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Critical Reviews in Oncology/hematology May 2023CPX-351, a dual-drug liposomal encapsulation of daunorubicin/cytarabine, was approved for newly diagnosed therapy-related acute myeloid leukemia (AML) and AML with... (Review)
Review
CPX-351, a dual-drug liposomal encapsulation of daunorubicin/cytarabine, was approved for newly diagnosed therapy-related acute myeloid leukemia (AML) and AML with myelodysplasia-related changes in adults in 2017 (US; updated to patients aged ≥1 year in 2021) and 2018 (EU/UK) based on improved survival and remission and comparable safety versus 7 + 3 chemotherapy in a randomized trial in older adults. Real-world studies have since evaluated CPX-351 in routine practice across several countries and addressed important data gaps (e.g., use in younger adults, measurable residual disease negativity, outcomes by mutation). This review discusses real-world studies of CPX-351 as AML treatment, with the aim of helping prescribers make informed treatment decisions.
Topics: Humans; Aged; Daunorubicin; Leukemia, Myeloid, Acute; Cytarabine; Liposomes; Antineoplastic Combined Chemotherapy Protocols
PubMed: 37028531
DOI: 10.1016/j.critrevonc.2023.103984 -
Leukemia Oct 2023This is the primary report of the randomized, placebo-controlled phase 3 BRIGHT AML 1019 clinical trial of glasdegib in combination with intensive chemotherapy... (Randomized Controlled Trial)
Randomized Controlled Trial
This is the primary report of the randomized, placebo-controlled phase 3 BRIGHT AML 1019 clinical trial of glasdegib in combination with intensive chemotherapy (cytarabine and daunorubicin) or non-intensive chemotherapy (azacitidine) in patients with untreated acute myeloid leukemia. Overall survival (primary endpoint) was similar between the glasdegib and placebo arms in the intensive (n = 404; hazard ratio [HR] 1.05; 95% confidence interval [CI]: 0.782-1.408; two-sided p = 0.749) and non-intensive (n = 325; HR 0.99; 95% CI: 0.768-1.289; two-sided p = 0.969) studies. The proportion of patients who experienced treatment-emergent adverse events was similar for glasdegib versus placebo (intensive: 99.0% vs. 98.5%; non-intensive: 99.4% vs. 98.8%). The most common treatment-emergent adverse events were nausea, febrile neutropenia, and anemia in the intensive study and anemia, constipation, and nausea in the non-intensive study. The addition of glasdegib to either cytarabine and daunorubicin or azacitidine did not significantly improve overall survival and the primary efficacy endpoint for the BRIGHT AML 1019 phase 3 trial was not met. Clinical trial registration: ClinicalTrials.gov: NCT03416179.
Topics: Humans; Antineoplastic Combined Chemotherapy Protocols; Leukemia, Myeloid, Acute; Daunorubicin; Cytarabine; Azacitidine; Anemia; Nausea
PubMed: 37604981
DOI: 10.1038/s41375-023-02001-z -
Blood Advances Nov 2023The pivotal RATIFY study demonstrated midostaurin (50 mg twice daily) with standard chemotherapy significantly reduced mortality in adult patients (<60 years) with...
The pivotal RATIFY study demonstrated midostaurin (50 mg twice daily) with standard chemotherapy significantly reduced mortality in adult patients (<60 years) with newly diagnosed (ND) FLT3mut acute myeloid leukemia (AML). Considering that AML often present in older patients who show poor response to chemotherapy, this open-label, multicenter phase 3b trial was designed to further assess safety and efficacy of midostaurin plus chemotherapy in induction, consolidation, and maintenance monotherapy in young (≤60 years) and older (>60 years) patients with FLT3mut ND-AML. Compared with RATIFY, this study extended midostaurin treatment from 14 days to 21 days, substituted anthracyclines (idarubicin or daunorubicin), and introduced variation in standard combination chemotherapy dosing ("7+3" or "5+2" in more fragile patients). Total 301 patients (47.2% >60 years and 82.7% with FLT3-ITDmut) of median age 59 years entered induction phase. Overall, 295 patients (98.0%) had at least 1 adverse event (AE), including 254 patients (84.4%) with grade ≥3 AE. The grade ≥3 serious AEs occurred in 134 patients. No difference was seen in AE frequency between age groups, but grade ≥3AE frequency was higher in older patients. Overall, complete remission (CR) rate including incomplete hematologic recovery (CR + CRi) (80.7% [95% confidence interval, 75.74-84.98]) was comparable between age groups (≤60 years [83.5%]; >60 to ≤70 years [82.5%]; in patients >70 years [64.1%]) and the type of anthracycline used in induction. CR + CRi rate was lower in males (76.4%) than females (84.4%). Overall, the safety and efficacy of midostaurin remains consistent with previous findings, regardless of age, sex, or induction regimen. The trial is registered at www.clinicaltrials.gov as #NCT03379727.
Topics: Male; Female; Humans; Aged; Middle Aged; Daunorubicin; Idarubicin; Leukemia, Myeloid, Acute; Staurosporine; Antibiotics, Antineoplastic; Anthracyclines; fms-Like Tyrosine Kinase 3
PubMed: 37581981
DOI: 10.1182/bloodadvances.2023009847 -
Journal of Nanobiotechnology Nov 2023To investigate the efficacy of an injectable hydrogel loaded with lysed OK-432 (lyOK-432) and doxorubicin (DOX) for residual liver cancer after incomplete radiofrequency...
OBJECTIVE
To investigate the efficacy of an injectable hydrogel loaded with lysed OK-432 (lyOK-432) and doxorubicin (DOX) for residual liver cancer after incomplete radiofrequency ablation (iRFA) of hepatocellular carcinoma (HCC), and explore the underlying mechanism.
MATERIALS AND METHODS
The effect of OK-432 and lyOK-432 was compared in activating dendritic cells (DCs). RADA16-I (R) peptide was dissolved in a mixture of lyOK-432 (O) and DOX (D) to develop an ROD hydrogel. The characteristics of ROD hydrogel were evaluated. Tumor response and mice survival were measured after different treatments. The number of immune cells and cytokine levels were measured, and the activation of cGAS/STING/IFN-I signaling pathway in DC was evaluated both in vitro and in vivo.
RESULTS
LyOK-432 was more effective than OK-432 in promoting DC maturation and activating the IFN-I pathway. ROD was an injectable hydrogel for effectively loading lyOK-432 and DOX, and presented the controlled-release property. ROD treatment achieved the highest tumor necrosis rate (p < 0.001) and the longest survival time (p < 0.001) compared with the other therapies. The ROD group also displayed the highest percentages of DCs, CD4 T cells and CD8 T cells (p < 0.001), the lowest level of Treg cells (p < 0.001), and the highest expression levels of IFN-γ and TNF-α (p < 0.001) compared with the other groups. The expression levels of pSTING, pIRF3, and IFN-β in DCs were obviously higher after treatment of lyOK-432 in combination with DOX than the other therapies. The surviving mice in the ROD group showed a growth inhibition of rechallenged subcutaneous tumor.
CONCLUSION
The novel ROD peptide hydrogel induced an antitumor immunity by activating the STING pathway, which was effective for treating residual liver cancer after iRFA of HCC.
Topics: Animals; Mice; Picibanil; Liver Neoplasms; Carcinoma, Hepatocellular; Hydrogels; CD8-Positive T-Lymphocytes; Doxorubicin; Cytokines; Radiofrequency Ablation
PubMed: 37919724
DOI: 10.1186/s12951-023-02170-0 -
Nature Cancer Dec 2023Ex vivo drug response profiling is a powerful tool to study genotype-drug response associations and is being explored as a tool set for precision medicine in cancer....
Ex vivo drug response profiling is a powerful tool to study genotype-drug response associations and is being explored as a tool set for precision medicine in cancer. Here we conducted a prospective non-interventional trial to investigate feasibility of ex vivo drug response profiling for treatment guidance in hematologic malignancies (SMARTrial, NCT03488641 ). The primary endpoint to provide drug response profiling reports within 7 d was met in 91% of all study participants (N = 80). Secondary endpoint analysis revealed that ex vivo resistance to chemotherapeutic drugs predicted chemotherapy treatment failure in vivo. We confirmed the predictive value of ex vivo response to chemotherapy in a validation cohort of 95 individuals with acute myeloid leukemia treated with daunorubicin and cytarabine. Ex vivo drug response profiles improved ELN-22 risk stratification in individuals with adverse risk. We conclude that ex vivo drug response profiling is clinically feasible and has the potential to predict chemotherapy response in individuals with hematologic malignancies beyond clinically established genetic markers.
Topics: Humans; Cytarabine; Daunorubicin; Hematologic Neoplasms; Leukemia, Myeloid, Acute; Prospective Studies; Antibiotics, Antineoplastic; Antimetabolites, Antineoplastic; Treatment Outcome
PubMed: 37783805
DOI: 10.1038/s43018-023-00645-5 -
Arquivos Brasileiros de Cardiologia Nov 2020
Topics: Animals; Cardiovascular Physiological Phenomena; Doxorubicin; Exercise; Mice
PubMed: 33295452
DOI: 10.36660/abc.20200551 -
Journal of Oleo Science Oct 2023In this study, we analyzed the properties of amphiphilic alkyldi(methoxy poly(ethylene glycol) (MePEG)350-lactate) phosphates based on ethyl lactate, the monomethyl...
In this study, we analyzed the properties of amphiphilic alkyldi(methoxy poly(ethylene glycol) (MePEG)350-lactate) phosphates based on ethyl lactate, the monomethyl ether of poly(ethylene glycol)350, and alkyldichloro phosphates. Interestingly, these triesters combine two biodegradable bonds, -P(O)-O-C and -C(O)-O-C-, and include hydrophilic (MePEG350-lactate) and hydrophobic (R-aliphatic chain of alcohols) moieties. The properties of these esters resemble those of phospholipids. After being placed in an aqueous solution, they self-assembled. We also determined the effects of ester composition on micelle formation, stability, and size using dynamic light scattering. Solubilization tests using Sudan III or doxorubicin hydrochloride (Dox·HCl) revealed that they could be incorporated into the hydrophobic cores of dodecyl di(MePEG350-lactate) phosphate and hexadecyl di(MePEG350-lactate) phosphate. Notably, dodecyl di(MePEG350-lactate) phosphate was stable for five days, whereas hexadecyl di(MePEG350-lactate) phosphate was stable for seven days in phosphate-buffered saline. Moreover, Dox·HCl release rates from the micelles were approximately 30-40, 70-80, and 90-100% after 1, 5, and 28 d, respectively.
Topics: Micelles; Polyethylene Glycols; Doxorubicin; Phosphates; Lactates; Drug Carriers
PubMed: 37704442
DOI: 10.5650/jos.ess23108 -
Nature Medicine Sep 2023Anthracycline-based chemotherapy is associated with increased subsequent breast cancer (SBC) risk in female childhood cancer survivors, but the current evidence is...
Anthracycline-based chemotherapy is associated with increased subsequent breast cancer (SBC) risk in female childhood cancer survivors, but the current evidence is insufficient to support early breast cancer screening recommendations for survivors treated with anthracyclines. In this study, we pooled individual patient data of 17,903 survivors from six well-established studies, of whom 782 (4.4%) developed a SBC, and analyzed dose-dependent effects of individual anthracycline agents on developing SBC and interactions with chest radiotherapy. A dose-dependent increased SBC risk was seen for doxorubicin (hazard ratio (HR) per 100 mg m: 1.24, 95% confidence interval (CI): 1.18-1.31), with more than twofold increased risk for survivors treated with ≥200 mg m cumulative doxorubicin dose versus no doxorubicin (HR: 2.50 for 200-299 mg m, HR: 2.33 for 300-399 mg m and HR: 2.78 for ≥400 mg m). For daunorubicin, the associations were not statistically significant. Epirubicin was associated with increased SBC risk (yes/no, HR: 3.25, 95% CI: 1.59-6.63). For patients treated with or without chest irradiation, HRs per 100 mg m of doxorubicin were 1.11 (95% CI: 1.02-1.21) and 1.26 (95% CI: 1.17-1.36), respectively. Our findings support that early initiation of SBC surveillance may be reasonable for survivors who received ≥200 mg m cumulative doxorubicin dose and should be considered in SBC surveillance guidelines for survivors and future treatment protocols.
Topics: Child; Female; Humans; Breast Neoplasms; Anthracyclines; Doxorubicin; Breast; Daunorubicin; Polyketides
PubMed: 37696934
DOI: 10.1038/s41591-023-02514-1 -
International Journal of Nanomedicine 2022The objective of this study was to investigate the antitumor activity, targeting capability, and mechanism of the developed nanodrug consisting of doxorubicin and...
PURPOSE
The objective of this study was to investigate the antitumor activity, targeting capability, and mechanism of the developed nanodrug consisting of doxorubicin and exosome (Exo-Dox) derived from mesenchymal stem cells in vitro and in vivo.
METHODS
The exosomes were isolated with Exosome Isolation Kit, and the Exo-Dox was prepared by mixing exosome with Dox-HCl, desalinizing with triethylamine and then dialyzing against PBS overnight. The exosome and Exo-Dox were examined by nanoparticle tracking analysis (NTA) and transmission electron microscopy (TEM). The antitumor activity, targeting capability, and mechanism of the developed Exo-Dox were evaluated by cell viability assay, histological and immunofluorescence analysis and in vivo imaging system.
RESULTS
NTA results showed the size of the exosomes had increased from 141.6 nm to 178.1 nm after loading with doxorubicin. Compared with free Dox, the Exo-Dox exhibited higher cytotoxicity against osteosarcoma MG63 cells, HOS cells, and 143B cells than free Dox, the half-maximal inhibitory concentrations (IC50) of Dox, Exo-Dox were calculated to be 0.178 and 0.078 μg mL in MG63 cells, 0.294 and 0.109μg mL in HOS cells, 0.315 and 0.123 μg mL in 143B cells, respectively. The in vivo imaging showed that MSC derived Exo could serve as a highly efficient delivery vehicle for targeted drug delivery. The immunohistochemistry and histology analysis indicated that compared with the free Dox group, the Ki67-positive cells and cardiotoxicity in Exo-Dox group were significantly decreased.
CONCLUSION
Our results suggested that MSC-derived Exo could be excellent nanocarriers used to deliver chemotherapeutic drug Dox specifically and efficiently in osteosarcoma, resulting in enhanced toxicity against osteosarcoma and less toxicity in heart tissue. We further demonstrated the targeting capability of Exo was due to the chemotaxis of MSC-derived exosomes to osteosarcoma cells via SDF1-CXCR4 axis.
Topics: Bone Neoplasms; Cell Line, Tumor; Doxorubicin; Excipients; Exosomes; Humans; Mesenchymal Stem Cells; Nanoparticles; Osteosarcoma; Receptors, CXCR4
PubMed: 35959282
DOI: 10.2147/IJN.S372851 -
Nucleic Acids Research Sep 2023Genotoxicants have been used for decades as front-line therapies against cancer on the basis of their DNA-damaging actions. However, some of their non-DNA-damaging...
Genotoxicants have been used for decades as front-line therapies against cancer on the basis of their DNA-damaging actions. However, some of their non-DNA-damaging effects are also instrumental for killing dividing cells. We report here that the anthracycline Daunorubicin (DNR), one of the main drugs used to treat Acute Myeloid Leukemia (AML), induces rapid (3 h) and broad transcriptional changes in AML cells. The regulated genes are particularly enriched in genes controlling cell proliferation and death, as well as inflammation and immunity. These transcriptional changes are preceded by DNR-dependent deSUMOylation of chromatin proteins, in particular at active promoters and enhancers. Surprisingly, inhibition of SUMOylation with ML-792 (SUMO E1 inhibitor), dampens DNR-induced transcriptional reprogramming. Quantitative proteomics shows that the proteins deSUMOylated in response to DNR are mostly transcription factors, transcriptional co-regulators and chromatin organizers. Among them, the CCCTC-binding factor CTCF is highly enriched at SUMO-binding sites found in cis-regulatory regions. This is notably the case at the promoter of the DNR-induced NFKB2 gene. DNR leads to a reconfiguration of chromatin loops engaging CTCF- and SUMO-bound NFKB2 promoter with a distal cis-regulatory region and inhibition of SUMOylation with ML-792 prevents these changes.
Topics: Humans; Daunorubicin; Leukemia, Myeloid, Acute; Esters; Chromatin
PubMed: 37462077
DOI: 10.1093/nar/gkad581