25 Improved survival in myelodysplastic syndromes patients receiving iron chelation therapy

Invited Lectures 25 Improved survival in myelodysplastic syndromes patients receiving iron chelation therapy H.A. Leitch ° . Division of Hematology, St. Paul’s Hospital and the University of British Columbia, Vancouver, BC, Canada Patients with myelodysplastic syndromes (MDS) and iron overload often receive iron chelation therapy (ICT). Patients with thalassaemia receiving ICT have improved survival and decreased end-organ toxicities. We performed a retrospective analysis of 178 patients seen from 1981 to 2006 with a bone marrow diagnosis of MDS. Clinical data were collected from the database of the practice, the Iron Chelation Program of British Columbia, and by chart review. Patients receiving ICT were treated with deferoxamine (DFO) 0.5−3 g by subcutaneous infusion over 12 hours, 5 days per week. Of the patients, 105 were male and 73 female. MDS diagnoses were: refractory anaemia, n = 36; refractory anaemia with ringed sideroblasts, n = 42; refractory anaemia with excess blasts, n = 28; refractory anaemia with excess blasts in transformation, or acute myeloid leukaemia (AML), n = 16, chronic myelomonocytic leukaemia, n = 25; other, n = 31. Median (range) age at diagnosis was 69 (18–94) years. Median absolute neutrophil count was 1.6 (33−155)×109 /L, haemoglobin 96.5 (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. IPSS score was feasible in 133 patients: low risk, n = 44; int-1, n = 55; int-2, n = 17; high, n = 17. Serum ferritin 2000 mg/mL was documented in 28 patients. Clinical evidence of iron overload was evident in 22: congestive heart failure, n = 5; liver disease n = 18; endocrine dysfunction, n = 4; other, n = 4; biopsy or imaging evidence was available in 6 patients. Of 18 patients receiving ICT, median duration was 15 (0−37) months. Reasons for initiating ICT were: elevated ferritin, n = 13; clinical and biochemical evidence of iron overload, n = 3; number of transfusions received, n = 2. In ICT patients, median ferritin level preICT 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; at follow-up, 3,188 (763−12,723) mg/L. There was a trend towards higher initial ferritin in ICT patients (p < 0.07) and significantly lower follow-up ferritin in ICT patients compared to non-ICT patients (p < 0.003). Cause of death in non-ICT patients: AML, n = 22; MDS-related, n = 21; infection/sepsis, n = 18 and non-MDS-related, n = 10; in ICT patients it was: AML, n = 1; MDS related, n = 1; iron overload, n = 1. Median overall survival for all patients was 36 (0.7–255.9) months. Age showed a trend for overall survival (p < 0.1); factors significant for overall survival were: IPSS score, (p < 0.0001); MDS

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diagnosis, (p < 0.0001); number of red blood cell units transfused, (p < 0.0001); 1 serious infectious episode, (p < 0.002); AML transformation, (p < 0.0001); MDSdirected 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 significant for overall survival were: IPSS score (p < 0.008) and ICT (p < 0.02). For patients with low- or int-1 IPSS, median overall survival for ICT was not reached at 160 months vs 40.1 (0.7–224) months for non-ICT patients (p < 0.03). In conclusion, although we were unable to demonstrate decreased organ dysfunction in patients receiving ICT for MDS, there was a significant improvement in overall survival. These are, to my knowledge the first data documenting improved survival in patients with MDS receiving ICT.

26 Guidelines on iron chelation therapy in patients with myelodysplastic syndrome and transfusion iron overload N. Gattermann ° . Department of Hematology/Oncology, Heinrich-Heine-Universit¨at, D¨usseldorf, Germany MDS patients start accumulating iron even before they receive their first blood transfusion. This is due to ineffective erythropoiesis stimulating intestinal iron uptake. That mechanism, however, is not the main cause of iron overload. Data from the D¨usseldorf MDS Registry indicate that serum ferritin at the time of diagnosis is usually not higher than 300–600 ng/ml. The most important cause of iron overload is transfusion therapy. About 80% of patients have a hemoglobin <10 g/dl at the time of diagnosis, and the majority of these become transfusion dependent. Although chelation therapy has been suggested to be beneficial in MDS, many patients are inadequately treated due to the demanding regimen of parenteral deferoxamine infusions, or to uncertainty regarding the value of iron chelation in MDS patients who may have a limited life expectancy. Since it is hard to assess how much morbidity and mortality in MDS is attributable to transfusion iron overload, and first evidence of improved survival with chelation therapy has only recently been obtained, expert opinion remains a basis for clinical decision making. On the occasion of the 8th International Symposium on Myelodysplastic Syndromes in Nagasaki, 2005, a consensus meeting on iron overload in MDS was convened. Based on previous recommendations by the Italian Society of Hematology (Alessandrino et al., Haematologica, 2002) and the UK MDS Guidelines Group (Bowen et al., Br J Haematol, 2003) the consensus conference discussed the available evidence and agreed on recommendations that were subsequently published (Gattermann et al., Hematology/Oncology Clinics of North America, 2005). The group agreed on the following