RECOMBINANT human erythropoietin (rHuEpo) became available for clinical trials in 1985 and was introduced into clinical practice for correction of anemia of renal failure in 1989. More than 300,000 renal patients throughout the world are now receiving rHuEpo.1 For several reasons this use can be presently regarded as the gold standard of Epo therapy. First, renal anemia is the prototype of the Epo-deficient state. Second, although coexisting conditions may decrease rHuEpo effectiveness,2,3 more than 95% of renal patients treated with rHuEpo have a positive response if adequate doses are administered and become transfusion-independent.4 Third, the commonly used weekly maintenance dose of less than 100 IU/kg body weight is cost-effective compared with a regular transfusion requirement of 2 to 3 U of blood per month. Finally, quality of life improves in dialysis patients whose hemoglobin (Hb) concentration increases from 6 to 7 g/dL to 9 to 10 g/dL.5 

Several clinical studies in the last few years have shown that rHuEpo can be remarkably effective also outside nephrology.6 Because only a portion of nonrenal patients benefit from treatment, there is a need for reliable criteria to predict potential responders and ensure appropriate uses of rHuEpo. The aim of this article is to define a rational approach to rHuEpo treatment outside the setting of uremia.

Epo Production

Epo is primarily made by a single organ, the kidney, outside the bone marrow and participates in a classic negative feedback control system.7-9 Hypoxia is the fundamental physiologic stimulus that causes a rapid increase in renal production of Epo through an exponential increase in the number of Epo-producing cells.10 

Factors other than tissue hypoxia might be involved in the regulation of Epo production or may influence serum concentration. Abnormally high Epo levels have been reported in patients with aplastic anemia,11 and dramatic changes in serum levels have been described after chemotherapy12,13 and during vitamin B12 or iron replacement therapy.14,15 These findings point to an inverse relationship between red blood cell (RBC) precursor mass and serum Epo level: the higher the number of RBC precursors, the faster the Epo clearance.16 

Inflammatory cytokines may interfere with Epo gene expression. Interleukin-1 (IL-1), tumor necrosis factor α (TNFα), and transforming growth factor β (TGFβ) have been found to inhibit hypoxia-induced erythropoietin production in vitro.17,18 These cytokines also inhibit erythroid progenitor cell proliferation, thus playing a major role in the pathogenesis of the anemia of chronic disease.19 At variance, IL-6 was shown to mimic hypoxia in vitro,17 and elevated levels in humans are associated with adequate endogenous Epo production.20 

Increased plasma viscosity inhibits Epo formation, thus contributing to anemia both in inflammation and monoclonal gammopathies.21 

Chemotherapeutic agents blunt Epo response.22 Cisplatin appears to be particularly toxic, causing a prolonged anemia.23,24 Cyclosporin A also attenuates the production of Epo,25,26 and this may contribute to the anemia of patients undergoing organ transplantation. Theophylline is another drug attenuating the production of Epo.27 Finally, a direct suppression of Epo formation by human immunodeficiency virus (HIV) has been observed in vitro,28 suggesting that this may have a role in the pathogenesis of HIV-related anemia.

Physiologic Role of Epo in Erythropoiesis: Implications for the Clinical Use of rHuEpo

Epo is the primary regulator of erythropoiesis and exerts its effects by binding to a surface receptor present on erythroid progenitors and precursors.29 Although only a few receptors (<100/cell) are found on early burst-forming units-erythroid (BFU-Es), their number increases with differentiation and a peak of about 1,100 receptors/cell is reached at the stages of colony-forming unit-erythroid (CFU-E) and proerythroblast.30-32 Receptor expression then decreases with erythroid maturation and almost undetectable levels are observed on peripheral reticulocytes.

Evidence has been provided that Epo may act both as a survival factor33 and a mitogen.34 However, enhancement of cell replication is only observed on mutated cell lines when the erythroid hormone is combined with stem cell factor.35 For normal human erythroid progenitors with high receptor number, ie, CFU-Es and proerythroblasts, Epo is mainly a survival factor. These cells vary widely in their Epo sensitivity, likely due to variations in internal signal transduction.36 Recent studies on knockout mice have shown that Epo is crucial in vivo for the proliferation and survival of CFU-Es and their irreversible terminal differentiation, whereas it is not required for generation of BFU-Es and their differentiation to CFU-Es.37 Epo can promote erythroid progenitor survival by repressing apoptosis through bcl-XL and bcl-2.38 

A model of erythropoiesis based on Epo prevention of programmed cell death in a population of erythroid progenitor cells with a wide heterogeneity of Epo-dependence has been proposed by Koury and Bondurant39 (Fig 1). In this model, which is consistent with the observations in knockout mice,37 erythropoiesis can be substantially and steadily expanded only through preamplification of Epo-dependent progenitors. Administration of rHuEpo to normal individuals triggers premature expulsion of immature reticulocytes from the bone marrow into the circulation,40 followed by a slow increase in Hb level,41 suggesting indeed an erythroid progenitor amplification followed by a gradual expansion of erythroblasts.42 43 

Fig. 1.

Model proposed by Koury and Bondurant33 for expansion of erythropoiesis by prevention of apoptosis in erythroid progenitors (see also Wu et al37 and Koury and Bondurant39 ). Late erythroid progenitors (CFU-Es and proerythroblasts) are dependent on the continuous presence of Epo to suppress apoptosis and are heterogeneous with respect to their Epo sensitivity. Under normal conditions (A), only a portion of late erythroid progenitors (those with lower Epo requirement) survive, generating erythroid precursors that produce normal amounts of mature RBCs. In conditions characterized by blunted Epo production (B), eg, renal failure, the large majority of erythroid progenitors undergo apoptosis due to the low Epo level within the bone marrow. Only a subpopulation of progenitors with very high Epo sensitivity and very low requirement survive; RBC production is inadequate and anemia develops. Administration of rHuEpo may allow a substantial expansion of erythropoiesis by preventing apoptosis of large numbers of late erythroid progenitors with intermediate Epo sensitivity. In anemia due to peripheral hemolysis or acute blood loss (C), renal Epo production is increased several fold and high levels of erythroid hormone are present in the bone marrow. Nearly all erythroid progenitors, even those with high Epo requirements, survive, with maximum preamplification of erythropoiesis. Administration of rHuEpo is unlikely to further enhance RBC production, because levels capable of preventing apoptosis of least sensitive cells cannot be reasonably achieved.

Fig. 1.

Model proposed by Koury and Bondurant33 for expansion of erythropoiesis by prevention of apoptosis in erythroid progenitors (see also Wu et al37 and Koury and Bondurant39 ). Late erythroid progenitors (CFU-Es and proerythroblasts) are dependent on the continuous presence of Epo to suppress apoptosis and are heterogeneous with respect to their Epo sensitivity. Under normal conditions (A), only a portion of late erythroid progenitors (those with lower Epo requirement) survive, generating erythroid precursors that produce normal amounts of mature RBCs. In conditions characterized by blunted Epo production (B), eg, renal failure, the large majority of erythroid progenitors undergo apoptosis due to the low Epo level within the bone marrow. Only a subpopulation of progenitors with very high Epo sensitivity and very low requirement survive; RBC production is inadequate and anemia develops. Administration of rHuEpo may allow a substantial expansion of erythropoiesis by preventing apoptosis of large numbers of late erythroid progenitors with intermediate Epo sensitivity. In anemia due to peripheral hemolysis or acute blood loss (C), renal Epo production is increased several fold and high levels of erythroid hormone are present in the bone marrow. Nearly all erythroid progenitors, even those with high Epo requirements, survive, with maximum preamplification of erythropoiesis. Administration of rHuEpo is unlikely to further enhance RBC production, because levels capable of preventing apoptosis of least sensitive cells cannot be reasonably achieved.

Close modal

This model of erythropoiesis is extremely relevant to the clinical use of rHuEpo (Fig 1). When endogenous Epo levels are inappropriately low for the degree of anemia, administration of rHuEpo can be effective in increasing the amount of hormone reaching the erythroid marrow, thus allowing survival of more CFU-Es and output of more RBCs. Pharmacologic doses of the erythroid hormone can expand erythropoiesis also in normal individuals, such as candidates to autologous blood donation, by preventing programmed death of a few additional CFU-Es. When the endogenous plasma level of Epo is adequate for the degree of anemia, the amount of hormone circulating within the bone marrow may be increased 1 to 2 log and nearly all available marrow CFU-Es already survive; it is very unlikely that pharmacologic doses of rHuEpo can further increase the marrow Epo supply and expand erythropoiesis on these conditions.

Evaluation of Endogenous Epo Production and Epo-Deficient States

Assessment of endogenous Epo production has become a routine diagnostic procedure with the availability of commercial immunoassays for serum Epo.44 Serum Epo levels in normal individuals are in the range of 5 to 30 mU/mL. Studies on different immunoassays have shown a wide range of estimates among normal individuals and among methods.45 Two-site (sandwich-type) enzyme-linked immunoassays appear to be more specific or at least to recognize only a proportion of Epo isoforms.46 From a practical point of view, every laboratory should use only one immunoassay and become familiar with it.

Levels found in anemic patients cannot be simply compared with normal values. In fact, as far as the Epo-generating apparatus in the kidney is efficient, serum levels increase exponentially as the hematocrit (Hct) decreases. Serum Epo must therefore be evaluated in relation to the degree of anemia and every single laboratory should determine the exponential regression of serum Epo versus Hct (or Hb) in a home-made reference population of anemic subjects and define the 95% confidence limits as reported in Fig 2. The patients gathered to calculate a reference regression equation should have no evidence of renal failure and inflammation. Patients with iron deficiency anemia, hemolytic anemia, or thalassemia intermedia may be studied as reference subjects.

Fig. 2.

Relationship between serum Epo levels and Hct in reference subjects. Area of parallel lines defines the 95% confidence limits. Values below the 95% reference range indicate a defective Epo response to anemia. Patients with aplastic or refractory anemia may show values above the reference range.

Fig. 2.

Relationship between serum Epo levels and Hct in reference subjects. Area of parallel lines defines the 95% confidence limits. Values below the 95% reference range indicate a defective Epo response to anemia. Patients with aplastic or refractory anemia may show values above the reference range.

Close modal

The definition of defective Epo production relies on a low serum Epo in comparison with reference patients with similar Hct (or Hb). Analysis of covariance is the most appropriate statistical method for comparing a population of patients with reference subjects.44 This has led us to define a number of states characterized by blunted Epo production; the most common clinical conditions are listed in Table 1. With the exception of prematurity and renal failure, serum Epo levels should be obtained in all anemic patients before initiating rHuEpo therapy.

In an individual patient, the adequacy of endogenous Epo production can be easily assessed by graphic evaluation, as shown in Fig 2, or through the observed/predicted log (serum Epo) ratio (O/P ratio); the predicted value is derived from the regression equation. The O/P ratio is less than 1 if the observed value is lower than the predicted one; in reference subjects, the 95% confidence interval ranged from 0.80 to 1.20.47 The O/P ratio provides a measure of the magnitude of inadequacy of Epo production.44 For practicing physicians to gainfully use the O/P ratio for evaluation of endogenous Epo production, every laboratory should routinely provide this ratio together with the serum Epo concentration.

Pharmacokinetics of rHuEpo and Route of Administration

There are substantial differences between intravenous (IV) and subcutaneous (SC) administration of rHuEpo. SC administration of rHuEpo induces lower peak plasma Epo concentrations, with an elimination half-life of about 19 to 22 hours versus the 4 to 5 hours of IV rHuEpo.41 48 SC administration of smaller doses of rHuEpo more closely resembles the physiology of Epo production and leads to greater efficacy than IV administration of larger doses. Therefore, rHuEpo should routinely be administered SC.

Dosing and Monitoring rHuEpo

A variety of dosages and administration schedules have been used for rHuEpo outside the uremia setting. Reported doses (from 150 to >1,000 IU/kg/wk) are clearly higher than those effective in renal anemia, indicating that rHuEpo is not just a replacement therapy in the nonrenal applications. Certain uses, in particular short-term treatments concerning prevention of anemia, involve fixed schedules (see below). However, when facing an individual anemic patient, practicing physicians must decide the initial dosage.

Erslev49 recommended a dosage of 80 IU/kg twice weekly for anemic patients with serum Epo levels less than 100 mU/mL and dosages at least 10 times higher for anemic patients with levels greater than 500 mU/mL. Besides endogenous Epo levels, additional factors determine the amount of rHuEpo required to expand erythropoiesis. A major factor is residual marrow function, which can be estimated from platelet count and transfusion requirement.50,51 Concomitant chemotherapy is also a crucial variable.51 The optimal interval between rHuEpo doses has not been established. A recent report suggests that, in normal subjects treated with IV iron, an interval of 72 hours between two doses of rHuEpo induces a higher reticulocyte response than a 24-hour interval.52 

Practical criteria for deciding the initial dosage of rHuEpo in an anemic patient are listed in Table 2. In view of the high cost of the therapy, it is mandatory to choose a dose that allows the optimal use of each vial and avoids wastage.

Indicators of response should be used to monitor patients treated with rHuEpo. Increments in Hb after 2 to 4 weeks have been shown to be a powerful predictor of responsiveness to rHuEpo treatment.51 However, this parameter may be useless in patients receiving transfusions and/or concomitant chemotherapy. Whereas changes in reticulocyte count after 2 weeks may simply reflect output of shift reticulocytes and not true expansion of erythropoiesis,42 an increase in reticulocyte count of ≥40 × 109/L after 4 weeks was found to be a significant predictor of response in cancer anemia.53,54 Thus, treatment efficacy should be assessed by measuring Hb and reticulocyte count after 4 weeks: patients showing a 4-week change in Hb level ≥1.0 g/dL and/or a change in reticulocyte count ≥40 × 109/L are those most likely to respond to rHuEpo.54 

A 2-week increment in circulating transferrin receptor ≥25% has been found to predict response to rHuEpo in both renal55 and nonrenal anemia.54 Because this parameter may show nonspecific increases (eg, variations not related to the RBC precursor mass) and its assay is not widely available, it cannot be recommended for use at this time.

Response to rHuEpo should be monitored for the possible appearance of signs of iron-deficient erythropoiesis (see below).

Only a portion of anemic patients respond to the initial dosage of rHuEpo, and some of the unresponsive ones can benefit from higher doses. Thus, after 4 weeks of treatment, if the Hb increase is less than 1 g/dL in untransfused individuals or there is no reduction in transfusion requirement in transfusion-dependent patients, the dosage should be increased (eg, it may be doubled). It is very unlikely that patients unresponsive to a rHuEpo dose of up to 900 IU/kg/wk will benefit from a further escalation; we therefore recommend not to exceed this dose, unless this is justified by very specific reasons.

When response is achieved, dose adjustments should be performed to maintain Hb within the optimal range; for each individual patient, this decision represents a compromise between subjective and objective benefits and treatment costs.

Epo and Iron: Functional Iron Deficiency

The bone marrow can be compared with a car engine, in which an adequate response to pushing on the accelerator (Epo) can be achieved only by a properly matched injection of fuel (iron). Administration of rHuEpo in excess of functionally available iron will lead to iron-deficient erythropoiesis, diminished erythroid marrow response, and a waste of this costly drug.

Two different patterns of iron-deficient erythropoiesis may develop with rHuEpo administration. True iron deficiency may develop during chronic rHuEpo administration due to a progressive shift of iron from body stores to the erythron.4 The term functional or relative iron deficiency is used to define a situation in which the body iron stores are normal (or even increased) but iron supply to the erythroid marrow is inadequate for the RBC precursor demand.56,57 Functional iron deficiency, or iron-restricted erythropoiesis, appears in the initial phase of RBC regeneration after the administration of rHuEpo to subjects with normal iron stores.42 Serum iron and transferrin saturation are low, serum ferritin is normal to low (presumably because the amount of readily exchangeable iron in the reticuloendothelial cells is insufficient), and iron procurement by transferrin is inadequate.42 

Functional iron deficiency has been described when rHuEpo is used to increase autologous blood donation, based on the appearance of RBCs with abnormally low Hb concentration58 and/or increased RBC protoporphyrin,59 and, in the absence of blood donation, on the appearance of reticulocytes with reduced Hb content.60 As shown in Fig 3, in individuals with normal iron stores, reticulocytes demonstrate earlier changes than RBCs. Interestingly, subjects with increased body iron stores60 and elevated transferrin saturation, in particular those with hereditary hemochromatosis,58 show no signs of functional iron deficiency and demonstrate a better response to rHuEpo. Functional iron deficiency has been found to be a frequent cause of poor response to rHuEpo in nonrenal anemia.50 

Fig. 3.

Functional iron deficiency in subjects receiving rHuEpo. (Top) Production of RBC with abnormally low Hb concentration in 3 normal subjects receiving rHuEpo to promote autologous blood donation. The percentage of RBCs with cell Hb concentration lower than 28 g/dL is plotted on the y-axis versus time (x-axis). The dose used in this trial was 200 IU/kg/d SC for 3 weeks. rHuEPO was started 1 week ahead of blood donations.58 (Bottom) Production of reticulocytes with abnormally low Hb content (CHr) in 24 normal males receiving 1,200 IU/kg of rHuEpo over 10 days. The dose was divided into either 4, 3, or 2 administrations (groups A, B, and C, respectively). Group C has higher baseline ferritin values compared with group A.60 103 

Fig. 3.

Functional iron deficiency in subjects receiving rHuEpo. (Top) Production of RBC with abnormally low Hb concentration in 3 normal subjects receiving rHuEpo to promote autologous blood donation. The percentage of RBCs with cell Hb concentration lower than 28 g/dL is plotted on the y-axis versus time (x-axis). The dose used in this trial was 200 IU/kg/d SC for 3 weeks. rHuEPO was started 1 week ahead of blood donations.58 (Bottom) Production of reticulocytes with abnormally low Hb content (CHr) in 24 normal males receiving 1,200 IU/kg of rHuEpo over 10 days. The dose was divided into either 4, 3, or 2 administrations (groups A, B, and C, respectively). Group C has higher baseline ferritin values compared with group A.60 103 

Close modal

Iron supplementation (200 mg of oral elemental iron daily, ie, 900 mg of iron sulfate) should be administered routinely during the first 4 to 6 weeks of rHuEpo treatment to all patients but those with increased serum iron and transferrin saturation. Although iron absorption can increase several fold when rHuEpo is used,42 oral iron supplementation may still be insufficient in matching iron demands by the rHuEpo-expanded erythroid marrow.60 

IV iron dextran (available in the United States) has about 0.1% incidence of anaphylaxis and, due to this potentially life-threatening complication, many hematologists are reluctant to use it routinely. Iron saccharate (available in Europe) is much safer: no anaphylactic reaction or any other life-threatening complication has been observed by us with over 1,000 IV administrations. Iron saccharate is effective in preventing the functional iron deficiency associated with rHuEpo treatment.50 61 The optimal treatment schedule is 100 mg of iron saccharate administered by intravenous infusion (250 mL of saline) 2 to 3 times weekly for 3 to 4 weeks. For the patient's convenience, 200 mg by slow IV infusion once weekly for 3 to 4 weeks may represent a satisfactory compromise. Autologous blood donors need a more aggressive iron supplementation, ie, 200 mg by slow IV infusion at each donation visit (see below). Iron saccharate may be administered routinely to all patients with normal to low values for serum iron, transferrin saturation, and serum ferritin.

Monitoring iron status in patients receiving rHuEpo may allow prompt detection of iron-deficient erythropoiesis. However, this is feasible only if the physician may rely on simple tests. An impaired iron supply to the erythroid marrow is indicated by low transferrin saturation (<20%)56,57; however, this measurement shows marked variation and is relatively time consuming. Serum ferritin levels less than 100 μg/L are generally associated with insufficient amounts of ready exchangeable iron in the reticuloendothelial cells and may be regarded as predictive of functional iron deficiency under rHuEpo treatment.50,60 Macdougall et al62 have proposed a simpler approach to the detection of functional iron deficiency during rHuEpo treatment. Using an automated cell counter, it is possible to obtain the percentage of hypochromic RBCs (defined as an individual cell Hb concentration <28 g/dL). These are normally lower than 2.5% of all RBCs. An increase to greater than 10% during rHuEpo would indicate the development of functional iron deficiency and the need for more intensive iron supplementation.62 Early detection of iron-restricted erythropoiesis can be achieved with the monitoring of reticulocyte Hb content (CHr).60 As shown in Fig 3, the appearance of reticulocytes with abnormally low CHr precedes by several days the detection of hypochromic RBCs. Any patient fulfilling at least one of the above criteria (transferrin saturation <20%, serum ferritin <100 μg/L, >10% hypochromic RBCs, or reticulocytes with low CHr) should be promptly considered for more aggressive iron supplementation therapy.

Side Effects of rHuEpo Treatment

rHuEpo is remarkably well tolerated. Adverse reactions have been described mostly in chronic renal failure, with development of hypertension and seizures. Outside of the renal setting, there are no reports of significant side effects. Aggravation of splenomegaly has been occasionally observed in myeloproliferative disorders.50 Although rHuEpo may slightly increase platelet count in occasional patients, no significant changes in any hemostatic variable can be shown in the vast majority of treated individuals.63 Very seldom (4 case reports in the literature)64 antibodies against Epo have been shown in patients treated with rHuEpo.

In the United States, rHuEpo is approved for treatment of anemia induced by zidovudine (AZT) therapy in HIV-infected patients with endogenous Epo levels less than 500 mU/mL, of anemia induced by chemotherapy of nonmyeloid malignancies, and for the reduction of allogeneic blood transfusion in elective surgery patients (with the exception of cardiac and vascular surgery). In some European countries, rHuEpo is now approved also for potentiation of preoperative autologous blood donation and for treatment of anemia of prematurity.

The clinical uses of rHuEpo in nonuremic patients can be schematically divided into prevention and treatment of anemia.

Patients facing surgery or chemotherapy are obviously at risk of developing anemia. Some of them may benefit from the prophylactic use of rHuEpo, as summarized in Table 3 and detailed below.

Potentiation of Preoperative Autologous Blood Donation and Perisurgical Use of rHuEpo

Different uses have been proposed for rHuEpo in transfusion medicine.65 rHuEpo may be used to enhance the collection of autologous blood in patients facing elective surgery, to correct anemia before surgery, and to accelerate postoperative erythropoietic response. The primary aim is to avoid the risks of blood transfusion from donors.66 In addition, patients who refuse transfusion on religious or ideological grounds or patients for whom it can be difficult to find compatible blood can undergo invasive surgical operations with a greater margin of safety.

Autologous blood transfusion.For surgical patients, particularly candidates for elective surgery, the safest alternative to transfusion with allogeneic blood is the use of the patient's own blood, obtained using various autotransfusion techniques.67-69 Autologous donation is poorly effective if the patient, during the relatively short time for which the collected units can be stored, is unable to predeposit sufficient blood to meet his/her transfusion needs.70 

The amount of blood that may be predeposited depends on the subject's RBC mass and ability to rapidly reconstitute the volume of RBCs withdrawn. Subjects of small size and/or with low baseline Hct do not generally succeed in predepositing the amount of blood required to cover their transfusion requirements. In a retrospective study on 2,500 cases, only two thirds of patients were found to be able to predeposit the optimal amount of autologous blood: the major cause for failure was a decrease in the Hct to less than the threshold of 33%, which often occurred after the first or second donation.71 

The ability to promptly reconstitute the RBC mass might be limited by endogenous Epo production.72 As shown in Fig 2, serum Epo levels increase significantly above normal only for Hct values of less than 30% (or Hb <10 g/dL).73 This Hct value is below the acceptable level for donation of autologous blood. According to American Association of Blood Banks (AABB) standards,74 donation should not take place when Hct is less than 33% and Hb is less than 11 g/dL. Therefore, the degree of anemia induced by autologous blood donations is never sufficient to increase endogenous Epo levels significantly.

Efficacy of rHuEpo in increasing the volume of predeposited blood.Several studies have shown that rHuEpo can increase autologous blood donation.61,75-80 In all of the clinical studies considered, rHuEpo was found to be effective in stimulating erythropoiesis and increasing new RBC production (although this was found to vary considerably [250 to 900 mL]) and the number of units predeposited. It was also effective in correcting anemia induced by blood collection.81 82 

The increase in the amount of blood deposited correlated fairly well with the dose of rHuEpo administered. The most common treatment protocol used involved IV administration twice weekly for 3 weeks together with oral iron supplements. Total doses of less than 600 IU/kg were ineffective in promoting sufficient erythropoiesis to significantly increase the volume of predeposited blood. Higher doses yield a dose-dependent production of new RBCs ranging from 250 mL for total doses of 600 IU/kg to more than 900 mL for doses of 3,600 IU/kg. It should be noted that, despite oral iron supplementation, the effect of rHuEpo therapy in autologous donors is very often restricted by iron depletion.83 IV iron administration allows a more adequate iron supply for erythropoiesis, with either an increased Hb response to the same dose of rHuEpo81 or a reduction in the dose of rHuEpo required. With the use of IV iron saccharate, RBC regeneration and volume of predeposited blood were identical when total rHuEpo doses of 1,800 and 3,600 IU/kg were compared.61 

The effectiveness of the SC route for rHuEpo has been shown in several studies.58,84 In our experience (Fig 4), SC administration of rHuEpo combined with intravenous iron is highly effective in autologous blood donation and, compared with intravenous administration, allows a marked reduction (approximately 50%) in the total rHuEpo dose. In a recent study, SC administration of rHuEpo combined with intravenous iron saccharate infusion has been shown to have facilitated the donation of autologous blood and reduced perioperative homologous blood transfusion in anemic patients with cancer.85 

Fig. 4.

Production of new RBCs in patients treated with IV rHuEpo at a total dose of 1,800 IU/kg and in patients treated with SC rHuEpo at a dose of 800 IU/kg. Both groups received IV iron supplements. Data are from the Department of Immunohematology and Blood Transfusion, Istituto Ortopedico Gaetano Pini (Milan, Italy). The study was performed on 22 patients suffering from rheumatoid arthritis and about to undergo total hip replacement or total knee replacement who were unsuitable for inclusion in the predeposit program due to anemia (Hct <34%). Patients enrolled in the study received 100 IU/kg rHuEpo SC twice a week for 3 weeks + one 200 IU/kg bolus of IV rHuEpo at the time of the first administration (total dose, 800 IU/kg; 11 patients) or 300 IU/kg IV rHuEpo twice a week for 3 weeks (total dose, 1,800 IU/kg; 11 patients). Apart from 1 patient in the group treated with IV rHuEpo, all the remaining were able to predeposit autologous blood units. SC administration of a rHuEpo dose 55% less than the IV dose was found to be equally effective in terms of average number of units predeposited (2.6 ± 0.9 v 2.6 ± 0.6), the number of allogeneic units transfused per patient (0.3 ± 0.8 and 0.8 ± 0.8, respectively), and the total number of units transfused per patient (3.1 ± 0.9 and 3.1 ± 0.6, respectively). A significant reduction in the number of allogeneic units transfused per patient was noted compared with an untreated historical group (0.5 ± 0.8 v 2.6 ± 1.6; P = .002).

Fig. 4.

Production of new RBCs in patients treated with IV rHuEpo at a total dose of 1,800 IU/kg and in patients treated with SC rHuEpo at a dose of 800 IU/kg. Both groups received IV iron supplements. Data are from the Department of Immunohematology and Blood Transfusion, Istituto Ortopedico Gaetano Pini (Milan, Italy). The study was performed on 22 patients suffering from rheumatoid arthritis and about to undergo total hip replacement or total knee replacement who were unsuitable for inclusion in the predeposit program due to anemia (Hct <34%). Patients enrolled in the study received 100 IU/kg rHuEpo SC twice a week for 3 weeks + one 200 IU/kg bolus of IV rHuEpo at the time of the first administration (total dose, 800 IU/kg; 11 patients) or 300 IU/kg IV rHuEpo twice a week for 3 weeks (total dose, 1,800 IU/kg; 11 patients). Apart from 1 patient in the group treated with IV rHuEpo, all the remaining were able to predeposit autologous blood units. SC administration of a rHuEpo dose 55% less than the IV dose was found to be equally effective in terms of average number of units predeposited (2.6 ± 0.9 v 2.6 ± 0.6), the number of allogeneic units transfused per patient (0.3 ± 0.8 and 0.8 ± 0.8, respectively), and the total number of units transfused per patient (3.1 ± 0.9 and 3.1 ± 0.6, respectively). A significant reduction in the number of allogeneic units transfused per patient was noted compared with an untreated historical group (0.5 ± 0.8 v 2.6 ± 1.6; P = .002).

Close modal

At least two studies have clearly shown that rHuEpo is safe and effective in stimulating erythropoiesis and allowing preoperative donation of blood for autologous use in patients who are unable to deposit blood preoperatively because of anemia.86 87 This appears to be one of the major indications to the use of rHuEpo in transfusion medicine.

Efficacy of rHuEpo in reducing the exposure to allogeneic blood transfusion within autotransfusion programs.The patient's basal Hct determines both the amount of blood that can be predeposited (direct relationship) and the transfusion requirement during and after surgery (inverse relationship). Patients with high Hcts (>40%) usually succeed in predepositing 4 U or more of blood before surgery without any rHuEpo treatment (provided that adequate iron supplements are administered).71 This amount of autologous blood is sufficient to cover transfusion requirements of most surgical operations. Therefore, for studies enrolling patients with high Hcts, it is difficult to show any efficacy of rHuEpo in reducing the risk of homologous transfusion, because patients in the placebo group also succeed in predepositing sufficient autologous units to cover their transfusion requirements.88 On the other hand, patients with a baseline Hct less than 37% generally predeposit insufficient autologous blood (0 to 1 U) to cover their transfusion requirements.71 For Hct values between 37% and 40%, requirements are covered by autologous blood in some 56% of cases.71 

Clinical trials enrolling selected patients at high risk for transfusion (anemic patients85,86 or individuals with low RBC mass and facing operations with high transfusion requirement80 ) have shown that treatment with rHuEpo significantly lowers homologous blood requirement in autologous blood donors. This observation indicates that rHuEpo use in autologous blood donation programs should be restricted to individuals who can benefit from it in terms of lower risk of exposure to allogeneic blood.

The issue of cost-effectiveness and indications to the use of rHuEpo in autologous donors.Routine use of rHuEpo for autologous donors is unlikely to be cost-effective. Cost-effectiveness of simple autologous donation has been questioned,89 given the improved safety of allogeneic transfusions and owing to the high cost of collecting and discarding units that are not used.90 In a recent study, 54% of the patients who received rHuEpo did not use the blood they had deposited.80 Despite the apparent financial disadvantage, reduction of allogeneic blood use via autologous blood donation should be recommended.91 92 Allogeneic transfusion is still to be regarded as an outcome to be avoided because, despite all technical and scientific achievements, a “zero risk” cannot exist in this setting.

In autologous blood donation programs, rHuEpo should be used in a carefully targeted approach for conditions likely to yield significant reductions in the transfusion of allogeneic blood, such as in anemic patients, individuals with a calculated blood volume less than 5 L, or with alloimmunization. At the present time, there is no consensus on the optimal schedule of rHuEpo administration. In orthopedic patients who donated 2 U of blood before surgery and received SC rHuEpo twice a week for 3 weeks, doses of 250 and 500 IU/kg yielded similar Hb levels that were higher than those of untreated controls or patients receiving 125 IU/kg.93 However, a recent study showed effective responses with dosages of 100 IU/kg administered to nonanemic patients twice a week in the 2 weeks before surgery.94 

We recommend a dosage of 250 to 300 IU/kg SC twice weekly for 3 weeks plus an optional initial IV administration of 150 to 200 IU/kg at the time of enrollment. Alternatively, the dose can be individualized using predictive algorithms.95 We recommend combination of rHuEpo with IV iron saccharate (200 mg by IV infusion at each donation visit). If this or any other safe preparation of IV iron is not available, oral supplementation should be provided by administering at least 200 mg of elemental iron daily.

Perisurgical use of rHuEpo.Although preoperative donation is now considered a viable and safe way to obtain autologous blood, there are subgroups of elective surgery patients for whom preoperative autologous blood donation is not feasible.96 These include patients with anemia or other disorders precluding donation, patients with limited time to surgery, and individuals who are unwilling to participate in an autologous blood donation program because of logistical problems or religious beliefs.97 For example, postponing the operation in cancer patients or candidates to heart surgery might be more detrimental than receiving allogeneic blood transfusion.

In these cases, rHuEpo can be used to turn the patient into his/her own blood bank by increasing RBC production before and immediately after surgery, without concomitant autologous blood donation. To test the hypothesis that the preoperative and postoperative administration of rHuEpo to patients undergoing elective hip replacement would increase the Hb level and decrease the rate of transfusion, the Canadian Orthopedic Perioperative Erythropoietin Study Group conducted a double-blind, placebo-controlled, randomized trial.98 Overall, this perisurgical use of rHuEpo decreased the need for transfusion. Most of the benefit of rHuEpo occurred in the 40% of patients whose Hb was less than 13.5 g/dL, in whom treatment reduced from 74% to 33% the portion of subjects requiring transfusion. The optimal treatment schedule in the Canadian study proved to be subcutaneous administration of 300 IU/kg daily for 14 days, starting 10 days before surgery and continuing until 3 days after surgery. This use was not cost-effective because the cost of perisurgical rHuEpo per patient ($2,880) balanced that of 17 U of allogeneic blood ($168 per unit). However, it should be noted that the Canadian study might considerably underestimate the transfusion costs. In fact, a more recent work99 has calculated a mean cost of $1,696 per transfusion episode for patients with the most common cancer types.

The American Erythropoietin Study Group has recently reported a randomized, double-blind, placebo-controlled study in 200 patients scheduled for elective orthopedic surgery who declined or were unable to donate autologous blood preoperatively.100 Patients were randomly assigned to one of three treatment groups: rHuEpo at 300 IU/kg/d (n = 60), rHuEpo at 100 IU/kg/d (n = 71), and placebo (n = 69). A total of 15 doses was administered SC, beginning 10 days before the operation and extending through postoperative day 4. All patients were maintained on iron supplementation orally. Fewer patients treated with rHuEpo (22%) received allogeneic transfusions compared with placebo-treated patients (54%; P < .001). Patients with a baseline Hb level of ≤13 g/dL were at significantly higher risk for transfusion than those with Hb level greater than 13 g/dL and benefited most from rHuEpo. A similar study in 316 patients undergoing orthopedic surgery (112 and 101 patients treated SC with 300 and 100 IU/kg rHuEpo, respectively, and 103 with placebo) showed a comparable reduction in exposure to allogeneic blood transfusion for patients receiving 300 IU/kg of rHuEpo when baseline Hb levels were greater than 10 and less than 13 g/dL.101 

Because blood transfusions might be associated with higher postoperative morbidity and tumor recurrence in colorectal cancer surgery,66 a trial was performed to investigate whether perisurgical Epo can reduce the need for transfusions in anemic patients who are not suitable for autologous blood donation.102 In a double-blind randomized study, 150 IU/kg body weight Epo was administered SC every 2 days beginning 10 days before the operation and continuing until postoperative day 2. There was no reduction in the need for transfusion in the rHuEpo-treated group, but selected patients with high iron availability (higher transferrin saturation) apparently benefited from treatment.

In a simulated perisurgical setting, administration of a total dose of 1,200 IU/kg of rHuEpo in conjunction with oral iron supplementation (300 mg elemental iron daily) over 10 days induced an increase of 6.2 Hct points in 24 normal males, corresponding to 2 U of RBCs.103 Thus, two doses of 600 IU/kg administered SC in the 10 days before surgery may be sufficient in patients with an expected blood loss of ≤2 U. A weekly SC dose of 600 IU/kg (total of 4 doses starting at surgery day −21) has been shown to provide a greater Hb increase than a daily SC regimen of 300 IU/kg (total of 15 doses, from surgery day −10 to +5) in patients undergoing major orthopedic surgery.104 This study and the study of Breyman et al52 in normal volunteers suggest that a proper interval between rHuEpo doses may have a significant influence on the erythropoietic response. As in other indications, the Hb response to perisurgical rHuEpo varies according to the iron stores and is higher in subjects with higher baseline serum ferritin60,101 or transferrin saturation.105 

A short-term perisurgical use of rHuEpo was studied at the Istituto Ortopedico Gaetano Pini in Milan. Sixteen patients for whom autologous blood donation was contraindicated for various clinical reasons and who were about to undergo major orthopedic surgery with a predicted transfusion requirement of 2 to 3 U of blood were enrolled in a pilot study. Treatment protocol involved SC administration of rHuEpo at a daily dose of 100 IU/kg from the preoperative day 4 (day −4) to the second postoperative day (day +2). On the first day of treatment, one 200 IU/kg bolus was also administered IV. IV iron saccharate was administered concomitantly at a total dose of 600 to 1,000 mg, according to baseline iron stores.61 71 This treatment produced a 2% to 7% increase in Hct, with an average increase in circulatory RBC mass of some 100 mL (from 0 to 245 mL) before surgery. Twelve of 16 patients did not require allogeneic transfusions, whereas a total of 6 U of blood was transfused in the remaining 4 patients. Although preliminary, these findings suggest that rHuEpo administered together with IV iron during a preoperative period of 4 to 5 days is able to stimulate erythropoiesis and reduce transfusion requirements in patients with very limited time to surgery who cannot deposit autologous units.

The combination of perisurgical rHuEpo with acute normovolemic hemodilution106-108 and/or perioperative RBC salvage109 may further decrease the need for autologous transfusion. In patients undergoing open-heart surgery, the use of rHuEPO induced higher oxygen half saturation tension (P50 ) and RBC 2.3 diphosphoglycerate (2.3-DPG) compared with placebo. This was shown to be associated with a significant increase in extractable O2 and a decrease in the occurrence of lactic acidosis postsurgery.109a 

Epo can also be used to improve postoperative erythropoietic recovery. In a study on 40 Jehovah's Witness patients with severe postsurgical anemia (Hct < 25%) refusing transfusion, administration of rHuEpo accelerated Hct recovery.110 

Current uses of rHuEpo in the surgical setting.rHuEpo has been approved by the FDA for the reduction of allogeneic blood transfusion in surgery patients. The approved indication includes anemic patients (Hb >10 and <13 g/dL) undergoing elective, noncardiac, and nonvascular surgery and patients at high risk for significant perioperative blood loss. This indication excludes anemic patients who are willing and capable of donating autologous blood.

Several different administration protocols have been used in the surgical setting.111 We suggest four alternative schedules, which are summarized in Fig 5. Criteria for selection among these four schedules should be primarily based on time to surgery and availability of an autologous blood donation program.

Fig. 5.

Uses of rHuEpo in surgical patients. (A) When the time to surgery is ≥3 weeks, the use of rHuEpo for facilitating autologous blood donation may be considered. Patients are treated with rHuEpo at 250 to 300 IU/kg twice weekly over the 3-week period before surgery. IV iron supplementation (iron saccharate at 200 mg) is administered at each of the six visits before surgery, when the patient donates 1 U of autologous blood (350 mL) if his/her Hct is ≥34%. If IV iron is not available, oral supplementation should involve the administration of at least 200 mg of elemental iron daily (900 mg iron sulphate) and rHuEpo doses should be doubled. (B) When the time to surgery is 2 to 3 weeks or when autologous donations are not possible, a preoperative use may be considered. We suggest SC administration of 6 doses of rHuEpo (250 to 300 IU/kg) and iron supplementation as detailed above in (A). These administrations may be distributed over a variable period, from 10 to 21 days. (C) Alternative protocol for perisurgical use of rHuEpo, based on 4 SC rHuEpo administrations of 600 IU/kg each, every 7 days, starting at surgery day −21.102 Daily oral iron supplementation is provided with 200 mg of elemental iron in the form of a polysaccharide-iron complex (Niferex; Central Pharmaceuticals Inc, Seymour, IN). (D) When time to surgery is 1 week or less, a short perisurgical use of rHuEpo may be considered. The schedule used at the Istituto Ortopedico Gaetano Pini (Milan, Italy) involves SC administration of rHuEpo at a daily dose of 100 IU/kg from preoperative day 4 (day −4) to postoperative day 2 (day +2). On the first day of treatment, one 200 IU/kg bolus is also administered IV. IV iron saccharate is administered concomitantly at a total dose of 600 to 1,000 mg, according to baseline iron stores.

Fig. 5.

Uses of rHuEpo in surgical patients. (A) When the time to surgery is ≥3 weeks, the use of rHuEpo for facilitating autologous blood donation may be considered. Patients are treated with rHuEpo at 250 to 300 IU/kg twice weekly over the 3-week period before surgery. IV iron supplementation (iron saccharate at 200 mg) is administered at each of the six visits before surgery, when the patient donates 1 U of autologous blood (350 mL) if his/her Hct is ≥34%. If IV iron is not available, oral supplementation should involve the administration of at least 200 mg of elemental iron daily (900 mg iron sulphate) and rHuEpo doses should be doubled. (B) When the time to surgery is 2 to 3 weeks or when autologous donations are not possible, a preoperative use may be considered. We suggest SC administration of 6 doses of rHuEpo (250 to 300 IU/kg) and iron supplementation as detailed above in (A). These administrations may be distributed over a variable period, from 10 to 21 days. (C) Alternative protocol for perisurgical use of rHuEpo, based on 4 SC rHuEpo administrations of 600 IU/kg each, every 7 days, starting at surgery day −21.102 Daily oral iron supplementation is provided with 200 mg of elemental iron in the form of a polysaccharide-iron complex (Niferex; Central Pharmaceuticals Inc, Seymour, IN). (D) When time to surgery is 1 week or less, a short perisurgical use of rHuEpo may be considered. The schedule used at the Istituto Ortopedico Gaetano Pini (Milan, Italy) involves SC administration of rHuEpo at a daily dose of 100 IU/kg from preoperative day 4 (day −4) to postoperative day 2 (day +2). On the first day of treatment, one 200 IU/kg bolus is also administered IV. IV iron saccharate is administered concomitantly at a total dose of 600 to 1,000 mg, according to baseline iron stores.

Close modal

Prevention of Anemia and Transfusion Requirement in Patients Undergoing Platinum-Based Combination Chemotherapy

A randomized trial has shown that cisplatin-induced anemia can be corrected by rHuEpo.112 The efficacy of rHuEpo in reducing transfusion requirements has been tested in women with ovarian carcinoma treated with platinum-containing chemotherapy regimens.113 Eight of 87 patients (9.2%) in the rHuEpo group received at least one transfusion, compared with 13 of 33 patients (39.4%; P = .0002) in the control group. A dose of 150 IU/kg three times weekly was effective, and a low serum Epo was a predictor of response, confirming the validity of the model reported in Fig 1. Decreased transfusion requirements were demonstrated in patients receiving rHuEpo during intensive chemotherapy for small-cell lung cancer114 or primary malignant bone tumors.115 In the latter study, rHuEpo was equally effective in patients receiving platinum-based chemotherapy and those receiving intensive chemotherapy without cisplatin or carboplatin.

Patients who are anemic before chemotherapy or become so after the first cycle are more likely to require blood transfusions.113 These individuals will benefit from prophylactic use of rHuEpo. In addition, because there is a significant dose-related impact of the platinum-based chemotherapy on the severity of anemia, it is appropriate to restrict the use of rHuEpo to patients treated with doses prone to induce anemia (cisplatin 75 mg/m2/cycle or more; carboplatin 350 mg/m2/cycle or more).

Adjuvant Treatment for Regular Phlebotomy

Most patients with hereditary hemochromatosis tolerate the removal of 1 to 2 U of blood per week with only a slight decrease in Hb level. Occasional patients become severely anemic. These individuals may benefit from rHuEpo to continue phlebotomy therapy.116 rHuEpo and phlebotomy have also been used in patients with porphyria cutanea tarda.117 

Anemia of Prematurity

Otherwise healthy infants who are born prematurely undergo an exaggerated decrease in Hb concentration compared with term infants.118 Multiple factors play a role in determining the anemia of prematurity, including a defective Epo response to decreasing Hb levels.119 

Data from various clinical trials indicate that the use of rHuEpo reduces transfusions in premature infants weighing more than 1,000 g.120-122 In infants weighing less than 1,000 g or requiring artificial ventilation, the reduction in transfusion needs is less impressive. This limited response may be due to poor Epo responsiveness or insufficient iron supplements. There is probably no benefit in using rHuEpo for infants weighing more than 1,300 g, because they rarely require transfusion. Preterm infants who have received rHuEpo show a normal pattern of erythropoiesis after the drug has been discontinued, indicating that the anemia of prematurity is the result of a transient developmental abnormality in Epo production.123 The dosages of rHuEpo used have been in the range of 75 to 1,200 IU/kg/wk, with one recent study using 6,300 IU/kg/wk.124 

Adopting selective criteria, treatment can be cost-effective.125 126 However, in our opinion, the need of providing cost-effective care should not prevent the intuitive benefit of reducing use of allogeneic blood products in this particular setting. We recommend early rHuEpo treatment for the premature infants who have an intermediate weight of approximately 750 to 1,300 g. The optimal dosage is 250 IU/kg subcutaneously three times weekly, from week 1 to 6 of life. Iron supplementation (5 mg of oral elemental iron per kilogram daily) appears to be crucial.

Anemia of Rheumatoid Arthritis and Other Inflammatory Conditions

Anemic patients with rheumatoid arthritis generally have lower plasma Epo levels than patients with comparable anemia due to iron deficiency.127 However, only occasional patients have Hb levels lower than 8 to 9 g/dL and practically none of these patients is dependent on transfusion. Many severely anemic patients have coexistent iron deficiency and may benefit from IV iron administration.128,129 Thus, although patients with rheumatoid arthritis may show excellent hematologic responses to recombinant Epo,127,130 there is little rationale for widespread treatment. This does not exclude the use of rHuEpo in individual cases who are severely anemic and do not respond to iron therapy. On the other hand, the use of rHuEpo appears fully justified in the perisurgical setting.71 

It has been shown that rHuEpo treatment can increase Hb levels in patients with inflammatory bowel disease and anemia refractory to treatment with oral iron and vitamins.131 Many of these patients are likely to have iron deficiency associated with inflammation and, although resistant to oral iron, may respond to IV iron. A low mean corpuscular volume (MCV), a serum ferritin level below 70 μg/L or an increased serum transferrin receptor level can be used for defining iron depletion with concomitant inflammation.20 Bone marrow stainable iron is also a useful parameter, but this is an invasive test that cannot be used routinely in all patients. If any of these parameters suggests concomitant iron deficiency, a short treatment with IV iron should be performed before considering the use of rHuEpo in these individuals.

HIV Infection

Anemia is found in about two thirds of patients with acquired immunodeficiency syndrome (AIDS) and generally worsens during treatment with AZT. Dosages of rHuEpo of 100 to 200 IU/kg administered IV or SC three times a week induced increased Hct and reduction of transfusion requirements in patients with baseline serum Epo levels less than 500 mU/mL.132,133 A large study using weekly dosages of 24,000 to 48,000 U/wk in patients with baseline Epo less than 500 mU/mL and Hct less than 30% showed an increase in Hct of at least 6 Hct points and a decrease in transfusion requirement in 44% of the patients.134 Positive results have also been obtained with rHuEpo in the treatment of anemia induced by antiretroviral therapy in HIV+ children.135 Although widespread use of rHuEpo in HIV-related anemia is not justified, symptomatic AIDS patients with baseline Epo less than 500 mU/mL should be treated.

Anemia of Cancer

Anemia is a frequent finding in patients with cancer and may be due to different causes.136 In untreated subjects, the most common type is anemia of chronic disease, a condition characterized by excessive release of inflammatory cytokines and variable degrees of defective endogenous Epo production.19 Chemotherapy and radiotherapy frequently cause or exacerbate anemia in patients with cancer due to their suppressive effects on either erythropoiesis or renal production of Epo.

A very thorough review on the use of rHuEpo in cancer anemia has already been published in Blood.137  Following phase I-II clinical trials,138-141 two controlled studies have shown that rHuEpo at a dose of 100 to 150 IU/kg three times weekly corrects chemotherapy-induced anemia and reduces transfusion requirements.112,142 Epo has been found to be both safe and effective at increasing Hb levels in anemic patients receiving radiation therapy alone or combined with chemotherapy.143 144 

Improvement of anemia after rHuEpo treatment is seen in only a portion of cancer patients, and data on the relationship between response to rHuEPO and improvement of quality of life are preliminary and controversial.142,145,146 Therefore, we agree with Spivak137 that the most important issue is whom to treat. This is discussed below in the chapter on a patient-oriented approach to the use of rHuEpo outside nephrology. However, there is a need for prospective clinical trials aimed at evaluating the impact of rHuEpo treatment on the quality of life of anemic patients with malignant disease.

Anemia Associated With Multiple Myeloma and Non-Hodgkin Lymphoma

Although almost every patient with multiple myeloma (MM) eventually becomes anemic,147 anemia is more frequent and severe in subjects with advanced disease. A quarter of MM patients have inadequate Epo response and this proportion increases to more than 50% in advanced clinical stages.148 

In a pilot study, rHuEpo induced complete correction of anemia in 11 of 13 patients with myeloma-associated anemia without severe renal failure.149 Recent randomized trials have provided response rates of 55% to 65%.51,150 In a multicenter study, approximately three quarters of MM patients presenting with Epo levels inappropriately low for the degree of anemia responded to rHuEpo, whereas only one quarter of those with adequate Epo levels did so.51 A dose of 200 IU/kg/wk was effective in patients showing residual marrow function (as indicated by a platelet count >150 × 109/L), whereas 500 IU/kg/wk was required to achieve response in subjects with hypoproliferative marrow.51 A recent study on transfusion-dependent anemic patients with MM has shown that rHuEpo can eliminate transfusion needs in individuals with defective endogenous Epo production and a baseline platelet count ≥100 × 109/L.151 

The results obtained by using rHuEpo in the treatment of anemia associated with non-Hodgkin lymphoma are comparable to those obtained in MM.51 151 Only a few studies have treated patients with Hodgkin's disease, likely because anemia is less frequent in this condition than in non-Hodgkin lymphomas. However, rHuEpo appears equally effective in both conditions.

Hematopoietic Stem Cell Disorders

Anemia is a major clinical problem in conditions such as aplastic anemia, myelodysplastic syndromes (MDSs), and idiopathic myelofibrosis. Many patients are adversely affected by transfusion-dependency and secondary hemochromatosis.152 Unfortunately, the large majority of available studies on the use of rHuEpo in these conditions are uncontrolled.

There is no evidence of any effect in severe aplastic anemia, whereas occasional patients with pure RBC aplasia may respond despite elevated endogenous Epo levels.153 

Overall, 15% to 20% of patients with MDS respond to rHuEpo treatment, but the vast majority of responders are not transfusion-dependent and the doses required to achieve response are greater than 450 IU/kg/wk.154-156 Recognizing potential responders can be extremely important in individual cases. Refractory anemia (RA) is the class among the MDSs with reasonable response rates, and additional factors predicting response include serum Epo levels less than 100 mU/mL, female gender, and normal karyotype. Because the basic defect resides within the stem cell, the typical anemic MDS patient is expected to have a high serum Epo level, ie, appropriately increased endogenous Epo production. It is therefore unclear why some individuals show inappropriately low Epo levels.

The response rate to rHuEpo increases to approximately 40% when rHuEpo and granulocyte colony-stimulating factor (G-CSF ) are used in combination in MDS patients.157,158 About one half of responding patients require both G-CSF and rHuEpo to maintain an effective response, suggesting that synergy between these hematopoietic factors exists in vivo for the production of RBCs in MDS.159 

Fig. 6.

A patient-oriented approach to the use of rHuEpo for preventing allogeneic blood transfusion in individuals facing elective surgery. Mildly to moderate anemic individuals, patients with small body weight and low predicted blood volume (primarily females), and those with an anticipated blood loss of 1 to 2 L are most likely to benefit from rHuEpo treatment. See also Table 3 for details.

Fig. 6.

A patient-oriented approach to the use of rHuEpo for preventing allogeneic blood transfusion in individuals facing elective surgery. Mildly to moderate anemic individuals, patients with small body weight and low predicted blood volume (primarily females), and those with an anticipated blood loss of 1 to 2 L are most likely to benefit from rHuEpo treatment. See also Table 3 for details.

Close modal
Fig. 7.

A patient-oriented approach to the clinical use of rHuEpo in anemic patients or individuals who are very likely to become anemic. The use of rHuEpo should be limited to patients with symptomatic anemia and those who are transfusion-dependent or candidates for blood transfusion. This approach does not apply to the anemia of prematurity (see the pertinent section). Treatment should be considered only after the nature of the anemia has been clearly established. Furthermore, before using rHuEpo, other concomitant, correctable causes of anemia such as iron deficiency or folate/vitamin B12 deficiency should be recognized and remedied. Treatment should be started only after an inadequate Epo production has been documented, with the exception of patients undergoing chemotherapy, who may still have adequate endogenous Epo production but are likely to develop a defective one. Several studies have shown that a cutoff for serum Epo of 100 mU/mL allows the best discrimination between responders and nonresponders.51,54,154,156 This threshold has a high predictive power for Hb values less than 10 g/dL.54 For higher Hb values, the use of a threshold of 0.9 for the O/P ratio should be preferred. For AIDS patients, the most useful serum Epo level for deciding treatment has been found to be 500 mU/mL.132 Iron supplements should be routinely provided to prevent functional iron deficiency during the first 4 to 6 weeks, except in patients with iron overload and increased transferrin saturation. A safe preparation of IV iron is superior to oral iron. If iron saccharate is available, 100 mg should be administered by IV infusion three times weekly for 3 to 4 weeks. An impaired iron supply to the erythroid marrow will blunt the erythropoietic response to rHuEpo; “unresponsive” patients may become “responsive” after correction of the functional iron deficiency. Indicators of early response might allow clinicians to decide whether to continue or terminate rHuEpo therapy after 4 weeks. Changes in Hb concentration51,178 and reticulocyte count54 proved to be useful indicators for this purpose. These changes should be examined after 4 weeks of treatment in patients who do not receive concomitant chemotherapy and/or blood transfusion; for those who receive these concomitant treatments and are less likely to respond quickly, a second check after 8 weeks may be appropriate.

Fig. 7.

A patient-oriented approach to the clinical use of rHuEpo in anemic patients or individuals who are very likely to become anemic. The use of rHuEpo should be limited to patients with symptomatic anemia and those who are transfusion-dependent or candidates for blood transfusion. This approach does not apply to the anemia of prematurity (see the pertinent section). Treatment should be considered only after the nature of the anemia has been clearly established. Furthermore, before using rHuEpo, other concomitant, correctable causes of anemia such as iron deficiency or folate/vitamin B12 deficiency should be recognized and remedied. Treatment should be started only after an inadequate Epo production has been documented, with the exception of patients undergoing chemotherapy, who may still have adequate endogenous Epo production but are likely to develop a defective one. Several studies have shown that a cutoff for serum Epo of 100 mU/mL allows the best discrimination between responders and nonresponders.51,54,154,156 This threshold has a high predictive power for Hb values less than 10 g/dL.54 For higher Hb values, the use of a threshold of 0.9 for the O/P ratio should be preferred. For AIDS patients, the most useful serum Epo level for deciding treatment has been found to be 500 mU/mL.132 Iron supplements should be routinely provided to prevent functional iron deficiency during the first 4 to 6 weeks, except in patients with iron overload and increased transferrin saturation. A safe preparation of IV iron is superior to oral iron. If iron saccharate is available, 100 mg should be administered by IV infusion three times weekly for 3 to 4 weeks. An impaired iron supply to the erythroid marrow will blunt the erythropoietic response to rHuEpo; “unresponsive” patients may become “responsive” after correction of the functional iron deficiency. Indicators of early response might allow clinicians to decide whether to continue or terminate rHuEpo therapy after 4 weeks. Changes in Hb concentration51,178 and reticulocyte count54 proved to be useful indicators for this purpose. These changes should be examined after 4 weeks of treatment in patients who do not receive concomitant chemotherapy and/or blood transfusion; for those who receive these concomitant treatments and are less likely to respond quickly, a second check after 8 weeks may be appropriate.

Close modal

Early reports suggest that rHuEpo is unlikely to be effective in myelofibrosis with myeloid metaplasia.160 

Acceleration of Erythroid Repopulation After Bone Marrow Transplantation (BMT)

Endogenous Epo production is frequently inadequate in recipients of allogeneic BMT and this may delay erythropoietic recovery.161 A pilot study showed that rHuEpo administration can accelerate erythroid reconstitution after allogeneic BMT with no stem cell competition effect.162 Three randomized clinical trials have confirmed that rHuEpo in high doses reduces transfusion requirements during the first 2 months after BMT,163,164 whereas low doses are poorly effective.165 In one of the previous studies, rHuEpo appeared to be very useful in overcoming graft-versus-host disease that occurred with allogeneic BMT.164 Treatment adds approximately $2,000 to the cost of managing these patients. After autologous BMT or peripheral blood progenitor cell transplantation, the use of rHuEpo is not recommended because it does not significantly enhance recovery of erythropoiesis.166 167 

Use of rHuEpo in the transplantation setting can be extended to the potentiation of autologous blood collection in the donor plus stimulation of erythroid recovery in the recipient; predeposited blood was to be later used by the donor or the recipient.168 Donors were phlebotomized a median of 6 U of blood over a 5-week period; 5 of 11 BMT recipients underwent transplantation, receiving only donor-derived RBC transfusions.

Induction of Fetal Hb Synthesis in Sickle Cell Anemia and Thalassemia

Inappropriately low levels of serum Epo for the degree of anemia have been described in sickle cell disease.169 Use of rHuEpo to simply increase Hct would lead to increased viscosity and worsen vaso-occlusion and sickling. A possible beneficial effect of rHuEpo could be to increase the cellular concentration of Hb F at the expenses of Hb S when used either in combination with hydroxyurea or alone. Whereas one study reported no additional benefit from the addition of rHuEpo (maximum dosage of 1,500 IU/kg/wk, administered in 2 divided doses, 6 to 8 hours apart, IV) to a stable hydroxyurea regimen (9 to 23 mg/kg/d),170 a subsequent study using higher rHuEpo doses (maximum dosage 9,000 IU/kg/wk, administered in 3 daily IV doses of 3,000 U), lower hydroxyurea doses (20 to 25 mg/kg, 4 doses/wk) and oral iron sulfate supplemements showed that rHuEpo enhanced Hb F production compared with hydroxyurea alone.171 Anemia may be particularly severe in individual patients with sickle cell disease and renal failure. Treatment with rHuEpo can increase Hb from extremely low to moderate levels, providing enhanced function without enhanced cell crises.172 

Because of the ineffective erythropoiesis and the large expansion of the erythroid tissue characteristic of β-thalassemia, use of rHuEpo in this setting has been attempted with the aim of increasing Hb F synthesis and/or reducing the unbalance between the α and β globin chain synthesis, which is responsible for the premature death of both immature and circulating RBCs. Thalassemic patients have adequate or overexpressed serum Epo levels for their degree of anemia.173 Studies in small groups of patients indicate that rHuEpo increases Hb levels in thalassemia intermedia, with no or small changes in the percentage of Hb F.174 175 

The use of rHuEpo in patients with severe thalassemia or sickle cell disease must be considered experimental. Practicing physicians might consider it in selected individuals who show defective endogenous Epo production.

Miscellaneous Uses

Patients undergoing organ transplantation are treated with cyclosporin A to avoid rejection. As previously discussed, this drug reduces Epo production and therefore may be responsible for the development of hyporegenerative anemia. rHuEpo was shown to correct anemia and abolish transfusion requirement in children undergoing cardiac transplantation.176 

Patients with orthostatic hypotension caused by autonomic neuropathy frequently have a decreased RBC mass. Increasing the RBC volume with rHuEpo has been found to elevate blood pressure while standing,177 but this use has not proven to be beneficial.

Indications for the use of rHuEpo in nonrenal patients are listed in Table 4. These indications span from the three currently approved by the FDA to uncontrolled studies in patients with extremely rare disorders. Variable portions of patients within each condition are likely to respond to rHuEpo, based on the extent of defective endogenous Epo production, iron stores, and bone marrow functional capacity. The response will also vary greatly depending on the rHuEpo route of administration, dosing intervals, and concomitant iron supplementation.

rHuEpo primarily offers an alternative to blood transfusion. Based on the current hospital costs of rHuEpo ($9 to $8 per 1,000 IU), only to the extent that a dose of 75 U rHuEpo per kilogram per week in a 70-kg patient is successful in eliminating 1 U of blood transfused per month, rHuEpo affects the cost of transfusions. This simple calculation does not account for any improvement in quality of life, income productivity, and/or survival. Based on the prevention of transfusion complications, a mean incremental effectiveness per unit of allogeneic blood saved equal to 0.0003 quality-adjusted year of life (QALY) can be assumed.89 A dose of 10 U of rHuEpo per kilogram per week in excess of the above-reported dose (75 U) would impose a cost of $77,000 per QALY.

As discussed before, the figure of $168 per RBC unit could be a gross underestimate of the cost of blood. Mohandas and Aledort99 have calculated an overall mean cost per transfusion episode equal to $1,696 in cancer patients. Assuming that 2 U of RBCs is transfused each time, rHuEpo would affect the cost of transfusions to the extent that a dose of 433 U rHuEpo per kilogram per week in a 70-kg patient is successful in eliminating 1 U of blood transfused per month. Clearly, this latter figure would make rHuEpo highly cost-effective. To solve this problem, we need reliable calculations of costs of both rHuEpo treatments and transfusions.

A Patient-Oriented Approach to the Clinical Use of rHuEpo

Based on the published clinical trials, an effect of rHuEpo therapy can be shown for selected indications outside the setting of uremia in a variable portion of patients. Cost-effectiveness cannot be demonstrated for the majority of these indications, at least using death and dollars as primary endpoints. Physicians can prescribe rHuEpo for nonapproved indications, but they should do so only for patients who are likely to benefit from its administration. Ideally, rHuEpo should be indicated for treatment of defective endogenous Epo production.

We favor a patient-oriented approach in which the physician carefully evaluates the individual patient's symptoms, life style, and potential for response178 and follows the decision trees shown in Figs 6 and 7.

Premature infants should not be included in the above-mentioned algorithms. In fact, the criteria for deciding the use of rHuEpo in this setting do not include the serum Epo level, which can be assumed as inadequate in all cases.

When facing the issue of preventing anemia and allogeneic blood transfusion in a patient candidate to elective surgery, the algorithm reported in Fig 6 may help to decide the use of rHuEpo and its modality. Figure 7 reports a decision tree that may be used in an individual anemic patient or a subject who is very likely to become anemic (eg, because the patient is undergoing a platinum-based combination chemotherapy). Similar algorithms have already been shown to be useful in predicting response to rHuEpo.51 179 

A patient-oriented approach to the use of rHuEpo entails administration only to patients who are very likely to respond and benefit from this treatment, thus reducing rHuEpo wastage. Although this approach also maximizes the potential cost-effectiveness of rHuEpo therapy, it needs to be refined and validated in further studies. Additional studies are also needed to identify reliable and early indicators/predictors of the erythropoietic response to rHuEpo therapy.

We thank Dr Giovanni Barosi (Policlinico S. Matteo, Pavia, Italy) for comments and suggestions.

M.C.'s studies on the use of recombinant human erythropoietin in the treatment of anemia of malignancy were supported by grants from the Associazione Italiana per la Ricerca sul Cancro (Italian Association for Cancer Research), Milan, Italy.

Address reprint requests to Mario Cazzola, MD, Internal Medicine and Medical Oncology, IRCCS Policlinico S. Matteo, 27100 Pavia, Italy, or Carlo Brugnara, MD, Clinical Laboratories, The Children's Hospital, 300 Longwood Ave, Bader 760, Boston, MA 02115.

1
Eschbach JW: Erythropoietin: The promise and the facts. Kidney Int 45:70, 1994 (suppl 44)
2
Rao
DS
Shih
M-S
Mohini
R
Effect of serum parathyroid hormone and bone marrow fibrosis on the response to erythropoietin in uremia.
N Engl J Med
328
1993
171
3
Ifudu
O
Feldman
J
Friedman
EA
The intensity of hemodialysis and the response to erythropoietin patients with end-stage renal disease.
N Engl J Med
334
1996
420
4
Eschbach
JW
Abdulhadi
MH
Browne
JK
Delano
BG
Downing
MR
Egrie
JC
Evans
RW
Friedman
EA
Graber
SE
Haley
NR
Korbet
S
Krantz
SB
Lundin
AP
Nissenson
AR
Ogden
DA
Paganini
EP
Rader
B
Rutsky
EA
Stivelman
J
Stone
WJ
Teschan
P
van Stone
JC
van Wyck
DB
Zuckerman
K
Adamson
JW
Recombinant human erythropoietin in anemic patients with end-stage renal disease. Results of a phase III multicenter clinical trial.
Ann Intern Med
111
1989
992
5
McMahon
LP
Dawborn
JK
Subjective quality of life assessment in hemodialysis patients at different levels of hemoglobin following use of recombinant human erythropoietin.
Am J Nephrol
12
1992
162
6
Bergström
J
New aspects of erythropoietin treatment.
J Intern Med
233
1993
445
7
Jacobson
LO
Goldwasser
E
Fried
W
Plzak
L
Role of the kidney in erythropoiesis.
Nature
179
1957
633
8
Lacombe
C
Da Silva
JL
Bruneval
P
Fournier
JG
Wendling
F
Casadevall
N
Camilleri
JP
Bariety
J
Varet
B
Tambourin
P
Peritubular cells are the site of erythropoietin synthesis in the murine hypoxic kidneys.
J Clin Invest
81
1988
620
9
Koury
ST
Bondurant
MC
Koury
MJ
Localization of erythropoietin synthetizing cells in murine kidneys by in situ hybridization.
Blood
71
1988
524
10
Koury
ST
Koury
MJ
Bondurant
MC
Caro
J
Graber
SE
Quantitation of erythropoietin-producing cells in kidneys of mice by in situ hybridization. Correlation with hematocrit, renal erythropoietin mRNA, and serum erythropoietin concentration.
Blood
74
1989
645
11
Gaines
Das RE
Milne
A
Rowley
M
Gordon-Smith
EC
Cotes
PM
Serum immunoreactive erythropoietin in patients with idiopathic aplastic and Fanconi's anaemia.
Br J Haematol
82
1992
601
12
Schapira
L
Antin
JH
Ransil
BJ
Antman
KH
Eder
JP
McGarigle
CJ
Goldberg
MA
Serum erythropoietin levels in patients receiving intensive chemotherapy and radiotherapy.
Blood
76
1990
2354
13
Birgegård
G
Wide
L
Simonssson
B
Marked erythropoietin increase before fall in Hb after treatment with cytostatic drugs suggests mechanism other than anaemia for stimulation.
Br J Haematol
72
1989
462
14
Kendall RG, Cavill I, Norfolk DR: Serum erythropoietin levels during haematinic therapy. Br J Haematol 81:630, 1992 (letter)
15
Cazzola
M
Beguin
Y
New tools for clinical evaluation of erythropoiesis and iron status in man.
Br J Haematol
80
1992
278
16
Cazzola M, Guarnone R, Beguin Y: Red cell precursors mass as an independent determinant of serum erythropoietin level. Blood 88:348a, 1996 (abstr, suppl 1)
17
Faquin
WC
Schneider
TJ
Goldberg
MA
Effect of inflammatory cytokines on hypoxia-induced erythropoietin production.
Blood
79
1992
1987
18
Jelkmann
W
Pagel
H
Wolff
M
Fandrey
J
Monokines inhibiting erythropoietin production in human hepatoma cultures and in isolated perfused rat kidneys.
Life Sci
50
1992
301
19
Means
RT
Krantz
SB
Progress in understanding the pathogenesis of the anemia of chronic disease.
Blood
80
1992
1639
20
Cazzola
M
Ponchio
L
de Benedetti
F
Ravelli
A
Rosti
V
Beguin
Y
Invernizzi
R
Barosi
G
Martini
A
Defective iron supply for erythropoiesis and adequate endogenous erythropoietin production in the anemia associated with systemic-onset juvenile chronic arthritis.
Blood
87
1996
4824
21
Singh
A
Eckardt
KU
Zimmermann
A
Götz
KH
Hamann
M
Ratcliffe
PJ
Kurtz
A
Reinhart
WH
Increased plasma viscosity as a reason for inappropriate erythropoietin formation.
J Clin Invest
91
1993
251
22
Miller
CB
Jones
RJ
Piantadosi
S
Abeloff
MD
Spivak
JL
Decreased erythropoietin response in patients with the anemia of cancer.
N Engl J Med
322
1990
1689
23
Smith
DH
Goldwasser
E
Vokes
EE
Serum immunoerythropoietin levels in patients with cancer receiving cisplatin-based chemotherapy.
Cancer
68
1991
1101
24
Wood
PA
Hrushesky
WJ
Cisplatin-associated anemia: An erythropoietin deficiency syndrome.
J Clin Invest
95
1995
1650
25
Vannucchi
AM
Grossi
A
Bosi
A
Rafanelli
D
Guidi
S
Saccardi
R
Alterini
R
Rossi
Ferrini P
Impaired erythropoietin production in mice treated with cyclosporin-A.
Blood
78
1991
1615
26
Schrezenmeier
H
Noé
G
Raghavacar
A
Rich
IN
Heimpel
H
Kubanek
B
Serum erythropoietin and serum transferrin receptor levels in aplastic anaemia.
Br J Haematol
88
1994
286
27
Bakris
GI
Sauter
ER
Hussey
JL
Fisher
JW
Gaber
AO
Winsett
R
Effect of theophylline on erythropoietin production in normal subjects and in patients with erythrocytosis after renal transplantation.
N Engl J Med
323
1990
86
28
Wang
Z
Goldberg
M
Scadden
D
HIV-1 suppresses erythropoietin production in vitro.
Exp Hematol
21
1993
683
29
D'Andrea
AD
Zon
LI
Erythropoietin receptor. Subunit structure and activation.
J Clin Invest
86
1990
681
30
Sawada
K
Krantz
SB
Sawyer
ST
Civin
CI
Quantitation of specific binding of erythropoietin to human erythroid colony-forming cells.
J Cell Physiol
137
1988
337
31
Sawada
K
Krantz
SB
Dai
CH
Koury
ST
Horn
ST
Glick
AD
Civin
CI
Purification of human blood burst-forming units-erythroid and demonstration of the evolution of erythropoietin receptors.
J Cell Physiol
142
1990
219
32
Broudy
VC
Lin
N
Brice
M
Nakamoto
B
Papayannopoulou
T
Erythropoietin receptor characteristics on primary human erythroid cells.
Blood
77
1991
2583
33
Koury
MJ
Bondurant
MC
Erythropoietin retards DNA breakdown and prevents programmed death in erythroid progenitor cells.
Science
248
1990
378
34
Spivak
JL
Pham
T
Isaacs
M
Hankins
WD
Erythropoietin is both a mitogen and a survival factor.
Blood
77
1991
1228
35
Muta
K
Krantz
SB
Bondurant
MC
Wickrema
A
Distinct roles of erythropoietin, insulin-like growth factor I, and stem cell factor in the development of erythroid progenitor cells.
J Clin Invest
94
1994
34
36
Kelley
LL
Koury
MJ
Bondurant
MC
Koury
ST
Sawyer
ST
Wickrema
A
Survival and death of individual proerythroblasts results from differing erythropoietin sensitivities: A mechanism for controlled rates of erythrocyte production.
Blood
82
1993
2340
37
Wu
H
Liu
X
Jaenisch
R
Lodish
HF
Generation of committed erythroid BFU-E and CFU-E progenitors does not require erythropoietin or the erythropoietin receptor.
Cell
83
1995
59
38
Silva
M
Grillot
D
Benito
A
Richard
C
Nuñez
G
Fernández-Luna
JL
Erythropoietin can promote erythroid progenitor survival by repressing apoptosis through bcl-XL and bcl-2.
Blood
88
1996
1576
39
Koury
MJ
Bondurant
MC
Control of red cell production: The role of programmed cell death (apoptosis) and erythropoietin.
Transfusion
30
1990
673
40
Major
A
Bauer
C
Breymann
C
Huch
A
Huch
R
Rh-erythropoietin stimulates immature reticulocyte release in man.
Br J Haematol
87
1994
605
41
McMahon
FG
Vargas
R
Ryan
M
Jain
AK
Abels
RI
Perry
B
Smith
IL
Pharmacokinetics and effects of recombinant human erythropoietin after intravenous and subcutaneous injection in healthy volunteers.
Blood
76
1990
1718
42
Skikne
BS
Cook
JD
Effect of enhanced erythropoiesis on iron absorption.
J Lab Clin Med
120
1992
746
43
Beguin
Y
Loo
M
R'Zik
S
Sautois
B
Lejeune
F
Rorive
G
Fillet
G
Quantitative assessment of erythropoiesis in haemodialysis patients demonstrates gradual expansion of erythroblasts during constant treatment with recombinant human erythropoietin.
Br J Haematol
89
1995
17
44
Barosi
G
Inadequate erythropoietin response to anemia. Definition and clinical relevance.
Ann Hematol
68
1994
215
45
Cotes PM: Anomalies in circulating erythropoietin levels, in Rich IN, Lappin TRJ (eds): Molecular, Cellular and Developmental Biology of Erythropoietin and Erythropoiesis. New York, NY, New York Academy of Sciences, 1994, p 103
46
Storring
PL
Gaines
Das RE
The international standard for recombinant DNA-derived erythropoietin: Collaborative study on four recombinant DNA-derived erythropoietins and two highly purified human urinary erythropoietins.
J Endocrinol
134
1992
459
47
Beguin
Y
Clemons
G
Pootrakul
P
Fillet
G
Quantitative assessment of erythropoiesis and functional classification of anemia based on measurements of serum transferrin receptor and erythropoietin.
Blood
81
1993
1067
48
Salmonson
T
Danielson
BG
Wikström
B
The pharmacokinetics of recombinant human erythropoietin after intravenous and subcutaneous administration to healthy subjects.
Br J Clin Pharmacol
29
1990
709
49
Erslev
A
Erythropoietin.
N Engl J Med
324
1991
1339
50
Cazzola
M
Ponchio
L
Beguin
Y
Rosti
V
Bergamaschi
G
Liberato
NL
Fregoni
V
Nalli
G
Barosi
G
Ascari
E
Subcutaneous erythropoietin for treatment of refractory anemia in hematologic disorders. Results of a phase I/II clinical trial.
Blood
79
1992
29
51
Cazzola
M
Messinger
D
Battistel
V
Bron
D
Cimino
R
Enller-Ziegler
L
Essers
U
Greil
R
Grossi
A
Jäger
G
LeMevel
A
Najman
A
Silingardi
V
Spriano
M
van Hoof
A
Ehmer
B
Recombinant human erythropoietin in the anemia associated with multiple myeloma or non-Hodgkin lymphoma: Dose finding and identification of predictors of response.
Blood
86
1995
4446
52
Breymann
C
Bauer
C
Major
A
Zimmermann
R
Gautschi
K
Huch
A
Huch
R
Optimal timing of repeated rh-erythropoietin administration improves its effectiveness in stimulating erythropoiesis in healthy volunteers.
Br J Haematol
92
1996
295
53
Henry
D
Abels
R
Larholt
K
Prediction of response to recombinant human erythropoietin (r-HuEPO/Epoetin-a) therapy in cancer patients (letter).
Blood
85
1995
1676
54
Cazzola
M
Ponchio
L
Pedrotti
C
Farina
G
Cerani
P
Lucotti
C
Novella
A
Rovati
A
Bergamaschi
G
Beguin
Y
Prediction of response to recombinant human erythropoietin (rHuEpo) in anemia of malignancy.
Haematologica
81
1996
434
55
Beguin
Y
Loo
M
R'Zik
S
Sautois
B
Lejeune
F
Rorive
G
Fillet
G
Early prediction of response to recombinant human erythropoietin in patients with the anemia of renal failure by serum transferrin receptor and fibrinogen.
Blood
82
1993
2010
56
Finch
CA
Huebers
HA
Perspectives in iron metabolism.
N Engl J Med
306
1982
1520
57
Cazzola
M
Pootrakul
P
Bergamaschi
G
Huebers
HA
Eng
M
Finch
CA
Adequacy of iron supply for erythropoiesis: In vivo observations in humans.
J Lab Clin Med
110
1987
734
58
Brugnara
C
Chambers
LA
Malynn
E
Goldberg
MA
Kruskall
MS
Red cell regeneration induced by subcutaneous recombinant erythropoietin: Iron-deficient erythropoiesis in iron-replete subjects.
Blood
81
1993
956
59
Biesma
DH
van de Wiel
A
Beguin
Y
Kraaijenhagen
RJ
Marx
JJM
Erythropoietic activity and iron metabolism in autologous blood donors during recombinant human erythropoietin therapy.
Eur J Clin Invest
24
1994
426
60
Brugnara
C
Colella
GM
Cremins
J
Langley
RC
Schneider
TJ
Rutherford
CJ
Goldberg
MA
Effects of subcutaneous recombinant human erythropoietin in normal subjects: Development of decreased reticulocyte hemoglobin content and iron deficient erythropoiesis.
J Lab Clin Med
123
1994
660
61
Mercuriali
F
Zanella
A
Barosi
G
Inghilleri
G
Biffi
E
Vinci
A
Colotti
MT
Use of erythropoietin to increase the volume of autologous blood donated by orthopedic patients.
Transfusion
33
1993
55
62
Macdougall
IC
Cavill
I
Hulme
B
Bain
B
McGregory
E
McKay
P
Sanders
E
Coles
GA
Williams
JD
Detection of functional iron deficiency during erythropoietin treatment: A new approach.
Br Med J
304
1992
225
63
Biesma
DH
Bronkhorst
PJH
de Groot
PG
van de Wiel
A
Kraaijenhagen
RJ
Marx
JJM
The effect of recombinant human erythropoietin on hemostasis, fibrinolysis, and blood rheology in autologous blood donors.
J Lab Clin Med
124
1994
42
64
Peces R, de la Torre R, Alcázar R, Urra JM: Antibodies against recombinant human erythropoietin in a patient with erythropoietin-resistant anemia. N Engl J Med 335:523, 1996 (letter)
65
Spivak
JL
Recombinant human erythropoietin and its role in transfusion medicine.
Transfusion
34
1994
1
66
Williamson
L
Homologous blood transfusion: the risk and alternatives.
Br J Haematol
88
1994
451
67
Thomas
MJG
Gillon
J
Desmond
MJ
Consensus conference on autologous transfusion. Preoperative autologous donation.
Transfusion
36
1996
633
68
Gillon
J
Thomas
MJG
Desmond
MJ
Consensus conference on autologous transfusion. Acute normovolaemic haemodilution.
Transfusion
36
1996
640
69
Desmond
MJ
Thomas
MJG
Gillon
J
Fox
MA
Consensus conference on autologous transfusion. Perioperative red cell salvage.
Transfusion
36
1996
644
70
Goodnough
LT
Wassman
J
Corlucci
K
Chernosky
A
Limitation to donating adequate autologous blood prior to elective orthopedic surgery.
Arch Surg
124
1989
494
71
Mercuriali F, Biffi E, Inghilleri G, Vinci A: Low haematocrit: Limiting factor in autologous blood predonation programme, in Castelli D, Genetet B, Habibi B, Nyddeger Y (eds): Transfusion in Europe, Proceedings of the First ISBT Regional Congress. Paris, France, Arnette, 1989, p 291
72
Goodnough
LT
Brittenham
GM
Limitations of the erythropoietic response to serial phlebotomy: Implications for autologous blood donor programs.
J Lab Clin Med
115
1990
28
73
Kickler
TS
Spivak
JL
Effect of repeated whole blood donations on serum immunoreactive erythropoietin levels in autologous donors.
JAMA
260
1988
65
74
Klein HG: Standards for Blood Banks and Transfusion Services (ed 17). Bethesda, MD, American Association of Blood Banks, 1996
75
Goodnough
LT
Rudnick
S
Price
TH
Ballas
SK
Collins
ML
Crowley
JP
Kosmin
M
Kruskall
MS
Lenes
BA
Menitove
JE
Silberstein
LE
Smith
KJ
Wallas
CH
Abels
R
Von Tress
M
Increased preoperative collection of autologous blood with recombinant human erythropoietin therapy.
N Engl J Med
321
1989
1163
76
Kyo S, Omoto R, Hirashima K, Eguchi S, Fujita T: Effect of human recombinant erythropoietin on reduction of homologous blood transfusion in open-heart surgery. A Japanese multicenter study. Circulation 86:413, 1992 (suppl II)
77
Kulier
AH
Gombotz
H
Fuchs
G
Vuckovic
U
Metzler
H
Subcutaneous recombinant human erythropoietin and autologous blood donation before coronary artery bypass surgery.
Anesth Analg
76
1993
102
78
Beris
P
Mermillod
B
Levy
G
Laubriat
M
Soulier
Lauper M
Tullen
E
Hugli
A
Miescher
PA
Recombinant human erythropoietin as adjuvant treatment for autologous blood donation. A prospective study.
Vox Sang
65
1993
212
79
Goodnough
LT
Price
TH
Friedman
KD
Johnston
M
Ciavarella
D
Khan
N
Sacher
R
Vogler
WR
Wissel
M
Abels
RI
A phase III trial of recombinant human erythropoietin therapy in nonanemic orthopedic patients subjected to aggressive removal of blood for autologous use: Dose, response, toxicity, and efficacy.
Transfusion
34
1994
66
80
Biesma
DH
Marx
JJM
Kraaijenhagen
RJ
Franke
W
Messinger
D
van de Wiel
A
Lower homologous blood requirement in autologous blood donors after treatment with recombinant human erythropoietin.
Lancet
344
1994
367
81
Watanabe
Y
Fuse
K
Konishi
T
Kobayasi
T
Takazawa
K
Konishi
H
Shibata
Y
Autologous blood transfusion with recombinant human erythropoietin in heart operations.
Ann Thorac Surg
51
1991
767
82
Biesma
DH
Kraaijenhagen
RJ
Marx
JJ
van de Wiel
A
The efficacy of subcutaneous recombinant human erythropoietin in the correction of phlebotomy-induced anemia in autologous blood donors.
Transfusion
33
1993
825
83
Biesma
DH
Van de Wiel
A
Beguin
Y
Kraaijenhagen
RJ
Marx
JJ
Erythropoietic activity and iron metabolism in autologous blood donors during recombinant human erythropoietin therapy.
Eur J Clin Invest
24
1994
426
84
Hayashi
J
Kumon
K
Takanashi
S
Kawashima
Y
Eguchi
S
Takaku
F
Yamamura
H
Subcutaneous administration of recombinant human erythropoietin before cardiac surgery: A double-blind, multicenter trial in Japan.
Transfusion
34
1994
142
85
Braga
M
Gianotti
L
Vignali
A
Gentilini
O
Servida
P
Bordignon
C
Di Carlo
V
Evaluation of recombinant human erythropoietin to facilitate autologous blood donation before surgery in anaemic patients with cancer of the gastrointestinal tract.
Br J Surg
82
1995
1637
86
Mercuriali
F
Gualtieri
G
Sinigaglia
L
Inghilleri
G
Biffi
E
Vinci
A
Colotti
MT
Barosi
G
Lambertenghi deliliers G
Use of recombinant human erythropoietin to assist autologous blood donation by anemic rheumatoid arthritis patients undergoing major orthopedic surgery.
Transfusion
34
1994
501
87
Price
TH
Goodnough
LT
Vogler
WR
Sacher
RA
Hellman
RM
Johnston
MFM
Bolgiano
DC
Abels
RI
The effect of recombinant human erythropoietin on the efficacy of autologous blood donation in patients with low hematocrits: A multicenter, randomized, double-blind, controlled trial.
Transfusion
36
1996
29
88
Goodnough
LT
Price
TH
Friedman
KD
Johnston
M
Ciavarella
D
Khan
N
Sacher
R
Vogler
WR
Wissel
M
Abels
RI
A phase III trial of recombinant human erythropoietin therapy in nonanemic orthopedic patients subjected to aggressive removal of blood for autologous use: Dose, response, toxicity, and efficacy.
Transfusion
34
1994
66
89
Etchason
J
Petz
L
Keeler
E
Calhoun
L
Kleinman
S
Snider
C
Fink
A
Brook
R
The cost effectiveness of preoperative autologous blood donations.
N Engl J Med
332
1995
719
90
Birkmeyer
JD
Goodnough
LT
Aubuchon
JP
Noordsij
PG
Littenberg
B
The cost-effectiveness of preoperative autologous blood donation for total hip and knee replacement.
Transfusion
33
1993
544
91
Rutherford
CJ
Kaplan
HS
Autologous blood donation — Can we bank on it?
N Engl J Med
332
1995
740
92
Goldfinger
D
Haimowitz
M
Controversies in transfusion medicine: Is autologous blood transfusion worth the cost?
Pro Transfusion
34
1994
75
93
Biesma
DH
Kraaijenhagen
RJ
Dalmulder
J
Marx
JM
van De Wiel
A
Recombinant human erythropoietin in autologous blood donors: A dose-finding study.
Br J Haematol
86
1994
30
94
Sans
T
Bofill
C
Joven
J
Cliville
X
Simo
JM
Llobet
X
Pero
A
Galbany
J
Effectiveness of very low doses of subcutaneous recombinant human erythropoietin in facilitating autologous blood donation before orthopedic surgery.
Transfusion
36
1996
822
95
Goodnough
LT
Verbrugge
D
Marcus
RE
Goldberg
V
The effect of patient size and dose of recombinant human erythropoietin therapy on red blood cell volume expansion in autologous blood donors for elective orthopedic operation.
J Am Coll Surg
179
1994
171
96
Adamson J: Perisurgical use of epoetin alfa in orthopedic surgery patients. Semin Hematol 33:55, 1996 (suppl 2)
97
Sparling EA, Nelson CL, Lavender R, Smith J: The use of erythropoietin in the management of Jehovah's witnesses who have revision total hip arthroplasty. J Bone Joint Surg 78-A:1548, 1996
98
Canadian
Orthopedic Perioperative Erythropoietin Study Group
Effectiveness of perioperative recombinant human erythropoietin in elective hip replacement.
Lancet
341
1993
1227
99
Mohandas
K
Aledort
L
Transfusion requirements, risks, and costs for patients with malignancy.
Transfusion
35
1995
427
100
Faris
PM
Ritter
MA
Abels
RI
The effects of recombinant human erythropoietin on perioperative transfusion requirements in patients having a major orthopaedic operation. The American Erythropoietin Study Group.
J Bone Joint Surg Am
78
1996
62
101
deAndrade
JR
Jove
M
Landon
G
Frei
D
Guilfoyle
M
Young
DC
Baseline hemoglobin as a predictor of risk of transfusion and response to Epoietin alfa in orthopedic surgery patients.
Am J Orthoped
25
1996
533
102
Heiss
MM
Tarabichi
A
Delanoff
C
Allgayer
H
Jauch
KW
Hernandezrichter
T
Mempel
W
Beck
KG
Schildberg
FW
Messmer
K
Perisurgical erythropoietin application in anemic patients with colorectal cancer: A double-blind randomized study.
Surgery
119
1996
523
103
Rutherford
CJ
Schneider
TJ
Dempsey
H
Kirn
D
Brugnara
C
Goldberg
MA
Efficacy of different dosing regimens for recombinant human erythropoietin in a simulated perisurgical setting: The importance of iron availability in optimizing response.
Am J Med
96
1994
139
104
Goldberg
MA
McCutchen
JW
Jove
M
Di Cesare
P
Friedman
RJ
Poss
R
Guilfoyle
M
Frei
D
Young
DC
A safety and efficacy comparison study of two dosing regimens of Epoietin alfa in patients undergoing major orthopedic surgery.
Am J Orthoped
25
1996
544
105
Heiss
MM
Tarabichi
A
Delanoff
C
Allgayer
H
Jauch
KW
Hernandez-Richter
T
Mempel
W
Beck
KG
Schildberg
FW
Messmer
K
Perisurgical erythropoietin application in anemic patients with colorectal cancer: A double-blind randomized study.
Surgery
119
1996
523
106
Weiskopf
RB
Mathematical analysis of isovolemic hemodilution indicates that it can decrease the need for allogeneic blood transfusion.
Transfusion
35
1995
37
107
Brecher
ME
Rosenfeld
M
Mathematical and computer modeling of acute normovolemic hemodilution.
Transfusion
34
1994
176
108
Monk
TG
Goodnough
LT
Birkmeyer
JD
Brecher
ME
Catalona
WJ
Acute normovolemic hemodilution is a cost-effective alternative to preoperative autologous blood donation by patients undergoing radical retropubic prostatectomy.
Transfusion
35
1995
559
108a
Kick O, Daniel E: Mathematical considerations in the practice of acute normovolemic dilution. Transfusion 34:141, 1997
108b
Sowade O, Warnke H, Scigalla P, Sowade B, Franke W, Messinger D, Gross J: Avoidance of allogeneic blood transfusion by treatment with epoietin beta (recombinant human erythropoietin) in patients undergoing open-heart surgery. Blood 89:411, 1997
109
Thompson
JF
Intraoperative blood salvage.
Haematol Rev
7
1992
55
109a
Sowade O, Gross J, Sowade B, Warnke H, Franke W, Messinger D, Scigalla P, Lun A, Glatzel E: Evaluation of oxygen availability with oxygen status algorithm in patients undergoing open-heart surgery treated with epoietin beta. J Lab Clin Med 129:97, 1997
110
Atabek
U
Alvarez
R
Pello
MJ
Alexander
JB
Camishion
RC
Curry
C
Spence
RK
Erythropoietin accelerates hematocrit recovery in post-surgical anemia.
Am Surg
61
1995
74
111
Messmer K: Consensus statement: Using epoetin alfa to decrease the risk of allogeneic blood transfusion in the surgical setting. Semin Hematol 33:78, 1996 (suppl 2)
112
Cascinu
S
Fedeli
A
Del Ferro
E
Luzi
Fedeli S
Catalano
G
Recombinant human erythropoietin treatment in cis-platin-associated anemia: A randomized, double-blind trial with placebo.
J Clin Oncol
12
1994
1058
113
ten Bokkel-Huinink W: Controlled multicenter study of the influence of two different dosages of subcutaneous rhEPO on the development of anemia and transfusion dependency in patients with ovarian carcinoma treated with platinum-based combination chemotherapy, in Smyth JF, Boogaerts MA, Ehmer B (eds): rhErythropoietin in Cancer Supportive Treatment. New York, NY, Marcel Dekker, 1996, p 99
114
de Campos
E
Radford
J
Steward
W
Milroy
R
Dougal
M
Swindell
R
Testa
N
Thatcher
N
Clinical and in vitro effects of recombinant human erythropoietin in patients receiving intensive chemotherapy for small-cell lung cancer.
J Clin Oncol
13
1995
1623
115
Wurnig
C
Windhager
R
Schwameis
E
Kotz
R
Zoubek
A
Stockenhuber
F
Kurz
RW
Prevention of chemotherapy-induced anemia by the use of erythropoietin in patients with primary malignant bone tumors (a double-blind, randomized, phase III study).
Transfusion
36
1996
155
116
Bilgrami
S
Bartolomeo
A
Synnot
V
Rickels
FR
Management of hemosiderosis complicated by coexistent anemia with recombinant human erythropoietin and phlebotomy.
Acta Haematol
89
1993
141
117
Anderson
KE
Goerger
DE
Carson
RW
Lee
A-MK
Stead
RB
Erythropoietin for the treatment of porphyria cutanea tarda in a patient on long-term hemodialysis.
N Engl J Med
322
1990
315
118
Stockman
JA III
Garcia
JF
Oski
FA
The anemia of prematurity: Factors governing the erythropoietin response.
N Engl J Med
296
1977
647
119
Stockman
JA III
Graeber
JE
Clark
DA
McClellan
K
Garcia
JF
Kavey
RW
Anemia of prematurity: Determinants of the erythropoietin response.
J Pediatr
105
1984
786
120
Meyer
MP
Meyer
JH
Commerford
A
Hann
FM
Sive
AA
Moller
G
Jacobs
P
Malan
AF
Recombinant human erythropoietin in the treatment of the anemia of prematurity: Results of a double-blind, placebo-controlled study.
Pediatrics
93
1994
918
121
Maier
RF
Obladen
M
Scigalla
P
Linderkamp
O
Duc
G
Hieronimi
G
Halliday
HL
Versmold
HT
Moriette
G
Jorch
G
Verellen
G
Semmekrot
BA
Grauel
EL
Holland
BM
Wardrop
CAJ
The effect of epoetin beta (recombinant human erythropoietin) on the need for transfusion in very-low-birth-weight infants.
N Engl J Med
330
1994
1173
122
Shannon
KM
Keith JF 3rd
Mentzer
WC
Ehrenkranz
RA
Brown
MS
Widness
JA
Gleason
CA
Bifano
EM
Millard
DD
Davis
CB
et al
Recombinant human erythropoietin stimulates erythropoiesis and reduces erythrocyte transfusions in very low birth weight preterm infants.
Pediatrics
95
1995
1
123
Soubasi
V
Kremenopoulos
G
Diamanti
E
Tsantali
C
Sarafidis
K
Tsakiris
D
Follow-up of very low birth weight infants after erythropoietin treatment to prevent anemia of prematurity.
J Pediatr
127
1995
291
124
Gumy-Pause F, Brighi L, Berner M, Bittar-Fulpius L, Wacker P, Halperin DS, Humbert J: Prevention of transfusions in the anemia of prematurity by high dose erythropoietin. Blood 88:145a, 1996 (abstr, suppl 1)
125
Ohls
RK
Osborne
KA
Christensen
RD
Efficacy and cost analysis of treating very low birth weight infants with erythropoietin during their first two weeks of life: A randomized, placebo-controlled trial.
J Pediatr
126
1995
421
126
Fain
J
Hilsenrath
P
Widness
JA
Strauss
RG
Mutnick
AH
A cost analysis comparing erythropoietin and red cell transfusions in the treatment of anemia of prematurity.
Transfusion
35
1995
936
127
Pincus
T
Olsen
NJ
Russell
IJ
Wolfe
F
Harris
ER
Schnitzer
TJ
Boccagno
JA
Krantz
SB
Multicenter study of recombinant human erythropoietin in correction of anemia in rheumatoid arthritis.
Am J Med
89
1990
161
128
Martini
A
Ravelli
A
Di Fuccia
G
Rosti
V
Cazzola
M
Barosi
G
Intravenous iron therapy for severe anaemia in systemic-onset juvenile chronic arthritis.
Lancet
344
1994
1052
129
Montecucco CM, Caporali R, Invernizzi R: Iron status in Still's disease. Lancet 345:58, 1995 (letter)
130
Salvarani
C
Lasagni
D
Casali
B
Macchioni
P
Boiardi
L
Rossi
F
Rivasi
P
Portioli
I
Recombinant human erythropoietin therapy in patients with rheumatoid arthritis with the anemia of chronic disease.
J Rheumatol
18
1991
1168
131
Schreiber
S
Howaldt
S
Schnoor
M
Nikolaus
S
Bauditz
J
Gasche
C
Lochs
H
Raedler
A
Recombinant erythropoietin for the treatment of anemia in inflammatory bowel disease.
N Engl J Med
334
1996
619
132
Fischl
M
Galpin
JE
Levine
JD
Groopman
JE
Henry
DH
Kennedy
P
Miles
S
Robbins
W
Starrett
B
Zalusky
R
Abels
RI
Tsai
HC
Rudnick
SA
Recombinant human erythropoietin for patients with AIDS treated with zidovudine.
N Engl J Med
322
1990
1488
133
Henry
DH
Beall
GN
Benson
CA
Carey
J
Cone
LA
Eron
LJ
Fiala
M
Fischl
M
Gabin
SJ
Gottlieb
MS
Galpin
JE
Groopman
JE
Hooton
TM
Jemsek
JG
Levine
RL
Miles
SA
Rinehart
JJ
Rios
A
Robbins
WJ
Ruckdeschel
JC
Smith
JA
Spruance
SL
Starrett
B
Toney
J
Zalusky
R
Abels
IRI
Bryant
EC
Larholt
KM
Sampson
AR
Rudnick
SA
Recombinant human erythropoietin in the treatment of anemia associated with human immunodeficiency virus (HIV) infections and zidovudine therapy. Overview of four clinical trials.
Ann Intern Med
117
1992
739
134
Phair
JP
Abels
RI
McNeill
MV
Sullivan
DJ
Recombinant human erythropoietin treatment: Investigational new drug protocol for the anemia of the acquired immunodeficiency syndrome.
Arch Intern Med
153
1993
2669
135
Rendo P, Freigerio D, Braier J, Donato H, Dreliehman G, Barboni G: Double-blind multicentric randomized study of recombinant human erythropoietin in HIV+ children with anemia treated with antiretrovirals. Blood 88:348a, 1996 (abstr, suppl 1)
136
Doll
DC
Weiss
RB
Neoplasia and the erythron.
J Clin Oncol
3
1993
429
137
Spivak
JL
Recombinant human erythropoietin and the anemia of cancer.
Blood
84
1994
997
138
Oster
W
Herrmann
F
Gamm
H
Zeile
G
Lindemann
A
Müller
G
Brune
T
Kraemer
H-P
Mertelsmann
R
Erythropoietin for the treatment of anemia of malignancy associated with neoplastic bone marrow infiltration.
J Clin Oncol
8
1990
956
139
Platanias
LC
Miller
CB
Mick
R
Hart
RD
Ozer
H
McEvilly
J-M
Jones
RJ
Ratain
MJ
Treatment of chemotherapy-induced anemia with recombinant human erythropoietin in cancer patients.
J Clin Oncol
9
1991
2021
140
Miller
CB
Platanias
LC
Mills
SR
Zahurak
ML
Ratain
MJ
Ettinger
DS
Jones
RJ
Phase I-II trial of erythropoietin in the treatment of cisplatin-associated anemia.
J Natl Cancer Inst
84
1992
98
141
Cascinu
S
Fedeli
A
Luzi
Fedeli S
Catalano
G
Cisplatin-associated anaemia treated with subcutaneous erythropoietin. A pilot study.
Br J Cancer
67
1993
156
142
Case
DC
Bukowski
RM
Carey
RW
Fishkin
EH
Henry
DH
Jacobson
RJ
Jones
SE
Keller
AM
Kugler
JW
Nichols
CR
Salmon
SE
Silver
RT
Storniolo
AM
Wampler
GL
Dooley
CM
Larholt
KM
Nelson
RA
Abels
RI
Recombinant human erythropoietin therapy for anemic cancer patients on combination chemotherapy.
J Natl Cancer Inst
85
1993
801
143
Dusenbery
KE
McGuire
WA
Holt
PJ
Carson
LF
Fowler
JM
Twiggs
LB
Potish
RA
Erythropoietin increases hemoglobin during radiation therapy for cervical cancer.
Int J Radiat Oncol Biol Phys
29
1994
1079
144
Lavey
RS
Dempsey
WH
Erythropoietin increases hemoglobin in cancer patients during radiation therapy.
Int J Radiat Oncol Biol Phys
27
1993
1147
145
Bukowski R, Glaspy J, Steinberg D, Taylor CW, Vadhan-Raj S, Danna RP, Sarokan B, Lonczak L, McNeill M: Phase IV evaluation of clinical outcomes of Procrit® (Epoietin alfa) in anemic cancer patients receiving chemotherapy. Blood 84:129a, 1994 (abstr, suppl 1)
146
Quirt I, Couture F, Pichette R, Olweny C, White D, King M, Sawka C, Huan S, Clinch J, Lau C: The role of recombinant human erythropoietin in reducing red blood cell transfusions and maintaining quality of life in patients with lymphoma and solid tumors receiving cytotoxic chemotherapy. Results of a randomized, double-blind, placebo-controlled trial. Blood 88:347a, 1996 (abstr, suppl 1)
147
Kyle
RA
Multiple myeloma. Review of 869 cases.
Mayo Clin Proc
50
1975
29
148
Beguin
Y
Yerna
M
Loo
M
Weber
M
Fillet
G
Erythropoiesis in multiple myeloma: Defective red cell production due to inappropriate erythropoietin production.
Br J Haematol
82
1992
648
149
Ludwig
H
Fritz
E
Kotzmann
H
Höcker
P
Gisslinger
H
Barnas
U
Erythropoietin treatment of anemia associated with multiple myeloma.
N Engl J Med
322
1990
1693
150
Garton
GP
Gertz
MA
Witzig
TE
Greipp
PR
Lust
JA
Schroeder
G
Kyle
RA
Epoetin alfa for the treatment of the anemia of multiple myeloma.
Arch Intern Med
155
1995
2069
151
Österborg
A
Boogaerts
MA
Cimino
R
Essers
U
Holowiecki
J
Juliusson
G
Jäger
G
Najman
A
Peest
D
Recombinant human erythropoietin in transfusion-dependent anemic patients with multiple myeloma and non-Hodgkin's lymphoma — A randomized multicenter study.
Blood
87
1996
2675
152
Cazzola
M
Barosi
G
Gobbi
PG
Invernizzi
R
Riccardi
A
Ascari
E
Natural history of idiopathic refractory sideroblastic anemia.
Blood
71
1988
305
153
Martelli
M
Ponchio
L
Beguin
Y
Meloni
G
Mandelli
F
Cazzola
M
Pure red cell aplasia following peripheral stem cell transplantation: Complete response to a short course of high-dose recombinant human erythropoietin.
Haematologica
79
1994
456
154
Stenke
L
Wallvik
J
Celsing
F
Hast
R
Prediction of response to treatment with human recombinant erythropoietin in myelodysplastic syndromes.
Leukemia
7
1993
1324
155
Hellström-Lindberg
E
Efficacy of erythropoietin in the myelodysplastic syndromes: A meta-analysis of 205 patients from 17 studies.
Br J Haematol
89
1995
67
156
Rose
EH
Abels
RI
Nelson
RA
McCullough
DM
Lessin
L
The use of r-HuEpo in the treatment of anaemia related to myelodysplasia (MDS).
Br J Haematol
89
1995
831
157
Negrin
RS
Stein
R
Vardiman
J
Doherty
K
Cornwell
J
Krantz
S
Greenberg
PL
Treatment of the anemia of myelodysplastic syndromes using recombinant human granulocyte colony stimulating factor in combination with erythropoietin.
Blood
82
1993
737
158
Hellström-Lindberg
E
Birgegård
G
Carlsson
M
Carneskog
J
Dahl
IM
Dybedal
I
Grimfors
G
Merk
K
Tangen
JM
Winquist
I
Öst
A combination of granulocyte-colony-stimulating factor and erythropoietin may synergistically improve the anaemia in patients with myelodysplastic syndromes.
Leuk Lymphoma
11
1993
221
159
Negrin
RS
Stein
R
Doherty
K
Cornwell
J
Vardiman
J
Krantz
S
Greenberg
PL
Maintenance treatment of the anemia of myelodysplastic syndromes with recombinant human erythropoietin: Evidence for in vivo synergy.
Blood
87
1996
4076
160
Tefferi
A
Silverstein
MN
Recombinant human erythropoietin therapy in patients with myelofibrosis with myeloid metaplasia (letter).
Br J Haematol
86
1994
893
161
Beguin
Y
Clemons
GK
Oris
R
Fillet
G
Circulating erythropoietin after bone marrow transplantation: Inappropriate response to anemia in allogeneic transplants.
Blood
77
1991
868
162
Locatelli
L
Zecca
M
Beguin
Y
Giorgiani
G
Ponchio
L
De Stefano
P
Cazzola
M
Accelerated erythroid repopulation with no stem-cell competition effect in children treated with recombinant human erythropoietin after allogeneic bone marrow transplantation.
Br J Haematol
84
1993
752
163
Klaesson
S
Ringdén
O
Ljungman
P
Lönnqvist
B
Wennberg
L
Reduced blood transfusion requirements after allogeneic bone marrow transplantation: Results of a randomised, double-blind study with high-dose erythropoietin.
Bone Marrow Transplant
13
1994
397
164
Link
H
Boogaerts
MA
Fauser
AA
Slavin
S
Reiffers
J
Gorin
NC
Carella
AM
Mandelli
F
Burdach
S
Ferrant
A
Linkesch
W
Tura
S
Bacigalupo
A
Schindel
F
Heinrichs
H
A controlled trial of recombinant human erythropoietin after bone marrow transplantation.
Blood
84
1994
3327
165
Biggs
JC
Atkinson
KA
Booker
V
Concannon
A
Dart
GW
Dodds
A
Downs
K
Szer
J
Turner
J
Worthington
R
Prospective randomised double-blind trial of the in vivo use of recombinant human erythropoietin in bone marrow transplantation from HLA-identical sibling donors. The Australian Bone Marrow Transplant Study Group.
Bone Marrow Transplant
15
1995
129
166
Locatelli
F
Zecca
M
Pedrazzoli
P
Prete
L
Quaglini
S
Comoli
P
De Stefano
P
Beguin
Y
Robustelli della Cuna
G
Severi
F
Cazzola
M
Use of recombinant human erythropoietin after bone marrow transplantation in pediatric patients with acute leukemia: Effect on erythroid repopulation in autologous versus allogeneic transplants.
Bone Marrow Transplant
13
1994
403
167
Pirelli
L
Scambia
G
Menichella
G
d'Onofrio
G
Salerno
G
Benedetti
Panici P
Foddai
ML
Vittori
M
Lai
M
Ciarli
M
Puglia
G
Mancuso
S
Bizzi
B
The combination of erythroid and granulocyte colony-stimulating factor increases the rate of haemopoietic recovery with clinical benefit after peripheral blood progenitor transplantation.
Br J Haematol
92
1996
287
168
Mitus
AJ
Antin
JH
Rutherford
CJ
McGarigle
CJ
Goldberg
MA
Use of recombinant human erythropoietin in allogeneic bone marrow transplant donor/recipient pairs.
Blood
83
1994
1952
169
Sherwood
JB
Goldwasser
E
Chilcote
R
Carmichael
LD
Nagel
RL
Sickle cell anemia patients have low erythropoietin levels for their degree of anemia.
Blood
67
1986
46
170
Goldberg
MA
Brugnara
C
Dover
GJ
Schapira
L
Charache
S
Bunn
HF
Treatment of sickle cell anemia with hydroxyurea and erythropoietin.
N Engl J Med
323
1990
366
171
Rodgers
GP
Dover
GJ
Uyesaka
N
Noguchi
CT
Schechter
AN
Nienhuis
AW
Augmentation by erythropoietin of the fetal-hemoglobin response to hydroxyurea in sickle cell disease.
N Engl J Med
328
1993
73
172
Steinberg MH: Erythropoietin for anemia of renal failure in sickle cell disease. N Engl J Med 324:1369, 1991 (letter)
173
Galanello
R
Barella
S
Turco
MP
Giagu
N
Cao
A
Dore
F
Liberato
NL
Guarnone
R
Barosi
G
Serum erythropoietin and erythropoiesis in high and low-fetal hemoglobin β-thalassemia intermedia patients.
Blood
83
1994
561
174
Olivieri NF, Freedman MH, Perrine SP, Dover GJ, Sheridan B, Essentine DL, Nagel RL: Trial of recombinant human erythropoietin: Three patients with thalassemia intermedia. Blood 80:3258, 1992 (letter)
175
Rachmilewitz
EA
Aker
M
Perry
D
Dover
G
Sustained increase in haemoglobin and RBC following long-term administration of recombinant human erythropoietin to patients with homozygous beta-thalassaemia.
Br J Haematol
90
1995
341
176
Locatelli
F
Zecca
M
Mamprin
F
Gamba
A
Giorgiani
G
De Stefano
P
Recombinant human erythropoietin may correct erythropoietin-deficient hyporegenerative anaemia in children given cardiac transplantation.
Br J Haematol
88
1994
623
177
Hoeldtke
RD
Streeten
D
Treatment of orthostatic hypotension with erythropoietin.
N Engl J Med
329
1993
611
178
Barosi
G
Cazzola
M
De Vincentiis
A
Grossi
A
Tura
S
Guidelines for the use of recombinant human erythropoietin.
Haematologica
79
1994
526
179
Ludwig
H
Fritz
E
Leitgeb
C
Percherstorfer
M
Samonigg
H
Schuster
J
Prediction of response to erythropoietin treatment in chronic anemia of cancer.
Blood
84
1994
1056
Sign in via your Institution