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![Mean change from baseline in QTcF (a) and QTcB (b). Mean values are shown with their 95% CIs. Mean changes in QTcF were < 10 ms at all time points and upper limits of the 2-sided 90% CI exceeded 10 ms at only 2 time points (Day 1 at 3 h post-SOI: 10.7 ms [mean = 5.3]; Day 1 at 4 h post-SOI: 12.3 ms [mean = 8.0]). QTcF Fridericia's corrected QT interval, CI confidence interval, QTcB Bazett's corrected QT interval, SOI start of infusion](publication/333159716/figure/fig2/AS:960057072160785@1605906851436/Mean-change-from-baseline-in-QTcF-a-and-QTcB-b-Mean-values-are-shown-with-their-95.png)
Mean change from baseline in QTcF (a) and QTcB (b). Mean values are shown with their 95% CIs. Mean changes in QTcF were < 10 ms at all time points and upper limits of the 2-sided 90% CI exceeded 10 ms at only 2 time points (Day 1 at 3 h post-SOI: 10.7 ms [mean = 5.3]; Day 1 at 4 h post-SOI: 12.3 ms [mean = 8.0]). QTcF Fridericia's corrected QT interval, CI confidence interval, QTcB Bazett's corrected QT interval, SOI start of infusion
Source publication
Purpose
Daunorubicin can induce left ventricular dysfunction and QT interval prolongation. This study assessed the effects of CPX-351, a liposomal encapsulation of cytarabine and daunorubicin, on cardiac repolarization.
Methods
Twenty-six adults with acute leukemia were treated with CPX-351 for 1–2 induction cycles and ≤ 4 consolidation cycles. Th...
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Introduction
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Background
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Methods
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Citations
... Since the volume of distribution for both drugs was approximately the same as the blood volume (5.2-7.5 L), the extent of NS-87/CPX-351 distribution was considered to be mostly restricted to the blood. The pharmacokinetic parameters for NS-87/CPX-351 in Japanese patients were similar to those seen in Caucasian patients with AML [16]. In the Japanese P1/2 study and the study overseas, the molar ratio of cytarabine to daunorubicin was maintained at the targeted ratio of 5:1 in plasma for 24 h after administration, which could have contributed to the potent antileukemic action of NS-87/CPX-351. ...
Objectives
NS-87/CPX-351 is a dual-drug liposomal encapsulation of cytarabine and daunorubicin. NS-87/CPX-351 exerts antileukemic action by maintaining a synergistic molar ratio of cytarabine to daunorubicin of 5:1 within the liposome while in circulation. Patients with high-risk acute myeloid leukemia (AML), which includes therapy-related AML and AML with myelodysplasia-related changes (AML-MRC), have poorer outcomes than those with other AML.
Methodology
This open-label phase 1/2 (P1/2) study was conducted in 47 Japanese patients aged 60–75 years with newly diagnosed high-risk AML to evaluate the pharmacokinetics, safety, and efficacy of NS-87/CPX-351.
Results
In the 6 patients enrolled in the P1 portion, no dose-limiting toxicities (DLTs) were reported, and 100 units/m ² during the induction cycle was found to be acceptable. Cytarabine and daunorubicin had a long half-life in the terminal phase (32.8 and 28.7 h, respectively). In the 35 patients enrolled in the P2 portion, composite complete remission (CRc; defined as complete remission [CR] or CR with incomplete hematologic recovery [CRi]) was achieved in 60.0% (90% CI: 44.7–74.0) of the patients. Adverse events due to NS-87/CPX-351 were well tolerated.
Outcomes
NS-87/CPX-351 can be considered as a frontline treatment option for Japanese patients with high-risk AML.
... Drug encapsulation can be achieved through physical encapsulation, chemical conjugation and electrostatic interactions, depending on the chemical nature of the drug molecule (Iyer et al. 2013, Xu et al. 2015, Hu et al. 2016. Currently, this co-loading approach is applied to systems such as liposomes (Morton et al., 2014, Liu et al. 2019, Lin et al. 2019, poly(lactic-co-glycolic acid)-based (PLGA) (Kolishetti et al. 2010, Tian et al. 2017, Do et al. 2018) and polycaprolactone-based (PCL) particles (Milane et al. 2011), polysaccharide (Xiao et al. 2015a(Xiao et al. , 2015b and polypeptide-based nanoparticles (Zheng et al. 2013, PEG conjugate , and polyphosphazene-based multilayer nanoparticles (Mehnath et al. 2018). Many liposomal and polymeric formulations are being investigated in the preclinical/ clinical studies. ...
The present study was aimed to prepare and examine in vitro novel dual-drug loaded delivery systems. Biodegradable nanoparticles based on poly(L-glutamic acid-co-D-phenylalanine) were used as nanocarriers for encapsulation of two drugs from the paclitaxel, irinotecan, and doxorubicin series. The developed delivery systems were characterised with hydrodynamic diameters less than 300 nm (PDI < 0.3). High encapsulation efficiencies (≥75%) were achieved for all single- and dual-drug formulations. The release studies showed faster release at acidic pH, with the release rate decreasing over time. The release patterns of the co-encapsulated forms of substances differed from those of the separately encapsulated drugs, suggesting differences in drug-polymer interactions. The joint action of encapsulated drugs was analysed using the colon cancer cells, both for the dual-drug delivery sytems and a mixture of single-drug formulations. The encapsulated forms of the drug combinations demonstrated comparable efficacy to the free forms, with the encapsulation enhancing solubility of the hydrophobic drug paclitaxel.
... We also analyzed cardiac events restricted to the first line (censoring at relapse or refractory status). Interestingly, the rate of all cardiac grade events in 1L patients undergoing intensive chemotherapy was 42.7%, similar to the 46% reported by investigators of a phase 2 206 study assessing the effects of the cardiac repolarization of CPX-351 on patients with acute leukemias [31]. It should be noted that cardiac events were seen in 20% of patients receiving venetoclax with hypomethylating agents for the 1L treatment of AML in 170 lessfit patients treated at the Mayo Clinic [32]. ...
Simple Summary
The incidence of cardiac morbimortality in acute myeloid leukemia (AML) is not well known. We aim to estimate the cumulative incidence (CI) of cardiac events in AML patients and to identify risk factors for their occurrence. We observed a high incidence of cardiac events (58.5%) among 525 treated patients, coupled with significant mortality due to cardiotoxicity (3.6%). The presence of relevant cardiac antecedents was the main risk factor for developing fatal cardiac events (hazard ratio (HR) = 1.9). Age ≥ 65 (HR = 2.2), relevant cardiac antecedents (HR = 1.4), and non-intensive chemotherapy (HR = 1.8) were associated with non-fatal cardiac events. We observed that, among 285 intensive therapy patients, median overall survival was decreased in those experiencing grade 3–4 cardiac events (p < 0.001). We identified prognostic factors that increase the risk of cardiac events, which may be useful in selecting high-risk patients for stringent cardiac monitoring and management.
Abstract
The incidence of cardiac morbimortality in acute myeloid leukemia (AML) is not well known. We aim to estimate the cumulative incidence (CI) of cardiac events in AML patients and to identify risk factors for their occurrence. Among 571 newly diagnosed AML patients, 26 (4.6%) developed fatal cardiac events, and among 525 treated patients, 19 (3.6%) experienced fatal cardiac events (CI: 2% at 6 months; 6.7% at 9 years). Prior heart disease was associated with the development of fatal cardiac events (hazard ratio (HR) = 6.9). The CI of non-fatal cardiac events was 43.7% at 6 months and 56.9% at 9 years. Age ≥ 65 (HR = 2.2), relevant cardiac antecedents (HR = 1.4), and non-intensive chemotherapy (HR = 1.8) were associated with non-fatal cardiac events. The 9-year CI of grade 1–2 QTcF prolongation was 11.2%, grade 3 was 2.7%, and no patient had grade 4–5 events. The 9-year CI of grade 1–2 cardiac failure was 1.3%, grade 3–4 was 15%, and grade 5 was 2.1%; of grade 1–2, arrhythmia was 1.9%, grade 3–4 was 9.1%, and grade 5 was 1%. Among 285 intensive therapy patients, median overall survival decreased in those experiencing grade 3–4 cardiac events (p < 0.001). We observed a high incidence of cardiac toxicity associated with significant mortality in AML.
... We also analyzed cardiac events restricted to the rst-line (censoring at relapse or refractory status). Interestingly, the rate of all grade cardiac events in 1L patients undergoing intensive chemotherapy was 42.7%, similar to 46% reported by investigators of the phase 2 206 study to assess the effects on cardiac repolarization of CPX-351 in patients with acute leukemias (20). It should be noted that cardiac events were seen in 20% of patients receiving venetoclax with hypomethylating agents for the 1L treatment of AML in 170 less t patients treated at Mayo Clinic (21). ...
The incidence of cardiac morbi-mortality in acute myeloid leukemia (AML) is not well known. We aim to estimate the cumulative incidence (CI) of cardiac events in AML patients (pts) and to identify risk factors for their occurrence.
Among 571 newly diagnosed AML pts, 26 (4.6%) developed fatal cardiac events and 19 (3.6%) among 525 treated pts (CI: 2% at 6 months; 6.7% at 9 years). Prior heart disease was associated with development of fatal cardiac events [Hazard Ratio (HR) = 1.9]. The CI of non-fatal cardiac events was 43.7% at 6 months and 56.9% at 9 years. Age ≥ 65 (HR = 2.2), relevant cardiac antecedents (HR = 1.4) and non-intensive chemotherapy (HR = 1.8) were associated with non-fatal cardiac events. The 9-years CI of grade 1–2 QTcF prolongation was 11.2%, grade 3 was 2.7%, and no patient had grade 4–5 event. The 9-years CI of grade 1–2 cardiac failure was 1.3%, grade 3–4 was 15%, and grade 5 2.1%; of grade 1–2 arrhythmia was 1.9%, grade 3–4 was 9.1%, and grade 5 1%. Among 285 intensive therapy pts, median overall survival decreased in those experiencing grade 3–4 cardiac events (p < 0.001). We observed a high incidence of cardiac toxicity associated with significant mortality in AML.
... The pharmacokinetics of the two drugs are very different: cytarabine peak concentrations of 2-50 μM are measurable in plasma after intravenous injection of 30-300 mg/m 2 but fall rapidly (t1/2 ≈ 10 min) and less than 10% of the injected dose is excreted unchanged in the urine within 12-24 h [24]. In contrast, the plasma disappearance curve for daunorubicin is multiphasic, with a terminal t1/2 of 30 h. ...
Simple Summary
Secondary AML (s-AML) including therapy-related acute myeloid leukemia (t-AML) and acute myeloid leukemia with myelodysplasia-related changes (AML-MRC) represent approximately one quarter of all AML cases. These AML subcategories are predominantly associated with advanced age and present a specific biologic profile including adverse genetics and a multidrug resistance phenotype, which often determine dramatically poor outcomes after conventional chemotherapy. In 2017, the 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 t-AML and MRC-AML. Since the approval, many trials have been conducted or are still ongoing in order to assess the role of CPX-351 as frontline treatment in different AML subcategories, as a potential bridge to transplant or in combination with target therapies. In this review, we will discuss the current role of CPX-351 in treating these high-risk AML, focusing on how its use may potentially change the treatment paradigms of AML.
Abstract
Therapy-related acute myeloid leukemia (t-AML) and acute myeloid leukemia with myelodysplasia-related changes (AML-MRC) represent aggressive diseases characterized by a dismal prognosis if compared with de novo acute myeloid leukemia, especially in older patients. In these AML subsets, standard chemotherapy regimens produce poor response rates and unsatisfactory outcomes. Historically, conventional approaches consisted of an anthracycline combined with continuous infusion of cytarabine for 7 days, the “3+7” regimen. Several attempts have been conducted to ameliorate this combination regimen but inconsistent improvements in response rates and no significant changes in overall survival have been observed, until the recent introduction of targeted molecules. A liposomal formulation of traditional chemotherapy agents cytarabine and daunorubicin, termed CPX-351, enhances pharmacodynamics and synergistic effects through the maintenance of the optimal 5:1 molar ratio, which extends the treatment’s half-life and increases the bone marrow tropism of the drug. The use of CPX-351 in newly diagnosed AML-MRC and t-AML patients aged 60–75 years has demonstrated superior remission rates compared to conventional chemotherapy and improvements in event-free and overall survival. Recently, published data from a 5-year follow-up highlighted evidence that CPX-351 has the ability to produce and contribute to long-term remission and survival in older patients with newly diagnosed high-risk/secondary AML. Future perspectives include evaluation of dose intensification with CPX-351 in high-risk settings, combining this agent with targeted therapies, and better understanding the mechanism of improved responses in t-AML and AML-MRC. In this review, we will examine the role of CPX-351 inside the new AML therapeutic scenario and how its employment could potentially modify the treatment algorithm of high-risk and elderly patients with AML
... In clinical trials, CPX-351 had no clinically meaningful effects on heart rate, QRS interval, PR interval, or QT interval length in patients with acute leukemias. 21 However, further investigation is needed to better understand the potential cardioprotective benefit of CPX-351. In summary, this study demonstrated: (1) slow, coordinated release of drugs by CPX-351 liposomes; (2) prolonged tissue exposure to CPX-351 across tested species; (3) similar metabolism of both cytarabine and daunorubicin following administration of CPX-351 versus non-liposomal drugs; (4) dramatically different tissue distribution of both cytarabine and daunorubicin following administration of CPX-351 versus nonliposomal drugs; and (5) dramatically lower unbound plasma and tissue concentrations of cytarabine and daunorubicin following administration of CPX-351 versus non-liposomal drugs. ...
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.
... Therefore, they conclude that it is not clear whether echocardiography, especially in younger patients, provides valuable results in identifying cardiac injuries from chemotherapy. [18] Although in our study, echocardiography has been assessed in children with ALL, the results of this research are largely in line with our findings. ...
Introduction:
Acute lymphoblastic leukemia (ALL) is the most common malignancy in children. Anthracyclines are among the most common and effective drugs for the treatment of children ALL. However, long-term consumption and higher doses of these drugs may lead to toxic effects on the heart of children. For this purpose, in the present study, the baseline and posttreatment echocardiography status was evaluated in children with ALL during 7 years.
Materials and methods:
This retrospective cross-sectional study was performed on 53 children with ALL who were under the age of 18 years. Different factors including risk groups, age, gender, white blood cells, dosage, and duration of treatment, as well as baseline and posttreatment echocardiography findings including EF, E/E/, E//A/, MVE/A were evaluated in all patients.
Results:
All enrolled patients had not any abnormalities in the baseline echocardiography preventing the beginning of chemotherapy. The results of this study did not show a significant difference in mean baseline echocardiography parameters after treatment including EF̨E/E/˛E//A/˛, MVE/A. In addition, there was no significant difference in mean EF, E//A/˛, MVE/A, and ˛E/E/ before and after treatment among SR, IR, and HR groups. Although there was no significant difference in the mean EF, E//A/, and MVE/A before and after treatment between male and female sex, the mean E/E/ after chemotherapy in girls (8.5 ± 0.7) was significantly higher than the mean before treatment (6.85 ± 1.5) (P < 0.001). It was also higher than the mean in boys (7.04 ± 0.99) (P = 0.019). Although there was no significant relationship between the duration of chemotherapy and the mean of EF̨E/E/˛E//A/˛, MVE/A after treatment, high dose of the drug was found to be significantly associated with a gradual decrease of EF or systolic function of the heart (P < 0.001). There was no significant relationship between drug dose and other parameters of echocardiography including E/ A/, MVE/A, and E/E/ after treatment.
Conclusion:
It appears that chemotherapy should not be delayed by echocardiography. Based on the findings presented herein, increasing the dose of anthracycline can be considered as an effective factor in reducing the systolic function of the heart (EF reduction). On the other hand, chemotherapy in the period of 1 to 5.3 years does not seem to have a significant effect on the mean parameters of EF, E/E/, E//, and MVE/A although another study with higher sample size and follow-up is needed to confirm these results.
... However, the pharmacokinetics of CPX-351 suggest off-target tissue exposure is generally limited [20]. In a recently published phase 2 study that characterized cardiac repolarization in patients with acute leukemia who received CPX-351, no clinically meaningful changes in corrected QT interval were observed, even among those patients who received multiple cycles of induction/consolidation [21]. Similarly, no clinically significant effects on heart rate, QRS interval, or PR interval were observed. ...
CPX-351 is a dual-drug liposomal encapsulation of cytarabine/daunorubicin. In a phase 3 study (ClinicalTrials.gov Identifier: NCT01696084), patients aged 60–75 years with newly diagnosed, high-risk/secondary AML received 1–2 induction cycles with CPX-351 or 7 + 3 chemotherapy; those achieving complete remission (including with incomplete platelet or neutrophil recovery) could receive up to 2 consolidation cycles with CPX-351 or 5 + 2 chemotherapy, respectively. In this exploratory analysis of the subgroup of patients who received consolidation, median overall survival was prolonged among patients receiving CPX-351 induction/consolidation versus 7 + 3/5 + 2 (25.43 vs. 8.53 months; HR = 0.44 [95% CI: 0.25–0.77]). The safety profile of CPX-351 consolidation was consistent with that of the overall study. Outpatient administration of CPX-351 consolidation occurred in 51%–61% of patients and did not diminish overall survival. These findings suggest consolidation with CPX-351 in this patient population contributed to the prolonged overall survival versus 7 + 3/5 + 2, building upon findings from the overall study population, and provide evidence that, with careful monitoring, some patients can successfully receive CPX-351 as outpatients.
In recent years, advancements in the treatment of hematologic neoplasms have led to more effective and less toxic therapeutic schemes, resulting in prolonged patient life expectancy. However, the success of these treatments has also brought about an increased prevalence of cardiovascular adverse events, becoming a significant concern for the growing population of cancer survivors. Antineoplastic therapies, targeting both tumor and organ vessels, contribute to vascular toxicity, influenced by genetic factors and pre-existing vascular diseases. Chemotherapeutic agents and targeted treatments can induce cardiovascular toxicity by affecting endothelial cells and cardiomyocytes through various mechanisms, including hypoxia, vasculature abnormalities, and direct effects on cardiomyocytes. Cardiovascular adverse events encompass a wide range, from cardiac dysfunction to an elevated risk of arrhythmias. While early cardiac events are well-described in clinical trials, delayed toxicities are gaining relevance due to prolonged patient survival. The review focuses on the cardiac and vascular toxicity of antineoplastic drugs in hematological disorders, providing insights into the molecular physiopathology of cancer therapy-associated cardiotoxicity. Understanding how these drugs interact with the heart and blood vessels is essential for predicting, detecting, and managing chemotherapy-related heart issues.
CPX-351, a liposomal combination of cytarabine plus daunorubicin, has been approved for the treatment of adults with newly diagnosed, therapy-related acute myeloid leukaemia (t-AML) or AML with myelodysplasia-related changes as it improves survival and outcome of haematopoietic stem cell transplanted patients as compared to the continuous infusion of cytarabine plus daunorubicin (referred to as "7+3" combination). Because gut dysbiosis occurring in patients with AML during induction chemotherapy heavily impacts on the subsequent phases of therapy, we have assessed whether the superior activity of CPX-351 versus "7+3" combination in the real-life setting implicates an action on and by the intestinal microbiota. To this purpose, we have evaluated the impact of CPX-351 and "7+3" combination on mucosal barrier function, gut microbial composition and function and antifungal colonization resistance in preclinical models of intestinal damage in vitro and in vivo and fecal microbiota transplantation. We found that CPX-351, at variance with "7+3" combination, protected from gut dysbiosis, mucosal damage and gut morbidity while increasing antifungal resistance. Mechanistically, the protective effect of CPX-351 occurred through pathways involving both the host and the intestinal microbiota, namely via the activation of the aryl hydrocarbon receptor-IL-22-IL-10 host pathway and the production of immunomodulatory metabolites by anaerobes. This study reveals how the gut microbiota may contribute to the good safety profile, with a low infection-related mortality, of CPX-351 and highlights how a better understanding of the host-microbiota dialogue may contribute to pave the way for precision medicine in AML.
