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The Medical Letter on Drugs and... Oct 2023
Topics: Humans; Leukemia, Myeloid, Acute; Daunorubicin; Benzothiazoles; Phenylurea Compounds; Mutation
PubMed: 37871118
DOI: 10.58347/tml.2023.1687d -
BMC Health Services Research Jan 2023Based on the results from the ALFA-0701 study, gemtuzumab ozogamicin (GO) has been approved by the European Medicine Agency and by the Italian Drug Agency for the first...
BACKGROUND
Based on the results from the ALFA-0701 study, gemtuzumab ozogamicin (GO) has been approved by the European Medicine Agency and by the Italian Drug Agency for the first line treatment of de novo acute-myeloid leukemia (AML). In this analysis, we assessed the cost-effectiveness of GO in combination with daunorubicin and cytarabine (DA), vs DA alone, adopting the perspective of the Italian National Health Service.
METHODS
For this analysis, a cohort state transition model was developed. The model was designed to capture health states and events that occur throughout the entire disease course and that impact costs and outcomes. The ALFA-0701 study was the main source of clinical data for this analysis. In the model, patients had the same baseline characteristics and experienced the same clinical improvements as in the ALFA-0701 study. Economic data (resource consumption and unit costs) were adapted to reflect expenditure for the Italian National Health Service. Utilities per health state and disutilities due to adverse events were based on the literature and on the general population for those functionally cured. A lifetime horizon was adopted, with both costs and outcome being discounted of 3.0%, annually. Deterministic and probabilistic sensitivity analyses were conducted to assess the robustness of results.
RESULTS
In the base case (lifetime horizon; primary source of data: study ALFA-0701; perspective: Italian National Health Service; discount rate on costs and outcomes: 3.0%), GO + DA was more effective DA both in terms of life-year (LY) survival (6.42 LY vs 5.75 LY, respectively) and quality-of-life adjusted survival (4.69 QALY vs 4.19 QALY, respectively). The overall costs were almost similar in the two groups (slightly lower with GO + DA than with DA; €162,424 and €162,708, respectively). The use of GO increased the costs of drug therapy but saved costs of relapse and costs associated with transplantation (HSCT).
CONCLUSIONS
If results of the ALFA-0701 study are applied to the Italian healthcare environment, then gemtuzumab ozogamicin, in combination with daunorubicin and cytarabine, would clinical outcomes and reduce lifetime costs, compared with daunorubicin and cytarabine alone for the first line treatment of de novo AML.
TRIAL REGISTRATION
Not applicable.
Topics: Humans; Gemtuzumab; Cost-Effectiveness Analysis; State Medicine; Antineoplastic Combined Chemotherapy Protocols; Leukemia, Myeloid, Acute; Daunorubicin; Cytarabine; Italy; Treatment Outcome; Sialic Acid Binding Ig-like Lectin 3
PubMed: 36642712
DOI: 10.1186/s12913-023-09054-x -
Best Practice & Research. Clinical... Jun 2019Initial therapy for acute myeloid leukemia (AML) remained stagnant for approximately four decades despite advances in improved understanding of pathogenesis and... (Review)
Review
Initial therapy for acute myeloid leukemia (AML) remained stagnant for approximately four decades despite advances in improved understanding of pathogenesis and prognostication of the disease. Treatment has typically consisted of an anthracycline combined with continuous infusion of cytarabine for 7 days, the "7 + 3" regimen. Attempts have been made to improve on this regimen with modest improvements in response rates but no change in overalll survival, until the recent introduction of mutation-specific agents. However, the re-vamping of the delivery of both daunorubicin and cytarabine in a liposomal encapsulation, known as CPX-351, did show improvements of overall survival compared to traditional 7 + 3 in newly diagnosed secondary and therapy-related AML in patients aged 60-75. This led to the Food and Drug Administration (FDA) approval of the agent for both of these subtypes of AML in August of 2017. Herein we will review the rationale and preclinical development of CPX-351 and discuss the pivotal studies that led to its FDA approval.
Topics: Aged; Cytarabine; Daunorubicin; Disease-Free Survival; Female; Humans; Leukemia, Myeloid, Acute; Male; Survival Rate
PubMed: 31203994
DOI: 10.1016/j.beha.2019.05.005 -
British Journal of Haematology Jan 2020Secondary acute myelogenous leukaemia (AML), as compared to de novo AML, occurs in the more elderly population, is independently more resistant to cytotoxic... (Review)
Review
Secondary acute myelogenous leukaemia (AML), as compared to de novo AML, occurs in the more elderly population, is independently more resistant to cytotoxic chemotherapy, has a higher relapse rate, and a worse prognosis. Secondary AML (sAML) is a heterogeneous disease, both biologically and clinically, even within the World Health Organization subgroups of sAML. Outcomes are the poorest in subgroups with sAML arising from an antecedent haematologic disorder which has been previously treated (ts-AML), and sAML in patients <55 years of age. This review describes the suboptimal outcomes of contemporary therapy, to support the notion of an unmet need for innovative treatment strategies in sAML. Despite the recent approval of CPX-351, long-term outcomes for this high-risk disease remain dismal. Resistance mechanisms to intensive chemotherapy contribute to relapse. Targeted immune therapy may avoid multidrug resistance mechanisms, but are unlikely to provide long-term remission due to a complex and rapidly evolving clonal disease profile. Advances for sAML will likely be accomplished by CAR T cell therapy or bispecific antibodies providing a bridge to allogeneic stem cell transplantation. Therefore, focus should be placed on novel strategies that can augment the untargeted effector function of allogeneic grafts.
Topics: Age Factors; Allografts; Antibodies, Bispecific; Antineoplastic Agents, Immunological; Cytarabine; Daunorubicin; Disease-Free Survival; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Humans; Immunotherapy, Adoptive; Leukemia, Myeloid, Acute; Remission Induction; Stem Cell Transplantation
PubMed: 31863469
DOI: 10.1111/bjh.16354 -
BMC Cancer Jun 2017Acute myeloid leukemia (AML) accounts for more than two thirds of leukemia during pregnancy and has an incidence of 1 in 75,000 to 100,000. Its clinical management... (Review)
Review
BACKGROUND
Acute myeloid leukemia (AML) accounts for more than two thirds of leukemia during pregnancy and has an incidence of 1 in 75,000 to 100,000. Its clinical management remains a challenging therapeutic task both for patient and medical team, given to the therapy-attributable risks for mother and fetus and the connected counseling regarding pregnancy continuation.
METHODS
We provided a review of updated literature and a comprehensive description of five maternal/fetal outcomes of AML cases diagnosed concomitantly to pregnancy and treated at our Institution from 2006 to 2012.
RESULTS
Median age at AML diagnosis was 32 years (31-39). One diagnosis was performed in first trimester and the patient asked for therapeutic abortion before starting chemotherapy. Three cases were diagnosed in second/third trimester; in one case leukemia was diagnosed concomitantly with intrauterine fetal death, while the remaining two patients continued pregnancy and delivered a healthy baby by cesarean section. In only one of these two cases chemotherapy was performed during pregnancy (at 24 + 5 weeks) and consisted of a combination of daunorubicine and cytarabine. Therapy was well tolerated and daily fetus monitoring was performed. After completion of 30 weeks of gestation a cesarean section was carried out; the newborn had an Apgar score of 5/1'-7/5'-9/10', oxygen therapy was temporarily given and peripheral counts displayed transient mild leukopenia. One patient had diagnosis of myelodysplastic syndrome rapidly progressed to AML after delivery. Four out of the 5 described women are currently alive and disease-free. Three children were born and long-term follow-up has shown normal growth and development.
CONCLUSIONS
The treatment of AML occurring during pregnancy is challenging and therapeutic decisions should be taken individually for each patient. Consideration must be given both to the immediate health of mother and fetus and to long-term infant health. Our series confirmed the literature data: fetal toxicity of cytostatic therapy clusters during the first trimester; while chemotherapy can be administered safely during second/third trimester and combination of daunorubicin and cytarabine is recommended for induction.
Topics: Abortion, Therapeutic; Adult; Cesarean Section; Child; Cytarabine; Daunorubicin; Female; Fetal Death; Humans; Infant, Newborn; Leukemia, Myeloid, Acute; Pregnancy; Pregnancy Complications, Neoplastic
PubMed: 28645262
DOI: 10.1186/s12885-017-3436-9 -
International Journal of Molecular... Dec 2022Chemoresistance is one of the major challenges for the treatment of acute myeloid leukemia. Epigallocatechin gallate (EGCG), a bioactive polyphenol from green tea, has...
Chemoresistance is one of the major challenges for the treatment of acute myeloid leukemia. Epigallocatechin gallate (EGCG), a bioactive polyphenol from green tea, has attracted immense interest as a potential chemosensitizer, but its application is limited due to the need for effective formulations capable of co-delivering EGCG and anti-leukemic drugs. Herein, we describe the formation and characterization of a micellar nanocomplex self-assembled from EGCG and daunorubicin, an anthracycline drug for the first-line treatment of acute myeloid leukemia. This nanocomplex was highly stable at pH 7.4 but stimulated to release the incorporated daunorubicin at pH 5.5, mimicking an acidic endosomal environment. More importantly, the nanocomplex exhibited superior cytotoxic efficacy against multidrug-resistant human leukemia cells over free daunorubicin by achieving a strong synergism, as supported by median-effect plot analysis. The observed chemosensitizing effect was in association with enhanced nucleus accumulation of daunorubicin, elevation of intracellular reactive oxygen species and caspase-mediated apoptosis induction. Our study presents a promising strategy for circumventing chemoresistance for more effective leukemia therapy.
Topics: Humans; Daunorubicin; Apoptosis; Drug Resistance, Neoplasm; Leukemia, Myeloid, Acute; Catechin; Tea
PubMed: 36613821
DOI: 10.3390/ijms24010381 -
Biochimie Mar 2023Along with bright fluorescence in the near-IR range, heptamethine carbocyanine dyes possess affinity to cancer cells. Thus, these dyes could be utilized as fluorescent...
Along with bright fluorescence in the near-IR range, heptamethine carbocyanine dyes possess affinity to cancer cells. Thus, these dyes could be utilized as fluorescent labels and vectors for drug delivery as covalent conjugates with cytotoxic compounds. To test the properties, structure-activity relationship, and scope of such conjugates, we synthesized drug-dye dyads of tricarbocyanine dyes with anthracycline drug daunorubicin. We used hydrophilic zwitterionic and hydrophobic positively charged benzoindoline-benzothiazole-based heptamethine dyes as terminal alkyne derivatives and N-acylated or oxime-linked daunorubicin as azido-derivatives. These two alkynes and two azides were coupled to each other by Cu-catalyzed Huisgen-Meldal-Sharpless cycloaddition (click reaction) to afford four conjugates. Molecules based on hydrophobic dyes possess submicromolar cytotoxicity to HCT116 cells. Cytotoxicity, cell penetration, intracellular distribution, apoptosis induction and the effect of antioxidants on toxicity were evaluated. The results show that the structure of the cyanine-anthracycline conjugate (hydrophilicity/hydrophobicity, charge, linker, attachment site) is important for its biological activity, thus, expansion of the chemical space of such conjugates could provide new molecular research tools for diagnostics and therapy.
Topics: Fluorescent Dyes; Anthracyclines; Carbocyanines; Alkynes; Daunorubicin; Azides; Click Chemistry
PubMed: 36179940
DOI: 10.1016/j.biochi.2022.09.015 -
Microbiological Research Sep 2017DrrC is a DNA-binding protein of Streptomyces peucetius that provides self-resistance against daunorubicin, the antibiotic produced by the organism. DrrC was expressed...
DrrC is a DNA-binding protein of Streptomyces peucetius that provides self-resistance against daunorubicin, the antibiotic produced by the organism. DrrC was expressed in E.coli and purified by using N-terminal MBP-tag which retained DNA-binding property in spite of the tag. Mobility shift assay confirmed the interaction of 313bp DNA that has the dnrI promoter, daunorubicin and MBP-DrrC in the presence of ATP. Biotinylated and immobilized 313bp DNA was intercalated with daunorubicin to observe the release of the drug when MBP-DrrC is allowed to act on the DNA. The release of daunorubicin was recorded by absorption and fluorescence spectroscopy. The experiments proved that daunorubicin was released from DNA in the presence of MBP-DrrC. Fluorescence emission of daunorubicin had a maximum peak at 591nm. However, emission spectrum of released daunorubicin showed hypochromism with a maximum peak at 584nm that is possibly because it is in complex with MBP-DrrC. We propose that DrrC naturally binds at intercalated sites to eject daunorubicin; in the process both drug and protein are dislodged from DNA. Like UvrA, DrrC possibly scans the DNA for intercalated daunorubicin. When it encounters daunorubicin, DrrC dislodges it, thereby allowing DNA replication and transcription to go on unhindered. Thus a novel self resistance mechanism by DNA repair is mediated by DrrC.
Topics: Antibiotics, Antineoplastic; Bacterial Proteins; Base Sequence; Cloning, Molecular; DNA Repair; DNA, Bacterial; DNA-Binding Proteins; Daunorubicin; Drug Resistance, Microbial; Escherichia coli; Escherichia coli Proteins; Gene Expression Regulation, Bacterial; Genes, Bacterial; Promoter Regions, Genetic; Streptavidin; Streptomyces
PubMed: 28647120
DOI: 10.1016/j.micres.2017.05.002 -
Blood Cancer Journal Sep 2022The benefit of three-drug induction chemotherapy over a two-drug induction has not been evaluated in pediatric acute myeloid leukemia (AML). We, therefore, conducted a... (Randomized Controlled Trial)
Randomized Controlled Trial
The benefit of three-drug induction chemotherapy over a two-drug induction has not been evaluated in pediatric acute myeloid leukemia (AML). We, therefore, conducted a randomized controlled trial to ascertain the benefit of a three-drug induction regimen. Patients aged 1-18 years with newly diagnosed AML were randomized to two cycles of induction chemotherapy with daunorubicin and ara-C (DA) or two cycles of ara-C, daunorubicin, and etoposide (ADE). After induction, patients in both arms received consolidation with two cycles of high-dose ara-C. The study's primary objective was to compare the event-free survival (EFS) between the two arms. The secondary objectives included comparing the composite complete remission (cCR) rates, overall survival (OS), and toxicities. The study randomized 149 patients, 77 in the DA and 72 in the ADE arm. The median age was 8.7 years, and 92 (62%) patients were males. The median follow-up was 50.9 months. The cCR rate in the DA and ADE arm were 82% and 79% (p = 0.68) after the second induction. There were 13 (17%) induction deaths in the DA arm and 12 (17%) in the ADE arm (p = 0.97). The 5-year EFS in the DA and ADE arm was 34.4% and 34.5%, respectively (p = 0.66). The 5-year OS in the DA and ADE arms was 41.4% and 42.09%, respectively (p = 0.74). There were no significant differences in toxicities between the regimens. There was no statistically significant difference in EFS, OS, CR, or toxicity between ADE and DA regimens in pediatric AML. The trial was registered with the Clinical Trial Registry of India (Reference number: CTRI/2014/11/005202).
Topics: Antineoplastic Combined Chemotherapy Protocols; Child; Cytarabine; Daunorubicin; Female; Humans; Induction Chemotherapy; Leukemia, Myeloid, Acute; Male; Remission Induction
PubMed: 36068213
DOI: 10.1038/s41408-022-00726-1 -
Journal of Clinical Pharmacology May 2019CPX-351, a dual-drug liposomal encapsulation of cytarabine and daunorubicin at a synergistic ratio, is approved in the United States for adults with newly diagnosed...
CPX-351, a dual-drug liposomal encapsulation of cytarabine and daunorubicin at a synergistic ratio, is approved in the United States for adults with newly diagnosed therapy-related acute myeloid leukemia or acute myeloid leukemia with myelodysplasia-related changes. Population pharmacokinetics analyses were performed using nonlinear mixed-effect modeling on pooled data from 3 clinical studies, and the impact of CPX-351 exposures on efficacy and safety was assessed. The pharmacokinetics of cytarabine and daunorubicin were described using 2-compartment models with linear elimination. None of the evaluated covariates had a clinically significant impact on plasma exposure to total cytarabine or daunorubicin, while bilirubin and formulation showed statistically significant effects on pharmacokinetic parameters of cytarabine and daunorubicin, respectively. In patients with mild/moderate renal impairment or serum bilirubin ≤3 mg/dL, plasma exposures to cytarabine and daunorubicin following CPX-351 were within the variability range for patients with normal kidney function or serum bilirubin levels. Exposure-response analysis demonstrated that better efficacy outcomes were associated with higher CPX-351 exposure quartiles. Early mortality rates in all CPX-351 exposure quartiles were lower vs the 7 + 3 control group, and lower mortality rates were associated with higher exposure quartiles. A trend toward greater frequency of grade 3 treatment-emergent adverse events (but not grade 4/5 events) was observed at higher CPX-351 exposure quartiles. Overall, the population pharmacokinetic analyses indicate no adjustments to the recommended dose and schedule of CPX-351 are warranted for patients with mild/moderate renal impairment or serum bilirubin ≤3 mg/dL. Results from the exposure-response analyses suggest the current CPX-351 regimen provides a favorable risk-benefit profile.
Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Daunorubicin; Dose-Response Relationship, Drug; Female; Hematologic Neoplasms; Humans; Leukemia, Myeloid, Acute; Liposomes; Male; Middle Aged; Renal Insufficiency; Treatment Outcome
PubMed: 30566230
DOI: 10.1002/jcph.1366