case study

Review Series

HEMATOLOGIC DISEASE AT OLDER AGE

Anemia at older age: etiologies, clinical implications, and management Reinhard Stauder,1 Peter Valent,2,3 and Igor Theurl4

1Department of Internal Medicine V (Hematology and Oncology), Innsbruck Medical University, Innsbruck, Austria; 2Division of Hematology & Hemostaseology, Department of Internal Medicine I, and 3Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Vienna, Austria; and 4Department of Internal Medicine II (Infectious Diseases, Immunology, Rheumatology, Pneumology), Innsbruck Medical University, Innsbruck, Austria

Anemia is quite frequently diagnosed in older individuals and is a key indicator of various reactive and clonal conditions. Many underlying diseases, like myelodys- plastic syndrome (MDS), develop preferentially in el- derly individuals. The prevalence of anemia at older age is increasing, and this is mainly attributable to more frequently applied diagnostics and demographic changes in our societies. The etiology of anemia at older age is complex and ranges from bone marrow failure syndromes to chronic kidney disease, and from nutri- tional deficiencies to inflammatory processes including inflammaging in immunosenescence. In a smaller num- ber of cases, no clear-cut etiology is identified. These patients are referred to as unexplained anemia or idi- opathic cytopenia of unknown significance. In others, somatic mutations in leukocytes are found, but diagnostic

criteria for MDS or other hematologic diseases are not ful- filled, a condition termed clonal cytopenia of undetermined significance. Management of anemias at older age depends on (1) the severity of the anemia, (2) underlying condition(s), and (3) patient-related factors, including comorbidities. Even a mild anemia may substantially affect physical and cogni- tive capacities and quality of life. An underestimated aspect is that because of age-related changes, organ function such as erythropoietin production in the kidney may become suboptimal. Management and treatment of anemia in older patients often require a multidisciplinary approach and de- tailed investigations of organ function. In this article, we review current concepts around anemias at older age, with special emphasis on etiologies, clinical implications, and in- novative concepts in the management of these patients. (Blood. 2018;131(5):505-514)

Introduction Anemia is most frequent at older age, reaching a prevalence of ;17% in the cohort of older persons .65 years of age.1 Improved diagnostics and demographic changes in our societies have resulted in an increase in the incidence and prevalence of anemia in past decades. In fact, many underlying disorders, such as myelo- dysplastic syndrome (MDS), other blood cell disorders, cancer, chronic kidney disease (CKD), or certain gastrointestinal (GI) dis- eases develop more frequently at advanced age. In many patients, different etiologies may act together and thereby contribute to the development of anemias at older age.2,3

Based on the etiology, anemias can be divided into nutritional deficiency anemias, bleeding anemias, anemias developing in the context of chronic inflammation and in CKD, and clonal anemias. In a small number of cases, however, no etiology is found. These patients may initially be diagnosed as unexplained anemia (UA).4 However, when applying recent classifications and a thorough workup including bone marrow (BM) studies, these cases are diagnosed as idiopathic cytopenia of unknown sig- nificance (ICUS) with isolated anemia (ICUS-A).5-7 In some cytopenic patients, somatic mutations are detected in blood leukocytes, but diagnostic criteria for MDS or other BM

neoplasms are not fulfilled, a condition termed clonal cytopenia of undetermined significance (CCUS).7,8

The management of anemias in older individuals is a clinical challenge, especially when the etiology remains uncertain and/ or (multiple) comorbidities are present. An underestimated aspect is that because of age-related changes, organ function such as erythropoietin (EPO) production in the kidney or red cell production in the BM may be too low to prevent anemia under certain path- ologic conditions. Management and treatment of anemia in older patients usually require a multidisciplinary approach as well as de- tailed investigations of organ function. In many cases, supplemen- tation therapy or elimination of the underlying etiology can correct the anemia. In other cases, long-term treatment with interventional drugs, continuous therapy with EPO, or transfusions are required to control the anemia. With all these therapies, efficacy and benefit have to be balanced against safety and quality of life (QoL).9 In this article, we review current concepts surrounding clinical relevance, pathogenesis, and management of anemia in older patients.

Definition of anemia at older age World Health Organization (WHO) thresholds were established in 1968 in a cohort of persons ,65 years old, defining anemia as

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a hemoglobin (Hb) level of ,130 g/L in men and ,120 g/L in women.10 However, Hb levels decline with age and are distinct in different ethnic groups. So far, the WHO definition10 of anemia has been applied in the majority of studies at older age. Analyses of the American databases National Health and Nutrition Exami- nation Survey (NHANES) III11 and the Scripps-Kaiser database12

have suggested higher reference values to define anemia for white men but have in general supported the validity of the WHO thresholds on the prevalence of anemia.13

A relevant approach might be to base the definition of anemia on Hb concentrations relevant to clinical outcomes in older persons. In fact, correlations between unfavorable outcome and Hb levels have been demonstrated. For ex- ample, “optimal” Hb concentrations of $137 g/L for men and $126 g/L for women have been described in connection with better survival in the Cardiovascular Health Study (CHS).14

Similarly, the optimal Hb value to avoid hospitalization and mortality was 130 to 150 g/L for women and 140 to 170 g/L for men.15

In summary, the authors believe that the WHO definition should be used in general for the classification of anemia in older persons. However, Hb ranges associated with best possible outcome parameters might be discussed and con- sidered in daily practice and in clinical studies to optimize clinical benefit.

Epidemiology of anemia in senior adults Anemia in older persons is common and relevant, thus posing new challenges to health care systems worldwide. Large pro- spective registry studies have revealed an overall prevalence of anemia ranging from 10% to 24% in older individuals.3 Senior adults admitted to the hospital are more frequently affected by anemia (40%), and the prevalence is even higher (47%) in nursing home residents. Considering the global prevalence of 17%,1 as many as 15 million older persons may suffer from anemia in the European Union, and the same may hold true for North America. Prevalence increases with age, reaching

nearly 50% in men older than 80 years in both hospital in- patients and outpatients (Figure 1).16 Moreover, the number of anemic patients is likely to increase dramatically in the coming years because of an aging population in Western societies.2,16,17

Clinical relevance of anemia at older age Anemia has been associated with a number of clinically relevant conditions in many epidemiological studies (Table 1).2 Low Hb levels are a risk factor for cardiovascular diseases,15 cognitive impairment,18-20 insomnia,21 impaired mood,19,22 and restricted QoL.23-26 Moreover, anemia is associated with reduced execu- tive function27 and physical performance.23,28 Low Hb levels are associated with an increased risk for falls and fractures.25,26 In addition, the presence of anemia is significantly associated with more frequent hospitalization29 and longer hospital stays.15,30

Whereas these studies highlight the relevance of prevalent Hb levels at diagnosis, future analyses should address and consider the clinical impact of the Hb decline and thus the dynamics of anemia development.24,31

Importantly, accumulating evidence suggests that anemia is a marker for mortality14,24,30,32 (Table 1). The essential question is whether anemia per se determines unfavorable outcome or whether anemia is a surrogate marker for underlying processes such as inflammation or CKD. To investigate the complex in- terplay between anemia and confounding factors, epidemio- logical studies have been performed.11,14,19,20,22-24,31 In particular, these studies analyzed a possible association between anemia and mortality, adjusted for confounding factors including markers of inflammation or CKD.11,14,19,20,22-24,31 In support of the concept of the additive adverse effect of anemia and underlying disorders, the highest mortality has been found for nutritional disorders, chronic renal disease, and chronic inflammation as compared with UA (Table 1).11 However, epidemiological studies cannot figure out what causal role anemia plays in the restrictions and declines mentioned previously. Moreover, the underlying cause of anemia was not explicitly determined in many studies. Studies have often focused on inflammation and

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on CKD but might have missed other confounding factors (Table 1).

In summary, even mild anemia is a relevant prognostic param- eter. Moreover, in most cases anemia is considered to be a surrogate marker for underlying overt or subclinical diseases. Therefore, anemia in older individuals should definitely be taken seriously and worked up.

Pathogenesis and basic mechanisms of anemia at older age A wide range of causes and underlying diseases are known to result in anemia at older age (Table 2; Figure 2). In a given disease, often .1 factor may contribute to the development of anemia. Based on pathophysiological concepts, underlying diseases may be divided into the following 3 groups.

Anemias based on iron, folate, and/or vitamin B12 deficiency Lack of iron is by far the most frequent nutritional deficiency anemia. Similar to folate deficiency, iron depletion is often as- sociated with malnutrition. Age-dependent alterations in func- tion of GI tract, polypharmacy, and social isolation may lead to malnutrition and subsequent anemia.33 However, in our clinical routine we experienced several times how important it is to consider that bleeding because of a variety of medications (eg, acetylsalicylic acid, standard or direct oral anticoagulants) or GI diseases, including cancer, is the most frequent cause of iron- deficient anemia in older patients. Thus, apart from iron re- placement therapy, a careful GI diagnostic workup is mandatory to define a possible site of blood loss in these patients.34

Malnutrition, particularly in association with alcohol abuse, may result in folate deficiency. In addition, drugs like anticonvulsants and methotrexate are further causes. Pernicious anemia, the classic vitamin B12-deficient anemia, is relatively rare based on data from the literature and our clinical experience. By contrast, Helicobacter pylori infections, acid-reducing agents, or atrophic gastritis may cause hypochlorhydria, more frequently leading to a food-cobalamin malabsorption syndrome.35

Importantly, for these subtypes of anemia effective medication is available. For example, in vitamin B12 deficiency anemia, neu- rologic symptoms are often detected and usually resolve im- mediately on initiation of vitamin B12 supplementation.

Thus, early and correct diagnosis is essential. Therefore, we always include folate and vitamin B12 measurement in our basic laboratory screening in elderly anemic patients.

Anemias developing in the context of chronic inflammation and in CKD At least one-third of anemic patients older than 65 years show a hyperinflammatory state typical for CKD or for AI (cancer, au- toimmune disease, and chronic infection). Underlying patho- physiological mechanisms in AI are manifold, are overlapping, and show differences in extent between patients.

Table 2. Diseases frequently associated with anemia in the elderly

Category and subtypes Specific examples

Chronic inflammatory diseases Rheumatologic diseases Rheumatoid arthritis,

polymyalgia rheumatica

Chronic infectious diseases Chronic hepatitis, osteomyelitis

Inflammaging Frailty, cachexia, geriatric syndromes

Miscellaneous Chronic leg ulcers

Nonhematopoietic neoplasms Gastrointestinal tumors Colorectal cancer, gastric

cancer, etc Multiorgan metastasis End-stage carcinomas BM metastasis Various cancer types

including breast and prostate

Endocrinologic and metabolic causes Low production of EPO Renal anemia or pure

EPO deficiency* Thyroid dysfunction Hypothyroidism or

hyperthyroidism Insulin deficiency Diabetes mellitus

Blood loss Gastrointestinal tract bleeding Peptic ulcer, ulcerative

colitis, etc Diffuse GI tract bleeding Anticoagulant-mediated

bleeding Surgical procedures Multiple abdominal

surgeries Different locations Epistaxis, hematuria

Increased consumption or destruction of erythrocytes

Chronic nonmechanical hemolysis Autoimmune hemolytic anemia

Mechanical destruction of red cells Heart valve–mediated red cell lysis

Hypersplenism Hepato-/splenomegaly

Lack of nutrients Vitamin deficiency Vitamin B12 and/or folate

deficiency Trace element deficiency Copper deficiency† Iron deficiency Blood loss

Drug-induced anemia Chemotherapy Chemotherapy-induced

pancytopenia Antimetabolites, anticonvulsants Folate deficiency Toxic drug reactions Drug-induced hemolysis

Typical and more common causes of anemia in the elderly are listed. Many more underlying disorders may be identified. In addition, in many elderly individuals, .1 disease is present and may substantially aggravate the anemia.

*Insufficiently low EPO production in response to anemia is typically seen in patients with CKD but is sometimes also seen in elderly patients without impaired excretory renal function. This pure form of impaired EPO production is typically seen in elderly patients with mild anemia and may be an underestimated cause of anemia at older age or ICUS-A.

†Copper deficiency may be associated with marked BM dysplasia and may even mimic MDS.

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First, reduced EPO production that is too low to counteract anemia and a blunted response of erythroid progenitors to EPO represent essential underlying mechanisms.36

A direct negative effect of different cytokines, like tumor necrosis factor a, interleukin-1 (IL-1), and transforming growth factor b, on proliferation and differentiation of erythroid progenitor cells has also been reported37 and is at least partly because of a down- regulation of EPO receptor expression on erythroid progenitors. In addition, these cytokines promote myelopoiesis with the overall net effect of reduced erythropoiesis.38 Alterations in energy metabolism and body composition have also been re- ported to potentially regulate erythropoiesis in the elderly.39

Second, an essential mechanism driving the development of AI is an increased uptake and retention of iron (in the form of senescent/damaged erythrocytes) within the reticuloendothelial system leading to an iron-restricted erythropoiesis.40

Hepcidin, a mainly liver-derived antimicrobial acute phase protein, reduces both duodenal iron absorption and iron release from macrophages.41 These effects can be explained by the interaction of hepcidin and the transmembrane protein ferro- portin, the only so far known iron exporter in mammalians.42 In macrophages, which have a general turnover of ;20 to 25 mg of iron per day as a result of being recycled from senescent red blood cells (RBCs), this produces iron restriction with an accompanying increase in ferritin levels and decrease in transferrin saturation (TSAT), resulting in a relative iron-deficient erythropoiesis.

Increased hepcidin levels have been reported in cancer patients and patients suffering from autoimmune disease and CKD.43

Remarkably, elevated hepcidin levels have also been reported in older patients, with an age-related increase.44 As hepcidin seems

to be the central player in iron metabolism, several mechanisms are involved in tightly controlling hepcidin. Hepcidin expression is upregulated by inflammatory cytokines like IL-6 and different bone morphogenic proteins (BMPs), mainly BMP6 and BMP2.45

Moreover, endoplasmic reticulum stress46 and reactive oxygen species (ROS),47 as well as reduced levels of estrogen and testosterone,48,49 seem to directly increase hepcidin expression. This helps in understanding why endocrine changes at meno- pause or andropause result not only in a constitutively increased presence of inflammatory mediators,50 but also in increased hepcidin levels.48,49

Third, eryptosis, the phagocytosis of aging erythrocytes trig- gered by changes in their plasma membrane, is often discussed as a further hallmark in the development of AI. Recycling of aged and/or damaged RBCs occurs under physiological conditions mainly in the spleen. It is well known that in distinct situations including in- flammation, RBC numbers and Hb levels drop much faster than can be explained by a pure reduction in RBC production and Hb synthesis. In fact, translocation of phosphatidylserine to the membrane surface is a first step in this process.51 It enables mac- rophages to engulf erythrocytes and ultimately eliminate them from circulation. Lupescu et al showed that ROS production leads to a much higher frequency of phosphatidylserine-presenting erythro- cytes in older than in younger patients.52 Other reports have shown that disorders that are quite common at advanced age, including dehydration, diabetes mellitus, or chronic heart disease, might also affect RBC stability.53

In addition, the concept of a proinflammatory state or “inflammaging,” offers a potential model to explain the high prevalence of anemia and age-associated disorders including sarcopenia, asthenia, weight loss, and frailty. The term inflam- maging was first used in 2000 by Franceschi et al54 to describe a low-grade proinflammatory state associated with the aging process and immunosenescence. This condition is characterized by an age-associated chronic upregulation of the inflammatory immune response with increased levels of proinflammatory cy- tokines like IL-1, IL-6, and tumor necrosis factor.55-57 In addition, activation of NF-kB signaling has been reported in older patients.58 It is known and well described that a reduction in autophagy, as found in senior persons, leads to NF-kB activa- tion, which in turn is known to be a potent inducer of NLRP3 inflammasome activation. The same holds true for ROS.59 Thus, both pathways seem to activate the inflammasome response.

However, whether this state of chronic proinflammation reflects a primary age-related immune response or a systemic response to an unrecognized comorbid condition is not clear. More recent data suggest that age-related clonal hematopoiesis of in- determinate potential (CHIP) mutations in macrophages may lead to proinflammatory responses.60 It would be plausible that mildly elevated IL-6 levels caused by age alone, body compo- sition change, or smoldering inflammatory disease result in in- hibition of EPO production and/or activation of hepcidin, both of which cause anemia.55,56 Yet, one of the biggest limitations of this concept is the lack of methods that can be used to de- termine the suggested subclinical and often local inflammation in a clinical setting.

In fact, the cause of anemia for a relatively large proportion of UAs remains obscure, despite extended hematologic evaluation.61

AI, CKD, Inflammation

+

–

–

– – – –

Kidney RES

Erythropoiesis

EPO Cytokine production

Iron retention Eryptosis

Hepcidin

Bone marrow

Liver

+ + ++

+

Nutritional deficiency

Clonal anemia

Figure 2. Possible mechanisms of anemia in older adults. A hyperinflammatory state is typical in anemia of inflammation (AI), CKD, and inflammaging. This state is characterized by increased hepcidin production in the liver, resulting in a direct negative impact on erythropoiesis and increased iron retention in the re- ticuloendothelial system (RES). Moreover, production of EPO is insufficient in response to anemia, and EPO response in the erythropoiesis is blunted. A further hallmark in the pathogenesis of AI is the increased phagocytosis of aging eryth- rocytes (eryptosis). Clonal disorders in leukocytes increase the risk of developing cardiovascular complications and anemia. This association may be caused by the promotion of inflammatory processes. Plus signs symbolize stimulation, and minus signs inhibition.

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Namely, iron deficiency (ID), borderline CKD, and low-grade local inflammation may go unrecognized in a number of patients because of inappropriate cutoff levels or technical limits of laboratory tests.

UAs and clonal anemias Clonal leukocytes are detectable in a considerable proportion of older individuals. Such clonal hematopoiesis is associated with increased mortality and an augmented prevalence of hemato- logic malignancies, such as MDS. Remarkably, numbers of so- matic mutations in blood leukocytes increase with age.8,60,62,63 In otherwise healthy individuals without cytopenia, this condition is termed CHIP.8 However, as soon as mild anemia develops, the diagnosis changes to CCUS8 or to overt MDS when criteria for MDS are fulfilled.7 Indeed, the clinical features and the course of CCUS patients and MDS patients are quite similar. In addition, most CCUS patients may progress to overt MDS over time. However, CHIP and CCUS patients may also develop another hematologic neoplasm, such as acute myeloid leukemia. Based on the obvious clinical implications, we recommend that leuko- cytes be screened for the presence of somatic mutations in all patients with unexplained cytopenia. In addition, BM cells should be examined for the presence of cytogenetic abnormalities and flow cytometric abnormalities (Table 3).

Cytopenic patients lacking molecular aberrations and not ful- filling the criteria of MDS or of any other underlying disease (causing cytopenia) are termed ICUS. ICUS presenting with anemia is termed ICUS-A.7 As ICUS-A is often detected in older individuals,6,64,65 it has been hypothesized that ICUS-A may be regarded as the classical prototype of an “anemia at older age.”5

As outlined previously, a clue to the etiology of ICUS-A may be the observation that endogenous EPO levels are often quite low, suggesting insufficient EPO production in response to anemia.5

Because low EPO production is found in ICUS-A independent of the excretory kidney function, one hypothesis is that an endo- crine defect in EPO production because of an aged kidney or a decrease in testosterone or estrogen synthesis in elderly indi- viduals is causative in the development of ICUS-A.5,66 In this regard, it is also noteworthy that such a decrease in EPO

production may also be found in MDS patients, namely, those who respond to treatment with recombinant EPO.67,68 In other words, individuals with CHIP or IDUS may convert to overt MDS as soon as they also develop ICUS-A during aging. This concept is supported by the Nordic score that predicts responsiveness to EPO therapy in those MDS patients who have an inadequately low EPO level.67 Whether these EPO thresholds might be ap- plied in other subgroups of anemia remains to be determined. A remaining question is whether true cases of ICUS-A with adequate EPO production really exist. An interesting point worth noting is that the age-related decrease in EPO production can contribute to the manifestation of an overt neoplasm, namely, MDS from a preexisting CHIP or IDUS.65,69

Diagnostic aspects Primary laboratory evaluation in older anemic patients should include basic parameters including Hb, differential blood count, MCV, mean corpuscular hemoglobin, reticulocyte count, ferritin, reticulocyte Hb, TSAT, EPO level, CRP, fibrinogen, creatinine/glomerular filtration rate, vitamin B12, serum folate, copper, thyrotropin, lactate dehydrogenase, haptoglobin, alanine aminotransferase/aspartate aminotransferase, and serum elec- trophoresis. In quite a number of cases, this profile will help identify and classify nutritional deficiency including iron-deficient anemia, AI, and CKD. Depending on the clinical evaluation, more detailed investigations may be needed including gastro- and colonoscopy and ultrasound of the abdomen and kidney. BM aspiration and biopsy are mandatory to exclude hematologic disorders including MDS and to make an appropriate diagnosis, especially when additional blood count abnormalities or other signs of a clonal hematologic disease are found.

These diagnostic procedures including BM evaluation should, however, be discussed in light of the burden of the procedure and weighed against the possible therapeutic consequences of the suspected diagnosis as well as life expectancy and burden of anemia. The authors feel the patient should have a life ex- pectancy of minimum 3 months in order to justify BM aspiration in an anemic elderly patient.

Table 3. Classification of UA, ICUS-A, and pre-MDS conditions

Condition UA ICUS-A CCUS IDUS CHIP

MDS

Low risk High risk

Cytopenia* 1 1 1 2 2 1 1

Dysplasia nd 2 2 1 2 1 1

BM blasts, % nd ,5% ,5% ,5% ,5% ,5% .20%

Cytogenetic abnormalities nd 2/1 2 2/1 1/2 1 11

Molecular aberrations nd 2 1 2 1 1 111

Comment Workup needed Cytopenic patients Noncytopenic patients Classification of MDS is based on WHO definition

“Unexplained anemia” (UA) is the term used in the literature so far. In these patients, a thorough workup including BM and molecular analyses is recommended. These investigations will enable classification of the diagnosis ICUS-A, CCUS, or MDS or will help exclude other malignant hematologic disorders. Based on Valent et al.7

IDUS, idiopathic dysplasia of undetermined significance; nd, not detected or not done.

*The definition of anemia in cytopenia is based on WHO criteria: Hb ,130 g/L in men and Hb ,120 g/L in women.10

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In those with unclear results molecular, cytogenetic, and/or flow cytometry studies may help reach the conclusion that the patient is suffering from a clonal BM disorder such as MDS. In such studies, detection of clonality of myeloid cells may cause a change in the diagnosis, for example from ICUS to CCUS or even to MDS.7

There are a number of other complex conditions and pitfalls that may pose diagnostic problems in elderly patients, especially those who suffer from comorbidities. For example, it may be difficult to assess the extent of iron deficiency in patients suf- fering from inflammatory bowel disease and pronounced in- flammatory bowel disease–related inflammation. In these cases, soluble transferrin receptor (sTfR), the sTfR/log ferritin index, and serum hepcidin may assist in estimating the degree of iron deficiency. An index above a certain cutoff level indicates the presence of a true iron deficiency that may be overseen in an inflammatory state when using ferritin and TSAT levels only.41

Specific cutoff levels have been published. A ratio of ,1 sug- gests AI, whereas a ratio of .2 suggests absolute iron deficiency coexisting with AI.41 Yet, it is important to understand that sTfR assays are not standardized, and therefore, a cutoff level for the sTfR/log ferritin index has to be established by each laboratory individually, depending on the sTfR assay.70

Other parameters like reticulocyte Hb content and percentage of hypochromic erythrocytes have proved to be informative to predict the response rate to iron therapy in CKD patients.71,72

Therapeutic options Before establishing a treatment plan, the primary diagnosis and accompanying diseases with emphasis on treatable disorders should be properly defined. As mentioned before, often several causes contribute to anemia in the elderly. Then, optimal age- adjusted therapy is introduced, with recognition of potential side effects and impact on QoL. Even a weekly referral (transport bur- den) for injections may already interfere with QoL in frail patients. Whenever possible, the primary goal is to treat and thus eliminate the underlying disease and thereby the etiology of anemia.

In most patients suffering from true ID, oral iron substitution seems to be sufficient.73 Moreover, in recent years new oral iron formulations like ferric maltol74 and Sucrosomial Iron75 showing

higher efficacy and fewer side effects have been approved, thus further reducing the need for intravenous iron. Yet, sometimes oral application in the elderly is not effective because of reduced uptake in the GI tract, impaired compliance, and/or an in- flammatory state leading to decreased iron utilization.76,77

In this situation, when oral iron does not ameliorate anemia, IV iron therapy may be a valuable alternative. Actually, a number of IV iron formulations are available including iron sucrose, ferric gluconate, and ferumoxytol. In recent years, new and safer formulations have been approved with mainly ferric carbox- ymaltose and iron isomaltoside being prescribed. Still, especially ferric carboxymaltose, but also to some extent iron isomaltoside, may rarely lead to severe hypophosphatemia with subsequent osteomalacia and bone fractures,78 especially when high doses are needed in patients with severe ID and relatively normal kidney function. This is of special concern in elderly patients already presenting with metabolic bone diseases. Therefore, we are of the opinion that IV iron supplementation should be rec- ommended when oral iron preparations are not tolerated, in patients nonadherent to oral iron substitution, in case of ongoing blood loss, or if iron uptake in the GI tract is insufficient.

Erythropoiesis-stimulating agents (ESAs) are so far registered for the treatment of anemia in CKD and in European Union countries in patients with MDS. Data on application of ESAs in other subtypes of anemia are limited. Nevertheless, 1 study suggested that EPO may be beneficial in a patient cohort of age 65 and older African American women with no obvious explanation for the existing anemia.79 In that study, ESAs significantly increased Hb levels and also patients’ QoL. Yet, considering studies reporting a reduced EPO response in a large portion of UA patients, larger studies are definitely needed to support the idea of ESA therapy in UA patients.80 In general, the risk for throm- boembolic complications increases at higher Hb levels, so that the current recommendation is to maintain Hb levels between 9 and 11.5 g/dL.

Blood transfusions are the first and most effective option for the treatment of elderly patients with severe, symptomatic anemia.

Although no specific cutoff level is available for Hb, elderly anemic patients should always be transfused with recognition of

Table 4. New targeted drugs that may counteract anemia in older patients

Drug Lexaptepid-pegol

NOX-94H PRS-080 RO62 CSJ137 H5F9-AM8

Target Hepcidin Hepcidin BMP6 BMP6? HJV (RGMc)

Modality PEGylated Spiegelmer Anticalin scaffold Engineered heparins IgG1 Unclear

Mechanism Hepcidin binding Hepcidin binding BMP6 binding BMP6 binding (?) Unclear

Indications MM, CKD, cancer CKD Unknown Functional iron deficiency by CKD

CKD likely

Phase Phase 2 Phase 1 Discovery Phase 1/2 Phase 1 (?)

Company Noxxon Pieris Glycolsplit heparins Novartis AbbVie

IgG1, immunoglobulin G1; MM, multiple myeloma; PEG, polyethylene glycol.

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comorbidities and an adequate oxygen supply that needs to be maintained. Transfusion numbers and frequency in the individual patient have to be based on many different factors and the overall situation in each case. In those with severe cardiovascular disorders, blood should be transfused more slowly and on a unit- by-unit basis, and Hb levels should be kept above 9 or even 10 g/ dL in these patients.81

Thanks to a better understanding of mechanisms regulating erythropoiesis, new drugs are currently being developed such as hepcidin inhibitors (Table 4). Currently, these drugs are mainly developed for anemia in CKD and cancer patients. However, they may be a future therapeutic approach for a defined group of elderly patients. Another group of agents are the hypoxia inducible factor (HIF)–prolyl hydroxylase inhibitors. Especially older patients with low endogenous EPO levels may benefit from these drugs. Yet, persons at advanced age may be more vulnerable to HIF stabilization. Finally, activin type II receptor agonists are currently being investigated in patients with MDS and CKD and might present a future option for the treatment of anemia at advanced age. As sufficient clinical data are not yet available, these drugs still await final approval.

Concluding remarks and future perspectives Anemia in older persons poses a clinical challenge in daily practice as the population ages. In many cases, 1 or more eti- ologies are detected, and a thorough investigation immediately leads to the correct diagnosis. In these patients, management is largely dependent on the underlying etiology, and in many cases, anemia can be corrected by interventional therapy in- dependent of age. Good examples are iron, vitamin B12, or folate deficiency. EPO deficiency with or without overt exocrine kidney insufficiency can be detected quite often in older per- sons. A large number of patients turn out to have an underlying (chronic) inflammatory disease. The concept of a subclinical proinflammatory state called inflammaging may be a good explanation for the development of anemia in senior persons. In other cases, a clonal myeloid or other neoplasm is detected. In a relevant proportion of patients, no underlying cause of anemia is found after a first examination, resulting in the provisional

diagnosis of UA. However, in many cases no underlying etiology is found even after a thorough diagnostic workup that includes an examination of all organ systems including the BM and also cytogenetic and molecular studies. These patients may have a pre-MDS condition and are often diagnosed as ICUS-A or CCUS.

The definition of the underlying mechanisms of anemia at older age will form the basis for individualized treatment algorithms including iron supplementation, application of ESAs, and promising new drugs directed at regulation of hepcidin or HIF.

Acknowledgments The manuscript was edited by Mary Heaney Margreiter, native-speaker translator/interpreter/editor. In addition, Bojana Borjan edited the ref- erences, and Karin Koinig edited the tables and designed Figure 2.

This work was supported by Verein Senioren-Krebshilfe (R.S.) and Horizon 2020 research and innovation program (grant 634789), MDS-RIGHT, within Personalising Health and Care program PHC-2014-634789 (R.S.). Additionally, this work was supported by Translational Imple- mentation of Genetic Evidence in the Management of MDS (TRIAGE- MDS, Austrian Science Found I 1576) within the TRANSCAN–Primary and secondary prevention of cancer call (ERA Net) (R.S.) and by the Austrian Science Fund (SFB grant F4704-B20 [P.V.] and project P 28302-B30 [I.T.]).

Authorship Contribution: R.S., P.V., and I.T. were responsible for conception and design, manuscript writing, and final approval of the manuscript.

Conflict-of-interest disclosure: R.S. received research funding and hon- oraria from Celgene, Teva, and Novartis. P.V. received honoraria from Celgene, Teva, and Novartis. I.T. received research funding and hono- raria from Gilead, Novartis, and Kymab.

Correspondence: Reinhard Stauder, Department of Internal Medicine V (Hematology and Oncology), Innsbruck Medical University, Anichstr 35, 6020 Innsbruck, Austria; e-mail: [email protected].

Footnote Submitted 6 July 2017; accepted 5 October 2017. Prepublished online as Blood First Edition paper, 15 November 2017; DOI 10.1182/blood-2017- 07-746446.

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