Laboratory observations suggest that, in some
myelodysplastic syndromes (MDS), immune mechanisms may contribute to the impaired blood cell production.
Tumor necrosis factor alpha (
TNF-alpha), a potent inhibitor of haematopoiesis, has been hypothesized to mediate suppressive effects in MDS:
TNF-alpha levels are elevated and correlated with marrow apoptosis and
cytopenia. Inhibition of
TNF-alpha 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-alpha production by marrow cells in MDS;
TNF-alpha production was elevated (> mean + 2 x 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 x 10(9)/l to 0.84 x 10(9)/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-alpha levels. Although anti-TNF
therapy with
Enbrel was well tolerated at the dosages used in MDS, its efficacy as a single agent appears low.