Abstract
Introduction: The 26S proteasome is an important regulator of proteins involved in cell cycle progression, cell survival, and transcription of anti-apoptotic proteins via activation of NF-κB. Bortezomib, (VELCADE®) is a potent, selective, reversible inhibitor of the 26S proteasome with demonstrated clinical activity in multiple myeloma for which it gained FDA and EMEA approval. On the basis of encouraging phase I data in lymphoma, a phase II clinical study was undertaken to examine the efficacy and toxicity of bortezomib in pts with relapsed, refractory NHL and HD.
Methods: 1.3 mg/m2 bortezomib was administered twice weekly for 2 of 3 weeks to pts who had adequate ECOG performance status (PS) >2, and haematological function with an absolute neutrophil count >1.0 x109/l (0.5 x109/l if bone marrow involvement) and platelets >30 x109/l. Pts were assessed for toxicity at each cycle, re-staged after 4 cycles and received up to 8 cycles of treatment.
Results: 32pts, 20 male and 12 female with a median age of 58 yrs (35–75) received a total of 119 cycles of treatment. 11 pts had mantle cell lymphoma (MCL), 10 follicular lymphoma (FL), 4 Waldenstrom’s macroglobulinaemia (WM), and 1 lymphoplasmacytic lymphoma. Other diagnoses included HD (n=3), diffuse large B-cell lymphoma (n=1), ATL (n=1), and diffuse follicle centre lymphoma (n=1). Pts were heavily pre-treated with a median of 3.5 previous therapies (range 1–8) and 12 pts (38%) had received prior HDT. Sixteen pts (50%) had bone marrow involvement and 13 (40%) a raised LDH. 13 pts (40%) had a ECOG PS of 1 and 7 pts (22%) a PS of 2. The most common grade III-IV toxicities observed in patients, who received a median of 4 cycles of treatment (range 1–8), were thrombocytopenia in 14 pts (45%); fatigue in 8 pts (26%), anaemia in 5 pts (16%) and peripheral neuropathy in 2 pts (6%). Four of 11 pts with MCL initially responded to treatment, 3PR, 1 CR (ORR of 36%); one pt progressed at the end of 8 cycles having required 2 dose reductions. No patients with FL had an objective response at the outcome assessment after a median of 4 cycles (range 1–8) and within a month of completing therapy; however 4 had stable disease and 2 achieved a ‘late response’ with reduction in tumour volumes of 76.7% and 56.1% when assessed 3 mths later. Two pts with WM achieved a PR on the basis of >50% reduction in paraprotein, but with no change in the bone marrow. No patients with HD or other diagnoses responded to treatment. The sensitivity of tumour biopsy samples to bortezomib was examined in vitro in a CD40 ligand primary culture system in 5 pts on the clinical trial, where sensitivity correlated with clinical response. In a larger group of patients the median EC50 for MCL (n=5) was 209nM, and FL (n=8) 1311nM (p<0.05).
Conclusion: The first European report of bortezomib in pts with relapsed/refractory NHL/HD demonstrates encouraging efficacy in MCL, evidence of activity in WM, and a suggestion of ‘late responses’ in FL. Clinical activity correlated with in vitro sensitivity to bortezomib and continues to be assessed as a potential predictor for response to treatment.
Lycopene inhibits DNA synthesis in primary prostate epithelial cells in vitro and its administration is associated with a reduced prostate-specific antigen velocity in a phase II clinical study
