Managing the Patient With MDS and Iron Overload

Aristoteles Giagounidis, MD, PhDAssociate Professor of Medicine

Head, Hematology/Oncology Clinical Research Unit St. Johannes Hospital

Duisburg, Germany

Case History

• 68-year-old financial advisor

CABG = coronary artery bypass graft; NIDDM = noninsulin-dependent diabetes mellitus; PRBC = packed red blood cell

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

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

MCV = mean corpuscular volume; WBC = white blood cells

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%)

Diagnostic Tests: Other Blood Tests

EPO = erythropoietin; LDH = lactate dehydrogenase

Test ResultViral 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)

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

IPSS = International Prognostic Scoring System; RCMD = refractory cytopenia with multilineage dysplasia

3 cytopenias< 1% peripheral blastsTrilineage dysplasia< 5% bone marrow blastsNormal karyotype

International Prognostic Scoring System (IPSS)

ScorePrognostic variable 0 0.5 1.0 1.5 2.0Bone marrow blasts (%) < 5 5-10 11-20 21-30

Karyotype* Good Intermediate Poor

Cytopenias 0/1 2/3

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

Greenberg P, et al. Blood. 1997;89:2079-2088.

*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/LANC = absolute neutrophil count

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 PropertiesTo 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 DeferasiroxUsual dose 20-30 mg/kg/d (to maximum of 40 mg/kg/d)

Route Oralonce 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

• Deferasirox was initiated at 20 mg/kg

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

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/dLto 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

Num

ber x

ULN

Card

iac

EF (%

)

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

Serum ferritin > 1000-2000 ng/mLTransfusion

dependency 20-30 x

IPSS risk

Low risk

High risk

ICT: Yes

ICT: Maybe

Sensible Iron Chelation Therapy in MDS

ICT = iron chelation therapy.

Sensible Iron Chelation Therapy in MDS (cont)

High-risk IPSS

Palliative? Curative? Time gain?

Consider ICT in selected cases

Consider ICT in selected cases

No ICT

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