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Effect of bendamustine in combination with rituximab on QT interval duration in patients with advanced de novo indolent non-Hodgkin or mantle cell lymphoma

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Abstract

Purpose

Bendamustine is used in chronic lymphocytic leukemia (first-line) and indolent B-cell non-Hodgkin lymphoma (NHL) that progressed during/within 6 months of treatment with rituximab or a rituximab-containing regimen. This study was a postapproval commitment to investigate bendamustine’s effect on cardiac repolarization in treatment-naïve adults with advanced indolent NHL/mantle cell lymphoma (MCL).

Methods

In this multicenter, open-label, phase 3 study, patients received 6–8 28-day cycles of bendamustine (90 mg/m2, days 1 and 2) and rituximab (375 mg/m2, day 1). Exclusions included a history of cardiac conditions with potential for QT prolongation. The primary endpoint was change in Fridericia-corrected QT (QTcF; 3 electrocardiograms per time point) on day 2 of cycle 1, from just before infusion to end of infusion (immediately postinfusion, coinciding with maximum plasma concentration of bendamustine). Change 1 h postinfusion was also measured. Exploratory assessments included specific QTcF outlier analyses (new QTcF >500 ms, change >60 ms) and morphological changes.

Results

Of the 54 enrolled patients (mean age, 62.9 years), 53 received ≥1 dose; 49 completed ≥6 cycles. Mean QTcF change from baseline was 6.7 ms at end of infusion; no mean changes >20 ms were detected ≤1 h postinfusion. No patients met specific outlier criteria at end of infusion or 1 h postinfusion. No morphological changes were detected.

Conclusions

In this small treatment-naïve population with advanced NHL/MCL, bendamustine did not produce a clinically relevant increase in mean QTcF on the second infusion day. The potential for delayed effects on QT interval after 1 h was not evaluated.

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Acknowledgments

This research was sponsored and conducted by Teva Branded Pharmaceutical Products R&D, Inc., Frazer, PA.

Conflict of interest

John M. Burke has served as a consultant or on the scientific advisory board of Seattle Genetics, Dr. Reddy’s Laboratories, Incyte, Millenium, and Janssen; and conducted clinical research projects funded, in whole or in part, by Genentech. Richard H. C. van der Jagt has served as a consultant or on the scientific advisory board of Lundbeck and Teva; received honoraria from Roche, Celgene, and Novartis; and conducted clinical research projects funded, in whole or in part, by Lundbeck, Roche, Teva, Celgene, and CTI. Ian W. Finn has conducted clinical research projects funded, in whole or in part, by Teva. Joel Morganroth has served as a consultant or on the scientific advisory board of ERT, and has stock ownership in ERT. Mihaela C. Munteanu and Ling Chen are employees of and have stock ownership in Teva. David MacDonald has served as a consultant or on the scientific advisory board of Lundbeck Canada and Roche. Michael D. Craig declares that he has no conflict of interest.

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Authors and Affiliations

  1. Rocky Mountain Cancer Centers, 1700 S. Potomac Street, Aurora, CO, 80012, USA

    John M. Burke

  2. US Oncology Research, 10101 Woodloch Forest Drive, The Woodlands, TX, 77380, USA

    John M. Burke

  3. The Ottawa Hospital, University of Ottawa, L2251B, General Campus, 501 Smyth Road, Ottawa, ON, K1H 8L6, Canada

    Richard H. C. van der Jagt

  4. Sarah Cannon Research Institute, 3322 West End Avenue, Suite 900, Nashville, TN, 37203, USA

    Ian W. Flinn

  5. Osborn Hematopoietic Malignancy and Transplant Program, West Virginia University, 1 Medical Center Drive, Morgantown, WV, 26506, USA

    Michael D. Craig

  6. Teva Branded Pharmaceutical Products R&D, Inc., 41 Moores Road, Frazer, PA, 19355, USA

    Ling Chen & Mihaela C. Munteanu

  7. ERT, 1818 Market St. Suite 1000, Philadelphia, PA, 19103, USA

    Joel Morganroth

  8. Queen Elizabeth II Health Sciences Center, Dalhousie University, 1276 South Park Street, Bethune Building Room 422, Halifax, NS, B3H2Y9, Canada

    David A. MacDonald

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  1. John M. Burke
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  2. Richard H. C. van der Jagt
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  3. Ian W. Flinn
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  4. Michael D. Craig
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  5. Ling Chen
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  7. Mihaela C. Munteanu
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  8. David A. MacDonald
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Correspondence to John M. Burke.

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Burke, J.M., van der Jagt, R.H.C., Flinn, I.W. et al. Effect of bendamustine in combination with rituximab on QT interval duration in patients with advanced de novo indolent non-Hodgkin or mantle cell lymphoma. Cancer Chemother Pharmacol 76, 211–216 (2015). https://doi.org/10.1007/s00280-015-2776-x

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  • DOI: https://doi.org/10.1007/s00280-015-2776-x

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