Novel Scoring System May Improve Risk Stratification in MDS Subtype

“We can conclude that the standard MDS scoring systems fail to stratify the risk of MDS-del(5q), and that male sex, cytopenias, and complex genetic background worsen the prognoses of these patients,” according to study author Maria Julia Montoro.

The International Prognostic Scoring System (IPSS)–del(5q) Scoring System may enhance the identification of risks associated with myelodysplastic syndrome (MDS) harboring isolated 5q deletions (MDS-del[5q]) compared with standard MDS scoring systems, according to results presented at the 2024 American Society of Hematology Annual Meeting & Exposition (ASH).

Among 609 patients who were evaluated per Revised IPSS (IPSS-R) criteria, 575 (97%) were classified as having a lower risk of MDS-del(5q), and 15 (3%) had higher-risk disease. When using Molecular IPSS (IPSS-M) criteria to stratify 559 patients with MDS, 478 (86%) had lower-risk disease, and 81 (14%) had higher-risk disease.

When evaluating patient outcomes per IPSS-R criteria, the C-index was 0.53 for overall survival (OS), 0.53 for leukemia-free survival (LFS), and 0.35 for acute myeloid leukemia (AML) evolution. Data showed no significant differences in outcomes between patients with lower-risk and higher-risk disease using the IPSS-R system.

Based on IPSS-M criteria, the C-index was 0.54 for OS, 0.55 for LFS, and 0.51 for AML evolution. Additionally, use of this system yielded significant differences in OS (P <.01), LFS (P <.01), and AML evolution (P <.01) between patients with lower-risk and higher-risk disease.

Risk-stratifying patients with the IPSS-del(5q) Scoring System showed a median LFS of 32.0 months among patients classified as having high-risk disease and 70 months for those with standard-risk disease; the C-index for evaluating LFS with these criteria was 0.60 (P <.01). Use of the IPSS-del(5q) Scoring System showed that patients with standard-risk disease experienced significantly better OS (P <.01) and a significantly lower risk of AML evolution (P <.01).

When conducting prognostic restratification of patients with MDS-del(5q), 9.4% and 14.8% of patients had higher-risk disease per IPSS-R and IPSS-M criteria, respectively, which increased to 25.6% using the IPSS-del(5q) Scoring System. Additionally, the rates of lower-risk prognoses went from 90.6% and 85.2% with IPSS-R and IPSS-M guidelines to 74.4% per IPSS-del(5q) criteria.

“We can conclude that the standard MDS scoring systems fail to stratify the risk of MDS-del(5q), and that male sex, cytopenias, and complex genetic background worsen the prognoses of these patients,” Maria Julia Montoro, of the Department of Hematology and Oncology at Vall d’Hebron University Hospital, in Barcelona, Spain, said in the presentation. “The IPSS-del(5q) Scoring System enhances the identification of high-risk MDS-del(5q) and achieves a modest improvement of the predictive capacity compared with the current MDS scoring systems.”

According to Montoro, those with MDS-del(5q) typically experience better survival outcomes compared with the general MDS population, although approximately 25% of these patients have progression to AML within 5 years of diagnosis. With this background in mind, Montoro and colleagues aimed to assess the prognostic impact of clinical and biological factors in the MDS-del(5q) population while developing a prognostic score that was specifically associated with this subgroup.

Patients with de novo MDS-del(5q) per World Health Organization 2017 guidelines with mutational analysis were eligible for inclusion in the analysis. Investigators collected data on factors including patient demographics, blood counts, and bone marrow blast percentages. Per IPSS-R criteria, patients were classified as having lower-risk disease if they scored no more than 3.5 points, while those with higher-risk disease had more than 3.5 points. Per IPSS-M guidelines, patients with very low, low, or moderate-low risks were considered to have lower-risk disease, and those with moderate-high, high, and very high risks made up the higher-risk group.

The study involved an assessment of biological data using G-banding for del(5q) breakpoints as well as next-generation sequencing to detect aberrations in genes including ASXL1, CALR, CBL, CEBPA, and CSF3R, among others. Patients were classified as having non-high risk TP53 status—including those with TP53 wild-type disease or TP53-monoallelic with a variant allele frequency (VAF) of less than 20%—or having high-risk TP53 status—consisting of those with TP53-multihit disease or those with TP53-monoallelic with a VAF of at least 20%.

Investigators generated risk scores using the LASSO minimum lambda test with LFS as an event of interest. The assessment also included a multivariate Cox proportional hazard model to round hazard ratios for scoring.

Overall, 682 patients were included in the analysis, and the median age was 74 years (IQR, 66-80). Overall, most patients were female (73.3%), and of those with available treatment data (n = 439), the most common therapy was lenalidomide (Revlimid; 67%). Additionally, patients had a median hemoglobin of 9.2 g/dl (IQR, 8.1-10.3), white blood cell count of 4.1 x 10⁹/L (IQR, 3.0-5.5), neutrophil count of 2.0 x 10⁹/L (IQR, 1.3-3.1), platelet count of 249 x 10⁹/L (IQR, 169-347), and a bone marrow blast percentage of 2% (IQR, 1.0%-3.5%).

Across the overall cohort, the median follow-up was 69 months (95% CI, 63%-81%), and the median OS was 74 months (95% CI, 63%-83%). Additionally, 23% of patients had AML evolution at 60 months, and the median time to AML evolution was 32 months (95% CI, 18%-57%).

Regarding genetic characterization, most patients had isolated del(5q) (n = 568/682; 83%) and type 1 5q deletion breakpoints (n = 513/644; 80%). Molecular characterization data showed that most patients had mutated disease (n = 444/626; 71%) and non-high risk TP53 status (n = 601/626; 88%).

When evaluating the prognostic impact of the quantity of mutations, patients with at least 2 mutations had significantly worse OS (P <.01) and LFS (P <.01) compared with those who had 0 or 1 mutations. Additionally, having 2 or more mutations correlated with a higher risk of AML evolution (P = .05).

Findings from a multivariate analysis revealed that factors correlating with OS included being 70 years or older (HR, 2.1), being male (HR, 1.4), having a hemoglobin count of no more than 10 g/dL (HR, 1.4), a platelet count of no more than 100 x 10⁹/L (HR, 1.7), the addition of 1 chromosomal abnormality (HR, 1.5), and having 2 or more mutations (HR, 2.0). Factors associated with LFS included being older than 70 years (HR, 1.5), male sex (HR, 1.4), a hemoglobin count of 10 or fewer g/dL (HR, 1.4), a platelet count of 100 x 10⁹/L or lower (HR, 2.0), and having 2 or more mutations (HR, 2.0).

Regarding progression to AML, risk factors included being younger than 70 years (HR, 1.7), having a platelet count of no more than 100 x 10⁹/L (HR, 2.5), a bone marrow blast percentage of more than 2%, SFB31 mutations (HR, 1.7), and high-risk TP53 status (HR, 1.8).

Disclosures: Montoro did not have any financial relationships to disclose.

Reference

Montoro MJ, Palomo L, Haferlach C, et al. Newly developed prognostic score for myelodysplastic syndrome (MDS) with isolated 5q deletion (IPSS-del(5q)). Blood. 2024;144(suppl 1):666. doi:10.1182/blood-2024-194405