Overcoming Barriers to Erythropoietic Therapy
Overcoming Barriers to Erythropoietic Therapy
It is clear that erythropoietic therapy reduces risk for red blood cell (RBC) transfusion and improves quality of life in cancer patients. There is accumulating evidence that such intervention may also improve outcome of treatment and prolong survival in cancer patients (see other Glaspy article, "The Potential for Anemia Treatment to Improve Survival in Cancer Patients," elsewhere in this supplement). Despite its proven and potential benefits, most patients eligible for erythropoietic therapy on the basis of having hemoglobin levels < 10 mg/dL during chemotherapy do not receive treatment; it is estimated that only 20% to 30% of eligible patients in the United States and 10% of those in Europe receive erythropoietic treatment. This underutilization can be attributed to a number of factors. The failure of available erythropoietic treatment to induce response in a significant proportion of patients blunts enthusiasm for its use, with enthusiasm being further blunted by the related effect on overall cost-effectiveness of treatment. Indeed, cost of treatment is an issue, irrespective of cost-effectiveness. In addition, quality of life is still conceived of as a "soft" endpoint, with many physicians desiring to see proof of benefit demonstrated using physiologic correlates of correction of anemia. Finally, there is an issue with inconvenience related to need to administer an additional therapy in patients and practices already overburdened with chemotherapy schedules. Work has been ongoing to identify new agents with characteristics that might permit erythropoietic therapy to surmount these barriers to use. The novel agent darbepoetin alfa exhibits a number of desirable characteristics that may facilitate effective use of erythropoietic therapy.
With the discovery that recombinant human erythropoietin (rHuEPO) is composed of a number of different isoforms that differ in the amount of posttranslation glycosylation, investigations were undertaken to determine whether these isoforms differed in terms of activity. Administration of separated isoforms in animal studies showed that increasing potency in promoting erythropoiesis was related to increasing number of sialic acids present on the isoforms. This increased potency results from longer half-life and greater area under the concentration-time curve (not from increased receptor affinity, since increased sialic acid content actually reduces receptor affinity). On the basis of these findings, a project was undertaken to develop new erythropoietin genes via site-directed mutagenesis that added glycosylation sites to the molecule without interfering with receptor binding, inducing the resultant protein to unfold, or resulting in immunogenicity. These attempts reached fruition in the development of darbepoetin alfa. This molecule, resulting from 5 amino acid substitutions in the rHuEPO gene, possesses two additional (5 vs 3) sialic acid-containing carbohydrates and up to eight additional sialic acids (maximum of 22 vs 14) and has a greater molecular weight (37,400 vs 30,400 D) compared with its predecessor, epoetin alfa.[2,3] As shown in initial animal studies, the hematopoietic potency of darbepoetin alfa was increased compared with that of epoetin alfa, with the potency of a candidate agent with four glycans being intermediate (Figure 1). Initial pharmacokinetic studies in hemodialysis patients showed that darbepoetin alfa had a threefold increased half-life compared with epoetin alfa after intravenous administration.
In a pivotal phase III trial performed in Europe, patients with small-cell or non-small-cell lung cancer with at least 12 further weeks of cisplatin-containing chemotherapy scheduled were randomized to placebo or once-weekly subcutaneous (SC) injections of darbepoetin alfa, 2.25 mg/kg for 12 weeks. Study drug was withheld if hemoglobin level increased to > 15 g/dL for men or > 14 g/dL for women, and was reinstated at 50% of the previous dose if hemoglobin level decreased to ≤ 13 g/dL. As shown in Figure 2, darbepoetin alfa treatment was associated with a significant reduction in proportion of patients requiring RBC transfusion and a significant increase in the proportion of patients achieving hematopoietic response, defined as an increase in hemoglobin of ³ 2 g/dL or a level of ³ 12 g/dL without RBC transfusion in the previous 28 days.Darbepoetin Alfa Dose-Finding Studies
In the United States, studies were undertaken to define optimal darbepoetin alfa dose level and schedule in cancer patients. In a study of weekly dosing, patients were randomized (4:1, darbepoetin alfa:epoetin alfa) to darbepoetin alfa, 0.5, 1.0, 1.5, 2.25, 4.5, 6.0, or 8.0 µg/kg once weekly, or to epoetin alfa, 150 U/kg three times weekly for 12 weeks (Figure 3). Patients in the epoetin alfa group had their dose doubled at 8 weeks for inadequate hemoglobin response (< 1 g/dL increase from baseline). In a study of biweekly dosing, patients were randomized (1:1:1:1:1) to darbepoetin alfa, 3.0, 5.0, 7.0, or 9.0 µg/kg every 2 weeks, or epoetin alfa 40,000 U weekly for 12 weeks, with the epoetin alfa dose being increased to 60,000 U weekly for inadequate hemoglobin response at 6 weeks (Figure 3).
In both studies, darbepoetin alfa was withheld if hemoglobin levels increased to ³ 15 mg/dL in men or ³ 14 g/dL in women. Treatment was reinstated at the next lowest dose level or at 50% of the previous dose in the group receiving 0.5 µg/kg in the weekly dosing study and at 75% of the previous dose in the biweekly dosing study if hemoglobin subsequently decreased to ≤ 13 g/dL.
In the once-weekly dosing study, hemoglobin response was defined as an increase of at least 2 g/dL in the absence of RBC transfusion during the prior 28 days. The findings among the darbepoetin alfa dose groups indicated a dose-response effect, with peak response occurring at the 4.5 mg/kg dose. Mean changes in hemoglobin from baseline were 1.14 g/dL in the epoetin alfa group and 0.49, 0.62, 1.07, 1.31, 1.87, 1.85, and 2.17 in the darbepoetin alfa, 0.5, 1.0, 1.5, 2.25, 4.5, 6.0, and 8.0 µg/kg groups, respectively. Time to hemoglobin response was reduced in the darbepoetin alfa, 4.5 µg/kg group (approximately 8 weeks) compared with lower darbepoetin alfa doses and the epoetin alfa group (approximately 10 weeks). Findings in the once-weekly and once-every-2-weeks dosing studies were analyzed by comparing hematopoietic response (ie, hemoglobin increase of ³ 2 g/dL or hemoglobin level of ³ 12 g/dL in the absence of RBC transfusion within the prior 28 days) at matched total planned dosesie, by comparing response at a dose of 1.5 µg/kg once weekly with response at a dose of 3.0 µg/kg biweekly. This analysis showed that administration of a similar total dose every 2 weeks resulted in no loss of dose-efficiency compared with once-weekly dosing (Figure 4), indicating the absence of a need to increase the overall dose with biweekly dosing.
An additional study, performed in Europe, Asia, and Australia, has examined the potential for every-3-week darbepoetin alfa dosing in patients receiving chemotherapy for solid tumors. In this study, patients were randomized (1:4) to placebo or darbepoetin alfa, 4.5, 6.75, 9.0, 12.0, 13.5, or 15.0 µg/kg every 3 weeks for 12 weeks. Peak hemoglobin response appeared to occur at the 12.0 to 13.5 µg/kg dose levels, corresponding to a weekly dose of 4.0 to 4.5 µg/kg. Mean changes in hemoglobin from baseline were -0.02 g/dL in the placebo group and 0.54, 0.86, 0.89, 1.63, 1.45, and 1.23 g/dL in the 4.5, 6.75, 9.0, 12.0, 13.5, and 15.0 µg/kg every-3-week darbepoetin alfa dose groups, respectively.
Overall, these findings indicate that darbepoetin alfa produces high dose-related response rates and dose-related time to response in cancer patients and may permit dosing intervals to be extended to as long as 3 weeks. Such characteristics may have considerable impact on overall effectiveness, overall cost and cost-effectiveness, and convenience of erythropoietic treatment. Darbepoetin alfa treatment in controlled trials was safe, with adverse events being similar to those observed with placebo or epoetin alfa, and no neutralizing antibodies to the molecule have been reported to date.Potential for Increasing Dose-Efficiency
The traditional approach to erythropoietic treatment in cancer patients involves initial treatment at a dose that does not produce response in all patients who will eventually respond to treatment. Although dose increases after a designated period result in response in an additional group of patients, a sizable proportion of patients (approximately 30% overall) receive a full 12 to 16 weeks of treatment without response. It has been hypothesized that efficiency of treatment can be markedly improved by using the dose of an agent that produces peak response as a loading dose followed by reduced dose maintenance treatment (Figure 5).
The viability of such an approach with darbepoetin alfa was suggested by findings in murine studies showing that bolus administration of high doses was associated with maintenance of a dose-response effect, with no dose-response effect being observed with epoetin alfa. We have subsequently performed a pilot study of the front loading/maintenance approach in cancer patients. Patients were randomized to receive darbepoetin alfa, 4.5 µg/kg once weekly, followed by (1) reduction to 1.5 µg/kg weekly if hemoglobin increased to ³ 12 g/dL, (2) reduction to 2.25 µg/kg once weekly after 4 weeks, or (3) reduction to 3.0 µg/kg every 2 weeks after 4 weeks or to receive epoetin alfa, 40,000 U weekly, increased to 60,000 U weekly at week 6 if hemoglobin response was inadequate (< 1 g/dL increase).6 Overall, hemoglobin response (increase of ³ 2 g/dL from baseline) was observed in 62% of all darbepoetin alfa patients and in 48% of epoetin alfa patients at 12 weeks. The predicted improvement in time to hemoglobin response was observed in darbepoetin alfa groups 1 and 2, with more than 50% of patients in both groups responding by 8 weeks. Quality of life as assessed by the Functional Assessment of Cancer Therapy (FACT)-Fatigue subscale score was markedly improved with darbepoetin alfa treatment compared with epoetin alfa treatment. The mean increase in scores among all darbepoetin alfa patients was 3.8 at week 4 and ranged from 5.8 to 7.5 thereafter.
Figure 6 shows data obtained from the once-weekly and once-every-2-weeks dosing studies of darbepoetin alfa at a dose of 3 µg/kg q2wk, which produced similar effectiveness to epoetin alfa, 40,000 to 60,000 U/wk.Timing of Erythropoietic Therapy and Chemotherapy
Available data indicate that there is an increase in endogenous erythropoietin levels on the days immediately following administration of chemotherapy, with this pattern being consistent over multiple chemotherapy cycles. The increase appears to be of relatively short duration, as concentrations return to near-baseline levels prior to each subsequent chemotherapy cycle. Since this increase in erythropoietin concentration may reflect dropout of responsive cells, the issue of whether erythropoietic therapy should be administered during the period of increase needs to be addressed. This issue may be especially important in the context of potential biweekly or every-3-week dosing schedules with darbepoetin alfa, since any potential resistance to effect would occur during the period of maximum darbepoetin alfa blood concentrations. A randomized synchrony study has been initiated to assess effects of timing of darbepoetin alfa and chemotherapy dosing.
Barriers to use of erythropoietic therapy include issues of effectiveness, convenience, and cost-effectiveness. Darbepoetin alfa treatment has been shown to produce dose-related increases in hemoglobin level, reduce risk of RBC transfusion, and produce dose-related rapidity of response in cancer patients. Treatment with this agent appears to allow flexible dosing on a weekly, biweekly, or every 3 weeks schedule; preliminary findings also suggest that the agent may be suitable for use in a frontloading/maintenance therapy schedule that would further improve dosing efficiency. Together with its effectiveness in correcting anemia, the flexibility in dosing with darbepoetin alfa may allow novel approaches to dosing and scheduling that could improve erythropoietic therapy overall and, thus, renew enthusiasm for its use in patients who stand to benefit from such therapy.
1. Egrie JC, Dwyer E, Lykos M, et al: Novel erythropoiesis stimulating protein (NESP) has a longer serum half-life and greater in vivo biological activity than recombinant human erythropoietin (abstract 243). Blood 90(10):56a, 1997.
2. Elliot SG, Lorenzini T, Strickland T, et al: Rational design of novel erythropoiesis stimulating protein (Aranesp): A super-sialated molecule with increased biological activity (abstract 352). Blood 96(11):82a, 2000.
3. Egrie JC, Browne JK: Development and characterization of novel erythropoiesis stimulating protein (NESP). Br J Cancer 84(suppl 1):3-10, 2001.
4. Macdougall IC, Gray SJ, Elston O, et al: Pharmacokinetics of novel erythropoiesis stimulating protein compared with epoetin alfa in dialysis patients. J Am Soc Nephrol 10:2392-2395, 1999.
5. Glaspy J, Jadeja J, Justice G, et al: Darbepoetin alfa administered every 1 or 2 weeks alleviates anemia (with no loss of dose efficiency) in patients with solid tumors (abstract 1256). Blood 98(11):298a, 2001.
6. Glaspy J, Jadeja J, Justice G, et al: Optimizing the management of anemia in patients with cancer: A randomized, active-controlled study investigating the dosing of darbepoetin alfa (abstract 1446). Proc Am Soc Clin Oncol 21:362a, 2002.