Title: [1470] Deferasirox (ICL670; Exjade ) Reduces Serum Ferritin (SF) and Labile Plasma
Iron (LPI) in Patients with Myelodysplastic Syndromes (MDS).
Authors: Alan F. List, M.R. Baer, D. Steensma, A. Raza, J. Esposito, J. Virkus, J. Feigert,
E. Besa, C. Paley H Lee Moffitt Cancer Ctr, FL, USA; Roswell Pk Cancer Inst, NY, USA; Mayo
Clinic, MN, USA; Univ Massachusetts, MA, USA; Novartis Pharma Corp, NJ, USA; Arlington Fairfax
Hematology/Oncology, VA, USA; Thomas Jefferson Univ, PA, USA
Introduction: The majority of patients (pts) with MDS become red blood cell (RBC) transfusion
dependent with escalating risk for transfusional hemosiderosis and its adverse effect on
morbidity and mortality. The US03 trial is designed to evaluate long-term efficacy and safety
of the oral iron chelator, deferasirox (DFX), in pts with lower risk MDS. In this ongoing study
53 pts have completed 12 months (mos) treatment.
Methods: US03 is a Phase II, open-label, 3-year trial in pts with Low- or Int-1 IPSS risk MDS
and transfusional iron overload (SF 1000 g/L and >20 units RBC transfusions [tx]), with serum
creatinine (SCr) 2-fold the upper limit of normal (ULN). Initial DFX dose was 20 mg/kg/day
and could be increased to 40 mg/kg/day based on tolerability and response. SF was monitored
monthly; LPI, the reactive species of non-transferrin-bound iron, was assessed quarterly.
Baseline Features: 176 pts were enrolled at 45 centers. Mean age was 70 years (range, 21 90),
including 102 men, 71 women; and IPSS risk groups of Low 46 pts (27%), Int-1 123 (71%), other 4
(2%). Mean baseline iron status: SF 3398 g/L (range, 863 36,280); LPI 0.4 mol/L (0.0 3.6); mean
lifetime txs prior to study, 63; years of prior tx 3.5 (0 34). MDS therapy at study entry included
chemotherapy, 22 pts; growth factors, 46. Estimated creatinine clearance: normal (>80 mL/min),
77 pts; mild (51 80 mL/min), 68; moderate, (30 50 mL/min) 25; severe (<30 mL/min) 2. Over
12 mos the mean dose was 21 mg/kg/day, and the mean tx rate was 4.1 units/mo. Forty percent of
pts had elevated LPI at baseline ( 0.5 mol/L).
Results: Mean SF SD ( g/L) values: baseline 3398 3088; 3 mos 3065 1743; 6 mos 2775 1355; 9 mos
2759 1562; 12 mos 2603 1336. Sustained suppression of mean LPI to the normal range was achieved
after 3 mos of treatment. (Figure shows changes in SF and LPI). Hematologic improvement by IWG
criteria: 5 pts (6%); erythroid response: 3 (major 1; minor 2); platelet 2 (major); neutrophil 1 (major).
Safety: Of 165 pts, only 10 (6%) discontinued secondary to suspected adverse events (AEs), and 7
(4%) serious AEs. There were 11 deaths (7%), all unrelated to DFX. Of 140 pts with normal baseline
SCr, 35 (25%) increased >ULN (2.2 mg/dL max SCr). SCr increased >33% above baseline in 11 pts (8%)
abnormal at baseline. New onset of thrombocytopenia and neutropenia were 52/165 (32%) and 22/165
(13%), respectively.
Conclusions: DFX therapy decreased mean SF over 1 year in this heavily iron-replete MDS population.
Trough LPI normalized in 100% of pts over 12 mos, indicating 24-hour sustained suppression. DFX had a
manageable safety profile in this population; new cytopenias were consistent with hematologic progression
of MDS. Recent reviews show a 30% increase in hazard ratio for every 500 ng/mL increase in SF >1000 ng/mL;
NCCN guidelines recommend consideration of iron chelation in iron-overloaded MDS pts. Ongoing assessments
evaluating cardiac, hepatic and endocrine function will evaluate the impact of iron reduction on morbidity
and mortality in MDS.
Abstract #1470 appears in Blood, Volume 110, issue 11, November 16, 2007
Keywords: Iron Chelation / Iron Overload / Clinical Trial
