Elevated serum erythropoietin level is associated with unique clinical and genomic features, response to treatment, and outcomes in lower-risk myelodysplastic syndromes

Abstract

Abstract Introduction Elevated endogenous serum erythropoietin level (EPO) is a biomarker of erythropoiesis and is used in clinical practice to predict response to erythroid stimulating agents (ESA). The majority of patients (pts) with myelodysplastic syndromes (MDS) have EPO levels of <200 IU/L. We examined the clinical and molecular features of patients with high EPO levels and their response to various available therapies. Methods We identified lower-risk MDS (LR-MDS) pts defined by R-IPSS, excluding del5q, with known EPO levels at the time of diagnosis or before any treatment. We compared clinical features, genomic landscape, responses to treatment, and outcomes among 3 groups stratified by EPO levels of <200, 200-500, and >500. Results We identified 1211 LR-MDS patients with established baseline serum EPO, where 1009 pts (83%) had EPO <200, 109 pts (9%) had EPO 200-500, and 93 pts (8%) had EPO >500. Baseline characteristics comparison between the 3 groups demonstrated that pts with >500 EPO were younger (median age 67.5 yrs, p=0.0009), had more severe anemia (mean Hgb level 7.2 g/dl, p<0.001), and were more red blood cell transfusion-dependent (RBC-TD,64.5%, p<0.001). The genomic comparison revealed a statistically significant increase in frequency of EZH2 (20.3%,11%, 5.3%), p<0.001), U2AF1 (35.4%, 29.7%,18.6%),p<0.001), ZRSR2 (30.4%, 8.7%,11.2%), p<0.001), and RUNX1 (20.3%,15.6%, 9.9%), p=0.008) among pts with EPO >500 compared to EPO 200-500 and <200, respectively. Interestingly, we have previously shown that EZH2 and U2AF1 mutations are enriched in pts with Coombs-negative hemolysis in MDS. There was a trend of a higher percentage of pts with lower haptoglobin levels <10 among those with EPO >500 (8.5%) but was also present in those with EPO 200-500, and <200 (6.3%, and 4.1%, respectively). ESA was the first-line treatment among 384 (38%), 58 (53%), and 30 (32%) pts with EPO <200, 200-500, and >500, respectively. The rate of hematological improvement (HI) was 47.5%, 36.2%, and 30% among those 3 groups (p=0.063). Based on RBC-TD at baseline, ESA responses in pts with EPO <200 were 52.2% for RBC-TD vs 31.4% for non-RBC-TD pts. Among pts with EPO 200-500, ESA response was 48.4% for RBC-TD pts vs 22.2% for non-RBC-TD. For pts with EPO >500, the response rate was 38.5% for RBC-TD vs 23.5% for non-RBC-TD pts. Among pts treated with luspatercept (n=80, 21 ESA naïve and 59 ESA treated), the response rate was 42.1% (24/57), 33.3% (5/15), and 0.0% (0/8) by EPO groups (p=0.028). The response rate to luspatercept was 10/21 (47.6%) for ESA naïve and 19/59 (32.2%) in ESA-treated pts. Among pts treated with azacitidine for LR-MDS (n=196), the response rate was 31.1% (46/148), 25% (5/20), and 32.1% (9/28) for the EPO groups, respectively (p=0.84). Finally, among 65 non-del5q LR-MDS pts who received lenalidomide, the HI rates were 22% (4/41), 50% (6/12), and 33.3% (4/12) based on EPO groups. We did not have mature data on imetelstat responses, but it was reported to be similar irrespective of EPO level in clinical trials. There was a trend for higher AML transformation rate among pts with EPO >500,16/93 (17.2%), compared to 11/109 (10.1%) for pts with EPO 200-500, and 130/1009 (12.9%) for those with EPO <200 (p=0.32). There was a non-statistically significant trend for worse overall survival, HR 1.18 (95% CI 0.87-1.159), p=0.28) for EPO >500 compared to <200. The 5-year survival was 58%, 52.5%, and 41.5% for EPO <200, 200-500, and >500, respectively. Conclusions Patients with higher EPO are younger and have more severe anemia with higher rates of RBC-TD. We observed an increased frequency of EZH2, U2AF1, ZRSR2, and RUNX1 mutations amongst patients with EPO >500. The response to ESA and luspatercept is EPO-dependent, while treatment with azacitidine and lenalidomide maintain similar responses across EPO levels.