1. Slide 1 of 16 Dose Titration in a Patient with Myelodysplastic Syndromes

2. Slide 2 of 16 Background The cornerstone of therapy in patients with myelodysplastic syndromes (MDS) is supportive care with blood transfusions With a median survival of 40–60 months, International Prognostic Scoring System (IPSS) low-risk and intermediate-1-risk MDS patients live long enough to develop clinical consequences of iron overload

3. Slide 3 of 16 Background Complications of iron overload include heart failure/arrhythmias, liver disease, and diabetes mellitus Transfusion dependency has a significant impact on survival in MDS 1 –A 30% greater risk of death was evident for every 500 ng/mL increase in serum ferritin above 1000 ng/mL 1 1. Malcovati L, et al. J Clin Oncol. 2005;23:7594-7603.

4. Slide 4 of 16 Patient Presentation 69-year-old female patient with IPSS Int-1- risk MDS presented with baseline serum ferritin level of 3214 ng/mL

5. Slide 5 of 16 Treatment History Patient has been transfusion-dependent for 2 years, receiving 2 units of packed red blood cells per month She has had no prior chelation therapy

6. Slide 6 of 16 Question Should this patient be started on chelation therapy? A. No B. Yes, with deferiprone C. Yes, with deferasirox

7. Slide 7 of 16 Initiation of Chelation Therapy Iron chelation should be initiated when serum ferritin levels ≥ 1000 ng/mL The patient’s serum ferritin is considerably above that level and she is expected to live long enough to be at risk of clinical complications of iron overload Chelation therapy should be initiated

8. Slide 8 of 16 Choosing a Chelator Although deferasirox is approved for use in patients with MDS, deferiprone is not approved for this indication and thus is not an appropriate choice Therefore, treatment with deferasirox was initiated at 20 mg/kg/day Desferrioxamine, also approved for use in MDS, would be an acceptable alternative. However, the IV infusions required with desferrioxamine would place an unnecessary burden on an elderly patient

9. Slide 9 of 16 Question After 2 weeks, the patient began to experience moderately severe diarrhea. How should the diarrhea be managed? A.Supportive therapy with antidiarrheal medication and hydration only B.Supportive therapy as above, plus dose reduction C.Interruption of therapy until diarrhea resolves

10. Slide 10 of 16 Managing Deferasirox-Related Diarrhea Mild to Moderate The patient was given an antidiarrheal medication and adequate hydration was maintained –Despite these measures, diarrhea episodes continued to occur Deferasirox dose was reduced to 10 mg/kg/day After 1 week, diarrhea episodes had fully resolved Deferasirox dose was gradually increased over the subsequent 2 weeks to 20 mg/kg/day in increments of 5 mg/kg/day With severe diarrhea, deferasirox should be interrupted, then reintroduced at 10 mg/kg/day and gradually escalated; if diarrhea continues to be unmanageable on reintroduction, deferasirox should be discontinued

11. Slide 11 of 16 Response to Treatment Serum Ferritin Following 6 months of treatment, patient’s serum ferritin levels remained essentially unchanged from baseline (3145 ng/mL)

12. Slide 12 of 16 Question What should the next step be? A. Switch to desferrioxamine B. Consider deferiprone C. Increase dosage of deferasirox

13. Slide 13 of 16 Dosage Titration Since inadequate dose titration may be the cause of suboptimal response, this possibility should be explored Deferasirox dose was increased to 30 mg/kg/day By month 9, serum ferritin levels had decreased to 2759 ng/mL and by month 12 they had been further reduced to 2504 ng/mL Patient is continuing to receive deferasirox 30 mg/kg/day and steady decreases in serum ferritin levels have been observed No further adverse events have been noted

14. Slide 14 of 16 Deferasirox Therapy in MDS Induces Dose-Dependent Changes in Iron Burden Planned Starting Deferasirox Dose (mg/kg/d) 5 102030 LIC n = 3 n = 6 n = 7 n = 12 -20 -15 -10 -5 0 5 10 15 Change in LIC (mg Fe/g dw) In MDS patients, iron balance was achieved with 10 mg/kg/d and negative iron balance with 20 and 30 mg/kg/d LIC = liver iron concentration. Porter JB, et al. Eur J Haematol. 2008;80:168-176.

15. Slide 15 of 16 Conclusions Diarrhea Mild diarrhea can be managed with supportive care, without the need for dose reduction/discontinuation of treatment Depending on severity, moderate diarrhea may require temporary dose adjustment Once the diarrhea has resolved, deferasirox dosage can be gradually escalated from 10 mg/kg/day in steps of 5 mg/kg/day until the target dose is reached

16. Slide 16 of 16 Conclusions Serum Ferritin MDS patients receiving regular blood transfusions are at risk of developing chronic iron overload and may require chelation therapy –According to current guidelines, chelation therapy should be initiated once serum ferritin levels ≥ 1000 ng/mL Deferasirox dose should be reviewed regularly at 3- to 6-month intervals and adjusted according to trends in serum ferritin levels Gattermann N. Leuk Res. 2007;31(Suppl 3):S10-S15.