Doxorubicin Variants for Hematological Malignancies

Keywords::

• anthracyclines
• efficacy
• liposomes
• lymphomas
• safety

In recent years, several nanotechnology platforms in the area of medical biology, including both diagnostics and therapy, have gained significant attention. New strategies to self-assemble biocompatible materials into nanoscale, drug-loaded packages with improved therapeutic efficacy are needed for nanomedicine. Design principles of these nanoparticles, including nanoemulsions, dendrimers, nanogold, liposomes, drug–carrier conjugates, antibody–drug complexes and magnetic nanoparticles, are primarily based on unique assemblies of synthetic, natural, or biological components, including, but not limited to, synthetic polymers, metal ions, oils and lipids as their building blocks. However, the potential success of these particles in the clinical setting relies on consideration of important parameters, such as nanoparticle fabrication strategies, their physical properties, drug loading efficiencies, drug release potential and, most importantly, minimum toxicity of the carrier itself [1]. The most important parameter of the delivery vehicle pertains to low or no toxicity of the carrier itself either in vivo or in the environment as a by-product. Therefore, nanoparticles fabricated using an assembly of natural biomolecules, such as lipids, proteins and carbohydrates, are expected to be an appropriate choice for clinical applications [2]. In this view, liposomes (the so-called honorary nanoparticles) are the classical example of a lipid-based formulation that gained remarkable interest and success as a drug carrier [3,4]. Liposomes may vary in size: most of them are 200 nm or smaller and are termed ‘nanoliposomes‘. Indeed, liposome products were the first nanopharmaceuticals approved by the US FDA.

Daunorubicin, which acts as a cell cycle nonspecific anthracycline antibiotic, is highly effective in treating a wide range of cancer diseases [5–7]. Its antineoplastic mechanisms are through DNA topoisomerase II inhibition, DNA intercalation, RNA synthesis inhibition, cell membrane interaction, free radical production and induction of apoptosis [8–10]. However, the clinical use of daunorubicin is hampered by two major problems: cardiotoxicity [11] and drug resistance, as daunorubicin is a substrate for P-glycoprotein (MDR1; ABCB1) [12] and breast cancer resistance protein (BCRP; ABCG2) [13]. These limits of standard doxorubicin have highlighted new liposomal formulations of the drug, which changed the scenario of the therapy for hematological malignancies and, in particular, for the treatment of B-cell malignancies.

In the early 1980s, liposomes (lipid vesicles) were found to be useful as anthracycline carriers, ‘buffering’ toxicity while retaining potent antitumor activity and therefore improving the therapeutic index of anthracyclines [14]. Liposomes are formed spontaneously when amphiphilic lipids, such as phospholipids, are dispersed in water. The liposome is a supramolecular assembly, whereby phospholipids form a closed bilayer, creating a vesicle with an entrapped water phase that is separated physically from the external medium [15].

Liposomal formulations of doxorubicin have been developed with the aim of improving the therapeutic index of doxorubicin by reducing the drug‘s cardiotoxicity. Nevertheless, liposomal conjugation of doxorubicin results in preferential distribution of the drug in the tumor compared with normal tissue, maintaining its antitumor efficacy.

Marketed nanoliposomal anthracyclines formulations

Two liposomal formulations are currently available: non-PEGylated liposomal doxorubicin (NPLD; Myocet^®, Cephalon [PA, USA]) and PEGylated liposomal doxorubicin (PLD; Caelix^®/Doxil^®; Schering-Plough [NJ, USA]/Orto Biotech [PA, USA]).

Non-PEGylated liposomal doxorubicin (Myocet) is a liposome-encapsulated formulation of doxorubicin, which differs from PEGylated liposomal doxorubicin, as well as from unencapsulated, conventional doxorubicin, resulting in an alteration in the pharmacokinetics and biodistribution. This results in a higher area under the curve, a smaller volume of distribution and a preferential distribution to liver, spleen and lymphatics, when compared with conventional doxorubicin [16]. Preclinical studies comparing equal doses of liposome-encapsulated doxorubicin and conventional doxorubicin showed that the use of NPLD resulted in a significantly lower cardiac and gastrointestinal toxicity, with similar antitumor efficacy [16].

In patients with metastatic breast cancer, Myocet was shown to be associated with a significantly reduced risk of cardiac toxicity, significantly less mucositis and absence of palmar-plantar erythrodysesthesia while maintaining antitumor efficacy [17].

In patients with non-Hodgkin‘s lymphoma, several studies tested the safety and the efficacy of Myocet when substituted for conventional doxorubicin in the CHOP-14 or -21 regimen (doxorubicin, cyclophosphamide, vincristine, prednisone given every 2 or 3 weeks), with or without addition of rituximab [18–21]. The results of these studies demonstrate that NPLD has at least the same efficacy with reduced cardiotoxicity for the treatment of patients with aggressive B-cell NHL, with remarkable results in frail and elderly patients not suitable for standard doxorubicin-based chemotherapy cycles. Reported overall response rates varied between 75 and 95%, with a complete response rate of 65–80%, a median duration of responses of approximately 2 years and a 3-year overall survival of 55–75%. These results are impressive if we take into account the patient population of these studies that enrolled only elderly or fragile patients also bearing important comorbidities [18–21].

Furthermore, some of these papers demonstrated that this NPLD-based regimen was equally effective in both MDR-1-positive and MDR-1-negative cases [18]. The authors postulated that the efficacy of this regimen was related to the ability of NPLD to overcome excessive drug efflux due to P-gp (MDR-1) overexpression [18]. MDR-1 expression did not correlate with response in this study, suggesting that NPLD might evade this resistance mechanism [18].

The other liposomal compound, PLD (Caelix/Doxil), is a liposomal formulation with a distinct pharmacokinetic profile characterized by an extended circulation time and a reduced volume of distribution [22]. Biodistribution animal studies indicate preferential accumulation of PLD into various implanted mouse–human tumors, with an enhancement of liposomal drug tumor levels compared with free drugs [22]. The extended circulation time of PEGylated liposomes and their ability to extravasate through the leaky vasculature of tumors results in the enhanced delivery of liposomal drug and/or radiotracers to the tumor site in patients with cancer. PLD has been approved for clinical use in a variety of cancer types due to its antitumor efficacy and exclusive safety profile. However, hand-foot syndrome remains a dose-limiting toxic effect of Doxil, perhaps due to the considerable amount of drug being delivered to the skin owing to the drug‘s long circulation in the bloodstream.

PEGylated liposomal doxorubicin has been substituted for conventional doxorubicin in the CHOP regimen in a number of trials. In Phase II studies in elderly patients with diffuse large B-cell lymphoma, overall response rate of approximately 65% was achieved: 50% complete response and 15% partial response, an estimated 1-year overall survival of 55%, and an estimated 2-year event-free survival of 45%. Neutropenia was the only grade III–IV toxicity observed [23,24].

Cutaneous T-cell lymphoma is a specific niche in which PLD has proven to be very active at low doses in a similar fashion to Kaposi‘s sarcoma [25]. A response rate of 88% (44% complete response) with mean overall survival of 18 months was observed in a retrospective analysis of 31 patients receiving PLD at doses varying from 20 to 40 mg/m² every 4 weeks. These patients had recurrent or unresponsive disease, or rapidly progressive disease [25].

Indeed, PLD has been shown to have equal efficacy and a better safety profile in the treatment of multiple myeloma, when compared with conventional doxorubicin combinations. In controlled clinical trials, PLD combined with vincristine and dexamethasone provided response rates comparable with the doxorubicin-based standard vincristine/doxorubicin/dexamethasone) therapy, but the former required less hospitalization, no central venous catheter, with a reported lower toxicity in terms of alopecia and severe leukopenia [26]. There are ongoing studies trying to establish the usefulness of newer compounds in combination with liposomal anthracycline for the therapy of multiple myeloma.

Conclusion & future perspective

Even if liposomal formulation of anthracyclines have improved the therapeutic index of the native drugs, analytical approaches that reflect the properties of the liposomes and the released kinetics of the encapsulated drug in tissues are required, in addition to plasma pharmacokinetics [27]. For this reason, the third generation of liposomes, the so-called ligand-targeted liposomes, have been and still are extensively studied, in order to gain advantage from the combination of long circulation effect and active intracellular drug delivery. It is also expected that the targeting drug delivery system, such as ligand-targeted liposomes, will reach clinical use in years to come, with a further improvement of the therapeutic index of anticancer drugs. Until then, liposomal anthracyclines will definitively help us in the daily fighting against cancer.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Additional information

Funding

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.