Impact of Molecular Aberrations on Discordance Among Modalities of Blast Enumeration for Risk Stratification in Myelodysplastic Neoplasms

Introduction: To determine prognosis and treatment of myelodysplastic neoplasms (MDS), adequate risk stratification is a crucial element in handling MDS patients. In the Revised International Prognostic Scoring System (IPSS-R), cytogenetical data and the amount of blasts in the bone marrow (BM) smear have substantial weight. With platelet count, hemoglobin level and absolute neutrophil count as explicit parameters and defined risk categories for evaluating karyotypes, morphology-based blast enumeration remains a relatively subjective part of risk scoring. BM cytology (BM-c), BM histology (BM-h) and BM flow cytometry (BM-f) are widely used to determine the amount of blasts in MDS patients. In the cohort of MDS patients treated since 2012 in our institution, we found significant blast count discordance among these three modalities, impairing overall survival (OS) of discordant (dis) patients. Previous research has shown remarkable impact of molecular genetic aberrations on OS in MDS. Therefore, we went out to define such markers which may help to discriminate discordant diagnostic cases.

Methods/Results: We analyzed molecular genetic data of 145 MDS patients and compared the blast counts in the three modalities to determine concordant (con, n=83, 57%) and dis samples (n=62, 43%). Although there were no significant differences between these two groups regarding age, sex, hemoglobin level, platelet count and IPSS-R karyotype risk groups (all p > 0.05), a pronounced difference in overall survival of low-risk MDS patients according to IPSS-R was observed (con vs. dis, median OS 72 vs. 35 months, p = 0.036). In dis cases, further analysis showed significantly more mutations regarding -7/7q deletion (9 vs. 1 cases, p = 0.04) and BCOR (6 vs. 0 cases, p = 0.03). In case of the splicing factor mutations SF3B1 (6 vs. 16 cases, p = 0.003) and U2AF1 mutations (2 vs. 7 cases, p = 0.04), significant differences in favor of concordant samples were found. Interestingly, when low-risk con and dis patients were re-stratified using IPSS-M, OS was markedly higher and differences in OS between con and dis patients vanished (72 vs. 146 months, p = 0.46).

Conclusion: Our study reveals molecular genetic features that impact the assessment of blasts by the classically used modalities BM-c, BM-h and BM-f. Samples mutated in BCOR or with -7/7q deletion showed a distinct tendency towards blast discordance, while splicing factor mutations were mostly found in con patients. As previously shown, blast discordance is relevant for OS of patients and may significantly alter therapeutic decisions, highlighting that especially in discordant cases molecular data should be considered.

Nowak:Affimed GmbH: Research Funding.