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Current Oncology Reports Aug 2021With the recent approval of multiple new drugs for the treatment of acute myeloid leukemia (AML), the relevance of conventional treatment approaches, such as... (Review)
Review
PURPOSE OF REVIEW
With the recent approval of multiple new drugs for the treatment of acute myeloid leukemia (AML), the relevance of conventional treatment approaches, such as daunorubicin and cytarabine ("3+7") induction chemotherapy, has been challenged. We review the AML risk stratification, the efficacy of the newly approved drugs, and the role of "3+7".
RECENT FINDINGS
Treatment of AML is becoming more niched with specific subtypes more appropriately treated with gemtuzumab, midostaurin, and CPX-351. Although lower intensity therapies can yield high response rates, they are less efficient at preventing relapses. The only curative potential for poor-risk AML is still an allogeneic stem cell transplant. The number of AML subtypes where 3+7 alone is an appropriate therapeutic option is shrinking. However, it remains the backbone for combination therapy with newer agents in patients suitable for intensive chemotherapy.
Topics: Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Daunorubicin; Gemtuzumab; Hematopoietic Stem Cell Transplantation; Humans; Induction Chemotherapy; Leukemia, Myeloid, Acute; Risk Assessment; Staurosporine
PubMed: 34350512
DOI: 10.1007/s11912-021-01108-9 -
European Journal of Medicinal Chemistry Oct 2023Nowadays, with the advent of cutting-edge technologies in the field of biotechnology, some highly advanced medical methods are introduced to treat cancers more... (Review)
Review
Nowadays, with the advent of cutting-edge technologies in the field of biotechnology, some highly advanced medical methods are introduced to treat cancers more efficiently. In the chemotherapy processes, anti-cancer drugs can be encapsulated in a stimuli-responsive coating which is capable of being functionalized by diverse ligands to increase the biocompatibility and control drug release behavior in a targeted drug delivery system. Nanoparticles (NPs) are playing an important role as nanocarriers in chemotherapy procedures, recently, numerous novel drug delivery systems have been studied which employed diverse types of NPs with remarkable structural features like porous nanocarriers with active and extended surface areas to enhance the drug loading and delivery efficacy. In this study, Daunorubicin (DAU) as an effective anti-cancer drug for treating various cancers introduced, and its application for novel drug delivery systems either as a single chemotherapy agent or co-delivery alongside other drugs with diverse NPs has been reviewed.
Topics: Humans; Daunorubicin; Antineoplastic Agents; Nanoparticles; Drug Delivery Systems; Neoplasms; Drug Carriers
PubMed: 37327678
DOI: 10.1016/j.ejmech.2023.115547 -
Best Practice & Research. Clinical... Dec 2021The traditional cytotoxic induction regimen for acute myeloid leukemia (AML) is seven days of standard-dose cytarabine and three days of an anthracycline antibiotic... (Review)
Review
The traditional cytotoxic induction regimen for acute myeloid leukemia (AML) is seven days of standard-dose cytarabine and three days of an anthracycline antibiotic (such as daunorubicin or idarubicin), commonly known as "7 + 3." Many studies have been conducted to find an additional agent that might improve efficacy. Data from select studies has shown, in certain populations, benefit to adding cladribine, clofarabine and lomustine to a traditional backbone. For mutation-based chemotherapy regimens, midostaurin with 7 + 3 is the current standard of care for FLT3-mutant, younger AML patients. As we learn more about the synergism of molecular agents and traditional anti-cancer treatments, we can hopefully develop novel regimens without abandoning some of the benefits of these mutation agnostic historical therapies.
Topics: Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Daunorubicin; Humans; Idarubicin; Induction Chemotherapy; Leukemia, Myeloid, Acute; Remission Induction
PubMed: 34865698
DOI: 10.1016/j.beha.2021.101326 -
American Journal of Clinical Pathology Nov 2020Acute myeloid leukemia (AML) with myelodysplasia-related changes (AML-MRC) represents a high-risk and somewhat diverse subtype of AML, and substantial confusion exists... (Review)
Review
OBJECTIVES
Acute myeloid leukemia (AML) with myelodysplasia-related changes (AML-MRC) represents a high-risk and somewhat diverse subtype of AML, and substantial confusion exists about the pathologic evaluation needed for diagnosis, which can include the patient's clinical history, cytogenetic analysis, mutational analysis, and/or morphologic evaluation. Treatment decisions based on incomplete or untimely pathology reports may result in the suboptimal treatment of patients with AML-MRC.
METHODS
Using a PubMed search, diagnosis of and treatment options for AML-MRC were investigated.
RESULTS
This article reviews the current diagnostic criteria for AML-MRC, provides guidance on assessments necessary for an AML-MRC diagnosis, summarizes clinical and prognostic features of AML-MRC, and discusses potential therapies for patients with AML-MRC. In addition to conventional chemotherapy, treatment options include CPX-351, a liposomal encapsulation of daunorubicin/cytarabine approved for treatment of adults with AML-MRC; targeted agents for patients with certain mutations/disease characteristics; and lower-intensity therapies for less fit patients.
CONCLUSIONS
Given the evolving and complex treatment landscape and the high-risk nature of the AML-MRC population, a clear understanding of the pathology information necessary for AML-MRC diagnosis has become increasingly important to help guide treatment decisions and thereby improve patient outcomes.
Topics: Aged; Aminopyridines; Antineoplastic Agents; Blood Cells; Bone Marrow; Bone Marrow Examination; Chromosome Aberrations; Cytarabine; Cytogenetic Analysis; DNA Mutational Analysis; Daunorubicin; Genetic Predisposition to Disease; Humans; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Prognosis; PubMed; Triazines
PubMed: 32864703
DOI: 10.1093/ajcp/aqaa107 -
Journal of Pharmaceutical and... Nov 2020This report presents improved analysis methods of daunorubicin (DAUN) and its metabolite daunorubicinol (DAUNOL) in small volumes of plasma, as total and unbound...
Analysis of daunorubicin and its metabolite daunorubicinol in plasma and urine with application in the evaluation of total, renal and metabolic formation clearances in patients with acute myeloid leukemia.
This report presents improved analysis methods of daunorubicin (DAUN) and its metabolite daunorubicinol (DAUNOL) in small volumes of plasma, as total and unbound concentrations, as well as in urine. This study also presents the pharmacokinetics of DAUN and DAUNOL in patients (n = 12) diagnosed with acute myeloid leukemia treated with intravenous DAUN (60 mg/m/day, for three days). Serial blood and urine samples were collected up to 144 h after the beginning of the first infusion. The analytical methods presented no significant matrix effect. The linear ranges were 0.1-1000 ng/mL in plasma, 0.05-40 ng/mL in ultrafiltrate and 0.5-3000 ng/ml in urine. The precision and accuracy presented coefficients of variation and standard errors lower than 15 % in the three matrices. The methods allowed for the quantification of samples up to 144 h after the beginning of the first infusion. Unbound fractions for DAUN and DAUNOL were 23.91 % (17.33-32.99) and 29.23 % (25.84-33.07), respectively. The fraction recovered in urine was 4.40 % (3.87-5.03) for DAUN and 7.91 % (6.86-9.19) for DAUNOL. Total 292.96 L/h (261.74-327.90), renal 13.01 L/h (11.44-14.88), and hepatic 280.26 L/h (248.40-317.91) clearances of DAUN, as well as the DAUNOL formation clearance 23.41 L/h (19.09-28.97), were evaluated.
Topics: Body Fluids; Daunorubicin; Humans; Kidney; Leukemia, Myeloid, Acute
PubMed: 32889347
DOI: 10.1016/j.jpba.2020.113576 -
Hematological Oncology Mar 2024Venetoclax plus 3 + 7 daunorubicin and cytarabine chemotherapy (DAV) has shown safety and efficacy in eligible patients with newly diagnosed acute myeloid leukemia...
Venetoclax plus 3 + 7 daunorubicin and cytarabine chemotherapy (DAV) has shown safety and efficacy in eligible patients with newly diagnosed acute myeloid leukemia (AML). However, there are no direct comparisons between DAV and 3 + 7 daunorubicin and cytarabine chemotherapy (DA) alone. We performed a propensity score-matched analysis to compare the outcomes of DAV group with historical DA group and identify the clinical and molecular characteristics of patients who might benefit from the DAV regimen. The DAV group had a higher Complete remission (CR) rate than the DA group (90% vs. 55%, p = 0.008). 25 (96%) patients in the DAV group had a higher MRD-negative CRc rate compared with 13 (62%) patients in the DA group (p = 0.006). After a median follow-up duration of 19.15 (IQR 17.13-21.67) months, the DAV group had an improved overall survival (p = 0.001) and event-free survival (p = 0.069), but not disease-free survival (p = 0.136). Collectively, DAV regimen induced high CR rates and deep MRD-negative CRc rates after one cycle of induction therapy, as well as prolonged the overall survival, in young adult patients with AML who were eligible for intensive chemotherapy. The addition of venetoclax to intensive chemotherapy should be considered in the future to achieve better survival advantages in eligible AML patients.
Topics: Young Adult; Humans; Propensity Score; Leukemia, Myeloid, Acute; Daunorubicin; Cytarabine; Pathologic Complete Response; Sulfonamides; Bridged Bicyclo Compounds, Heterocyclic
PubMed: 38415873
DOI: 10.1002/hon.3260 -
The Oncologist Sep 2020On June 28, 2018, the Committee for Medicinal Products for Human Use adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal... (Review)
Review
EMA Review of Daunorubicin and Cytarabine Encapsulated in Liposomes (Vyxeos, CPX-351) for the Treatment of Adults with Newly Diagnosed, Therapy-Related Acute Myeloid Leukemia or Acute Myeloid Leukemia with Myelodysplasia-Related Changes.
On June 28, 2018, the Committee for Medicinal Products for Human Use adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Vyxeos, intended for the treatment of acute myeloid leukemia (AML). Vyxeos was designated as an orphan medicinal product on January 11, 2012. The applicant for this medicinal product was Jazz Pharmaceuticals Ireland Limited. Vyxeos is a liposomal formulation of a fixed combination of daunorubicin and cytarabine, antineoplastic agents that inhibit topoisomerase II activity and also cause DNA damage. The strength of Vyxeos is 5 units/mL, where 1 unit equals 1.0 mg cytarabine plus 0.44 mg daunorubicin. The marketing authorization holder Jazz Pharmaceuticals had found that this was an optimal ratio for the efficacy of the product. Study CLTR0310-301, a phase III, multicenter, randomized, trial of Vyxeos (daunorubicin-cytarabine) liposome injection versus standard 3+7 daunorubicin and cytarabine in patients aged 60-75 years with untreated high-risk (secondary) AML, showed a statistically significant difference between the two groups in overall survival (OS) with a median OS of 9.56 months in the daunorubicin-cytarabine arm compared with 5.95 months for standard chemotherapy (hazard ratio, 0.69; 95% confidence interval, 0.52-0.90; one-sided p = .003). The most common side effects were hypersensitivity including rash, febrile neutropenia, edema, diarrhea/colitis, mucositis, fatigue, musculoskeletal pain, abdominal pain, decreased appetite, cough, headache, chills, arrhythmia, pyrexia, sleep disorders, and hypotension. IMPLICATIONS FOR PRACTICE: Vyxeos has demonstrated a clinically significant improvement in overall survival compared with the standard of care 7+3 in the proposed population of patients with newly diagnosed acute myeloid leukemia (AML) with myelodysplasia-related changes and therapy-related AML. This is remarkable given the very poor prognosis of these patients and their unmet medical need. Secondary endpoints support the primary outcome, in particular an increased rate of hematopoietic stem cell transplantation, which is potentially the only curative treatment in AML.
Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Daunorubicin; Humans; Ireland; Leukemia, Myeloid, Acute; Liposomes
PubMed: 32282100
DOI: 10.1634/theoncologist.2019-0785 -
Pediatric Blood & Cancer Sep 2020Approximately 40% children with acute myeloid leukemia (AML) invariably relapse, after attaining the first complete remission (CR), with dismal long-term outcome. There...
Outpatient ADE (cytarabine, daunorubicin, and etoposide) is feasible and effective for the first relapse of pediatric acute myeloid leukemia: A prospective, phase II study.
BACKGROUND
Approximately 40% children with acute myeloid leukemia (AML) invariably relapse, after attaining the first complete remission (CR), with dismal long-term outcome. There is little consensus regarding choice of optimal induction chemotherapy regimen for relapsed pediatric AML.
PROCEDURE
A prospective single arm phase II study (CTRI/2017/02/007757) was carried out at our center to evaluate the safety and efficacy of outpatient cytarabine, daunorubicin, and etoposide (ADE) regimen in pediatric AML (≤18 years) at the first relapse. Response evaluation was done by bone marrow aspiration morphology along with minimal residual disease (MRD) assessment. All adverse events including need and duration of hospitalization, transfusion support, and antimicrobial use were recorded.
RESULTS
Total 45 patients were included with median age of 12 years. The CR rate of the cohort was 66% and 54% of patients were MRD negative. The estimated 2-year event-free survival (EFS) and overall survival (OS) were 29% (±7%) and 34% (±7%), respectively. The presence of fever at relapse was associated with inferior CR rate (P = .001), positive MRD (P = .01), and inferior EFS (P = .02), while not achieving nadir absolute neutrophil count of zero during induction was associated with inferior CR rate (P = .03) and inferior OS (P = .04). Approximately all patients developed ≥Grade 3 cytopenia and febrile neutropenia. Twenty-six (59%) patients required hospitalization for management of toxicity and there were four (9%) deaths attributed to infection.
CONCLUSION
ADE is an effective induction regimen for pediatric AML patients at the first relapse with reasonable toxicity profile. Outpatient administration of the regimen is feasible in the presence of proper support structure and rigorous follow up.
Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Cytarabine; Daunorubicin; Disease-Free Survival; Etoposide; Female; Follow-Up Studies; Humans; Leukemia, Myeloid, Acute; Male; Prospective Studies; Recurrence; Survival Rate
PubMed: 32672904
DOI: 10.1002/pbc.28404 -
Clinical Lymphoma, Myeloma & Leukemia Aug 2022Acute myeloid leukemia (AML) treatment landscape had evolved over the last decades with better understanding of the disease genomics and the use of the targeted therapy,... (Review)
Review
Acute myeloid leukemia (AML) treatment landscape had evolved over the last decades with better understanding of the disease genomics and the use of the targeted therapy, despite this treatment evolution, 7 + 3 remains the mainstay treatment for most AML cases. Many attempts had been made to improve the treatment outcome with 7 + 3 like manipulating the doses or the duration, but with no significant change in the outcome. In 2017 FDA approved CPX-351,a liposomal formulation of cytarabine and daunorubicin at a fixed 5:1 molar ratio, for the treatment of adults with newly diagnosed AML with myelodysplasia-related changes and therapy-related AML (t-AML). Since the approval, many trials were conducted or still ongoing in assessing the role of CPX-351 in treating different patient populations, AML subcategories or when combined with different agents. In this review, we will summarize the current role of CPX-351 in treating this largely heterogeneous disease.
Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Daunorubicin; Humans; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes
PubMed: 35418351
DOI: 10.1016/j.clml.2022.02.008 -
Minerva Medica Oct 2020Over the last few years, we assisted to an increasing knowledge about acute myeloid leukemia (AML) pathobiology. However, outcomes remain unsatisfactory particularly for... (Review)
Review
Over the last few years, we assisted to an increasing knowledge about acute myeloid leukemia (AML) pathobiology. However, outcomes remain unsatisfactory particularly for adult patients over 60 years old. Not surprisingly several cases of therapy-related AML (tAML) and secondary AML, both characterized by poorer prognosis, are more common in older population. For several decades initial therapy for AML remained unchanged and typically treatment consisted of an anthracycline combined with continuous infusion of cytarabine for 7 days, the so-called "7+3" standard regimen. The efforts made by the researchers to improve this standard schedule, have led to only modest improvement in the response rate (RR) but no change in overall survival (OS), until the recent evolution seen with new target specific mutation therapies. In 2017, a new liposomal-encapsulated formulation with daunorubicin and cytarabine (CPX-351) was approved by the US Food and Drug Administration for the treatment of newly diagnosed tAML or AML with myelodysplasia-related changes (AML-MRCs). Based on the findings that ratiometric delivery may be more effective than administration of either drug at their maximum tolerated dose (MTD), CPX-351 was designed to deliver a fixed 5:1 molar ratio of the two molecules historically used in the standard "7+3" regimen, cytarabine and daunorubicin respectively. CPX-351 did show improvements of overall survival compared to traditional "7+3" in newly diagnosed secondary and therapy-related AML in adult patients. However, questions remain regarding how to select across AML patient subgroups to maximize the clinical benefit. Possible future directions include evaluating CPX-351 dose intensification, combining this liposomal formulation with targeted therapies and not least important a better understanding about the mechanism of improved responses in tAML and AML-MRC, two entities recognized to be less chemo-sensitive than other hematologic malignancies. In summary, CPX-351 offers finally something new in the landscape of AML therapy. Herein we will review the rationale behind this new drug product development, the main pharmacological characteristics, and discuss the results of clinical trials that led to its FDA approval at first and by EMA in 2018.
Topics: Age Factors; Antimetabolites, Antineoplastic; Clinical Trials as Topic; Cytarabine; Daunorubicin; Humans; Leukemia, Myeloid, Acute; Liposomes; Middle Aged; Mutation; Myelodysplastic Syndromes
PubMed: 32955826
DOI: 10.23736/S0026-4806.20.07017-2