Newly Developed Prognostic Score for Myelodysplastic Syndrome (MDS) with Isolated 5q Deletion (IPSS-del(5q))

Background & aim: Patients (pts) with MDS-del(5q), including those with TP53 multihit mutations, exhibit better outcomes compared to the general MDS population (Montoro et al., Blood 2024). However, approximately 20% of MDS-del(5q) eventually progress to acute myeloid leukemia (AML). Because the defining criteria of MDS-del(5q) exclude the presence of blasts and adverse cytogenetics, current prognostic scoring systems, such as the Revised International Prognostic Scoring System (IPSS-R) and its molecular counterpart (IPSS-M), fail to effectively stratify the risk of this MDS subtype. This study aimed to comprehensively evaluate the prognostic impact of clinical and genetic parameters in MDS-del(5q) pts. Additionally, we developed a specific risk score for MDS-del(5q) [IPSS-del(5q)] and compared it with the standard MDS risk scores (IPSS-R and IPSS-M).

Methods: We included de novo MDS-del(5q) pts according to 2017 WHO criteria, which also includes those with TP53 multihit alterations, and collected data on mutations, survival, and progression to AML. Clinical and biological characteristics were recorded at diagnosis. Genetic profiling included G-banding cytogenetics and NGS to analyze mutations in myeloid-related genes. Pts were classified based on the breakpoint of the 5q deletion into common breakpoints (q13q31, q13q33, q22q33, q12q33, q14q34) or alternative breakpoints. Only mutations with variant allele frequency (VAF) >2% were considered. Clinical and molecular variables were evaluated for their associations with AML evolution, overall survival (OS) and event free survival (EFS), with AML progression considered as events of interest. Model discrimination was evaluated using Harrell's C concordance index. Statistical analysis was performed using R (version 4.2.2).

Results: A total of 682 pts with MDS-del(5q) from 19 international institutions were included. The median follow-up for the entire cohort was 68.5 months (95%CI 62.3-81.1). The median age at diagnosis was 74 years (IQR, 66-80), and 73.3% (n=500) were female. IPSS-R was analyzed in 77.3% (n=527) of pts. Among these, 90.3% (n=476) were classified as very low or low-risk, while 9.7% (n=51) fell into the intermediate-risk category. Similarly, IPSS-M was assessed in 82.0% (n=559) of pts. Among these, 67.6% (n=378) were classified as very low or low-risk, 25.6% (n=143) as moderate low or high-risk, and 6.8% (n=38) fell into the higher-risk categories. The median OS for the entire cohort was 73.8 months (CI95% 63.2-83.4). A total of 22.7% (n=115/507) pts progressed to AML at a median time of 32 months (IQR 18-57). In the multivariable analysis, age ³70 years (HR 0.6), platelets > 100x10⁹/L (HR 0.4), bone marrow blasts >2% (HR 1.9), TP53-multihit and TP53 VAF >20% (HR 1.8), and SF3B1-mut (HR 1.7), were independent parameters for AML evolution. For OS, female (HR 0.6), Hb >10 g/dL (HR 0.6), platelets > 100x10⁹/L (HR 0.4), and CSNK1A1-mut (HR 0.5), were independent variables. Finally, age ³70 (HR 1.5), female (HR 0.7), Hb >10 g/dL (HR 0.7), platelets > 100x10⁹/L (HR 0.5), and SF3B1-mut (HR 1.4), predicted for EFS.

IPSS-del(5q) was built as a weighted sum of 6 prognostic variables: hemoglobin, platelets, sex, number of mutations, SF3B1-mut and TP53-multihit/TP53-monoallelic with VAF ³20%. Accordingly, three risk-groups were defined: low (51.6%, n=221), intermediate (31.3%, n=134), and high-risk (17.1%, n=73), with a median EFS of 78.2 (CI95% 63.9-90), 45.1 (CI95% 36.3-63.7) and 28.2 months (CI95% 22-42.6), respectively; p<0.01. Using IPSS-del(5q), 33% (n=140) of pts stratified as low/very low risk according to IPSS-M were upstaged, whereas 6% (n=27) were downstaged. Interestingly, 2% (n=10) of pts considered very low or low-risk by IPSS-M were reallocated to the high-risk category by IPSS-del(5q). Model discrimination analysis proved IPSS-R inadequate for the risk stratification of MDS-del(5q), while IPSS-M demonstrated adequacy only for lower-risk pts (c-index of 0.58 for EFS and 0.58 for OS). IPSS-del(5q) outperformed IPSS-M in EFS (c-index of 0.63) and OS (c-index of 0.62).

Conclusions:

The newly developed IPSS-del(5q), built from the largest cohort of MDS-del(5q) described to date, stratifies pts into three distinct risk groups. It proved to be more accurate than the IPSS-R and IPSS-M for the risk prognostication of MDS-del(5q). These findings could have significant implications for guiding treatment decisions.

Haferlach:Abbvie: Consultancy, Honoraria. Chan:Syndax: Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Jazz: Research Funding; Abbvie: Honoraria, Research Funding; Aptitude Health: Honoraria. Bosch:AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: payment for expert testimony; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: payment for expert testimony; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: payment for expert testimony; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: payment for expert testimony; Mundipharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: payment for expert testimony; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: payment for expert testimony; Celgene/BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: payment for expert testimony; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: payment for expert testimony; Lilly: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: payment for expert testimony; BeiGene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: payment for expert testimony; Enterome: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: payment for expert testimony; TG Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: payment for expert testimony; Lava Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: payment for expert testimony; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: payment for expert testimony; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: payment for expert testimony; Advantage Allogene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: payment for expert testimony. Jerez:Aztrazeneca: Research Funding; GILEAD: Research Funding; Novartis: Consultancy; BMS: Consultancy. Santini:Ascentage, AbbVie, Bristol Myers Squibb, CTI BioPharma, Geron, Gilead, Novartis, Servier, Syros Pharmaceuticals: Other: Advisory Board. Kubasch:Curis: Research Funding; BMS: Honoraria; Janssen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Platzbecker:Amgen: Consultancy, Research Funding; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; MDS Foundation: Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Research Funding; Curis: Consultancy, Honoraria, Research Funding; Geron: Consultancy; Janssen: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Novartis: Consultancy, Research Funding. Haase:Jazz Pharmaceuticals: Honoraria, Research Funding. Diez-Campelo:BMS/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory board fees; Gilead: Other: Travel reimbursement; SYROS: Membership on an entity's Board of Directors or advisory committees; HEMAVAN: Membership on an entity's Board of Directors or advisory committees; CURIS: Membership on an entity's Board of Directors or advisory committees; AGIOS: Consultancy, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; ASTEX/OTSUKA: Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL TO MEETINGS; KEROS: Honoraria, Membership on an entity's Board of Directors or advisory committees; BLUEPRINT MEDICINES: Consultancy, 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. Della Porta:Bristol Myers Squibb: Consultancy. Garcia-Manero:Janssen: Research Funding; Curis: Research Funding; Astex: Other: Personal fees; Novartis: Research Funding; AbbVie: Research Funding; Helsinn: Other: Personal fees; Astex: Research Funding; H3 Biomedicine: Research Funding; Onconova: Research Funding; Merck: Research Funding; Bristol Myers Squibb: Other: Personal fees, Research Funding; Genentech: Research Funding; Forty Seven: Research Funding; Aprea: Research Funding; Helsinn: Research Funding; Amphivena: Research Funding; Genentech: Other: Personal fees. Germing:Novatis: Honoraria; JAZZ: Research Funding; BMS: Research Funding; Abbvie: Research Funding; BMS: Honoraria. Maciejewski:Alexion: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Speakers Bureau. Komrokji:PharmaEssentia: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; DSI: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sumitomo Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sobi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; DSI: Honoraria, Membership on an entity's Board of Directors or advisory committees; CTI biopharma: Membership on an entity's Board of Directors or advisory committees; Rigel: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Servio: Honoraria; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Servio: Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy; Taiho: Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy; Keros: Membership on an entity's Board of Directors or advisory committees; Geron: Consultancy, Membership on an entity's Board of Directors or advisory committees. Valcarcel:AbbVie: Consultancy, Other: Meeting and travel accommodation; Agios: Honoraria, Other: Meeting and travel accommodation, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Meeting and travel accommodation, Speakers Bureau; Astellas: Consultancy, Honoraria; Bristol Myers Squibb/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Meeting and travel accommodation, Research Funding, Speakers Bureau; Gebro: Honoraria, Speakers Bureau; Grifols: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Meeting and travel accommodation, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Jazz Pharmaceuticials: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Meeting and travel accommodation, Speakers Bureau; Kite/Gilead: Consultancy, Honoraria, Speakers Bureau; MSD: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Meeting and travel accommodation, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; Sanofi: Consultancy, Honoraria, Other: Meeting and travel accommodation, Speakers Bureau; Servier: Membership on an entity's Board of Directors or advisory committees; SOBI: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Meeting and travel accommodation, Speakers Bureau; TAKEDA: Consultancy, Honoraria, Speakers Bureau.