These clinical data were obtained from different studies, and as far back as 1993 phase, I studies proposed the human experimentation of DepoCyt in patients with neoplastic meningitis
[53][65][90,102]. One of these studies reported that single lateral ventricle injection could maintain a therapeutic drug concentration of DepoCyt in the CSF for a period of 9 +/− 2 days, while intra-lumbar administration was maintained for up to 14 days
[53][90]. The authors claimed that DepoCyt permitted patients treatment once every 2 weeks, greatly enhancing drug efficacy (7 patients out of 9 showed cytologic responses). Moreover, the minimum cytotoxic Ara-C concentration (0.1 μg/mL) was observed for a period of >14 days. The same research group produced an additional work that analyzed the clinical effects of DepoCyt: 9 patients were subjected to 1 to 7 cycles in doses ranging from 25 to 125 mg
[65][102]. It has been shown that toxic episodes were transient and reversible (except one) and consequently well tolerated, thanks to malignant cells cleaning in most patients within 3 weeks of initial therapy. Also, DepoCyt did not evade CSF, as measurable plasma concentration of Ara-C or its metabolite uracil arabinoside was virtually absent (detection limit of 0.25 μg/mL). These results gave input to the use of DepoCyt. Indeed they decisively demonstrated a pure pharmacokinetic advantage if compared to unencapsulated intrathecally-administered Ara-C
[71][107]. Later in 1995, the same study group demonstrated that intra-lumbar administration of DepoCyt guaranteed sufficient cytotoxic Ara-C concentrations in both lumbar and ventricular regions and permitted a scheduled drug administration every 14 days
[66][103]. A more wide and randomized study investigated DepoCyt versus free Ara-C in 28 patients with lymphoma and positive CSF cytology
[72][108]. DepoCyt 50 mg every 2 weeks or Ara-C 50 mg twice a week were evaluated for 1 month (induction therapy) and both consolidation (3 months) and maintenance therapy (4 months) were administered to patients without neurologic progression and CSF cytologically negative after treatment. The study demonstrated a response rate of 71% vs. 15%, a time to neurologic progression of 78.5 vs. 42 days and survival trend of 99.5 vs. 63 days, for DepoCyt and free Ara-C, respectively. Also, the better quality of life was sustained by DepoCyt, as measured by the Karnofsky score. Similarly, another randomized trial compared DepoCyt to methotrexate (both administered by intrathecal injection) in 61 patients with neoplastic meningitis
[68][105]. Again, this study underlined as DepoCyt increased the time to neurological progression if compared to methotrexate and emphasized as DepoCyt was administered in less frequent drug-dosing with the same response rate of methotrexate. More recently, the pharmacokinetics of DepoCyt intrathecal administration up to 14 days was evaluated (as part of a phase III study), afresh showing as DepoCyt reached cytotoxic concentrations of Ara-C (>0.02 µg/mL) in CSF with the constant release of Ara-C from the DepoCyt particles
[69][47]. A case report investigating the effects of intrathecally-administered DepoCyt in a diffuse leptomeningeal gliomatosis (due to a glioma-infiltrating leptomeninges) showed that induction and consolidation therapies improved patient clinical status
[70][106]. The result of this case report does not differ substantially from the previous studies, but still highlights once again the effectiveness of DepoCyt in leptomeningeal neoplasia. A retrospective work of Chamberlain (the same author of the first clinical studied on DepoCyt) summarizes the neurotoxicity of DepoCyt in a small group of patients (12.5%)
[52][89]. Bacterial meningitis, chemical meningitis, communicating hydrocephalus, conus medullaris/cauda equina syndrome, decreased visual acuity, encephalopathy, leukoencephalopathy, myelopathy, radiculopathy, and seizures were observed in 120 patients treated for leptomeningeal metastasis. Even if well tolerated, DepoCyt can have serious side effects: this should always prompt stringent clinical observation, waiting for rapid identification of the patients’ subgroup suffering neurological complications.
Table 3 summarizes the clinical efficacy of DepoCyt.
Table 3. Clinical efficacy of DepoCyt
] |
Open-label study |
8 |
Concentration of free and encapsulated cytarabine in the ventricular and lumbar CSF: 0.01 to 1500 µg/mL |
[ | 69 | ][47] |
Case-report |
1 |
Duration of response with D: 6 months |
[74][110] |
Retrospective case series |
120 |
D well tolerated, but 12.5% had serious treatment-related neurological complications |
[52][89] |
There are numerous studies on the therapeutic efficacy of DepoCyt, but in our opinion it is not sufficiently remarked the positive effects of the drug on humans, if compared to other pharmacological options. DepoCyt (encapsulated cytarabine) was superior in multiple aspects compared to free cytarabine. Probably the most important one is related to the clinical practice and to patient benefit. It is not necessary to constantly infuse the drug in CNS if the doctor uses DepoCyt, as the concentration reached is higher and longer enough to guarantee a real advantage
[75][76][77][111,112,113]. Undoubtedly, this has decreased infection risk, higher when using a prolonged perfusion of a substance in a such sensitive compartment. Another DepoCyt advantage is that it has been revealed to have a sustained therapeutic concentration in CNS up to 14 days
[53][77][90,113]. Moreover, in intraventricular dosing, the concentration difference between free and encapsulated cytarabine within 5 h ranged from 1.5 to 116 µg/mL and from 3.8 to 779 µg/mL, respectively. From post-dose day 1 to 14, the concentration ranged from 0.01 to 4.2 µg/mL and from 0.01 to 28.6 µg/mL, respectively. After day 14, the concentration ranged from 0.01 to 8.23 µg/mL and from 0.07 to 213 µg/mL, respectively. Differently in lumbar dosing, the concentration difference between free and encapsulated cytarabine within 5 h ranged from 0.1 to 79 µg/mL and from 2.82 to 1540 µg/mL, respectively. From post-dose day 1 to 14, the concentration ranged from 0 to 0.3 µg/ml and from 0.02 to 5.15 µg/mL, respectively
[69][47]. It is perceivable as DepoCyt can reach a significant concentration in CSF and importantly it maintains this concentration higher than free cytarabine
[69][47]. In vitro studies with multiple cancer cell lines with cytarabine for 24 h showed that the minimum cytotoxic concentration for cytarabine was 0.1 µg/mL, clearly in line with the data above. Another advantage of DepoCyt is half-life elimination: elimination half-life of free cytarabine after intra-CSF injection of DepoCyt is several times longer than after intra-CSF injection of free cytarabine
[69][47]. Taken together, all these data suggest that DepoCyt is firmly better than free cytarabine and advocate for its rational use in patients with neoplastic meningitis.
Of note, in 2017 FDA approved Vyxenos, the dual-drug liposomal combination of daunorubicin and Ara-C (above described) for the treatment of acute myeloid leukemia
[78][79][80][114,115,116]. The drug guarantees a synergistic ratio (fixed 5:1 molar ratio of Ara-C and daunorubicin) for over 24 h after intravenous injection in the plasma and is based on CombiPlex platform, i.e., a technology-based system for the development of drug combinations that involves a dual-drug screening. This system is suitable for preclinical evaluation (determining synergistic drug ratios in vitro) of new compounds making the drug development process more rapid and efficient.
As suggested above, liposomal cytarabine was very recently studied in 19 patients affected by neoplastic meningitis to understand if sustained cytotoxic cerebrospinal fluid (CSF) concentrations were still available after 14 days from drug injection
[77][113]. The aim was to compare short peak concentration to lower cytarabine concentration in CSF and the authors effectively showed that the 2 methods are clinically equivalent for liposomal cytarabine.