Deferasirox Reduces Serum Ferritin and Labile Plasma Iron in RBC Transfusion Dependent Patients With Myelodysplastic Syndrome

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1 VOLUME 30 NUMBER 17 JUNE JOURNAL OF CLINICAL ONCOLOGY O R I G I N A L R E P O R T Deferasirox Reduces Serum Ferritin and Labile Plasma Iron in RBC Transfusion Dependent Patients With Myelodysplastic Syndrome Alan F. List, Maria R. Baer, David P. Steensma, Azra Raza, Jason Esposito, Noelia Martinez-Lopez, Carole Paley, John Feigert, and Emmanuel Besa Alan F. List, H. Lee Moffitt Cancer Center, Tampa, FL; Maria R. Baer, Roswell Park Cancer Institute, Buffalo; Azra Raza, Columbia University, New York, NY; David P. Steensma, Dana-Farber Cancer Institute, Boston, MA; Jason Esposito, Noelia Martinez- Lopez, and Carole Paley, Novartis Pharmaceuticals Corporation, East Hanover, NJ; John Feigert, Fairfax Northern Virginia Hematology/Oncology, Arlington, VA; and Emmanuel Besa, Thomas Jefferson University, Philadelphia, PA. Submitted December 16, 2010; accepted February 29, 2012; published online ahead of print at on April 30, Supported by Novartis Pharmaceuticals. Presented in part at the 50th Annual Meeting of the American Society of Hematology, December 6-9, 2008, San Francisco, CA. Authors disclosures of potential conflicts of interest and author contributions are found at the end of this article. Clinical Trials repository link available on JCO.org. Corresponding author: Alan F. List, MD, H. Lee Moffitt Cancer Center and Research Institute, Magnolia Dr, Tampa, FL 33612; alan.list@ moffitt.org by American Society of Clinical Oncology X/12/ /$20.00 DOI: /JCO A B S T R A C T Purpose This 3-year, prospective, multicenter trial assessed the safety and efficacy of deferasirox in lowor intermediate-1 risk myelodysplastic syndrome (MDS). Patients and Methods Eligible patients had serum ferritin 1,000 g/l and had received 20 units of RBCs with ongoing transfusion requirements. The starting dose of deferasirox was 20 mg/kg/d, with dose escalation up to 40 mg/kg/d permitted. Results A total of 176 patients were enrolled, and 173 patients received therapy. Median serum ferritin decreased 23% in the 53% of patients who completed 12 months of treatment (n 91), 36.7% in patients who completed 2 years (n 49), and 36.5% in patients who completed 3 years (n 33) despite continued transfusion requirement. Reduction in serum ferritin significantly correlated with ALT improvement (P.001). Labile plasma iron (LPI) was measured quarterly during the first year of the study. Sixty-eight patients (39.3%) had elevated LPI at baseline. By week 13, LPI levels normalized in all patients with abnormal baseline level. Fifty-one (28%) of 173 patients experienced hematologic improvement by International Working Group 2006 criteria; of these, only seven patients received growth factors or MDS therapy. Over the 3-year study, 138 (79.8%) of 173 patients discontinued therapy, 43 patients (24.8%) because of adverse events or disease progression and 23 patients (13.2%) because of abnormal laboratory values. The most common drug-related adverse events were gastrointestinal disturbances and increased serum creatinine. There were 28 deaths, none of which were considered related to deferasirox. Conclusion Deferasirox reduces serum ferritin and LPI in transfusion-dependent patients with MDS. A subset of patients had an improvement in hematologic and hepatic parameters. J Clin Oncol 30: by American Society of Clinical Oncology INTRODUCTION The majority of patients with myelodysplastic syndromes (MDSs) require RBC transfusions for management of symptomatic anemia, with high cumulative transfusion needs placing them at risk for development of iron overload. 1,2 Several retrospective studies have shown that increasing transfusion burden and elevated serum ferritin levels are associated with an incremental decrease in overall and leukemia-free survival The relative risk of iron loading compared with the intrinsic risk of the disease is most pronounced in patients with refractory anemia, refractory anemia with ringed sideroblasts, or lower risk MDS with isolated chromosome 5q deletion patient subgroups for whom survival is sufficiently long to manifest potential organ complications. Cardiac failure and infection were the most common nonleukemic causes of mortality, accounting for 51% and 31% of deaths, respectively. 7 Organ complications arising in transfusiondependent patients with MDS may derive in part from direct toxicities of parenchymal iron, but also from chronic exposure to nontransferrin-bound iron (NTBI) accumulating after saturation of iron storage capacity. NTBI encompasses all forms of serum iron that are not associated with transferrin. Labile plasma iron (LPI) represents the most toxic fraction of NTBI that is both redox active and chelatable. 12 Sustained levels of LPI over time may compromise organ function (eg, the heart) and overall by American Society of Clinical Oncology

2 Deferasirox in Low- and Intermediate-1 Risk MDS survival. 13 Iron chelators such as deferoxamine can decrease NTBI that is sustained only for the duration of plasma drug exposure. 14 Several published case reports and small studies have reported improvements in hematologic parameters and transfusion requirements during iron chelation therapy with deferasirox. 15 Limited evidence of hematologic improvement in patients with MDS also exists with deferoxamine treatment, 16 although the exact mechanism of hematologic response to iron chelators is unknown. We report the results of a prospective, multicenter trial in lower risk RBC transfusion dependent patients with MDS evaluating the safety and efficacy of deferasirox administered over 3 years. This study differs from a recently published European study of deferasirox in patients with MDS 17,18 in that the current study patients were observed for 3 years, eligibility was restricted to International Prognostic Scoring System 19 low- or intermediate-1 risk patients with MDS, and patients with elevated serum creatinine (up to 2 upper limit of normal [ULN]) could enroll. PATIENTS AND METHODS Patients Eligibility was restricted to patients age 18 years with low- or intermediate-1 risk MDS according to International Prognostic Scoring System criteria 19 who had received at least 20 units of RBCs and had a serum ferritin 1,000 g/l. Patients were either naive to iron chelation or had received previous treatment with deferoxamine (Desferal; Novartis, East Hanover, NJ) or deferasirox (Exjade; Novartis) that was discontinued at least 1 day before the initiation of deferasirox. Eligible patients had an Eastern Cooperative Oncology Group performance status 2, life expectancy of 6 months, serum creatinine 2 ULN and minimal or no proteinuria, and serum AST/ALT 500 U/L. The study was conducted in accordance with Good Clinical Practice guidelines and the Declaration of Helsinki; all patients provided written informed consent. Study Design and Treatment This was an open-label, single-arm, 3-year phase II trial (1-year core and 2-year extension) conducted at 45 centers throughout the United States and Canada. The primary objective of the trial was to evaluate the safety and tolerability of deferasirox in this population. Secondary objectives included measurement of changes in serum ferritin and LPI; assessment of hematologic improvement; prevalence of gene mutations associated with hereditary hemochromatosis; assessment of deferasirox pharmacokinetics; and assessment of cardiac, endocrine, and hepatic function. Additional analyses were performed to compare safety and efficacy of deferasirox in patients with baseline serum creatinine levels less than or equal to the ULN and patients with baseline serum creatinine levels greater than the ULN. Deferasirox was supplied as 125-, 250-, and 500-mg tablets to be taken daily 30 minutes before breakfast after dissolving in water or apple or orange juice. The starting dose of deferasirox was 20 mg/kg/d with subsequent dose adjustments based on changes in serum ferritin, patient weight, serum creatinine, and skin rash. Doses were increased by 10 mg/kg/d (up to a maximum dose of 40 mg/kg/d) based on responses in serum ferritin and treatment tolerance. Deferasirox was held if serum creatinine increased 50% above baseline in patients with normal baseline creatinine levels or 33% in patients with levels above the ULN at baseline. Deferasirox could be resumed after normalization of baseline serum creatinine levels. Deferasirox was interrupted for moderate or severe skin rash and reinstated at 10 mg/kg/d on resolution; dose re-escalation was permitted if there was no further recurrence. Treatment with growth factors and US Food and Drug Administration approved specified therapies for MDS was permitted, but investigational treatments were excluded. Monitoring Serum ferritin, total iron, transferrin, and transferrin saturation levels (measured in a central laboratory); creatinine; and CBCs were assessed every 4 weeks. LPI was assessed (Aferrix, Tel-Aviv, Israel, using the FeROS assay) at screening and every 12 weeks during the first year of study. This assay measures the redox activity of iron in serum. A reducing agent (ascorbate) and an oxidizing agent (atmospheric oxygen) cause the labile iron in the tested sample to oscillate between its oxidized (Fe 3 ) and reduced (Fe 2 ) form, generating reactive oxygen species (ROSs) via the Fenton reaction. The ROSs are detected by an oxidation-sensitive probe (dihydrorhodamine), which becomes fluorescent when oxidized by ROS. The assay employs a selective iron chelator that blocks redox cycling of iron to specifically identify iron-mediated ROS generation. Comparison of the fluorescence generated in the reaction in the presence and absence of the iron chelator translates into an accurate estimate of the quantity of LPI in the tested sample. The number of transfusions was recorded at each visit, and CBCs and MDS hematologicresponsedatawerecollectedmonthly.hereditaryhemochromatosisassociated gene mutations (HFE) were assessed at baseline to evaluate whether those mutations impacted the total iron burden or the rate of iron clearance. Clinical effects were assessed by yearly echocardiogram, monthly evaluations of liver function tests, and hematologic parameters. Safety assessments were performed at all study visits with ophthalmologic and audiometric examinations performed at baseline and as indicated. Pharmacokinetics were assessed by trough plasma levels of deferasirox and the iron complex, iron-[deferasirox] 2, and were analyzed during the first study year from samples collected at weeks 13, 25, 37, and 49 by using a liquid chromatography-mass spectrometry/mass spectrometry method. Statistical Methods All patients who received at least one dose of the study drug were included in the full analysis set and safety populations. Descriptive statistics were used to summarize demographics, dosing, safety, and the prevalence of HFE gene mutations. Descriptive statistics were calculated for the change in ironmarker parameters (serum ferritin and LPI), hematologic parameters, and transfusion requirements from baseline. Hematologic response was assessed in a post-hoc analysis using the International Working Group 2006 criteria. 20 Drug tolerability in the safety population was assessed by adverse event (AE) severity according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 3), laboratory data, and periodic ophthalmologic and audiometric assessments. RESULTS Demographics A total of 176 patients were enrolled onto the study, and 173 patients received study treatment. Two patients withdrew consent and one patient died after enrollment but before initiating treatment. Treated patients were predominantly elderly (median age, 71.0 years; range, 21 to 90 years), white (91.9%), and with intermediate-1 MDS (71.7%; Table 1). Patients were heavily transfused at baseline, having received a median of 41 transfusions over a median of 3 years. Median baseline serum ferritin in the full analysis set (n 173) was 2,771 g/l (range, 863 to 9,993 g/l; normal females, 150 g/l; normal males, 300 g/l). Median baseline LPI available for 163 patients was 0.3 LPI units (1 LPI unit quantity of ROSs produced by approximately 1.5 mol/l iron; normal, 0.5 LPI units). Median baseline transferrin saturation available for 172 patients was 91% (standard deviation, %; normal females, 12% to 45%; normal males, 15% to 50%). Patient Disposition Over the course of 3 years, 138 patients (79.7% of enrolled population) discontinued deferasirox. The annual discontinuation rate by American Society of Clinical Oncology 2135

3 List et al Table 1. Baseline Demographics and Clinical Characteristics of Treated Patients Demographic or Clinical Characteristic No. of Patients (N 173) % Age, years Median 71.0 Range Sex Female 70 Male 103 Race White African American Asian Other IPSS risk group Low Intermediate Other Time since initial MDS diagnosis, years Median 4.5 Range year to 3 years years Lifetime transfusions prior to study (n 57), No. Median 41.1 Range 17 to 435 Years of transfusions prior to study Median 3.0 Range 1-34 Patients with prior chelation therapy Deferoxamine Deferasirox Baseline serum ferritin, g/l Median 2, Range ,993.0 Baseline LPI, LPI units Median 0.30 Range Baseline transferrin saturation, % Median Range Abbreviations: IPSS, International Prognostic Scoring System; LPI, labile plasma iron; MDS, myelodysplastic syndrome. One LPI unit quantity of reactive oxygen species produced by approximately 1.5 mol/l of iron. was 45% during year 1, 43% during year 2, and 35% during year 3. The reasons for treatment discontinuation were AEs (n 43; 24.8%), death (n 28; 16.1%), administrative problems (n 27; 15.4%), abnormal laboratory values (n 23; 13.2%), did not enroll in extension phase (n 12; 6.9%), unsatisfactory therapeutic effect (n 3; 1.7%), and patients condition no longer required study drug (n 2; 1.1%). The AEs primarily consisted of MDS progression (n 16; 9.2%) and GI events. The most common abnormal laboratory value was elevated serum creatinine level (n 16; 9.2%), including four patients whose baseline serum creatinine exceeded the ULN. The most common causes of death were MDS progression/transformation to acute myeloid leukemia (n 6), respiratory failure (n 3), and congestive heart failure (n 2; Table 2). Table 2. Deaths During the Core and Extension Study (safety set) Preferred Term No. of Patients (N 173) % Sepsis/infection MDS progression/aml Respiratory failure Intracranial bleed/stroke Congestive heart failure Cardiopulmonary arrest Acute renal failure Myocardial infarction Abbreviations: AML, acute myeloid leukemia; MDS, myelodysplastic syndrome. Dosing and Pharmacokinetics The mean daily dose of deferasirox administered over the 3-year study period ranged from 18.8 mg/kg/d at weeks 1 to 12 (n 173) to 23.4 mg/kg/d at weeks 85 to 96 (n 56). The median duration of exposure overall was 375 days (range, 1 to 1,082 days). The median trough plasma levels of deferasirox were 21.1 mol/l at week 13 (n 129), 26.7 mol/l at week 25 (n 114), 25.2 mol/l at week 37 (n 99), and 30.7 mol/l at week 49 (n 77). Mean trough plasma levels of iron-[deferasirox] 2 were similar at all time points measured (2.090, 2.515, 2.430, and mol/l at weeks 13, 25, 37, and 49, respectively). HFE Gene Mutations Among 94 patients evaluated for HFE gene mutations, nine patients (9.6%) were heterozygous for the C282Y mutation, 24 (25.5%) were heterozygous for H63D, and two (2.1%) were heterozygous for S65C. These frequencies were similar to those seen in the general population, and there was no difference in baseline serum ferritin or the rate of decline in serum ferritin during study treatment in the 35 patients with HFE mutations compared with HFE wild-type study patients. Iron Parameters and Transfusion Requirements RBC transfusions were administered as clinically indicated throughout the study, with a mean transfusion rate of 4.1 RBC units per month over 12 months. Median baseline serum ferritin (n 173) was 2,771.5 g/l (range, 863 to 9,993 g/l). Efficacy was assessed by performing paired comparisons of median baseline serum ferritin to median serum ferritin at the end of years 1, 2, and 3. Over the first year, the median serum ferritin decreased 23.2% (n 91; Fig 1). At the end of year 2, the decrease from baseline was 36.36% among actively treated patients (n 49). For patients who completed 3 years on study, the median decrease from baseline was 36.53% (n 33). Among 163 patients who had assessments of baseline LPI, 68 patients had elevated levels ( 0.5 LPI units; mean, LPI units), and 95 patients were within the normal range ( 0.5 LPI units). Concentrations of LPI normalized in the 47 patients with elevated baseline levels who were assessed at week 25 and remained normal for the remainder of the study (0.0 LPI units by week 49; Fig 2). Change in median transferrin saturation paralleled the decline in mean LPI and decreased from a baseline level of 91% (n 172) to 67% (n 90) at the end of the study. At by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY

4 Deferasirox in Low- and Intermediate-1 Risk MDS Median Serum Ferritin (µg/l) 3,500 3,000 2,500 2,000 1,500 1, *P =.6063 *P <.001 Time (weeks) *P <.001 Baseline No. at risk Median change from baseline (µg/l) Fig 1. Median serum ferritin ( SEM) in patients who completed 12 months of deferasirox. (*) Versus baseline. week 49, mean LPI significantly and positively correlated with transferrin saturation (n 69; r 0.363; P.002). Clinical Outcomes Hepatic. The relationship between change in serum ferritin and change in ALT was evaluated in this trial based on a previous published report. 24 There was a significant positive relationship between decline in serum ferritin and improvement in hepatic transaminases. Regression analysis showed a positive relationship between serum ferritin and AST (slope 47.22; P.001) and ALT (slope 23.30; P.001) from baseline to week 53. Over 1 year, there was a statistically significant correlation between change in serum ferritin and change in ALT (P.001; Fig 3), which indicated that a decrease in serum ferritin of 716 g/l was associated with a decrease in ALT of 25 U/L. Hematologic response. A post-hoc analysis was performed during the first year of treatment to evaluate hematologic response by Mean LPI (µmol/l) Threshold of normal LPI (< 0.5 µmol/l) Baseline Time (weeks) No. at risk Fig 2. Mean labile plasma iron (LPI; SEM) over 12 months in patients with abnormal LPI ( 0.5 mol/l) at baseline. Change From Baseline in ALT (U/L) ,000 n = 91 R = P.001-4,000-2, ,000 4,000 6,000 Change From Baseline in Serum Ferritin (µg/l) Fig 3. Plot of change from baseline in ALT by change from baseline in serum ferritin. International Working Group 2006 criteria. 20 Among the 173 patients enrolled, all met the erythroid inclusion criteria for response analysis, 77 met the platelet inclusion criteria, and 52 met the neutrophil inclusion criteria. Erythroid responses were observed in 15% of patients (26 of 173 patients). Three of these patients were also on other MDS therapies (one on lenalidomide and two on erythropoietin [EPO]). Platelet responses were observed in 22% of patients (17 of 77 patients). One of these patients was on EPO and azacitidine. Neutrophil responses were observed in 15% of patients (eight of 52 patients). Three of these patients were on additional therapies (one on EPO, one on EPO and decitabine, and one on lenalidomide). Multilineage responses were seen in eight patients (neutrophil erythroid, n 2; platelet erythroid, n 3; neutrophil platelet, n 1; and erythroid neutrophil platelet, n 2). Median time to hematologic response was 169 days (range, 84 to 382 days). Median baseline serum ferritin was higher in patients with hematologic improvement (3,045 g/l) than in patients without hematologic improvement (2,751 g/l; Table 3); however, the median absolute change in ferritin from baseline to end of study was greater in the patients with hematologic improvement ( 693 g/l v 228 g/l, respectively). Improvement from baseline to end of study in mean LPI was reported in both patients with hematologic improvement and those without hematologic improvement (mean, 0.47 mol/l v 0.32 Table 3. Change in Serum Ferritin From Baseline to End of Study in Patients With and Without Hematologic Response Serum Ferritin Level Patients Without Hematologic Improvement (n 123) Patients With Hematologic Improvement (n 41) Baseline serum ferritin, g/l Median 2,751 3,045 Range 863-9,238 1,160-36,280 Change in serum ferritin from baseline to end of study, g/l Median Range 4,227 to 5,317 30,313 to 5, by American Society of Clinical Oncology 2137

5 List et al mol/l, respectively). There was no discernable difference in LPI improvement in hematologic responders and nonresponders. There was a trend toward improved overall survival in responders compared with nonresponders. Cardiac. Transthoracic echocardiograms were performed at baseline and at the end of years 1, 2, and 3. At baseline, all patients had normal echocardiogram findings or clinically insignificant abnormalities. During the 3-year trial, 44 patients (25%) experienced a cardiac event (eg, dysrhythmia, myocardial infarction) of which five were fatal; all were assessed by local investigators to be unrelated to study drug (Table 2). It was difficult to assess the impact of deferasirox on cardiac outcomes because there was no comparator arm. Safety. A program safety monitoring committee reviewed safety data collected during this study every 18 months. Of the 173 patients enrolled onto the study, 149 patients had baseline serum creatinine values less than or equal to the ULN, and 24 patients had baseline serum creatinine values greater than the ULN (up to 2 ULN). Of the 149 patients with normal serum creatinine, 33 completed 3 years on study. Of the 24 patients with abnormal baseline serum creatinine, only two completed the full 3-year study. The most common moderate to severe AEs were GI (diarrhea, nausea, and vomiting), dyspnea, fatigue, and blood creatinine increase. Moderate to severe treatment-related AEs occurring in 5% of patients were limited to diarrhea in 34 patients (19.6%) and serum creatinine increase (15 patients; 8.7%). Serious AEs (SAEs) were similar to those reported in other studies of deferasirox. Pneumonia was the most commonly reported SAE, experienced by 20 patients (11.5%), followed by febrile neutropenia and pyrexia (12 patients; 6.9% each). All other SAEs were reported in 5% of patients. Treatment discontinuation as a result of AEs occurred in 24.8% of patients (n 43) over the 3-year study period. AEs that led to discontinuation in 3% of patients included disease progression to acute myeloid leukemia, GI disorders, general disorders and administration site conditions, infections, and nervous system disorders. A total of 28 patients (16.1%) died; none of the deaths were considered by investigators to be related to study drug (Table 2). Laboratory abnormalities that led to study drug discontinuation included increased serum creatinine (18 patients; 10.4%), thrombocytopenia (three patients; 1.7%), neutropenia (one patient; 0.6%), and increased ALT, AST, bilirubin, lactate dehydrogenase, and -glutamyltransferase (one patient each; 0.6%). The rates of renal AEs were higher in patients with abnormal baseline serum creatinine (41.7%) than in patients with normal baseline serum creatinine (31.5%). Additionally, the number of renal SAEs and renal AEs that led to study drug discontinuation was higher in patients who had abnormal baseline serum creatinine values compared with patients with normal values (8.3% v 6% renal SAEs, respectively; 4.7% v 0.7% renal AEs that led to study drug discontinuation, respectively). The one death in which renal failure occurred was in a patient with abnormal baseline serum creatinine. 53% of patients completed 12 months of chelation treatment, whereas only 20.2% of patients (n 35) completed the 3-year study. The mean daily dose of deferasirox taken over the 3-year period ranged from 18.8 to 23.4 mg/kg/d. Forty-three patients (24.8%) discontinued therapy as a result of AEs, and 23 patients (13.2%) discontinued as a result of changes in laboratory findings. Although most patients experienced AEs, the majority were manageable with supportive measures and deferasirox dose adjustments. The results from this 3-year study show that deferasirox effectively reduced iron burden in iron-overloaded patients with low- or intermediate-1 risk MDS as measured by reduction in serum ferritin and LPI. Serum ferritin levels decreased more than 36% over the course of the study, and LPI levels normalized by week 13. There was a significant correlation between decline in serum ferritin and improvement in hepatic transaminases, an observation that was previously reported in chelated patients with MDS. 18 Although patients with abnormal baseline serum creatinine had a higher rate of study discontinuation, patients who were able to continue therapy achieved comparable rates of reduction in serum ferritin. Over 1 year of deferasirox treatment, lineage-specific improvements in hematologic parameters were noted in 15% to 22% of patients, including 44 patients who did not receive MDS-specific therapy. These findings support prior retrospective observations that hematologic improvement may occur with chelation therapy in MDS patients, suggesting that medullary toxicity from iron overload may further compromise effective hematopoiesis in patients with MDS. 16,17 Overall, this study demonstrated improvements in iron parameters with prolonged deferasirox chelation in a cohort of heavily transfused lower risk patients with MDS accompanied by improvements in hepatic transaminases and hematologic improvement. The safety profile of deferasirox was manageable. Approximately 50% of patients discontinued annually, although the majority were unrelated to study drug. A randomized controlled trial is warranted to better ascertain the clinical impact of deferasirox therapy in lower risk patients with MDS. AUTHORS DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a U are those for which no compensation was received; those relationships marked with a C were compensated. For a detailed description of the disclosure categories, or for more information about ASCO s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: Jason Esposito, Novartis (C); Noelia Martinez-Lopez, Novartis (C); Carole Paley, Novartis Oncology (C) Consultant or Advisory Role: David P. Steensma, Novartis (C) Stock Ownership: Jason Esposito, Novartis; Carole Paley, Novartis Honoraria: None Research Funding: Alan F. List, Novartis; Emmanuel Besa, Celgene, Novartis Expert Testimony: None Other Remuneration: None DISCUSSION In this 3-year study of deferasirox efficacy and tolerability in lower risk, transfused, elderly patients with MDS and elevated serum ferritin, AUTHOR CONTRIBUTIONS Conception and design: Alan F. List, David P. Steensma, Jason Esposito, Noelia Martinez-Lopez, Carole Paley by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY

6 Deferasirox in Low- and Intermediate-1 Risk MDS Provision of study materials or patients: David P. Steensma, John Feigert, Emmanuel Besa Collection and assembly of data: Alan F. List, Maria R. Baer, Azra Raza, Jason Esposito, Noelia Martinez-Lopez, Carole Paley, John Feigert Data analysis and interpretation: Alan F. List, Maria R. Baer, David P. Steensma, Azra Raza, Jason Esposito, Noelia Martinez-Lopez, Carole Paley, Emmanuel Besa Manuscript writing: All authors Final approval of manuscript: All authors REFERENCES 1. Brechignac S, Hellstrom-Lindberg E, Bowen DT, et al: Quality of life and economic impact of red blood cell (RBC) transfusions on patients with myelodysplastic syndromes (MDS). Blood 104:4716, 2004 (abstr) 2. Hellström-Lindberg E: Management of anemia associated with myelodysplastic syndrome. Semin Hematol 42:S10-S13, 2005 (suppl) 3. Delea TE, Hagiwara M, Phatak PD: Retrospective study of the association between transfusion frequency and potential complications of iron overload in patients with myelodysplastic syndrome and other acquired hematopoietic disorders. Curr Med Res Opin 25: , Della Porta MG, Kuendgen A, Malcovati L, et al: Myelodysplastic syndrome (MDS)-specific comorbidity index for predicting the impact of extrahematological comorbidities on survival of patients with MDS. Blood 112:2677, 2008 (abstr) 5. Goldberg SL, Chen E, Corral M, et al: Influence of RBC transfusions on clinical outcomes among USA Medicare beneficiaries with newly diagnosed myelodysplastic syndromes. Leuk Res 33: S116, 2009 (suppl; abstr P099) 6. Jaeger M, Aul C, Sohngen D, et al: Iron overload in polytransfused patients with MDS: Use of L1 for oral iron chelation. Drugs Today 28: , 1992 (suppl A) 7. Malcovati L, Della Porta MG, Pascutto C, et al: Prognostic factors and life expectancy in myelodysplastic syndromes classified according to WHO criteria: A basis for clinical decision making. J Clin Oncol 23: , Rose C, Brechignac S, Vassilief D, et al: Positive impact of iron chelation therapy (CT) on survival in regularly transfused MDS patients: A prospective analysis by the GFM. Blood 110:249, 2007 (abstr) 9. Rose C, Brechignac S, Vassilief D, et al: Does iron chelation therapy improve survival in regularly transfused lower risk MDS patients? A multicenter study by the GFM (Groupe Francophone des Myélodysplasies). Leuk Res 34: , Chee CE, Steensma DP, Wu W, et al: Neither serum ferritin nor the number of red blood cell transfusions affect overall survival in refractory anemia with ringed sideroblasts. Am J Hematol 83: , Patnaik MM, Lasho TL, Finke CM, et al: WHO-defined myelodysplastic syndrome with isolated del(5q) in 88 consecutive patients: Survival data, leukemic transformation rates and prevalence of JAK2, MPL and IDH mutations. Leukemia 24: , Kohgo Y, Ikuta K, Ohtake T, et al: Body iron metabolism and pathophysiology of iron overload. Int J Hematol 88:7-15, Cabantchik ZI, Breuer W, Zanninelli G, et al: LPI-labile plasma iron in iron overload. Best Pract Res Clin Haematol 18: , Porter JB, Abeysinghe RD, Marshall L, et al: Kinetics of removal and reappearance of nontransferrin-bound plasma iron with deferoxamine therapy. Blood 88: , Messa E, Cilloni D, Messa F, et al: Deferasirox treatment improved the hemoglobin level and decreased transfusion requirements in four patients with the myelodysplastic syndrome and primary myelofibrosis. Acta Haematol 120:70-74, Jensen PD, Jensen IM, Ellegaard J: Desferrioxamine treatment reduces blood transfusion requirements in patients with myelodysplastic syndrome. Br J Haematol 80: , Gattermann N, Schmid M, Della Porta M, et al: Efficacy and safety of deferasirox (Exjade) during 1 year of treatment in transfusion-dependent patients with myelodysplastic syndromes: Results from EPIC trial. Blood 112:633, 2008 (abstr) 18. Gattermann N, Finelli C, Porta MD, et al: Hematologic responses in myelodysplastic syndromes (MDS) patients treated with deferasirox: An EPIC post-hoc analysis using International Working Group (IWG) 2006 criteria. Blood 116:2912, 2010 (abstr) 19. Greenberg P, Cox C, LeBeau MM, et al: International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 89: , Cheson BD, Greenberg PL, Bennett JM, et al: Clinical application and proposal for modification of the International Working Group (IWG) response criteria in myelodysplasia. Blood 108: , Adams PC, Reboussin DM, Barton JC, et al: Hemochromatosis and iron-overload screening in a racially diverse population. N Engl J Med 352: , Gochee PA, Powell LW, Cullen DJ, et al: A population-based study of the biochemical and clinical expression of the H63D hemochromatosis mutation. Gastroenterology 122: , Olynyk JK, Cullen DJ, Aquilia S, et al: A population-based study of the clinical expression of the hemochromatosis gene. N Engl J Med 341: , Gattermann N, Finelli C, Porta MD, et al: Deferasirox in iron-overloaded patients with transfusion-dependent myelodysplastic syndromes: Results from the large 1-year EPIC study. Leuk Res 34: , by American Society of Clinical Oncology 2139