Management of Anemia in Patients With Hematologic Malignancies

Anemia is common in patients with hematologic malignancies, and it has negative effects on their quality of life. The current clinical practice guidelines recommend erythropoietic therapy in patients with cancer- or chemotherapy-related anemia, but anemia is often undertreated in patients with hematologic malignancies. Several randomized controlled trials have shown that treatment with erythropoiesis-stimulating proteins such as epoetin alfa (Procrit), epoetin beta, and darbepoetin alfa (Aranesp) increases hemoglobin levels, reduces the need for red blood cell transfusions, and improves quality of life in patients with hematologic malignancies and anemia receiving chemotherapy. Furthermore, preliminary data from a recent open-label study suggest that early treatment of mild anemia in patients with hematologic malignancies treated with chemotherapy produces marked improvements in quality of life and productivity. Increasing patients' hemoglobin levels may also improve their cognitive function. These findings support the use of erythropoietic therapy to manage anemia in patients with hematologic malignancies who are treated with chemotherapy.

Anemia is a common complication in patients with hematologic malignancies. A number of factors contribute to low hemoglobin (Hgb) levels in these patients, including insufficient erythropoiesis caused by tumor infiltration of the bone marrow or chemotherapy-induced myelosuppression, anemia of chronic disease caused by decreased production of serum erythropoietin, nutritional deficiency, hemolysis, and bleeding.[1] The prevalence of anemia in patients with hematologic malignancies varies by cancer type and stage, with approximately one-quarter to one-half of patients having anemia at the time of diagnosis.[2-5] In the European Cancer Anaemia Survey, anemia (Hgb < 12 g/dL) was seen at least once in the 6-month survey period in 73% of the subjects with lymphoma or myeloma and in 68% of those with leukemia.[6] The consequences of anemia in patients with cancer include fatigue, weakness, impaired concentration, and diminished quality of life (QOL).[7-9] Furthermore, low Hgb levels may have a negative effect on prognosis and survival.[10]

Current clinical practice guidelines recommend erythropoietic therapy in patients with cancer- or chemotherapy-related anemia. The clinical practice guidelines of the American Society of Clinical Oncology and the American Society of Hematology recommend that erythropoietic therapy be initiated in patients with chemotherapy-induced anemia and Hgb levels of 10 g/dL or less.[11] These guidelines suggest that erythropoietic therapy should be initiated in patients with hematologic malignancies only if an increase in Hgb levels has not been achieved through cytoreduction with chemotherapy. The clinical practice guidelines of the National Comprehensive Cancer Network recommend that erythropoietic therapy be considered in symptomatic patients with cancer- or chemotherapy-related anemia and Hgb levels of less than 11 g/dL.[12]

Treatment with the erythropoiesis-stimulating protein epoetin alfa (Procrit, recombinant human erythropoietin) significantly increases Hgb levels, decreases the need for red blood cell transfusions, and improves QOL in patients with chemotherapy-related anemia.[13-17] Similarly, treatment with darbepoetin alfa (Aranesp), a novel erythropoiesis-stimulating protein with a longer half-life than that of epoetin alfa, has been shown to improve hematologic measures, fatigue, QOL, and productivity in patients with chemotherapy-induced anemia.[18-24] However, despite the known benefits of treating anemia in patients with cancer, it is often undertreated in those with hematologic malignancies.[6]

Management of Anemia in Hematologic Malignancies

Several clinical trials of erythropoietic therapy in patients with hematologic malignancies have been conducted in the past few years. Epoetin alfa was shown to correct anemia and improve QOL in a randomized placebo-controlled double-blind trial in anemic patients with solid or nonmyeloid hematologic malignancies treated with nonplatinum chemotherapy.[25, 26] Patients were given epoetin alfa (150-300 IU/kg) or placebo by subcutaneous (SC) injection three times a week for up to 28 weeks. In a subset analysis of data from patients with hematologic malignancies (46% of patients), the mean pretreatment Hgb level was 9.9 g/dL in the epoetin alfa group and 9.7 g/dL in the placebo group.[25]

Outcomes in the patients with hematologic malignancies are shown in Table 1. Fewer patients with hematologic malignancies treated with epoetin alfa required red blood cell transfusions after week 4 than those treated with placebo (25% vs 43%), and the mean increase in Hgb levels was also markedly greater in patients treated with epoetin alfa (2.2 vs 0.3 g/dL), with differences between the groups evident after 2 weeks of treatment. Furthermore, more patients with hematologic malignancies treated with epoetin alfa had a response (defined as an increase in Hgb level of 2 g/dL or more that was unrelated to transfusions) than those treated with placebo (75% vs 17%). These efficacy results paralleled those in the overall study population; however, statistical analyses of efficacy measures were not performed by tumor subgroup because the trial lacked the power to discriminate treatment differences by subgroup.

Quality of life was also evaluated in this trial by using the Functional Assessment of Cancer Therapy-General (FACT-G) and the FACT-Anemia (FACT-An, including the FACT- Fatigue [FACT-F] subscale), as well as the Linear Analog Scale Assessment. There was an improvement on all QOL scales and subscales in patients with hematologic malignancies treated with epoetin alfa; in contrast, QOL decreased in the patients treated with placebo, despite their Hgb levels being maintained with transfusions.[25]

Epoetin beta was shown to reduce transfusion requirements and improve QOL in a randomized double-blind placebo-controlled trial in patients with low-grade non-Hodgkin's lymphoma (NHL), chronic lymphocytic leukemia (CLL), or multiple myeloma (MM) and severe anemia.[27] Patients had Hgb levels of 10 g/dL or less with a transfusion requirement of two or more units of packed red blood cells in the 3 months before study entry and inadequately low endogenous serum erythropoietin levels. Patients were randomized to epoetin beta 150-300 IU/kg (n = 170) or placebo (n = 173) by SC injection three times a week for 16 weeks. The mean pretreatment Hgb levels were 9.2 g/dL in the epoetin beta group and 9.3 g/dL in the placebo group.

Between weeks 5 and 16, epoetin beta recipients had significantly greater transfusion-free survival and a significantly greater transfusion- and severe anemia-free survival relative to placebo, with relative risk reductions of 43% and 51%, respectively (P ≤ .001 for both endpoints). At the end of the study, there were responses (defined as no transfusion requirements and an increase in Hgb level of ≥ 2 g/dL) in 67% of the patients treated with epoetin beta and in 27% of those treated with placebo (P < .001). Treatment with epoetin beta was associated with significantly greater improvements on the FACT-An total and FACT-G total scales, compared with the placebo group (both P < .05), but there were no significant between-treatment differences on the FACT-F subscale or the individual FACT-An dimensions.

In a subset analysis of data from patients who had a response to epoetin beta, most QOL dimensions, particularly those associated with anemia-related symptoms and fatigue, were notably improved, suggesting that an increase in Hgb level of 2 g/dL or more may be as important in improving QOL as achieving a target Hgb level. A meta-analysis of five randomized trials found that epoetin beta does not adversely affect short-term survival, tumor progression, or thromboembolic events in patients with hematologic malignancies treated with chemotherapy.[28]

A small randomized placebo-controlled phase II study found that once-weekly darbepoetin alfa increased Hgb levels and reduced transfusion requirements in patients with hematologic malignancies who had anemia.[29] These findings were extended in a randomized double-blind, placebo-controlled phase III study of darbepoetin alfa in patients with NHL, Hodgkin's disease, CLL, or MM and anemia who were treated with chemotherapy.[30] In the phase III trial, patients were randomized to either darbepoetin alfa 2.25-4.5 µg/kg(n = 174) or placebo (n = 170) given by SC injection once a week for 12 weeks. The mean pretreatment Hgb levels were 9.6 g/dL in the darbepoetin alfa group and 9.5 g/dL in the placebo group.

Hemoglobin levels increased by 1.8 g/dL in the darbepoetin alfa group and by 0.2 g/dL in the placebo group (P < .001), and there was a response, defined as an increase in Hgb level of 2 g/dL or more in the absence of a transfusion in the previous 28 days, in significantly more patients treated with darbepoetin alfa than in those treated with placebo (60% vs 18%; P < .001) (Figure 1). Transfusions were required between weeks 5 and 12 in significantly fewer patients treated with darbepoetin alfa than in those treated with placebo (31% vs 48%; P < .001); similar results were seen in the subgroups of patients with lymphoma (27% vs 49%; P = .002) and myeloma (35% vs 48%; P = .04).

Treatment with darbepoetin alfa was associated with the greatest improvements in FACT-F scores compared to placebo among patients with low baseline values. However, even after adjustment for pretreatment values, improvements in FACT-F scores were significantly greater with darbepoetin alfa than with placebo (P = .03). Moreover, darbepoetin alfa was associated with greater improvements in FACT-F scores than placebo regardless of patients' level of fatigue before treatment (Figure 2). Improvements in FACT-F scores were correlated with increases in hemoglobin (P < .001).

The greatest improvements in QOL in two large community-based trials occurred between Hgb levels of 11 and 12 g/dL, [13] suggesting that even patients with mild anemia can benefit from erythropoietic therapy. This was investigated in a study that evaluated the effects of once-weekly epoetin alfa during chemotherapy for CLL, MM, or lymphoma in patients with mild anemia (Hgb 10-12 g/dL) who were randomized to immediate treatment (epoetin alfa 40,000-60,000 IU SC once a week for 16 weeks; n = 135) or observation and delayed treatment (treatment delayed for ≥ two chemotherapy cycles [6-8 weeks], after which time epoetin alfa was administered only if Hgb levels had fallen to < 9 g/dL; n = 134).[31,32] Patients with Hgb levels higher than 12 g/dL were not randomized until their levels had decreased to 12 g/dL or lower. The mean pretreatment Hgb levels were 11.1 g/dL in the immediate-treatment group and 11.2 g/dL in the delayed-treatment groups. Preliminary results suggest that compared with delayed treatment, immediate treatment with epoetin alfa was associated with significant improvements with respect to hematologic response, QOL, and productivity.[32]

Changes in cognitive function with erythropoietic therapy in patients with hematologic malignancies treated with chemotherapy who had anemia were recently evaluated in EPOLYM, an international multicenter open-label phase IIIb trial in which patients were treated with epoetin alfa 40,000 IU weekly for 24 weeks. In an interim analysis of data from 568 patients (of a planned 1,000), the target Hgb levels were achieved within 3 to 5 weeks after initiation of treatment and were maintained throughout the study.[33] At week 24, there was an 8% improvement in speed of memory and a 3% improvement in quality of memory, which paralleled the increase in Hgb levels. These findings await confirmation in the final analysis of data from the entire study population.

Summary

Alleviating anemia is important in the management of patients with hematologic malignancies who are treated with chemotherapy. Several randomized trials have shown that erythropoietic therapy increases Hgb levels and improves QOL in these patients. Emerging data suggest that these effects are apparent even in patients with mild anemia. Preliminary data also suggest that small changes in cognitive function may be seen with the treatment of anemia in patients receiving chemotherapy for hematologic malignancies.

Disclosures:

The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

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