Evaluation of Tumor Necrosis Factor-α and Erythropoietin Serum Levels in B-Cell Chronic Lymphocytic Leukemia Patients with Anemia

Abstract

Serum levels of tumor necrosis factor-α (TNF-α) and of erythropoietin (Epo) have been evaluated in 100 patients with B-cell chronic lymphocytic leukemia (CLL) in order to determine whether these factors could be significant in the development of anemia, which was observed in some cases with advanced disease. In our series of patients, TNF-α serum levels had an inverse correlation with hemoglobin levels (r = –0.813). In patients with anemia, the serum levels of TNF-α were significantly higher (p = 0.022) than in those without anemia (186.7 ± 84.7 vs. 39.8 ± 20.7 pg/ml). Serum Epo levels were also significantly (p = 0.0003) increased in CLL patients with anemia compared to those without (134.1 ± 225.9 vs. 12.3 ± 4.8 mU/ml). The ratio of observed/predicted (O/P) serum Epo was adequate (>0.8) for the degree of anemia in 70% of patients with anemia and inadequate in the remaining 30%. In the latter, the mean serum TNF-α level was significantly higher (p = 0.005) than the mean for the anemic cases with an adequate O/P ratio of serum Epo (234.1 vs. 166.4 pg/ml). These data suggest that although CLL anemia is not characterized by inadequate Epo production, in some CLL patients this factor may be correlated. In these cases, the levels of TNF-α were significantly higher than in other anemic cases. Compared to other CLL patients with anemia, these CLL patients might better respond to therapy with recombinant human Epo in pharmacological doses.

Disease-Related Anemia in Chronic Lymphocytic Leukemia Is Not Due to Intrinsic Defects of Erythroid Precursors: A Possible Pathogenetic Role for Tumor Necrosis Factor-Alpha

“…However, Capalbo et al [7], studying anemic CLL patients, reported that the degree of anemia in CLL was not related to leukemic BM infiltration. These findings are in keeping with previous observations [22], suggesting that in chronic lymphoproliferative disorders anemia is not solely due to BM infiltration by the neoplastic clone.…”

“…Once bound to its receptor (EPOR), it promotes the survival, proliferation and differentiation of colony-forming unit erythroids (CFU-Es) and erythroid precursors by activating distinct signaling pathways [5]. EPO deficiency alone can hardly explain anemia, since appropriate serum EPO levels for the degree of anemia have been found in the majority of CLL patients [6, 7]. However, although erythroid progenitors appear sensitive to EPO in semisolid cultures [8], it is unclear whether anemia might be attributed to intrinsic defects of hematopoietic stem cells and/or to defective response to EPO due to dysfunctional EPO-EPOR signaling pathway.…”

“…B-CLL cells are capable of spontaneously secreting increased amounts of TNF-α in vitro [12, 13]. Moreover, elevated serum TNF-α levels have been observed in CLL patients [7, 14], and have been associated with anemia and shorter survival [14]. Whether TNF-α mediates disease-related anemia in CLL and which is the precise mechanism for the induction of anemia remains elusive.…”

Changes in red blood cell osmotic fragility induced by total plasma and plasma fractions obtained from rats bearing progressive and regressive variants of the Walker 256 tumor

“…It has been suggested that the activation of the immune and inflammatory systems through the increasing levels of proinflammatory cytokines such as interleukins 1 and 6, TNF-α and INF-δ would induce iron retention by the reticuloendothelial system, gastrointestinal tract and liver, therefore exerting an inhibitory effect on erythroid precursors (18)(19)(20). The erythropoietin production and bone marrow response to it are decreased in cancer anemia (4,18,20,21) and treatment with recombinant erythropoietin has been reported to be only of temporary help (14,22). Macro-and/or microscopic alterations of bone marrow have long been ruled out as factors involved in cancer anemia in humans (23) and rats (4).…”

Linking anemia to inflammation and cancer: The crucial role of TNFα

“…Indeed anemia is considered as a common symptom induced by inflammation and cancer pathologies. In patients with B-cell chronic lymphocytic leukemia suffering from anemia, the serum levels of TNFα were significantly higher than in those without anemia [63]. The incidence of anemia was shown to vary with A c c e p t e d M a n u s c r i p t tumor type, stage and patient age.…”