ALTERNATIF OF BLOOD ALTERNATIF OF BLOOD TRANSFUSIONTRANSFUSION

OPTIONS FOR ANAEMIA MANAGEMENT

No treatment(60%)

Iron alone(7%)

Epoetin(18%)

Transfusion(15%)

European Cancer Anaemia Survey (ECAS), Ludwig et al. Ann Oncol 2002; 13 (Suppl 5): 169 [A623PD]

Management Anemia :

Blood Transfusion (erytrocyte) : No Transfusion : HB >10g/dl

Indication Hb <7g/dlHb 7-10 g/dl UnclearHb <8g/dl for age >65th,

Kardiovascular Disease and Pulmonary Disease

Drawbacks of Transfusion

Emergency treatment for acute, severe anaemia.

Usually not given until symptomatic severe anaemia (Hb 8–9 g/dl).

Effects are immediate, but transient and unsustainable.1

Associated with serious side effects.2, 3

(iron overload, immunosuppression, haemolysis, infections).1. Österborg. Med Oncol 1998; 15 (Suppl 1): S47–9

2. Williamson et al. BMJ 1999; 319: 16–193. Jensen et al. Blood 2003; 101: 91–6

Drawbacks of Transfusion

Transfused red blood cells are functionally defective with shorter survival time.

Blood supply becoming less available owing to decreasing donor pool1 and requirement for more stringent processing.2

Inconvenient for both the patient and healthcare professional.

1. Brittenham et al. Hematology (Am Soc Hematol Educ Program) 2001: 422–32 2. Goodnough. Curr Opin Hematol 2001; 8: 405–10

Transfusion - Transmitted Infections

Indonesian Red Cross (Position on Screening):– All blood supply screened

– Major blood-borne diseases screened (HIV, HCV, HBV, Syphylis ).

Historical data in Indonesia: Incidence of HIV and hepatitis C from blood donor have been documented (Syaifullah Noer, 1994).

Up to 60% haemodialysis patients infected Hepatitis C (Haemodialysis center Indonesian multi center study-2005, PIT Pernefri july ’05).

Several Private Hospitals re-screen blood supply to avoid blood-borne diseases (additional cost to patients).

Adverse Events Associated with Blood Transfusions

Incorrect blood/component transfused

Acute transfusion reaction

Delayed transfusion

reaction

Graft vs host disease

Acute lung injury

Post-transfusion purpura

Transfusion-transmitted infections

52%

15%

14%

2%8%

6%

3%

Williamson et al. BMJ 1999; 319: 16–19

ALTERNATIF OF BLOOD TRANSFUSION:

Intravenous iron: when to use it?Intravenous iron: when to use it?

Eritropoetin: when to use it?Eritropoetin: when to use it?

Erythropoietin: Properties

Glycoprotein 34 Kda, regulating erythropoiesis.

Produced in kidney and liver; trace amounts in brain.

Produced primarily by renal peritubular fibroblasts and transported via bloodstream to bone marrow.

Production is upregulated under anaemic or hypoxic conditions.

Binds to specific receptor on erythroid progenitor cells.

Stimulates proliferation, differentiation, and survival of erythroid progenitors.

Fisher. Exp Biol Med 2003; 228: 1–14

Lacombe (1998, 1999) Krantz (1991) Bernaudin (2000)

Decrease in oxygen delivery to the kidneysDecrease in oxygen delivery to the kidneys

Peritubular interstitial cells detect low oxygen levels in the blood

Proerythroblasts in red bone marrow mature more quickly into reticulocytes

More reticulocytes enter circulating blood

Larger number of RBCs in circulation

Increased oxygen delivery to tissues

Increased oxygen delivery to tissues

Return to homeostasis when response brings oxygen delivery to kidneys back to normal

Return to homeostasis when response brings oxygen delivery to kidneys back to normal

EPO

Peritubular interstitial cells secrete EPO into the blood

Mulcahy L. Semin Oncol. 2001;28(2 suppl 8):19-23.

The Physiologic Role of EPO

Initial Categorization of Anemia

Reticulocyte Production Index

> 2% ≤ 2%

Hemolytic Hypoproliferative Ineffective

Smear N Macrocytic/microcytic

No fragments Fragments

LDH N LDH

Bilirubin N - Bilirubin N -

Cellularity Cellularity

Normal morphology Megaloblastoid/reduced hemoglobinization

Anemia of Chronic Disease

Second most common form of anemia, after iron deficiency anemia.

Develops after 1 or 2 months of sustained disease.

Severity proportional to severity of underlying disease.

Huguley CM Jr. In: Hurst J W, ed. Medicine for the Practicing Physician. Woburn, Mass: Butterworth; 1983.

Anemia of Chronic Disease: Etiology

Chronic infections

Noninfectious inflammatory diseases

Renal disease

Neoplastic disorders

Huguley CM Jr. In: Hurst J W, ed. Medicine for the Practicing Physician. Woburn, Mass: Butterworth; 1983.

Anemia of Chronic Disease: Mechanisms

Huguley CM Jr. In: Hurst J W, ed. Medicine for the practicing physician. Woburn, Mass: Butterworth; 1983.

Exact cause of anemia of chronic disease is not fully understood.

However, at least 3 elements are involved– Impaired reutilization of iron– Shortened life span of erythrocytes – Reduced production of EPO

Anemia of Chronic Disease: Laboratory Values

Laboratory Variable ResultHematocrit Low normal to below normal

Hb Low

Reticulocyte count Low to normal

Serum ferritin level Normal to elevated

Serum iron Low

Total iron binding capacity Normal to reduced

Bone marrow iron stores Elevated

Ph

arm

aceu

ticals

Prevalence of Anemia of Cancer

Chemotherapy-related anemiaAnemia of cancer,

no cancer treatment

Groopman JE, et al. J Natl Cancer Inst. 1999;91:1616-1634. Health Care Industries Association Inc., 1998.

38%

Cancer-Related Anemia, Total Population = 870,000

62%

79%

21%

Hematologic malignancies (n = 2956) Solid tumors (n = 11,071)

36%* anemic at enrollment

66% became anemic during 6-month study

36% received treatment for anemia

Initiated when median Hb = 9.6 g/dL

53%* anemic at enrollment

72% became anemic during 6-month study

47% received treatment for anemia

Initiated when median Hb = 8.8 g/dL

*Anemia defined as Hb <12 g/dL.

Ludwig H, et al. ASCO 2002. Abstract 884.

Prevalence of Anemia in Various Cancer Populations

Activatedimmune system

Anemia

Shortenedsurvival

Anemia-inducing substance

RBCs

ReducedEPO

production

Impairediron

utilization

SuppressedBFU-ECFU-E

TNFErythrophagocytosis

Dyserythropoiesis

IFN-IL-1TNF1-antitrypsin

IFN-IL-1TNF

IL-1 , TNF

Macrophages

Tumor cells

Nowrousian M et al. In: Smyth JF, et al, eds. rhErythropoietin in cancer supportive treatment. New York, NY: Marcel Dekker Inc; 1996:13-34.

Etiology of Cancer-Related Anemia Is Multifactorial

Erythropoietic agents produce a smooth and sustained Hb increase

Österborg. Med Oncol 1998;15(Suppl 1):S47–9Ludwig et al. N Engl J Med 1990;322:1693–9

Erythropoietic agents

Transfusions

0 30 60 90 120 150 180 210

Hb

(g

/dL

)

Days of treatment

8

12

14

10

4

6

transfusion given

Advantages of Epoetin over Transfusion

Epoetin

– can be used for treatment of mild-to-moderate anaemia1, 2

– produces smooth and sustained increase in Hb3

– improves Quality of Life by maintaining higher Hb targets

– is well tolerated

– is more convenient than transfusions

– induces red blood cells that function normally1

1. Ludwig et al. Hematol J 2002; 3: 121–302. Rizzo et al. J Clin Oncol 2002; 20: 4083–1073. Ludwig et al. N Engl J Med 1990; 322: 1693–9

History of Anemia Rx in Oncology

1907-1991– Red cell transfusion only

available therapy

– Focus on severe anemia (Hb < 8 g/dL)

1991-1997– rhuEPO to decrease

transfusion risk

– Focus on prevention/ treatment of severe anemia

1998-2003– ESAs to improve quality

of life

– Focus on mild/moderate anemia (Hb 10-12 g/dL)

2004-2008– Flexible dosing

– Iron

Evidence-based guidelines recommend Hb levels be maintained between Evidence-based guidelines recommend Hb levels be maintained between 11 and 12-13 g/dL during erythropoietic therapy11 and 12-13 g/dL during erythropoietic therapy

Recommendation ASCO/ASH[1] NCCN[2] EORTC[3]

Initiate ESA therapy

Hb ≤ 10 g/dL (clinical decision if Hb

> 10 to ≤ 12 g/dL)

Hb ≤ 11 g/dL Hb 9-11 g/dL(clinical decision if

Hb ≤ 11.9 g/dL)

Goal of treatment Maintain Hb at or near 12 g/dL

Maintain between10-12 g/dL

Target Hb should be 11-13 g/dL

1. Rizzo JD, et al. J Clin Oncol. 2008;26:132-149. 2. NCCN Clinical Practice Guidelines in Oncology. Available at: http://www.nccn.org. Accessed May 27, 2008. 3. Bokemeyer C, et al. Eur J Cancer. 2004;40:2201-2216.

Summary of International Evidence-Based Guidelines

Options for Erythropoietic Therapy

FDA-approved doses Epoetin alfa[1]

– 150 U/kg SQ TIW

– 40,000 U SQ weekly

Darbepoetin alfa[2]

– 2.25 µg/kg SQ weekly

– 500 µg SQ every 3 weeks

Epoetin beta [3]

- 30.000 U SQ weekly

Other commonly used doses Darbepoetin alfa

– 200 µg every 2 weeks

– 300 µg every 3 weeks

1. Epoetin alfa [package insert]. Thousand Oaks, Calif; Amgen Inc: 2008. 2. Darbepoetin alfa [package insert]. Thousand Oaks, Calif; Amgen Inc: 2008

3. Bokemeyer et al. Eur J Cancer 2006, doi:10.1016/j.ejca.2006.10.014

Ph

arm

aceu

ticals

Iron Supplement forIron Deficiency Anemia

Intravenous iron: when to use it?Intravenous iron: when to use it?

1316

13-16

13-1612-14

Iron values in the development of iron deficiency anaemia

TREATMENT

Therapeutic Trial•Should be via oral route

* Expect - peak reticulocytosis at 1 to 2 week - significant increase in Hb concentration at 3-4 weeks - one-half of Hb deficit corrected at 4-5 weeks - Hb level normal at 2 to 4 months

•Unless there is continued bleeding, absence of these changes indicates that iron deficiency is not cause of anemia. Iron treatment should be stopped and another mechanism sought

Oral Iron Therapy* Dietary sources may not be sufficient for treatment

* Safest, cheapest are oral ferrous salt* Nonenteric coated forms are preferred* Avoid multiple hematinics* Do not give with meals or antacids or inhibitor acid productions* Continue for 12 months after Hb level is normal to replenish iron stores* Daily total 150-200 mg elemental iron in 3 to 4 doses, each 1 h before meals

TREATMENT

Intravenous iron: when to use it?Intravenous iron: when to use it?

Parental Iron Therapy Routine use rarely justifed* Indications are: - malabsorpsi - intolerance to oral iron preparations (colitis, enteritis) - needs in excess of amount that can be given orally - patient uncooperative or unavailable for follow-up

* Continue therapy for 12 months after Hb level is normal, in order to replenish iron stores.* Therapy may be needed indefinitely if bleeding continues.

TREATMENT

Stepwise approach to use of iv iron in pregnancy

Max single dose 200mg / Cumulative 1600mg

Hb >10

Hb 9-10

Hb<9

Oral Fe

Iron sucrose 100 -200mg iv1-2 weekly

IronSucrose200mg 2 weekly

Reports by Breymann over 2000 women treated

IV Iron Therapy and AEs

FDA Medwatch reports (2001-2003) show iron dextran was associated with a 3.4-fold increase in odds of life-threatening AEs[1]

4 separate reports confirm 2- to 8-fold increase in reactions with high molecular-weight dextran compared with low molecular-weight dextran[2-

5]Lif

e-T

hre

aten

ing

AE

s p

er 1

Mill

ion

A

dm

inis

trat

ion

s

1. Chertow GM, et al. Nephrol Dial Transplant. 2006;21:378-382. 2. Fletes R, et al. Am J Kidney Dis. 2001;37:743-749. 3. McCarthy JT, et al. Am J Nephrol. 2000;20:455-462. 4. Mamula P, et al. J Pediatr Gastroenterol Nutr. 2002;34:286-290. 5. Coyne DW, et al. Kidney Int. 2003;63:217-224.

High molecular- weight dextranLow molecular- weight dextran

Ferric gluconateIron sucrose

0

2

4

6

8

10

12

Ph

arm

aceu

ticals

Update on adverse drug events associated with parenteral iron

Chertow GM et al Nephrology Dialysis Transplantation. 2006 21(2):378-382

Iron sucrose 0.6 per millionSodium ferric gluconate 0.9.per millionLMW iron dextran 3.3 per millionHMW iron dextran 11.3 per million

Treatment Correction

To increased Hb 1 gr/dL Need Fe endogen ± 2,5 mg/bw initial Fe:

– Fe = ( Fe serum x 0,2 x BW) mg, or– Fe = (Hb x 2,5 x BW) mg

Iron Dextran max. 1,5 mg/kgBW/day– Jectofer ® 75 mg/2mL amp.– Injektion 75 mg/deep im

Iron Sucrose– Cosmofer, Venofer ® 100 mg/amp– Cara infusi 100 mg in 100cc NS 1jam

Iron sucrose 125 mg/d iv infusions– Dose (mg) = (15 - patient's hemoglobin in g/dL) ×

(body weight in kg) × 3

Management Options for Anaemia : Summary

Red blood cell transfusion has many disadvantages

Eritropoetin treatment produces smooth and sustained Hb increases and is an alternative treatment option to transfusion

Pada anemia def fe pemberian Iron Supplement harus adequat untuk optimalisasi sebaiknya menggunakan Parenteral Iron therapy

No treatment is not an appropriate option