ABC Transporter Expression in Acute Myeloid Leukemia: Association with in Vitro Cytotoxicity and Prognostic Markers
Ajay AbrahamSavitha VaratharajanSreeja KarathedathAshok kumar JeyaveluShaji R VelayudhanRayaz AhmedAby AbrahamBiju GeorgeMammen ChandyAlok SrivastavaVikram MathewsPoonkuzhali Balasubramanian
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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.
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Acute myeloid leukemia (AML) treatment has always been a challenge to the treating physician. Continuous efforts are being made to improve treatment outcomes in AML. CPX-351 is a pharmacologic advancement in this direction. It is a liposomal fixed drug combination of cytarabine and daunorubicin. Early studies indicate that it will play a big role in AML treatment. This is a short review about this drug.
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What is daunorubicin and cytarabine liposome? Daunorubicin and cytarabine liposome is the first dual-drug liposomal encapsulation product approved by the FDA. How does this drug work? Daunorubicin inhibits DNA and RNA synthesis by forming complexes with DNA, inhibiting topoisomerase II activity, inhibiting DNA polymerase activity, affecting regulation of gene expression, and producing DNA-damaging free radicals. Cytarabine decreases DNA synthesis by inhibiting DNA polymerase. The fixed 1:5 molar ratio of daunorubicin:cytarabine was shown to be the most synergistic ratio for killing leukemia cells in vitro and in murine models. What is it approved for? Daunorubicin and cytarabine liposome is approved for the treatment of adults with newly diagnosed therapy-related acute myeloid leukemia (t-AML) or AML with myelodysplasia-related changes (AML-MRC). Daunorubicin and cytarabine liposome was approved based on results from an open-label, multicenter, randomized, phase III trial. Patients with newly diagnosed t-AML or AML-MRC between the ages of 60 and 75 years old were eligible for inclusion. A total of 309 patients were randomized to daunorubicin and cytarabine liposome or cytarabine and daunorubicin (7+3 or 5+2) induction and consolidation. The complete remission rate was higher with daunorubicin and cytarabine liposome (38% vs. 26%, p=0.036). Median event-free survival (2.5 vs. 1.3 months, p=0.021) and overall survival (9.6 vs. 5.9 months, p=0.005) were significantly better in patients who received daunorubicin and cytarabine liposome (J Clin Oncol 2016;34:15_suppl.7000). How do you administer this drug? Induction with daunorubicin 44 mg/m2 and cytarabine 100 mg/m2 liposome is given intravenously over 90 minutes on days 1, 3, and 5. If second induction is needed, the same dose is given on days 1 and 3. Daunorubicin 29 mg/m2 and cytarabine 65 m/m2 liposome is given on days 1 and 3 for up to 2 cycles of consolidation. Are there any premedications needed for daunorubicin and cytarabine liposome? Prophylactic antiemetics, such as ondansetron and dexamethasone, should be administered prior to daunorubicin and cytarabine liposome since this medication has a moderate emetic risk. What are side effects associated with daunorubicin and cytarabine liposome (≥ 10%)? Side effects more commonly observed with daunorubicin and cytarabine liposome included (≥ 5% over control arm): Hematologic: hemorrhage, prolonged thrombocytopenia, prolonged neutropenia Infections: fungal, upper respiratory, catheter/device/injection site Other: rash, pruritus, cough, headache, visual impairment What are some other side effects? Patients may develop cardiotoxicity, hypersensitivity reactions, and tissue necrosis. Before administering daunorubicin and cytarabine liposome, the patient's cumulative anthracycline exposure should be calculated and assessed for appropriateness. Since daunorubicin and cytarabine liposome contains copper gluconate, copper overload may also occur. Are there any important drug interactions? Monitor cardiac and hepatic function at baseline and when used with other cardiotoxic and hepatotoxic agents, respectively. How do I adjust the dose in the setting of renal or hepatic insufficiency? Dose adjustments are not required for renal or hepatic insufficiency. Daunorubicin and cytarabine liposome is metabolized in the liver and excreted renally, but has not been studied in patients with severe renal impairment/end-stage renal disease or bilirubin levels greater than 3 mg/dL. Practical tips: If patients develop a hypersensitivity reaction, premedicate patients with an antihistamine and/or corticosteroid prior to subsequent doses. Do not interchange daunorubicin and cytarabine liposome with other daunorubicin and/or cytarabine products. Daunorubicin and cytarabine liposome has unique preparation instructions that pharmacy staff should be trained on. The total preparation time takes close to an hour with key steps including equilibration to room temperature, reconstitution followed by swirling vial contents, and aseptically transferring the medication to an infusion bag. What should my patients know? Patients should be educated on the administration schedule of daunorubicin and cytarabine liposome, as well as side effects, and contact their health care provider if they develop a hypersensitivity reaction, uncontrolled nausea or vomiting, or fever or chills. Side effects that patients should be educated on include low blood counts, increased risk of infection, hypersensitivity reactions, and cardiotoxicity. What else should I know? Daunorubicin and cytarabine liposome should only be used in patients with t-AML or AML-MRC. Patients who received daunorubicin and cytarabine liposome had more prolonged thrombocytopenia and neutropenia leading to increased infections and hemorrhage. Daunorubicin and cytarabine liposome has unique preparation instructions and should not be interchanged with other daunorubicin and/or cytarabine products. What useful links are available? https://vyxeos.com/ https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm569950.htm Any ongoing clinical trials related to daunorubicin and cytarabine liposome? Multiple clinical trials with daunorubicin and cytarabine liposome are ongoing including trials in adult patients with newly diagnosed, relapsed/refractory AML, and myelodysplastic syndromes as well as exploration of use in the pediatric population. More can be found at https://clinicaltrials.gov. MALLORY L. CRAIN, PHARMD, is PGY2 Oncology Resident, Department of Pharmacy at Barnes-Jewish Hospital, St. Louis, Mo. RAMASWAMY GOVINDAN, MD, Professor of Medicine; Anheuser Busch Chair in Medical Oncology; and Director, Section of Medical Oncology, Division of Oncology, Washington University School of Medicine, serves as the Pharmacy Forum column physician advisor.Mallory L. Crain, PharmD: Mallory L. Crain, PharmDRamaswamy Govindan, MD: Ramaswamy Govindan, MD
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Acute myeloid leukemia (AML) is a hematological malignancy commonly found in adult patients. Low overall survival and resistance to therapy are the main issues in AML. The first line of treatment for AML chemotherapy is the induction phase, namely, the phase to induce remission by administering a combination of daunorubicin (DNR) for three days followed by administration of cytarabine (Ara-C) with continuous infusion for seven days, which is referred to as "3 + 7." Such induction therapy has been the standard therapy for AML for the last four decades. This review article is made to discuss daunorubicin and cytarabine from their chemical structure, pharmacodynamics, pharmacokinetics, and mechanisms of resistance in AML.
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VYXEOS™ is a liposomal-encapsulated formulation of daunorubicin and cytarabine delivering a fixed, synergistic 1:5 molar ratio (hereafter referred to as daunorubicin/cytarabine liposome). Daunorubicin/cytarabine liposome is approved in several countries worldwide for the treatment of adults with therapy-related acute myeloid leukaemia (tAML) and AML with myelodysplasia-related changes (MRC). Approval was based on its clinical benefit in older patients with newly diagnosed high-risk/secondary AML in a pivotal phase III trial. In this study, daunorubicin/cytarabine liposome significantly prolonged overall survival (OS) and event-free survival (EFS) relative to conventional chemotherapy with cytarabine plus daunorubicin (hereafter referred to as 7 + 3). Daunorubicin/cytarabine liposome was also associated with significantly higher rates of complete remission (CR) and CR with incomplete haematological recovery (CRi) compared with 7 + 3. Daunorubicin/cytarabine liposome had an acceptable tolerability profile in older patients with newly diagnosed high-risk/secondary AML. The safety profile of daunorubicin/cytarabine liposome, including types and severities of adverse events, was generally similar to that of 7 + 3. Therefore, daunorubicin/cytarabine liposome is an important treatment option for adults with newly diagnosed tAML or AML-MRC.
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Haem oxygenase-1 (HO-1) is increasingly regarded as a pro-tumoral target in the treatment of human cancers. Currently, little is known about HO-1 and its role in human acute myeloid leukaemia (AML) to regulate apoptosis in response to chemotherapy. Recently, we showed that HO-1 protects AML samples from tumour necrosis factor-α (TNF)-induced apoptosis - it being regulated by transcription factors Nrf2, NF-ĸB and AP-1. This study aims to analyse the role of HO-1 in regulating apoptosis in AML cells in response to two front-line chemotherapeutic agents used for AML, cytarabine and daunorubicin. Here we show that HO-1 expression in AML samples was increased in response to both cytarabine and daunorubicin treatment, and micro RNA (miRNA) silenced HO-1 expression in combination with either daunorubicin or cytarabine induced a greater apoptotic responses in AML cells. Moreover, we showed that both daunorubicin and cytarabine induced reactive oxygen species (ROS) accumulation to induce apoptosis in AML. However, ROS-dependent induction of HO-1 was limiting the apoptotic response that is seen in AML towards cytarabine and daunorubicin treatment. These findings suggest concurrent inhibition of HO-1 expression in conjunction with chemotherapeutic treatment would improve the number of cases who reach complete remission.
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