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

Pettengell, Ruth; Coiffier, Bertrand; Narayanan, Geetha; Mendoza, Fernando Hurtado de; Digumarti, Raghunadharao; Gómez, Henry L.; Zinzani, Pier Luigi; Schiller, Gary J.; Rizzieri, David A.; Boland, Giles W.; Cernohous, Paul; Wang, Lixia; Kuepfer, Christine; Gorbatchevsky, Igor; Singer, Jack W.

doi:10.1016/s1470-2045(12)70212-7

Cited by 117 publications

(186 citation statements)

References 20 publications

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“…The safety profile of pixantrone in patients with aggressive B‐cell NHL was in line with the previously published results of the main study (Pettengell et al , 2012) and current knowledge on the agent. Uncomplicated neutropenia was more common in the pixantrone group than in the comparator group: all grades represented 50·0% pixantrone vs. 23·9% comparator; grades 3 or 4 represented 41·2% pixantrone, 19·4% comparator.…”

Section: Resultssupporting

confidence: 86%

“…The design and methods of this phase 3 study have been described (Pettengell et al , 2012). Briefly, this multicentre, open‐label, randomized trial included patients with aggressive de novo or transformed NHL [according to the Revised European American Lymphoma (REAL) and World Health Organization (WHO) classifications], who had relapsed or were refractory to two or more previous lines of chemotherapy regimens, including at least one standard anthracycline‐based regimen with response ≥24 weeks.…”

Section: Methodsmentioning

confidence: 99%

“…The patients in the pixantrone group received 28‐d cycles of 85 mg/m 2 pixantrone dimaleate (equivalent to 50 mg/m 2 in the base formulation approved by the European regulatory authorities) by intravenous infusion over 1 h on days 1, 8 and 15. The choice of comparator was left to the treating physician and could be vinorelbine, oxaliplatin, ifosfamide, etoposide, mitoxantrone or gemcitabine, all of which were given at prespecified standard doses and schedules (Pettengell et al , 2012). Randomization was achieved by an interactive voice response system and was stratified by region (USA versus Western Europe versus the rest of the World), International Prognostic Index (≤1 vs. ≥2) and previous stem cell transplantation.…”

Section: Methodsmentioning

confidence: 99%

“…Pixantrone is conditionally approved in Europe for the management of multiply relapsed or refractory aggressive B‐cell non‐Hodgkin lymphoma (NHL), on the basis of results from an open‐label, randomized phase 3 study comparing pixantrone with physician's choice of treatment in 140 patients with relapsed or refractory aggressive NHL (Pettengell et al , 2012). Treatment of heavily pre‐treated patients with pixantrone was reported to be efficacious and tolerable.…”

mentioning

confidence: 99%

“…This report describes a post hoc analysis of the phase 3 study described above (Pettengell et al , 2012) with the aim of investigating the effect of pixantrone in a subpopulation of patients with relapsed or refractory aggressive B‐cell NHL, as confirmed by centralized independent pathological review. We also explored the effect of pixantrone or comparator in this population divided according to whether they were receiving the study treatment as their 3rd or 4th line of therapy or as any line of therapy (i.e.…”

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confidence: 99%

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Monotherapy with pixantrone in histologically confirmed relapsed or refractory aggressive B‐cell non‐Hodgkin lymphoma: post‐hoc analyses from a phase III trial

et al. 2016

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This post hoc analysis of a phase 3 trial explored the effect of pixantrone in patients (50 pixantrone, 47 comparator) with relapsed or refractory aggressive B‐cell non‐Hodgkin lymphoma (NHL) confirmed by centralized histological review. Patients received 28‐d cycles of 85 mg/m2 pixantrone dimaleate (equivalent to 50 mg/m2 in the approved formulation) on days 1, 8 and 15, or comparator. The population was subdivided according to previous rituximab use and whether they received the study treatment as 3rd or 4th line. Median number of cycles was 4 (range, 2–6) with pixantrone and 3 (2–6) with comparator. In 3rd or 4th line, pixantrone was associated with higher complete response (CR) (23·1% vs. 5·1% comparator, P = 0·047) and overall response rate (ORR, 43·6% vs. 12·8%, P = 0·005). In 3rd or 4th line with previous rituximab (20 pixantrone, 18 comparator), pixantrone produced better ORR (45·0% vs. 11·1%, P = 0·033), CR (30·0% vs. 5·6%, P = 0·093) and progression‐free survival (median 5·4 vs. 2·8 months, hazard ratio 0·52, 95% confidence interval 0·26–1·04) than the comparator. Similar results were found in patients without previous rituximab. There were no unexpected safety issues. Pixantrone monotherapy is more effective than comparator in relapsed or refractory aggressive B‐cell NHL in the 3rd or 4th line setting, independently of previous rituximab.

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Section: Resultssupporting

confidence: 86%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Monotherapy with pixantrone in histologically confirmed relapsed or refractory aggressive B‐cell non‐Hodgkin lymphoma: post‐hoc analyses from a phase III trial

et al. 2016

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DNA Topoisomerase Targeting Drugs

Thomas

Bates

Figg

et al. 2017

Holland‐Frei Cancer Medicine

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Overview DNA topoisomerase targeting drugs are widely used in the treatment of multiple cancers. These drugs act by generating topoisomerase‐linked DNA breaks and by blocking the religation of the cleavage complexes. Although topoisomerase targeting drugs have a wide spectrum of activity, structural, pharmacokinetic, and pharmacodynamic characteristics somewhat limit their efficacy and safety. To circumvent these limitations and to further exploit its activity, newer inhibitors‐ including novel formulations and those that achieve targeted delivery‐ are being developed. Recently described mechanisms that underlie cellular sensitivity to these agents will enable us to predict the activity of topoisomerase targeting drugs and to precisely select patients who are most likely to benefit. Understanding the genetic variants in drug metabolizing enzymes, transporters, and other proteins that influence the pharmacology of these drugs will allow for further individualizing the use of these drugs.

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DNA Topoisomerase Targeting Drugs

Thomas¹,

Bates²,

Figg³

et al. 2022

Holland‐Frei Cancer Medicine

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Overview Topoisomerases are an important class of enzymes that are ubiquitously expressed across all organisms, and function to resolve deoxyribonucleic acid (DNA) supercoiling and prevent and resolve ribonucleic acid (RNA) entanglements. These biochemically distinct enzymes play a critical role in DNA replication, transcription, and cellular division. Inhibitors that target specific topoisomerases, therefore, represent a major component of the anticancer chemotherapeutic armamentarium. In this chapter, we provide an overview of topoisomerase biology and topoisomerase inhibitors. We review the common and specific mechanisms of action and the molecular pharmacology of the drugs that target the topoisomerase cleavage complexes by interfacial inhibition. Molecular pathways for cancer cell death and DNA repair associated with each specific topoisomerase inhibitor are discussed. Other mechanisms of anticancer activity of selected topoisomerase inhibitors that include DNA intercalation and/or generation of oxygen radicals destabilizing and damaging chromatin structure are described. We summarize the clinical use, toxicity profile, and the molecular basis of sensitivity and resistance to topoisomerase inhibitors. We also discuss the pharmacogenomics focusing on genetic variants in drug‐metabolizing enzymes, transporters, and other proteins associated with topoisomerase inhibitors. Evolving data demonstrate the important role of molecular profiling and analysis of genetic variants in individuals that enable personalized dosing and enhance therapeutic efficacy, minimizing toxicity. Ongoing efforts focus on optimization of treatment selection, identification of novel combination therapies, elucidation of the molecular basis of response and resistance, and development of strategies for tumor‐targeted delivery based on tumor molecular signatures.

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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

Cited by 117 publications

References 20 publications

Monotherapy with pixantrone in histologically confirmed relapsed or refractory aggressive B‐cell non‐Hodgkin lymphoma: post‐hoc analyses from a phase III trial

Monotherapy with pixantrone in histologically confirmed relapsed or refractory aggressive B‐cell non‐Hodgkin lymphoma: post‐hoc analyses from a phase III trial

DNA Topoisomerase Targeting Drugs

DNA Topoisomerase Targeting Drugs

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