IPSS-M was also applicable to the newly proposed h-MDS WHO 2022 category. Generalized use of this tool will likely result in more accurate prognostic assessment and optimize therapeutic decisions.

Tinsley-Vance:Abbvie: Consultancy; Novartis: Consultancy; Jazz: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; CTI: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau. Kuykendall:Pharmaessentia: Consultancy, Honoraria, Speakers Bureau; Imago Biosciences: Consultancy, Honoraria, Speakers Bureau; Incyte: Consultancy, Honoraria, Speakers Bureau; Blueprint: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Abbvie: Consultancy, Honoraria, Speakers Bureau; GSK - Sierra Oncology: Consultancy, Honoraria, Other: Research Support, Speakers Bureau; Prelude Pharmaceuticals: Other: Research Support; BMS: Consultancy, Honoraria, Other: Research Support, Speakers Bureau; Morphosys: Other: Research Support; Protagonist: Other: Research Support; CTI Biopharma: Consultancy, Honoraria, Speakers Bureau. Sweet:Astellas: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Mablytics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead Sciences, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Syntrix Pharmaceuticals: Research Funding; berGenBio: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Curis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AROG: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Lancet:Agios/Servio: Consultancy; Jazz: Consultancy; Dedham Group: Consultancy; Boxer Capital: Consultancy; Syntrix Pharmaceuticals: Research Funding; Dava Oncology: Consultancy; Novartis: Consultancy; Jasper Therapeutics: Consultancy; Astellas: Consultancy; BerGenBio: Consultancy; Millenium Pharma/Takeda: Consultancy; ElevateBio Management: Consultancy; Daiichi Sankyo: Consultancy; Celgene/BMS: Research Funding; AbbVie: Consultancy; Servier: Consultancy. Padron:Kura: Research Funding; Incyte: Research Funding; Blueprint: Honoraria; Syntrix Pharmaceuticals: Research Funding; Stemline: Honoraria; Taiho: Honoraria; BMS: Research Funding. Sallman:Syntrix Pharmaceuticals: Research Funding; Agios: Membership on an entity's Board of Directors or advisory committees; Intellia: Membership on an entity's Board of Directors or advisory committees; Syndax: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; Magenta: Consultancy; Incyte: Speakers Bureau; Aprea: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Lixte: Patents & Royalties: LB-100; Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Nemucore: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy. Komrokji:Servio: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CTI biopharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; PharmaEssentia: Honoraria, Other, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Geron: Honoraria, Membership on an entity's Board of Directors or advisory committees; Taiho: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.