A. Di Veroli, Bellis ED, Rossi V, Biagi A, Rapisarda V, Maurillo L, Principe MID, Voso MT, Journal of Venditti A, Buccisano F. J Rare Dis Res Treat. (2017) 2(6): 41-44 Rare Diseases Research www.rarediseasesjournal.com & Treatment

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Clinical use of ESAs in Low-Risk Myelodysplastic Syndromes Ambra Di Veroli1, Eleonora De Bellis1, Valentina Rossi1, Annalisa Biagi1, Vito Rapisarda1, Luca Maurillo1, Maria Ilaria Del Principe1, Maria Teresa Voso1, Adriano Venditti1 and Francesco Buccisano1 1Hematology, Department of Biomedicine and Prevention, Tor Vergata University, Rome, Italy

Article Info Introduction Article Notes Myelodysplastic syndromes (MDS) are a heterogeneous group Received: July 27, 2017 of clonal hematological diseases characterized by ineffective Accepted: October 21, 2017 maturation of blood cells progenitors. The incidence of MDS is *Correspondence: Dr. Ambra Di Veroli, MD Ematologia, Dipartimento di Biomedicina e Prevenzione the years and the lack of an systematic registration of patients. Università di Roma Tor Vergata Adifficult recent to publication assess because based of onthe thechange SEER of databasediagnostic suggests criteria overthat Via Montpellier 1 –00133 Rome, Italy the incidence of MDS is as high as 75 per 100,000 persons aged Tel: +39 06 20903228 Fax:+390620903221; Email: [email protected] predominantly a disease of the elderly and have a higher incidence ≥65 years. Available data consistently suggest that MDS are © 2017 A. Di Veroli. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License. among white male people; approximately 86% of patients1. The impairment with MDS ofwere hematopoietic aged ≥60 years bone at marrow diagnosis function (median determines age, 76 years), variable and grades only of6% peripheral of cases were cytopenias diagnosed and in patientsa propensity ≤50 years to evolve into acute myeloid leukemia (AML). Prognosis is poor for patients with MDS,

with 3-year survival rates estimated at less than 50%. Anemia duringis observed clinical in course. approximately In low-risk 70% MDS, of MDSanemia patients is the major at diagnosis, clinical leading to a relevant transfusion dependence in >80% of patients more than other cytopenias, is associated with an increase risk of transfusion–relatedproblem and may give complications, rise to significant alloimmunization, morbidity. This iron condition, overload,

For these reasons one of the major goal of MDS treatment is the improvementcardiac failure of and anemia a significant with the impairment aim of avoiding of quality or delaying of life chronic (QoL). transfusional support. Erythropoiesis stimulating factors (ESAs), alone or in combination with other grow factors, are indicated to treat anemia in low risk MDS and widely used in this setting with

results of ESAs therapy in treating anemia in low risk MDS patients andencouraging their impact results. on the In naturalthis paper course we ofwill the briefly disease. review the main Pathogenesis of Anemia in Mds Pathogenesis of MDS is a multistep process occurring at level of totipotent hemopoietic stem cells (HSC). Several factors may contribute to ineffective hematopoiesis in MDS: 1) an abnormal activation of proapoptotic signals in progenitor cells; 2) a disregulation of signal transduction causing an excess of

cells; 3) a limited responsiveness to erythroid-stimulating growth factorsproinflammatory2-67,8. Different cytokines studies andhave an beenaltered conducted immune responseson erythroid in T progenitors (Erythroid colony forming units-CFU-E and Erythroid

Page 41 of 44 A. Di Veroli, Bellis ED, Rossi V, Biagi A, Rapisarda V, Maurillo L, Principe MID, Voso MT, Journal of Rare Diseases Research & Treatment Venditti A, Buccisano F. J Rare Dis Res Treat. (2017) 2(6): 41-44 burst-forming units-BFU-E) to explain the pathogenesis Table 1. of anemia. It is well known that erythroid progenitors of Study Most significant ESAs studiesN°pts in low risk MDS.ORR MDS patients show an altered formation of CFU-E and Rossi Ferrini, P.R (1998) 87 36% 9 BFU-E in response to endogenous EPO , and a profound Terpos, E.(2002) 281 45·1% alteration of other functional parameters such as EPO- Park, S. (2008) 403 50% dependent DNA synthesis and induction of GATA-1 binding Golshayan AR (2007) 1587 39·5% activity10. Moreover a correlation was observed between Jädersten, M (2008) 121 39% a STAT5defective activation after EPO stimulation (with conserved STAT5 phosphorylation upon stimulation Table 1 summarizes the most important ESAs studies in with IL3) and a block in the EPO signal transduction pathway at an early stage of erythroid development9. Furthermore, dyserythropoiesis has been directly linked MDS. There is general agreement that ESAs have a 40%– to greater expression of proapoptotic molecules as the low50% risk response MDS rate,with ina termsmedian of duration erythroid of hematological response of transmembrane mediator of apoptotic cell death Fas/CD95 approximatelyimprovement as2 years defined21. There by IWG is no response difference criteria, between in in the glycophorin A subpopulation11. In the last decades different ESAs formulations. Current guidelines developed the application of sophisticated genetic and molecular by the National Comprehensive Cancer Network22, tools at diagnosis and at progression have allowed European LeukemiaNet (ELN)23, and European Society for to better understanding the pathogenesis of anemia. Medical Oncology (ESMO)23 are generally consistent with Cytogenetic and molecular analyses have demonstrated that both normal and malignant precursor erythroid cells MDS. Pre-emptive treatment of asymptomatic patients are stimulated by cytokine therapy. More recently the role isthe not management recommended of patients and treatment with lower-risk should be non-del(5q) reserved of Ten-Eleven-Translocation 2 and 3 (TET2 and TET3) genes for those with symptomatic anemia. In addition there is in human erythropoiesis has been demonstrated, opening a limited role for addition of G-CSF based on data from a a new scenario in understanding this phenomenon in randomized phase 3 study that evaluated the role of G-CSF MDS. TET2 encodes a member of TET family enzymes and found no difference between EPO versus EPO plus that alters the epigenetic status of DNA by oxidizing G-CSF25 5-methylcytosine to 5-hydroxymethylcytosine (5hmC). as which patients are the ideal candidates to treatment and . However, many issues still need to be clarified, such TET3 encodes a dioxygenase that catalyzes the conversion which is the best schedule available. Predictive Models of ESAs Response into 5-hydroxymethylcytosine (5hmC) and plays a key role It has become increasingly evident that treatment with of the modified genomic base 5-methylcytosine12 (5mC) in reprogramming epigenetic chromatin . Knockdown r-Hu-EPO should become “patient oriented” and different experiments have demonstrated that suppression of types, schedules, and duration of treatment have to be TET3 in CD34+ cells markedly impaired terminal eythroid likely predict, for each individual patient, the best chance effect on erytrhoid progenitors. TET2 knockdown led designed according to the specific criteria which most differentiation as reflected by increased apoptosis without to hyperproliferation and impaired differentiation of Hellström-Lindberg and al.13, included 94 patients across 12 erythroid progenitors . threeof response. ESA studies The firstto determine predictive predictors model, developed of response by Clinical Use of ESAs to a combination of ESAs and G-CSF. The model was able Given the normal presence of EPO receptors on to discriminate 3 classes of patients with a probability progenitor cells in MDS patients, erythropoiesis stimulating agents (ESAs) may represent an useful tool to overcome Patients with low transfusion needs (< 2 units packed the maturation arrest and restore a normal red blood redof response blood cell to ESAstransfusions of 94%, [pRBC]17%, and monthly) 11%, respectively. and a low cells production. ESAs treatment has been demonstrated baseline serum erythropoietin level (less than 500 IU) in clinical trials to substantially reduce or eliminate with erythropoietin and darbepoetin alfa in low-risk MDS andhad a a high 74% serum chance erythropoietin of responding level to (> ESAs, 500 IU) while had those only transfusion need in roughly 60% of the patients. Studies with high transfusion needs (≥ 2 units pRBC per month) asidentified International transfusion Working independence Group criteria: as major significant erythroid for werea 7% reported:chance of lowresponding. IPSS score, Further baseline studies haemoglobin, have tried noto QOL and showed primarily erythroid responses defined excessrefine thisof blasts predictive in bone model. marrow, Other iron predictors status ofat responsebaseline, granulocyteshematological13-19 improvement.Recombinant in 29%-47%Human (HI-E)Erythropoietin and minor subtypes RA (refractory anemia) and RARS (RA with ring (R-Hu-EPO)HI-E in 26%-30% alpha withoutand darbepoetinalpha improvements inare platelets the more or sideroblasts)WHO classification, and ESA karyotype,‐naïve at baseline hypoplastic. A bone model marrow, based 20. on IPSS-R score, serum EPO, and serum26,29 ferritin level may frequently used ESAs for the treatment of anemia in MDS Page 42 of 44 A. Di Veroli, Bellis ED, Rossi V, Biagi A, Rapisarda V, Maurillo L, Principe MID, Voso MT, Journal of Rare Diseases Research & Treatment Venditti A, Buccisano F. J Rare Dis Res Treat. (2017) 2(6): 41-44 provide additional value in predicting the response to ESAs27. In multivariate analysis, IPSS-R score, serum EPO, correctthese results decision an makingaccurate process. prognostic Even classification if an improvement of MDS of OSpatient in low at risk diagnosis MDS patients is a fundamental treated with prerequisiteESAs is reported, of a and serum ferritin level were significantly associated with suggesting a potential role as a disease modifying agent, dateerythroid transfusion response need, (from the 85% percentage response of inbone IPSS-R marrow Very blastsLow-risk and patients EPO serum to 31%level seems in Very to High-risk be the major patients). variables To able to predict response to ESAs in low risk MDS patients30. darbopoietindefinitive data have are beenstill lacking. reported, No but substantial no studies differences of direct For these reasons, other studies are ongoing to improve the comparisonof efficacy have or safety been conducted. between r-Hu-EpoThe optimal alpha dosage and existing predictive models of ESAs response. varies from 40.000 IU to 80.000 IU per week of r-Hu- Epo alpha corresponding to 150 to 300 of darbopoietin. Recently a new predictive score named ITACA, that Treatment should be administered at least for 12 weeks before response evaluation. ESAs are generally well tolerated and, even if they could expand red blood mass, an lifebetter Italian identifies and Canadian ESAs non-responders, ‘good risk’ MDS has patients been developed derived increased thromboembolic risk has not been demonstrated. fromITACA a scorelarge hasinternational been validated dataset, in considers a cohort oftransfusion 996 real- In conclusion, in the last decade ESAs therapeutic approach independence, erythropoietin level <100 IU/L and IPSS have dramatically changed the natural history of low risk low-risk as independently predictive factors of response31. MDS patients. However, prospective randomized trials are warranted to clarify critical issues such as clinical or the aberrant phenotype on bone marrow precursors as biological features predictive of response, the best timing stronglyMoreover, associated flow cytometry with no responders analysis have to ESAs been32-33 evaluated. and schedule to administer the treatment and the impact on survival. Safety of ESAs Treatment ESAs therapy in low risk MDS patients is generally References 1. Xiaomei Ma, PhD. Epidemiology of Myelodysplastic Syndromes. with ESAs therapy are vascular events as thrombosis Am J Med. 2012 Jul; 125(7 Suppl): S2–S5. doi: amjmed.2012.04.014 andsafe. hypertension The most frequentbut these adverse events have events been associated almost 10.1016/j. exclusively observed in solid cancer34. The American 2. Marcondes AM, Mhyre AJ, Stirewalt DL, et al. Dysregulation of IL-32 in myelodysplastic syndrome and chronic myelomonocytic leukemia Society of Clinical Oncology and Hematology recommend modulates apoptosis and impairs NK function. Proc Natl Acad Sci USA. caution when using ESAs with chemotherapeutic agents in diseases associated with increased risk of 3. 2008;Kordasti 105: SY, 2865-70. Afzali B, Lim Z, et al. IL-17-producing CD4(+) T cells, thromboembolic complications. Randomized clinical trials and systematic reviews demonstrate an increased risk of pro-inflammatory cytokines and apoptosis are increased in low risk thromboembolism in cancer patients receiving epoetin or 4. myelodysplasticBenesch M, Platzbecker syndrome. U, BrWard J Haematol. 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