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

Abstract

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.

Chemodynamic nanomaterials for cancer theranostics

“…Combination therapy, which integrates multiple therapeutic agents into one nanoplatform, is generally more effective than monotherapy [ 116 , 117 ]. For example, Vyxeos, a FDA-approved liposomal anticancer nanomedicine that is comprised of daunorubicin and cytarabine in fixed ratio, has been shown to increase the survival time of patients [ 118 ]. Nanomedicines combining Fenton/Fenton-like reactions with other therapeutic modalities may further improve anticancer efficiency.…”

The Dynamic Interface Between the Bone Marrow Vascular Niche and Hematopoietic Stem Cells in Myeloid Malignancy

“…A potential alternative to releasing leukemic cells from their protective niche is to exploit the rapid advances in biotechnology to more effectively deliver existing drugs to these regions. Liposomal formulations can deliver more robust and consistent doses to BM niches, the most prominent example being CPX-351, a liposomal formulation combining daunorubicin and cytarabine that is now standard-of-care first-line therapy for some AML subgroups ( Tzogani et al, 2020 ). Nanoparticles as a delivery system to sequestered sites holds great promise ( Vinhas et al, 2017 ), although remains largely experimental and few have yet reached clinical trials.…”

Cancer Nanomedicine and Immune System—Interactions and Challenges

“…Marqibo is demonstrated to increase the circulation time with targeted and intense delivery of Vincristine without augmented toxicities including hematologic toxicity (Deitcher et al, 2014). Most common adverse events for Onivyde and Vyxeos are neutropenia, abdominal pain, and diarrhea that are considered manageable, except for prolonged severe neutropenia in patients receiving Vyxeos (Zhang, 2016;Tzogani et al, 2020). Cardiotoxicity is another toxicity induced by chemotherapeutic drugs including nanomedicine.…”