A pilot study of the recombinant soluble human tumour necrosis factor receptor (p75)‐Fc fusion protein in patients with myelodysplastic syndrome

Abstract

Summary. Laboratory observations suggest that, in some myelodysplastic syndromes (MDS), immune mechanisms may contribute to the impaired blood cell production. Tumor necrosis factor α (TNF‐α), a potent inhibitor of haematopoiesis, has been hypothesized to mediate suppressive effects in MDS: TNF‐α levels are elevated and correlated with marrow apoptosis and cytopenia. Inhibition of TNF‐α production using the soluble TNF receptor (Enbrel) has been successful in rheumatoid arthritis, and we have now applied the same principle to MDS. We determined spontaneous TNF‐α production by marrow cells in MDS; TNF‐α production was elevated (> mean + 2 × SD of controls) in > 1/3 of patients, but did not correlate with clinical parameters. Sixteen patients participated in a 3‐month pilot study of Enbrel. The drug was well tolerated and 15 patients were evaluable. Of these, one became temporarily (14 weeks) transfusion independent. In another patient, absolute neutrophil count (ANC) rose from 0·5 × 109/l to 0·84 × 109/l. Serious infections were seen in two out of six neutropenic patients. Progression to refractory anaemia with excess blasts in transformation (RAEBt) or leukaemia was observed in three patients. When the effects of Enbrel on haematopoietic colony formation were studied, no significant increase was seen in MDS and there was no correlation with TNF‐α levels. Although anti‐TNF therapy with Enbrel was well tolerated at the dosages used in MDS, its efficacy as a single agent appears low.

p38 MAP Kinase Regulates Stem Cell Apoptosis in Human Hematopoietic Failure

“…In fact, anti-TNF therapeutic strategies (monoclonal antibodies and TNF receptor blockers) have only shown minimal clinical efficacy. [9][10][11] Thus it would be important to identify common signaling pathways that would be regulated by many cytokines. Our previous studies have established that Interferons (IFNab and g), TGFb and TNFa can activate members of the MAP (mitogen activated protein kinases) family of kinases, including Erk-kinase and the p38 Map kinase.…”

Induction of Allospecific Tolerance by Immature Dendritic Cells Genetically Modified to Express Soluble TNF Receptor

“…sTNFRs compete with membrane-bound receptors for available TNF-␣, but cannot induce cell signaling, and thus function as specific inhibitors of TNF activity in target tissues (26,27). sTNFRI and sTNFRII have both been effectively used to block TNF-␣-mediated immunostimulation in the treatment of immunological disorders such as rheumatoid arthritis and experimental autoimmune encephalomyelitis (28,29). However, it remains unclear whether blockade of TNF-␣ by sTNFRI can inhibit the maturation of DC and potentiate imDC tolerogenicity.…”

Myelodysplastic Syndromes

“…87 At NIH, only 1 patient of 15 evaluable became temporarily red cell transfusion-independent (as did a patient in an Italian case report); 89 progression to leukemia was seen in 3 cases. 88 In both trials, TNF had inconsistent effects on marrow hematopoietic progenitor cell growth pre-and post-treatment, nor was there correlation with TNF plasma levels.…”

“…In small pilot trials from multiple institutions, the soluble receptor, Enbrel, has been well tolerated, but treatment has produced very modest clinical responses in a minority of patients. [87][88][89] In one study from Seattle and Stanford, among 12 evaluable patients, 4 showed increased hemoglobin levels, and 2 each also had somewhat higher platelet or neutrophil numbers. 87 At NIH, only 1 patient of 15 evaluable became temporarily red cell transfusion-independent (as did a patient in an Italian case report); 89 progression to leukemia was seen in 3 cases.…”