A phase 1 dose escalation study of bortezomib combined with rituximab, cyclophosphamide, doxorubicin, modified vincristine, and prednisone for untreated follicular lymphoma and other low-grade B-cell lymphomas

Authors

  • Rajni Sinha MD, MRCP,

    1. Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University-School of Medicine, Atlanta, Georgia
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  • Jonathan L. Kaufman MD,

    1. Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University-School of Medicine, Atlanta, Georgia
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  • Hanna Jean Khoury Jr. MD,

    1. Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University-School of Medicine, Atlanta, Georgia
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  • Nassoma King PA,

    1. Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University-School of Medicine, Atlanta, Georgia
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  • Pareen J. Shenoy MBBS, MPH,

    1. Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University-School of Medicine, Atlanta, Georgia
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  • Carol Lewis MHA,

    1. Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University-School of Medicine, Atlanta, Georgia
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  • Kevin Bumpers MPA,

    1. Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University-School of Medicine, Atlanta, Georgia
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  • Amanda Hutchison-Rzepka BA,

    1. Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University-School of Medicine, Atlanta, Georgia
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  • Mourad Tighiouart PhD,

    1. Department of Biostatistics and Bioinformatics, Winship Cancer Institute, Emory University-School of Medicine, Atlanta, Georgia
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  • Leonard T. Heffner MD,

    1. Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University-School of Medicine, Atlanta, Georgia
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  • Mary Jo Lechowicz MD,

    1. Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University-School of Medicine, Atlanta, Georgia
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  • Sagar Lonial MD,

    1. Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University-School of Medicine, Atlanta, Georgia
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  • Christopher R. Flowers MD, MS

    Corresponding author
    1. Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University-School of Medicine, Atlanta, Georgia
    • Winship Cancer Institute, Emory University, 1365 Clifton Road, N.E., Building B, Suite 4302, Atlanta, GA 30322

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    • Fax: (404) 778-3366


  • S. Lonial, R. Sinha, J. L. Kaufman, H. J. Khoury, Jr., M. J. Lechowicz, L. T. Heffner, M. Tighiouart, and C. R. Flowers conceived and designed the study; R. Sinha, P. J. Shenoy, C. Lewis, N. King, A. Hutchison-Rzepka, K. Bumpers, M. Tighiouart, and C. R. Flowers were responsible for data collection and assembly; R. Sinha, P. J. Shenoy, A. Hutchinson-Rzepka, K. Bumpers, J. L. Kaufman, H. J. Khoury, Jr., S. Lonial, M. J. Lechowicz, L. T. Heffner, M. Tighiouart, and C. R. Flowers were responsible for data analysis and interpretation; and R. Sinha, P. J. Shenoy, J. L. Kaufman, H. J. Khoury, Jr., M. J. Lechowicz, M. Tighiouart, and C. R. Flowers wrote the article.

Abstract

BACKGROUND:

Bortezomib has demonstrated efficacy in patients with relapsed B-cell non-Hodgkin lymphoma (NHL) both alone and in combination with other agents; however, limited data exist regarding its toxicity in combination with common frontline therapies for indolent NHL. A phase 1 study of bortezomib combined with rituximab, cyclophosphamide, doxorubicin, modified vincristine, and prednisone (R-CHOP) was conducted in patients with untreated follicular lymphoma (FL) and other indolent NHLs.

METHODS:

Nineteen patients, including 10 patients with FL, were enrolled. The median patient age was 59 years (range, 29-71 years). Seven patients had a FL International Prognostic Index score ≥3. R-CHOP with the vincristine dose capped at 1.5 mg was administered on a 21-day cycle for 6 to 8 cycles, and 1 of 3 dose levels of bortezomib (1.0 mg/m2 [n = 1], 1.3 mg/m2 [n = 6], or 1.6 mg/m2 [n = 12]) was administered on days 1 and 8 of each cycle using a Bayesian algorithm for dose escalation.

RESULTS:

The maximum tolerated dose (MTD) of bortezomib with modified R-CHOP was reached at 1.6 mg/m2. Dose-limiting toxicity was observed in 5 patients (1 patient at a bortezomib dose of 1.0 mg/m2, 1 patient at a bortezomib dose of 1.3 mg/m2, and 3 patients at a bortezomib dose of 1.6 mg/m2). Neuropathy occurred in 16 patients (84%), including 2 patients (11%) who experienced grade 3 sensory neuropathy. Grade 4 hematologic toxicity occurred in 4 patients. Of 19 evaluable patients, 100% responded, and the complete response rate was 68%. At a median follow-up of 32 months, the 3-year progression-free survival rate was 89.5%.

CONCLUSIONS:

Bortezomib combined with modified R-CHOP produced high response rates without substantial increases in toxicity. A phase 2 study of R-CHOP and bortezomib given at this established MTD is currently ongoing. Cancer 2012;3538–3548. © 2012 American Cancer Society.

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