Invited Lectures S15

25 Improved survival in myelodysplasticsyndromes patients receiving iron chelationtherapy

H.A. Leitch°. Division of Hematology, St. Paul’s Hospitaland the University of British Columbia, Vancouver, BC,Canada

Patients with myelodysplastic syndromes (MDS) and ironoverload often receive iron chelation therapy (ICT). Patientswith thalassaemia receiving ICT have improved survivaland decreased end-organ toxicities. We performed aretrospective analysis of 178 patients seen from 1981 to2006 with a bone marrow diagnosis of MDS. Clinicaldata were collected from the database of the practice,the Iron Chelation Program of British Columbia, and bychart review. Patients receiving ICT were treated withdeferoxamine (DFO) 0.5−3 g by subcutaneous infusion over12 hours, 5 days per week. Of the patients, 105 were maleand 73 female. MDS diagnoses were: refractory anaemia,n = 36; refractory anaemia with ringed sideroblasts, n = 42;refractory anaemia with excess blasts, n = 28; refractoryanaemia with excess blasts in transformation, or acutemyeloid leukaemia (AML), n = 16, chronic myelomonocyticleukaemia, n = 25; other, n = 31. Median (range) ageat diagnosis was 69 (18–94) years. Median absoluteneutrophil count was 1.6 (33−155)×109/L, haemoglobin96.5 (33–155) g/L and platelet count 115 (7−644)×109/L.Cytogenetic analysis was available in 128 patients: low risk(defined by the International Prognostic Scoring System[IPSS]), n = 85; intermediate, n = 22; high, n = 21. IPSSscore was feasible in 133 patients: low risk, n = 44;int-1, n = 55; int-2, n = 17; high, n = 17. Serum ferritin�2000mg/mL was documented in 28 patients. Clinicalevidence of iron overload was evident in 22: congestive heartfailure, n = 5; liver disease n = 18; endocrine dysfunction,n = 4; other, n = 4; biopsy or imaging evidence was availablein 6 patients. Of 18 patients receiving ICT, medianduration was 15 (0−37) months. Reasons for initiatingICT were: elevated ferritin, n = 13; clinical and biochemicalevidence of iron overload, n = 3; number of transfusionsreceived, n = 2. In ICT patients, median ferritin level pre-ICT was 4,215 (1,500−8,400) mg/L and 2,659 (567−5,228)mg/L post-ICT. In non-ICT patients with elevated ferritin,median ferritin after diagnosis, 1,647 (265−5,009) mg/L; atfollow-up, 3,188 (763−12,723) mg/L. There was a trendtowards higher initial ferritin in ICT patients (p< 0.07)and significantly lower follow-up ferritin in ICT patientscompared to non-ICT patients (p< 0.003). Cause of deathin non-ICT patients: AML, n = 22; MDS-related, n = 21;infection/sepsis, n = 18 and non-MDS-related, n = 10; inICT patients it was: AML, n = 1; MDS related, n = 1;iron overload, n = 1. Median overall survival for allpatients was 36 (0.7–255.9) months. Age showed atrend for overall survival (p< 0.1); factors significant foroverall survival were: IPSS score, (p< 0.0001); MDS

diagnosis, (p< 0.0001); number of red blood cell unitstransfused, (p< 0.0001); �1 serious infectious episode,(p< 0.002); AML transformation, (p< 0.0001); MDS-directed treatment, (p< 0.04); elevated ferritin, (p< 0.004);clinical evidence of iron overload, (p< 0.001); and ICT(p< 0.001). In Cox regression analysis, factors significantfor overall survival were: IPSS score (p< 0.008) and ICT(p< 0.02). For patients with low- or int-1 IPSS, medianoverall survival for ICT was not reached at 160 monthsvs 40.1 (0.7–224) months for non-ICT patients (p< 0.03).In conclusion, although we were unable to demonstratedecreased organ dysfunction in patients receiving ICTfor MDS, there was a significant improvement in overallsurvival. These are, to my knowledge the first datadocumenting improved survival in patients with MDSreceiving ICT.

26 Guidelines on iron chelation therapy inpatients with myelodysplastic syndrome andtransfusion iron overload

N. Gattermann°. Department of Hematology/Oncology,Heinrich-Heine-Universitat, Dusseldorf, Germany

MDS patients start accumulating iron even before theyreceive their first blood transfusion. This is due to ineffectiveerythropoiesis stimulating intestinal iron uptake. Thatmechanism, however, is not the main cause of iron overload.Data from the Dusseldorf MDS Registry indicate that serumferritin at the time of diagnosis is usually not higher than300–600 ng/ml.The most important cause of iron overload is transfusiontherapy. About 80% of patients have a hemoglobin <10 g/dlat the time of diagnosis, and the majority of these becometransfusion dependent. Although chelation therapy hasbeen suggested to be beneficial in MDS, many patientsare inadequately treated due to the demanding regimenof parenteral deferoxamine infusions, or to uncertaintyregarding the value of iron chelation in MDS patientswho may have a limited life expectancy. Since it ishard to assess how much morbidity and mortality inMDS is attributable to transfusion iron overload, andfirst evidence of improved survival with chelation therapyhas only recently been obtained, expert opinion remainsa basis for clinical decision making. On the occasionof the 8th International Symposium on MyelodysplasticSyndromes in Nagasaki, 2005, a consensus meeting oniron overload in MDS was convened. Based on previousrecommendations by the Italian Society of Hematology(Alessandrino et al., Haematologica, 2002) and the UKMDS Guidelines Group (Bowen et al., Br J Haematol, 2003)the consensus conference discussed the available evidenceand agreed on recommendations that were subsequentlypublished (Gattermann et al., Hematology/Oncology Clinicsof North America, 2005). The group agreed on the following

S16 Invited Lectures

profile of MDS patients who might benefit from thetreatment of iron overload. Patients should have a lower-risk MDS (IPSS low or int-1), usually corresponding toWHO types RA, RARS, 5q− syndrome, and a section ofRCMD. Patients with higher-risk MDS generally do notlive long enough to experience the complications of ironoverload. Irrespective of FAB or WHO type, candidates forallografting may also be candidates for chelation therapy,because it is particularly important to avoid iron-relatedorgan damage in these patients. In case of unfavorableFAB or WHO type, patients should not be excluded ifthey have documented stable disease. Ferritin levels shouldbe above 1000 or 2000 ng/ml, or, in cases where serumferritin is suspected to be unreliable, there should be otherevidence (e.g. MRI) of significant tissue iron overload.The latest MDS guidelines by the National ComprehensiveCancer Network take a similar view, recommending thatiron chelation therapy should predominantly be used forpatients with relatively lower risk MDS, whose clinicalcourse suggests ongoing chronic RBC transfusion need, andfor those with concurrent cardiac or hepatic dysfunction.The NCCN guidelines also state that chelation therapyis generally administerefor patients who have previouslyreceived 20−30 units of RBCs, for whom ongoing RBCtransfusions are anticipated and for those with serum ferritinlevels above 2500mg/l.

27 Deferasirox – the novel, once a day oral ironchelator

S.L. Goldberg°. Division of Leukemia, The Cancer Centerat Hackensack University Medical Center, HackensackNJ, USA

Red blood cell transfusions are a mainstay of thesupportive care of patients with myelodysplastic syndromes,including the 39−50% of low and intermediate-1 IPSSrisk patients who are transfusion dependent. Althoughcomplications of transfusion related iron overload arewell recognized in pediatric populations with sickle cellanemia and thalassemia, iron overload has gone largelyignored in adult myelodysplastic syndrome with only 30%of transfusion dependent patients receiving subcutaneousdeferoxamine chelation therapy in a 2005 MyelodysplasticSyndrome Foundation Centers of Excellence survey.Furthermore, recent studies have suggested MDS patientsrequiring chronic transfusions may experience increasedmortality, primarily from cardiac complications, and thateffective iron chelation may alter survival outcomes. Theavailability of a convenient, once-daily, oral iron chelationtherapy, deferasirox (Exjade, ICL670, Novartis Oncology)is allowing a reexamination of the role of iron overloadmanagement in MDS. Deferasirox is a tridentate ironchelator, selective for iron in the ferric (Fe3) state andbinding to iron with a 2:1 stoichiometry. Both deferasirox

and the chelate are primarily excreted in the feces. It islipid soluble but highly protein bound, and with a longplasma half-life of 8−16 hours, may be administered daily.Exjade is supplied as a tablet that is dispersed in wateror juice. In the US registration trials that included variousbone marrow failure syndromes, Exjade was noted to causea dose dependent decrease in both liver iron concentrationand serum ferritin. In trial 108, which included patients withMDS, iron chelation efficiency was found to be consistentacross disease states, suggesting that drug efficiency is notinfluenced by the type of underlying anemia. Various otherfactors, such as age and gender, also did not impact onefficiency, but efficiency was influenced by the rate oftransfusional iron intake. In a subset analysis of 28 patientswith MDS the mean decrease of LIC was 5.7mg iron pergram dry weight of liver over one year. Among the 47 MDSpatients enrolled on the trial, the mean decrease in serumferritin was 268 ng/mL. The iron excretion to intake ratiowas 1.7. The 5mg/kg dosage was insufficient to preventan increase, the 10mg/kg dosage was able to stabilizelevels, and the 20 and 30mg/kg dosages achieved significantdecreases in hepatic iron overload. Studies in thalassemiaand other anemias have suggested improvement in cardiacT2 after >1 year of Exjade chelation therapy and ongoingtrials are exploring cardiac issues in patients with MDS.Exjade has been well tolerated with the most commonadverse effect being mild gastrointestinal disturbancesincluding nausea and diarrhea. A non-progressive increasein serum creatinine has been identified in approximately athird of patients, with adjustments in dosing recommendedif the creatinine exceeds 33% of baseline. Additional studieswith Exjade in MDS are examining efficacy and tolerabilitywill hopefully improve transfusion management in MDSpatients.

28 Increased apoptosis as a mechanism ofineffective erythropoiesis in myelodysplasticsyndromes

R. Invernizzi °, E. Travaglino. Department of InternalMedicine, University of Pavia & Fondazione IRCCSPoliclinico S. Matteo, Pavia, Italy

Ineffective hematopoiesis, with premature death of marrowerythroid and myeloid precursors, is a hallmark ofmyelodysplastic syndromes (MDS), with the apparent para-dox of peripheral cytopenia associated with hypercellularbone marrow. Excessive apoptosis has been demonstratedin MDS by studies using different methods, ranging frommorphological to molecular techniques. This phenomenonis well documented also in vitro, where hematopoieticprogenitors do not form colonies in spite of the presenceof hematopoietic growth factors, and appears relevantespecially in low-risk MDS. On the contrary, in theMDS groups at high risk of leukemic evolution the