Evaluating Anemia in Patients With Cancer
Evaluating Anemia in Patients With Cancer
Anemia is a major cause of morbidity in patients with cancer. There are multiple causative factors, including absolute iron deficiency due to blood loss and/or nutritional deficiencies, anemia of chronic disease, and myelosuppressive effects of chemotherapy, as well as metastatic infiltration of the bone marrow. The identification of iron deficiency in patients with cancer is particularly important in patients being considered for therapy with erythropoiesis-stimulating agents. Approximately 30% to 50% of patients with cancer with chemotherapy-related anemia have been reported to experience poor to absent responses to erythropoiesis-stimulating agents, and iron therapy has been shown to improve the response in some of these patients. In addition, iron therapy has been associated with a reduction in the RBC transfusion requirements in women with gynecologic cancers treated with chemoradiotherapy. Since the identification of iron deficiency has important therapeutic implications in oncology patients, current recommendations are to investigate the cause of anemia if the Hb falls below 11 g/dL.
The present study supports the use of RET-He to rapidly rule out iron deficiency, defined by traditional serum biochemical markers, in a complex patient population with cancer, during routine automated CBC and reticulocyte analysis. To evaluate RET-He in the broadest possible oncology population, we did not stratify patients by malignancy, staging, treatment, or transfusion therapy. In this unselected patient population with cancer, a high negative predictive value for ruling out iron deficiency was achieved using an RET-He cutoff of 31 to 32 pg, when iron deficiency was defined by serum iron and transferrin saturation, with or without ferritin. In this setting, RET-He outperformed the combination of Hb and MCV. The MCV (mean RBC volume) is of limited utility in oncology patients, because is it observed in the later stages of iron deficiency and is influenced by reticulocytosis, liver disease, myelodysplastic syndrome, aplasia, myelofibrosis, and impaired DNA synthesis and cell division due to chemotherapy.
Despite the excellent negative predictive value of RET-He for ruling out iron deficiency in the present study, the corresponding specificity was low. This was expected based on the high selected RET-He threshold relative to established reference ranges and the high incidence of anemia of chronic disease in the oncology population. All false-positive cases identified by an RET-He threshold of 32 pg (n = 50) were examined by chart review. Indeed, in 40 cases, the anemia was characterized as anemia of chronic disease in the patient record. Since anemia of chronic disease is characterized by iron-restricted hematopoiesis, RET-He levels are expected to be low and to overlap with those found in iron deficiency.
In the remaining 10 cases with falsely positive RET-He values and normal biochemical iron studies, one case of a hemoglobinopathy combined with β-thalassemia trait (heterozygous Hb Mississippi/β-thalassemia) was identified with expected low RET-He, two patients were found to be iron deficient by biochemical tests on a follow-up visit, and seven patients had borderline serum iron (<45 μg/dL) and transferrin saturation (<25%). Further studies are required to determine how well RET-He distinguishes iron-deficient or iron-restricted hematopoiesis from bone marrow suppression. Data from a small subanalysis of patients with low reticulocyte counts in the present study appear promising.
The hemoglobin content of erythrocytes, measured either as ADVIA 2120 CHr or Sysmex RET-He, has been reported to be a reliable indicator of iron-deficient erythropoiesis in diverse patient populations, including pediatrics, geriatrics, pregnancy, and particularly chronic kidney disease. Its performance characteristics in evaluating anemia in patients with cancer, however, are not well understood. This study provides insight into the utility of measuring RET-He in an oncology setting, in which patients are routinely monitored for cytopenias, typically in an outpatient setting. Biochemical iron studies are often ordered in conjunction with a CBC and other laboratory tests as part of automated order sets designed to expedite the interpretation of anemia in patients at risk. Thus, the ability to obtain information regarding the availability of iron for erythropoiesis, as part of routine peripheral blood CBC and reticulocyte analysis, performed in an outpatient setting before the patient is evaluated by a specialist, would significantly benefit patient management.
To focus on patients at risk for iron deficiency, we evaluated RET-He only in patients with orders for CBC and serum iron studies. This method may have introduced an unintended bias into the analysis, since only those patients who had further laboratory studies ordered were included in the current study. This limitation precludes understanding the role of RET-He in a broader patient population with cancer. Other limitations of the study include the small number of patients who actually had iron deficiency anemia, in the context of a significant population with iron-restricted erythropoiesis secondary to inflammation and chronic disease. In addition, the diagnosis of iron deficiency was inferred from biochemical studies and medical record review, in the absence of a gold standard for iron deficiency such as bone marrow iron studies. Standard biochemical tests of iron metabolism, such as serum iron, ferritin, and transferrin, are affected by the acute phase response. During the acute phase, serum iron and ferritin are increased, whereas transferrin is decreased. Therefore biochemical markers of iron status are less than ideal standards for diagnosing iron deficiency. In current clinical practice, however, bone marrow evaluation to assess iron status is not performed in most patients with cancer who have anemia, and iron deficiency is diagnosed based on results of serum iron studies.
In summary, the data support the use of RET-He to rapidly rule out iron-deficient erythropoiesis, reduce unnecessary iron studies, and provide rapid diagnostic information when the automated CBC and reticulocyte counts are reported. Based on data from the present study, using RET-He to rule out iron deficiency would reduce the number of required iron studies by 66% (from 209 to 70) at our center. If a combination of RET-He (<32 pg) and anemia (Hb <11 g/dL) were used to rule out iron deficiency anemia, the number of required iron studies would decrease by approximately 80% (from 209 to 43). Since RET-He and its CHr equivalent are routinely available with automated reticulocyte analysis on Sysmex XE/XN series and Siemens ADVIA hematology analyzers, respectively, this parameter can be integrated readily into the diagnostic algorithm of anemia evaluations. RET-He and CHr cutoff values reported for the identification of iron deficiency vary widely in the literature, from 26 to 33 pg, depending on the study patient population. Thus, customizing the RET-He threshold to rule out iron deficiency in specific patient populations is recommended. Of note, the RET-He threshold of 32 pg/cell, selected in the present study to rule out iron deficiency, was applicable also to an independent study cohort described by Canals et al to correctly rule out iron deficiency anemia and iron-restricted hematopoiesis.
Discussion
Anemia is a major cause of morbidity in patients with cancer. There are multiple causative factors, including absolute iron deficiency due to blood loss and/or nutritional deficiencies, anemia of chronic disease, and myelosuppressive effects of chemotherapy, as well as metastatic infiltration of the bone marrow. The identification of iron deficiency in patients with cancer is particularly important in patients being considered for therapy with erythropoiesis-stimulating agents. Approximately 30% to 50% of patients with cancer with chemotherapy-related anemia have been reported to experience poor to absent responses to erythropoiesis-stimulating agents, and iron therapy has been shown to improve the response in some of these patients. In addition, iron therapy has been associated with a reduction in the RBC transfusion requirements in women with gynecologic cancers treated with chemoradiotherapy. Since the identification of iron deficiency has important therapeutic implications in oncology patients, current recommendations are to investigate the cause of anemia if the Hb falls below 11 g/dL.
The present study supports the use of RET-He to rapidly rule out iron deficiency, defined by traditional serum biochemical markers, in a complex patient population with cancer, during routine automated CBC and reticulocyte analysis. To evaluate RET-He in the broadest possible oncology population, we did not stratify patients by malignancy, staging, treatment, or transfusion therapy. In this unselected patient population with cancer, a high negative predictive value for ruling out iron deficiency was achieved using an RET-He cutoff of 31 to 32 pg, when iron deficiency was defined by serum iron and transferrin saturation, with or without ferritin. In this setting, RET-He outperformed the combination of Hb and MCV. The MCV (mean RBC volume) is of limited utility in oncology patients, because is it observed in the later stages of iron deficiency and is influenced by reticulocytosis, liver disease, myelodysplastic syndrome, aplasia, myelofibrosis, and impaired DNA synthesis and cell division due to chemotherapy.
Despite the excellent negative predictive value of RET-He for ruling out iron deficiency in the present study, the corresponding specificity was low. This was expected based on the high selected RET-He threshold relative to established reference ranges and the high incidence of anemia of chronic disease in the oncology population. All false-positive cases identified by an RET-He threshold of 32 pg (n = 50) were examined by chart review. Indeed, in 40 cases, the anemia was characterized as anemia of chronic disease in the patient record. Since anemia of chronic disease is characterized by iron-restricted hematopoiesis, RET-He levels are expected to be low and to overlap with those found in iron deficiency.
In the remaining 10 cases with falsely positive RET-He values and normal biochemical iron studies, one case of a hemoglobinopathy combined with β-thalassemia trait (heterozygous Hb Mississippi/β-thalassemia) was identified with expected low RET-He, two patients were found to be iron deficient by biochemical tests on a follow-up visit, and seven patients had borderline serum iron (<45 μg/dL) and transferrin saturation (<25%). Further studies are required to determine how well RET-He distinguishes iron-deficient or iron-restricted hematopoiesis from bone marrow suppression. Data from a small subanalysis of patients with low reticulocyte counts in the present study appear promising.
The hemoglobin content of erythrocytes, measured either as ADVIA 2120 CHr or Sysmex RET-He, has been reported to be a reliable indicator of iron-deficient erythropoiesis in diverse patient populations, including pediatrics, geriatrics, pregnancy, and particularly chronic kidney disease. Its performance characteristics in evaluating anemia in patients with cancer, however, are not well understood. This study provides insight into the utility of measuring RET-He in an oncology setting, in which patients are routinely monitored for cytopenias, typically in an outpatient setting. Biochemical iron studies are often ordered in conjunction with a CBC and other laboratory tests as part of automated order sets designed to expedite the interpretation of anemia in patients at risk. Thus, the ability to obtain information regarding the availability of iron for erythropoiesis, as part of routine peripheral blood CBC and reticulocyte analysis, performed in an outpatient setting before the patient is evaluated by a specialist, would significantly benefit patient management.
To focus on patients at risk for iron deficiency, we evaluated RET-He only in patients with orders for CBC and serum iron studies. This method may have introduced an unintended bias into the analysis, since only those patients who had further laboratory studies ordered were included in the current study. This limitation precludes understanding the role of RET-He in a broader patient population with cancer. Other limitations of the study include the small number of patients who actually had iron deficiency anemia, in the context of a significant population with iron-restricted erythropoiesis secondary to inflammation and chronic disease. In addition, the diagnosis of iron deficiency was inferred from biochemical studies and medical record review, in the absence of a gold standard for iron deficiency such as bone marrow iron studies. Standard biochemical tests of iron metabolism, such as serum iron, ferritin, and transferrin, are affected by the acute phase response. During the acute phase, serum iron and ferritin are increased, whereas transferrin is decreased. Therefore biochemical markers of iron status are less than ideal standards for diagnosing iron deficiency. In current clinical practice, however, bone marrow evaluation to assess iron status is not performed in most patients with cancer who have anemia, and iron deficiency is diagnosed based on results of serum iron studies.
In summary, the data support the use of RET-He to rapidly rule out iron-deficient erythropoiesis, reduce unnecessary iron studies, and provide rapid diagnostic information when the automated CBC and reticulocyte counts are reported. Based on data from the present study, using RET-He to rule out iron deficiency would reduce the number of required iron studies by 66% (from 209 to 70) at our center. If a combination of RET-He (<32 pg) and anemia (Hb <11 g/dL) were used to rule out iron deficiency anemia, the number of required iron studies would decrease by approximately 80% (from 209 to 43). Since RET-He and its CHr equivalent are routinely available with automated reticulocyte analysis on Sysmex XE/XN series and Siemens ADVIA hematology analyzers, respectively, this parameter can be integrated readily into the diagnostic algorithm of anemia evaluations. RET-He and CHr cutoff values reported for the identification of iron deficiency vary widely in the literature, from 26 to 33 pg, depending on the study patient population. Thus, customizing the RET-He threshold to rule out iron deficiency in specific patient populations is recommended. Of note, the RET-He threshold of 32 pg/cell, selected in the present study to rule out iron deficiency, was applicable also to an independent study cohort described by Canals et al to correctly rule out iron deficiency anemia and iron-restricted hematopoiesis.
