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% . though high levels of endogenous erythropoietin ( > 500  /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 . patients with mds have multiple somatically acquired genetic abnormalities leading to gene expression defect including deregulation of cytokine signaling pathways [ 36 ] . in rheumatoid arthritis ( ra ) , a similar repertoire of deranged cytokines is responsible for chronic inflammation . 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- level . we hypothesize that the use of ssris in patients with mds has the potential to modulate manifestations of this disease through similar effects on cytokine derangements . here , we report a case of sequential reversal of esa refractoriness , transfusion and growth factor dependence in a patient with lr - mds who received sertraline for treatment of underlying depression . 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 ) . erythroid and megakaryocytic dysplasia with a myeloid : erythroid ( m : e ) ratio of 10:1 consistent with rcmd by who 2008 classification was detected ( fig . 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 [ 7  g / dl]=1.5 ; platelets [ 135,000/l]=0 ; anc[1500/l]=0 ] . iu / l and 1600  ng / 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 . the patient initially received 40,000  iu of subcutaneous ( sq ) r - h - epo per week . in view of his co - morbid major depressive disorder , he was initiated on sertraline at 100  mg orally daily on week ( w ) 8 of treatment . clinical response to esa therapy 2 ) , 480  mcg of sq g - csf 5 times a week was added due to esa refractoriness ( esa+g - csf schedule ) ( w12w26 ) . 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 . sequential resolution of esa dependence was observed from w37 to w90 . over the entire treatment period , 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 10.4  g / 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 70.3 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 . our case demonstrates feasibility for improvement in erythropoiesis in a patient with poor predictor of esa / g - csf response / growth factor refractory , low - risk mds who was treated with sertraline for co - morbid depression . within 100 days concurrent administration of sertraline , esa and g - csf , the patient experienced resolution of transfusion dependence . in addition , sensitivity to endogenous epo was demonstrated with rise in hemoglobin by more than 4 points and fall in endogenous epo levels from 449  iu / l to 70.3  iu / l . to the best of our knowledge , this is the first description of a potential therapeutic role for ssris in patients with mds . mds is clinically heterogeneous with a variable risk aml progression , an observation that can be partially explained by the underlying genetic heterogeneity among patients . gene expression profiling of patients with early mds has identified multiple derangements in cell signaling pathways , including immunoregulation , apoptosis , and chemokine secretion . abnormal levels of pro - inflammatory cytokines such as il-12 , il-7 , ifn- , and rantes have been observed in marrow samples from these patients . these changes were associated with an increased number of inflammatory cd3 + cd4 + th17 cells , leading to amplification in marrow apoptotic signaling and resulting in ineffective hematopoiesis and eventual marrow failure . recent work found higher levels of pro - inflammatory cytokines such as il-2 , il-12 , and tnf- and lower levels of anti - inflammatory cytokines such as il-4 in patients with major depressive disorder as compared to normal controls . an 8-week course of sertraline treatment resulted in an objective improvement in depression as well as normalization of many of the cytokine derangements . serotonin is known to have diverse immunoregulatory actions including activation of helper t cells , enhancement of nk cell activity , and induction of b - cell proliferation ; thus the anti - inflammatory effect of ssri treatment are likely directly related to their modulation of inflammatory process . these effects of ssri treatment have been explored in relation to other related disease processes , namely rheumatoid arthritis , a state of chronic inflammation . in a recent study , the use of sertraline showed a significant reduction in clinical arthritis in a mouse model accompanied by a measured decrease in tnf- serum levels . our case leads us to hypothesize that the anti - inflammatory effect of sertraline could similarly be used to modulate the immune dysfunction proposed to underlie mds , thus resolving cytokine derangements , normalizing the pro - inflammatory t - cell environment in the bone marrow , and improving ineffective hematopoiesis . , g - csf was added after sertraline prior to the development of transfusion independence in our patient . though sertraline may have a synergistic effect in combination with growth factors , this may affect our ability to assign an independent role to ssris in the eventual achievement of hemoglobin stabilization . another limitation is the delayed six month time course required to see hemoglobin stabilization in our patient , though earlier administration of g - csf in combination with sertraline and esa may have allowed this effect to occur more quickly . in addition , given our patient high m : e ratio , atypical cml should be considered within differential diagnosis . further studies are needed to elucidate the specific immunologic mechanisms that underpin the pathophysiology of mds . in addition , retrospective cohort studies and eventually , prospective clinical trials are necessary to validate these therapeutic possibilities for patients with and without growth factor refractory lr - mds .
refractoriness to growth factor therapy is commonly associated with inferior outcome in patients with low - risk myelodysplastic syndrome ( lr - mds ) who require treatment for cytopenias . 
 however , the mechanisms leading to refractoriness are unknown . here 
 we describe a clinically depressed 74-year - old male with refractory cytopenia with multilineage dysplasia ( rcmd ) and documented growth factor refractory anemia after erythropoeisis stimulating agent ( esa ) therapy , who attained transfusion and growth factor independence after the addition of sertraline to his medication regimen . 
 our case demonstrates hematological improvement - erythroid ( hi - e ) in growth factor refractory , low risk mds and highlights a potential mechanistic link between common inflammatory diseases and lr - mds .