Prognostic Significance of Tissue Necrosis Factor-Alpha in Newly Diagnosed Acute Myeloid Leukemia and High-Risk Myelodysplastic Syndromes.

Background: Tissue necrosis factor (TNF)-α is a naturally occurring cytokine involved in the pathogenesis of several hematologic malignancies, but an independent prognostic role for TNF-α in acute myeloid leukemia (AML) and high-risk myelodysplastic syndromes (MDS) has not been established. The purpose of this study was to determine the association between TNF-α levels and pretreatment characteristics and clinical outcomes in these diseases.

Methods: From 9/94 through 1/01, serum levels of TNF-α were prospectively measured in 198 patients with AML or high-risk MDS. Serum TNF-α was quantified using commercially available ELISA kits (R&D Systems, Minneapolis, MN) (lower limits of sensitivity were 4.4 pg/mL). The appropriate recombinant cytokine was used to create a standard curve for each cytokine, and serum level was ascertained using the appropriate standard curve. All values represent the means of 3 sets of duplicate experiments.

Results: The median patient age of the 198 patients with serum TNF-α measurements was 65 years (range, 21–84 years); 62% were ≥ 60 years. Cytogenetics were favorable in 6% of patients, intermediate in 53%, poor-risk in 38%, and 3% of patients had insufficient metaphases or unknown cytogenetics. Zubrod performance status (PS) was 0–1 in 66% of patients, 2 in 25%, and 3–4 in 9%. Forty-nine percent had a history of an antecedent hematologic disorder (AHD), and 93% received ara-C-based therapy. High TNF-α levels were associated with poor Zubrod PS (cor= .28); high levels of β₂ microglobulin (cor=.50), creatinine (cor=.35), uric acid (p=.35), or LDH (p=.32); low albumin levels (cor=−.22); and longer duration of AHD (cor=.74) (p<.0001 for all variables). High TNF-α levels were more common in patients with AML (vs. MDS, p=.026) and M4-M5 subtypes according to the French-American-British classification (p=.02). The median follow-up of surviving patients was 5.6 years. Clinical outcomes by TNF-α are shown in the Table:

In multivariate analysis, independent factors predicting response to therapy were younger age (p=.03), shorter duration of AHD (p=.007), higher hemoglobin levels (p=.04), lower TNF-α levels (p=.038), and better PS (p=.02). Factors independently prognostic of longer survival were younger age (p=.0008), better-risk cytogenetics (p=.049), lower TNF-α levels (p=.049), lower leukocyte counts (p=.003), higher hemoglobin levels (p=.03), lower β₂-microglobulin levels (p=.03), female gender (p=.02), no history of chemotherapy or radiotherapy (p=.02), and race other than African American (p=.02). Factors independently prognostic of longer event-free survival (EFS) were better-risk cytogenetics (p=.002), lower β₂-microglobulin levels (p=.008), lower leukocyte counts (p=.03), and younger age (p=.04).

Conclusions: These data indicate that an elevated serum TNF-α level is associated among others with poorer Zubrod PS and higher levels of β₂ microglobulin and it is an independent adverse prognostic factor for response and survival in the context of established prognostic factors for AML.