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Promising activity of the proteasome inhibitor bortezomib in the treatment of indolent Non-Hodgkins lymphoma and mantle cell lymphoma


Promising activity of the proteasome inhibitor bortezomib in the treatment of indolent Non-Hodgkins lymphoma and mantle cell lymphoma



Blood 102(11): 636a



ISSN/ISBN: 0006-4971

The ubiquitin proteasome pathway plays an essential role in the degradation of most intracellular proteins in eukaryotic cells. At the heart of this degradative pathway is the 26S proteasome, an ATP dependent, multicatalytic protease. The 26S proteasome plays a vital role is degrading regulatory proteins that govern cell cycle, transcription factor activation, apoptosis and cell trafficking. Some of the targets of ubiquitin proteasome mediated degradation include p53, p21, NF-kB, IkB and bcl-2. Phase I trials have confirmed tolerability of the drug and provided important pharmacodynamic data regarding the degree of proteasome inhibition as a function of dose. To date, we have administered over 77 cycles of bortezomib (average 2.5 per patient) to 21 previously treated patients with relapsed or refractory indolent lymphomas (small lymphocytic lymphoma-CLL type (n=3); follicular lymphoma (n=9). mantle cell lymphoma (n=8), and one patient with nodeal marginal zone lymphoma. All patients were required to sign and informed consent and had to have adequate hepatic and renal function. Adequate hematologic counts including an ANC of >1000 cells/ml and a platelet count >100,000/ml were also required. All patients had received some form of treatment prior to receiving bortezomib, including: CHOP; CVP; cyclophosphamide/fludarabine; rituximab (n=5); radioimmunotherapy, interferon, and one patient who had received two regimens of a complex combination chemotherapy program that included alkylating agents, tubulin inhibitors, anthracyclines and antimetabolites. Patients were treated at a dose of 1.5 mg/m2 twice weekly for two consecutive weeks with a one week rest period. No Grade III or IV toxicities were observed, save one patient who developed a grade 3 sensory and motor neutopathy. Re-staging studies were routinely performed after two complete cycles of therapy. All patients with small lymphocytic lymphoma were found to have stable disease after 2 and 4 cycles respectively. Six of the 8 evaluable patients with follicular lymphoma achieved a major response, with one patient obtaining a durable complete remission. The one patient with marginal zone lymphoma achieved a PR after 2 cycles of therapy. Major responses were also seen in three patients with refractory mantle cell lymphoma. One of these patients, who experienced a 7 month duration of remission from his preceding CHOP/rituximab, achieved a durable PR lasting 17 months following 4 cycles of bortezomib. Per protocol, he is presently being re-treated, and to date has achieved a 30% reduction in his disease. He continues on active treatment. These data continue to support the biological activity of bortezomib in patients with indolent lymphomas, and suggests that analysis of this drugs activity may well be very sub-type dependent.

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Accession: 035570449

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