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

Abstract

the European Commission issued a conditional marketing authorization valid throughout the European Union for pixantrone for the treatment of adult patients with multiply relapsed or refractory aggressive non-Hodgkin's B-cell lymphoma (NHL). Pixantrone is a cytotoxic aza-anthracenedione that directly alkylates DNAforming stable DNA adducts and cross-strand breaks. The recommended dose of pixantrone is 50 mg/m 2 administered on days 1, 8, and 15 of each 28-day cycle for up to 6 cycles. In the main study submitted for this application, a significant difference in response rate (proportion of complete responses and unconfirmed complete responses) was observed in favor of pixantrone (20.0% vs. 5.7% for pixantrone and physician's best choice, respectively), supported by the results of secondary endpoints of median progression-free and overall survival times (increase of 2.7 and 2.6 months, respectively). The most common side effects with pixantrone were bone marrow suppression (particularly of the neutrophil lineage) nausea, vomiting, and asthenia. This article summarizes the scientific review of the application leading to approval in the European Union. The detailed scientific assessment report and product information, including the summary of product characteristics, are available on the European Medicines Agency website (http://www.ema.europa.eu). The Oncologist 2013;18: 625-633 Implications for Practice: On February 16 2012, the European Medicines Agency (EMA) recommended the granting of a conditional marketing authorization for pixantrone, 29 mg, powder for concentrate for solution for infusion for the treatment of patients with multiply relapsed aggressive non-Hodgkin's Lymphoma (NHL) as monotherapy. In the main study submitted for this application, a significant difference in response rate (proportion of complete responses and unconfirmed complete responses) was observed in favor of pixantrone (20.0% vs. 5.7% for pixantrone and physician's best choice, respectively), supported by the results of secondary endpoints of median progression-free and overall survival times (increase of 2.7 and 2.6 months, respectively). The most common side effects are neutropenia, leucopoenia, anaemia, thrombocytopenia, asthenia, pyrexia, cough, decreased ejection fraction, and nausea. Haematological side effects are also the most common associated with grade 3 or 4 toxicity. Detailed recommendations for the use of this product are available on the EMA website. INTRODUCTION

A Phase 2/3 Multicenter, Randomized, Open-Label Study to Compare the Efficacy and Safety of Lenalidomide Versus Investigator's Choice in Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma

“…Currently, no agents are approved for relapsed/refractory DLBCL by the FDA. The European Medicines Agency has granted conditional approval for the cytotoxic azaanthracenedione pixantrone for multiply relapsed/refractory NHL (6).…”

Impressive Response to Pixantrone after Allogeneic Transplant in a Multiple Relapsed Diffuse Large B-Cell Lymphoma

“…Pixantrone is an antineoplastic drug derived from mitoxantrone, but with a lower cardiac toxicity [5]. It acts as both a topoisomerase II inhibitor and an intercalating agent [3,4].…”

“…For this reason, a new therapy was started, this time using pixantrone dimaleate. This drug was chosen taking into account both the previous therapy lines and the recent approval by the European Medicines Agency for its usage in multiple relapsed/refractory aggressive non-Hodgkin lymphomas [3,4,5,6,7]. Pixantrone was administered on days +1, +8, and +15 of each 28-day cycle at a dose of 50 mg/m 2 (reduced by 20% because of the numerous previous lines of therapy and the high risk of hematologic toxicity), with the first infusion happening on August 10, 2015.…”

Single-Agent Pixantrone as a Bridge to Autologous Stem Cell Transplantation in a Patient with Refractory Diffuse Large B-Cell Lymphoma

“…Pixantrone directly alkylates DNA-forming stable DNA adducts and long-lived crosslinks. Furthermore, pixantrone has less potential for generating reactive oxygen species, binding iron, and forming alcohol metabolites that are believed to cause the cardiac toxicity of anthracyclines [8]. According to most recent reports, pixantrone induces a latent type of DNA damage that impairs the fidelity of mitosis, without triggering anthracycline-like DNA damage, but is lethal after successive rounds of aberrant division [9].…”

“…Pixantrone was generally well tolerated in PIX301, with a manageable adverse event profile. It is approved in the EU for use as monotherapy in adult patients with multiple relapsed or refractory aggressive B-cell non-Hodgkin lymphoma [8]. However, evidence of a long-term benefit from pixantrone is still awaited.…”