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Past, present and future of erythropoietin use
in anemia in older adults
The Ageing Process: Does it Matter when Considering
Lymphoproliferative Disorders and Supportive Care?
Lisboa, October 23rd from 15.30 – 17.00
Reinhard STAUDER MD, MSc, Associate Professor
Department of Internal Medicine V (Haematology and Oncology)
Innsbruck Medical University
Anichstraße 35, 6020 Innsbruck, Austria
Disclosures – Reinhard Stauder
Research Support/P.I. Celgene, Novartis, Teva
Employee 0
Consultant 0
Major Stockholder 0
Honoraria Celgene, Novartis, Teva
Scientific Advisory Board Celgene
Anemia in the elderly
Intro
Definition
Prevalence & relevance
Causes and classification
Therapy with focus on erythropoietins
� Anemia of chronic disease (ACD)
� Anemia of chronic kidney disease (CKD)
� Cancer-related or chemotherapy-induced anemia (CRA, CIA)
� Myelodysplastic Syndromes (MDS)
Conclusions
Recombinant erythropoietins in the EU
Type Generic name Trade nameRegistered in
CKD CRA, CIA ACD MDS
1st generation
Epoetin alfaEpoetin alfa Hexal®
Abseamed®
Binocrit®
+++
++–
–––
–––
Epoetin beta NeoRecormon® + + – –
Epoetin zetaRetacrit®
Silapo®
++
++
––
––
Epoetin thetaEporatio®
Biopoin®
+ *
+++
––
––
2nd generation
Darbepoetin alfa Aranesp® + + – –
Methoxy polyethylene glycol-epoietin beta
Mircera® + – – –
CKD, chronic kidney disease; Cancer-related or chemotherapy-induced anemia (CRA, CIA); Anemia of chronic disease (ACD); Myelodysplastic Syndromes (MDS)
* A starting dose of 20,000 IU/w is sufficient in a relevant proportion of patients (Tjulandin SA, et al. Arch Drug Inf. 2011;4(3):33-41.)
Anemia in the elderly
� Intro
� Definition
� Prevalence & relevance
� Causes and classification
� Therapy with focus on erythropoietins
� Anemia of chronic disease (ACD)
� Anemia of chronic kidney disease (CKD)
� Cancer-related or chemotherapy-induced anemia (CRA, CIA)
� Myelodysplastic Syndromes (MDS)
� Conclusions
� WHO definition1
� Hb <13 g/dL (<130 g/L) men
� Hb <12 g/dL (<120 g/L) non-pregnant women
� Challenge: established in 1960s in persons <65 yrs
� Widespread definition
Anemia in the elderly – definition
1 Nutritional anaemias. Report of a WHO scientific group. World Health Organ Tech Rep Ser. 1968;405:5-37.
Anemia in the elderly
� Intro
� Definition
� Prevalence & relevance
� Causes and classification
� Therapy with focus on erythropoietins
� Anemia of chronic disease (ACD)
� Anemia of chronic kidney disease (CKD)
� Cancer-related or chemotherapy-induced anemia (CRA, CIA)
� Myelodysplastic Syndromes (MDS)
� Conclusions
Anaemia prevalence according to size of
cohort analysed (non-linear inset scale).
POPULATIONANEMIA
PREVALANCE (%)
Elderly living in community 12
Hospital admission 40
Elderly in nursing home 47
All studies 17
• WHO criteria (♀< 12 g/dL; ♂< 13 g/dL)• Data poled from 45 studies (n = 85,400)
Anemia in the elderly – prevalence
Gaskell H, et al. BMC Geriatr. 2008;8:1.
Anemia in the elderly – prevalence
� Late-life anemia is frequent
� About 15 million citizens 65+ years in European Union are affected (based on prevalence of 17% in elderly1)
� Anemia increases dramatically with advanced age reaching a prevalence of nearly 50% in elderly men
� Number will increase in the next years due to ageing of societies
1 Gaskell H, et al. BMC Geriatr. 2008;8:1.
Anemia impacts hospitalization & mortality
• Anemia is correlated withincreased hospitalization(HR 2.7; 95% CI: 2.5-2.9) and mortality (HR 5.0; 95% CI: 4.4-5.7).
• Optimal Hb-value in elderly is 13-15 w and 14-17g/dL m
• New definition based on favourable outcome?
� 17,030 community-dwelling
persons; 66+ yrs
� Based on Calgary lab. data
services, Canada
Culleton B, et al. Blood. 2006;107:3841-6.
Anemia in the elderly – clinical relevance
Anemia has been associated with
� increased morbidity, mortality, and hospital stays
� higher incidence of cardiovascular disease, cognitive impairment, decreased physical function, and quality of life
� increased risk of falls and fractures
� might be an early sign of an undiagnosed malignant disease
Despite clinical importance, anemia is often neglected and evidence-based guidelines are lacking
Penninx B, et al. J Gerontol A Biol Sci Med Sci. 2006;61:474-9; Culleton B, et al. Blood. 2006;107:3841-6;Denny S, et al. Am J Med. 2006;119:327-34; Penninx B, et al. J Am Geriatr Soc. 2004;52:719-24;den Elzen W, et al. CMAJ. 2009;181:151-7; Beghé C, et al. Am J Med. 2004;116 Suppl 7A:3S-10S;Balducci L. Transfus Clin Biol. 2010;17:375-81; Guralnik J, et al. Blood. 2004;104:2263-8;Edgren G, et al. Int J Cancer. 2010;127:1429-36; Stauder R & Thein SL. 2014 Haematologica, 99(7):1127-30.
Anemia in the elderly
Intro
Definition
Prevalence & relevance
Classification and therapy with focus on erythropoietins
� Anemia of chronic disease (ACD)
� Anemia of chronic kidney disease (CKD)
� Unexplained anemia (UA)
� Myelodysplastic Syndromes (MDS)
� Cancer-related or chemotherapy-induced anemia (CRA, CIA)
Conclusions
Anemia in the elderly – possible causes
� Nutritient deficiency1
� Iron (iron deficiency anemia = IDA)
� Vitamin B12 , Folate
� Anemia of chronic disease (ACD), anemia of (chronic) inflammation (A(C)I), & anemia secondary to chronic kidney disease (CKD)2
� Unexplained anemia (UA)3 prevalence 34-44%4
� Cancer-related/chemotherapy-induced anemia (CRA, CIA)5
� Myelodysplastic Syndromes (MDS)6
1 Carmel R. Semin Hematol. 2008;45:225-34; 2 Patel K. Semin Hematol. 2008;45:210-7; 3 Guralnik J, et al. Blood. 2004;104:2263-8; 4Pang & Schrier. Curr Opin Hematol. 2012;19:133-40;5 Aapro & Link. Oncologist. 2008; 13 Suppl 3:33-6; 6 Malcovati L , et al. Blood. 2013;122:2943-64.
Iron deficiency anemia (IDA)
� Absolute IDA� Serum ferritin low
� <30 mcg/L if no inflammation
� <100 mcg/L in inflammatory status (ferritin-levels rise with inflammation & age)
� Low transferrin saturation (<20%)
� Determine site of blood loss!
� Treat by iron supplementation
� Functional IDA� Low transferrin saturation (<20%)
� Serum ferritin >30 mcg/L (>100 mcg/L in inflammation)
Busti F, et al. Front Pharmacol. 2014;5:83. eCollection 2014.
Anemia of chronic disease (ACD)
� Includes anemia secondary to inflammation, auto-immune disease, malignancy, chronic kidney disease (CKD), advanced age, heart failure…
� Mediators of hyperinflammation
� Interleukins (eg, IL-1 and IL-6) & tumor necrosis factor (TNF-alpha)
� Hepcidin, CRP….
� Relative decrease in EPO production & blunted response to EPO
� Functional (relative) iron deficiency (trapping of iron in RES)
Therapy
� Treat underlying cause
� ESAs ± iron?
� Anti-hepcidin approaches
RES, reticuloendothelial systemWeiss & Goodnough. N Engl J Med. 2005;352:1011-23.
Hepcidin – regulator of iron hemostasis
Young & Zaritsky. Clin J Am Soc Nephrol. 2009;4:1384-7.Ganz & Nemeth. Hematology Am Soc Hematol Educ Program. 2011;2011:538-42.
RBCs, red blood cells; Fe-Tf, iron-transferrin complex.
Erythro-
Ferron?
Anemia secondary to chronic renal disease
(CKD)
� Reduction in functioning renal mass results in reduced glomerular filtration rate and low EPO-levels (threshold?)
� Anemia is common in CKD even in predialysispatients
� Prevalence increases as GFR declines <60 mL/min/1.73 m2
1 Gertz B, et al. Curr Med Res Opin. 2010;26:2393-402; 2 Gertz B, et al. Curr Med Res Opin. 2012;28:1101-10;3 KDIGO Clinical Practice Guideline for Anemia in Chronic Kidney Disease. Kidney Int Suppl. 2012;2:279-335.
Association of kidney function with anemia
Decrease of Hb even in mild renal insufficiency
Predicted prevalence of hemoglobin level <11, <12, and <13 g/dL in persons ≥ 20 years.
Third National Health and Nutrition Examination Survey (1988-1994).
Estimates and 95% confidence intervals are demarcated.
Astor B, et al. Arch Intern Med. 2002;162:1401-8.
Men Women
Anemia secondary to chronic renal disease
(CKD)
� ESAs are active1,2 and registered in this type of anemia (threshold? “renal failure”, “renal insufficiency”)
� Non-renal causes of anemia should be excluded (iron status, B12, folate, bleeding)
� CKD patients often suffer from iron deficiency
� Recommendations from relevant societies exist3
� Indication for treatment: symptoms attributable to anemia, Hb<10g/dL4
� Hb target: maintain 10.0-11.5 g/dL; not >13g/dL4
� Hb targets should be achieved with lowest effective ESA doses as cumulative high ESA doses seem to be associated with an increased risk of mortality, cardio- and cerebrovascular events as determined in pooled analyses4
� Escalation of ESA doses in patients with poor ESA response should be avoided4
1 Gertz B, et al. Curr Med Res Opin. 2010;26:2393-402; 2 Gertz B, et al. Curr Med Res Opin. 2012;28:1101-10;3 KDIGO Clinical Practice Guideline for Anemia in Chronic Kidney Disease. Kidney Int Suppl. 2012;2:279-335.4 10 July 2014. EMA/PRAC/418466/2014. Patient Health Protection
ESAs in anemia in elderly
� Data are rare and definition of anemia of included patients is often vague
� Double-blind, placebo-controlled, crossover exploratory study with epoetin alfa1
� 62 community-dwelling persons 65+ yrs with chronic anemia (Hb ≤11.5 g/dL); predominantly African-American women
� 69% of EPO-patients responded
� Direct relationship between increases in Hb during ESA-therapy and improvements in fatigue and QOL
� Excluded were:� history of bleeding or bleeding disorders; active cancer; GFR less than 30
mL/min per 1.73m2; iron, vitamin B12, or folate deficiency; uncontrolled hypertension; hospitalization within 1 month
� bone marrow biopsy was not conducted to exclude MM or MDS; any patient who had abnormal serum proteins, thrombocytopenia, or neutropenia was also excluded
1 Agnihotri P, et al. J Am Geriatr Soc. 2007;55:1557-65.
ESAs in anemia in elderly
� Correction of Anemia in the Frail Elderly (CAFÉ): Results of a Randomized, Double-Blind, Placebo-Controlled Study with Darbepoetin Alfa in Elderly Patients with Chronic Unexplained Anemia1
� Double-blind, placebo-controlled clinical trial
� 80 community-dwelling, pre-frail or frail (Hopkins Frailty Index score 1 to 3) patients 70+ yrs with chronic anemia (Hb <11. 5 g/dL)
� Significantly greater hematopoietic response (mean 1.13 ± 0.59 g/dL) in the participants treated with DA than in those receiving placebo (0.3 ± 0.18 g/dL)
1 Loaiza-Bonilla A, et al. ASH 2012: Abstract 5153.
ESAs in anemia in elderly
� Congestive heart failure (CHF)1
� Double-blind randomised study on darbepoietin alfa in systolic heart failure (EF<40%); Hb 9-12 g/dL
� Early and sustained increase in Hb values; symptoms improved
� Clinical outcome (death or hospitalization) not altered
� Thromboembolic events increased (13.5 vs 10%; p=0.01)
1 Swedberg K, et al. N Engl J Med. 2013;368:1210-9.
Treatment of anemic low-risk MDS
(IPSS Low-grade and Int-1)
Adapted from Stauder R. Ann Hematol. 2012;91:1333-43.
LenalidomideESA
Symptomatic anemia
ESA ± G-CSF
CyA (ATG)
Valproic acid
Del(5q)
Supportive therapy including transfusions & iron-chelation
EPO < 500 U/L and/or low transfusion need
(<2U/month)
EPO ≥ 500 U/L and/or high
transfusion need
Hypoplastic MDSHLA-DR15
(Azacitidine)(Lenalidomide)
Recommendations of the Austrian MDS-Platform
ESAs in MDS
1 Greenberg P, et al. Blood. 2009;114:2393-400; 2 Park S, et al. Blood. 2008;111:574-582; 3 Jädersten M, et al. J Clin Oncol. 2008;26:3607-13; 4 Hellstrom-Lindberg E, et al. Br J Haematol. 2003;120:1037-46;5 Santini V, et al. Blood. 2013;122:2286-8.
� Reduce transfusion need and increase Hb-levels and QoL in low-risk MDS
� No evidence for negative impact on survival or AML evolution in
prospective1 or historical controls2,3
� ESAs even improve survival in treated patients2,3; however, improvement
in prospectively randomized trials has so far not been shown1
� A predictive model exists (Nordic score)4
� Low IPSS-R, low serum EPO, and low serum ferritin are significantly
associated with better erythroid response5
� Results of two prospective phase III trials will be presented at ASH 2014
Cancer-related/chemotherapy-induced anemia
(CRA, CIA)
� Frequent complication (European Cancer Anemia
Survey [ECAS])1
� Associated with fatigue, impaired physical function and
reduced QoL
61%29%
9% 1%Hb ≥ 12g/dl
Hb 10.0-11.9 g/dl
Hb 8.0-9.9 g/dl
Hb <8.0 g/dl
1 Ludwig H, et al. Eur J Cancer. 2004;40:2293-306.
Guidelines on ESAs in CIA
Recommendation ASCO/ASH1 NCCN2 EORTC3 ESMO4 EORTC5
When to start
Hb ≤ 10 g/dL(clinical
decision if Hb10-12 g/dL)
Hb ≤ 11 g/dLHb 9-11 g/dL
(clinical decision if Hb ≤
11.9 g/dL)
Hb ≤ 10 g/dL Hb ≤10 g/dL
Target range
Lowest Hblevel needed
to avoid transfusions
Maintain10-12 g/dL
Symptomatic patients target Hb should be
around 12 g/dL
Should not exceed 12
g/dL10-12 g/dL
General
recommendation
• Iron deficiency should be corrected before ESA treatment• Blood transfusions should be kept to a minimum!• Benefits of ESA-therapy should be carefully weighed along with its
safety concerns when determining anaemia treatment options 1 Rizzo J, et al. Blood. 2010;116:4045-59; 2 NCCN Clinical Practice Guidelines in Oncology: Cancer- and Chemotherapy-Induced Anemia. Version 3.2014; 3 Bokemeyer C, et al. Eur J Cancer. 2007;43:258-70; 4 Schrijvers D, et al. Ann Oncol. 2010;21 Suppl 5:v244-7; 5 Aapro M, et al., in preparation.
Potential new parameters in the classification of AE
1Ikram & Hassan. Haematology Updates. 2011:17-22; 2http://www.irondisorders.org/anemia-of-chronic-disease; 3Goodnough L, et al. Blood. 2010;116:4754-61; 4Greer J, et al. Wintrobe’s Clinical Hematology; 5Erslev A. N Engl J Med. 1991;324:1339-44; 6http://www.ifcc.org/ifccfiles/docs/publications/eJIFCC/vol20/02/eJIFCC-02-02.pdf; 7Nemeth E, et al. Science. 2004;306:2090-3; 8Kautz L, et al. Nat Genet. doi: 10.1038/ng.2996. [Epub ahead of print]; 9Zhang A. Adv Nutr. 2010;1:38-45; 10Andriopoulos B Jr, et al. Nat
Genet. 2009;41:482-7; 11Ambaglio I, et al. Haematologica. 2013;98:420-3; 12Petrak & Vyoral. Int J Biochem Cell Biol. 2005;37:1173-8.
Parameter Comments
Serum ferritin1 Low levels indicate IDANormal levels do not rule out an IDA, as ferrtin represents an acute phase reactant
Transferrin saturation (TSAT)2 Reduced in ID and in ACD
Reticulocyte hemoglobin content (CHr)3 Short term indicator of ID erythropoiesis
Inflammation markers(CRP, IL-6, ….)4 Useful in the definition of ACD
Erythropoietin (EPO)5 Glycoprotein growth factor that is the primary stimulus of erythropoiesis
Hepcidin6
Acute phase peptide produced in liver; key negative regulator of intestinal iron adsorption and iron release from RES and enterocytes; mutations cause juvenile hemochromatosisDifferent techniques of measuring serum hepcidin levels (ELISA, mass spectrometry)not generally available and not standardized yet
Ferroportin7 Cellular iron exporter, is regulated by hepcidin
Erythroferrone (Erfe)8 Erythroid regulator; suppresses hepcidin
Hemojuvelin9Cell-bound form: relevant positive regulator of hepcidin, coreceptor of BMP6Soluble form (sHJV): produced by cleavage in hypoxia and in iron deficiency, downregulates hepcidin, ELISAs available
Bone morphogenetic protein 6 (BMP6)10
Cytokine produced in iron overload, coreceptor of hemojuvelin, induces hepcidinactivation
Hepcidin/ferritin ratio11 A measure of adequacy of hepcidin levels relative to body iron stores
Hephaestin12 Transmembrane ferroxidase in enterocytes, transporting dietary iron into the circulation
Anemia in the elderly
Intro
Definition
Prevalence & relevance
Causes and classification
Therapy with focus on erythropoietins
� Anemia of chronic disease (ACD)
� Anemia of chronic kidney disease (CKD)
� Cancer-related or chemotherapy-induced anemia (CRA, CIA)
� Myelodysplastic Syndromes (MDS)
Conclusions
Anemia in the elderly (AE) – Conclusions 1
� Relevant challenge for individual, society and hematologists
� Underlying mechanisms are complex & so far poorly defined
� ESAs are, and will be, relevant in the treatment of AE
Type of anemia Evidence 1-4 Guidelines Registration
Chronic kidney disease +++ +++ +
Anemia of chronic disease + – –
Unexplained anemia – – –
Myelodysplastic syndrome ++ +++ –
Chemotherapy-induced anemia ++ +++ +
1 Gertz B, et al. Curr Med Res Opin. 2010;26:2393-402; 2 Gertz B, et al. Curr Med Res Opin. 2012;28:1101-10;3 Tjulandin S, et al. Arch Drug Inf. 2011;4:33-41; 4 Tjulandin S, et al. Arch Drug Inf. 2010;3:45-53.
Anemia in the elderly (AE) – Conclusions 2
� Goal is the definition of refined pathologic algorithms based on new
parameters; these will form the basis for evidence-based clinical
strategies and clinical studies including ESA
� Outcome measures relevant for elderly should be integrated including
functional capacities and patient-reported outcomes (PROs) like QoL
� Possible side effects of ESAs, particularly hypertension, thrombo-embolic
complications, flu-like illness & headache have to be considered and
discussed with patient
Past, present and future of erythropoietin use
in anemia in older adults
The Ageing Process: Does it Matter when Considering
Lymphoproliferative Disorders and Supportive Care?
Lisboa, October 23rd from 15.30 – 17.00
Reinhard STAUDER MD, MSc, Associate Professor
Department of Internal Medicine V (Haematology and Oncology)
Innsbruck Medical University
Anichstraße 35, 6020 Innsbruck, Austria