CPX-351: An Old Scheme with a New Formulation in the Treatment of High-Risk 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

Targeting Acute Myeloid Leukemia Using Sphingosine Kinase 1 Inhibitor-Loaded Liposomes

“…41,44,45 In an effort to improve patient survival, liposomal delivery of anticancer agents improves targeted drug delivery to cancer cells and thus enhances drug efficacy. 22,25 In this study, biodistribution data demonstrated a significant increase of MP-A08 accumulation in the bone marrow of mice treated with MP-A08-liposomes compared with MP-A08 as a free compound, despite approximately 100 times lower dosing of MP-A08 employed for MP-A08-liposomes. It is worth noting that liposomes rely on passive targeting to leukemic cells in the bone marrow, and we have strategically engineered our liposomes with DMPC and DPPG lipids, comprising a mixture of zwitterionic and negatively charged phospholipids, that enhance MP-A08 uptake by phospholipid binding with the high level of scavenger receptor class Bl expression on leukemic cells.…”

“…In addition, MP-A08-liposomes demonstrate enhanced bone marrow biodistribution (Figure A), which could be another factor contributing to the survival of mice engrafted with AML. One of the root causes of AML poor prognosis is the presence of leukemic stem and progenitor cells (LSPC) in the bone marrow microenvironment. − These cells are resistant to conventional chemotherapy regimens, persist within the bone marrow microenvironment during patient therapy, and drive disease relapse. ,, In an effort to improve patient survival, liposomal delivery of anticancer agents improves targeted drug delivery to cancer cells and thus enhances drug efficacy. , In this study, biodistribution data demonstrated a significant increase of MP-A08 accumulation in the bone marrow of mice treated with MP-A08-liposomes compared with MP-A08 as a free compound, despite approximately 100 times lower dosing of MP-A08 employed for MP-A08-liposomes. It is worth noting that liposomes rely on passive targeting to leukemic cells in the bone marrow, and we have strategically engineered our liposomes with DMPC and DPPG lipids, comprising a mixture of zwitterionic and negatively charged phospholipids, that enhance MP-A08 uptake by phospholipid binding with the high level of scavenger receptor class Bl expression on leukemic cells .…”

“…A common strategy used to overcome the solubility, biodistribution and clearance challenges of novel compounds (including SPHK1 inhibitors) is encapsulation within nanocarrier systems that improve anticancer drug potency and efficacy by delivering the drug to cancer cells. − A commonly employed nanoparticle approach for delivering anticancer therapeutics is liposomes, lipid-based nanoparticles with high biocompatibility that can encapsulate both hydrophobic and/or hydrophilic drugs for improved solubility, enhanced uptake within cancer cells, and improved pharmacokinetic and pharmacodynamic profiles. − The clinical relevance of this approach has been highlighted recently through the regulatory approval of CPX-351, a liposomal coformulation of conventional cytarabine and daunorubicin chemotherapy for the treatment of AML. ,, Liposomal CPX-351 improves overall patient survival by 31% compared with traditional free drug formulation of cytarabine and daunorubicin; however, disease relapse is still prevalent, likely because cytarabine and daunorubicin do not effectively eradicate the leukemic stem cells present in the bone marrow, which are a major driver for AML relapse. , Thus, this issue highlights the urgent need for new AML therapies that effectively target disease relapse driving cell populations by delivering anti-AML drugs to the bone marrow and the site of LSPCs.…”

“…20−24 The clinical relevance of this approach has been highlighted recently through the regulatory approval of CPX-351, a liposomal coformulation of conventional cytarabine and daunorubicin chemotherapy for the treatment of AML. 19,25,26 Liposomal CPX-351 improves overall patient survival by 31% compared with traditional free drug formulation of cytarabine and daunorubicin; however, disease relapse is still prevalent, 27 likely because cytarabine and daunorubicin do not effectively eradicate the leukemic stem cells present in the bone marrow, which are a major driver for AML relapse. 1,4 Thus, this issue highlights the urgent need for new AML therapies that effectively target disease relapse driving cell populations by delivering anti-AML drugs to the bone marrow and the site of LSPCs.…”

Combating Acute Myeloid Leukemia via Sphingosine Kinase 1 Inhibitor-Nanomedicine Combination Therapy with Cytarabine or Venetoclax

“…The implementation of liposomal-based drug delivery has the potential to significantly improve patient outcomes. Recent evidence of novel liposomal CPX-351 (also known as Vyxeos ® ), a cytarabine and daunorubicin liposomal formulation approved by the FDA to treat newly diagnosed therapy-related AML or AML with myelodysplasia-related changes [ 23 , 37 , 38 , 39 , 40 , 41 , 42 ], has emphasized the importance of nanomedicine in the treatment of AML. Indeed, recent work in our laboratory employing a reliable platform of liposomal encapsulation to effectively deliver MP-A08 to eradicate human AML cells engrafted in mice and significantly enhance mice survival was a remarkable breakthrough [ 17 ], demonstrating the potential of the MP-A08 liposomal formulation as a promising monotherapy against AML.…”