Managing the Patient With MDS and Iron Overload

1. Managing the Patient With MDS and Iron Overload Aristoteles Giagounidis, MD, PhD Associate Professor of Medicine Head, Hematology/Oncology Clinical Research Unit St. Johannes Hospital Duisburg, Germany

2. Case History • 68-year-old financial advisor CABG = coronary artery bypass graft; NIDDM = noninsulin-dependent diabetes mellitus; PRBC = packed red blood cell

3. Clinical Examination

4. Diagnostic Tests: Peripheral Blood Count MCV = mean corpuscular volume; WBC = white blood cells

5. Diagnostic Tests: Other Blood Tests EPO = erythropoietin; LDH = lactate dehydrogenase

6. Diagnostic Tests: Other

7. Final Diagnosis: RCMD Features IPSS = International Prognostic Scoring System; RCMD = refractory cytopenia with multilineage dysplasia

8. International Prognostic Scoring System (IPSS) *Good: normal, -Y, del(5q), del(20q); poor: complex (≥ 3 abnormalities) or chr 7 anomalies; intermediate: other abnormalities. Hb < 10.0 g/dL; ANC < 1.8 x 109/L; platelet count < 100 x 109/L ANC = absolute neutrophil count Greenberg P, et al. Blood. 1997;89:2079-2088.

9. Hematologist: Patient Prognosis • Patient was told by general practitioner that he should be evaluated at a specialized hematology center • Comments from hematologist: • No sensible treatment option at this stage for this lower-risk patient • Patient should remain on transfusions only • Iron chelation would not be indicated (probably due to short life expectancy) • Patient was severely depressed

10. Initial Treatment • Patient had a hypoplastic bone marrow with normal karyotype • Was treated with antithymocyte globulin and cyclosporine A within a clinical trial • Became transfusion independent within 3 months of therapy

11. Patient Developed Iron Overload • After 4 months of treatment, iron chelation was started after reduction of both corticosteroids and cyclosporine A ALT/AST = alanine transaminase/aspartate transaminase; EF = ejection fraction; ULN = upper limit of normal

12. Properties of an Ideal Chelator

13. Overview of Deferasirox Deferasirox Summary of Product Characteristics, 09/12/2009.

14. Patient Status at Initiation of Chelation Therapy • Deferasirox was initiated at 20 mg/kg

15. Overview: Outcomes With Deferasirox

16. Cardiac and Liver Function Outcomes With Deferasirox Therapy Number x ULN Cardiac EF (%)

17. Disease Progression • In 2007, the patient progressed to RAEB-II • Treatment with AZA was begun • Result: SD after 6 courses of therapy • Deferasirox discontinued at this point due to short predicted OS • AZA continued for another 7 courses • Patient ultimately developed frank AML and passed away quickly AML = acute myeloid leukemia; AZA = azacitadine; OS = overall survival; RAEB = refractory anemia with excess blasts; SD = stable disease

18. Sensible Iron Chelation Therapy in MDS Serum ferritin > 1000-2000 ng/mL Transfusion dependency 20-30 x Low risk ICT: Yes IPSS risk High risk ICT: Maybe ICT = iron chelation therapy.

19. Sensible Iron Chelation Therapy in MDS (cont) High-risk IPSS Palliative? Time gain? Curative? Consider ICT in selected cases No ICT Consider ICT in selected cases

20. Conclusions: Lessons Learned • Identifying candidates for ICT depends on risk scoring and goals of MDS treatment • Transfusion-dependent lower-risk patients with serum ferritin >1000-2000 ng/mL are appropriate candidates • Deferasirox therapy reduced serum ferritin, increased cardiac EF, and decreased LFTs in this lower-risk patient • After progression to higher-risk disease: • Consider continuing ICT in patients whose treatment has potential for cure and/or lengthened survival • Discontinue ICT in patients with higher-risk MDS whose treatment is palliative