Erythropoietin and anemia of cancer.

Anemia is a common complication of cancer but its causes differ widely. However, a significant number of patients with even early cancer experience a suppression of the action of erythropoietin on the bone marrow, presumably caused by the release of cytokines. The ensuing anemia may be mild and "asymptomatic". Nevertheless, it drains physical and emotional vigor so necessary in the fight against the underlying disorder. The therapeutic use of recombinant human erythropoietin has been gratifying and in many cases restored to near normal not only the hemoglobin concentration but also the quality of life.

Platelet kinetics in autosomal dominant macrothrombocytopenia.

A family with autosomal dominant macrothrombocytopenia is described. Despite severe thrombocytopenia, only a moderate hemorrhagic tendency was observed. Kinetic studies revealed a normal platelet survival, normal megakaryocytic numbers, and normal bone marrow responsiveness. The rate of platelet production was set low, despite moderately impaired hemostasis and thrombocytopenia; it apparently was set to maintain another platelet parameter at an optimal level. Measurements of total circulating platelet mass and platelet surface suggested that the platelet production was set to maintain the platelet surface rather than the platelet mass at a normal value.

Clinical erythrokinetics: a critical review.

The hemoglobin concentration and the hematocrit percentage are usually used to diagnose anemias and erythrocytoses and to monitor their treatment and progress. However, they may be misleading because of dehydration or dilution and it is imperative to keep in mind their relationship to the size of the red-cell mass. This size is determined by the cellular kinetics of four distinct compartments which make up the erythron: the stem cells, the progenitor cells, the precursor cells and the mature cells. Under normal physiologic conditions, the kinetics of the progenitor-cell compartment determines the size of the red-cell mass but, under abnormal conditions, the kinetics of each of the compartments may affect the size. In this review, normal and abnormal kinetics of the four compartments are defined and related to the size of the red-cell mass and the pathogenesis of anemias and erythrocytoses.

Pure red-cell aplasia: a review.

Pure red-cell aplasia is an anemia characterized by a near absence of nucleated red blood cells. It can be congenital or acquired. The congenital form is probably induced by intrauterine damage to early erythroid stem cells. The acquired form can be transient and self-limited or sustained and lifelong. Many, if not most, cases of transient pure red-cell aplasia are caused by the B19 parvovirus, which has a special affinity for erythroid progenitor cells. When complicating an underlying hemolytic anemia, the anemia may be acute and severe. Sustained aplasia is caused by viral invasion, immune rejection or toxic destruction of progenitor or precursor cells. It occurs most often in patients with a benign or malignant lymphoid disease. Treatment with immunosuppressive drugs--especially corticosteroids--will in most cases cause a temporary or permanent remission. The final outcome depends primarily on the underlying disorder.

The rate and control of baseline red cell production in hematologically stable patients with uremia.

It is generally accepted that the anemia of uremia is caused by decreased production of erythropoietin. Nevertheless, the erythropoietin titers are not lower than but equal to or higher than in normal non-anemic individuals. To examine this discrepancy, erythrokinetic studies were made of 22 hematologically stable dialysis patients without clinical or laboratory evidence of extrarenal inflammation, infection, or neoplastic disorders. The red cell life span was normal in 14, and because of stable hematocrits, their daily rate of red cell production had to equal their daily rate of red cell destruction, which could be determined by dividing the red cell mass by red cell life span. These rates were about one half the rates of normal stable individuals, despite the same or higher erythropoietin titers. This suggests that the anemia of uremia is caused in part by a decreased bone marrow response to endogenous erythropoietin.

The discovery of erythropoietin.

A personal vignette of life as a resident and fellow at the Yale New Haven Hospital in the early 1950s follows. John Peters and his associates created a superb renal center at Yale New Haven, and they instilled in me a respect for quantitative measurements and a love for simple physiologic concepts. The environment was ideal for clinical and laboratory research, and it enabled me to show the existence of a regulatory erythropoietic hormone. I consider it a tribute to Dr. Peters that erythropoietin was later found to be produced by the kidneys and that it, as a recombinant drug, has helped ameliorate the anemia of uremia.

The therapeutic role of recombinant erythropoietin in anemic patients with intact endogenous production of erythropoietin.

Recombinant human erythropoietin (r-HuEPO) has been shown to be remarkably effective in raising the hemoglobin concentrations and improving the quality of life of patients with chronic renal disease. It is currently under investigation for treatment of patients with nonrenal anemias associated with cancer chemotherapy, acquired immunodeficiency syndrome, rheumatoid arthritis, and other chronic illnesses. To date, investigators have shown that patients with mild anemia and low endogenous erythropoietin (EPO) production may be good candidates for such treatment. Conversely, studies have shown that patients with severe anemia and serum EPO concentrations of above 500 mU/mL apparently do not respond to doses used for patients with mild anemia or chronic renal disease. Large doses of r-HuEPO may be of use in such patients, and clinical trials are in progress to determine if it is at least possible to make these patients transfusion-independent.

Clinical pharmacology and economics of recombinant human erythropoietin in end-stage renal disease: the case for subcutaneous administration.

The clinical pharmacology of human recombinant erythropoietin (epoetin) was studied in order to compare the effectiveness of various routes and dosing schedules in dialysis patients. Thirty-six patients received epoetin beta three times a week i.v. for at least 12 wk. The mean dose needed to achieve target hemoglobin was 225 +/- 36 U/kg per week (median dose, 180 U/kg per week). Twenty-eight of 36 patients who were converted to a once-a-week i.v. schedule increased their requirements to 429 +/- 50 U/kg per week in order to maintain a target hematocrit of 33 to 40 vol%. Twelve of 28 patients could maintain their target hematocrit when dosed once a week s.c. at 84 +/- 10 U/kg. The other 16 patients required 137 +/- 15 U/kg per week divided into two doses. In the entire group of 28 patients, the weekly requirement for epoetin was reduced by 50% when the s.c. route was used two or three times a week. Pharmacokinetic studies performed during chronic therapy indicated rapid clearance of erythropoietin (t1/2 of 6.8 +/- 0.3 h). Single i.v. doses greater than 150 U/kg were required to increase basal erythropoietin by 30 mU/mL at 44 h postdosing. With s.c. dosing, such increments in erythropoietin levels frequently persisted beyond 60 h because of prolonged and slow absorption. Pharmacokinetic simulations in conjunction with clinical correlation of the erythropoietic response suggest that the duration that the erythropoietin levels are maintained, and not the absolute peaks, is the primary determinant of efficacy. This may result from nonlinearity in the dose response. Pharmacokinetic simulation also indicated that i.v. dosing could not maintain adequate interdialytic erythropoietin levels, whereas s.c. dosing could. Cost analysis indicated that the use of s.c. dosing two or three times a week at an average total weekly dose of 110 to 120 U/kg is effective treatment of anemia in most dialysis patients.

Erythropoietin life span in rats with hypoplastic and hyperplastic bone marrows.

The metabolic fate of erythropoietin (EPO) remains unknown. Urinary excretion does not appear to play a major role and liver catabolism has been shown to occur only after terminal sugars on the hormone have been removed. However, it has been proposed that EPO is eliminated by consumption in the bone marrow. In order to examine the extent of such consumption we measured the half-life of radioidinated recombinant EPO injected intravenously (IV) to rats with bone marrows suppressed by cyclophosphamide or hypertransfusion and marrows stimulated by phenylhydrazine or bleeding. The mean half-life or erythropoietin in normal rats was 179 +/- 16 min, with similar half-lives found in the other rats regardless of decreased or increased bone marrow activity. The results indicate that it is unlikely that erythroid activity determines EPO life span and catabolism.

Pharmacokinetics and erythropoietic response to human recombinant erythropoietin in healthy men.

To assess the safety, pharmacokinetics, and erythropoietic responses to human recombinant erythropoietin (epoetin beta), single intravenous doses (10, 50, 150, and 500 IU/kg) were administered at monthly intervals to 16 healthy subjects in a two-panel, placebo-controlled, double-blind ascending-dose trial. A 1000 IU/kg dose was subsequently administered in an open manner. Epoetin concentrations were determined in serum and urine by radioimmunoassay. Reticulocyte, hemoglobin, and hematocrit values were serially measured after each dose. Mean epoetin apparent half-lives ranged from 4.42 to 11.02 hours. The apparent volume of distribution was between 40 and 90 ml/kg, consistent with plasma water, and the apparent clearance values ranged from 4 to 15 ml/kg/hr, with both parameters having the highest values at the 10 IU/kg dose level. Clearance tended to decrease as a function of dose. Maximum reticulocyte counts were dose-dependent and occurred 3 to 4 days after the epoetin dose. Epoetin was well tolerated, and no antibodies were detected.

Erythropoietin.

The remarkable capacity of the bone marrow to compensate for blood loss and for reduced atmospheric oxygen tension has been found to be mediated by a renal hormone, named erythropoietin. It is produced by peritubular interstitial cells in response to renal hypoxia, but molecular engineering has permitted large scale production of an identical recombinant erythropoietin in vitro. When used as a replacement hormone in patients with impaired endogenous production it has been found to be capable of improving or eliminating the anemia of chronic kidney disease and the anemia of prematurity. In the future it may also be used as a pharmacologic agent and possibly be able to control the anemia of patients with bone marrow failure and make them transfusion-independent.