Phase II of less Frequent Dosing of Procrit Therapy
1.1 To determine the hematologic response and transfusion requirements of chemotherapy-related moderate anemia to the administration of high, less frequent dose followed by low maintenance dose Epoetin alfa in multiple myeloma patients.
1.2 To determine the effect of moderate anemia on patient quality of life.
1.3 to correlate changes in quality of life with changes in anemia associated with treatment with Epoetin alfa
1.4 To determine the effect of Epoetin alfa therapy on transfusion requirements, as well as outpatient hydration procedures
2.1 Multiple Myeloma and Anemia
Anemia is present in two-thirds of patients with multiple myeloma at diagnosis, with 8% of patients having Hgb values less than 8g/dL1. Several mechanisms have been implicated in the pathogenesis of multiple myeloma-associated anemia, most of which result in inadequate erythropoietin production. These include marrow infiltration of plasma cells2, excessive cytokines production, increased plasma viscosity3, reduced red blood cell (RBC) survival, tumor proliferation4, hypervolemic dilution5, chemotherapy-induced marrow suppression, nutritional deficiency and chronic renal insufficiency.
Fatigue and weakness due to anemia are common symptoms in multiple myeloma1, as in other types of cancer and correlate with poorer quality of life and inability to work6. Other consequences include mental confusion, respiratory distress and decreased performance status that may affect chemotherapy options and participation in clinical trials. More importantly, anemia could hinder tolerance to the new biologic therapeutic agents that are currently being introduced in the management of myeloma. RBC transfusions can potentially treat anemia and its symptoms; however, these are associated with risks of transfusion reactions, viral infections, fluid overload and possibly decreased survival.
2.2 Erythropoietin and Its Mechanism of Action
Erythropoietin (EPO) is a glycoprotein growth factor, produced by peritubular endothelial cells in the proximal renal tubules. Under normal conditions, EPO is present in the plasma at a concentration that is sufficient for producing erythrocytes to replace senescent red blood cells. It is regulated by renal oxygen sensing mechanisms, which stimulates EPO production during hypoxia, hypotension, blood loss and anemia. Red cell production is then promoted by proliferation and differentiation of erythroid progenitor cells, as well as by prolonging their survival.
2.3 Epoetin alfa: Pharmacodynamics
Epoetin alfa (r-HuEPO, Epoetin alfa, PROCRIT) is a recombinant glycoprotein from EPO that has been cloned and expressed in Chinese hamster ovary cells7. Epoetin alfa mainly increase the number of progenitor cells with the ability to differentiate into mature erythroblasts, augment hemoglobin synthesis, enhance the release of reticulocytes from bone marrow and improve red blood cell viability. Other than its role in red cell production, it also influences tumor regression using a T cell-mediated mechanism8.
Most of the adverse effects of long-term epoetin alfa have been extensively documented during its use in patients with chronic renal failure. Hypertension, thrombotic events and seizures that are relatively frequent with epoetin alfa treatment in patients with renal insufficiency, are considerably lower in cancer (5.2% vs 30% in renal failure) patients, even in patients with concomitant multiple myeloma and renal insufficiency. Other adverse events that have been described include pain at the injection site, fever, fatigue, headache, cough, nausea, vomiting, diarrhea, rash, dyspnea, edema, dizziness and asthenia.
2.4 Recombinant Erythropoietin and Multiple Myeloma
Clinical evidence has demonstrated the usefulness of epoetin alfa in anemia associated with different cancers and their chemotherapy 9-11 and non-myeloid malignancies such as multiple myeloma12-17.
In a large community-based trial of over 2,000 patients10, 23% of anemic cancer patients in this population had non-myeloid malignancies which included multiple myeloma. Utilizing a mean epoetin alfa dose of about 450 IU/kg/wk, Glaspy et al were able to demonstrate statistically significant increase (1.8 g/dL, P<0.001) in hemoglobin levels, reduction in patients needing transfusion (50%, P<0.001), and overall improvement of quality-of-life scores (P<0.001). The degree of improvement of quality-of-life parameters directly correlated with the magnitude of increase in hemoglobin level from baseline (r=.27-.30, P<0.001), which was observed throughout all tumor response categories. This was observed in both hematologic and non-hematologic cancers.
Several randomized clinical trials have documented improvement in hemoglobin and blood transfusion requirements in 60-80% of multiple myeloma patients on Epoetin alfa 12-17. Response was significantly predicted by low pretreatment erythropoietin concentrations and not by the degree of marrow infiltration. Even though different hematological response criteria (usually increase> 2 g/dL) and epoetin alfa dosing regimen (3 studies had 150 IU/kg three times a week) were incorporated in these studies, results consistently show greater percentage of patients who received epoetin alfa compared to placebo or no therapy, had improved Hgb levels and transfusion requirements.
The largest multicenter, randomized, double blind trial of 145 multiple myeloma patients evaluated the efficacy of Epoetin alfa 150 IU/kg three times a week, while patients were receiving concomitant chemotherapy 17. The Epoetin alfa arm, compared to placebo, did not only show significant increase in Hgb values (P<0.001), remarkable reduction in blood transfusion requirements (P=0.017) and minimal toxicities, but also better performance status (P=0.038) at the end of the study. Significant improvements in quality of life scores were demonstrated by univariate analysis within the Epoetin alfa group.
2.5 Epoetin: Pharmacokinetics
Epoetin alfa has been administered subcutaneously up to a maximum single dose of 2400 U/kg and intravenously up to 1500 IU/kg 3 times a week 7, 19. After subcutaneous administration, absorption of epoetin alfa is slow from the injection site. Peak concentrations are usually about 10% of the equivalent intravenous route, and normally occurs between 8 to 24 hours post dosing. Serum concentrations after subcutaneous administration are more sustained with increased doses. Metabolism of recombinant EPO is thought to occur mainly by erythrocyte-extraction in the bone marrow, and by other pathways such as urinary excretion (<5%) and possible hepatic degradation (controversial). The carbohydrate moieties are important in protecting EPO from rapid degradation. Subcutaneously administered epoetin alfa, when compared to intravenous dosing, has a bioavailability of less than 50% and elimination half life is prolonged, reflecting delayed absorption. A recent study by Gabrilove et al demonstrated that three-times-a-week epoetin schedule was found to be equivalent to the once-a-week dosing regimen in terms of hematologic response, quality of life scores and tolerability in patients undergoing chemotherapy18. However, this once weekly regimen still does not coincide with clinic visits for chemotherapy in multiple myeloma patients. Pharmacokinetic studies of epoetin alfa given subcutaneously in healthy volunteers demonstrate decreased mean clearance with increasing dose, thereby increasing the mean EPO area under the concentration-time curve (AUC). Single doses up to 1,800 IU/kg showed linear correlation between the mean EPO AUC and mean percentage of reticulocytes AUC (correlation coefficient=0.931). This suggests possible saturation of the EPO receptors after this dose19.
2.6 Dosing Rationale
In an attempt to further improve the hematologic response of multiple myeloma patients and decrease the frequency of dosing of Epoetin alfa over the long run, a prospective, single arm pilot trial of once-every-2-weeks Epoetin alfa will be conducted in 24 multiple myeloma patients with or without concomitant chemotherapy. The selection of this dose was based on the results of a published study19 in which percentage of reticulocytes AUC only continued to increase up to dose of Epoetin alfa 1,800 IU/kg. The resulting reticulocytosis was sustained above baseline through day 15 and declined on day 22, when patients did not get further Epoetin alfa. Farrell et all recently presented data demonstrating a 3-4 g/dL increase in Hgb in nonhuman primates using 17,000 or 25,000 IU/kg of epoetin alfa every 2-3 weeks20. It would be interesting to determine whether it is possible to further increase the time between doses by use of a high single dose of epoetin alfa, thereby improving convenience of administration, and possibly the time to response and this the quality of life.
3. PATIENT ELIGIBILITY
3.1 Inclusion Criteria
3.2 Exclusion Criteria
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