Cilloni, Daniela

Crasto, Francesca

De Gobbi, Marco

Di Savino, Augusta

Familiari, U.

Gaidano, Valentina

Gottardi, Enrico Marco

Nicoli, Paolo

Palmieri, Antonietta

Papotti, Mauro Giulio

Roetto, Antonella

Saglio, Giuseppe

Scaravaglio, P.

Volpengo, Alessandro

English

DI SAVINO, Augusta

Gottardi, ENRICO MARCO

DE GOBBI, Marco

Institutional Research Information System University of Turin

PostersAzacitidine (AZA) improves long-term outcomes of higher-risk MDSpatients and is now the reference frontline therapy of higher-risk MDSnot eligible for allogeneic stem cell transplant. Anaemia is the most com-mon symptom of MDS and most patients become transfusion-depen-dent with the risk of iron overload. Deferasirox is an orally availableiron chelator administered once-daily in transfusion-dependent patientswith iron overload. We report our experience on using the azacitidinein patients with high-risk MDS, evaluating the efficacy and safety. Con-comitant treatment with deferasirox was performed in a routine clinicalsetting following Consensus Guidelines on Iron Chelation Therapy. Inour Institution from October 2009 to December 2014 we have treated29 elderly patients (19 male and 10 female, median age 76 years, r. 72-88) affected by HIGH-RISK MDS (IPSS INT-2/HIGH). Patients receivedsubcutaneous azacitidine at 75mg/m(2) daily for 7 days every 4 weeks.All patients completed at least 6 cycles of therapy. 11/29 (38%) patientsunderwent more than 8 cycles of therapy. 17/29 patients underwent aswell iron chelation therapy with deferasirox receiving a starting dosageof 10 mg/kg/day, subsequently titrated according to serum ferritin (SF)measured monthly. Complete response (CR), partial response (PR), andhematologic improvement (HI) were observed in 2 (7%), 5 (21%), and11 (38%) patients, respectively. The median number of cycles to clinicalresponse was 4 (range 4-8). The 2-year rate of acute myeloid leukemia-free survival was 48%. Five serious adverse events occurred in five pa-tients with one fatal outcome. 15 out of 18 patients who showed anyhematologic response (CR+PR+HI) meeting International WorkingGroup 2006 criteria had also performed deferasirox therapy. No in-creased toxicity was noted when deferasirox was used concomitantlywith azacitidine. Our results confirm the effectiveness of the therapywith azacitidine in HIGH-RISK MDS elderly patients with acceptabletoxicity profile. Peripheral cytopenias were the most commonly occur-ring adverse event, with gastrointestinal adverse events and injection-site reactions among the most commonly occurring non-haematologicaladverse events. In conclusion, azacitidine is an important agent for usein the treatment of elderly patients with MDS. Furthermore concurrentuse of deferasirox in patients with iron overload seems to significantlyimprove the hematologic response by reducing transfusion requirement. P124DOES G6PD-DEFICIENCY RELATED OXYDATIVE STRESS AND HEMOLYSIS AFFECTERYTHROID RESPONSE TO ERYTHROPOIETIN STIMULATING AGENTS INMYELODYSPLASTIC PATIENTS?F. Pilo, A.A. Di Tucci, I. Tandurella, E. AngelucciUO Ematologia e CTMO Ospedale Oncologico “A. Businco” Cagliari, ItalyBackground: Anemia is the most frequent cytopenia in Myelodysplas-tic Syndrome (MDS). Epoetin a, Epoetin b and Darbepoetin a (ESA)have been investigated in several studies as useful to treat anemia in thiscategory of patients.Available pre-clinical data support oxidative stressand hemolysis contributing to ESA resistance but not clinical data istoday available. G6PD deficiency is an X-linked condition characterizedby a markedly reduced capability to protect red blood cells from oxida-tive stresses. In the island of Sardinia the prevalence is reported to be ashigh as 12%. Patients and Methods:We retrospectively analyzed all MDSpatients who had received ESA in our centre. Diagnosis of MDS wasmade according to WHO criteria. Patients were stratified based on In-ternational Prognostic Scoring System (IPSS). At diagnosis baseline EPOlevel and G6PD quantitative estimation were detected. Red blood cell(RBC) transfusions requirement before starting treatment was evaluated.Erythroid hematologic improvement (HI-E) was evaluated according tothe International Working Group (IWG) response criteria (Cheson et al.JCO 2006). Results: Thirty patients met the above specified criteria. Ofthem 7 were G6PD-defiecient and 23 had normal G6PD level values.Seventeen were male and 13 female, median age was 71 years (range51-96). Twenty patients presented with refractory anemia (RA), 8 re-fractory anemia with ringed sideroblasts (RARS), 2 refractory cytopeniaswith multilineage dysplasia (RMCD). Twenty-four patients were IPSSlow- risk and 6 Intermediate I. At baseline serum EPO level was lessthen 200 IU/L in all patients. Forty percent required RBC transfusion be-fore starting ESA treatments. Twenty patients (80%) achieved an HI-E(14 major and 10 minor). In the G6PD-deficient group HI-E was ob-served in 7 over 7 patients (major in 4 and minor in 3). In the controlgroup HI-E was observed in 17 over 23 patients (major in 10 minor in7). (P=0.29). Conclusions:We evaluated 30 MDS low- risk and Int I IPSSpatients who received ESA in the last 20 years in our centre. Despite thecommon belief that oxidative stress and hemolysis may contribute toESA resistance, no statistically significant difference to potentially re-sistance to ESA treatment in G6PD deficiency have been observed. Weconclude that G6PD-deficiency does not contraindicate the use of ESAin this setting of patients.Table 1. Patients’ characteristics.P125TFR2 AND EpoR EXPRESSION AT DIAGNOSIS AS POSSIBLE PREDICTORS OFERYTHROPOIETIN TREATMENT RESPONSE IN MDS PATIENTSA. Di Savino, U. Familiari, A. Palmieri, F. Crasto, A. Volpengo,P. Scaravaglio, V. Gaidano, P. Nicoli, E. Gottardi, M. Papotti, A. Roetto,G. Saglio, D. Cilloni, M. De GobbiUniversità di Torino, Dipartimento di Scienze Cliniche e Biologiche, Orbassano,TO, ItalyThe myelodysplastic syndromes (MDS) are heterogeneoushematopoietic diseases associated with bone marrow failure, periph-eral cytopenias, and a tendency to progress to acute myeloidleukemia. Anemia and transfusion dependency constitute major prob-lems for MDS patients. Treatment with erythropoiesis stimulatingagents is a first-line treatment for the anemia of most patients withMDS. However not all MDS respond and a majority of patients even-tually relapse with transfusion dependent anemia. Erythropoietin(Epo) is the principal regulator of red blood cell production. Upon Epobinding to its cognate receptor (R), the Epo-R promote the activationof JAK2 and Lyn, which in turn phosphorylate the signal transducerand activator of transcription 5 (STAT5). Dimerization of phospho (P)-STAT5 enables its translocation to the nucleus and binding to targetgene promoters, ultimately promoting the expansion, differentiation,and survival of red blood cell precursors. Transferrin receptor 2 (TFR2)is a second transferrin (Tf) receptor that binds to Tf with a 25-foldlower affinity but acts as an iron sensor regulating hepatic hepcidinproduction. At least 2 alternatively spliced forms of transcripts, a andb, are transcribed from the TFR2 gene. Several recent findings (Fore-jtnikova et al., Blood 2010; Wallace et al., Br J Haematol. 2015; Nai etal., Blood 2015) highlight the interconnection between the hepaticand erythroid functions of TFR2 in regulating iron metabolism anderythropoiesis. Our monocentric and retrospective study aimed toidentify the possible impact of TFR2 and EpoR mRNA expression atdiagnosis in MDS patients. We report the expression pattern of TFR2a, b and EpoR in various subtype of MDS in comparison to normalcontrols and we found heterogeneous expression with a tendency ofTFR2 being less expressed in RAEB-2. Moreover a positive and signif-icant correlation between TFR2 and EpoR expression was seen. Fi-nally, to further assess the clinical implication of the correlationobserved, we analysed the erythroid response in the cohort of patientsthat underwent to Epo treatment and we noticed that only patientswith TFR2 and EpoR levels comparable to normal controls reachedan increase in hemoglobin level of ≥1.5 g/dl after 12 weeks of treat-ment. Taken together, our results provide evidence suggesting TFR2and EpoR as potential molecular markers in predicting at diagnosisthe response of Epo treatment in MDS patients.104 | haematologica| 2015; 100(s3)2015_SIE_ok.qxp_Layout 1  22/09/15  12:36  Pagina 104

TFR2 AND EpoR EXPRESSION AT DIAGNOSIS AS POSSIBLE PREDICTORS OF
ERYTHROPOIETIN TREATMENT RESPONSE IN MDS PATIENTS

https://iris.unito.it/bitstream/2318/1609070/1/Di%20Savino%20Haematol%202015%20Abstract.pdf

TFR2 AND EpoR EXPRESSION AT DIAGNOSIS AS POSSIBLE PREDICTORS OF

ERYTHROPOIETIN TREATMENT RESPONSE IN MDS PATIENTS

TFR2 AND EpoR EXPRESSION AT DIAGNOSIS AS POSSIBLE PREDICTORS OF ERYTHROPOIETIN TREATMENT RESPONSE IN MDS PATIENTS

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