Myelofibrosis (MF) is the most serious myeloproliferative disorder, characterized by clonal myeloproliferation associated with cytokine-mediated bone marrow stromal reaction including fibrosis and osteosclerosis. Because the NF-κB pathway is implicated in the abnormal release of cytokines in MF, the proteasome inhibitor bortezomib might be a potential therapy. We conducted a phase 1 trial of intravenously administered bortezomib (Velcade®) in 12 adults with advanced primary MF (11 patients) or post-PV/post-ET MF (1 patient). Eligibility was defined as refractory or not suitable to first line chemotherapy. Median age was 57 years (range, 22 to 69 years). Three cohorts of patients were treated with bortezomib at day 1, 4, 8, and 11 from 0.8 to 1.3 mg/m2, every 21 days x 6 cycles. Three patients received less than 5 cycles and are not considered evaluable for response (cutaneous vasculitis, respiratory distress syndrome and peripheral neuropathy). Dose-limiting toxicity (DLT) occurred in 1 patient treated with bortezomib in the 1.3 mg/m2 cohort, consisting on respiratory distress syndrome. The patient was hospitalised and improved with corticosteroid therapy. The maximum-tolerated dose was 1.3 mg/m2 for 4 days every 3 weeks. Other frequent non-DLTs were thrombocytopenia (2/12), fatigue (3/12), oedema (1/12), cutaneous rash (2/12). No complete, major or moderate responses according EUMNET response criteria were documented. One minor response was documented due to complete response in platelet count (platelet count 150–400 x 109/L at the end of the sixth cycle of therapy). Our results show that bortezomib in MF is clinically tolerable at the 1.3 mg/m2 every 21 days x 6 cycles. The efficacy of the drug is under examination in a phase II study.

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Disclosure: Research Funding: Research funding by Janssen Cilag.