Clinical Considerations for Managing Iron Overload in MDS: Analysis From EHA Aristoteles Giagounidis, MD, PhD Associate Professor of Medicine Head, Hematology/Oncology Clinical Research Unit St. Johannes Hospital Duisburg, Germany

2 units/month Iron Accumulation Due to Transfusion Therapy in MDS Serum ferritin ~ 1000 μg/L Moderate transfusion requirement Normal body iron: 3-4 g No physiological mechanism to excrete excess iron 24 units/year ≥ 5 g iron/year Porter JB. Br J Haematol. 2001;115:

Nonleukemic Cause of Death and Relationship to Iron Overload in MDS Malcovati L, et al. J Clin Oncol. 2005;23: Death in low-risk MDS Cardiac failure is more common in transfused than in nontransfused patients (P =.01) N = Cardiac failure InfectionHemorrhageHepatic cirrhosis Percentage

Assessment of Iron Overload in MDS Serum ferritin MRI – Heart – Liver Prognostic risk category influences management decisions – IPSS – WPSS: incorporates transfusion dependency, karyotype, WHO subgroup IPSS = International Prognostic Scoring System; MRI = magnetic resonance imaging

Prognostic Impact of Development of Iron Overload Is Independent of WPSS Score in MDS * Multivariate analyses including WPSS and development of iron overload (time dependent) (n = 580). Cases with < 3 serum ferritin measurements were excluded. Sanz G, et al. Presented at 50th Annual Meeting of the American Society of Hematology. San Francisco, CA, 8 December Abst 640. WPSS = WHO classification-based Prognostic Scoring System Overall survival Variable*HRP value Iron overload4.34<.001 WPSS1.60<.001 Leukemia-free survival Variable*HRP value WPSS2.24<.001 Iron overload2.13<.001

EHA 2010: Independent Impact of Transfusion Dependence and IO on Survival in MDS Arnan M, et al Annual Meeting of the European Hematology Association. Abst 314. Survival Time (years) Cumulative Proportion Surviving Transfusion independent Transfusion dependent P <

EPIC: Iron Chelation With Deferasirox Reduces Iron Burden in MDS After 12 months, significant reductions from baseline observed in: – Median serum ferritin (-253 ng/mL; P =.002) – Mean ALT (-27.7 ± 37.4 U/L; P <.0001) Gattermann N, et al. Leuk Res [Epub ahead of print].

EPIC: Iron Chelation With Deferasirox Reduced LPI at Each Time Point Gattermann N, et al. Leuk Res [Epub ahead of print]. Mean LPI (+SD) pre- and post-deferasirox administration at baseline and after repeat doses *P <.0001; †P =.0037 vs pre-administration at baseline. LPI = labile plasma iron. Mean LPI (μmol/L) * * † Normal threshold (n = 225)(n = 222)(n = 210)(n = 220)(n = 165)(n = 164)(n = 147)(n = 138)

Matched-Pair Analysis: Iron Chelation Therapy vs Transfusion Therapy Only in MDS Retrospective matched-pair analysis: – 94 MDS patients undergoing long-term chelation therapy – 93 patients in Düsseldorf MDS Registry receiving supportive care only Pairs matched according to age at diagnosis, gender, MDS type (WHO classification), and IPSS score All patients had iron overload (serum ferritin > 500 ng/mL) Patients were followed until death or June 30, 2009 Aim: To evaluate survival in patients with MDS following chelation therapy by matched-pair analysis Fox F, et al. Blood. 2009;114(11):abst 1747.

Matched-Pair Analysis Results: Patient Survival Fox F, et al. Presented at ASH 2009 [Blood. 2009;114(11):abst 1747]. Iron chelation group Supportive care groupP value Mortality during observation period 52%58% Median survival74 mo49 mo0.002 Cumulative risk of AML transformation 5 years after diagnosis 19%18%0.73 (NS) AML = acute myeloid leukemia

Survival and Causes of Death in IPSS Low-Risk or INT-1 Patients with MDS by Chelation History Multivariate analysis of data from regularly transfused patients followed for 2.5 yrs (N = 97) No significant difference in causes of death between the 2 groups (P =.51) Multivariate Cox analysis: adequate chelation strongest independent factor associated with better OS Pts chelated ≥ 6 mo (n = 53) Nonchelated pts (n = 44)P value Mortality during follow-up51%73%-- Median OS124 mo53 mo<.0003 Rose C, et al. Leuk Res. 2010;34: OS = overall survival

RBC-transfusion-dependent MDS Serum ferritin > 1000 µg/L Risk score YESNO RA, RARS, RCMD, RCMD-RS, 5q− Low and Int-1 WPSS IPSS RAEB Int-2 and High Co-morbidities? Iron chelation? Iron Chelation in MDS: Patient Selection Gattermann N, et al. Hematol Oncol Clin North Am. 2005;19(suppl 1): RAEB = refractory anemia with excess blasts

Iron Chelator Treatment Selection in MDS: Considerations DeferoxamineDeferiproneDeferasirox Delivery route Parenteral 8-24 hr x 5-7 d/wk Oral, TIDOral, QD Half-life (hrs) Common toxicities Infusion-site reaction Allergic reaction Auditory Ocular Neutropenia Agranulocytosis Nausea/vomiting Arthropathy Transient nausea Diarrhea Rash Renal toxicity Greenberg PL, et al. JNCCN. 2009;7(Suppl 9):S1-S16.

Ongoing Studies TELESTO: Myelodysplastic Syndromes (MDS) Event- Free Survival With Iron Chelation Therapy Study – Phase 3, multicenter, randomized, double-blind, placebo-controlled trial of deferasirox in patients with Low/Int-1–risk MDS and transfusional iron overload – Primary endpoint: Event-free survival (composite endpoint including death and nonfatal events related to cardiac and liver function) – Secondary endpoints: overall survival, TSH, glucose- tolerance testing, IPSS score, change in hematologic function expressed in total number of blood transfusions

Conclusions Transfusion dependency and iron overload: adverse effects on morbidity and mortality of patients with MDS – Particular issue in low-risk MDS due to longer-term transfusion therapy Assessment: serum ferritin, liver/heart MRI, IPSS/WPSS prognostic scoring Iron chelation shown to reduce iron burden and LPI, improve survival in patients with MDS and iron overload Treatment selection considerations with iron chelators: – Efficiency, administration route/treatment compliance, tolerability in primarily elderly patients