By Robert E. Smith, Jr., MD, South Carolina Oncology Associates, PA
January 2005

Introduction

Of the chemotherapy toxicities, anemia receives less attention than thrombocytopenia and granulocytopenia. This is due to the potentially life-threatening complications resulting from the latter. However, anemia is the most common hematologic abnormality seen in the malignant conditions, occurring in more than 50% of patients,¹ which translates to almost 900,000 patients in the United States.²  Anemia leads to debilitating symptoms, impaired health related quality of life (HRQOL), may reduce survival outcomes, and may cause cognitive impairment.

Among cancer patients, anemia may be due to many possible etiologic factors including blood loss, nutritional deficiency, hemolysis, hypersplenism, hemophagocytosis, and impairment of bone marrow function through such mechanisms as myelosuppression, tumor involvement, hypoplasia, myelofibrosis, and myelodysplasia. However, even in the absence of these complicating factors, and in the absence of concomitant chemotherapy, anemia remains prevalent among cancer patients.³ This anemia, termed chronic anemia, is caused by inflammatory cytokines, especially IL-1, IFN-gamma, and TNF, which reduce erythropoietin production, suppress the bone marrow’s response to erythropoietin, and alter ferrokinetics.⁴

Chronic anemia of cancer is the focus of this paper. The majority of anemic cancer patients will not represent a “pure” chronic anemia of cancer because most will have had chemotherapy and/or irradiation at some point in their treatment history. However, for purposes of this article, we consider patients to have chronic anemia of cancer if they have not had recent chemotherapy or irradiation and are not found to have another etiology to explain the anemia. We also define anemia by the traditional gender-based hemoglobin levels, realizing however, that patients with compromised cardiorespiratory function may well suffer from the effects of anemia despite hemoglobin levels within the normal range.

Erythropoietic therapy is approved for patients with chemotherapy-induced anemia (CIA) and has provided a great deal of benefit to these patients. Despite the fact that patients with chronic anemia of cancer have the same transfusion requirements, anemia-related symptoms, and quality of life impact as those with CIA, erythropoietic therapy has not been approved for these patients. However, historical research and recent findings suggest that erythropoietic therapy produces a strong response in patients with chronic anemia of cancer.

Erythropoietin

Erythropoietin is the primary regulator of erythropoiesis in mammalian systems. In 1977, erythropoietin had been isolated and by 1985, DNA probes led to cloning of the gene.^5,6,7 Rapidly after that, rhEPO was produced by recombinant DNA technology and gained regulatory approval in 1989 as epoetin alfa for the treatment of anemia in patients on dialysis with chronic renal failure, which is a pure hormonal deficiency of erythropoietin. Erythropoietin is the only true hormonal bone marrow growth factor and is structurally similar to growth hormone. It functions primarily through inhibition of apoptosis rather than as a mitogen. Its primary target cells are late BFU-e and CFU-e, rather than at the committed stem cell level.

Structure of erythropoietin: Erythropoietin is a 30,400 dalton heavily glycosylated protein hormone.5 Structurally, erythropoietin is comprised of an invariant 165 amino acid single polypeptide chain with 4 carbohydrate side chains, which occur as a post-translational event.^8,9,10 It was recognized that in vivo activity was extremely low in the absence of this post-translational glycosylation, which led to the development of darbepoetin alfa (Aranesp®).¹¹

Forms of rhEPO: RhEPO is available as epoetin alfa and epoetin beta. Both forms vary in sialic acid content from native erythropoietin and differ between each other in their original source of the cloned gene, in products used to stabilize the final preparations and slightly in their isoforms based on sialic acid content. However, neither product demonstrates a clear superiority in efficacy. Epoetin alfa is available in the U.S. as Epogen® for use in patients undergoing dialysis and as Procrit® for renal anemia in patients not dialysis dependent and in chemotherapy induced anemia (CIA). Outside of the U.S., Eprex® is available and is the drug implicated in pure red-cell aplasia in a dialysis population in Europe.¹³ Epoetin beta (NeoRecormon®) is not available in the U.S. Notably, a pegylated form of this drug with a very prolonged half-life is now in an early stage of clinical testing.

rhEPO in Cancer

Cancer-related anemia is due to a relative hormonal deficiency as well as reduced bone marrow responsiveness to erythropoietin.⁴ rhEPO was thought to benefit patients with this condition and clinical trials were initiated shortly after rhEPO was made available in 1985.¹⁴ Abels’ trial led to regulatory approval of epoetin alfa (Procrit®) for use in chemotherapy-induced anemia (CIA) but not for the chronic anemia of cancer.¹⁵ Clinical use of rhEPO for CIA expanded as the open-label trials showed quality of life benefit and, finally, more user-friendly dosing schedules.^16,17,18

Ultimately, faulty study design was probably the major factor that contributed to non-approval of erythropoietic therapy for the treatment of chronic anemia of cancer. Abels’ original trial included one arm comprised of patients with chronic anemia of cancer who were not on chemotherapy.¹⁵ Early data suggested that these patients were more responsive to erythropoietic therapy, as one would predict in the absence of chemotherapy-induced myelosuppression.¹⁴ However, the trial failed to meet the primary endpoint of reduced transfusion requirements, and thus did not provide evidence for regulatory approval in chronic anemia of cancer. The results of this trial were probably due to the fact that the dose was smaller (100 UI/kg given three times weekly compared to 150 IU/kg in the CIA arm), and more importantly, patients were only treated for 8 weeks as opposed to 12 weeks in the two CIA arms. We now know that the time period utilized in the study was inadequate for producing a response to epoetin alfa.

In contrast, a Canadian study by Quirt and colleagues showed an improvement in quality of life with epoetin alfa (Eprex®). Surprisingly, they reported that a 16-week course only produced a 48% hemoglobin response (defined as a greater than 2 gram increase in hemoglobin from baseline without transfusion). The regimen used in this study was the standard 150 IU/kg three-times-weekly, then increased to 300 IU/kg three-times-weekly after four weeks if the hemoglobin increase was less than a 1 g/dl.¹⁹

Development of Darbepoetin alfa (Aranesp®)

The development of darbepoetin alfa (Aranesp®) was enhanced by an exhaustive series of experiments utilizing site-directed mutagenesis. These experiments were undertaken based on the observation that in vivo potency of rhEPO was dependent upon post-translational glycosylation.²⁰ Hyperglycosylation, or increasing the carbohydrate content of the molecule, resulted in a three-fold greater prolongation of half-life compared to epoetin alfa and a 4.5-fold reduction in binding affinity to the erythropoietin receptor. Both factors, paradoxically in the second instance, increased the in vivo biologic activity of Aranesp®.

Aranesp® in Cancer

In the management of CIA, Aranesp® has been utilized in weekly and every other week regimens with no loss of efficiency or efficacy.²¹ Furthermore, Aranesp® has been shown to effectively treat CIA when dosed as infrequently as q3 and q4 weeks.²² There have been no cases of antibodies detected in clinical trials, nor cases of pure red-cell aplasia in patients treated with Aranesp® in renal or cancer settings.

Because patients with chronic anemia of cancer have the same transfusion requirement, anemia-related symptoms, and quality of life impact as those with CIA, it is thought that rhEPO would be of therapeutic benefit to this population. Patients with chronic anemia of cancer may even experience greater improvement in HRQOL from erythropoietic therapy than those with CIA because they are not burdened with chemotherapy-associated toxicities. Also these patients tend to visit their physicians less frequently making Aranesp®, with its less frequent dosing requirements, particularly advantageous.

Aranesp® in Chronic Anemia of Cancer: Recent Findings

A recent multicenter trial confirmed what was expected of erythropoietic therapy for chronic anemia of cancer based on early testing of rhEPO in the 1980’s. The robust effect of Aranesp® in chronic anemia of cancer was demonstrated with high response rates (up to 100%), rapidity of response (as low as 27 days median time to response), and high mean hemoglobin increase (up to 2.9 g/dl corrected for any transfusion).

Based on the similarities between chronic anemia of cancer and CIA previously noted and the potential benefit of less frequent dosing, we undertook a multicenter trial with Aranesp® in chronic anemia of cancer.23 Included were 188 adult patients with hemoglobin levels less than 11 grams. These patients were iron replete, had adequate hepatic and renal function, and received no chemotherapy or radiation therapy within eight weeks of enrollment. The most frequent diagnosis was breast cancer, but lung, gastrointestinal, gynecologic, genitourinary, and lymphoid malignancies were all well represented. Eighty-three percent of patients had had prior chemotherapy and/or radiation therapy with three-fourths of these patients having at least a six-month interval between last treatment and trial entry.

Initial cohorts were treated once weekly for twelve weeks with Aranesp®, open label, sequentially escalated doses of 0.5, 1.0, 2.25, and 4.5 mcg/kg. In a second double-blind and placebo-controlled phase, patients were treated on q3 and q4 week schedules. An optional twelve-week open-label treatment was offered to all patients after they completed the twelve-week blinded treatment phase. The doses employed in this phase of the trial were basically multiples of the 2.25 mcg/week dosage. No dose escalation for inadequate response was employed in this trial.

Results: This study indicates that chronic anemia of cancer is very responsive to erythropoietic therapy. All patients achieved a hematopoietic response to the 4.5 mcg/kg weekly dose (defined as achieving a 2 gram hemoglobin increase and/or a hemoglobin of 12) and all weekly dosages showed a 70% or higher response rate, as shown in table 1. In the q3 and q4 week cohorts, responses range from 60-70%. Median time to response, with imputed analysis in the event of transfusion, was only 27 days in the 4.5 mcg/kg group and was surprisingly good even in the q3 and q4 groups. The study was not powered to look at transfusion reduction but a tendency towards fewer transfusions was seen as dose increased in the weekly groups and fewer transfusions were needed in the q3 and q4 week groups compared to their placebo controls.

Mean increase in hemoglobin is probably the best measure of efficacy of an erythropoietic agent. The weekly regimens were surprisingly robust, again with values imputed if transfused, showing a definite dose-response relationship. The lack of hemoglobin increase in the placebo group and then prompt subsequent response in the open label phase for the placebo controls validated the study as representing a true anemia of cancer population and not just patients recovering from prior myelosuppressive therapy.

Table 1: Hemoglobin endpoints and red blood cell transfusions

a: Proportion calculated using Kaplan-Meier estimate. b: Change from baseline calculated using last available haemoglobin value not within 28 days of a transfusion (imputed analysis), and for patients with haemoglobin value at week 13 not within 28 days of a transfusion (alternate analysis). QW, once weekly; Q3W, once every 3 weeks; Q4W, once every 4 weeks; N, number in cohort; CI, confidence interval; RBC, red blood cell; EOTP, end of treatment period; n, number in subset; NE, not estimable (median not reached)

The FACT-Fatigue subscale had a mean baseline score of 26.9 out of a possible maximum of 52. The mean increase was 8.5 for patients who had a greater than 2 g/dl hemoglobin increase compared to a 0.6 point decline in patients with no increase in hemoglobin (see table 2). All subscales showed similar results in regard to hemoglobin change except the FACT-Social/Family and the FACT-Emotional. As expected, this is because the latter two subgroups focused on social support and family communication rather than on anemia-correlated symptoms.

Table 2: Change in FACT scales with change in hemoglobin concentration (QW, Q2W, and Q3W schedules combined).

a: n=182 for the FACT-G Functional scale, 179 for the Social/Family scale, and 178 for the Overall and Anaemia Total scales.
b: n=73 for the FACT-G Social/Family, Overall, and Anemia Total scales.
c: n=84 for the FACT-G Social/Family and Functional scales and 83 for the Overall and Anemia Total scales.
d: Anemia subscale score = Fatigue + Anemia symptoms.
e: FACT-G Overall score = Physical well-being + Social/family well-being + Emotional well-being + Functional well-being.
f: FACT Anaemia total score = FACT-G + Anaemia subscale score.

The response of patients with chronic anemia of cancer to erythropoietic therapy rivaled the response seen in the pure hormonal deficiency state of renal anemia, as evidenced by an 80% response rate in the 0.5 mcg/kg/week cohort. However, interpretation of data in this group must be limited because only six patients were enrolled at this dosage with resulting wide confidence limits.

The data indicates excellent responses in the q3 and q4 week cohorts compared to historic findings, showing that infrequent treatment is adequate for the majority of patients. Also, it is expected that this regimen would maintain patients after achieving a target hemoglobin count of 12, the level thought to yield optimal HRQOL and symptom benefit in most patients.

Dosage recommendations: We recommend dosing patients, based on these results, with treatment individualized to the patient’s given situation. For a patient starting with a hemoglobin of <10 or in the patient with significant symptoms even if at higher hemoglobin levels, an initial fixed dosage of 200 mcg q2 weeks until hemoglobin target is reached appears to be appropriate, followed by 500 mcg q4 weeks. Data suggests that fixed dose schedules can be substituted for weight-based dosing without compromise of response and without increased complications.24 For those patients who do not require as rapid a response or for patients whose hemoglobin level is above 10 at initiation of treatment, this study suggests that 500 mcg q4 weeks is an appropriate dose for treatment. If shown to be cost effective and efficient, front-end loading strategies may be employed in the future for patients with co-morbid health conditions who require a rapid hemoglobin increase.

Conclusion

While the Abels trial led to a great deal of benefit for patients with CIA, faulty study design has denied erythropoietic therapy to patients with chronic anemia of cancer for the past decade. Furthermore, patients with other types of anemia of chronic disease, such as congestive heart failure, rheumatoid arthritis, inflammatory bowel disease, and anemia in the elderly that limits rehabilitative physical therapy have also been denied this therapy. These are groups of patients who have the same inflammatory cytokine-mediated anemia and yet have bone marrows never subjected to the myelosuppressive effects of chemotherapy and irradiation, making them prime candidates for small, infrequent doses of darbepoetin alfa.

Based on historical research and recent findings, a continuum of responsiveness to erythropoietin can be postulated, with CIA being the least responsive, then chronic anemia of cancer, anemia of chronic disease, and finally the most responsive, renal anemia. It is our expectation that patients with anemia of chronic diseases will be enrolled in trials in the near future. The future may well be marked by more benefit in these populations than even the considerable benefit already shown in renal failure and cancer-related anemia.

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