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Annals of Hematology Sep 2019Outcomes for patients with non-Hodgkin's lymphoma (NHL) that proves refractory to treatment remain poor. Treatment of such patients is individualized and can include... (Review)
Review
Outcomes for patients with non-Hodgkin's lymphoma (NHL) that proves refractory to treatment remain poor. Treatment of such patients is individualized and can include enrolment in a clinical trial of novel agents or use of one of a wide array of drug regimens. Initial treatment with anthracyclines such as doxorubicin limits options at later stages of treatment because of anthracycline-related cumulative cardiotoxicity. The aza-anthracenedione pixantrone was developed to reduce the likelihood of cardiotoxicity without compromising efficacy and is currently conditionally approved for use as monotherapy in patients with multiply-relapsed or refractory aggressive B cell NHL. The use of pixantrone in combination therapy, often to replace doxorubicin or mitoxantrone, has or is currently being investigated in numerous studies in patients with aggressive or indolent NHL and is the focus of this review. These include the R-CPOP regimen (rituximab, cyclophosphamide, pixantrone, vincristine, prednisone) for aggressive NHL in the first-line setting, including a study in elderly patients with limited cardiac function, and for patients with relapsed NHL with prior anthracycline exposure; the PSHAP regimen (pixantrone, cytarabine, prednisone, cisplatin), also in the latter setting; the PREBen/PEBen regimen (pixantrone, bendamustine and etoposide with or without rituximab) as salvage therapy; and pixantrone in combination with fludarabine, dexamethasone, and rituximab (FPD-R) for relapsed indolent NHL.
Topics: Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Doxorubicin; Humans; Isoquinolines; Lymphoma, B-Cell; Mitoxantrone; Prednisone; Rituximab; Salvage Therapy; Vidarabine; Vincristine
PubMed: 31312929
DOI: 10.1007/s00277-019-03749-0 -
Expert Review of Hematology Jul 2018Pixantrone is a first-in-class aza-anthracenedione approved as monotherapy for treatment of relapsed or refractory aggressive diffuse B-cell non-Hodgkin's lymphoma... (Review)
Review
Pixantrone is a first-in-class aza-anthracenedione approved as monotherapy for treatment of relapsed or refractory aggressive diffuse B-cell non-Hodgkin's lymphoma (NHL), a patient group which is notoriously difficult to treat. It has a unique chemical structure and pharmacologic properties distinguishing it from anthracyclines and anthracenediones. Areas covered: The chemical structure and mode of action of pixantrone versus doxorubicin and mitoxantrone; preclinical evidence for pixantrone's therapeutic effect and cardiac tolerability; efficacy and safety of pixantrone in clinical trials; ongoing and completed trials of pixantrone alone or as combination therapy; and the risk of cardiotoxicity of pixantrone versus doxorubicin and mitoxantrone. Expert commentary: Currently, pixantrone is the only approved therapy for multiply relapsed or refractory NHL, an area with few available effective treatment options. Pixantrone is currently being investigated as combination therapy with other drugs including several targeted therapies, with the ultimate goal of improved survival in heavily pretreated patients. In order for pixantrone to be acknowledged in the treatment of aggressive NHL, the perception of pixantrone as an anthracycline-like agent that has anthracycline-like activity and cardiotoxicity needs to be changed. Further data from ongoing clinical trials will help in confirming pixantrone as an effective and safe option.
Topics: Clinical Trials as Topic; Disease-Free Survival; Doxorubicin; Humans; Isoquinolines; Lymphoma, Large B-Cell, Diffuse; Mitoxantrone; Survival Rate
PubMed: 29912583
DOI: 10.1080/17474086.2018.1476848 -
Annals of Hematology Nov 2019Treatment results for multiple myeloma and plasma cell leukemia have considerably improved, but cure remains elusive and establishing new therapeutic approaches... (Review)
Review
Treatment results for multiple myeloma and plasma cell leukemia have considerably improved, but cure remains elusive and establishing new therapeutic approaches constitutes a major unmet clinical need. We analyzed the anti-myeloma properties of the aza-anthracenedione pixantrone which has been successfully used in a phase III study for the treatment of patients with aggressive non-Hodgkin's lymphoma as monotherapy as well as in combination regimes in vitro and in an adapted in vivo model (ex ovo chicken chorioallantoic membrane (CAM) assay). Pixantrone significantly inhibited proliferation and metabolic activity of all investigated myeloma cell lines. Importantly, anti-myeloma effects were more pronounced in tumor cell lines than in stromal cells, mesenchymal stem cells, and peripheral blood mononuclear cells of healthy controls. Apoptosis of myeloma cell lines was observed only after a 7-day incubation period, indicating a fast cytostatic and a slower cytotoxic effect of this drug. Pixantrone reduced the viability of primary plasma cells of patients and induced downregulation of myeloma-cell growth in the CAM assay. Additionally, we demonstrate in vitro synergism between pixantrone and the histone deacetylase inhibitor panobinostat with respect to its anti-proliferative features. From these data, we conclude that systematic investigations of the clinical usefulness of pixantrone in the framework of controlled clinical trials are clearly indicated (e.g., in penta-refractory patients).
Topics: Aged; Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Division; Cell Line, Tumor; Chick Embryo; Chorioallantoic Membrane; Clinical Trials as Topic; Drug Screening Assays, Antitumor; Drug Synergism; Energy Metabolism; Female; Humans; Isoquinolines; Leukemia, Plasma Cell; Leukocytes, Mononuclear; Male; Middle Aged; Mitochondria; Multiple Myeloma; Panobinostat; Retrospective Studies
PubMed: 31628518
DOI: 10.1007/s00277-019-03797-6 -
Drugs Oct 2016Pixantrone (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... (Review)
Review
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.
Topics: Adult; Antineoplastic Agents; Deoxycytidine; Humans; Isoquinolines; Lymphoma, B-Cell; Lymphoma, Non-Hodgkin; Rituximab; Gemcitabine
PubMed: 27757832
DOI: 10.1007/s40265-016-0650-8 -
Expert Opinion on Pharmacotherapy Nov 2018The overall prognosis for patients with relapsed or refractory aggressive non-Hodgkin's lymphomas is poor. Only a minority of patients are able to receive autologous... (Review)
Review
The overall prognosis for patients with relapsed or refractory aggressive non-Hodgkin's lymphomas is poor. Only a minority of patients are able to receive autologous stem cell transplantation. Patients not transplant-eligible or patients relapsing after transplantation have an urgent need for effective treatment options. Pixantrone is the only compound approved in Europe for this situation. Areas covered: This review describes the clinical development of pixantrone, starting with phase I trials up to phase III trials in order to define the role of pixantrone in treatment algorithms. The effectiveness of pixantrone is considered in relation to alternative therapeutic options. Furthermore, the similarities and differences between pixantrone and anthracyclines is highlighted, with a special focus on the mode of action and on cardiotoxicity. Expert opinion: Pixantrone is a valuable treatment option in relapsed and refractory aggressive lymphomas, with documented disease responses, manageable toxicities and clear distinctions to anthracyclines. Additional studies are needed to evaluate the role of pixantrone in combination with other compounds, especially with upcoming targeted therapies, and to confirm the effectiveness of pixantrone in other lymphoma subtypes, e.g. follicular lymphomas.
Topics: Female; Humans; Isoquinolines; Lymphoma, Non-Hodgkin; Male; Prognosis; Topoisomerase II Inhibitors
PubMed: 30269614
DOI: 10.1080/14656566.2018.1528232 -
Therapeutics and Clinical Risk... 2021Not many treatment options exist for patients with relapsed or refractory (R/R) B-cell non-Hodgkin lymphoma (NHL) in whom first- and second-line therapies were... (Review)
Review
Not many treatment options exist for patients with relapsed or refractory (R/R) B-cell non-Hodgkin lymphoma (NHL) in whom first- and second-line therapies were unsuccessful. This is especially true for patients with aggressive lymphomas. The innovative agent pixantrone has shown some promising results in terms of disease-free and overall survival, both in monotherapy as well as in combinations. However, recent trials (Phase III and real-world studies) reported unsatisfactory results, thereby raising the question about the role of pixantrone in the current treatment of R/R aggressive lymphomas. Nonetheless, there might still be a potential position for this drug in combinations, for use as first-line treatment of patients with cardiac dysfunction. This article summarizes the definition, structure, mechanism of action and reduced cardiotoxicity of pixantrone as well as efficacy and toxicity both in monotherapy and in combinations, as treatment for aggressive and indolent non-Hodgkin lymphomas.
PubMed: 33688197
DOI: 10.2147/TCRM.S269324 -
Drugs of Today (Barcelona, Spain : 1998) Nov 2009Pixantrone (BBR-2778) is a novel aza-anthracenedione anthracycline derivative developed by Cell Therapeutics Incorporated, WA, USA. Pixantrone is similar in structure to... (Review)
Review
Pixantrone (BBR-2778) is a novel aza-anthracenedione anthracycline derivative developed by Cell Therapeutics Incorporated, WA, USA. Pixantrone is similar in structure to the anthracenedione mitoxantrone but lacks the 5, 8-dihydroxy substitution groups implicated in mitoxantrone-induced cardiotoxicity. The PIX301 phase III single-agent trial of pixantrone for patients with relapsed or refractory aggressive non-Hodgkin's lymphoma randomized patients to receive either pixantrone or another single agent of the investigators' choice. The rate of confirmed and unconfirmed remissions in patients treated with pixantrone was significantly higher than in those receiving other agents, as was the overall response rate and progression-free survival. There is evidence that pixantrone is well tolerated when substituted for anthracyclines in combination regimens for aggressive non-Hodgkin's lymphoma with comparable rates of complete remission. Pixantrone has also been used for the treatment of indolent non-Hodgkin's lymphomas and the combination of pixantrone and rituximab has been shown to be superior to rituximab alone in relapsed or refractory disease in the phase III PIX302 study. On the basis of these data, the United States Food and Drug Administration is considering pixantrone for use in adult patients with relapsed or refractory aggressive and indolent non-Hodgkin's lymphoma on a fast-track basis.
Topics: Adult; Animals; Antineoplastic Agents; Clinical Trials as Topic; Drug Evaluation, Preclinical; Humans; Isoquinolines; Lymphoma, Non-Hodgkin; Topoisomerase II Inhibitors
PubMed: 20126672
DOI: 10.1358/dot.2009.45.11.1438459 -
Chemotherapy 2017
Topics: Antineoplastic Combined Chemotherapy Protocols; Cardiotoxicity; Clinical Trials as Topic; Cyclophosphamide; Doxorubicin; Humans; Isoquinolines; Lymphoma, Non-Hodgkin; Prednisone; Stem Cell Transplantation; Vincristine
PubMed: 28334703
DOI: 10.1159/000464276 -
Microbiology Spectrum Dec 2022The emergence of bacterial drug resistance poses a severe threat to global public health. In particular, antimicrobial-resistant pathogens lead to a high rate of...
The emergence of bacterial drug resistance poses a severe threat to global public health. In particular, antimicrobial-resistant pathogens lead to a high rate of treatment failure and significantly increase mortality. Repurposing FDA-approved compounds to sensitize superbugs to conventional antibiotics provides a promising strategy to alleviate such crises. Pixantrone (PIX) has been approved for treating aggressive B-cell non-Hodgkin's lymphoma. By high-throughput drug screening, we profiled the synergistic activity between PIX and rifampin (RFP) against Gram-negative extensively drug-resistant isolates by checkerboard assay. Mechanistic studies demonstrated that PIX impacted the flagellum assembly, induced irreversible intracellular reactive oxygen species accumulation and disrupted proton motive force. In addition, the combination of PIX with RFP possesses effective antimicrobial activity against multidrug-resistant strains without detected toxicity. Collectively, these results reveal the potential of PIX in combination with RFP as a therapy option for refractory infections caused by Gram-negative pathogens. Bacterial resistance has become increasingly serious because of the widespread use and abuse of antibiotics. In particular, the emergence of multidrug-resistant bacteria has posed a serious threat to human public health. Drug repurposing, the process of finding new uses for existing drugs, provide a promising pathway to solve antimicrobial resistance. Compared to the development of novel antibiotics, this strategy leverages well-characterized pharmacology and toxicology of known drugs and is more cost-effective.
Topics: Humans; Rifampin; Anti-Bacterial Agents; Isoquinolines; Drug Resistance, Multiple, Bacterial; Microbial Sensitivity Tests; Gram-Negative Bacteria
PubMed: 36318018
DOI: 10.1128/spectrum.02114-22 -
Free Radical Biology & Medicine Sep 2022Radioresistance towards radiation therapy has generated the need for the development of radiosensitizers as a potential drug. KRAS mutation brings radioresistance in...
Radioresistance towards radiation therapy has generated the need for the development of radiosensitizers as a potential drug. KRAS mutation brings radioresistance in tumor cells. The present work proves sensitization of cancer cells towards radiotherapy through inhibition of KRAS activation. Acquiring a drug repurposing approach, the in-silico screening revealed that pixantrone, an antineoplastic drug, possesses a high affinity towards KRAS G12C and G12D subtypes. The SPR study suggests that maximum affinity of pixantrone was observed with KRAS G12C>WT>G12D and G12S. Pixantrone potentially inhibited the KRAS activation in stable transfectants G12C and G12D cell lines and radiosensitized distinct KRAS mutant subtype cells. The combination of pixantrone with radiation causes enhanced dsDNA breaks along with enhanced ATM expression, and increased late apoptosis. The preclinical studies on NCr-fox1 xenograft mice showed potent inhibition of tumor progression and prolonged survival of mcie due to the radiosensitizing effect of pixantrone. Radiation-induced activation of key effector proteins of RAS downstream pathways, like MAPK and PI3K/Akt/mTOR pathways, were downregulated in tumor cells upon combination treatment. Interestingly, a robust upregulation of senescence marker p21 was observed in the tumor cells in combination treatment. These findings reveal a convergence between KRAS signaling, pixantrone treatment, and radiation conferring tumor cell death.
Topics: Animals; Cell Line, Tumor; Humans; Isoquinolines; Lung Neoplasms; Mice; Mutation; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins p21(ras); Radiation-Sensitizing Agents
PubMed: 35970251
DOI: 10.1016/j.freeradbiomed.2022.08.015