Abstract
Purpose
The Stanford V chemotherapy regimen has been used to treat Hodgkin lymphoma (HL) patients since 2002 with excellent cure rates; however, mechlorethamine is no longer available. Bendamustine, a drug structurally similar to alkylating agents and nitrogen mustard, is being substituted for mechlorethamine in combination therapy in a frontline trial for low- and intermediate-risk pediatric HL patients, forming a new backbone of BEABOVP (bendamustine, etoposide, doxorubicin, bleomycin, vincristine, vinblastine, and prednisone). This study evaluated the pharmacokinetics and tolerability of a 180 mg/m2 dose of bendamustine every 28 days to determine factors that may explain this variability.
Methods
Bendamustine plasma concentrations were measured in 118 samples from 20 pediatric patients with low- and intermediate-risk HL who received a single-day dose of 180 mg/m2 of bendamustine. A pharmacokinetic model was fit to the data using nonlinear mixed-effects modeling.
Results
Bendamustine concentration vs time demonstrated a trend toward decreasing clearance with increasing age (p = 0.074) and age explained 23% of the inter-individual variability in clearance. The median (range) AUC was 12,415 (8,539, 18,642) µg hr/L and the median (range) maximum concentration was 11,708 (8034, 15,741) µg/L. Bendamustine was well tolerated with no grade 3 toxicities resulting in treatment delays of more than 7 days.
Conclusions
A single-day dose of 180 mg/m2 of bendamustine every 28 days was safe and well tolerated in pediatric patients. While age accounted for 23% of inter-individual variability observed in bendamustine clearance, the differences did not affect the safety and tolerability of bendamustine in our patient population.
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Data availability
Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.
References
Metzger ML, Billett A, Link MP (2012) The impact of drug shortages on children with cancer–the example of mechlorethamine. N Engl J Med 367(26):2461–2463
Wang ML et al (2022) Ibrutinib plus bendamustine and rituximab in untreated mantle-cell lymphoma. N Engl J Med 386(26):2482–2494
Sehn LH et al (2022) Polatuzumab vedotin plus bendamustine and rituximab in relapsed/refractory DLBCL: survival update and new extension cohort data. Blood Adv 6(2):533–543
Ghia P et al (2020) ASCEND: phase III, randomized trial of acalabrutinib versus idelalisib plus rituximab or bendamustine plus rituximab in relapsed or refractory chronic lymphocytic leukemia. J Clin Oncol 38(25):2849–2861
Cheson BD, Rummel MJ (2009) Bendamustine: rebirth of an old drug. J Clin Oncol 27(9):1492–1501
Leoni LM (2011) Bendamustine: rescue of an effective antineoplastic agent from the mid-twentieth century. Semin Hematol 48(Suppl 1):S4-11
Korycka-Wolowiec A, Robak T (2012) Pharmacokinetic evaluation and therapeutic activity of bendamustine in B-cell lymphoid malignancies. Expert Opin Drug Metab Toxicol 8(11):1455–1468
Owen JS et al (2010) Bendamustine pharmacokinetic profile and exposure-response relationships in patients with indolent non-Hodgkin’s lymphoma. Cancer Chemother Pharmacol 66(6):1039–1049
Moon Y, E J, Garnett C, et al (2011) Clinical Pharmacology Review Document. https://www.022405orig1s000clinpharmr.pdf (fda.gov)
Jeha S et al (2021) Phase 1 study of bendamustine in combination with clofarabine, etoposide, and dexamethasone in pediatric patients with relapsed or refractory hematologic malignancies. Cancer 127(12):2074–2082
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2008/22249s000_MedR_P1.pdf.
Moskowitz AJ et al (2013) Phase II study of bendamustine in relapsed and refractory Hodgkin lymphoma. J Clin Oncol 31(4):456–460
Metzger M, Stanford V et al (2012) chemotherapy and involved field radiotherapy for children and adolescents with unfavorable risk Hodgkin lymphoma results of a multi-institutional prospective clinical trial. J Clin Oncol 30(15):9502–9502
Rasschaert M et al (2007) A phase I study of bendamustine hydrochloride administered day 1+2 every 3 weeks in patients with solid tumours. Br J Cancer 96(11):1692–1698
Acknowledgements
This study was supported in part by the NIH Cancer Center Support Grant CA21765 and the American Lebanese Syrian Associated Charities (ALSAC). Jamie Flerlage is supported by the Lymphoma Research Foundation. Special thanks to our pharmacokinetic nurses: Sherri Ring, Paula Davies, Katie Duncan, Margaret Edwards, Terri Kuehner, and to Christie Daniels and Lindsay Wilemon for trial and data management.
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Bendamustine was received from TEVA pharmaceuticals in support of this study.
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Purvis, K.N., Swanson, H.D., Niloy, K.K. et al. Pharmacokinetics and safety of bendamustine in the BEABOVP regimen for the treatment of pediatric patients with Hodgkin lymphoma. Cancer Chemother Pharmacol 92, 1–6 (2023). https://doi.org/10.1007/s00280-023-04540-9
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DOI: https://doi.org/10.1007/s00280-023-04540-9