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

Case History 68-year-old financial advisor Past medical history NIDDM, coronary artery disease, CABG x 3 in 2001 Developed macrocytic anemia in Jan 2003 (MCV 109 fl) Transfusion frequency Initial transfusion frequency: 2 PRBC/month Over next 2 years: increasing transfusion dependence, reaching 3-4 U/wk in 2005 CABG = coronary artery bypass graft; NIDDM = noninsulin-dependent diabetes mellitus; PRBC = packed red blood cell

Clinical Examination History and physical exam Reduced overall condition, peripheral edemas, dyspneic at little exertion, depressed Pulse 112/min, RR: 125/65 mm Hg No fever present No splenomegaly, hepatomegaly, or lymphadenopathy present

Diagnostic Tests: Peripheral Blood Count Hemoglobin 7.6 g/dL MCV 108 fL Platelets 72  109/L WBC 1.2  109/L Neutrophils 0.6  109/L (50%) Monocytes 0.4  109/L (33%) Lymphocytes 0.2  109/L (18%) MCV = mean corpuscular volume; WBC = white blood cells

Diagnostic Tests: Other Blood Tests Result Viral serology Negative Anti-platelet antibodies Absent Vitamin B12 and folic acid levels Normal LDH 221 U/L (normal range: ≤ 240 U/L) Serum ferritin 5600 µg/L (normal range: 15-350 µg/L) EPO 1280 U/L (normal range: 6-25 U/L) EPO = erythropoietin; LDH = lactate dehydrogenase

Diagnostic Tests: Other Bone marrow aspiration Hypocellular bone marrow (1+) Reduction and dysplasia of megakaryocytes Dyserythropoiesis Significant dysgranulopoiesis 3% blasts Karyotype: 46, XY [20]

Final Diagnosis: RCMD Features 3 cytopenias < 1% peripheral blasts Trilineage dysplasia < 5% bone marrow blasts Normal karyotype IPSS = International Prognostic Scoring System; RCMD = refractory cytopenia with multilineage dysplasia

International Prognostic Scoring System (IPSS) Score Prognostic variable 0.5 1.0 1.5 2.0 Bone marrow blasts (%) < 5 5-10 11-20 21-30 Karyotype* Good Intermediate Poor Cytopenias 0/1 2/3 *Good: normal, -Y, del(5q), del(20q); poor: complex (≥ 3 abnormalities) or chr 7 anomalies; intermediate: other abnormalities. Score IPSS subgroup Median survival (years) Low 4.8 0.5-1.0 Int-1 2.7 1.5-2.0 Int-2 1.1 > 2.5 High 0.5 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.

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

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

Patient Developed Iron Overload Overall transfusion load > 100 U without iron chelation Cardiac EF 33% by echocardiography ALT/AST (LFTs) 5X ULN Direct bilirubin 1.4 mg/dL 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

Properties of an Ideal Chelator Goal Properties To control body iron High and specific affinity for Fe3+ High chelating efficiency To minimize iron toxicity 24-hour coverage Slow metabolism and elimination rate Good tissue penetration with stable iron complex Acceptable toxicity-efficacy profile Clear drug-dose relationship to efficacy and toxicity No iron redistribution Patient acceptance/ compliance Simplicity and ease of monitoring Oral bioavailability Suitable for monotherapy

Overview of Deferasirox Property Deferasirox Usual dose 20-30 mg/kg/d (to maximum of 40 mg/kg/d) Route Oral once daily Half-life 8-16 h Excretion Fecal Adverse effects GI disturbances, rash, mild nonprogressive creatinine increase, ophthalmologic, auditory, elevated liver enzymes Status Licensed Approved indications Treatment of chronic iron overload due to frequent blood transfusions Deferasirox Summary of Product Characteristics, 09/12/2009. 13 13

Patient Status at Initiation of Chelation Therapy Serum ferritin 6200 ng/mL Creatinine Value: 0.9 mg/dL Clearance: 82 mL/min Concomitant medications: Furosemide 40 mg Enalapril 10 mg Bisoprolol 10 mg Metformin 850 mg bid Deferasirox was initiated at 20 mg/kg

Overview: Outcomes With Deferasirox Transfusion burden No change Serum ferritin Decreased from 6200 ng/mL to 2100 ng/mL Creatinine Increased from 0.9 mg/dL to 1.3 mg/dL Blood values Platelets slightly increased to 95,000/µL WBC slightly increased to 1700/µL

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

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

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. 18

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

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