Originally published as JCO Early Release 10.1200/JCO.2005.04.6789 on April 10 2006

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Bortezomib Therapy in Patients With Relapsed or Refractory Lymphoma: Potential Correlation of In Vitro Sensitivity and Tumor Necrosis Factor Alpha Response With Clinical Activity

Sandra J. Strauss, Lenushka Maharaj, Susan Hoare, Peter W. Johnson, John A. Radford, Sarah Vinnecombe, Lynda Millard, Ama Rohatiner, Anthony Boral, Elizabeth Trehu, David Schenkein, Frances Balkwill, Simon P. Joel, T. Andrew Lister

From the Cancer Research UK Medical Oncology Unit, St Bartholomew's Hospital; Cancer Research UK Translational Oncology Laboratory, Barts and The London, Queen Mary's Medical School, London; Cancer Research UK Clinical Centre, Southampton General Hospital, Southampton; Cancer Research UK Department of Medical Oncology, Christie Hospital, Manchester, United Kingdom; and Millennium Pharmaceuticals Inc, Cambridge, MA.

Address reprint requests to T. Andrew Lister, MD, FRCP, FRCPath, Cancer Research UK Medical Oncology Unit, St Bartholomew's Hospital, W Smithfield, London, EC1A 7BE, United Kingdom; e-mail: andrew.lister{at}cancer.org.uk

PURPOSE: To determine the efficacy of bortezomib in patients with lymphoid malignancy, correlating clinical response with effect on plasma cytokines and in vitro activity in primary cultures.

PATIENTS AND METHODS: Patients received bortezomib (1.3 mg/m²) on days 1, 4, 8, and 11 of a 3-week cycle. Plasma tumor necrosis factor alpha (TNF-) and interleukin-6 were measured before each treatment, and bortezomib activity was examined in patient samples grown in primary culture.

RESULTS: Fifty-one patients received a total of 193 cycles of treatment. Twenty-four patients had mantle cell lymphoma (MCL), 13 had follicular lymphoma (FL), six had lymphoplasmacytic lymphoma, six had Hodgkin's disease (HD), and one each had diffuse large B-cell lymphoma and adult T-cell leukemia/lymphoma. Patients were heavily pretreated with a median of four previous therapies. Significant grade 3 to 4 toxicities were thrombocytopenia (n = 22), fatigue (n = 10), and peripheral neuropathy (n = 3). Seven patients with MCL responded to treatment (one complete response, six partial responses [PRs]; overall response rate, 29%). Two patients with FL achieved a late PR 3 months after discontinuing therapy. Two patients with Waldenström's macroglobulinemia and one patient with HD achieved a PR. MCL primary cultures demonstrated greater sensitivity to bortezomib than FL (median 50% effective concentration for viability, 209 nmol/L v 1,311 nmol/L, respectively; P = .07), which correlated with clinical response. A median reduction in plasma TNF- of 98% was observed in six patients with MCL who responded to bortezomib compared with a reduction of 38% in six nonresponders (P = .07).

CONCLUSION: Bortezomib demonstrates encouraging efficacy in MCL in heavily pretreated individuals. Response was associated with a reduction in plasma TNF- and in vitro sensitivity in a small number of patients.

Supported by Cancer Research UK and Millennium Pharmaceuticals Inc, Cambridge, MA.

Presented in part at the 46th Annual Meeting of the American Society of Hematology, San Diego, CA, December 3-7, 2004; and 9th International Conference on Malignant Lymphoma, Lugano, Switzerland, June 8-11, 2005.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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