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Brief Communication |
Address correspondence to Jong Weon Choi MD PhD, Department of Laboratory Medicine, Inha University Hospital, 7-206, 3-ga, Shinheung-dong, Jung-gu, Inchon, 400-711, South Korea; tel 82-32-890-2503; fax 82-32-890-2529; e-mail: jwchoi{at}inha.ac.kr.
Abstract
Erythropoietic activities and immature reticulocyte production were investigated in a total of 157 patients (81 men, 76 women, median age = 42 yr, range = 23 to 65 yr) with acute lymphoid leukemia (ALL, n = 31), acute myeloid leukemia (AML, n = 39), or non-Hodgkin’s lymphoma (NHL, n = 87), based on assays of the hemogram, red cell indices, reticulocyte subpopulations, and intramedullary erythroid precursors. There were no significant differences in red blood cell (RBC) counts, blood hemoglobin levels, or erythroid precursors between ALL and AML patients. Reticulocytes in AML patients averaged 1.7 ± 0.8%, which was higher than in patients with ALL (0.8 ± 0.3%, p <0.01); the proportion of high-fluorescence reticulocytes (HFR) averaged 4-fold higher in AML versus ALL (p <0.01) and the reticulocyte maturity index (RMI) was higher in AML (20.8 ± 8.3 %) versus ALL (12.4 ± 6.5%, p <0.01). The RMI was higher in NHL patients with bone marrow (BM) involvement (15.6 ± 9.4%), compared to those without BM involvement (4.3 ± 2.1%, p <0.01). The proportion of HFR averaged 11-fold higher in NHL with BM involvement versus NHL without BM involvement. In summary, erythropoietic activity is significantly more active in patients with AML compared to ALL and in patients with NHL with BM involvement, compared to NHL without BM involvement.
(received 21 May 2003; accepted 2 July 2003)
Keywords: acute lymphoid leukemia (ALL), acute myelogenous leukemia (AML), non-Hodgkin’s lymphoma, erythropoiesis
Introduction
Anemia is a frequent finding in patients with hematologic malignancies, such as acute leukemia or malignant lymphoma. The anemia is caused by a variety of mechanisms, including neoplastic cell infiltration into bone marrow (BM), nutritional deficiencies, and defects in erythropoiesis as a result of the disease itself or overproduction of cytokines, such as interleukin-1 and tumor necrosis factor, which are capable of inhibiting erythropoiesis [1,2]. Flow cytometric reticulocyte counting has provided an accessible measure of erythropoietic activity. Measurement of the RNA content of reticulocytes enables the identification of young macroreticulocytes prematurely released from BM in conditions of increased erythropoietic stimulation [3].
There have been few studies that have closely examined immature reticulocyte production in patients with acute leukemia or malignant lymphoma. In this study we tested whether significant differences exist in erythropoietic activities between acute lymphoid leukemia (ALL) and acute myelogenous leukemia (AML), and between non-Hodgkin’s lymphoma (NHL) with BM involvement and without BM involvement.
Materials and Methods
A total of 157 patients with acute leukemia (ALL, n = 31; AML, n = 39) or NHL (n = 87) were investigated by measurements of the hemogram, red cell indices, reticulocyte subpopulations, and intramedullary erythroid precursors. The subject populations comprised 81 men and 76 women with a median age of 42 yr (range 23 to 65 yr). Blood samples were collected from the patients at the time of BM study, and none of the patients had received any specific therapy prior to the study.
Acute leukemia was diagnosed on the basis of criteria of the French-American-British (FAB) classification [4]. Bilateral BM aspirations and trephine biopsies obtained at initial staging from NHL patients were evaluated for the presence of lymphoma. Histologic classification of NHL was based upon the revised European-American lymphoma classification of lymphoid malignancies (REAL classification) [5]. The NHL patients were assigned into three groups: subjects with BM involvement (group A, n = 23), subjects who had no evidence of BM involvement (group B, n = 64), and subjects with hemoglobin <9.0 g/dl within group B (group C, n = 21).
Three patients were excluded who had a history of blood transfusion or recent infection, because episodes of infection or blood transfusion have any significant impact on trends of reticulocytes. None of the patients had a history of bleeding, hemolysis, or renal insufficiency.
Complete blood cell count was measured using an electronic counter (SE 9000; Sysmex, Kobe, Japan). Reticulocytes and their subpopulations were automatically analyzed by flow cytometry (R-3000; Sysmex). Reticulocytes were classified into three categories by the fluorescence intensity of auramine O staining: low-, middle-, and high-fluorescence reticulocytes (LFR, MFR, and HFR, respectively). Corrected reticulocyte count was calculated, based on a normal hematocrit of 45%, using the following formula: corrected reticulocyte (%) = (subject’s hematocrit/45) x reticulocyte count (%). RMI was calculated using the equation: RMI = (MFR + HFR) x 100/LFR and expressed as a percentage. The number of erythroid precursors was counted and expressed as the percentage of total erythroblasts among 1000 bone marrow nucleated cells. The Mann-Whitney U test was used to compare differences of mean values. All p values <0.01 were considered statistically significant.
Results and Discussion
There were no significant differences in the mean values of red blood cells (RBCs), blood hemoglobin levels, and erythroid precursors between ALL and AML. However, reticulocytes and corrected reticulocytes in patients with AML averaged 1.7 ± 0.8% and 0.9 ± 0.5%, which were significantly higher than those for patients with ALL (0.8 ± 0.3% and 0.4 ± 0.2%, p <0.01, respectively). In particular, the proportion of HFR was 4-fold higher in AML than in ALL (p <0.01) (Table 1
). Because RMI is the earliest and most sensitive predictor of erythropoiesis, the marked elevation of HFR and RMI that was observed in the AML patients, who showed no significant differences in age, gender, and severity of anemia from the ALL patients, suggests that erythropoietic activity is more active in AML, compared to ALL.
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Our results are in partial agreement with a previous study in which significantly high mean values of immature reticulocytes with normal or reduced reticulocyte count were observed in patients with dyserythropoietic or ineffective erythropoietic conditions, such as AML or myelodysplastic syndromes [7].
As shown in Table 2, reticulocyte subpopulations and RMI were significantly higher in NHL patients with BM involvement than in those with out BM involvement. It is conceivable that a significantly low hemoglobin level, which was observed in the patients with NHL and BM involvement, may lead to elevation of immature reticulocyte production. To exclude the influence of hemoglobin values on reticulocyte production, among the patients who had NHL but no BM involvement (group B), we selected only the subjects (group C) with similar hemoglobin levels to the NHL patients showing BM involvement. Mean values of reticulocyte subpopulations and RMI were still significantly higher in NHL with BM involvement than in NHL with no BM involvement (group C), although no significant differences were observed in hemoglobin levels between the two groups.
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In conclusion, this study suggests that erythropoietic activity is more active in patients with AML than in those with ALL. Immature reticulocyte production is significantly elevated in NHL with BM involvement, compared to NHL without BM involvement. Further studies regarding cytokines, such as erythropoietin, interleukin-1, and tumor necrosis factor, are needed to verify and elucidate the pathophysiology of the enhanced erythropoiesis.
References
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