Daunorubicin

Article Author:
Tabinda Saleem
Article Editor:
Anup Kasi
Updated:
6/9/2020 11:35:57 AM
PubMed Link:
Daunorubicin

Indications

Daunorubicin is an anti-neoplastic agent that has approval from the Food and Drug Administration (FDA) as a remission induction therapy along with another cytotoxic agent in acute non-lymphocytic leukemias including acute myelogenous, promyelocytic and erythroid leukemias in adults and acute lymphocytic leukemia (ALL) in both children and adults.

In adult non-lymphocytic leukemias, daunorubicin hydrochloride has seen to produce a complete remission rate of 40 to 50% when used as a single agent and 53 to 65% complete remission rate when used with cytarabine. The cumulative dose of 270 mg/m^2, along with cytarabine, has shown to be most effective with the lowest toxicity rates.[1][2]

Clinical studies showed that daunorubicin prolongs the complete remission duration of childhood ALL when used in combination with vincristine-prednisone as compared to using vincristine and prednisone alone, although no evidence is available regarding its impact as a part of the consolidation therapy. Whereas in adult ALL, daunorubicin significantly increases the rate of complete remission rate from 47% to 83% when added to the triple therapy with vincristine, prednisone, and L asparaginase, however, it does not affect the duration of the complete remission.[3]

Daunorubicin is also used as part of the aggressive CHOP (cyclophosphamide, daunorubicin, vincristine, and prednisone) regime to treat adult T cell leukemia caused by human T-lymphotropic virus (HTLV) and other chronic lymphomas, although the longterm remission effects are limited.[4]

In 2017 the liposomal co-formulation of daunorubicin and cytarabine was approved by FDA for the treatment of adults with therapy-related AML or AML with myelodysplasia-related changes (AML-MRC), these two types of AML are known for their poor prognosis.[5][4]

Off-label, the liposomal form of daunorubicin, is also used as a first-line agent to treat Kaposi sarcoma in patients with advanced human immunodeficiency virus (HIV) syndrome along with HAART therapy.[6]

Mechanism of Action

Danorubincin belongs to the anthracycline class of antibiotics. It exerts its anti-neoplastic properties through various mechanisms that include both anti-mitotic and anti-cytotoxic activities. It acts by intercalating between the DNA base pairs causing the DNA double helix to uncoil and inhibit the topoisomerase II enzyme, which results in single and double-strand breaks and thus inhibiting DNA and RNA synthesis.

Daunorubicin also inhibits the activity of polymerase enzyme dysregulating the gene expression and resulting in free radical damage to the DNA and ultimately resulting in apoptosis, mitochondrial injury, and programmed cell death.

Administration

Daunorubicin can only be administered intravenously through rapidly flowing infusions. Its administration cannot be subcutaneous or intramuscular as it can cause severe local tissue necrosis through extravasation of the drug into the surrounding tissue. In the event of extravasation, the infusion should stop immediately, and cold compresses should be applied. 

Adverse Effects

Daunorubicin cause both dose-limiting and non-limiting adverse effects. Some of the common and most serious dose-limiting adverse effects include bone marrow suppression and cardiotoxicity. Bone marrow suppression usually occurs in all patients given the therapeutic dose of daunorubicin; therefore, it should be used cautiously in patients with pre-existing bone marrow suppression. It usually manifests as severe infections or hemorrhage. 

Daunorubicin can cause potential cardiac toxicity, especially in children and the elderly. Pre-existing heart disease and concomitant treatment with other cytotoxic agents or radiotherapy involving the field of the heart can enhance the risk of developing daunorubicin induced cardiotoxicity. It usually presents with new-onset congestive heart failure, although rarely it can present as myocarditis or pericarditis. In adults, usually, the cardiac toxic effects are seen after a cumulative dose exceeding 400 to 550 mg/m^2, although it may also occur on doses as low as 200 mg/m^2.[7] Symptomatic heart failure can occur during and even months to years later after the cessation of the therapy. Therefore, serial electrocardiograms (EKG) and echocardiogram are indicated before the initiation and with successive chemotherapy sessions with daunorubicin.[8]

Other more common dose non-limiting adverse effects include reversible alopecia, mucositis, nausea, vomiting, and local skin necrosis, cellulitis, or induration due to extravasation of the drug into the tissues.

Rarely it causes secondary leukemias, hypersensitivity reactions, urticaria, local dermatitis, tumor lysis syndrome, and hyperuricemia.

Contraindications

The only contraindication to the administration of daunorubicin is pre-existing hypersensitivity reactions. Though caution should be taken in patients with hepatic and renal impairment as this can increase the risk of toxicity and relative dose reduction is necessary.

Daunorubicin can cross the placenta, and it can cause fetal harm when administered to pregnant women. Although no human study is available, researchers found daunorubicin to cause multiple fetal abnormalities and spontaneous abortions in reproductive animal studies. Therefore, effective contraception is the recommendation in women of reproductive age. It is not known if daunorubicin is secreted in breast milk or not, but due to the potential harm, breastfeeding is generally not recommended during the ongoing therapy.

Monitoring

Therapy with daunorubicin generally requires close patient observation and follow-ups. Serial measurement of complete blood count, hepatic, and renal functions is recommended before each chemotherapeutic session. Monitoring for bone marrow suppression and infections requires care and vigilance, and any systemic infection should be treated effectively before the next course of daunorubicin.

The American College of Clinical Oncology (ASCO) recommends cardiac monitoring that includes a thorough history and physical exam, screening for cardiovascular risk factors, EKGs, and serial echocardiogram. For patients who become symptomatic, the initial diagnostic test should be transthoracic echocardiography (echo). If the echo is inconclusive, a cardiac MRI or MUGA scan is an alternative. It is also a recommendation to obtain cardiac markers if necessary.[8]

Toxicity

Daunorubicin causes cardiotoxicity by forming complexes with topoisomerase IIb enzyme in cardiomyocytes like forming complexes with topoisomerase IIa in tumor cells, resulting in mitochondrial damage and hence myocardial cell death. Dexrazoxane is a cardio-protectant agent. Research has shown it to decrease the incidence and severity of cardiotoxicity when given from the first dose of anthracyclines without reducing the effectiveness of the chemotherapeutic agent. It acts by inhibiting the isomer of topoisomerase and decrease the free radical damage by chelating free iron.[7][9] It is administered intravenously in a ratio of 10 to 1 of dexrazoxane: daunorubicin.  Cardiac monitoring is still a recommendation despite concurrent therapy, and if a patient develops a decline in the left ventricular function or develops symptomatic heart failure, treatment should discontinue immediately.

Enhancing Healthcare Team Outcomes

Due to the serious toxic effects related to daunorubicin therapy, strong interprofessional communication, and care coordination is recommended among physicians, nurses, and pharmacists. Administration of the drug should only be by a team trained in leukemia chemotherapy and centers with training on monitoring drug tolerance, toxic monitoring, and surveillance. There should also be effective resources available to treat any adverse effects related to daunorubicin therapy especially acute fatal infections or severe hemorrhage related to bone marrow suppression and decompensations due to acute congestive heart, in that case, cardiology referral is immediately necessary. 

Dexarozoxane is recommended to prevent the cardiotoxic effects and has shown effective results in large randomized clinical trials.[9]


References

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[2] What Is the Best Daunorubicin Dose and Schedule for Acute Myeloid Leukemia Induction?, Pophali P,Litzow M,, Current treatment options in oncology, 2017 Jan     [PubMed PMID: 28154969]
[3] The role of targeted therapy in the management of patients with AML., Perl AE,, Hematology. American Society of Hematology. Education Program, 2017 Dec 8     [PubMed PMID: 29222237]
[4] Adult T-Cell Leukemia/Lymphoma., Mehta-Shah N,Ratner L,Horwitz SM,, Journal of oncology practice, 2017 Aug     [PubMed PMID: 28796966]
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[6] Petre CE,Dittmer DP, Liposomal daunorubicin as treatment for Kaposi's sarcoma. International journal of nanomedicine. 2007;     [PubMed PMID: 18019828]
[7] Pharmacogenetics of Chemotherapy-Induced Cardiotoxicity., Chang VY,Wang JJ,, Current oncology reports, 2018 Apr 30     [PubMed PMID: 29713898]
[8] Armenian SH,Lacchetti C,Barac A,Carver J,Constine LS,Denduluri N,Dent S,Douglas PS,Durand JB,Ewer M,Fabian C,Hudson M,Jessup M,Jones LW,Ky B,Mayer EL,Moslehi J,Oeffinger K,Ray K,Ruddy K,Lenihan D, Prevention and Monitoring of Cardiac Dysfunction in Survivors of Adult Cancers: American Society of Clinical Oncology Clinical Practice Guideline. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2017 Mar 10;     [PubMed PMID: 27918725]
[9] Marty M,Espié M,Llombart A,Monnier A,Rapoport BL,Stahalova V, Multicenter randomized phase III study of the cardioprotective effect of dexrazoxane (Cardioxane) in advanced/metastatic breast cancer patients treated with anthracycline-based chemotherapy. Annals of oncology : official journal of the European Society for Medical Oncology. 2006 Apr;     [PubMed PMID: 16423847]