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 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

3. 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

4. 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

5. 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: µg/L)
EPO
1280 U/L (normal range: 6-25 U/L)
EPO = erythropoietin; LDH = lactate dehydrogenase

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

7. 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

8. 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
Int-1
2.7
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:

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
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

12. 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

13. 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

14. 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

15. 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

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

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 > ng/mL
Transfusion dependency
20-30 x
Low risk
ICT: Yes
IPSS risk
High risk
ICT: Maybe
ICT = iron chelation therapy. 18

19. 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

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 > 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