Phase II clinical experience with the proteasome inhibitor bortezomib (formerly PS-341) in patients with indolent lymphomas.

Reviewer: Tracy d'Entremont, MD
OncoLink
Last Modified: June 1, 2003

Presenter: Owen A. O'Connor
Presenter's Affiliation: Memorial Sloan Kettering Cancer Center
Type of Session: Scientific

Background

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

Materials and Methods

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.

Results

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.

Author's Conclusions

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.

Clinical/Scientific Implications

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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