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Leukemia & Lymphoma Feb 2020For decades, the standard induction for patients with acute myeloid leukemia (AML) has been the combination of cytarabine with anthracycline (7 + 3 regimen). In... (Review)
Review
For decades, the standard induction for patients with acute myeloid leukemia (AML) has been the combination of cytarabine with anthracycline (7 + 3 regimen). In August 2017 the US FDA approved CPX-351 (vyxeos), 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 (AML-MRC) and therapy-related AML (t-AML). This is the first approved treatment specifically for patients with this subgroup of AML. The approval was based on findings from a multicenter, randomized, open-label, phase III study of CPX-351 Versus 7 + 3 in patients 60-75 years old with newly diagnosed AML-MRC or t-AML. In this study CPX-351 had a higher median OS than 7 + 3 (9.56 vs 5.95 months, HR 0.69; 95% CI: 0.52 to 0.90, = 0.005). In this profile, we review preclinical and clinical data, and discuss limitations and future directions with CPX-351 use in AML.
Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Daunorubicin; Humans; Leukemia, Myeloid, Acute; Middle Aged; Multicenter Studies as Topic; Myelodysplastic Syndromes; Randomized Controlled Trials as Topic
PubMed: 31547736
DOI: 10.1080/10428194.2019.1660970 -
Anti-cancer Agents in Medicinal... 2021Doxorubicin (DOX) is widely used as a clinical first-line anti-cancer drug. However, its clinical application is severely limited due to the lack of tumor specificity of... (Review)
Review
Doxorubicin (DOX) is widely used as a clinical first-line anti-cancer drug. However, its clinical application is severely limited due to the lack of tumor specificity of the drug and severe side effects such as myelosuppression, nephrotoxicity, dose-dependent cardiotoxicity, and multi-drug resistance. To improve the bioavailability of DOX, maximize the therapeutic effect, and reduce its toxicity and side effects, many studies have been done on the nanoformulations of DOX, such as liposomes, polymer micelles, dendrimer, and nanogels. Herein, we review the latest progress of DOX nano-preparations and their anti-tumor effects, hoping to provide theoretical references and new research ideas for the development of new dosage forms of the drug and the technical methods available for clinical application.
Topics: Antibiotics, Antineoplastic; Cell Proliferation; Doxorubicin; Humans; Molecular Conformation; Nanoparticles; Neoplasms
PubMed: 33372884
DOI: 10.2174/1871520621666201229115612 -
The Lancet. Haematology Jul 2021Daunorubicin and cytarabine are used as standard induction chemotherapy for patients with acute myeloid leukaemia. CPX-351 is a dual-drug liposomal encapsulation of... (Randomized Controlled Trial)
Randomized Controlled Trial
CPX-351 versus 7+3 cytarabine and daunorubicin chemotherapy in older adults with newly diagnosed high-risk or secondary acute myeloid leukaemia: 5-year results of a randomised, open-label, multicentre, phase 3 trial.
BACKGROUND
Daunorubicin and cytarabine are used as standard induction chemotherapy for patients with acute myeloid leukaemia. CPX-351 is a dual-drug liposomal encapsulation of daunorubicin and cytarabine in a synergistic 1:5 molar ratio. Primary analysis of the phase 3 trial in adults aged 60-75 years with newly diagnosed high-risk or secondary acute myeloid leukaemia provided support for approval of CPX-351 by the US Food and Drug Administration and European Medicines Agency. We describe the prospectively planned final 5-year follow-up results.
METHODS
This randomised, open-label, multicentre, phase 3 trial was done across 39 academic and regional cancer centres in the USA and Canada. Eligible patients were aged 60-75 years and had a pathological diagnosis of acute myeloid leukaemia according to WHO 2008 criteria, no previous induction therapy for acute myeloid leukaemia, and an Eastern Cooperative Oncology Group performance status of 0-2. Patients were randomly assigned 1:1 (stratified by age and acute myeloid leukaemia subtype) to receive up to two induction cycles of CPX-351 (100 units/m administered as a 90-min intravenous infusion on days 1, 3, and 5; on days 1 and 3 for the second induction) or standard chemotherapy (cytarabine 100 mg/m per day continuous intravenous infusion for 7 days plus intravenous daunorubicin 60 mg/m on days 1, 2, and 3 [7+3]; cytarabine for 5 days and daunorubicin on days 1 and 2 for the second induction [5+2]). Patients with complete remission or complete remission with incomplete neutrophil or platelet recovery could receive up to tw cycles of consolidation therapy with CPX-351 (65 units/m 90-min infusion on days 1 and 3) or chemotherapy (5+2, same dosage as in the second induction cycle). The primary outcome was overall survival analysed in all randomly assigned patients. No additional adverse events were collected with long-term follow-up, except data for deaths. This trial is registered with ClinicalTrials.gov, NCT01696084, and is complete.
FINDINGS
Between Dec 20, 2012, and Nov 11, 2014, 309 patients with newly diagnosed high-risk or secondary acute myeloid leukaemia were enrolled and randomly assigned to receive CPX-351 (153 patients) or 7+3 (156 patients). At a median follow-up of 60·91 months (IQR 60·06-62·98) in the CPX-351 group and 59·93 months (59·73-60·50) in the 7+3 group, median overall survival was 9·33 months (95% CI 6·37-11·86) with CPX-351 and 5·95 months (4·99-7·75) with 7+3 (HR 0·70, 95% CI 0·55-0·91). 5-year overall survival was 18% (95% CI 12-25%) in the CPX-351 group and 8% (4-13%) in the 7+3 group. The most common cause of death in both groups was progressive leukaemia (70 [56%] of 124 deaths in the CPX-351 group and 74 [53%] of 140 deaths in the 7+3 group). Six (5%) of 124 deaths in the CPX-351 group and seven (5%) of 140 deaths in the 7+3 group were considered related to study treatment.
INTERPRETATION
After 5 years of follow-up, the improved overall survival with CPX-351 versus 7+3 was maintained, which supports the previous evidence that CPX-351 can contribute to long-term remission and improved overall survival in patients aged 60-75 years with newly diagnosed high-risk or secondary acute myeloid leukaemia.
FUNDING
Jazz Pharmaceuticals.
Topics: Aged; Cytarabine; Daunorubicin; Drug Administration Schedule; Female; Follow-Up Studies; Hematopoietic Stem Cell Transplantation; Humans; Infusions, Intravenous; Kaplan-Meier Estimate; Leukemia, Myeloid, Acute; Male; Middle Aged; Neoplasms, Second Primary; Proportional Hazards Models; Treatment Outcome
PubMed: 34171279
DOI: 10.1016/S2352-3026(21)00134-4 -
Genes Jul 2020Acute myeloid leukemia (AML) with myelodysplasia-related changes (AML-MRC) is a distinct biologic subtype of AML that represents 25-34% of all AML diagnoses and... (Review)
Review
Acute myeloid leukemia (AML) with myelodysplasia-related changes (AML-MRC) is a distinct biologic subtype of AML that represents 25-34% of all AML diagnoses and associates with especially inferior outcomes compared to non-MRC AML. Typically, patients with AML-MRC experience low remission rates following intensive chemotherapy and a median overall survival of merely 9-12 months. In light of these discouraging outcomes, it has become evident that more effective therapies are needed for patients with AML-MRC. Liposomal daunorubicin-cytarabine (CPX-351) was approved in 2017 for adults with newly diagnosed AML-MRC and those with therapy-related AML (t-AML), and remains the only therapy specifically approved for this patient population. Other studies have also demonstrated the efficacy of the hypomethylating agent (HMA) azacitidine as upfront therapy for AML-MRC patients, which, to date, is the most common treatment employed for patients unable to tolerate the more intensive CPX-351. HMAs and venetoclax combinations have also been evaluated, but additional studies utilizing these agents in this specific subgroup are needed before conclusions regarding their role in the therapeutic armamentarium of AML-MRC patients can be reached. Currently, many studies are ongoing in attempts to further improve outcomes in this historically ill-fated patient group.
Topics: Cytarabine; Daunorubicin; Humans; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Prognosis
PubMed: 32722092
DOI: 10.3390/genes11080845 -
Blood Advances Aug 2023Liposomal daunorubicin and cytarabine (CPX-351) improved overall survival (OS) compared with 7+3 chemotherapy in older patients with secondary acute myeloid leukemia... (Randomized Controlled Trial)
Randomized Controlled Trial
Liposomal daunorubicin and cytarabine (CPX-351) improved overall survival (OS) compared with 7+3 chemotherapy in older patients with secondary acute myeloid leukemia (AML); to date, there have been no randomized studies in younger patients. The high-risk cohort of the UK NCRI AML19 trial (ISRCTN78449203) compared CPX-351 with FLAG-Ida in younger adults with newly diagnosed adverse cytogenetic AML or high-risk myelodysplastic syndromes (MDS). A total of 189 patients were randomized (median age, 56 years). Per clinical criteria, 49% of patients had de novo AML, 20% had secondary AML, and 30% had high-risk MDS. MDS-related cytogenetics were present in 73% of the patients, with a complex karyotype in 49%. TP53 was the most common mutated gene, in 43%. Myelodysplasia-related gene mutations were present in 75 (44%) patients. The overall response rate (CR + CRi) after course 2 was 64% and 76% for CPX-351 and FLAG-Ida, respectively. There was no difference in OS (13.3 months vs 11.4 months) or event-free survival in multivariable analysis. However, relapse-free survival was significantly longer with CPX-351 (median 22.1 vs 8.35 months). There was no difference between the treatment arms in patients with clinically defined secondary AML or those with MDS-related cytogenetic abnormalities; however, an exploratory subgroup of patients with MDS-related gene mutations had significantly longer OS with CPX-351 (median 38.4 vs 16.3 months). In conclusion, the OS of younger patients with adverse risk AML/MDS was not significantly different between CPX-351 and FLAG-Ida.
Topics: Adult; Humans; Aged; Middle Aged; Daunorubicin; Cytarabine; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Karyotype; United Kingdom
PubMed: 37171402
DOI: 10.1182/bloodadvances.2023010276 -
Blood Oct 2019We investigated and modeled the mesenchymal stromal cell (MSC) niche in adult acute lymphoblastic leukemia (ALL). We used gene expression profiling, cytokine/chemokine...
We investigated and modeled the mesenchymal stromal cell (MSC) niche in adult acute lymphoblastic leukemia (ALL). We used gene expression profiling, cytokine/chemokine quantification, flow cytometry, and a variety of imaging techniques to show that MSCs, directly isolated from the primary bone marrow specimens of patients with ALL, frequently adopted an activated, cancer-associated fibroblast phenotype. Normal, primary human MSCs and the MSC cell line HS27a both were activated de novo, when exposed to the reactive oxygen species (ROS)-inducing chemotherapy agents cytarabine (AraC) and daunorubicin (DNR), a phenomenon blocked by the antioxidant N-acetyl cysteine. Chemotherapy-activated HS27a cells were functionally evaluated in a coculture model with ALL targets. Activated MSCs prevented therapy-induced apoptosis and death in ALL targets, via mitochondrial transfer through tunneling nanotubes (TNTs). Reduction of mitochondrial transfer by selective mitochondrial depletion or interference with TNT formation by microtubule inhibitors, such as vincristine (VCR), prevented the "rescue" function of activated MSCs. Corticosteroids, also a mainstay of ALL therapy, prevented the activation of MSCs. We also demonstrated that AraC (but not VCR) induced activation of MSCs, mitochondrial transfer, and mitochondrial mass increase in a murine NSG model of disseminated SEM cell-derived ALL, wherein CD19+ cells closely associated with nestin+ MSCs after AraC, but not in the other conditions. Our data propose a readily clinically exploitable mechanism for improving treatment of ALL, in which traditional ROS-inducing chemotherapies are often ineffective at eradicating residual disease, despite efficiently killing the bulk population.
Topics: Adult; Aged; Animals; Antineoplastic Agents; Cell Line, Tumor; Cells, Cultured; Coculture Techniques; Cytarabine; Daunorubicin; Female; Humans; Male; Mesenchymal Stem Cells; Mice; Middle Aged; Mitochondria; Oxidative Stress; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Young Adult
PubMed: 31501154
DOI: 10.1182/blood.2019001398 -
Journal of Hematology & Oncology Oct 2022CPX-351 (Europe: Vyxeos liposomal; United States: Vyxeos) is a dual-drug liposomal encapsulation of daunorubicin and cytarabine in a synergistic 1:5 molar ratio. In a... (Randomized Controlled Trial)
Randomized Controlled Trial
Efficacy and safety of CPX-351 versus 7 + 3 chemotherapy by European LeukemiaNet 2017 risk subgroups in older adults with newly diagnosed, high-risk/secondary AML: post hoc analysis of a randomized, phase 3 trial.
CPX-351 (Europe: Vyxeos liposomal; United States: Vyxeos) is a dual-drug liposomal encapsulation of daunorubicin and cytarabine in a synergistic 1:5 molar ratio. In a phase 3 study in older adults with newly diagnosed, high-risk/secondary AML, CPX-351 improved the remission frequency, overall survival, and post-transplant survival versus 7 + 3. This post hoc analysis evaluated the final 5-year follow-up outcomes according to the European LeukemiaNet 2017 risk classification. CPX-351-treated patients had a higher remission frequency (adverse risk: 41% vs 26%; intermediate risk: 58% vs 39%) and longer median overall survival (adverse risk: 7.59 vs 5.52 months; intermediate risk: 11.86 vs 7.75 months) and post-transplant survival (adverse risk: 43.14 vs 7.08 months; intermediate risk: not reached vs 13.57 months) versus 7 + 3, with outcomes generally poorer among patients with adverse-risk AML. The safety profile of CPX-351 among patients with adverse-risk or intermediate-risk AML was consistent with that of the overall study population. Early mortality was lower, and hospitalization length of stay per patient-year was shorter with CPX-351 versus 7 + 3 within the adverse-risk and intermediate-risk subgroups. The favorable outcomes observed with CPX-351 in this post hoc analysis are consistent with results for the overall study population and further support the use of CPX-351 in these patients.ClinicalTrials.gov Identifier: NCT01696084.
Topics: Aged; Humans; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Daunorubicin; Leukemia, Myeloid, Acute; Neoplasms, Second Primary
PubMed: 36289532
DOI: 10.1186/s13045-022-01361-w -
The Lancet. Haematology Jun 2022Adults with acute myeloid leukaemia have unsatisfactory clinical outcomes and rates of complete remission. Venetoclax combined with azacytidine or low-dose cytarabine...
Venetoclax plus 3 + 7 daunorubicin and cytarabine chemotherapy as first-line treatment for adults with acute myeloid leukaemia: a multicentre, single-arm, phase 2 trial.
BACKGROUND
Adults with acute myeloid leukaemia have unsatisfactory clinical outcomes and rates of complete remission. Venetoclax combined with azacytidine or low-dose cytarabine has shown efficacy in adults aged 75 years or older (or 18-74 years with comorbidities precluding intensive chemotherapy) with acute myeloid leukaemia. We aimed to investigate the activity and safety of venetoclax plus 3+7 daunorubicin and cytarabine chemotherapy in adults with acute myeloid leukaemia.
METHODS
We conducted a two-stage, single-arm, phase 2 trial at three public hospitals in China. We enrolled patients aged 18-60 years with previously untreated de novo acute myeloid leukaemia and an Eastern Cooperative Oncology Group performance status of 0-2. Patients received induction treatment with intravenous daunorubicin (60 mg/m on days 1-3), intravenous cytarabine (100 mg/m on days 1-7), and oral venetoclax (100 mg on day 4, 200 mg on day 5, and 400 mg on days 6-11; DAV regimen). For induction therapy, the length of the treatment was 28-35 days per cycle and the number of treatment cycles was one or two. The primary endpoint was the composite complete remission rate (complete remission plus complete remission with incomplete blood cell count recovery) after one cycle of induction treatment, assessed in the as-treated population. Secondary endpoints were bone marrow measurable residual disease by flow cytometry, event-free survival, overall survival, and adverse events. This trial is ongoing and is registered with Chinese Clinical Trial Registry, ChiCTR2000041509.
FINDINGS
Between Dec 25, 2020, and July 7, 2021, 36 patients were assessed for eligibility and 33 were enrolled. 15 (45%) patients were men and 18 (55%) were women, and all were Asian. The composite complete remission rate after one cycle of DAV regimen was 91% (95% CI 76-98; 30 of 33 patients) in the entire cohort. 29 (97%) of 30 patients who reached complete remission had undetectable measurable residual disease (ie, <0·1%). Grade 3 or worse adverse events included neutropenia in 33 (100%) of 33 patients, thrombocytopenia in 33 (100%), anaemia in 33 (100%), febrile neutropenia in 18 (55%), pneumonia in seven (21%), and sepsis in four (12%). No treatment-related deaths occurred. With a median follow-up of 11 months (IQR 9-12), estimated 1-year overall survival was 97% (95% CI 91-100) and 1-year event-free survival was 72% (56-94).
INTERPRETATION
The DAV regimen represents an effective induction therapy for newly diagnosed adults with acute myeloid leukaemia, which resulted in a high rate of complete remission. These findings are an important contribution to the field, showing a safe strategy to incorporate venetoclax into the most common induction regimen used to treat newly diagnosed acute myeloid leukaemia internationally.
FUNDING
Leading Innovative and Entrepreneur Team Introduction Program of Zhejiang, National Natural Science Foundation of China, Key Research and Development Program of Zhejiang.
TRANSLATION
For the Chinese translation of the abstract see Supplementary Materials section.
Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Cytarabine; Daunorubicin; Female; Humans; Leukemia, Myeloid, Acute; Male; Neoplasm, Residual; Sulfonamides
PubMed: 35512726
DOI: 10.1016/S2352-3026(22)00106-5 -
The Lancet. Haematology Nov 2023Many older patients with acute myeloid leukaemia die or cannot undergo allogeneic haematopoietic stem-cell transplantation (HSCT) due to toxicity caused by intensive... (Randomized Controlled Trial)
Randomized Controlled Trial
10-day decitabine versus 3 + 7 chemotherapy followed by allografting in older patients with acute myeloid leukaemia: an open-label, randomised, controlled, phase 3 trial.
BACKGROUND
Many older patients with acute myeloid leukaemia die or cannot undergo allogeneic haematopoietic stem-cell transplantation (HSCT) due to toxicity caused by intensive chemotherapy. We hypothesised that replacing intensive chemotherapy with decitabine monotherapy could improve outcomes.
METHODS
This open-label, randomised, controlled, phase 3 trial was conducted at 54 hospitals in nine European countries. Patients aged 60 years and older who were newly diagnosed with acute myeloid leukaemia and had not yet been treated were enrolled if they had an Eastern Cooperative Oncology Group performance status of 2 or less and were eligible for intensive chemotherapy. Patients were randomly assigned (1:1) to receive decitabine or standard chemotherapy (known as 3 + 7). For the decitabine group, decitabine (20 mg/m) was administered for the first 10 days in the first 28-day cycle, followed by 28-day cycles consisting of 5 days or 10 days of decitabine. For the 3 + 7 group, daunorubicin (60 mg/m) was administered over the first 3 days and cytarabine (200 mg/m) over the first 7 days, followed by 1-3 additional chemotherapy cycles. Allogeneic HSCT was strongly encouraged. Overall survival in the intention-to-treat population was the primary endpoint. Safety was assessed in all patients who received the allocated treatment. This trial is registered at ClinicalTrials.gov, NCT02172872, and is closed to new participants.
FINDINGS
Between Dec 1, 2014, and Aug 20, 2019, 606 patients were randomly assigned to the decitabine (n=303) or 3 + 7 (n=303) group. Following an interim analysis which showed futility, the IDMC recommended on May 22, 2019, that the study continued as planned considering the risks and benefits for the patients participating in the study. The cutoff date for the final analysis presented here was June 30, 2021. At a median follow-up of 4·0 years (IQR 2·9-4·8), 4-year overall survival was 26% (95% CI 21-32) in the decitabine group versus 30% (24-35) in the 3 + 7 group (hazard ratio for death 1·04 [95% CI 0·86-1·26]; p=0·68). Rates of on-protocol allogeneic HSCT were similar between groups (122 [40%] of 303 patients for decitabine and 118 [39%] of 303 patients for 3+7). Rates of grade 3-5 adverse events were 254 (84%) of 302 patients in the decitabine group and 279 (94%) of 298 patients in the 3 + 7 group. The rates of grade 3-5 infections (41% [125 of 302] vs 53% [158 of 298]), oral mucositis (2% [seven of 302] vs 10% [31 of 298]) and diarrhoea (1% [three of 302] vs 8% [24 of 298]) were lower in the decitabine group than in the 3 + 7 group. Treatment-related deaths were reported for 12% (35 of 302) of patients in the decitabine group and 14% (41 of 298) in the 3 + 7 group.
INTERPRETATION
10-day decitabine did not improve overall survival but showed a better safety profile compared with 3 + 7 chemotherapy in older patients with acute myeloid leukaemia eligible for intensive chemotherapy. Decitabine could be considered a better-tolerated and sufficiently efficacious alternative to 3 + 7 induction in fit older patients with acute myeloid leukaemia without favourable genetics.
FUNDING
Janssen Pharmaceuticals.
Topics: Humans; Middle Aged; Aged; Decitabine; Leukemia, Myeloid, Acute; Cytarabine; Daunorubicin; Transplantation, Homologous; Antineoplastic Combined Chemotherapy Protocols
PubMed: 37914482
DOI: 10.1016/S2352-3026(23)00273-9 -
Environmental Research Jun 2023Nanomedicine is a field that combines biology and engineering to improve disease treatment, particularly in cancer therapy. One of the promising techniques utilized in... (Review)
Review
Nanomedicine is a field that combines biology and engineering to improve disease treatment, particularly in cancer therapy. One of the promising techniques utilized in this area is the use of micelles, which are nanoscale delivery systems that are known for their simple preparation, high biocompatibility, small particle size, and the ability to be functionalized. A commonly employed chemotherapy drug, Doxorubicin (DOX), is an effective inhibitor of topoisomerase II that prevents DNA replication in cancer cells. However, its efficacy is frequently limited by resistance resulting from various factors, including increased activity of drug efflux transporters, heightened oncogenic factors, and lack of targeted delivery. This review aims to highlight the potential of micelles as new nanocarriers for delivering DOX and to examine the challenges involved with employing chemotherapy to treat cancer. Micelles that respond to changes in pH, redox, and light are known as stimuli-responsive micelles, which can improve the targeted delivery of DOX and its cytotoxicity by facilitating its uptake in tumor cells. Additionally, micelles can be utilized to administer a combination of DOX and other drugs and genes to overcome drug resistance mechanisms and improve tumor suppression. Furthermore, micelles can be used in phototherapy, both photodynamic and photothermal, to promote cell death and increase DOX sensitivity in human cancers. Finally, the alteration of micelle surfaces with ligands can further enhance their targeted delivery for cancer suppression.
Topics: Humans; Micelles; Cell Line, Tumor; Doxorubicin; Hydrogen-Ion Concentration
PubMed: 36948284
DOI: 10.1016/j.envres.2023.115722