SIOG 2014 Satellite Session Teva-stauder_reinhard.pdf

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

reinhard.stauder@i-med.ac.at

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

reinhard.stauder@i-med.ac.at