Limited efficacy of pixantrone in refractory diffuse large B-cell lymphoma

Novakovic,Aleksander; Boltezar,Lucka; Novakovic,Barbara  Jezersek

doi:10.3892/ol.2020.11288

Limited efficacy of pixantrone in refractory diffuse large B-cell lymphoma

Authors:
- Aleksander Novakovic
- Lucka Boltezar
- Barbara Jezersek Novakovic
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Affiliations: Medical Faculty, University of Ljubljana, 1000 Ljubljana, Slovenia, Department of Lymphoma Treatment, Division of Medical Oncology, Institute of Oncology Ljubljana, 1000 Ljubljana, Slovenia
Published online on: January 10, 2020 https://doi.org/10.3892/ol.2020.11288
Pages: 2028-2034
Copyright : © Novakovic et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY 4.0].

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Abstract

Relapsed or refractory diffuse large B‑cell lymphoma (DLBCL) is an aggressive disease with poor outcomes in patients ineligible for autologous stem cell transplantation. In this setting, novel treatment approaches are urgently required and the innovative agent pixantrone has shown some promising results in terms of disease‑free and overall survival (OS). The present study retrospectively analyzed 12 patients routinely treated with pixantrone in monotherapy or in combinations at the Institute of Oncology Ljubljana, Slovenia, between January 2016 and October 2018. All 12 patients had refractory lymphoma to last treatment and a large proportion of them had other high risk features (high proliferation index, high disease stage, high international prognostic index (IPI) score, high percentage of primary refractory disease and high percentage of refractoriness to anthracyclines) at initiation of pixantrone. All patients progressed during treatment and none of the patients were alive at the time of analysis due to progressive lymphoma. Pixantrone specific median OS was 3.5 months (range, 0.5‑10 months). A somewhat superior median OS (P=0.065) was observed in patients primarily sensitive to anthracyclines. Pixantrone has shown only limited efficacy in the present real world study comparable to the results of another real world UK retrospective analysis and substantially worse than the efficacy observed in the PIX301 registration trial. Therefore, an appropriate selection of patients for this treatment is crucial. Despite the limited experience due to a small number of patients, it was recommended to consider only patients with relapsed (and not refractory) disease, patients with non‑primary refractory disease and those with fewer lines of prior therapy.

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1	Tilly H, Gomes da Silva M, Vitolo U, Jack A, Meignan M, Lopez-Guillermo A, Walewski J, André M, Johnson PW, Pfreundschuh M, et al: Diffuse large B-cell lymphoma (DLBCL): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 26:v116–v125. 2015. View Article : Google Scholar : PubMed/NCBI
2	Keating GM: Pixantrone: A review in relapsed or refractory aggressive non-Hodgkin's lymphoma. Drugs. 76:1579–1586. 2016. View Article : Google Scholar : PubMed/NCBI
3	Gregoric B, Zadnik V and Jezersek Novakovic B: The diffuse large B-cell lymphoma-where do we stand now in everyday clinical practice. Radiol Oncol. 46:153–159. 2012. View Article : Google Scholar : PubMed/NCBI
4	Horvat M, Zadnik V, Južnič Šetina T, Boltežar L, Pahole Goličnik J, Novaković S and Jezeršek Novaković B: Diffuse large B-cell lymphoma: 10 years' real-world clinical experience with rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisolone. Oncol Lett. 15:3602–3609. 2018.PubMed/NCBI
5	Volpetti S, Zaja F and Fanin R: Pixantrone for the treatment of adult patients with relapsed or refractory aggressive non-Hodgkin B-cell lymphomas. Onco Targets Ther. 7:865–872. 2014. View Article : Google Scholar : PubMed/NCBI
6	Krapcho AP, Maresch MJ, Hacker MP, Menta E, Oliva A, Giuliani FC and Spinelli S: Aza and diaza bioisosteric anthracene-9,10-diones as antitumor agents. Acta Biochim Pol. 42:427–432. 1995.PubMed/NCBI
7	Singal PK and Iliskovic N: Doxorubicin-induced cardiomyopathy. N Engl J Med. 339:900–905. 1998. View Article : Google Scholar : PubMed/NCBI
8	Mordente A, Meucci E, Silvestrini A, Martorana GE and Giardina B: New developments in anthracycline-induced cardiotoxicity. Curr Med Chem. 16:1656–1672. 2009. View Article : Google Scholar : PubMed/NCBI
9	Borchmann P, Morschhauser F, Parry A, Schnell R, Harousseau JL, Gisselbrecht C, Rudolph C, Wilhelm M, Günther H, Pfreundschuh DM, et al: Phase-II study of the new aza-anthracenedione, BBR 2778, in patients with relapsed aggressive non-Hodgkin's lymphomas. Haematologica. 88:888–894. 2003.PubMed/NCBI
10	Hasinoff BB, Wu X, Patel D, Kanagasabai R, Karmahapatra S and Yalowich JC: 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. 356:397–409. 2016. View Article : Google Scholar : PubMed/NCBI
11	Pettengell R, Coiffier B, Narayanan G, de Mendoza FH, Digumarti R, Gomez H, Zinzani PL, Schiller G, Rizzieri D, Boland 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. 13:696–706. 2012. View Article : Google Scholar : PubMed/NCBI
12	Pettengell R, Coiffier B, Egorov A, Singer J and Sivcheva L: Long-term response and remission with pixantrone in patients with relapsed or refractory aggressive non-Hodgkin lymphoma: Post-hoc analysis of the multicenter, open-label, randomized PIX301 trial. Clin Drug Investig. 38:527–533. 2018. View Article : Google Scholar : PubMed/NCBI
13	Eyre TA, Linton KM, Rohman P, Kothari J, Cwynarski K, Ardeshna K, Bailey C, Osborne WL, Rowntree C, Eden D, 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. 173:896–904. 2016. View Article : Google Scholar : PubMed/NCBI
14	d'Amore F, Leppä S, Larsen TS, Brown P, Relander T, Mannisto S, Jørgensen JM, Holte H, Lauritzsen GF, Enblad G, et al: A phase 1/2 study of pixantrone, etoposide, bendamustine and, in CD20⁺ tumors, rituximab in patients with relapsed aggressive B- or T-cell lymphomas-the P[R]EBEN study. Hematol Oncol. 35:423–424. 2017. View Article : Google Scholar
15	Mareschal S, Lanic H, Ruminy P, Bastard C, Tilly H and Jardin F: The proportion of activated B-cell like subtype among de novo diffuse large B-cell lymphoma increases with age. Haematologica. 96:1888–1890. 2011. View Article : Google Scholar : PubMed/NCBI
16	Scott DW, Mottok A, Ennishi D, Wright GW, Farinha P, Ben-Neriah S, Kridel R, Barry GS, Hother C, Abrisqueta P, et al: Prognostic significance of diffuse large B-cell lymphoma cell of origin determined by digital gene expression in formalin-fixed paraffin-embedded tissue biopsies. J Clin Oncol. 33:2848–2856. 2015. View Article : Google Scholar : PubMed/NCBI
17	Iqbal J, Meyer PN, Smith LM, Johnson NA, Vose JM, Greiner TC, Connors JM, Staudt LM, Rimsza L, Jaffe E, et al: BCL2 predicts survival in germinal center B-cell-like diffuse large B-cell lymphoma treated with CHOP-like therapy and rituximab. Clin Cancer Res. 17:7785–7795. 2011. View Article : Google Scholar : PubMed/NCBI
18	Iqbal J, Neppalli VT, Wright G, Dave BJ, Horsman DE, Rosenwald A, Lynch J, Hans CP, Weisenburger DD, Greiner TC, et al: BCL2 expression is a prognostic marker for the activated B-cell-like type of diffuse large B-cell lymphoma. J Clin Oncol. 24:961–968. 2006. View Article : Google Scholar : PubMed/NCBI
19	Petrella T, Copie-Bergman C, Brière J, Delarue R, Jardin F, Ruminy P, Thieblemont C, Figeac M, Canioni D, Feugier P, et al: BCL2 expression but not MYC and BCL2 coexpression predicts survival in elderly patients with diffuse large B-cell lymphoma independently of cell of origin in the phase 3 LNH03-6B trial. Ann Oncol. 28:1042–1049. 2017. View Article : Google Scholar : PubMed/NCBI
20	Song MK, Chung JS, Lee JJ, Yang DH, Kim IS, Shin DH and Shin HJ: High Ki-67 expression in involved bone marrow predicts worse clinical outcome in diffuse large B cell lymphoma patients treated with R-CHOP therapy. Int J Hematol. 101:140–147. 2015. View Article : Google Scholar : PubMed/NCBI
21	Li ZM, Huang JJ, Xia Y, Zhu YJ, Zhao W, Wei WX, Jiang WQ, Lin TY, Huang HQ and Guan ZZ: High Ki-67 expression in diffuse large B-cell lymphoma patients with non-germinal center subtype indicates limited survival benefit from R-CHOP therapy. Eur J Haematol. 88:510–517. 2012. View Article : Google Scholar : PubMed/NCBI
22	Tang YL, Zhou Y, Cheng LL, Su YZ and Wang CB: BCL2/Ki-67 index predict survival in germinal center B-cell-like diffuse large B-cell lymphoma. Oncol Lett. 14:3767–3773. 2017. View Article : Google Scholar : PubMed/NCBI