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 23 rd 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
[email protected] 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
Registered in Type Generic name Trade name CKD CRA, CIA ACD MDS Epoetin alfa Hexal ® + + – – Epoetin alfa Abseamed ® + + – – Binocrit ® + – – – Epoetin beta NeoRecormon ® + + – – 1st generation Retacrit ® + + – – Epoetin zeta Silapo ® + + – – Eporatio ® + * + – – Epoetin theta Biopoin ® + + – – Darbepoetin alfa Aranesp ® + + – – 2nd generation Methoxy polyethylene Mircera ® + – – – glycol-epoietin beta
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 Anemia in the elderly – definition
1 WHO definition
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
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 Anemia in the elderly – prevalence
• WHO criteria (♀< 12 g/dL; ♂< 13 g/dL) • Data poled from 45 studies (n = 85,400)
ANEMIA POPULATION PREVALANCE (%)
Elderly living in community 12
Hospital admission 40
Elderly in nursing home 47
All studies 17 Anaemia prevalence according to size of cohort analysed (non-linear inset scale).
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 elderly 1)
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 with increased 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
1 Nutritient deficiency
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 3 4 Unexplained anemia (UA) prevalence 34-44% 5 Cancer-related/chemotherapy-induced anemia (CRA, CIA) 6 Myelodysplastic Syndromes (MDS)
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 system Weiss & Goodnough. N Engl J Med. 2005;352:1011-23. Hepcidin – regulator of iron hemostasis
Erythro- Ferron?
RBCs, red blood cells; Fe-Tf, iron-transferrin complex.
Young & Zaritsky. Clin J Am Soc Nephrol. 2009;4:1384-7. Ganz & Nemeth. Hematology Am Soc Hematol Educ Program. 2011;2011:538-42. 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 predialysis patients
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
Men Women
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. Anemia secondary to chronic renal disease (CKD)
1,2 ESAs are active 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 3 Recommendations from relevant societies exist 4 Indication for treatment: symptoms attributable to anemia, Hb<10g/dL 4 Hb target: maintain 10.0-11.5 g/dL; not >13g/dL 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 analyses 4 Escalation of ESA doses in patients with poor ESA response should be avoided 4
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 alfa 1 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 1.73m 2; 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 Anemia 1
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
1 Congestive heart failure (CHF)
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)
Symptomatic anemia
Supportive therapy including transfusions & iron-chelation
Del(5q) EPO < 500 U/L and/or EPO ≥ 500 U/L low transfusion need and/or high (<2U/month) transfusion need Lenalidomide ESA ESA ± G-CSF Valproic (Azacitidine) acid (Lenalidomide)
Recommendations Hypoplastic MDS of the Austrian HLA-DR15 MDS-Platform CyA (ATG) Adapted from Stauder R. Ann Hematol. 2012;91:1333-43. ESAs in MDS
Reduce transfusion need and increase Hb-levels and QoL in low-risk MDS
No evidence for negative impact on survival or AML evolution in prospective 1 or historical controls 2,3
2,3 ESAs even improve survival in treated patients ; however, improvement in prospectively randomized trials has so far not been shown 1
4 A predictive model exists (Nordic score)
Low IPSS-R, low serum EPO, and low serum ferritin are significantly associated with better erythroid response 5
Results of two prospective phase III trials will be presented at ASH 2014
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. Cancer-related/chemotherapy-induced anemia (CRA, CIA)
Frequent complication (European Cancer Anemia Survey [ECAS]) 1
9% 1% Hb ≥ 12g/dl Hb 10.0-11.9 g/dl 29% 61% Hb 8.0-9.9 g/dl Hb <8.0 g/dl
Associated with fatigue, impaired physical function and reduced QoL 1 Ludwig H, et al. Eur J Cancer. 2004;40:2293-306. Guidelines on ESAs in CIA
Recommendation ASCO/ASH 1 NCCN 2 EORTC 3 ESMO 4 EORTC 5 Hb ≤ 10 g/dL Hb 9-11 g/dL (clinical Hb ≤ 11 g/dL (clinical When to start Hb ≤ 10 g/dL Hb ≤10 g/dL decision if Hb decision if Hb ≤ 10-12 g/dL) 11.9 g/dL) Lowest Hb Symptomatic Should not level needed Maintain patients target Target range exceed 12 10-12 g/dL to avoid 10-12 g/dL Hb should be g/dL transfusions around 12 g/dL • Iron deficiency should be corrected before ESA treatment General • Blood transfusions should be kept to a minimum! recommendation • 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 Parameter Comments
1 Low levels indicate IDA Serum ferritin Normal 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 Acute phase peptide produced in liver; key negative regulator of intestinal iron adsorption and iron release from RES and enterocytes; mutations cause juvenile Hepcidin 6 hemochromatosis Different techniques of measuring serum hepcidin levels (ELISA, mass spectrometry) not generally available and not standardized yet Ferroportin 7 Cellular iron exporter, is regulated by hepcidin Erythroferrone (Erfe)8 Erythroid regulator; suppresses hepcidin Cell-bound form: relevant positive regulator of hepcidin, coreceptor of BMP6 Hemojuvelin 9 Soluble form (sHJV): produced by cleavage in hypoxia and in iron deficiency, downregulates hepcidin, ELISAs available Bone morphogenetic protein 6 Cytokine produced in iron overload, coreceptor of hemojuvelin, induces hepcidin (BMP6) 10 activation Hepcidin/ferritin ratio 11 A measure of adequacy of hepcidin levels relative to body iron stores
12 Transmembrane ferroxidase in enterocytes, transporting dietary iron into the Hephaestin circulation
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; 10 Andriopoulos B Jr, et al. Nat Genet. 2009;41:482-7; 11 Ambaglio I, et al. Haematologica. 2013;98:420-3; 12 Petrak & Vyoral. Int J Biochem Cell Biol. 2005;37:1173-8. 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 Chronickidney disease +++ +++ + Anemiaof chronic disease + – – Unexplainedanemia – – – 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 23 rd 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