Erythropoietin treatment for non-uremic patients:

The Netherlands Journal of Medicine 54 (1999) 10–15

Invited review

Erythropoietin treatment for non-uremic patients: a personal view Douwe H. Biesma* Department of Internal Medicine, St. Antonius Ziekenhuis, Koekoekslaan 1, 3435 CM Nieuwegein, The Netherlands Received 31 October 1997; received in revised form 3 August 1998; accepted 29 September 1998

Abstract The correction of anemia in patients with chronic renal failure (CRF) has become the most important application of recombinant human erythropoietin (rHuEpo). The merits of rHuEpo therapy in patients with CRF are overt. Firstly, patients with CRF have an absolute deficiency in endogenous erythropoietin production and a relatively low maintenance dose of rHuEpo (often less than 100 IU / kg body weight per week) is effective in avoiding regular transfusions in the majority of the patients with CRF. Secondly, rHuEpo is able to avoid long-term complications of frequent transfusions (hemochromatosis, transfusion-transmissible diseases). Thirdly, patients with uremia notice a considerable improvement in quality of life (QOL) after initiation of rHuEpo. These advantages justify administration of this costly drug in CRF patients. The use of rHuEpo outside the setting of uremia do, however, not cover the complete spectrum of beneficial effects as compared to its use in (pre)dialysis patients. The aim of this overview is to provide some annotations on recently approved (cisplatin-induced anemia, preoperative anemia, zidovudine-related anemia) and possibly future (several types of malignancy and inflammation) indications for rHuEpo in non-uremic patients, leaving out the correction of anemia due to relatively uncommon disorders in the Dutch population (such as sickle cell anemia and thalassemia).  1999 Elsevier Science B.V. All rights reserved. Keywords: Recombinant human erythropoietin; Non-uremic anemia

Approved indications Cisplatin-induced chemotherapy The pathogenesis of anemia in treated and untreated patients with malignancy is multifactorial. Inflammatory cytokines (interleukin-1, tumor necrosis factor a, transforming growth factor b) produced in untreated patients with malignancy inhibit the in vitro erythropoietin production induced by hypoxia *Tel: 1 31-30-6099111: Fax: 1 31-30-6056357

[1]. Blunted erythropoietin responses have been observed in patients treated with chemotherapeutics [2], especially after treatment with cisplatin which can result in prolonged anemia [3]. Patients on platinum-based chemotherapy who were treated with rHuEpo had reduced transfusion requirements. Patients who are anemic before chemotherapy or became anemic after the first cycle of chemotherapy and patients who are treated with more than 75 mg / m 2 cisplatinum per cycle have a considerable risk for the development of anemia; for those patients, treatment with rHuEpo is recommended.

0300-2977 / 99 / $ – see front matter  1999 Elsevier Science B.V. All rights reserved. PII: S0300-2977( 98 )00124-7

D.H. Biesma / The Netherlands Journal of Medicine 54 (1999) 10 – 15

Comment: The mainstay for the approval of rHuEpo for the correction of cisplatin-induced anemia is improvement in QOL. Issues related to blood safety are less important in most of these patients with a limited life expectancy. Avoidance of iron accumulation due to frequent homologous blood transfusion has also no priority in this group of patients with a limited period of anemia. Although blood transfusion may be inconvenient to cancer patients, it results in a more rapid correction of anemia as compared to rHuEpo. Randomized, controlled trials about QOL scores of rapid restoration of anemia (obtained by transfusions) versus slow correction of anemia by rHuEpo in patients receiving platinum-based chemotherapy are limited. More data about this aspect are needed to evaluate cost effectiveness of rHuEpo in patients with cisplatin-based chemotherapy. Anemia induced by zidovudine (AZT) In vitro studies have shown an inhibition of endogenous erythropoietin production by human immunodeficiency virus (HIV) [4]. Treatment with AZT often results in a further decline in hemoglobin concentration. Patients with HIV infection who have endogenous erythropoietin levels less than 500 U / l are likely to respond to rHuEpo [5]. Dosages of 24 000 to 48 000 U rHuEpo per week in patients with baseline erythropoietin levels below 500 U / l resulted in a decrease in transfusion requirement in 44% of the patients [6]. Comment: In a selected group of AIDS patients with symptomatic anemia and serum erythropoietin levels less than 500 U / l, rHuEpo is successful and results in improvement in QOL. The degree of anemia induced by newer anti-retroviral therapy is, however, less prominent than AZT-associated anemia; anemia is, therefore, no more a major problem in clinical practice. Anemia in the perioperative period The primary aim of perisurgical use of rHuEpo is to avoid transfusion-transmissible diseases. Incidentally, rHuEpo is given to patients who refuse transfu-

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sions on religious grounds or to alloimmunized patients undergoing elective surgery. Although the safest blood is the patient’s own blood, autologous blood donation programs are limited by the development of anemia and insufficient collection of blood to compensate for the perioperative blood loss. The degree of anemia induced by several phlebotomies is inadequate to result in a substantial increase in endogenous erythropoietin production to restore hemoglobin concentration before surgery [7]. Perioperative rHuEpo therapy can be applied with different aims. Firstly, it is effective in stimulating erythropoiesis and results in an increasing number of predeposited units [8]. Secondly, the fall in hematocrit, induced by the drawing of a limited number of units, can be corrected preoperatively [9]. Thirdly, it allows preoperative donation of blood for autologous use in patients who are unable to deposit blood preoperatively because of anemia [10]. Fourthly, it can increase hematocrit and can be used to perform normovolemic hemodilution in surgical patients who are excluded from autologous blood programs because of a time to surgery , 3 weeks or for logistical reasons. The optimal treatment schedule for autologous blood donors is 250–300 IU / kg rHuEpo twice weekly, given subcutaneously over a 3-week period before surgery. Because there is a direct relationship between hematocrit and volume of blood that can be collected, patients with hematocrit . 40% usually donate four or more units of blood before surgery without support of rHuEpo. The use of rHuEpo in autologous blood donors should, therefore, be restricted to patients with anemia (hematocrit , 40%) and to small individuals with low bloodvolume [9–11]. Comment: When restricted to this small subpopulation, rHuEpo is successful in reducing allogeneic transfusions. This implicates that routine administration should be avoided. Arguments in favor of rHuEpo may be the ultimate effort to avoid allogeneic blood, because of the persistent risk for transfusion-transmissible diseases, the beneficial effect of autologous blood transfusion on postoperative infectious complications [12], and the, albeit inconsistent, data with regard to possibly increased risk for recurrence of (colorectal) carcinoma after allogeneic transfusions [13,14]. Arguments against the use of rHuEpo in

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D.H. Biesma / The Netherlands Journal of Medicine 54 (1999) 10 – 15

autologous donors are based on the improved safety of allogeneic transfusions, the disappointing cost effectiveness of simple autologous donation [15], and the high costs of discarded units.

Potential indications

concentration and a favorable tumor response to chemotherapy with regard to improvement in QOL. According to the data provided by Glaspy et al. [16], administration of rHuEpo can be limited to a subgroup of patients with malignancy. Their observation deserves further placebo-controlled trials in this subgroup with emphasis on cost effectiveness outcomes.

Solid tumors Myelodysplasia ( MDS) The effect of rHuEpo has been studied in a large, non-randomized, non-controlled study of 2342 patients with non-myeloid malignancy and ongoing cytostatic chemotherapy [16]. In this study, improvement of QOL and reduction in transfusion requirement was apparent. Although the study design is not optimal (transfusion requirement was compared with the patient’s transfusion history; effect of tumor response or progress of disease on QOL scores can not be excluded in a non-randomized, non-controlled design), several interesting data about the use of rHuEpo for patients with a malignancy were obtained. Only 1047 out of 2030 (52%) patients with available data completed a 4-months-period of rHuEpo therapy. Treatment with rHuEpo was discontinued because of complications of underlying disease (death, intercurrent illnesses) and because of inadequate therapeutic response in a minority of patients. In 75.1% of patients who showed an increase in hemoglobin of $ 0.6 mmol / l during the first month of therapy, a substantial increase in hemoglobin was observed at the end of the study. Treatment with rhuEpo was less beneficial in patients who received blood transfusions during the first episode of rHuEpo. Comment: Improvement in QOL observed after rHuEpo therapy can be compared with treatment of cancer pain and should, therefore, not be underestimated. However, guidelines on the appropriate usage of rHuEpo in a wide variety of malignancy have to be based on placebo-controlled studies. In a recently published study, rHuEpo was administered to patients with advanced gastrointestinal cancer [17]. The authors were, however, not able to discriminate between a rHuEpo-induced increase in hemoglobin

A substantial proportion of patients with MDS, characterized by the FAB subtype refractory anemia (RA) or RA with ringed sideroblasts (RARS), has an overall survival that is long enough to be exposed to long-term side-effects of regular transfusions (iron accumulation, transfusion reactions). In a single study, the response rates to rHuEpo treatment were 39% (17 / 44) in patients with RA and 17.5% (7 / 40) in patients with RARS, whereas other subtypes of MDS had significantly lower responses to rHuEpo [18]. In a meta-analysis, including 17 original studies with a total of 205 patients with MDS who had been treated with rHuEpo, only 33 patients (16%) had a significant response to treatment [19]. Patients with MDS who had normal TNF-alpha levels had a significantly better response to rHuEpo as compared to patients with elevated TNF-alpha levels [20]. Patients with baseline erythropoietin levels , 100 U / l were most likely to respond to therapy [18]. Without taking into account improvement in QOL and energy levels from rHuEpo, its use counterbalanced transfusion cost in a small study in patients with RA and RARS [21]. Comment: The highest efficacy of rHuEpo treatment for patients with MDS was found in patients who had no previous transfusion requirement; the overall efficacy of rHuEpo in patients with MDS is low (16%). Therapy with rHuEpo has a role in a small number of patients with RA who are receiving transfusions on a regular base and who have low endogenous erythropoietin production (erythropoietin concentration , 50–100 U / l). When no response can be observed during a period of 4 weeks rHuEpo administration, treatment must be discontinued.

D.H. Biesma / The Netherlands Journal of Medicine 54 (1999) 10 – 15

Multiple myeloma Several factors can contribute to anemia in myeloma patients: replacement of normal hemopoiesis by tumor cells, renal failure, cytokine production with blunted erythropoietin response, and tubular damage induced by toxic paraproteins. The likelihood of rHuEpo response seemed to be decreased in patients with prolonged ( . 12 months) cytotoxic (especially alkylating agents) therapy and in patients with pre-treatment erythropoietin levels . 100 U / l. Comment: Anemia is most prominent in myeloma patients with advanced stage of disease and is associated with a relatively short life expectancy. As long as there is no firm evidence about improvement in QOL following treatment with rHuEpo as compared to blood transfusions, routine administration of rHuEpo to patients with multiple myeloma should not be encouraged. Rheumatoid arthritis In patients with rheumatoid arthritis (RA), the increase in endogenous erythropoietin concentration is less than would be found in an equally anemic patient with iron deficiency [22]. This blunted erythropoietin response provides a rationale for the use of rHuEpo in anemic patients with RA. In 1990, Pincus et al demonstrated the successful correction of anemia in patients with RA, treated with rHuEpo [23]. More recent data were, however, less convincing with regard to the efficacy of rHuEpo in anemic patients with RA: only 14.6% of patients had an adequate response, defined as elevation of hemoglobin . 120 g / l ( . 7.4 mmol / l) [24]. The response to rHuEpo was associated with the availability of iron and with the degree of inflammation. Comment: Anemia is not a frequent finding in patients with RA. Only few RA patients who had no iron deficiency or signs of increased activity of the disease will, therefore, benefit from long-term administration of rHuEpo. Treatment with rHuEpo in the perisurgical period is less questionable. Goodnough demonstrated that patient with RA participating in an

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autologous blood transfusion program before orthopedic surgery had equal responses to rHuEpo as compared to non-RA patients [25].

General issues The following issues about the use rHuEpo for non-uremic indications deserve to be discussed more extensively: initial dosage, monitoring erythropoietic response, iron supplementation, and side effects. Initial dosage Initial dosages vary widely from 80 to . 1000 IU / kg / week. Some base their initial dose on endogenous erythropoietin levels, others use fixed schedules. Cazzola et al. presented some practical criteria for deciding the initial dosage of rHuEpo in an anemic patient [26]. They recommend a dosage of 200 to 250 IU / kg / week, divided in 3 subcutaneous administrations, in patients who had no regular need for transfusion and who had no signs of inflammation or concomitant chemotherapy; they advise to increase the initial dosage to 400 to 500 IU / kg / week in patients with regular transfusions, inflammation, or receiving chemotherapy. Monitoring erythropoietic response Guidelines to monitor the response to rHuEpo (such as based on increment in hemoglobin concentration) have limitations in patients receiving transfusion or sequential chemotherapy. Nonetheless, those who showed an increase in hemoglobin . 0.6 mmol / l and / or a change in absolute reticulocyte count . 40 x 10 9 / l after a 4-week period of rHuEpo therapy, are most likely to have an adequate response. In non-responders, the dosage may be doubled, although it is not to be expected that a rHuEpo dosage over 900 IU / kg / week will be effective. An interesting variable of red blood cell precursor mass is the serum transferrin receptor concentration. A more than 25% increase in serum transferrin receptor concentration, measured after 2 week rHuEpo

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D.H. Biesma / The Netherlands Journal of Medicine 54 (1999) 10 – 15

therapy in patients with malignancy, was an adequate predictor of response to rHuEpo [27]. Iron supplementation The development of functional iron deficiency (defined as normal body iron stores, but inadequate iron supply to the bone marrow) may develop during rHuEpo administration and may result in diminished response to the drug. In autologous blood donors, rHuEpo administration resulted in increased red blood cell protoporphyrin and production of red blood cells with abnormally low hemoglobin concentration [28,29]. Impaired release of iron from the mononuclear phagocytic system observed in inflammation may limit the response to rHuEpo in patients with inflammatory diseases and malignancy. Although oral iron supplementation (200 mg of oral elemental iron daily) is administered during at least the first weeks of rHuEpo treatment, it will often be insufficient to satisfy the iron demands. Intravenous administration of iron is effective in preventing functional iron deficiency. The use of intravenous iron saccharate has not been complicated by anaphylaxis in contrast to iron dextran. A dosage of 100 mg of iron saccharate (two to three times weekly for three to four weeks) is recommended [26], except for autologous blood donors who need a more intensive iron supplementation (200 mg at each donation). In practice, iron-restricted erythropoiesis can be found in patients with serum ferritin concentration , 100 mg / l and / or transferrin saturation , 20%; those patients are candidates for more intensive iron supplementation. Side effects The use of rHuEpo in dialysis patients has been associated with (aggravation of) hypertension and seizures. The adverse reactions are probably due to changes in hematocrit. Outside the setting of end stage renal disease, no important side effects of rHuEpo treatment have been reported. Variables of hemostasis, fibrinolysis, and blood rheology showed no significant changes in autologous blood donors who received high dosages of rHuEpo during a 3-week period [30].

Conclusions The clinical use of rHuEpo outside the setting of uremia will not provide all the benefits of rHuEpo treatment in (pre)dialysis patients. Dosages are often higher as compared to maintenance dose in uremic patients and the high costs of rHuEpo will not counterbalance its effectiveness for most applications. In contrast to uremic patients, rHuEpo therapy will not be effective in (almost) all patients treated for other indications and follow-up of early indicators of erythropoietic response is, therefore, necessary. It is unlikely that some patients (elderly, patients with malignancy) will benefit from the prevention of long-term complications of donor blood (transfusion-transmissible diseases) and additional studies are warranted to show improvement of QOL to support the use of rHuEpo in malignancy when compared to regular transfusions. The use of rHuEpo for non-uremic indications should only be considered in symptomatic anemia after ruling out other correctable causes of anemia in patients with a blunted erythropoietin production. Patients should receive adequate iron supplementation and the response to rHuEpo has to be evaluated within 4 weeks of treatment. Treatment with rHuEpo outside uremia can only be justified when the benefits of avoiding blood transfusions (prevention of transmission of diseases, prevention of iron accumulation, improvement in QOL) equal the costs of rHuEpo therapy. However, for most indications outside CRF, issues of appropriate patient selection, optimal dosage and duration of treatment, and cost benefit ratios are still unresolved.

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