Rapamycin Has Biological Activity in a Subset of Patients with Myelodysplastic Syndrome - Results of a Phase I/II Trial.

The pathophysiology of myelodysplastic syndrome (MDS) involves disturbed regulation of angiogenesis, apoptosis, proliferation and differentiation as well as immune surveillance. There is increasing evidence that rapamycin (sirolimus) might affect these pathways positively thus possibly being of therapeutic benefit in patients with this disease. These data prompted us to perform a phase I/II study to evaluate the safety and efficacy of rapamycin in the treatment of patients with MDS. Nineteen patients (median age 72 years) diagnosed with MDS according to the WHO classification received rapamycin orally with a target blood concentration of 3–12 ng/ml. Rapamycin was administered for a median of 3.7 months (range 0.3–11). Three patients (1 x RAEB-2, 1 x RAEB-1, 1 x RCMD) showed either a major (1 x platelet, 1 x neutrophil) or a minor (1 x erythroid, 2 x platelet) hematological response according to the IWG criteria. There was no statistically significant difference in the rapamycin plasma levels between the three responders (median plasma level 3.62, range 1.63–4.39) and non-responders (median plasma level 4.22, range 2.81–7.4). Major side effects were hyperlipidemia (n=4), stomatitis (n=3), thrombocytopenia (n=2) and urinary tract infection (n=1). Study medication had to be stopped due to side effects in five patients (26 %), one of them being a responder to rapamycin. Plasma levels of rapamycin were not elevated in patients experiencing toxicity.

Taken together these data demonstrate that rapamycin might have biological activity in patients with rather advanced MDS. New and possibly less toxic analogues of rapamycin are currently developed. They could be candidates for future trials in patients with MDS.