Esposito, Jason

Abstract Introduction: Recent reviews indicate that transfusional hemosiderosis may be associated with an increased risk of mortality in lower-risk pts with MDS. This trial is designed to evaluate the efficacy and long-term safety of deferasirox (Exjade®, ICL670) in MDS. Deferasirox is an oral iron chelator approved for use in pts with transfusional iron overload. Methods: This is a Phase II, open-label, 3-yr clinical trial in 55 US centers, enrolling 150 pts (aged ≥18 years) with Low- or Int-1-risk MDS (by IPSS criteria) and transfusional iron overload (serum ferritin ≥1000 ng/mL and >20 units RBC transfusions). Deferasirox dosing is 20–30 mg/kg/day. Serum ferritin, iron, transferrin and transferrin saturation are being assessed at screening and monthly in yr 1, then quarterly in yrs 2 and 3, while labile plasma iron (LPI) is assessed quarterly in yr 1. In addition, creatinine, calculated creatinine clearance, echocardiograms and endocrine and hematological status are being assessed. This report describes baseline data in these pts. Results: As of June 2006, 84 pts have enrolled. Demographic data are available from 79 pts: median age 71 years (range 47–87); sex (52 male, 27 female); ethnicity (74 Caucasian, 2 Black, 2 Hispanic, 1 Oriental); and IPSS Risk Group (Low: 22 pts; Int-1: 56 pts). Iron status is summarized in the table: Parameter n Mean ± SD Median Range Normal range n/a, not applicable Serum ferritin,μg/L 84 3779 ± 4070 2951 1160–36280 12–370 Serum iron, μg/dL 84 205 ± 64 201 48–409 37–180 Transferrin, mg/dL 82 153 ± 31 152 83–244 190–375 Transferrin saturation, % 83 85 ± 15 91 20–94 15–50 LPI, μmol/L 38 0.52 ± 0.63 0.25 0–2.9 0 Total transfusions, n 78 63.3 ± 66.3 41.5 14–435 n/a Years of transfusion 75 3.4 ± 1.9 3 1–12 n/a Baseline concurrent therapies: 5-azacytidine (Vidaza): 5 pts; lenalidomide (Revlimid): 1 pt. Calculated creatinine clearance: normal (>80 mL/min): 37 pts; mildly abnormal (51–80 mL/min): 30 pts; moderately abnormal (30–50 mL/min): 9 pts. Hematological parameters: Anemia was present in all pts; other cytopenias included: neutropenia (<1800/μL): 13 pts, thrombocytopenia (<100,000/μL): 15 pts; neutropenia and thrombocytopenia: 12 pts. A total of 53 pts had received chelation prior to enrolling: 51 deferoxamine (Desferal®); and 2 deferasirox. Conclusions: Despite the prior availability of deferoxamine, these baseline data demonstrate significant levels of iron overload among transfused pts with myelodysplasia. Serum iron, ferritin and LPI are all well above the clinically significant thresholds associated with increased complications. Since recent data has suggested that iron overload may be a poor prognostic indicator in MDS, increased attention to maintaining appropriate iron balance is warranted. The recent availability of an oral iron chelator may be more acceptable to MDS pts and their physicians. This ongoing trial is designed to assess the long-term efficacy, safety, and clinical benefits of deferasirox in pts with MDS.

Abstract INTRODUCTION: The majority of patients (pts) with MDS require red blood cell transfusions, which can result in iron overload and its clinical sequelae. The US03 trial is designed to evaluate the long-term efficacy and safety of the once-daily, oral iron chelator, deferasirox (DFX), in pts with lower-risk MDS. In this ongoing study 93/176 pts have now completed 12 months of 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 (serum ferritin [SF] 1000 μg/L and >20 units RBC transfusions), 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; labile plasma iron (LPI), the reactive species of non-transferrin-bound iron, was assessed quarterly. BASELINE FEATURES: 176 pts were enrolled at 45 centers. Mean age: 70 years (range 21–90); 105 men and 71 women; IPSS Low risk (n=47; 27%); Int-1 (n=126; 72%); other (n=3; 2%). Mean baseline iron status was: SF, 3397 μg/L (863–36,280); LPI, 0.4 μmol/L (0.0–3.6). Forty-one percent of pts had elevated LPI at baseline (≥0.5 μmol/L). Mean number of lifetime prior transfusions: 63; mean duration of transfusions: 3.5 years (0–34). MDS therapy at study entry included azacitidine, hydroxyurea, lenalidomide, thalidomide or decitabine in 25 pts, and growth factors in 48 pts. Calculated creatinine clearance was normal (>80 mL/min) in 77 pts and abnormal (abn) in 99: mildly abn (51– 80 mL/min) in 71; moderately abn (30–50 mL/min) in 25; severely abn (<30 mL/min) in 3. RESULTS: Over 12 months, the mean dose of DFX was 21 mg/kg/day, and the mean transfusion rate was 3.4 units/month. Mean SF±SEM (μg/L) values at baseline, 3, 6, 9 and 12 months were 3397±233 (n=176), 3057±144 (n=143), 2802±128 (n=126), 2635±148 (n=109) and 2501±139 (n=93), respectively. In pts with elevated baseline LPI, sustained suppression of mean LPI to the normal range was achieved after 3 months of treatment. The figures show reductions (±SEM) in SF, and in LPI in pts with baseline LPI ≥0.5 μmol/L. Hematological improvement by IWG 2000 criteria was achieved in 8 pts (5%): erythroid response in 5 (major 3; minor 2); platelet in 1 (major); neutrophil in 1 (major); and combined platelet and neutrophil in 1. SAFETY: Of 173 pts, 18 (10%) discontinued DFX because of suspected adverse events (AEs), and an additional 5 (3%) because of serious AEs (SAEs). The most common AEs were diarrhea (n=9), rash (n=3) and nausea (n=2), while the most common SAEs were rash (n=2) and diarrhea (n=1). Of 147 pts with normal baseline SCr, 26 (18%) increased >ULN on at least two occasions (3.0 mg/dL max SCr). There were 9/172 (5%) and 22/168 (13%) new onset cases of grade 3–4 thrombocytopenia and neutropenia, respectively, none suspected to be related to DFX; 7 and 11 of these pts, respectively, were receiving other MDS treatment therapies, including lenalidomide, decitabine, hydroxyurea and azacitidine. There were 17 deaths (10%), due to sepsis/infection (n=8), disease progression (n=4), intracranial bleed (n=2), cardio-respiratory arrest (n=2) and renal failure (n=1), all thought to be unrelated to DFX. CONCLUSIONS: In these heavily iron-overloaded pts, DFX was generally well tolerated. New onset cytopenias were consistent with the underlying disease. A 2-year extension phase of this study will assess the long-term safety and efficacy of DFX as well as the clinical impact on cardiac, hepatic and endocrine function. Figure Figure

Abstract 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 μg/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 μg/L (range, 863−36,280); LPI 0.4 μmol/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 μmol/L). RESULTS: Mean SF±SD (μg/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. Figure Figure