Page 92 - 2019_03-Haematologica-web

S. Park et al.
There were 22 patients with refractory cytopenia with multilineage dysplasia, 19 with refractory cytopenia with unilineage dysplasia, 14 with refractory anemia with ring sideroblasts, four with refractory anemia with excess blasts-1, six with chronic myelomonocytic leukemia, two with del5q- and three with unclassifiable myelodysplastic syndrome. According to the revised International Prognostic Scoring System, 13 had very low risk, 47 had low risk, nine intermediate risk and one had high-risk disease. Twenty patients were transfusion dependent. Forty-eight percent had an erythroid response and the median duration of the response was 26 months. At baseline, non-responders had significantly higher RED scores and lower hepcidin:ferritin ratios. In multivariate analysis, only a RED score >4 (P=0.05) and a hepcidin:ferritin ratio <9 (P=0.02) were statistically significantly associ- ated with worse erythroid response. The median response duration was shorter in patients with growth-differentiation factor-15 >2000 pg/mL and a hepcidin:ferritin ratio <9 (P=0.0008 and P=0.01, respectively). In multivariate analysis, both variables were associated with shorter response duration. Erythroid response to epoetin zeta was similar to that obtained with other erythropoiesis-stimulating agents and was correlated with higher baseline hepcidin:ferritin ratio and lower RED score. ClinicalTrials.gov registration: NCT 03598582.
Introduction
Myelodysplastic syndromes (MDS) are acquired, neo- plastic disorders of hematopoietic stem cells characterized by ineffective and dysplastic myeloid cell differentiation, in particular dyserythropoiesis leading to anemia in more than 80% of cases.1 The main prognostic factors in MDS, which define the risk of MDS progression to acute myeloid leukemia and patients’ survival, include the num- ber and importance of cytopenias as well as the percent- age of bone marrow blasts and the cytogenetic abnormal- ities. These factors are combined in a recently revised International Prognostic Scoring System (IPSS-R).2
For lower-risk MDS, essentially characterized by ane- mia related to ineffective erythropoiesis, first-line treat- ments generally include (in the absence of the 5q chromo- somal deletion) erythropoiesis-stimulating agents (ESA) (mainly epoetins and darbepoetin) with or without granu- locyte - colony - stimulating factors to improve anemia. Subsequent treatments include lenalidomide, hypomethy- lating agents, luspatercept and other investigational drugs (APG-101, imetelstat, etc.).
The response rate to ESA according to International Working Group 2006 criteria [i.e. erythroid hematologic improvement (HI-E), including red blood cell (RBC) trans- fusion independence or an increase of hemoglobin level >1.5 g/dL] is approximately 50% for patients with favor- able prognostic factors, with a median response duration of 20 to 24 months. Our results, confirmed by other groups, suggest that this treatment does not increase the risk of transformation into acute myeloid leukemia and improves overall survival.3,4
Known prognostic factors for a favorable response to ESA in MDS patients include early stage disease, serum erythropoietin (sEPO) levels below 500 U/L and no or low requirement for RBC transfusion,5 while trilineage dyspla- sia may be associated with a lower response rate to ESA and/or shorter duration of response.6 We also found that a score based on IPSS-R, serum ferritin level and sEPO con- centration can efficiently predict the response,7 while patients with mutations in at least three genes have a lower response rate.8 The mechanisms of primary resist- ance or loss of response are unknown. Relapse may be explained in only 25% to 30% of patients by a detectable progression of MDS with, as shown by worsening of
cytopenias other than anemia, increasing numbers of bone marrow blasts or frank progression to acute myeloid leukemia. Biomarkers of ineffective erythropoiesis may, therefore, help to predict the response to ESA.
Over the past 20 years, new approaches in multipara- meter flow cytometry have contributed to the diagnosis of MDS by quantifying myeloblasts, hematogones and dys- granulopoiesis using the Ogata score.9-13 However, few studies have specifically addressed the late stages of ery- throid differentiation.10,14 The flow cytometry RED score10 was developed as a whole bone marrow flow cytometry protocol using the nuclear dye CyTRAK orange to gate nucleated cells without lysing red blood cells. The RED score is based on the evaluation of dyserythropoiesis with CD71 and CD36 coefficient of variation values and hemo- globin levels according to gender. It ranges from 0 to 7, with a RED score ≥3 predicting MDS with a sensitivity of 77.5% and a specificity of 90%. By combining the RED and the Ogata scores, the sensitivity can reach 87.9% and the specificity 88.9%.10 Interestingly, ineffective erythro- poiesis has been correlated with high levels of serum growth differentiation factor-15 (GDF-15), a member of the transforming growth factor-b superfamily that is pro- duced by erythroid precursors at the end of the differenti- ation process.15,16
Upon chronic RBC transfusions, patients with lower- risk MDS may develop iron overload. A greater insight into iron homeostasis in MDS patients can be obtained by monitoring specific markers of iron metabolism including hepcidin, in correlation with ferritin and levels of transfer- rin saturation.
In this trial, we aimed to find biomarkers predicting response to epoetin zeta in patients with lower-risk MDS and to use these to evaluate the efficacy of a biosimilar drug to epoetin alfa in such patients.
Methods
Patients and study design
Eligibility criteria for inclusion in the study were: (i) a diagnosis of MDS according to the World Health Organization (WHO) 2008 criteria [refractory anemia (RA), refractory anemia with ring sideroblasts (RARS), refractory cytopenia with multilineage dys- plasia (RCMD), refractory cytopenia with unilineage dysplasia
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haematologica | 2019; 104(3)