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Transcript
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 • NIDDM, coronary artery disease, CABG x 3 in 2001
history
• 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
• Reduced overall condition, peripheral
History and
physical exam 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
Test
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
0.5
<5
5-10
Karyotype*
Good
Intermediate
Cytopenias
0/1
2/3
Bone marrow blasts (%)
1.0
1.5
2.0
11-20
21-30
Poor
*Good: normal, -Y, del(5q), del(20q); poor: complex (≥ 3 abnormalities) or chr 7 anomalies; intermediate:
other abnormalities.
Score
IPSS subgroup
Median survival (years)
0
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 toxicityefficacy 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.
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
Increased from 0.9 mg/dL
to 1.3 mg/dL
• Platelets slightly increased
to 95,000/µL
• WBC slightly increased to
Creatinine
Blood values
1700/µL
Number x ULN
Cardiac EF (%)
Cardiac and Liver Function Outcomes With
Deferasirox Therapy
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
Transfusion
dependency
ICT: Yes
20-30 x
Serum ferritin > 10002000 ng/mL
Low risk
IPSS risk
ICT: Maybe
High risk
ICT = iron chelation therapy.
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
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