AMG-900 Introduction Myelodysplastic Syndrome MDS is a

Introduction Myelodysplastic Syndrome (MDS) is a heterogeneous clonal disorder characterized by ineffective hematopoeisis and propensity for transformation into Acute Myelogenous Leukemia (AML). The Revised International Prognostic Scoring System (R-IPSS) is an accepted model used to predict overall survival and the risk of AML progression. Those with a lower risk R-IPSS score are treated supportively with ESAs, granulocyte colony stimulating factor (G-CSF), and transfusions as necessary. However, even when given in combination, response for growth factors remain approximately 35% [1]. Though high levels of endogenous erythropoietin (>500µ/ml), an increased proportion of blast, and a high transfusion requirement are associated with a poor ESA response, the subsequent treatment of cytopenias refractory to growth factor therapy remains largely unexplored, thus highlighting the need for novel therapies to restore transfusion independence [2]. Patients with MDS have multiple somatically acquired genetic abnormalities leading to gene AMG-900 defect including deregulation of cytokine signaling pathways [3–6]. In rheumatoid arthritis (RA), a similar repertoire of deranged cytokines is responsible for chronic inflammation [7,8]. Patients with RA often also suffer from major depressive disorder, and interestingly, Selective Serotonin Reuptake Inhibitors (SSRIs) prescribed for these patients׳ depression have been proposed to modulate their co-morbid rheumatoid arthritis due to the pleiotropic effects on cytokine pathways. Indeed, sertraline was recently shown to result in a significant reduction in clinical arthritis in a mouse model accompanied by a measured decrease in serum TNF-α level [8].
Case report A 74-year male was seen in our clinic with an 18-month history of transfusion dependent refractory anemia (8 units RBC in 8 weeks). His bone marrow biopsy showed no blasts or ring sideroblast. Erythroid and megakaryocytic dysplasia with a myeloid: erythroid (M:E) ratio of 10:1 consistent with RCMD by WHO 2008 classification was detected (Fig. 1A). Standard G-band karyotyping revealed 45, X,-Y in 4 of 20 metaphases analyzed. His resultant R-IPSS score was 1.5 [Cytogenetic=0; blast %=0; Hb [7g/dL]=1.5; Platelets [135,000/µL]=0; ANC[1500/µL]=0]. Initial erythropoietin (EPO) and ferritin levels were 449IU/L and 1600NG/ML, respectively. With these baseline characteristics, his predicted likelihood of response to EPO therapy was 23% based on a currently validated model for patients with LR-MDS [9]. The patient initially received 40,000IU of subcutaneous (SQ) R-H-EPO per week. In view of his co-morbid major depressive disorder, he was initiated on sertraline at 100mg orally daily on week (W) 8 of treatment. Clinical response to ESA therapy was assessed according to internal working group (IWG) 2000 criteria. After 3 months of weekly SQ R-H-EPO W1-W12 (Fig. 2), 480mcg of SQ G-CSF 5 times a week was added due to ESA refractoriness (ESA+G-CSF schedule) (W12–W26). Transfusion independence was observed by W23 of combined R-H-EPO+G-CSF with concurrent sertraline (Fig. 2). Progressive hemoglobin stabilization then resulted in G-CSF dose reduction to twice a week from W28 to W37 (Fig. 2). Sequential resolution of ESA dependence was observed from W37 to W90. Over the entire treatment period, the absolute increase in Hb level was 4.2g/dL from baseline. Restoration of ESA erythroid response to exogenous EPO was observed by W26–W37. Improved Hb levels were maintained after G-CSF discontinuation (W37) and ESA dose de-escalation/cessation while on sertraline treatment. To date, the patient has remained on single agent sertraline for 11 months with median hemoglobin values of 10.4g/dL (Fig. 2). His most recent EPO level, measured more than 32 months from the start of therapy and nearly a year after ceasing EPO injections was 70.3IU/L. His bone marrow evaluation 12 weeks after ESA discontinuation (W120) showed trilineage hematopoeisis, mild erythroid dysplasia and M:E normalization with a ratio of 2:1 (Fig. 1B).