Calvaruso, G

Campisi, S

Capra, M

Caruso, V

Ciancio, A

Cianciulli, P

Cuccia, L

Di Maggio, R

D’Ascola, G

Filosa,A

Gagliardotto, F

Gerardi, C

Lucania, G

Maggio, A

Pantalone, GR

Pitrolo, L

Prossomariti, L

Rigano, P.

Rizzo, M

VITRANO, Angela

Archivio istituzionale della ricerca - Università di Palermo

Long-term use of deferiprone significantly enhancesleft-ventricular ejection function in thalassemia major patientsAurelio Maggio,1* Angela Vitrano,2 Gaetano Lucania,3Marcello Capra,4 Liana Cuccia,4Francesco Gagliardotto,4 Lorella Pitrolo,5 Luciano Prossomariti,6 Aldo Filosa,7Vincenzo Caruso,8 Calogera Gerardi,9 Saveria Campisi,10 Paolo Cianciulli,11Michele Rizzo,12Giuseppe D’Ascola,13 Angela Ciancio,14 Rosario Di Maggio,15 Giuseppina Calvaruso,1Gaetano Restivo Pantalone,1 and Paolo Rigano1A multicenter randomized open-label long-term sequential deferi-prone–deferoxamine (DFP-DFO) versus DFP alone trial (sequentialDFP-DFO) performed in patients with thalassemia major (TM) was ret-rospectively reanalyzed to assess the variation in the left ventricularejection fraction (LVEF) [1].Serial observations of LVEF over 3 years, in the same patient, were retro-spectively assessed in 99 patients with TM during the sequential DFP-DFOmulticenter randomized open-label trial [1]. A generalized estimating equa-tion (GEE) model was used to demonstrate changes in mean LVEF overtime [2].The regression coefﬁcient of treatment suggested that the DFP-alonegroup showed a statistically signiﬁcant increase in mean LVEF over time(coefﬁcient 0.97, 95% CI (0.51; 1.44), P-value <0.0001).These ﬁndings suggest that long-term treatment with DFP-alone can sig-niﬁcantly enhance LVEF over time. These ﬁndings agree with a survivalanalysis reporting a substantial decline in cardiac deaths during recentyears, related to the switching of high-risk patients from DFO to chelationregimens that include the oral chelator DFP [3–5].Oral chelation treatment has improved greatly adherence and manage-ment of patients with TM [6,7].The improvement of the LVEF after 1-year DFP treatment has beenreported [8–11].However, the effects of DFP on LVEF after long-term treatment have notbeen fully investigated.This letter reports a retrospective survey performed on patients withTM, previously enrolled in a long-term randomized open-label trial carry-ing ahead in Italy on the behalf of the Italian Society for the Study ofThalassaemia and Haemoglobinopathies (SoSTE) [1]. Ninety-nine out of213 patients enrolled in the sequential DFP-DFO trial underwent long-term echocardiographic study of LVEF measured at baseline and every12 months over three consecutive years (Fig. 1). Among these, 39 and60 received sequential DFP (75 mg/kg for 4 days/week)–DFO (50 mg/kgfor 3 days/week) or DFP-alone (75 mg/kg for 7 days/week) treatment,respectively (Table I).The hematological and clinical ﬁndings at enrollment are shown in Table I.No differences were observed at baseline between the two randomizedgroups. Particularly, the main ﬁndings of body iron overloading, expressedas serum ferritin at baseline, liver iron concentration (LIC), baseline LVEF<55%, and total number of blood transfusions were not statistically signiﬁ-cantly different (Table I). Moreover, although baseline LVEF appears unlikebetween the two groups (Fig. 1), this was not statistically signiﬁcantly differ-ent (P-value 5 0.10, Table I).The DFP-alone group showed statistically signiﬁcant increase over time inmean LVEF in comparison with sequential DFO-FP treatment (coefﬁcient0.97, 95% CI (0.51; 1.44), P-value <0.0001).Furthermore, the regression coefﬁcient of treatment suggested that therewas a statistically signiﬁcant difference in mean LVEF between the twotreated groups favoring the sequential group (coefﬁcient 2.36, 95% CI (0.02;4.71), P-value 5 0.047, but this last treatment did not show a statisticallysigniﬁcant variation of mean LVEF over time (coefﬁcient 20.34, 95% CI(21.09; 0.39), P-value 5 0.359). These ﬁndings suggest that DFP-alonetreatment signiﬁcantly improves LVEF over time.As it is well known, the main cause of death in patients with TM remainsmechanical and electrophysiological myocardial dysfunction, the incidence ofwhich ranges from 11.4% to 15.1% [12].Several survival analyses have suggested a substantial decline in cardiacdeaths over recent years, which are related to the tendency to switch high-risk patients from subcutaneous DFO to chelation regimens that include theoral chelator DFP [3,4].Pennell et al. [9] suggested that, during an RCT of over 1 year, in a com-parison of DFO to DFP, LVEF increased signiﬁcantly in the DFP-treatedgroup (3.1% vs. 0.3% absolute units; P 5 0.003) whilst DFP in combinationwith DFO raised absolute LVEF by 2.6% [10]. Moreover, Pennel et al. [11]showed that these changes in LVEF (3.1% vs. 2.6%), measured by cardiacmagnetic resonance (CMR) during DFP-alone or combination, were associ-ated with risk reduction for development of heart failure over 12 months of46.4% or 25.5%, respectively.However, although the use of CMR is spreading [13], its availability is sofar limited, constituting worldwide for many centers, where thalassemia iscommon, one of the main crucial issue for the right management of patientsFigure 1. Estimated proﬁles from the ﬁtted GEE model for the DFP-alone groupand the sequential DFP-DFO group. [Color ﬁgure can be viewed in the onlineissue, which is available at wileyonlinelibrary.com.]TABLE I. Baseline Findings in the 99 Patients Included in the RetrospectiveCohort StudyFindings DFP group Sequential group P-valueNo. patients (99) 60 39Females (%) 22 (36.66) 21 (53.84) 0.25Age in years 31 ± 7.52 31 ± 8.66 0.96Hgb, (g/L) 9.24 ± 0.87 9.32 ± 0.68 0.78ALT, (IU/L) 49.73 ± 37.88 38.27 ± 45.97 0.43LIC, mg/g/dw 2946.03 ± 2026.56 2351.08 ± 2234.03 0.38Total blood transfusion,mL/kg/year8716.172 ± 2111.04 8268.02 ± 2561.87 0.34Mean ferritin, mg/L 1664.21 ± 846.62 1717.54 ± 497.79 0.84Baseline LVEF<55% (n)52 ± 2.19 (6) 50.66 ± 3.05 (3) 0.47Baseline LVEF 59.25 ± 4.25 60.89 ± 5.78 0.10Mean starting ageof DFO, years5.75 ± 4.34 5.03 ± 4.61 0.46Splenectomy (%) 33(55) 27 (69.23) 0.26Cirrhosis (%) 54 (90.00) 38 (97.43) 0.16Arrhythmia (%) 49 (81.66) 35 (89.74) 0.31HCV-RNA positive (%) 42 (70.00) 30 (76.92) 0.51letters732 American Journal of Hematologywith TM [14]. Instead, worldwide availability of echocardiography is surelygreater. Furthermore, several recent studies have shown the excellent inter-observer and intraobserver reproducibility of echocardiographic evaluationon LVEF [15,16]. This has been evaluated as similar to that of cardiac mag-netic resonance (CMR), even in patients with TM [17]. Finally, Otterstadet al. [18] suggested that 2-D echocardiography measurements of LVEF ismore accurate and reproducible if the determination is performed, as in ourstudy, by single operator.The most likely explanation for the improvement in LVEF function usingDFP could be due to its cardioprotective effect on mitochondrial function asit was suggested in cultured, iron-loaded heart cells, even at concentrationsbelow the iron-mobilizing effect [19], although, the exact mechanism of thiseffect remains unknown [11].In conclusion, this retrospective survey of the sequential DFP-DFO trialdata suggests that the long-term administration of DFP signiﬁcantly enhan-ces LVEF over time, as determined by echocardiography. However, becauseof limitations related to the design of this study, these ﬁndings should beconﬁrmed in a prospective randomized clinical trial.MethodsEcocardiographic measurement of LVEF. LVEF was measured by singleoperator with echocardiography by dividing the stroke volume by the end-diastolicvolume in each patient (Vivid S5, Gems Ultrasound, Tirat Carmel, Israel).Statistical analysis. The GEEs [2] model was used to evaluate possiblechanges in mean LVEF over time between the sequential DFP-DFO treat-ment and the treatment with DFP alone. This approach was implemented inthe ‘‘xtgee’’ procedure presented as part of the Stata 11 software (Stata-Corp, College Station, TX). All of the statistical analyses were performed atthe Department of Mathematical and Statistical Science ‘S. Vianelli’, Univer-sity of Palermo (Italy).Authors ContributionsAM was the principal investigator and takes primary responsibility for thispaper. Patients were recruited and treated in 25 centers of the Italian Soci-ety for the Study of Thalassaemia and Haemoglobinopathies (SosTE). AM,AV, and GL wrote the paper. AV performed the statistical analysis. Theauthor reported no potential conﬂict of interest.AcknowledgmentsAuthors are grateful for their support to Dr. C. Argento, Dr. R. Barone, Dr.G Colletta, Dr. F.V. Commendatore, Dr. C. Fidone, Dr. M.C. Galati, Dr. R.Giugno, Dr. A Quota, Dr. M.A. Romeo. They also thank the patients whoparticipated in this study. The support of Foundation Franco and PieraCutino was greatly appreciated.1U.O.C. Ematologia II con Talassemia, Ospedali Riuniti P.O. Cervello Palermo,Palermo, Italy; 2Department of Mathematical and Statistical Science ‘S. Vianelli’,University of Palermo, Palermo, Italy; 3U.O. Medicina Trasfusionale OspedaliRiuniti P.O. Cervello Palermo, Palermo, Italy; 4U.O.C. Centro di PrevenzioneDiagnosi e Cura della Talassemia, ARNAS Civico, Di Cristina, Benfratelli, Palermo,Italy; 5Pediatria II, Ospedali Riuniti P.O. Villa Soﬁa, Palermo, Italy; 6CentroRegionale per la Cura delle Microcitemie, A.O. Cardarelli, Napoli, Italy; 7U.O.C.Pediatria A.O. Cardarelli, Napoli, Italy; 8Unita` Operativa DipartimentaleTalassemia, P.O. S. Luigi-Curro, ARNAS Garibaldi, Catania, Italy; 9U.O.S.Talassemia, A.O.O.C.R. Sciacca, Italy; 10U.O.S. Centro Microcitemia, A.O.Umberto I, Siracusa, Italy; 11U.O. Talassemia, A.O. S. Eugenio, Roma, Italy;12U.O.C. Ematologia, A.O. S. Elia, Caltanissetta, Italy; 13Centro Microcitemia, A.O.B.M.M., Reggio Calabria, Italy; 14Ospedale Civile Madonna delle Grazie, U.O.Talassemia , Matera, Italy; 15Cattedra di Ematologia con trapianto A.O.U.P PaoloGiaccone Palermo, Palermo, Italy;Grant sponsor: Foundation Franco, Piera Cutino*Correspondence to: Aurelio Maggio, U.O.C. ‘‘Ematologia II con Talassemia’’, A.O.‘‘V. Cervello’’, Via Trabucco,180 90146 Palermo, Italy.E-mail: aurelio.maggio@ospedaliriunitipalermo.itConﬂict of interest: Nothing to report.Published online 4 April 2012 in Wiley Online Library(wileyonlinelibrary.com).DOI: 10.1002/ajh.23219References1. Maggio A, Vitrano A, Capra M, et al. Long-term sequential deferiprone-defer-oxamine versus deferiprone alone for thalassaemia major patients: A random-ized clinical trial. Br J Haematol 2009;145:245–254.2. Hedeker D, Gibbons RD. Longitudinal data analysis. Hoboken, New Jersey:Wiley; 2006.3. Borgna-Pignatti C, Cappellini MD, De Stefano P, et al. Cardiac morbidity andmortality in deferoxamine- or deferiprone-treated patients with thalassemiamajor. Blood 2006;107:3733–3737.4. Telfer P, Coen PG, Christou S, et al. Survival of medically treated thalassemiapatients in Cyprus. Trends and risk factors over the period 1980–2004. Hae-matologica 2006;91:1187–1192.5. Maggio A, Vitrano A, Capra M, et al. Improving survival with deferiprone treat-ment in patients with thalassemia major: A prospective multicenter rando-mised clinical trial under the auspices of the Italian Society for Thalassemiaand Hemoglobinopathies. Blood Cells Mol Dis 2009;42:247–251.6. Trachtenberg F, Vichinsky E, Haines D, et al. Iron chelation adherence todeferoxamine and deferasirox in thalassemia. Clinical Research Network. AmJ Hematol 2011;86:433–436.7. Wood JC, Glynos T, Thompson A, et al. Follow-up report on the 2-yearcardiac data from a deferasirox monotherapy trial. Am J Hematol 2010;85:818–819.8. Pepe A, Lombardi M, Positano V, et al. Evaluation of the efﬁcacy of oraldeferiprone in b-thalassemia major by multislice multiecho T2*. Eur J Haema-tol 2006;76:183–192.9. Pennell DJ, Berdoukas V, Karagiorga M, et al. Randomized controlled trial ofdeferiprone or deferoxamine in b-thalassemia major patients with asympto-matic myocardial siderosis. Blood 2006;107:3738–3744.10. Tanner MA, Galanello R, Dessi C, et al. A randomized, placebo controlled,double blind trial of the effect of combined therapy with deferoxamine anddeferiprone on myocardial iron in thalassemia major using cardiovascularmagnetic resonance. Circulation 2007;115:1876–1884.11. Pennell DJ, Carpenter JP, Roughton M, Cabantchik ZI. On improvement inejection fraction with iron chelation in thalassemia major and the risk of futureheart failure. J Cardiovasc Magn Reson 2011;12:13–45.12. Borgna-Pignatti C, Rugolotto S, De Stefano P, et al. Survival and complica-tions in patients with thalassemia major treated with transfusion and deferox-amine. Haematologica 2004;89:1187–1189.13. Wood JC. Diagnosis and management of transfusion iron overload: The roleof imaging. Am J Hematol 2007;82(12 Suppl.):1132–1135.14. Ademola AA. An appraisal of the cost beneﬁt of magnetic resonance imagingin Nigeria Niger. Postgrad Med J 2003;10:251–253.15. Shahgaldi K, Gudmudson P, Manouras A, et al. Visually estimated ejectionfraction by two dimensional and triplane echocardiography is closely corre-lated with quantitative ejection fraction by real-time three dimensional echo-cardiography. Cardiovasc Ultrasound 2009;25:41.16. Blondheim DS, Beeri R, Feinberg MS, et al. Reliability of visual assessmentof global and segmental left ventricular function: A multicenter study by theIsraeli Echocardiography Research Group. J Am Soc Echocardiogr 2010;23:258–264.17. Giakoumis A, Berdoukas V, Gorsis E, Aessopos A. Comparison of echocar-diographic (US) volumetry with cardiac magnetic resonance (CMR) imagingin transfusion dependent thalassemia major (TM). Cardiovasc Ultrasound2007;5:24.18. Otterstad JE, Froeland G, St John Sutton M, Holme I. Accuracy andreproducibility of biplane two-dimensional echocardiographic measure-ments of left ventricular dimensions and function. Eur Heart J 1997;18:507–513.19. Link G, Konijn AM, Hershko C. Cardioprotective effect of a-tocopherol, ascor-bate, deferoxamine, and deferiprone: Mitochondrial function in cultured, iron-loaded heart cells. J Lab Clin Med 1999;133:179–188.lettersAmerican Journal of Hematology 733

Long-term use of deferiprone significantly enhances
left-ventricular ejection function in thalassemia major patients

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Long-term use of deferiprone significantly enhances left-ventricular ejection function in thalassemia major patients

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Archivio istituzionale della ricerca - Università di Palermo