Phase II clinical experience with the proteasome inhibitor bortezomib (formerly PS-341) in patients with indolent lymphomas.
Last Modified: June 1, 2003
Presenter: Owen A. O'Connor
Presenter's Affiliation: Memorial Sloan Kettering Cancer Center
Type of Session: Scientific
- The ubiquitin proteasome pathway plays an essential role in the degradation of most intracellular proteins in eukaryotic cells.
- The 26S proteasome, a multicatalytic protease, degrades regulatory proteins involved in cell cycle control including p53, p21, NF-kB, IkB, and bcl-2.
- Preclinical data have confirmed that inhibitors of the proteasome act through multiple mechanisms to arrest tumor growth.
- Phase I studies have confirmed the tolerability of the drug
- This is a phase II single agent single institution study of 1.5 mg/m2 of Bortezomib given by i.v. push twice weekly for two weeks followed by one week of rest.
- There were 19 patients treated: 47% with follicular lymphoma; 37% with Mantle Cell Lymphoma; 11% with SLL; 5% with Marginal Zone Lymphoma
- The median age was 63. The population was essentially all white (17/19). 58% were male and the average KPS was 90%.
- 63% of patients previously had at least one course of Rituxan therapy, 22% had had at least 2 courses of Rituxan.
- 93% of patients had prior alkylator based therapy.
- The overall response rate was 53% (8/15); -Of the follicular lymphoma patients, there was 1 CR and 5 PR. -Of the mantle cell lymphoma patients there were 2 PR and 5 SD. -Both patients with SLL have SD.
- Main Hematologci Toxicity was thrombocytopenia with 14% grade 3, 43% grade 2 and 43% grade 1.
- Main non-hematologic toxicity was neuropathy with 7% each grade 3 and 4 sensory neuropathy and 7% grade 3 motor neuropathy.
- There was a 14% incidnece of small vessel necrotizing vasculitis
- 36% suffered from grade 3 lymphopenia.
- 26% of patients missed a dose due to thrombocytopenia
- 44% required one dose reduction and 22% required two dose level reductions, all due to thrombocytopenia.
- These data support the biological activity of PS-341 in patients with low-grade lymphomas.
- Future directions will include an expanded multicenter trial as well as individual trials of specific subtypes of lymphoma to better define the activity in specifc histologic types.
- In future studies, the authors have also recommended decreasing the minimum platelet count to 30K for those patients without bone marrow involvement and 25K for those with bone marrow involvement.
- Bortezomib has recently been approved by the FDA for use in multiple myeloma. Now with this exciting early data, it may indeed find a place in the care of lymphomas.
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