Clinical Considerations for Managing Iron Overload in MDS: Analysis From EHA

1. 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. Iron Accumulation Due to Transfusion Therapy in MDS Moderate transfusion requirement 2 units/month 24 units/year ≥ 5 g iron/year Serum ferritin ~ 1000 μg/L Normal body iron: 3-4 g No physiological mechanism to excrete excess iron Porter JB. Br J Haematol. 2001;115:239-252.

3. 100 N = 467 75 51 Percentage 50 31 25 8 8 0 Cardiac failure Infection Hemorrhage Hepaticcirrhosis Nonleukemic Cause of Death and Relationship to Iron Overload in MDS Death in low-risk MDS Cardiac failure is more common in transfused than in nontransfused patients (P = .01) Malcovati L, et al. J Clin Oncol. 2005;23:7594-7603.

4. 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

5. 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. WPSS = WHO classification-based Prognostic Scoring System Sanz G, et al. Presented at 50th Annual Meeting of the American Society of Hematology. San Francisco, CA, 8 December 2008. Abst 640.

6. EHA 2010: Independent Impact of Transfusion Dependence and IO on Survival in MDS 1.0 Transfusion independent 0.8 0.6 Cumulative Proportion Surviving 0.4 Transfusion dependent 0.2 P < .01 0.0 0.00 5.00 10.00 15.00 20.00 Survival Time (years) Arnan M, et al. 2010 Annual Meeting of the European Hematology Association. Abst 314.

7. 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) Serum ferritin (ng/mL) ALT (U/L) 70 3000 60 2500 50 2000 Median Serum Ferritin (ng/mL) 40 Mean ALT (U/L) 1500 30 1000 20 Mean actual dose: 19.2 ± 5.4 mg/kg/day 500 10 0 0 Baseline Baseline 3 3 6 6 9 9 12 12 Time (months) Gattermann N, et al. Leuk Res. 2010 [Epub ahead of print].

8. EPIC: Iron Chelation With Deferasirox Reduced LPI at Each Time Point Mean LPI (+SD) pre- and post-deferasirox administration at baseline and after repeat doses † Mean LPI (μmol/L) Normal threshold * * (n = 225) (n = 222) (n = 210) (n = 220) (n = 165) (n = 164) (n = 147) (n = 138) *P< .0001; †P = .0037 vs pre-administration at baseline. LPI = labile plasma iron. Gattermann N, et al. Leuk Res. 2010 [Epub ahead of print].

9. 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.

10. Matched-Pair Analysis Results: Patient Survival AML = acute myeloid leukemia Fox F, et al. Presented at ASH 2009 [Blood. 2009;114(11):abst 1747].

11. 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 OS = overall survival Rose C, et al. Leuk Res. 2010;34:864-870.

12. Iron Chelation in MDS: Patient Selection RBC-transfusion-dependent MDS Serum ferritin > 1000 µg/L Risk score Co-morbidities? WPSS RA, RARS, RCMD, RCMD-RS, 5q− RAEB IPSS Low and Int-1 Int-2 and High YES NO Iron chelation? RAEB = refractory anemia with excess blasts Gattermann N, et al. Hematol Oncol Clin North Am. 2005;19(suppl 1):18-25.

13. Iron Chelator Treatment Selection in MDS: Considerations Greenberg PL, et al. JNCCN. 2009;7(Suppl 9):S1-S16.

14. 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

15. 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