Abstract
Pixantrone (Pixuvri®) is an aza-anthracenedione with a novel mode of action that is conditionally approved in the EU for use as monotherapy in adult patients with multiply relapsed or refractory aggressive B-cell non-Hodgkin’s lymphoma (NHL). In the randomized, open-label, multinational, phase 3 PIX301 trial in patients with multiply relapsed or refractory aggressive NHL, the complete response (CR) plus unconfirmed CR (uCR) rate at the end of treatment (primary endpoint) was significantly higher with intravenous pixantrone monotherapy than with a single-agent comparator (vinorelbine, oxaliplatin, ifosfamide, etoposide, mitoxantrone or gemcitabine). Post hoc analysis also demonstrated a significantly higher CR/uCR rate in the subgroup of patients with centrally confirmed aggressive B-cell NHL who were receiving pixantrone versus a comparator agent as third- or fourth-line therapy. Pixantrone was generally well tolerated in PIX301, with a manageable adverse event profile. In conclusion, pixantrone is a useful option in patients with multiply relapsed or refractory aggressive B-cell NHL. Further results examining the use of pixantrone in combination with rituximab in patients previously treated with rituximab-containing regimens are awaited with interest.
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References
Ghielmini M, Vitolo U, Kimby E, et al. ESMO Guidelines consensus conference on malignant lymphoma 2011 part 1: diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL) and chronic lymphocytic leukemia (CLL). Ann Oncol. 2013;24(3):561–76.
Belada D, Georgiev P, Dakhil S, et al. Pixantrone-rituximab versus gemcitabine-rituximab in relapsed/refractory aggressive non-Hodgkin lymphoma. Future Oncol. 2016;12(15):1759–68.
Fanous I, Dillon P. Cancer treatment-related cardiac toxicity: prevention, assessment and management. Med Oncol. 2016;33(8):84.
Zinzani PL, Corradini P, Martelli M, et al. Critical concepts, practice recommendations and research perspectives of pixantrone therapy in non-Hodgkin lymphoma: a SIE, SIES. GITMO consensus paper. Eur J Haematol. 2016. doi:10.1111/ejh.12768.
Volpetti S, Zaja F, Fanin R. Pixantrone for the treatment of adult patients with relapsed or refractory aggressive non-Hodgkin B-cell lymphomas. Onco Targets Ther. 2014;7:865–72.
European Medicines Agency. Pixuvri (pixantrone): EU summary of product characteristics. 2016. http://www.ema.europa.eu/. Accessed 10 Oct 2016.
Pettengell R, Kaur J. Pixantrone dimaleate for treating non-Hodgkin’s lymphoma. Exp Opin Orphan Drugs. 2015;3(6):747–57.
Menna P, Salvatorelli E, Minotti G. Rethinking drugs from chemistry to therapeutic opportunities: pixantrone beyond anthracyclines. Chem Res Toxicol. 2016;29(8):1270–8.
Salvatorelli E, Menna P, Paz OG, et al. The novel anthracenedione, pixantrone, lacks redox activity and inhibits doxorubicinol formation in human myocardium: insight to explain the cardiac safety of pixantrone in doxorubicin-treated patients. J Pharmacol Exp Ther. 2013;344(2):467–78.
Evison BJ, Mansour OC, Menta E, et al. Pixantrone can be activated by formaldehyde to generate a potent DNA adduct forming agent. Nucl Acids Res. 2007;35(11):3581–9.
Hasinoff BB, Wu X, Patel D, et al. Mechanisms of action and reduced cardiotoxicity of pixantrone; a topoisomerase II targeting agent with cellular selectivity for the topoisomerase IIα isoform. J Pharmacol Exp Ther. 2016;356(2):397–409.
Beeharry N, Di Rora AGL, Smith MR, et al. Pixantrone induces cell death through mitotic perturbations and subsequent aberrant cell divisions. Cancer Biol Ther. 2015;16(9):1397–406.
Beggiolin G, Crippa L, Menta E, et al. BBR 2778, an aza-anthracenedione endowed with preclinical anticancer activity and lack of delayed cardiotoxicity. Tumori. 2001;87(6):407–16.
Cavalletti E, Crippa L, Mainardi P, et al. Pixantrone (BBR 2778) has reduced cardiotoxic potential in mice pretreated with doxorubicin: comparative studies against doxorubicin and mitoxantrone. Invest New Drugs. 2007;25(3):187–95.
Longo M, Della Torre P, Allievi C, et al. Tolerability and toxicological profile of pixantrone (Pixuvri®) in juvenile mice: comparative study with doxorubicin. Reprod Toxicol. 2014;46:20–30.
Faivre S, Raymond E, Boige V, et al. A phase I and pharmacokinetic study of the novel aza-anthracenedione compound BBR 2778 in patients with advanced solid malignancies. Clin Cancer Res. 2001;7(1):43–50.
Borchmann P, Schnell R, Knippertz R, et al. Phase I study of BBR 2778, a new aza-anthracenedione, in advanced or refractory non-Hodgkin’s lymphoma. Ann Oncol. 2001;12(5):661–7.
Lim S-T, Fayad L, Tulpule A, et al. A phase I/II trial of pixantrone (BBR2778), methylprednisolone, cisplatin, and cytosine arabinoside (PSHAP) in relapsed/refractory aggressive non-Hodgkin’s lymphoma. Leuk Lymphoma. 2007;48(2):374–80.
Dawson LK, Jodrell DI, Bowman A, et al. A clinical phase I and pharmacokinetic study of BBR 2778, a novel anthracenedione analogue, administered intravenously, 3 weekly. Eur J Cancer. 2000;36(18):2353–9.
Borchmann P, Morschhauser F, Parry A, et al. Phase-II study of the new aza-anthracenedione, BBR 2778, in patients with relapsed aggressive non-Hodgkin’s lymphomas. Haematologica. 2003;88(8):888–94.
Pettengell R, Coiffier B, Narayanan G, et al. Pixantrone dimaleate versus other chemotherapeutic agents as a single-agent salvage treatment in patients with relapsed or refractory aggressive non-Hodgkin lymphoma: a phase 3, multicentre, open-label, randomised trial. Lancet Oncol. 2012;13(7):696–706.
Cheson BD, Horning SJ, Coiffier B, et al. Report of an international workshop to standardize response criteria for non-Hodgkin’s lymphomas. NCI Sponsored International Working Group. J Clin Oncol. 1999;17(4):1244.
Pettengell R, Sebban C, Zinzani PL, et al. Monotherapy with pixantrone in histologically confirmed relapsed or refractory aggressive B-cell non-Hodgkin lymphoma: post-hoc analyses from a phase III trial. Br J Haematol. 2016;174(5):692–9.
European Medicines Agency. Pixuvri (pixantrone): CHMP assessment report. 2012. http://www.ema.europa.eu/. Accessed 10 Oct 2016.
National Institute for Health and Care Excellence. Pixantrone monotherapy for treating multiply relapsed or refractory aggressive non-Hodgkin’s B-cell lymphoma. 2014. https://www.nice.org.uk/Guidance/TA306. Accessed 10 Oct 2016.
Péan E, Flores B, Hudson I, et al. The European Medicines Agency review of pixantrone for the treatment of adult patients with multiply relapsed or refractory aggressive non-Hodgkin’s B-cell lymphomas: summary of the scientific assessment of the committee for medicinal products for human use. Oncologist. 2013;18(5):625–33.
Gisselbrecht C, Glass B, Mounier N, et al. Salvage regimens with autologous transplantation for relapsed large B-cell lymphoma in the rituximab era. J Clin Oncol. 2010;28(27):4184–90.
Beaven AW, Rizzieri D. Clinical evidence for the role of pixantrone in the treatment of relapsed or refractory aggressive non-Hodgkin’s lymphoma. Clin Invest. 2012;2(1):49–58.
Eyre TA, Linton KM, Rohman P, et al. Results of a multicentre UK-wide retrospective study evaluating the efficacy of pixantrone in relapsed, refractory diffuse large B cell lymphoma. Br J Haematol. 2016;173(6):896–904.
Muszbek N, Kadambi A, Lanitis T, et al. The cost-effectiveness of pixantrone for third/fourth-line treatment of aggressive non-Hodgkin’s lymphoma. Clin Ther. 2016;38(3):503–15.
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During the peer review process, the manufacturer of pixantrone was also offered an opportunity to review this article. Changes resulting from comments received were made on the basis of scientific and editorial merit.
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The preparation of this review was not supported by any external funding.
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Gillian Keating is a salaried employee of Adis/Springer, is responsible for the article content and declares no relevant conflicts of interest.
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The manuscript was reviewed by: C. Gisselbrecht, Institut d’Hématologie Hopital Saint Louis, Paris, France; R. Herbrecht, Department of Oncology and Hematology, Hôpital de Hautepierre and Université de Strasbourg, Strasbourg, France; P.L. Zinzani, Institute of Hematology “Seragnoli”, University of Bologna, Bologna, Italy.
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Keating, G.M. Pixantrone: A Review in Relapsed or Refractory Aggressive Non-Hodgkin’s Lymphoma. Drugs 76, 1579–1586 (2016). https://doi.org/10.1007/s40265-016-0650-8
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DOI: https://doi.org/10.1007/s40265-016-0650-8