11/17/2014
Iron Deficiency Anemia: Prevalence and Treatment in Oncology
Lawrence Tim Goodnough, MD
Professor of Pathology and Medicine
Stanford University School of Medicine
Director, Transfusion Services
Stanford University Medical Center
Stanford, CA
Educational Objectives
• Know the prevalence and importance of iron deficiency anemia in oncology patients
• Understand the implications of iron‐restricted erythropoiesis for the treatment of anemia in oncology patients
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Call to Reduce Transfusions:
National Summit on Overuse ‐ September 2012
“Overuse/inappropriate use is defined as the use of a health service in circumstances where the likelihood of benefit is negligible or zero, and the patient is exposed to the risk of harm.”
Blood transfusion is one of five “overuse” interventions targeted
http://www.jointcommission.org/two_leading_health_care_quality_organizations_hold_national_summit_to_build_co
nsensus_around_ways_to_minimize_overuse_of_five_treatments/
http://www.jointcommission.org/overuse_summit/
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Blood Risks
• Historic Blood Risks
“Blood is inherently risky and dangerous…” U.S. Blood Shield Laws
Zuck T. Legal liability for transfusion injury in the AIDS era.
Arch Pathol Lab Med 1990;114:309-15
• Current blood risks
• Emerging blood risks: age of stored blood and clinical
patient outcomes
Perkins H, Busch M. Transfusion 2010;50:2080-2099.
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Potential risks of blood transfusion
1. 2. Infectious Agents
Transfusion Reactions
a. Alloimmunization
b. Febrile
c. Allergic
3. 4. 5. 6. 7. 8. Medical Errors: (wrong blood to patient due to mislabeled specimen or patient misidentification)
Transfusion Associated Acute Lung Injury (TRALI)
Transfusion Associated Circulatory Overload (TACO) Iron Overload
Immunomodulation
Storage Lesions: Age of Blood
Goodnough, Levy, Murphy. Lancet 2013;381:1852-3.
Current status of red cell preservation (21 D) and National Blood Policy
Chaplin et al. N Engl J Med 1974;291:68-74.
• Unsettled questions regarding quality and availability of preserved RBC
• Periodic shortages of blood reflect inefficient management • Unresolved questions about effectiveness of 2,3 DPG‐
depleted RBC
Can blood transfusions be not only ineffective, but injurious? Shander AS, Goodnough LT. Ann Thor Surg 2014;97:11-14.
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Duration of red cell storage and complications after cardiac surgery
• 2872 patients with 8802 RBC ≤ 14 D 3130 patients with 10,782 RBC > 14D. • Median storage 11 D vs 20 D
• 1 year mortality: 7.4% vs 11.0%
• Composite complications: 22% vs 26% Koch et al. N Engl J Med 2008;258:1229‐38
NHLBI ‘Recess Trial’
•
•
•
•
Start date 11/1/09
Fresh (<10 D) vs old (≥ 21 D) blood
Primary outcome: MODS Secondary outcome: mortality Steiner M Transfusion 2009;49:1286‐1290
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Randomized Trial Results: Red Cell Storage Age is Not Associated with a Significant Difference in Multiple‐Organ Dysfunction Score or Mortality in Transfused Cardiac Surgery Patients
Steiner ME, et al. Transfusion 2014;54:s15A
Anemia of Chronic Disease: Underlying Causes
Associated Diseases
Infections (acute and chronic)
Estimated Prevalence
18%-95%
Viral infections, including human immunodeficiency virus infection
Bacterial
Parasitic
Fungal
Cancer
30%-77%
Hematologic
Solid tumor
Autoimmune
8%-71%
Rheumatoid arthritis
Systemic lupus erythematosus and connective-tissue diseases
Vasculitis
Sarcoidosis
Inflammatory bowel disease
Chronic rejection after solid-organ transplantation
8%-70%
Chronic kidney disease and inflammation
23%-50%
Weiss G, Goodnough LT. N Engl J Med. 2005;352:1011‐1023.
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Etiology of Anemia in Patients With Cancer
• Direct effects of the disease (eg, bone marrow infiltration, blunted erythropoietin response to hypoxia)
• Blood loss (eg, hemorrhage, surgery, phlebotomy)
• Effects of chemotherapy or radiation therapy
– Myelosuppression
– Nephrotoxicity
– Thrombocytopenia / bleeding
– Neutropenia / infection
• Nutritional deficiencies (eg, iron)
• Inflammation or infection • Autoimmune hemolysis
• Endocrine disorders (eg, hypothyroidism)
Adapted from Schwartz RN. Am J Health-Syst Pharm. 2007;64:S5-S13.
Causes and Frequency of Anemia in the Elderly Iron Deficiency 25%
Inflammation
25%
Chronic Kidney Disease
25%
Unexplained Anemia
25%
≥ 65 years of age
Goodnough LT. Am J Hematol 2014;89(1):88‐96.
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Conditions Associated with Absolute Iron Deficiency
• DIETARY
– Balance of source vs needs (growth/development)
• WOMEN’S HEALTH
– Pregnancy/breast feeding
– Menstrual blood losses
• CHRONIC BLOOD LOSS
– Blood donation
– Non‐steroidal anti‐inflammatory drugs (NSAIDs)
– GI neoplasms
– GI parasites (developing countries) Goodnough LT. Sem Hematol. 2009;46(4):325-327. See also Healthy People 2010: www.healthypeople.gov
Conditions Associated with Absolute Iron Deficiency
• DECREASED IRON ABSORPTION
– Celiac disease
– Heliobacter pylori infection
– Autoimmune atrophic gastritis
– Hereditary: iron refractory iron deficiency anemia (IRIDA)
Goodnough LT. Sem Hematol. 2009;46(4):325-327.
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Other Conditions Associated with Iron‐Restricted Erythropoiesis
– Inflammatory disease (inflammatory bowel disease, rheumatoid arthritis)
– Infection
– Malignancy
– Congestive heart failure
– Diabetes mellitus
– Chronic kidney disease
– Aging
Goodnough LT. Sem Hematol. 2009;46(4):325-327.
Anemia of Chronic Disease: Biology and Iron
Inflammation
(eg, Cancer)
IL-6
Macrophage
Activation
Liver
Hepcidin
Decreased
Red Cell
Survival
Decreased
Iron
Absorption
TNF-, IL1-, IFN-
Increased
Iron
Sequestration
Decreased
Erythropoietin
Response
to Anemia
Bone
Marrow
Suppression
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NCCN Guidelines: Symptomatic Anemia
Treatment
Transfuse as indicated based on
symptoms and institutional or
published guidelines
Consider ESA therapy after patient counseling
regarding risks and benefits of ESAs
Additional Evaluation
• Periodic re-evaluation for
symptoms and risk factors
• Transfuse as indicated based on
symptoms and institutional or
published guidelines
Iron studies: Serum iron, total
iron-binding capacity, serum
ferritin
National Comprehensive Cancer Network. Practice Guidelines in Oncology: Cancer- and Chemotherapy-Induced
Anemia 2009. Available at: www.nccn.org
Algorithm for the evaluation of anemia Hb Hemoglobin
SF Serum Ferritin
GFR Glomerular Filtration Rate
ACI Anemia of Inflammation
UAE Undifferentiated Anemia of the Elderly
MDS Myelodysplastic Syndrome
ESA Erythropoiesis Stimulating Agent
MH Malignant Hematology (e.g. chronic lymphocytic leukemia)
Goodnough LT. Am J Hematol 2014;89(1):88‐96.
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Clinical Situations Affecting Markers of Iron Status
Test
Elevated Values
Serum iron
• Evening sampling
Decreased Values
Inflammation / infection
• Recent iron intake
• Hemolysis
Serum transferrin
Serum ferritin
• Oral contraceptives
• Inflammation / infection
Inflammation / infection
• Vitamin C deficiency
• Hyperthyroidism
• Hypothyroidism
• Aging
• Vigorous exercise
• Malignancy
• Liver disease
• Alcohol consumption
• Oral contraceptives
For patients with chronic
inflammatory illnesses, including
cancer, the traditional non-RBC
iron parameters are unreliable
Bistrian BR et al. Am J Kidney Dis. 1999;34(suppl 2):S35‐S39. Brugnara C. Clin Chem. 2003;49:1573‐1578.
Percent Hypochromic Red Cells (%HYPO)
• Flow cytometry with 2 detectors
– High angle for Hb content
– Low angle for cell size
– Allows construction of a histogram for Hb content
Depleted Iron Stores
Intense Erythropoietic
Stimulus, eg, ESA
Goodnough et al Blood 2010; 116:4754-61.
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CHr Reflects Recent Iron Supply
(after IV Iron)
Normal
threshold
29pg
Mature RBCs
Reticulocytes
Hb content pg
Hb content pg
Hb content pg
Brugnara C et al. Blood. 1994;83:3100-3101.
Other Conditions Associated with Iron‐Restricted Erythropoiesis
• FUNCTIONAL IRON DEFICIENCY • Erythropoiesis Stimulating Agents (ESA) therapy
Goodnough LT. Sem Hematol. 2009;46(4):325-327.
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Change in Iron Status After Initiation
of ESA in Healthy Subjectsa
40
Ferritin, ng/mL
100
TSAT, %
30
20
10
0
75
50
25
0
0
2
4
6
Treatment Time, days
aAdministration
8
0
2
4
6
8
Treatment Time, days
of 4 doses of ESA over 7 days
Eschbach JW et al. Kidney Int. 1992;42:407-416.
Functional Iron Deficiency: Impact of Erythropoiesis on Iron Saturation
Transferrin Saturation (%)
25
20
15
Placebo
300 U/kg rHuEPO
10
600 U/kg rHuEPO
5
0
Basal
1
2
3
4
Time, days
5
6
After 3
weeks
Mean transferrin saturation in 24 patients receiving placebo, 300 U/kg rHuEPO, or 600 U/kg rHuEPO. All patients were supplemented with oral iron.
rHuEPO= recombinant human erythropoietin. Mercuriali F, et al. Transfusion 1993;33:55‐60.
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Hb Change (g/dL)
IV vs. Oral Iron: Effect on Hemoglobin
1.8
1.6
1.4
1.2
1.2
1
0.8
IV Iron (N=145)
Oral Iron (N=43)
IV Iron (N=83)
Oral Iron (N=33)
P=.0010
P=.0045
0.6
0.6
0.4
0.2
0.2
0.1
0
With ESA
Without ESA
Spinowitz BS, et al. J Am Soc Nephrol 2008;19:1599‐1605.
Enhanced Erythropoiesis With IV Iron in Patients With CKD Reduction
of ESA Dose
Achieved, %
Duration,
mo
Type of IV
Iron Used
Besarab1
6
Iron dextran
25 to 150 mg
q wk
40
Fishbane2
4
Iron dextran
200 mg
q wk
46
Senger3
12
Iron dextran
25 or 50 mg
q wk
75
SunderPlassmann4
12
Iron saccharate
10, 20,
or 40 mg q HD
70
Taylor5
6
Ferric gluconate
62.5 mg 2 × wk,
q wk, or q 2 wk
33
Author
Dose
1. Besarab A et al. J Am Soc Nephrol. 2000;11:530‐538.
2. Fishbane S et al. Am J Kidney Dis. 1995;26:41‐46.
3. Senger JM, Weiss RJ et al. ANNA J. 1996;23:319‐323.
4. Sunder‐Plassmann G, Hörl WH. Nephrol Dial Transplant. 1995;10:2070‐2076.
5. Taylor JE et al. Nephrol Dial Transplant. 1996;11:1079‐1083.
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Studies of IV Iron in Oncology
Patients, N
Study Period
Patient Population
Auerbach1
157
6 wks or until end
bolus treatments
Nonmyeloid malignancy
Chemotherapy
Henry2
187
8 wk
Nonmyeloid malignancy
Starting cycle of chemo
Hedenus3
67
16 wk
Lymphoproliferative
malignancy
No chemotherapy
Bastit4
396
16 wk
Nonmyeloid malignancy
Chemotherapy
Pedrazzoli5
149
12 wk
Nonmyeloid malignancy
Chemotherapy
Steinmetz6
420
12 wk
Solid tumors
1. Auerbach M et al. J Clin Oncol. 2004;22:1301‐1307.
2. Henry DH et al. Oncologist. 2007;12:231‐242.
3. Hedenus M et al. Leukemia. 2007;21:627‐632.
4. Bastit L et al. J Clin Oncol. 2008;26:1611‐1618.
5. Pedrazzoli P et al. J Clin Oncol. 2008;26:1619‐1625.
6. Steinmetz T, et al. Ann Oncol. 2013;2:475‐482.
Mean Change in Hb, g/dL
Mean Change in Hb (N=155)*
3.5
3.0
2.5
2.5
2.0
2.4
a,b
1.5
1.5
1.0
a,b
0.9
0.5
0.0
No Iron
Oral Iron
Bolus
TDI
Overall changes from baseline, P<.0001; overall difference between groups,
P<.0001; aDiffers from no iron group, P<.05; bDiffers from oral iron group, P<.05
*ITT population.
Auerbach M et al. J Clin Oncol. 2004;22:1301‐1307.
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Erythropoietic Response*
Percent of Patients With Peak Hb ≥12 g/dL
or Hb Increase of ≥2 g/dL
a,b
a,b
32%
32%
68%
68%
Responders
Patients, %
100
Nonresponders
80
60
64%
75%
40
20
36%
25%
0
No Iron
aDiffers
Oral Iron
Bolus
TDI
from no iron group; P<.01; bDiffers from oral iron group, P<.01
*ITT population
Auerbach M et al. J Clin Oncol. 2004;22:1301‐1307.
Study Schedule
Study Schedule
Baseline
3
4
5
6
7
Sodium Ferric Gluconate Dose,
125 mg/wk IV Iron Weekly for 8 Doses
Screening
and
Randomization
Oral Iron TID for 8 Weeks
8
9
10 11 12
Follow-Up
2
End Point
1
Weekly Visit Number
No Iron
Chemotherapy as Scheduled, Plus Weekly ESA
Henry DH et al. Oncologist. 2007;12:231-242.
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Change in Hb From Baseline
Mean Change in Hb, g/dL
2.8
2.4
2.0
1.6
1.2
2.4
0.8
1.6
1.5
Oral Iron
No Iron
0.4
0.0
Ferric
Gluconate
P=.0092, oral vs ferric gluconate; P=.0044, no iron vs ferric gluconate;
P=.7695, oral vs no iron
Henry DH et al. Oncologist. 2007;12:231-242.
Patients With ≥2 g/dL
Hb Increase, %
Hb Response Rate
90
80
70
60
50
40
30
20
10
0
73
Ferric
Gluconate
45
41
Oral Iron
No Iron
P=.0099, oral vs ferric gluconate; P=.0029, no iron vs ferric gluconate; P=.6687,
oral vs no iron
Henry DH et al. Oncologist. 2007;12:231-242.
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Mean Change in %HYPO
Change in %HYPO From Baseline
10
9
8
7
6
5
4
3
2
1
0
n=
7.7
6.1
4.0
Ferric
Gluconate
Oral Iron
No Iron
40
43
44
%HYPO, percent of red blood cells that were hypochromic
Henry DH et al. Oncologist. 2007;12:231-242.
NCCN Updated Guidelines:
Response Assessment
National Comprehensive Cancer Network. Practice Guidelines in Oncology: Cancer‐ and Chemotherapy‐Induced Anemia. v.2.2015,7/23/2014. Available at: www.nccn.org
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Currently Available IV Iron Preparations Trade Name
DexFerrum
High‐
molecular weight dextran
INFeD
Low‐
molecular
weight dextran
Venofer
Feraheme
Gluconate
Sucrose
Carboxy‐
methyl dextran
Mol. weight (Da)
265,000
165,000
289,000‐
440,000
34,000‐
60,000
750,000
150,000
150,000
Iron concentration (mg/mL)
50
50
12.5
20
30
50
100
Vial volume (mL)
Total‐dose or >500‐mg infusion
1‐2
2
5
5
17
2 or 10
1, 2, 5 or 10
Yes
Yes
No
No
Yes
Yes
Yes
Premedication
TDI only
TDI only
No
No
No
No
No
Yes
Yes
No
No
No
No
No
Yes
Yes
No
No
No
No
No
None
Benzyl alcohol
None
None
None
None
Carbohydrate
Test does required
Black box warning
Preservative
None
Ferrlecit
Injectafer
Monofer*
Ferric Isomaltoside
carboxymalto
1000
se
*Not approved in the US; Note: ferric gluconate and iron sucrose are also referred to as iron salts
TDI=Total‐dose infusion
Goodnough LT, Shander AS. Anesth Analg 2013;116:15‐34.
Calculated Adverse Event (AE) Rates*
Product
All AEs Combined Death (n=197)
(n=15)
Serious AE (n=119)
Other Major AE (n=48)
Iron sucrose
5.25 (5.24)
0.11 (0.11)
2.25 (2.24)
1.82 (1.82)
Ferumoxytol
745.76 (146.67)
50 (10)
583.3 (116.67)
83.3 (16.67)
Sodium ferric 6.85 (10.99)
gluconate
0.33 (0.52)
4.92 (7.85)
0.98 (1.57)
All iron dextran
27.08 (27.46)
4.86 (4.93)
9.02 (9.15)
12.5 (12.68)
HMW iron 66.47 (70.97)
dextran
6.04 (6.45)
18.13 (19.35)
42.30 (45.16)
LMW iron 9.01 (9.01)
dextran
4.50 (4.50)
2.70 (2.70)
0.90 (0.90)
Total
1.08
8.53
3.44
14.12
*Per million units
Bailie GR. Am J Health‐Syst Pharm 2012;69:310‐20.
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Rampton D, et al. Haematolgoica In Press
Conclusion
• Iron restricted erythropoiesis is a common cause of anemia
– Absolute iron deficiency
– Iron sequestration (anemia of inflammation)
– Functional iron deficiency
• Innovative alternatives to oral iron supplementation are needed to manage iron‐restricted erythropoiesis 20