Phase I/II study of single-agent bortezomib for the treatment of patients with myelofibrosis. Clinical and biological effects of proteasome inhibition.

A phase I/II trial was undertaken to determine maximum tolerated dose (MID), toxicity, clinical efficacy, and biological activity of bortezomib in patients with advanced stage primary or postpolycythemia vera/postessential thrombocythemia myelofibrosis (MF). Bortezomib (0.8, 1.0, or 1.3 mg/m(2)) was administered on days 1, 4, 8, and 11 by intravenous push to patients previously resistant to at least one line of therapy, or with an intermediate/high-risk score of International Working Group (IWG) [1]. Therapy was repeated every 28 days for six cycles. At 1.3 mg/m(2) dose, one of six patients experienced a dose limiting toxicity, and this was determined to be the MTD. Neither remissions nor clinical improvements were recorded in 16 patients treated at this dose level, fulfilling the early stopping rule in the Simon two-stage study design. Major toxicity was on thrombocytopenia. In 9 of 15 patients bortezomib proved that it is able to reduce bone marrow vessel density. However, the agent was associated with worsening of markers of disease activity, such as enhancement of hematopoietic CD34-positive progenitor cell mobilization, WT-1 gene expression in mononuclear cells, and downregulation of CXCR4 expression on CD34-positive cells. Occurrence of both beneficial and detrimental biological effects claims further investigation on the mechanisms of the drug in MF.