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Leukemia Apr 2024Molecularly defined secondary acute myeloid leukemia is associated with a prior myeloid neoplasm and confers a worse prognosis. We compared outcomes of molecularly...
Molecularly defined secondary acute myeloid leukemia is associated with a prior myeloid neoplasm and confers a worse prognosis. We compared outcomes of molecularly defined secondary AML patients (n = 395) treated with daunorubicin and cytarabine (7 + 3, n = 167), liposomal daunorubicin and cytarabine (CPX-351, n = 66) or hypomethylating agents (HMA) + venetoclax (VEN) (n = 162). Median overall survival (OS) was comparable between treatment groups among patients aged >60 years. In a multivariable model HMA + VEN vs. 7 + 3 was associated with better OS (hazard ratio [HR] 0.64 [95% confidence interval (CI) 0.42-0.98, p = 0.041]), whereas CPX-351 vs. 7 + 3 was not (HR 0.79 [CI 95% 0.50-1.25, p = 0.31]). Allogeneic hematopoietic stem cell transplantation, BCOR and IDH mutations were associated with improved OS; older age, prior myeloid disease, NRAS/KRAS mutations, EZH2 mutation, and monosomal karyotype were associated with worse OS. When analyzed in each treatment separately, the IDH co-mutations benefit was seen with 7 + 3 and the detrimental effect of NRAS/KRAS co-mutations with HMA + VEN and CPX-351. In pairwise comparisons adjusted for age, HMA + VEN was associated with improved OS vs. 7 + 3 in patients with SF3B1 mutation and improved OS vs. CPX-351 in those with RNA splicing factor mutations. In molecularly defined secondary AML treatment with HMA + VEN might be preferred but could further be guided by co-mutations.
Topics: Humans; Induction Chemotherapy; Proto-Oncogene Proteins p21(ras); Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Daunorubicin; Leukemia, Myeloid, Acute; Bridged Bicyclo Compounds, Heterocyclic; Neoplasms, Second Primary; Retrospective Studies; Sulfonamides
PubMed: 38378841
DOI: 10.1038/s41375-024-02175-0 -
Hematology. American Society of... Dec 2017Drug therapy for acute myeloid leukemia (AML) is finally undergoing major changes in 2017. This is due to the US Food and Drug Administration's approval of several new,... (Review)
Review
Drug therapy for acute myeloid leukemia (AML) is finally undergoing major changes in 2017. This is due to the US Food and Drug Administration's approval of several new, targeted agents (midostaurin, enasidenib, and gemtuzumab ozogamicin). Paired with the recent approval of a novel liposomal formulation of daunorubicin/cytarabine (CPX-351/Vyxeos), the standard of care is changing rapidly in AML for subgroups. This review will focus on currently approved agents and promising novel agents in development and will highlight controversial areas in targeted treatment.
Topics: Cytarabine; Daunorubicin; Drug Delivery Systems; Humans; Leukemia, Myeloid, Acute
PubMed: 29222237
DOI: 10.1182/asheducation-2017.1.54 -
Best Practice & Research. Clinical... Dec 2018Older adults with acute myeloid leukemia (AML) traditionally have very poor survival outcomes. Those who receive only supportive care have worse overall survival than... (Review)
Review
Older adults with acute myeloid leukemia (AML) traditionally have very poor survival outcomes. Those who receive only supportive care have worse overall survival than those who undergo treatment, regardless of treatment type, and improvements in overall survival in the last several decades are largely attributable to the increasing decision to treat rather than offer only supportive care. However, there are a few newer agents that appear promising; these include CPX-351 (a liposomal product with cytarabine and daunorubicin), glasdegib (a selective Hedgehog signaling pathway inhibitor), and venetoclax (potent small molecule inhibitor of BCL2). A systematic review and meta-analysis is being completed to help clinicians optimize standard therapies for older AML patients.
Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Cytarabine; Daunorubicin; Disease-Free Survival; Humans; Leukemia, Myeloid, Acute; Sulfonamides; Survival Rate
PubMed: 30466753
DOI: 10.1016/j.beha.2018.09.005 -
Cancer Chemotherapy and Pharmacology Jun 2019In the treatment of acute myeloid leukemia (AML), the "7 + 3"-based strategy, combining cytarabine 100-200 mg/m for 7 days with an anthracycline for 3 days,... (Meta-Analysis)
Meta-Analysis Review
In the treatment of acute myeloid leukemia (AML), the "7 + 3"-based strategy, combining cytarabine 100-200 mg/m for 7 days with an anthracycline for 3 days, remains the standard of care for younger and medically fit patients. Daunorubicin (DNR) and idarubicin (IDA) are the two anthracyclines most commonly used. DNR and IDA are used interchangeably with different conversion factors, as there is no high-level evidence on the equipotency of these two agents for AML treatment. To determine the equipotent doses of DNR and IDA, we first systematically reviewed studies directly comparing the clinical outcomes of AML induction therapy utilizing DNR and IDA. We found 15 articles that met our inclusion criteria and compared time-to-event survival end points as well as complete remission rates post-induction. The DNR:IDA equipotency ratio was estimated at 5.90 with 95% confidence interval (CI) 1.7-20.7. To validate the estimate from our meta-analysis biologically, we conducted in vitro tests comparing anti-AML activity of DNR and IDA against six AML cell lines and two primary AML cells from patients with different cytogenetic and molecular characteristics. Based on these in vitro data, the equipotency dose ratio between DNR and IDA was 4.06 with 95% CI 3.64-4.49. Combining the estimates from the meta-analysis and the in vitro data using inverse-variance weighting, the current best estimate of the DNR:IDA equipotent ratio is 4.1 with 95% CI 3.9-4.3. This estimate, however, is largely driven by the in vitro chemo-sensitivity data. Given clinical studies demonstrating the safety of IDA at higher doses, our work implies that dose intensification of IDA could be investigated in future clinical trials in AML.
Topics: Antineoplastic Combined Chemotherapy Protocols; Daunorubicin; Dose-Response Relationship, Drug; Humans; Idarubicin; Leukemia, Myeloid, Acute
PubMed: 30968179
DOI: 10.1007/s00280-019-03825-2 -
Journal of Medicinal Chemistry Nov 2021The synthesis and antiproliferative activity of Mes- and iPr-substituted gold(I) bis(1,2,3-triazol-5-ylidene) complexes in various cancer cell lines are reported,...
The synthesis and antiproliferative activity of Mes- and iPr-substituted gold(I) bis(1,2,3-triazol-5-ylidene) complexes in various cancer cell lines are reported, showing nanomolar IC values of 50 nM (lymphoma cells) and 500 nM (leukemia cells), respectively (Mes < iPr). The compounds exclusively induce apoptosis (50 nM to 5 μM) instead of necrosis in common malignant blood cells (leukemia cells) and do not affect non-malignant leucocytes. Remarkably, the complexes not only overcome resistances against the well-established cytostatic etoposide, cytarabine, daunorubicin, and cisplatin but also promote a synergistic effect of up to 182% when used with daunorubicin. The present results demonstrate that gold(I) bis(1,2,3-triazol-5-ylidene) complexes are highly promising and easily modifiable anticancer metallodrugs.
Topics: Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Coordination Complexes; Daunorubicin; Drug Resistance, Neoplasm; Drug Synergism; Gold; Humans; Triazoles
PubMed: 34670090
DOI: 10.1021/acs.jmedchem.1c01021 -
Expert Opinion on Pharmacotherapy 2015Intensive chemotherapy with cytarabine and an anthracycline for untreated acute myeloid leukemia (AML) has remained largely unchanged over the past 40 years, despite... (Review)
Review
INTRODUCTION
Intensive chemotherapy with cytarabine and an anthracycline for untreated acute myeloid leukemia (AML) has remained largely unchanged over the past 40 years, despite many large trials examining the choice and dosing of these agents.
AREAS COVERED
We will review the major published clinical trials for untreated AML that have established the dosing choice and schedule for intensive therapy, as well as trials for patients not eligible for more intensive therapy. We will also discuss treatment considerations for subgroups of patients.
EXPERT OPINION
While one or two cycles of anthracycline and cytarabine-based combination regimens remain the standard of care for younger and older patients with AML deemed fit to receive induction chemotherapy, controversy remains regarding the optimal selection and dosing schedule for anthracyclines. Low-intensity regimens, such as low-dose cytarabine and hypomethylating agents, can achieve a complete response even with adverse risk features, and can be used in a fit subset of older patients not eligible for clinical trial or transplant. Incorporation of new targeted agents, such as tyrosine kinase and small-molecule inhibitors, combined with better selection of drugs for unique patient cohorts, will likely be necessary to substantially improve outcomes in AML.
Topics: Antineoplastic Combined Chemotherapy Protocols; Clinical Trials, Phase III as Topic; Colony-Stimulating Factors; Cytarabine; Daunorubicin; Humans; Leukemia, Myeloid, Acute; Randomized Controlled Trials as Topic; Remission Induction
PubMed: 26364895
DOI: 10.1517/14656566.2015.1076795 -
European Journal of Medicinal Chemistry Jan 2021Despite the encouraging clinical progress of chemotherapeutic agents in cancer treatment, innovation and development of new effective anticancer candidates still... (Review)
Review
Despite the encouraging clinical progress of chemotherapeutic agents in cancer treatment, innovation and development of new effective anticancer candidates still represents a challenging endeavor. With 15 million death every year in 2030 according to the estimates, cancer has increased rising of an alarm as a real crisis for public health and health systems worldwide. Therefore, scientist began to introduce innovative solutions to control the cancer global health problem. One of the promising strategies in this issue is the multitarget or smart hybrids having two or more pharmacophores targeting cancer. These rationalized hybrid molecules have gained great interests in cancer treatment as they are capable to simultaneously inhibit more than cancer pathway or target without drug-drug interactions and with less side effects. A prime important example of these hybrids, the HDAC hybrid inhibitors or referred as multitargeting HDAC inhibitors. The ability of HDAC inhibitors to synergistically improve the efficacy of other anti-cancer drugs and moreover, the ease of HDAC inhibitors cap group modification prompt many medicinal chemists to innovate and develop new generation of HDAC hybrid inhibitors. Notably, and during this short period, there are four HDAC inhibitor hybrids have entered different phases of clinical trials for treatment of different types of blood and solid tumors, namely; CUDC-101, CUDC-907, Tinostamustine, and Domatinostat. This review shed light on the most recent hybrids of HDACIs with one or more other cancer target pharmacophore. The designed multitarget hybrids include topoisomerase inhibitors, kinase inhibitors, nitric oxide releasers, antiandrogens, FLT3 and JAC-2 inhibitors, PDE5-inhibitors, NAMPT-inhibitors, Protease inhibitors, BRD4-inhibitors and other targets. This review may help researchers in development and discovery of new horizons in cancer treatment.
Topics: Androgen Antagonists; Animals; Antineoplastic Agents; Benzimidazoles; Cyclic Nucleotide Phosphodiesterases, Type 5; Daunorubicin; Doxorubicin; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Molecular Targeted Therapy; Morpholines; Nicotinamide Phosphoribosyltransferase; Nitric Oxide; Pyrimidines; Quinazolines; Structure-Activity Relationship; Transcription Factors; fms-Like Tyrosine Kinase 3
PubMed: 33077264
DOI: 10.1016/j.ejmech.2020.112904 -
Drug Metabolism Reviews 2015Carbonyl reductase 1 (CBR1), an enzyme belonging to the short-chain dehydrogenases/reductases family, has been detected in all human tissues. CBR1 catalyzes the... (Review)
Review
Carbonyl reductase 1 (CBR1), an enzyme belonging to the short-chain dehydrogenases/reductases family, has been detected in all human tissues. CBR1 catalyzes the reduction of many xenobiotics, including important drugs (e.g. anthracyclines, nabumetone, bupropion, dolasetron) and harmful carbonyls and quinones. Moreover, it participates in the metabolism of a number of endogenous compounds and it may play a role in certain pathologies. Plant polyphenols are not only present in many human food sources, but are also a component of many popular dietary supplements and herbal medicines. Many studies reviewed herein have demonstrated the potency of certain flavonoids, stilbenes and curcuminoids in the inhibition of the activity of CBR1. Interactions of these polyphenols with transcriptional factors, which regulate CBR1 expression, have also been reported in several studies. As CBR1 plays an important role in drug metabolism as well as in the protection of the organism against potentially harmful carbonyls, the modulation of its expression/activity may have significant pharmacological and/or toxicological consequences. Some polyphenols (e.g. luteolin, apigenin and curcumin) have been shown to be very potent CBR1 inhibitors. The inhibition of CBR1 seems useful regarding the increased efficacy of anthracycline therapy, but it may cause the worse detoxification of reactive carbonyls. Nevertheless, all known information about the interactions of polyphenols with CBR1 have only been based on the results of in vitro studies. With respect to the high importance of CBR1 and the frequent consumption of polyphenols, in vivo studies would be very helpful for the evaluation of risks/benefits of polyphenol interactions with CBR1.
Topics: Alcohol Oxidoreductases; Animals; Bupropion; Butanones; Butyrophenones; Daunorubicin; Doxorubicin; Gene Expression Regulation, Enzymologic; Haloperidol; Humans; Indoles; Nabumetone; Neoplasms; Phenylpropionates; Polyphenols; Quinolizines; Substrate Specificity; Xenobiotics
PubMed: 26415702
DOI: 10.3109/03602532.2015.1089885 -
Journal of Chromatography. B,... Jun 2022Liposome encapsulating cytarabine (CYT) and daunorubicin (DNR) is applied for treating Acute Myeloid Leukemia (AML) patients. To evaluate and compare relationship...
Determination of free and encapsulated cytarabine and daunorubicin in rat plasma after intravenous administration of liposomal formulation using ultra-high performance liquid chromatography tandem mass spectrometry.
Liposome encapsulating cytarabine (CYT) and daunorubicin (DNR) is applied for treating Acute Myeloid Leukemia (AML) patients. To evaluate and compare relationship between the pharmacokinetics of free drug (drug which is not entrapped in liposomes) and liposome-encapsulated drug and the toxicity/efficacy, it is crucial to have trustworthy methods for separating the free and the encapsulated of the drug. In this study, methods were developed and validated to isolate and measure the free DNR/CYT (F-DNR/CYT), the encapsulated DNR/CYT (E-DNR/CYT) and the total DNR/CYT (T-DNR/CYT) in rat plasma. The methods involved solid-phase extraction (SPE) using reverse adsorbents for separating the F-DNR and E-DNR, SPE using cation exchange adsorbents for separating the E-CYT, ultrafiltration for isolating the F-CYT and protein precipitation (PPT) for releasing the T-DNR and T-CYT totally from the liposomal forms. The analytes were subsequently quantified on ultra-high performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) individually with multiple reaction monitoring (MRM) mode using positive electrospray ionization (ESI). The calibration curves showed good linear relationships over the concentration range of 0.22-44 μg/mL for E-DNR and T-DNR, 2-1000 ng/mL for F-DNR, 0.5-100 μg/mL for E-CYT and T-CYT, 4-2000 ng/mL for F-CYT respectively. For all the analytes, the within-and between-run precisions were less than13.6% and the accuracies (in terms of RE%) were within -12.5%. Besides, extraction recovery, matrix effect, dilution integrity and stability were also assessed. The methods were successfully applied to investigate the pharmacokinetics in Sprague-Dawley rats following i.v. administration liposomal formulation.
Topics: Administration, Intravenous; Animals; Chromatography, High Pressure Liquid; Chromatography, Liquid; Cytarabine; Daunorubicin; Humans; Liposomes; Rats; Rats, Sprague-Dawley; Tandem Mass Spectrometry
PubMed: 35551041
DOI: 10.1016/j.jchromb.2022.123275 -
Nanomedicine : Nanotechnology, Biology,... Nov 2020CPX-351, a liposomal encapsulation of cytarabine and daunorubicin at a synergistic 5:1 molar ratio, is indicated for adults with newly diagnosed, therapy-related acute...
CPX-351, a liposomal encapsulation of cytarabine and daunorubicin at a synergistic 5:1 molar ratio, is indicated for adults with newly diagnosed, therapy-related acute myeloid leukemia or acute myeloid leukemia with myelodysplasia-related changes. In preclinical species, this article demonstrated (1) similar release of cytarabine and daunorubicin by CPX-351 in plasma; (2) similar patterns of metabolism of cytarabine and daunorubicin following administration of CPX-351 versus non-liposomal cytarabine/daunorubicin combination; (3) prolonged tissue exposure to CPX-351; (4) dramatically different tissue distribution of cytarabine and daunorubicin following administration of CPX-351 versus non-liposomal combination (tissue:plasma ratios generally <1 versus >1, respectively); and (5) dramatically lower unbound plasma and tissue concentrations of cytarabine and daunorubicin following administration of CPX-351 versus non-liposomal combination. Together, these results provide insight into the safety profile of CPX-351, as well as mechanisms that drive the improved efficacy observed for CPX-351 versus the conventional 7 + 3 cytarabine/daunorubicin regimen in clinical studies.
Topics: Animals; Antineoplastic Agents; Area Under Curve; Bile; Chromatography, High Pressure Liquid; Cytarabine; Daunorubicin; Dogs; Drug Combinations; Feces; Female; Half-Life; Limit of Detection; Male; Mice; Rats; Spectrometry, Fluorescence; Spectrophotometry, Ultraviolet; Tissue Distribution
PubMed: 32750494
DOI: 10.1016/j.nano.2020.102275