A clinico-genomic prognostic model for primary myelodysplastic neoplasm in Asia

Abstract

A personalized prognostic model that takes into account the unique molecular features of primary myelodysplastic neoplasm (MDS) in Asia patients is lacking. Diagnostic clinicopathologic features, cytogenetic changes, and gene mutations of ethnic Asian patients with primary MDS were analyzed. Variables were evaluated for associations with overall survival (OS), leukemia-free survival (LFS), and time to progression to secondary AML (TTP-sAML). Prognostic scores were built as a weighted sum of prognostic variables for each patient. The cohort comprised 1225 patients, with at least one gene mutation identified in 1177 patients (96%). Genomic factors associated with inferior outcomes included monosomy 7, del(5q), and GNAS and TP53 mutations for OS; trisomy 19, del(5q), monosomy 7, and GNAS, PTPN11 and TP53 mutations for LFS; and i(17q), del(5q), and NPM1, NRAS, GNAS, IDH2, SF3B1 and RUNX1 mutations for TTP-sAML. The Asian Prognostic Scoring System (APSS) was determined, stratifying patients into six prognostic risk categories. The APSS, compared with the International Prognostic Scoring System molecular (IPSS-M), showed superior concordance indices (C-indices) for OS (0.73 versus 0.57), LFS (0.72 versus 0.59), and TTP-sAML (0.75 versus 0.65) for this Asian cohort. In conclusion, the APSS enhanced prognostication of primary MDS in Asia.

Fig. 1. Kaplan-Meier analysis of overall survival (OS), leukemia-free survival (LFS) and the impact of genomic factors on OS and LFS in 1225 patients with primary myelodysplastic neoplasm (MDS) in Asia.

A Overall survival of primary MDS in Asia; B Adverse prognostic impact of monosomy 7 (-7) on overall survival in primary MDS in Asia; C Adverse prognostic impact of del(5q) on overall survival in primary MDS in Asia; D Adverse prognostic impact of GNAS mutations on overall survival in primary MDS in Asia; E Adverse prognostic impact of TP53 mutations on overall survival in primary MDS in Asia; F Leukemia-free survival of primary MDS in Asia; G Adverse prognostic impact of trisomy 19 (+19) on leukemia-free survival in primary MDS in Asia; H Adverse prognostic impact of 5q deletion [del(5q)] on leukemia-free survival in primary MDS in Asia; I Adverse prognostic impact of monosomy 7 (-7) on leukemia-free survival in primary MDS in Asia; J Adverse prognostic impact of GNAS mutations on leukemia-free survival in primary MDS in Asia; K Adverse prognostic impact of PTPN11 mutations on leukemia-free survival in primary MDS in Asia; L Adverse prognostic impact of TP53 mutations on leukemia-free survival in primary MDS in Asia. All P-values were obtained using log-rank test. The genomic factors shown were significant on multivariable analysis (see Table 2).

Fig. 2. Kaplan-Meier analysis of time to progression (TTP) to secondary acute myeloid leukemia (AML) in 1225 patients with primary myelodysplastic neoplasm (MDS) in Asia.

A Time to progression to secondary AML in primary MDS in Asia; B Adverse prognostic impact of isochromosome 17q [i(17q)] on time to progression to secondary AML in primary MDS in Asia; C Adverse prognostic impact of 5q deletion [del(5q)] on time to progression to secondary AML in primary MDS in Asia; D Adverse prognostic impact of NPM1 mutations on time to progression to secondary AML in primary MDS in Asia; E Adverse prognostic impact of NRAS mutations on time to progression to secondary AML in primary MDS in Asia; F Adverse prognostic impact of GNAS mutations on time to progression to secondary AML in primary MDS in Asia; G Adverse prognostic impact of IDH2 mutations on time to progression to secondary AML in primary MDS in Asia; H Adverse prognostic impact of SF3B1 mutations on time to progression to secondary AML in primary MDS in Asia; I Adverse prognostic impact of RUNX1 mutations on time to progression to secondary AML in primary MDS in Asia. All P values were obtained using log-rank test. The genomic factors shown were significant on multivariable analysis (see Table 2).

Fig. 3. Outcome prediction and validation of the Asian Prognostic Scoring System (APSS).

A Prognostic risk categories for overall survival according to the APSS; B Distribution of prognostic risk categories for overall survival according to the APSS (X-axis represents the prognostic score); C Prognostic risk categories for leukemia-free survival according to the APSS; D Distribution of prognostic risk categories for leukemia-free survival according to the APSS (X-axis represents the prognostic score); E Prognostic risk categories for time-to-progression to secondary acute myeloid leukemia according to the APSS; F Distribution of prognostic risk categories for time-to-progression to secondary acute myeloid leukemia according to the APSS (X-axis represents the prognostic score); G Comparison of concordance (C) indices obtained using the APSS, molecular international prognostic scoring system (IPSS-M) and the Revised International Prognostic Scoring System (IPSS-R) in the current Asian primary myelodysplastic neoplasm cohort; H Validation of the APSS risk categories on overall survival (OS) in the external IPSS-M dataset; I Validation of the APSS risk categories on leukemia-free survival (LFS) in the external IPSS-M dataset; J Validation of the APSS risk categories on the time-to-progression (TTP) to secondary acute myeloid leukemia in the external IPSS-M dataset.